WHO Soft Tissue and Bone Tumours 2020 [5 ed.] 9789283245025, 9789283245032

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WHO Classification of Tumours • 5th Edition

Soft Tissue and Bone Edited by the WHO Classification of Tumours Editorial Board

Chromosome 12

MDM2

paybal：https://www.paypal.me/andy19801210 WHO Classification of Tumours • 5th Edition

Soft Tissue and Bone Tumours WHO Classification of Tumours Editorial Board

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Suggested citation WHO Classification of Tumours Editorial Board. Soft tissue and bone tumours. Lyon (Franee): International Agency for Research on Cancer; 2020.

(WHO classification of tumours series, 5th ed.; vol. 3). https://publications.iarc.fr/588.

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IARC Library Cataloguing-in-Publication Data Names: WHO Classification of Tumours Editorial Board.

Title: Soft tissue and bone tumours / edited by WHO Classification of Tumours Editorial Board.

Description: Fifth edition. | Lyon: Inter national Agen cy for Research on Cancer, 2020. | Series: World Health Organization classificati on of tumours. | Includes bibliographical references and index.

Identifiers: ISBN 9789283245025 (pbk.) | ISBN 9789283245032 (ebook)

Subjects: MESH: Bone neoplasms. | Neoplasms, connective and soft tissue.

Classification: NLM QZ 340

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The WHO classification of soft tissue and bone tumours presented in this book reflects the views of the WHO Classification of Tumours Editorial Board that convened at the International Agency for Research on Cancer, Lyon, France, 6-8 May 2019.

paybal：https://www.paypal.me/andy19801210 The WHO Classification of Tumours Editorial Board Expert members: Soft tissue and bone tumours Antonescu, Cristina R. Memorial Sloan Kettering Cancer Center

Folpe, Andrew L.

New York

Rochester

Blay, Jean-Yves Centre LOon Berard and Universite de Lyon

Hornick, Jason L. Brigham and Women's Hospital, Harvard Medical School

Lyon

Boston

Bovee, Judith V.M.G

Mertens, Fredrik

Leiden University Medical Center

Lund University

Leiden

Lund

Bridge, Julia A. Translational Genomics Research Institute (TGen) / Ashion

Miettinen, Markku

Phoe nix

Bethesda

Cun ha, Isabela Wer neck

Nielsen, G. Petur

Rede D'Or Sao Luiz

Massachusetts General Hospital

Sao Paulo

Boston

Dei Tos, Angelo Paolo University of Padua School of Medicine

Oda, Yoshinao Graduate School of Medical Sciences, Kyushu University

Treviso

Fukuoka

Flanagan, Adrienne M.

Yoshida, Akihiko

Mayo Clinic

National Cancer Institute / NIH

Royal National Orthopaedic Hospital

National Cancer Center Hospital

Stanmore, Middlesex

Tokyo

Fletcher, Christopher D.M. Brigham and Women's Hospital

Boston

For the complete list of all contributors and their affiliations, see pages 528-534.

paybal：https://www.paypal.me/andy19801210 The WHO Classification of Tumours Editorial Board (continued) Stan ding members Cameiro, Fatima

Oliva, Esther

lpatimup/i3S

Massachusetts General Hospital

Porto

Boston

Chan, John K.C.

Rous, Brian

Queen Elizabeth Hospital

Public Health England

Kowloon, Hong Kong SAR

Fulbou「n, Cambridge

Cheung, Annie Nga-Yin

Singh, Rajendra

University of Hong Kong

Mount Sinai School of Medicine

Hong Kong SAR

New York

Cree, Ian A. (Editorial Board Chair)

Soares, Fernando Augusto

International Agency for Research on Cancer

Rede D *Or

Lyon

Sao Paulo

Hospitals

Gill, Anthony J.

Srigley, John R.

Royal North Shore Hospital

Trillium Health Partners

St Leonards

Mississauga

Lakhani, Sunil R. University of Queensland and Pathology Queensland

Tan, Puay Hoon

Royal Brisbane and Women's Hospital

Singapore

Singapore General Hospital

Herst on Thompson, Lester D.R.

Lax, Sigurd F.

Woodland Hills Medical Center

General Hospital Graz II, Medical University of Graz

Woodland Hills

Graz

Tsao, Ming S.

Lazar, Alexander J.

University Health Network

University of Texas MD Anderson Cancer Center

Toronto

Houston

Tsuzuki, Toyonori Moch, Holger

Aichi Medical University Hospital

University of Zurich and University Hospital Zurich

Nagakute

Zurich Washington, Mary K.

Ochiai, Atsushi

Vanderbilt University Medical Center

Nat io nal Can cer Center

Nashville

Kashiwa

For the complete list of all contributors and their affiliations, see pages 528-534.

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WHO Classification of Tumours Soft Tissue and Bone Tumours

Edited by

IARC Editors

The WHO Classification of Tumours Editorial Board

Dilani Lokuhetty Valerie A. White

Ian A. Cree

Epidemiology

Ariana Znaor

Project Assistant

Asiedua Asante

Assista nts

Anne-Sophie Hameau

Laura Brispot

Technical Editor

Jessica Cox

Database

Alberto Machado

Layout

Meaghan Fortune

Printed by

Naturaprint

74370 Argonay, France

Publisher

International Agency for Research on Cancer (IARC) 150 Cours Albert Thomas 69372 Lyon Cedex 08, France

paybal：https://www.paypal.me/andy19801210 Conte nts

List of abbreviations

ix

Foreword

X

1

Soft tissue tumours

1

WHO classification of soft tissue tumours TNM staging of tumours of soft tissues TNM staging of gastrointestinal stromal tumours

2 4 5 6

Introducti on Adipocytic tumours Lipoma Lipomatosis Lipomatosis of nerve Lipoblastoma and lipoblastomatosis

Angiolipoma Myolipoma of soft tissue Chondroid lipoma Spindle cell lipoma and pleomorphic lipoma Hibernoma Atypical spindle cell / pleomorphic lipomatous tumour Atypical lipomatous tumour / well-differentiated liposarcoma Dedifferentiated liposarcoma Myxoid liposarcoma Pleomorphic liposarcoma Myxoid pleomorphic liposarcoma Fibroblastic and myofibroblastic tumours

13 16 18 20 23 25 27 29 31 34 36 39 42 45 47

Nodular fasciitis Proliferative fasciitis and proliferative myositis Myositis ossificans and fibro-osseous pseudotumour of

49 51

digits Ischaemic fasciitis Elastofibroma Fibrous hamartoma of infancy

53 55 57 59 61 63 65 67 69 71 74

Fibromatosis colli Juvenile hyaline fibromatosis Inclusion body fibromatosis Fibroma of tendon sheath Desmoplastic fibroblastoma Myofibroblastoma Calcifying aponeurotic fibroma EWSR1-SMAD3-pos\Y\\/e fibroblastic tumour (emerging) An giomyofibroblastoma Cellular angiofibroma An giofibroma of soft tissue

Nuchal-type fibroma Acral fibromyxoma Gardner fibroma Palmar fibromatosis and plantar fibromatosis Desmoid fibromatosis Lipofibromatosis Giant cell fibroblastoma Dermatofibrosarcoma protuberans Solitary fibrous tumour Inflammatory myofibroblastic tumour Low-grade myofibroblastic sarcoma Superficial CD34-positive fibroblastic tumour

Myxoinflammatory fibroblastic sarcoma Infantile fibrosarcoma Adult fibrosarcoma Myxofibrosarcoma Low-grade fibromyxoid sarcoma

76 78 80 82 84 86 88 90 93 96 98 100 104 109 112 114 116 119 122 124 127

Sclerosing epithelioid fibrosarcoma So-called fibrohistiocytic tumours Teno synovial giant cell tumour

Deep fibrous histiocytoma Plexiform fibrohistiocytic tumour Giant cell tumour of soft tissue Vascular tumours Haemangiomas Synovial haemangioma Intramuscular angioma Arteriovenous malformation/haemangioma Venous haemangioma Anastomosing haemangioma Epithelioid haemangioma Lymphangioma and lymphangiomatosis Tufted angioma and kaposiform haemangioendothelioma

Retiform haemangioendothelioma Papillary intralymphatic angioendothelioma Composite haemangioendothelioma

Kaposi sarcoma Pseudomyogenic haemangioendothelioma Epithelioid haemangioendothelioma

An giosarcoma Pericytic (perivascular) tumours Glomus tumour Myopericytoma, including myofibroma Angioleiomyoma Smooth muscle tumours Leiomyoma EBV-associated smooth muscle tumour

Inflammatory leiomyosarcoma Leiomyosarcoma Skeletal muscle tumours Rhabdomyoma Embryonal rhabdomyosarcoma Alveolar rhabdomyosarcoma Pleomorphic rhabdomyosarcoma Spindle cell / sclerosing rhabdomyosarcoma

Ectomesenchymoma Gastrointestinal stromal tumour

Chondro-osseous tumours Soft tissue chondroma Extraskeletal osteosarcoma Peripheral nerve sheath tumours Schwannoma Neurofibroma Perineurioma Granular cell tumour Dermal nerve sheath myxoma Solitary circumscribed neuroma Ectopic meningioma and meningothelial hamartoma Benign triton tumour / neuromuscular choristoma

Hybrid nerve sheath tumour Malignant peripheral nerve sheath tumour Maligna nt melanotic nerve sheath tumour Tumours of uncertain differentiation Intramuscular myxoma Juxta-articular myxoma Deep (aggressive) an giomyxoma Atypical fibroxanthoma Angiomatoid fibrous histiocytoma Ossifying fibromyxoid tumour

130 133 137 139 141

143 145 147 149 150 152 154 156 159 161 163 166 169 172 176 179 182 186

188 190 193 195 198 201 205 209 211 214 216

222 224

226 232

237 240 243 245 247 249 252 254 258

261 264 266 268 271 274

paybal：https://www.paypal.me/andy19801210 Myoepithelioma, myoepithelial carcinoma, and mixed tumour Pleomorphic hyalinizing angiectatic tumour of soft parts Haemosiderotic fibrolipomatous tumour Phosphaturic mesenchymal tumour NTRK-rearranged spindle cell neoplasm (emerging) Synovial sarcoma Epithelioid sarcoma Alveolar soft part sarcoma Clear cell sarcoma of soft tissue Extraskeletal myxoid chondrosarcoma Desmoplastic small round cell tumour Extrarenal rhabdoid tumour PEComa Intimal sarcoma Undifferentiated sarcoma

2

3

Un differentiated small round cell sarcomas of bone and soft tissue

Osteoclastic giant cell-rich tumours

277 280 282 284 287

290 294 297 300 303 306 309 312 315 318

321

WHO classification of undifferentiated small round cell sarcomas of bone and soft tissue Ewing sarcoma Round cell sarcoma with EWSR1 -non-ETS fusions C/C-rearranged sarcoma Sarcoma with BCOK genetic alterations

323 326 330 333

Bone tumours

337

WHO classification of bone tumours TMN staging of tumours of bone Introduction Chondrogenic tumours Subungual exostosis Bizarre parosteal osteochondromatous proliferation Periosteal chondroma Enchondroma Osteoch on droma Chondroblastoma Chondromyxoid fibroma Osteoch on dromyxoma Synovial chondromatosis Central atypical cartilagi nous tumour/ch on drosarcoma, grade 1 Secondary peripheral atypical cartilaginous tumour / chondrosarcoma, grade 1 Central chondrosarcoma, grades 2 and 3 Sec on dary peripheral chondrosarcoma, grades 2 and 3 Periosteal chondrosarcoma Clear cell chondrosarcoma Mesenchymal chondrosarcoma Dedifferentiated chondrosarcoma Osteogenic tumours Osteoma Osteoid osteoma Osteoblastoma Low-grade central osteosarcoma Osteosarcoma Parosteal osteosarcoma Periosteal osteosarcoma High-grade surface osteosarcoma Secondary osteosarcoma Fibrogenic tumours Desmoplastic fibroma of bone Fibrosarcoma of bone Vascular tumours of bone Haemangioma of bone Epithelioid haemangioma of bone Epithelioid haemangioendothelioma of bone Angiosarcoma of bone

338 339

322

340 345 348 351 353 356 359 362 365 368

4

Aneurysmal bone cyst Giant cell tumour of bone Non-ossifying fibroma Notochordal tumours

437 440 447

Benign notochordal cell tumour Conventional chordoma Dedifferentiated chordoma Poorly differentiated chordoma Other mesenchymal tumours of bone Chondromesenchymal hamartoma of chest wall Osteofibrous dysplasia Adamantinoma of long bones Simple bone cyst Fibrocartilaginous mesenchymoma Fibrous dysplasia Lipoma and hibernoma of bone Leiomyosarcoma of bone Undifferentiated pleomorphic sarcoma Bone metastases Haematopoietic neoplasms of bone Solitary plasmacytoma of bone Primary non-Hodgkin lymphoma of bone Langerhans cell histiocytosis Erdheim-Chester disease Rosai-Dorfman disease

449 451 454 456

486 489 492 495 498

Genetic tumour syndromes of soft tissue and bone

501

Introduction

502 506 510 514 517 520 522 525

Enchondromatosis Li-Fraumeni syndrome McCune-Albright syndrome Multiple osteochondromas Neurofibromatosis type 1 Rothmund-Thomson syndrome Werner syndrome

458 460 463 467 470 472

475 478 480 483

Contributors

528

Declaration of interests

535

370

IARC/WHO Committee for ICD-0

536

373 375 379 381 383 385 388

Sources

537

Refere nces

544

Subject index

598

Previous volumes in the series

607

391 394 397 400 403 410 414 417 419 422 424 426 428 431 434

paybal：https://www.paypal.me/andy19801210 List of abbreviations

aCGH AIDS AJCC ATP bp cAMP cDNA Cl CNS CT DNA EBV ER ESR EUS FDG FDG PET FISH FNA FNCLCC

array comparative genomic hybridization acquired immunodeficiency syndrome

American Joint Committee on Cancer

adenosine triphosphate base pair cyclic adenosine monophosphate

complementary DNA confidence interval

central nervous system

computed tomography

deoxyribonucleic acid Epstein-Barr virus estrogen receptor

erythrocyte sedimentation「ate endoscopic ultrasonography 18F-fluorodeoxyglucose

18F-fluorodeoxyglucose positron emission tomography

fluorescence in situ hybridization fine-needle aspiration

French Federation Nationale des Centres de Lutte

ig IRSG ITD kb kDa LC lincRNA M:F ratio MRI mRNA N:C ratio NCI NSAID NSE PAS PASD PCR PET PET-CT PET-MRI

germinal-centre B cell haematoxylin and eosin

highly active antiretroviral therapy

human immuno deficiency virus human papillomavirus International Agency for Research on Cancer

International Classification of Diseases, 11th Revision

In tergroup Rhabdomyosarcoma Study Group

internal tandem duplication kilobase

kilodalton Langerhans cell long intervening/intergenic non-coding RNA

male-to-female ratio magnetic resonance imaging messenge「ribonucleic acid

nuclear-to-cytoplasmic ratio

United States National Cancer Institute non-steroidal anti-inflammatory drug

neuron-specific enolase periodic acid-Schiff periodic acid-Schiff with diastase polymerase chain reaction positron emission tomography

positron emission tomography-computed tomography positron emission tomography-magnetic resonance

imaging

Contre le Cancer

GCB H&E HAART HIV HPV IARC ICD-11 ICD-0

immunoglobulin

PR RNA RT-PCR SEER Program SNP TNM UV

progesterone receptor

ribonucleic acid

reverse transcriptase polymerase chain reaction Surve川ance, Epidemiology, and End Results Program single-nucleotide polymorphism

tumour, node, metastasis ultraviolet

International Classification of Diseases for Oncology

List of abbreviations

ix

paybal：https://www.paypal.me/andy19801210 Foreword The WHO Classification of Tumours, published as a series of books (also known as the WHO Blue Books) and now as a website (https://tumourclassification.iarc.who.int), is an essential tool for standardizing diagnostic practice worldwide. The WHO classification also serves as a vehicle for the translation of cancer research into practice. The diagnostic criteria and standards that make up the classification are underpinned by evidenee evaluated and debated by experts in the field. About 200 authors and editors participate in the production of each book, and they give their time freely to this task. I am very grateful for their help; it is a remarkable team effort. This third volume of the fifth editi on of the WHO Blue Books has, like the precedi ng two volumes, been led by the WHO Classification of Tumours Editorial Board, which is composed of standing members nominated by pathology organizations and expert members selected on the basis of in formed bibliometric analysis. The diag no stic process is increasi ngly multidisciplinary, and we are delighted that several radiology and clinical experts have joined us to address specific needs.

The most con spicuous change to the format of the books in the fifth editi on is that tumour types comm on to multiple systems are dealt with together. Because soft tissue tumours occur in all regions of the body, the current volume will serve as the basis for the information on soft tissue tumours in all upcoming volumes of the fifth edition. The other volumes will include site-specific features of soft tissue tumours. Similarly, this volume contains the main discussion and classification of bone tumours for the entire fifth edition. There is also a chapter on gen etic tumour syn dromes; gen etic disorders are of in creasi ng importa nee to diag nosis in in dividual patie nts, and the study of these disorders has undoubtedly informed our understanding of tumour biology and behaviour over the past decade.

We have attempted to take a more systematic approach to the multifaceted n ature of turn our classification; each tumour type is described on the basis of its localization, clinical features, epidemiology, etiology, pathogenesis, histopathology, diagnostic molecular pathology, stagi ng, and prog nosis and predicti on. We have also included informati on on macroscopic appeara nee and cytology, as well as essential and desirable diagnostic criteria. This standardized, modular approach makes it easier for the books to be accessible on line, but it also en ables us to call atten tion to areas in which there is little information, and where serious gaps in our knowledge remain to be addressed.

The organization of the WHO Blue Books content now follows the normal progression from benign to malignant - a break with the fourth edition, but one we hope will be welcome. The volumes are still organized by anatomical site (digestive system, breast, soft tissue and bone, etc.), and each tumourtype is listed within a taxonomic classification that follows the format below, which helps to structure the books in a systematic manner: • • • • •

Site; e.g. soft tissue and bone Category; e.g. soft tissue tumours Family (class); e.g. adipocytic tumours Type; e.g. pleomorphic liposarcoma Subtype; e.g. epithelioid pleomorphic liposarcoma

The issue of whether a given tumour type represents a distinet entity rather than a subtype continues to exercise pathologists, and it is the topic of many publications in the scientific literature. We continue to deal with this issue on a case-by-case basis, but we believe there are in here nt rules that can be applied. For example, tumours in which multiple histological patter ns contain shared truncal mutations are clearly of the same type, despite the d if fere nces in their appeara nee. Equally, genetic heteroge neity within the same tumour type may have implications for treatme nt. A small shift in termi no logy in the fifth edition is that the term "varia nt" in reference to a specific kind of tumour has bee n wholly superseded by "subtype", in an effort to more clearly d iffere ntiate this mea ning from that of "variant" in referenee to a genetic alteration. The WHO Blue Books are much appreciated by pathologists and of increasing importanee to practitioners of other clinical disciplines invoIved in cancer management, as well as to researchers. The new editorial board and I certainly hope that the series will continue to meet the need for standards in diagnosis and to facilitate the translation of diagnostic research into practice worldwide. It is particularly important that cancers continue to be classified and diagnosed according to the same standards internationally so that patients can ben efit from multice ntre clinical trials, as well as from the results of local trials con ducted on different continents.

Dr Ian A. Cree Head, WHO Classification of Tumours Group International Agency for Research on Cancer December 2019

x

Foreword

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Soft tissue tumours Edited by: Antonescu CR, Bridge JA, Cunha IW, Dei Tos AP, Fletcher CDM, Folpe AL, Goldblum JR, Hornick JL, Miettinen M, Oda Y

Adipocytic tumours Fibroblastic and myofibroblastic tumours So-called fibrohistiocytic tumours Vascular tumours Pericytic (perivascular) tumours Smooth muscle tumours Skeletal muscle tumours Gastrointestinal stromal tumour Chon dro-osseous tumours Peripheral nerve sheath tumours Tumours of un certain d iff ere ntiati on

paybal：https://www.paypal.me/andy19801210 WHO classification of soft tissue tumours Adipocytic tumours Benign 8850/0 8856/0

8890/0 8862/0 8857/0 8857/0

Lipoma NOS Intramuscular lipoma Chondrolipoma Lipomatosis Diffuse lipomatosis Multiple symmetrical lipomatosis Pelvic lipomatosis Steroid lipomatosis HIV lipodystrophy Lipomatosis of nerve Lipoblastomatosis Localized (lipoblastoma) Diffuse (lipoblastomatosis) Angiolipoma NOS Cellular angiolipoma Myolipoma Chondroid lipoma Spindle cell lipoma Atypical spindle cell / pleomorphic lipomatous tumour

8880/0

Hiber noma

8881/0

8861/0

Intermediate (locally aggressive) 8850/1 Atypical lipomatous tumour Malignant 8851/3 8851/3 8851/3 8851/3 8858/3 8852/3 8854/3

Liposarcoma, well-differentiated, NOS Lipoma-like liposarcoma Inflammatory liposarcoma Sclerosing liposarcoma Dedifferentiated liposarcoma Myxoid liposarcoma Pleomorphic liposarcoma Epithelioid liposarcoma Myxoid pleomorphic liposarcoma

Lipofibromatosis Giant cell fibroblastoma

Intermediate (rarely metastasizing) 8832/1 Dermatofibrosarcoma protuberans NOS 8833/1 Pigmented dermatofibrosarcoma protuberans 8832/3 Dermatofibrosarcoma protuberans, fibrosarcomatous Myxoid dermatofibrosarcoma protuberans Dermatofibrosarcoma protuberans with myoid

8815/1

8825/1 8825/3 8810/1 8811/1 8814/3

differentiation Plaque-like dermatofibrosarcoma protuberans Solitary fibrous tumour NOS Fat-forming (lipomatous) solitary fibrous tumour Giant cell-rich solitary fibrous tumour Inflammatory myofibroblastic tumour Epithelioid inflammatory myofibroblastic sarcoma Myofibroblastic sarcoma Superficial CD34-positive fibroblastic tumour Myxoinflammatory fibroblastic sarcoma Infantile fibrosarcoma

Malignant 8815/3 Solitary fibrous tumour, malignant 8810/3 Fibrosarcoma NOS 8811/3 Myxofibrosarcoma Epithelioid myxofibrosarcoma 8840/3 Low-grade fibromyxoid sarcoma 8840/3 Sclerosing epithelioid fibrosarcoma

So-called fibrohistiocytic tumours Benign 9252/0 9252/1 8831/0

Tenosynovial giant cell tumour NOS Tenosynovial giant cell tumour, diffuse Deep benign fibrous histiocytoma

Fibroblastic and myofibroblastic tumours

Intermediate (rarely metastasizing) 8835/1 Plexiform fibrohistiocytic tumour 9251/1 Giant cell tumour of soft parts NOS

Benign 8828/0

Malignant 9252/3 Maligna nt tenos ynovial giant cell tumour

* 8859/3

8828/0 8828/0

8820/0 8992/0

8813/0 8810/0 8825/0 8816/0

8826/0 9160/0 9160/0 8810/0 8811/0 8810/0

Nodular fasciitis Intravascular fasciitis Cranial fasciitis Proliferative fasciitis Proliferative myositis Myositis ossificans and fibro-osseous pseudotumour of digits Ischaemic fasciitis Elastofibroma Fibrous hamartoma of infancy Fibromatosis colli Juvenile hyaline fibromatosis Inclusion body fibromatosis Fibroma of tendon sheath Desmoplastic fibroblastoma Myofibroblastoma Calcifying aponeurotic fibroma EVVSR7-S/VMD3-positive fibroblastic tumour (emerging) Angiomyofibroblastoma Cellular angiofibroma Angiofibroma NOS Nuchal fibroma Acral fibromyxoma Gardner fibroma

Intermediate (locally aggressive) 8815/0 Solitary fibrous tumour, benign 8813/1 Palmar/plantar-type fibromatosis 8821/1 Desmoid-type fibromatosis 8821/1 Extra-abdominal desmoid 8822/1 Abdominal fibromatosis

2

8851/1 8834/1

Soft tissue tumours

Vascular tumours Benign 9120/0 9132/0 9123/0 9122/0 9125/0

9170/0

9173/0 9161/0

Haemangioma NOS Intramuscular haemangioma Arteriovenous haemangioma Venous haemangioma Epithelioid haemangioma Cellular epithelioid haemangioma Atypical epithelioid haemangioma Lymphangioma NOS Lymphangiomatosis Cystic lymphangioma Acquired tufted haemangioma

Intermediate (locally aggressive) 9130/1 Kaposiform haemangioendothelioma Intermediate (rarely metastasizing) 9136/1 Retiform haemangioendothelioma 9135/1 Papillary intralymphatic angioendothelioma 9136/1 Composite haemangioendothelioma Neuroendocrine composite haemangioendothelioma 9140/3 Kaposi sarcoma Classic indolent Kaposi sarcoma Endemic African Kaposi sarcoma AIDS-associated Kaposi sarcoma Iatrogenic Kaposi sarcoma 9138/1 Pseudomyogenic (epithelioid sarcoma-like)

haemangioendothelioma

paybal：https://www.paypal.me/andy19801210 Malignant 9133/3 Epithelioid haemangioendothelioma NOS Epithelioid haemangioendothelioma with WWTFI1-CAMTA1 ^s\or\ Epithelioid haemangioendothelioma with YAP1-TFE3 ^s\o n 9120/3 Angiosarcoma

Pericytic (perivascular) tumours Benign and intermediate 8711/0 Glomus tumour NOS 8712/0 Glomangioma 8713/0 Gloma ngiomyoma 8711/1 Glomangiomatosis 8711/1 Glomus tumour of uncertain malignant potential 8824/0 Myopericytoma 8824/1 Myofibromatosis 8824/0 Myofibroma 8824/1 Infantile myofibromatosis 8894/0 Angioleiomyoma Malignant 8711/3 Glomus tumour, malignant

Smooth muscle tumours Benign and intermediate 8890/0 Leiomyoma NOS 8897/1 Smooth muscle tumour of uncertai n maligna nt potential Malignant 8890/3 Leiomyosarcoma NOS

Skeletal muscle tumours Benign 8900/0 8903/0 8904/0 8905/0 Malignant 8910/3 8910/3 8920/3 8901/3 8912/3

8921/3

Rhabdomyoma NOS Fetal rhabdomyoma Adult rhabdomyoma Genital rhabdomyoma Embryonal rhabdomyosarcoma NOS Embryonal rhabdomyosarcoma, pleomorphic Alveolar rhabdomyosarcoma Pleomorphic rhabdomyosarcoma NOS Spindle cell rhabdomyosarcoma Congenital spindle cell rhabdomyosarcoma with VGLL2/NCOA2/CITED2 rearrangements /wyOD7-mutant spindle cell / sclerosing rhabdomyosarcoma Intraosseous spindle cell rhabdomyosarcoma (with TFCP2/NCOA2 rearrangements) Ectomese nchymoma

Gastrointestinal stromal tumours 8936/3

Gastrointestinal stromal tumour

Chondro-osseous tumours Benign 9220/0

Chondroma NOS Chondroblastoma-like soft tissue chondroma

Malignant 9180/3 Osteosarcoma, extraskeletal

Peripheral nerve sheath tumours Benign 9560/0 9560/0 9560/0

__

Schwannoma NOS An cient schwan noma Cellular schwannoma

Plexiform schwannoma Epithelioid schwannoma M i c ro cy st i c/reti c u I ar schwa rinomm

9540/0

9550/0 9571/0

9580/0 9562/0 9570/0

9530/0 9563/0

Malignant 9540/3 9542/3 9540/3 9580/3 9571/3

Neurofibroma NOS Ancient neurofibroma Cellular neurofibroma Atypical neurofibroma Plexiform neurofibroma Perineurioma NOS Reticular perineurioma Sclerosing perineurioma Granular cell tumour NOS Nerve sheath myxoma Solitary circumscribed neuroma Plexiform solitary circumscribed neuroma Meningioma NOS Benign triton tumour / neuromuscular choristoma Hybrid nerve sheath tumour Perineurioma/schwa nnoma Schwa nnoma/neurofibroma Peri neurioma/neurofibroma

Maligna nt peripheral nerve sheath tumour NOS Maligna nt peripheral nerve sheath tumour, epithelioid Melanotic malignant peripheral nerve sheath tumour Granular cell tumour, maligna nt Peri neurioma, maligna nt

Tumours of uncertain differentiation Benign 8840/0 8841/0 8802/1 8990/0 8714/0 8860/0

Myxoma NOS Cellular myxoma Aggressive angiomyxoma Pleomorphic hyalinizing angiectatic tumour Phosphaturic mesenchymal tumour NOS Perivascular epithelioid tumour, benign Angiomyolipoma

Intermediate (locally aggressive) 8811/1 Haemosiderotic fibrolipomatous tumour 8860/1 An giomyolipoma, epithelioid Intermediate (rarely metastasizing) 8830/1 Atypical fibroxanthoma 8836/1 Angiomatoid fibrous histiocytoma 8842/0 Ossifying fibromyxoid tumour NOS 8940/0 Mixed tumour NOS 8940/3 Mixed tumour, malignant, NOS 8982/0 Myoepithelioma NOS

Malignant 8990/3 Phosphaturic mese nchymal tumour, maligna nt NTRK-rearranged spindle cell neoplasm (emerging) 9040/3 Synovial sarcoma NOS 9041/3 Synovial sarcoma, spindle cell 9043/3 Synovial sarcoma, biphasic Synovial sarcoma, poorly differentiated 8804/3 Epithelioid sarcoma Proximal or large cell epithelioid sarcoma Classic epithelioid sarcoma 9581/3 Alveolar soft part sarcoma 9044/3 Clear cell sarcoma NOS 9231/3 Extraskeletal myxoid chondrosarcoma 8806/3 Desmoplastic small round cell tumour 8963/3 Rhabdoid tumour NOS 8714/3 Perivascular epithelioid tumour, malignant 9137/3 Intimal sarcoma 8842/3 Ossifying fibromyxoid tumour, malignant 8982/3 Myoepithelial carci noma 8805/3 Un differentiated sarcoma 8801/3 Spindle cell sarcoma, undifferentiated 8802/3 Pleomorphic sarcoma, undifferentiated 8803/3 Round cell sarcoma, undifferentiated

rrit s.- morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) (1471). Behaviour is coded /0 for benign tumours; 门 Tor uiispecified, borderline, or uncertain behaviour; 12 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries. classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions. 'C°des marked with an asterisk were approved by the IARC/WHO Committee for ICD-0 at its meeting in January 2020.

Soft tissue tumours

3

paybal：https://www.paypal.me/andy19801210 TNM staging of tumours of soft tissues Soft Tissues (ICD-0-3 C38.1, 2, 3, C47-49)

Rules for Classification There should be histological confirmation of the disease and

division of cases by histological type and grade. The following are the procedures for assessing T, N, and M categories:

T categories N categories M categories

Physical examination and imaging Physical examination and imaging Physical examination and imaging

Head and Neck T1 Tumour 2 cm or less in greatest dimension T2 Tumour more than 2 cm but no more than 4 cm in greatest dimension Tumour more than 4 cm in greatest dimension Tumour invades the orbit, skull base or dura, central compartment viscera, facial skeleton, and/or pterygoid

T3 T4a

muscles Tumour invades the brain parenchyma, encases the

T4b

carotid artery, invades prevertebral muscle or invoIves the central nervous system by peri neural spread

Anatomical Sites 1. Connective, subcutaneous, and other soft tissues (C49),

peripheral nerves (C47) 2. Retroperitoneum (C48.0) 3. Mediastinum: anterior (C38.1); posterior (C38.2); mediastinum, NOS (C38.3)

Thoracic and Abdominal Viscera T1 Tumour confined to a single organ T2a Tumour invades serosa or visceral peritoneum T2b Tumour with microscopic extension beyond the serosa T3 Tumour invades another organ or macroscopic extension

T4a

beyond the serosa Multifocal tumour involving no more than two sites in one

T4b

organ Multifocal tumour involving more than two sites but not

T4c

more than 5 sites Multifocal tumour involving more than five sites

Histological Types of Tumour The following histological types are not included:

• • • • •

Kaposi sarcoma Dermatofibrosarcoma (protuberans) Fibromatosis (desmoid tumour) Sarcoma arising from the dura mater or brain Angiosarcoma, an aggressive sarcoma, is excluded because its natural history is not consistent with the classification.

Note Cystosarcoma phyllodes is staged as a soft tissue sarcoma of

the superficial trunk.

Regional Lymph Nodes The regional lymph nodes are those appropriate to the site of the primary tumour. Regional node invoIvement is rare and cases in which no dal status is not assessed either clin ically or

pathologically could be considered NO instead of NX or pNX.

N 一 Regional Lymph Nodes NX NO N1

M

TX TO

Primary tumour cannot be assessed No evidenee of primary tumour

Extremity and Superficial Trunk T1 Tumour 5 cm or less in greatest dimension T2 Tumour more than 5 cm but no more than 10 cm in greatest

T3

T4

dimensi on Tumour more than 10 cm but no more than 15 cm in greatest dimension Tumour more than 15 cm in greatest dimension

Retroperitoneum T1 Tumour 5 cm or less in greatest dimension T2 Tumour more than 5 cm but no more than 10 cm in greatest dime nsion T3 Tumour more than 10 cm but no more than 15 cm in

T4

greatest dimension Tumour more than 15 cm in greatest dimension

No regional lymph node metastasis Regional lymph node metastasis

一 Distant Metastasis

MO M1

No distant metastasis Distant metastasis

pTNM Pathological Classification The pT and pN categories correspond to the T and N categories.

pM TNM Clinical Classification T 一 Primary Tumour

Regi on al lymph nodes can not be assessed

一 Distant Metastasis *

pM1

Distant metastasis microscopically confirmed

Note * pMO and pMX are not valid categories

Stage 一 Extremity and Superficial Trunk and Retroperitoneum Stage Stage Stage Stage Stage

IA IB II IIIA IIIB

Stage IV

T1 T2,T3,T4 T1 T2 T3,T4 Any T Any T

NO NO NO NO NO * N1 Any N

M0 M0 M0 M0 M0 M0 M1

G1,GX G1.GX G2.G3 G2.G3 G2.G3 Any G Any G

Low Grade Low Grade High Grade High Grade High Grade

Note * AJCC classifies N1 as stage IV for extremity and superficial

trunk.

Stage 一 Head and Neck and Thoracic and Abdominal Viscera There is no stage for soft tissue sarcoma of the head and neck and thoracic and abdominal viscera.

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition {423,3126}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm-help-desk.

4

Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 TNM staging of gastrointestinal stromal tumours Gastrointestinal Stromal Tumour (GIST) Rules for Classification

pTNM Pathological Classification

The classification applies only to gastrointestinal stromal tumours. There should be histological confirmation of the disease. The following are the procedures for assessing the T, N, and M

The pT and pN categories.correspond to the T and N categories.

categories.

pM1

Tcategories

Physical examination, imaging, endoscopy, and/

N categories

or surgical exploration Physical exami nation, imaging, and/or surgical

M categories

exploration Physical examination, imaging, and/or surgical

explorati on

Anatomical Sites and Subsites • Oesophagus (C15) • Stomach (C16) • Small intestine (C17) 1. Duodenum (C17.0) 2. Jejunum (C17.1) 3. Ileum (C17.2) • Colon (C18) • Rectosigmoid junction (C19) • Rectum (C20) • Omentum (C48.1) • Mesentery (C48.1)

Regional Lymph Nodes The regional lymph nodes are those appropriate to the site of the primary tumour; see gastrointestinal sites {423} for details.

TNM Clinical Classification T 一 Primary Tumour TX TO T1 T2 T3 T4

N

Primary tumour cannot be assessed No evidence for primary tumour Tumour 2 cm or less Tumour more than 2 cm but not more than 5 cm Tumour more than 5 cm but not more than 10 cm Tumour more than 10 cm in greatest dimension

一 Regional Lymph

NX NO N1

pM

一 Distant Metastasis * Distant metastasis microscopically confirmed

Note * pMO and pMX are not valid categories

G Histopathological Grading

Grading for GIS〒 is dependent on mitotic rate *

Low mitotic rate: High mitotic rate:

5 or fewer per 50 hpf over 5 per 50 hpf

Note * The mitotic rate of GIST is best expressed as the number of mitoses per 50 high power fields (hpf) using the 40x objective (total area 5 mm2 in 50 fields).

Stage Staging criteria for gastric tumours can be applied in primary, solitary omental GISTs. Staging criteria for intestinal tumours can be applied to GISTs in less common sites such as oesophagus, colon, rectum, and mesentery.

Gastric GIST

Mitotic rate Stage IA Stage IB Stage II Stage IIIA Stage IIIB Stage IV

T1,T2 T3 T1,T2 T4 T3 T4 Any T Any T

NO NO NO NO NO NO N1 Any N

M0 M0 M0 M0 M0 M0 M0 M1

NO NO NO NO NO N1 Any N

M0 M0 M0 M0 M0 M0 M1

Low Low High Low High High Any rate Any rate

Small Intestinal GIST

Mitotic rate

Nodes

Regi on al lymph nodes cannot be assessed * No regi on al lymph node metastasis Regional lymph node metastasis

Note * NX: Regi on al lymph node invo Iveme nt is rare for GISTs, so

cases in which the nodal status is not assessed clinically or pathologically could be considered NO instead of NX or pNX.

Stage I Stage II Stage IIIA Stage IIIB Stage IV

T1,T2 T3 T1 T4 T2,T3,T4 Any T Any T

Low Low High Low High Any rate Any rate

M - Distant Metastasis MO

No distant metastasis

Distant metastasis

Not:

! he mitotic rates (counts) listed under the “G Histopathological Grading" heading above are based on a field area of 0.1 mm2 as used in the

°「iginal paper; modern microscopes are likely to have a field area of 0.2 mm2, but measurement of field area is advisable, because instruments vary.

r，e information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition {423,3126}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm-help-desk.

Soft tissue tumours

5

paybal：https://www.paypal.me/andy19801210 Soft tissue tumours: Introduction

Epidemiology Incidence Benign mesenchymal tumours outnumber sarcomas by a factor of at least 100. The annual clinical incidence (number of new patients consulting a doctor) of benign tumours of soft tissue has been estimated to be as high as 3000 cases per 1 million population {2232}, whereas the annual incidenee of soft tissue sarcoma is about 50 cases per 1 million population {1123,1262, 1122}, i.e. < 1% of all malignant tumours (but more frequent in children). There are no data to indicate a change in the inci­ dence of sarcoma, nor are there significant geographical differen ces.

Age and anatomical site distribution At least 30% of the benign tumours of soft tissue are lipomas, 30% are fibrohistiocytic and fibrous tumours, 10% are vascular tumours, and 5% are nerve sheath tumours. There is a relation­ ship between the tumour type, symptoms, and location and the patient age and sex. Lipomas are painless; rare in the hand, lower leg, and foot; and very uncommon in children {2232}. An giolipomas are often painful and most common in young men. Angioleiomyomas are often painful and comm on in the lower leg of middle-aged women. Half of the vascular tumours occur in patients aged < 20 years {1794,2697}. Of the benign tumours, 99% are superficial and 95% are < 5 cm in diameter {2697}. Soft tissue sarcomas may occur any where, but 75% are located in the extremities (most comm only in thigh) and 10% each in the trunk wall and retroperitoneum. There is a slight male predominance. Of the extremity and trunk wall tumours, 30% are superficial with a median diameter of 5 cm, and 60% are deep-seated with a median diameter of 9 cm {1262}. Retroperitoneal tumours are often much larger before they become symptomatic. The ICD-0 topographical coding for the main anatomical sites covered in this chapter is presented in Box 1.01. About 10% of patients with sarcoma have detectable metas­ tases (most comm only in the lun gs) at diagnosis of the primary tumour. Overall, at least one third of patients with soft tissue sarcoma die from tumour-related disease, most of them from lung metastases. About 65% of soft tissue sarcomas are his­ tologically classified as undifferentiated pleomorphic sarcoma (UPS; previously known as malignant fibrous histiocytoma [MFH]), liposarcoma, leiomyosarcoma, myxofibrosarcoma, synovial sarcoma, or malignant peripheral nerve sheath tumour (MPNST), and three quarters are highly malignant (see Grad­ ing and staging of sarcomas, p. 10) {2484}. The distribution of histotypes varies over time and between researchers, probably because of changing definitions of histotypes (as, for example, malignant fibrous histiocytoma in the 1990s). Age-related incidences vary: embryonal rhabdomyosar­ coma occurs almost exclusively in children, and synovial sarcoma mostly in young adults, whereas UPS, liposarcoma, 6

Soft tissue tumours

Fletcher CDM Baldini EH Blay JY Gronchi A

Lazar AJ Messiou C Pollock RE Sin ger S

Box 1.01 ICD-0 topographical coding for the main anatomical sites covered in this chapter (sarcomas arising in parenchymatous organs should be coded to those or­ gans) {1077}

C47 Peripheral nerves and autonomic nervous system C47.0 Peripheral nerves and autonomic nervous system of head, face, and neck C47.1 Peripheral nerves and autonomic nervous system of upper limb and shoulder Peripheral nerves and autonomic nervous system of lower limb and hip Peripheral nerves and autonomic nervous system of thorax Peripheral nerves and autonomic nervous system of abdomen Peripheral nerves and autonomic nervous system of pelvis Peripheral nerves and autonomic nervous system of trunk NOS Overlapping lesion of peripheral nerves and autonomic nervous system C47.9 Autonomic nervous system NOS C47.2 C47.3 C47.4 C47.5 C47.6 C47.8

C48 Retroperitoneum and peritoneum C48.0 Retroperitoneum C49 Connective, subcutaneous, and other soft tissues C49.0 Connective, subcutaneous, and other soft tissues of head, face, and neck C49.1 Connective, subcutaneous, and other soft tissues of upper limb and shoulder C49.2 Connective, subcutaneous, and other soft tissues of lower limb and hip C49.3 Connective, subcutaneous, and other soft tissues of thorax C49.4 C49.5 C49.6 C49.8 C49.9

Connective, subcutaneous, and other soft tissues of abdomen Connective, subcutaneous, and other soft tissues of pelvis Connective, subcutaneous, and other soft tissues of trunk NOS Overlapping lesion of connective, subcutaneous, and other soft tissues Connective, subcutaneous, and other soft tissues NOS

leiomyosarcoma, and myxofibrosarcoma dominate in the elderly. Like almost all other malignancies, soft tissue sarcomas become more common with increasing age; the median age at diagnosis is 65 years.

Etiology The etiology of most benign and malignant tumours of soft tissue is unknown. In rare cases (< 10%), genetic and envi­ ronmental factors, irradiation, viral infections, and immunodeficiency have been found to be associated with the development of usually malignant soft tissue tumours. There are also isolated reports of sarcomas arising in scar tissue, at fracture sites, and close to sur gieal impla nts {1642). Some an giosarco­ mas arise in chronic lymphoedema. However, the large major­ ity of soft tissue sarcomas seem to arise de novo, without an appare nt causative factor. Some maligna nt mese nchymal n eoplasms occur in the setting of familial cancer syndromes (see below and Chapter 4: Genetic tumour syndromes of soft tissue and bone, p. 501). Multistage tumorigenesis sequences with gradual accumulation of genetic alterations and an increasing histological degree of malignancy have not yet been clearly identified in most tumours of soft tissue. Four main types of etiological agents have been implicated in the literature: chemical carci no gens, radiati on, viral in fection and immu nodeficiency, and genetic susceptibility.

paybal：https://www.paypal.me/andy19801210 Chemical carcinogens Several studies, many of them from Sweden, have reported an increased incidenee of soft tissue sarcoma after exposure to phenoxy herbicides, chlorophenols, and their contaminants (dioxins) in agricultural or forestry work {926,1301}. Other stud­ ies have not found this association. One explanation for the different findings may be the use of herbicides that are contaminated with dioxins at different levels {2036,3383}.

Radiation About 5% of soft tissue sarcomas are radiati on-associated {2161}. The reported incidence of radiati on-associated osteo­ sarcoma ranges from a few cases per 1000 person-years to nearly 1 case per 100 person-years. Most incidence estimates are based on patients with breast cancer treated with radiation as adjuva nt therapy {1587}. The risk in creases with dose; most patients have received > 50 Gy, and the median time between exposure and tumour diagnosis is about 10 years, although there is some evidenee that this latency interval is decreasing. More than half of these tumours have been classified as UPS, most often being highly malignant. In skin, angiosarcoma is by far most common. Patients with a germline mutation in the retinoblastoma gene (RB1) have a significantly elevated risk of developing radiation-associated osteosarcoma {1653}, usually osteosarcoma. Similarly, patients with a germline mutation in TP53 (Li-Fraumeni syndrome) have a significantly higher risk of developi ng radiati on-associated osteosarcoma {1359}, as do patients with neurofibromatosis type 1 (NF1) {2827}.

Viral infection and immunodeficiency HHV8 infection plays a key role in the development of Kaposi sarcoma {338}, and the clinical course of the disease is dependent on the immune status of the patient {824}. EBV infection is associated with smooth muscle tumours in patients with immunodeficiency {811}.

Genetic susceptibility Several types of benign soft tissue tumours have been reported to occur on a familial or inherited basis. However, these reports are rare and comprise an insignificant number of tumours. The most common example is probably hereditary multiple lipoma (or an giolipoma) {1,1182}. Desmoid tumours occur in patients with the Gardner syndrome subtype of famil­ ial adenomatous polyposis {1259}. NF1 and neurofibromato­ sis type 2 (NF2) are associated with multiple benign nerve sheath tumours (and sometimes also non-neural tumours). In as many as 5-10% of patients with NF1, MPNSTs develop, usually in a benign nerve sheath tumour {3286}. Moreover, 5-7% of these patients may develop one or more gastrointestinal stromal tumours. Li-Fraumeni syndrome {1375} is a rare autosomal dominant disease caused by germline mutations in fhe TP53 tumour suppressor gene, which predispose indi­ viduals to the development of sarcoma {1187}. By the age of 30 vears, half of all patients with Li-Fraumeni syndrome have already developed malignant tumours, of which > 30% are sarcomas of soft tissue or bone. The inherited (or bilateral) form oi retinoblastoma, with a germline mutation of the RB1 gene, may also be associated with development of sarcoma. °ne iarge study suggested that as many as 50% of sarcoma patients may have potentially pathogenic germline variants

{216}, but this remains to be validated, and the clinical signifi­ cance of this finding remains uncertain.

Clinical features Clinical features are only occasi on ally sufficie nt to disti nguish benign from malignant tumours of soft tissue. Most soft tissue sarcomas of the extremities and trunk wall present as a large, pain less, in ciden tally noted mass that patie nts sometimes associate with an episode of injury. Conversely, some patients present with rapidly growing tumours that are occasionally painful, leading to a rapid medical opinion. Most patients with intra-abdominal or retroperitoneal sarcomas present with an asymptomatic abdomi nal mass that is con firmed on abdominal imagi ng. On occasi on, non specific abdomi nal pain is prese nt. Less comm on symptoms in elude gastr oin testi nal bleeding, incomplete obstruction, neurological or systemic symptoms (e.g. fever, fatigue, and an aemia), and occasi on ally also alterations of liver function tests. The seemingly innocent presentation and the rarity of sarcomas often lead to their ini­ tial misinterpretation as benign conditions. All superficial soft tissue lesions measuring > 5 cm, and all deep-seated lesions, are statistically likely to be sarcoma. Patients with such lesions should therefore be referred to specialized centres for a diagnostic biopsy and expert pathology review followed by treat­ ment {505,3206}.

Biopsy A biopsy is mandatory to establish malignancy and assess histological type, subtype, and grade, and is recommended in clinical practice guidelines for all deep-seated tumours > 5 cm. Possible exceptions, most often in expert centres, are what appear radiologically to be pure well-differentiated fatty tumours in the limbs or trunk. Most limb and superficial trunk masses are best sampled through multiple Trucut core biop­ sies obtained through a single tract, which should be placed so that it can be completely excised during definitive resection with minimal sacrifice of overlying skin. If biopsy is performed with at least 2 or 3 adequate cores, the accuracy of histologi­ cal classificati on, grading, and prog no sticati on is very high {1355,2964}. Additional sampling may be required for specific research protocols. When the Trucut core approach fails, an alternative for most extremity masses is an incisional biopsy with minimal extension into adjacent tissue planes. Excisional biopsy should be avoided, particularly for lesions > 2 cm, because the contamination of surrounding tissue planes renders definitive re-excision more extensive. Frozen section diagnosis and FNA are not gen erally recomme nded. FNA is proposed by some expert centres with specific cytological expertise and the capability for careful clinicoradiological correlatio n. Biopsy is important for decisions regarding neoadjuvant therapy because sensitivity to chemotherapy and radiation therapy varies among histological types and grades of sar­ coma. Histological type may also inform the surgical approach and selection of chemotherapy agents. However, although the histological type is concordant with final pathology in 80% of cases, given the heterogeneity and large size of these tumours at presentation, grade can be underestimated in 40% of retro­ peritoneal tumours {82}. In experieneed centres, pretreatment core biopsy is not required if the diagnosis is clear on imaging

Soft tissue tumours

7

paybal：https://www.paypal.me/andy19801210 (liposarcoma and leiomyosarcoma of the inferior vena cava), no neoadjuvant therapy is planned, and complete resection of the tumour is likely with minimal morbidity.

Management Once the histological diagnosis, size, and grade have been established and the work-up for distant metastasis performed, a multidisciplinary team of surgeons, radiati on on cologists, and medical oncologists can design the most effective treatment plan for the patient. The plan must balanee the goal of minimizing recurrence with preservation of function and qual­ ity of life. Surgery remains the principal therapeutic modality in soft tissue sarcoma, while the optimal combi nation of chemo­ therapy and radiotherapy must be tailored to the in dividual patient and the risk of local and distant recurrenee.

Surgery In principle, appropriate surgery for extremity and truncal sar­ comas should consist of wide en bloc removal of the tumour with a cuff of healthy tissue all around. Every attempt should be made to avoid microscopically positive surgical margins, which are associated with higher risk of local recurrence, dis­ tant metastasis, and death {1225,1229,2954,3382}. However, in certain situations a microscopically positive margin may be unavoidable because of the need to preserve critical neurovascular structures; such cases should always be assessed by ref ere nee cen tres. Whe n focal microscopically positive margins are planned in advance, the use of preoperative radi­ otherapy or chemotherapy plus radiotherapy may offset their n egative prog no stic impact on local recu rrence and outcome {1252,1234}. The scope of the excisi on is gen erally dictated by the tumour size, histological subtype, anatomical relation to normal structures (e.g. major vessels and neurovascular bun­ dles), and degree of morbidity and functional loss expected. Amputation is only indicated for soft tissue sarcoma on rare occasions and should be reserved for tumours that cannot be resected by any other means in patients without evidenee of metastatic disease and with potential for good long-term func­ tional rehabilitati on. Low-grade sarcomas of the extremities and trunk wall may be treated by surgery alone if negative margins are achieved. High-grade, large (> 5 cm) sarcomas most often receive pre­ operative or postoperative radiotherapy according to clinical practice guidelines, because randomized clinical trials have dem on strated reductio ns in the risk of local recurre nee with radiati on {3349}. For subcuta neous or in tramuscular high­ grade soft tissue sarcomas < 5 cm, or for low-grade sarcomas of any size, surgery alone should be considered if the tumour can be excised with a 1-2 cm cuff of surrounding fat and mus­ cle. If the excision margin is close or there is extramuscular involvement, adjuvant radiotherapy should be added. How­ ever, preoperative or postoperative radiotherapy is probably used more often than strictly necessary, irrespective of grade. In fact, a substantial subset of subcutaneous and intramuscular sarcomas can be treated by wide-margin excision alone, with a local recurrence rate of only 5-10% {2519,211,1007}. Retroperitoneal sarcomas tend to present at a later stage, often as very large tumours. As such, they have a tendency to invade adjacent organs, making the achievement of clean margins at the time of resection qncommon. Accordingly, the 8

Soft tissue tumours

survival rate for retroperitoneal sarcomas is much lower than that for extremity soft tissue sarcomas. The most imports nt prog no stic factors for survival in retrope riton eal sarcoma are completeness of surgical resection, histological grade, and histological type/：subtype {1233,3037,723,2867}. The utility of preoperative radiotherapy for these tumours remains contro­ versial, but the soon-to-be-published results of the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) 62092-22092 prospective randomized trial should help to address this question. Well-differentiated and dedifferentiated liposarGomas, which account for the majority of retroperitoneal sarcomas, frequently recur locally and multifocally {2867,894,1349}. Even with an aggressive surgical approach, locoregional recur­ rence is a substantial problem that leads to unresectable local disease and death in about 60% of patients {3037,2443}. However, dedifferentiated liposarcoma classified as grade 3 according to the French Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) Sarcoma Group system has a 30-50% risk of distant metastasis {1233,1231,1226}. In con­ trast, high-grade leiomyosarcoma has a lower 10-year cumu­ lative incidence of local recurrenee (25%), but it often gives rise to liver or lung metastases, with a 60% 10-year cumulative incidenee of distant recurrenee {3037}. Complete gross resection is the cornerstone of managerrent of retroperitoneal sarcomas, most achievable at the time of primary presentation. The extent of resection is affected by the tumour's proximity to important structures. Resection of the primary tumour should aim to achieve a macroscopically com­ plete resection as a single specimen with contiguous organs when they are directly invaded or encased by the sarcoma. For well-differentiated and dedifferentiated liposarcomas, all of the retroperitoneal fat on the side of the sarcoma should be removed, because it is often difficult to distinguish normal ret­ roperitoneal fat from well-differentiated liposarcoma. Preservation of specific orga ns (e.g. kidn ey, pan creas, duode num, and bladder) should be considered on an individualized basis and mandates specific expertise in the disease to appropriately judge the overall tumour extent and expected biology, as well as the in dividual patie nt's characteristics. Decisi ons regarding which neurovascular structures to sacrifice, as well as the appropriateness of en bloc resection of liver and pancreas, must weigh the potential for local control against the potential surgical morbidity and potential for Iong-term dysfunotion. The management of desmoid-type fibromatosis has recently undergone a paradigm shift. Desmoids are now most often treated conservatively by initial observation, avoiding ablative surgery because of the substantial rate of spontaneous growth arrest and regressi on {1009,2719}. Prog no stic factors pre­ dictive of in dole nt behaviour or spon taneous regressi on are lacking. However, a recent study found that the percentage of tumour volume characterized by hyperintense T2 signal on MRI is associated with desmoid progression during observation and may help disti nguish patie nts who would ben efit from early intervention from those who may simply be observed {509}. For patients who become increasingly symptomatic or exhibit progressive disease at multiple assessme nts, con sid­ erat i on should be give n to systemic therapy such as so rate nib {1197,1198}, surgical resection, or local ablative treatment (e.g. cryotherapy).

paybal：https://www.paypal.me/andy19801210 Radiotherapy The ben efit of radiotherapy for extremity sarcoma was first established by a US National Cancer Institute (NCI)-sponsored randomized trial comparing amputation and conservative surgery with radiation {2661}. Two subsequent Iandmark ran­ domized trials con firmed that addi ng radiatio n to conservative surgery improves local control, and this remains the standard approach for most intermediate- and high-grade soft tissue sar­ comas of the extremities and trunk {3349,2517}. Adjuvant radiation is not routinely recommended after surgery for low-grade soft tissue sarcoma unless there are special circumstances such as large tumour size, positive resection margins, or local recurrenee after initial surgery alone. Radiati on may be delivered preoperatively or postoperatively. The relative efficacy of preoperative versus postoperative radiation has been extensively studied, and a Canadian randomized trial dem on strated simila r rates of local con trol, regi onal con­ trol, and distant metastases for both approaches {2395}, although postoperative radiation was associated with morefrequent fibrosis {740}. The advantages of preoperative radiation in elude delivery of a lower radiation dose (50 Gy compared with 60-66 Gy for postoperative treatment) and treatment to a smaller volume of tissue. Preoperatively, the radiation volume in eludes gross tumour plus margins, whereas postoperatively the radiati on field must inc lude not only the tumour bed with margins, but also all tissues han died at surgery, in eluding the incision and drain sites. For these reasons, preoperative radiation is associated with less late radiati on morbidity {740}. The main disadva ntage of preoperative radiati on is a higher rate of acute wound complications: 35% versus 17% with postopera­ tive radiati on accordi ng to the Canadia n trial {2395,212}. The ndve nt of in tensity-modulated r adiati on therapy has en abled delivery of more-contormal dose distributions with maximal sparing of adjacent uninvoIved normal tissues, shown in one study to improve local control compared with conventional 3D techniques {1043}. Careful implementation of intensity-moduradiati on therapy will also hopefully further reduce wound complication rates. Finally, in some patients with high-grade sarcoma, radiation may be omitted without increasing risk of recurrence. One pro­ spective and several retrospective studies of resection without ⑺diation have shown excellent local control rates of > 85% (2519,211,2699}. However, it is not always clear which patient subsets can be safely treated with this approach. Those most likely to ben efit inc lude patie nts with un equivocally wide n egative margins > 1 cm or with an intact fascia. In our opinion, this a preach should r arely be con sidered for in itial unplanned exci­ sions, in patients in whom salvage treatment of a local recurrence would be associated with substantial morbidity, or in pdt& its who would not be compliant for close follow-up. For retroperitoneal sarcoma, the role of preoperative radiati on is less clear. Further study is warranted to optimally define the potential role of preoperative radiation therapy for the treatment of primary or locally recurrent retroperitoneal sarcoma.

Adjuvant and neoadjuvant chemotherapy The r；!ue of chemotherapy for sarcoma depends on the tumour's specific histological type and location. Because of their very high risk of metastasis and sensitivity to chemotherapy, Ewing sarcoma and alveolar/embryonal rhabdomyosarcoma

should always be treated with neoadjuvant chemotherapy. For other histological types of high-grade sarcoma, the choice to use chemotherapy depends on the risk of metastasis (governed by size, grade, and histology and computable by personalized no mograms, also available as a free app) {459}, the sen sitivity of the histological type/subtype to neoadjuvant chemotherapy, and the patient's age and oomorbidities. Many randomized trials (and one meta-analysis of these tri­ als' data) of soft tissue sarcoma have shown that chemotherapy improves disease-free survival, with improved local and locoregional control {88,398,2741,122}. An improvement in overall sur­ vival has bee n dem on strated in a single ran domized trial, which invoIved an anthracycline (epirubicin) plus ifosfamide, although the trial had relatively short follow-up {1080}. This overall sur­ vival ben efit was con firmed in a seco nd meta-a nalysis, with a hazard ratio of 0.77 (P = 0.01) {2497}, and in another recent reanalysis of the largest randomized trial {2457}. However, othe r ran domized trials have failed to dem on strate a ben efit for chemotherapy, and thus its role remai ns con troversial. Give n the relatively small ben efit, preoperative chemotherapy with an anthracycline and ifosfamide can be justified for large, high­ grade tumours in carefully selected patients and for the histo­ logical types most likely to respond (synovial sarcoma, myxoid / round cell liposarcoma, pleomorphic liposarcoma, and UPS). A recent trial has shown that 3 cycles of full-dose anthracycline and ifosfamide have an equivale nt outcome to 5 cycles {1228}; the more proIon ged treatment may merely in crease toxicity. Agents with activity against particular histological subtypes in elude gemcitabine and docetaxel for UPS and leiomyosar­ coma {1950}, trabectedin for myxoid / round cell liposarcoma and leiomyosarcoma {1236}, gemcitabine and taxanes for an giosarcoma {2483,2932}, and ifosfamide for myxoid / rou nd cell and pleomorphic liposarcoma {888} and synovial sarcoma {473,886}. However, none of these regime ns was found to be superior to 3 cycles of full-dose anthracycline and ifosfamide for the management of high-risk localized soft tissue sarcoma in another recent randomized study {1227}.

Multimodal treatment Surgery preceded or followed by radiotherapy, without preop­ erative or postoperative chemotherapy, remains the treatment of choice for most soft tissue sarcomas. For patients at high risk of distant metastases and death, chemotherapy may be considered in addition to the standard treatment of surgery and radiati on therapy. Chemotherapy is most likely to ben efit fit patients with large, rapidly growing, grade 3 tumours when the likelihood of R0 or R1 resection is uncertain. Because the efficacy of chemotherapy has not been clearly established, and this treatment has substantial toxicities, it is best proposed by an experieneed multidisciplinary team expert in sarcoma management. For the multimodal treatment of large, high-grade sarcomas at high risk of distant metastasis, several sequencing schedules have been developed, and their application should be selected on an in dividual case basis by an in terdiscipli nary team {2868}: (1) neoadjuvant chemotherapy, then surgery, then postoperative radiotherapy; (2) neoadjuvant concurrent or inter­ digitated chemotherapy and preoperative radiotherapy, then surgery, then optional adjuvant chemotherapy; and (3) neoadjuvant sequential chemotherapy, then preoperative radiotherapy, then surgery, possibly followed by adjuvant chemotherapy. An

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 advantage to the first and third approaches for patients with measurable disease is the ability to determine at an early stage whether the sarcoma is progressing on chemotherapy and, if so, to avoid further treatme nt with an age nt that appears inef­ fective.

increased glucose metabolism may indicate sarcomatous change of a neurofibroma to an MPNST {653}. FDG PET-CT or whole-body MRI is useful for problem-solving or staging before radical surgery and can also be helpful for sarcoma subtypes' such as an giosarcomas and myxoid liposarcomas where met­ astatic disease may be occult on standard CT.

Imaging of tumours of soft tissue Accurate clinical history is crucial to guide the choice of imag­ ing modality and differential diagnosis, although final diagno­ sis in most cases rests on biopsy {2197}. The sarcomas most commonly recognizable on imaging include UPS, liposarcoma, leiomyosarcoma, gastrointestinal stromal tumour, synovial sar­ coma, and MPNST. For masses that are clinically fixed to bone or extremely firm, plain film may be helpful to distinguish between a primary bone and soft tissue mass and to identify calcifications. Ultrasound is cost-effective and readily available, and therefore often the first-line imaging investigation for an extremity soft tissue lump. Although diagnostic accuracy is limited, ultrasound serves as a triage tool for further investigations {1737,2256}. MRI offers soft tissue contrast superior to that of other imaging modalities and is thus the imaging method of choice, par­ ticularly when tumours arise in the limbs or superficial tissue of the trunk. This is helpful not only for diagnosis but also surgical and radiotherapy planning and assessing response after radio­ therapy. For patients in whom radiotherapy is considered, MRI can be useful for assessing local tumour extent as well as surrounding oedema, which is optimally included in the treatment volume. For limb sarcomas, a combi nation of axial T2-weighted, T1-weighted, T1-weighted with fat saturation, T1-weighted fatsaturated contrast-enhanced, and coronal short-tau inversion recovery (STIR) and coronal T1-weighted sequences should be used. These sequences can be supplemented by diffusionweighted MRI sequences depending on local expertise {2104}. This complement of sequences allows for accurate staging of tumour margins; relati on ship to n eurovascular structures; presence of macroscopic fat, myxoid elements, haemorrhage, and necrosis; and bone invasion and oedema. The apparent diffusion coefficient map from diffusion-weighted MRI may help assess the tumour's response to systemic or local treatments. For patients with absolute contraindications to MRI, contrastenhanced CT can be used. Contrast-enhanced CT is the most useful and widely available primary imaging method for possible soft tissue sarcoma of the thorax, abdomen, or pelvis, and it also allows staging of distant sites of disease. Relationships of the tumour with viscera, bowel, and vascular structures are usually well dem on strated. MRI is reserved for patients with allergy to iodinated contrast agents or for problem-solving when, for example, muscle, bone, or neural foraminal involvement is equivocal on CT. MRI may also be useful for delineating disease in the pelvis. Although FDG PET has shown some ability to differentiate low-grade from high-grade sarcomas, the technique is not helpful for diag no sis, because it cannot reliably disti nguish low-grade from benign lesions {826}. However, for extremely heterogeneous tumours, FDG PET-CT may be used to target biopsy to the most FDG-avid comp on ent, because GLUT1 expression and glucose metabolism have been shown to cor­ relate with tumour grade in sarcoma {3054}. FDG PET-CT may also be able to detect malignant transformation in NF1, where

10

Soft tissue tumours

Terminology used to reflect biological potential Soft tissue tumours are divided into four categories: benign, in termediate (locally aggressive), i ntermediate (rarely metastasizing), and malignant, which were defined in the third edition of the WHO Classification of Tumours series in 2002 as follows. Benign: Most benign soft tissue tumours do not recur locally. Those that do recur do so in a non-destructive fashion and are almost always readily cured by complete local excision. Exceedingly rarely (almost certainly in < 1 in 50 000 cases and probably much less than that), a morphologically benign lesion may give rise to distant metastases. This is entirely unpredicta­ ble on the basis of conve ntional histological exami nation and to date has been best documented in cutaneous benign fibrous histiocytoma. Intermediate (locally aggressive): .Soft tissue tumours in this category often recur locally and may be associated with an infiltrative and locally destructive growth pattern. Lesions in this category very rarely if ever metastasize but typically require wide excision with a margin of normal tissue in order to ensure local control. The prototypical lesion in this category is desmoid fibromatosis. Intermediate (rarely metastasizing): Soft tissue tumours in this category are often locally aggressive (see above) but, in addition, show the well-documented ability to give rise to dis­ tant metastases in occasional cases. The risk of such metasta­ ses appears to be < 2% and is not reliably predictable on the basis of histomorphology. Metastasis in such lesions is usually to lymph node or lung. Prototypical examples in this category in elude plexiform fibrohistiocytic tumour and an giomatoid fibrous histiocytoma. Malignant: In addition to the potential for locally destructive growth and recurrence, malignant soft tissue tumours (known as soft tissue sarcomas) have a substantial risk of distant metastasis, ranging in most instances from 20% to almost 100%, depending on histological type and grade. Some (but not all) histologically low-grade sarcomas have a metastatic risk of only 2-10%, but such lesions may advanee in grade in a local recurrenee and thereby acquire a higher risk of distant spread (e.g. myxofibrosarcoma and leiomyosarcoma). It is important to note that in this classification scheme, the intermediate categories do not correspond to histologically determined intermediate grade in a soft tissue sarcoma (see below), nor do they correspond to the ICD-0 /1 behaviour cate­ gory described as uncertain whether benign or malignant. The locally aggressive subset of entities with no metastatic potential, as defi ned above, are gen erally give n ICD-0 /1 codes, and the rarely metastasizing lesions are given ICD-0 /3 codes.

Grading and staging of sarcomas Grading Except in a subset of sarcomas, histological typing alone does not provide sufficient information for predicting the clini­ cal course of disease; thus, this must be achieved by grading

paybal：https://www.paypal.me/andy19801210 and/or staging. Grading is based only on intrinsic qualities of the untreated primary tumour, whereas staging also takes into account tumour extent {1328,101}. Nomograms can assess mul­ tiple clinical and histological parameters to calculate the prob­ ability of recurrenee for a given patient {887}. Grading of sarcomas of soft tissue was first proposed in 1939 by Broders et al., but the first large-scale effort to use grade and stage in sarcomas was published in 1977 by Russell et al. {2692}. This study showed the prominent role of grade in predicting outcome for patients with sarcomas, although the grade used was determined subjectively.In the early 1980s, several grading systems based on various histological parameters were reported and dem on strated to correlate with prognosis {664, 2233,3104,3169}. Most grading systems rely on mitotic activity and necrosis. An important change in this edition of the WHO Classification of Tumours series is the conversion of mitotic count from the traditional denominator of 10 high-power fields to a defined area expressed in mm2. This serves to standardize the true area over which mitoses are enumerated, because different microscopes have high-power fields of different sizes. This cha nge will also be helpful for any one reporting using digital systems. The approximate number of fields per 1 mm2 based on the field diameter and its corresponding area is presented in Table 1.01. The two most widely used grading systems are those pro­ posed by NCI {664} and the FNCLCC {3104}. The FNCLCC sys­ tem appears to be more precisely defined and potentially more reproducible, and it is therefore the most widely used {814}. In accordance with College of American Pathologists (CAP) and American Joint Committee on Cancer (AJCC) recommendations, the FNCLCC system is preferred over the NCI system, at least in adults {2681,101}. Moreover, a comparison of the two sys­ tems showed greater efficiency of the FNCLCC system in terms of prognostic prediction and minimization of cases assigned to the in termediate category {1246}. Three in depende nt prog no stic factors are used for defining the grade: necrosis, mitotic activity, and degree of differentiation. A score is attributed independently to each parameter and the grade is obtained by summing the three attributed scores {3104}. The most challenging component of the system lies in the definition of differentiation score, which depends on histological type and subtype. The main value of grading is its ability to indicate the probabil­ ity of distant metastasis and overall survival in the whole group of sarcomas con sidered as a single en tity, but also in in dividual types such as UPSs and synovial sarcomas {642}. On the other hand, grading is of little value for predicting local recurrenee, which is strongly in flue need by the quality of surgical margins. Because of the pitfalls and limitations of grading, some rules must be respected: grading is not a substitute for an accurate histological diag no sis; it requires r epresentative and well-pro­ cessed material that must be obtained before administration of neoadjuvant therapy. Grading is less informative than histological type in some tumours (e.g. dedifferentiated and round cell liposarcomas, rhabdomyosarcoma, Ewing sarcoma, alveolar soft part sarcoma, epithelioid sarcoma, and clear cell sarcoma), and it should not be used in tumours that rarely metastasize (637,814}. The merits of grading in some tumours (e.g. MPNST and pare nchymal breast an giosarcoma) continue to be debated (2265,2254}.

Table 1.01 Approximate number of fields per 1 mm2 based on the field diameter and its corresponding area Field diameter (mm)

Field area (mm2)

Approximate number of fields per 1 mm2

0.40

0.126

8

0.41

0.132

8

0.42

0.138

7

0.43

0.145

7

0.44

0.152

7

0.45

0.159

6

0.46

0.166

6

0.47

0.173

6

0.48

0.181

6

0.49

0.188

5

0.50

0.196

5

0.51

0.204

5

0.52

0.212

5

0.53

0.221

5

0.54

0.229

4

0.55

0.237

4

0.56

0.246

4

0.57

0.255

4

0.58

0.264

4

0.59

0.273

4

0.60

0.283

4

0.61

0.292

3

0.62

0.302

3

0.63

0.312

3

0.64

0.322

3

0.65

0.332

3

0.66

0.342

3

0.67

0.352

3

0.68

0.363

3

0.69

0.374

3

Several criticisms have been made of histological grading. A universal grading system is not possible for all sarcomas given their diversity, but it is unrealistic to develop a grading system for every specific histological type of sarcoma. However, the systems currently in use perform correctly for the most frequent sarcoma types and represent an acceptable alternative. The reproducibility of the same grading system among patholo­ gists and of different grading systems for the same tumours is not ideal. Most grading systems are three-grade systems with an intermediate grade that in practice corresponds to unde­ termined prog nosis (ca nnot be definitively classified as either high or low grade), and this category can subsume up to half of cases. The almost universal use of core needle biopsies is another important limitation for grading. Although grading on core needle biopsies has been reported to show an acceptable

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 degree of accuracy {1385}, grade can be determined with certainty for high-grade sarcomas only, because low and inter­ mediate grades must be applied as provisi on al "at least" designations, due to the possibility of sampling error. Histological grading can be aided by imaging procedures for evaluating n ecrosis and by MIB1 or PHH3 scores in stead of mitotic count {1315}. Despite these clear limitations, grade remains the most important prog nostic factor in most sarcomas, and it is evide nt that clinicians will continue to expect pathologists to provide a grade for most sarcomas to guide treatment selection. Grading can be thought of as a morphological translation of molecular events that determine tumour aggressiveness; therefore, molecular parameters could eventually complement or even replace histological parameters. A molecular grading system based on the expression profile of 67 genes related to chromosome complexity and mitosis management, called CINSARC (Complexity Index in Sarcomas), has been described on a large series of sarcomas and other non-mesenchymal can­ cers with complex genomic profiles {1828}. This molecular grad­ ing system outperformed histological grading in this category of

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Soft tissue tumours

sarcomas, as well as in gastrointestinal stromal tumours {575, 1734,1784), but independent validation is still lacking.

Staging Staging of soft tissue sarcomas is based on histological and clinical information. The major staging systems used were developed by the Union for International Cancer Control (UICC) and AJCC and are clin ically useful and of prog no stic value. The TNM system incorporates histological grade as well as tumour size and depth, regional lymph node invoIvement, and distant metastasis {882}. Important prog nostic factors for relapse and death include patient characteristics (e.g. sex and age), tumour characteristics (histology, grade, size, site, depth, and presence of metastasis at diagnosis), and management by the medi­ cal team (biopsy and review, unplanned surgery, and quality of resection). Nomograms incorporating non-anatomical and sometimes continuous rather than discrete variables, including those based on tumour type, site of involvement, and/or treatrnent regimen, have been proposed to guide patient management {3037,456,1175,459,1232}.

paybal：https://www.paypal.me/andy19801210 Fritchie KJ Goldblum JR Mertens F

Lipoma

Definition Lipoma is a benign tumour composed of mature adipocytes.

ICD-0 coding 8850/0 Lipoma NOS

ICD-11 coding 2E80.0Y Lipoma

Related terminology None

Subtype(s)

i( iramuscular lipoma; chondrolipoma

Localization Lipomas are most comm on in the uppe r back, proximal extrem­ ity, and abdominal region, and the majority present as a superfi­ cial (subcutaneous) soft tissue mass. A smaller subset are deepseated, arising within skeletal muscle (intramuscular lipoma), on the surface of bone (parosteal lipoma), or within the tendon sheath, or they may involve the gastrointestinal tract, oral cav­ ity, or bronchial tree {1024,1635,2049,1599,2646,355,529,3056, 898,2955,440}. Intramuscular lipomas mostfrequently involve the thigh (40-50%), followed by the shoulder, chest wall, and upper limb {1635,2301}. Rare examples of retroperitoneal lipomas with cytogenetic and molecular confirmation have also been reported {1459,1924}. Synovial lipomatosis (lipoma arborescens) is a lipon ：3tous proliferation of subsynovial connective tissue often asso­ ciated with chronic joint disease, and recent work has shown that this adipocytic proliferation lacks HMGA2 overexpression, supung a non-neoplastic reactive process {2381,2581}.

Fig. 1.01 Lipoma. Gross examination shows a glistening yellowish-tan cut surface.

八，

Fig. 1.02 Lipoma. Histological sections show a homogeneous population of mature

Clinical features Lipomas typically prese nt as a pain less mass; however, large r tumours may compress peripheral nerves and result in pain or Lenderness. Gastrointestinal lipomas may cause abdominal discomfort, melaena, or obstruction {529}. Approximately 5% of patients have multiple tumours, most often males in the back / posterior shoulder region (2698). Individuals with PTEN hamar­ toma tumour syndrome, an autosomal dominant syndrome that iiudes Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, may also have multiple lipomas {520,906}.

adipocytes.

measure < 2 mm due to muscle fibres, blood vessels, or fibrous septa, but they typically show no substantial internal enhance­ ment on CT or MRI.

Epidemiology Lipoma is the most comm on mese nc hymal n eoplasm in adults, is slightly more common in males, and tends to be associated with obesity {2698}. These tumours usually present in the fifth to seventh decades of life and are rare in the paediatric population.

Imaging Lipomas have characteristic features on both CT and MRI, presenting as discrete encapsulated masses with imaging features similar to those of the subcutaneous fat on both modalities. On CT hpomas demonstrate homogeneous low attenuation (-120 to -65 Hounsfield units). On MRI, lipomas are homogeneous and isointense with subcutaneous fat on all pulse sequences. Lipomas may contain a few subtle thin internal striations that

Etiology Unknown

Pathogenesis The pathogenesis of lipomas is related to reactivated expression of the HMGA2 protein, which plays a role in the development of the mesodermal lineage during embryogenesis {169,1858,1388}.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210

Fig. 1.03 Intramuscular lipoma. A These often show skeletal muscle fibres surrounded by mature adipocytes. B Atrophic skeletal muscle in intramuscular lipoma can mimic the atypical hyperchromatic stromal cells of atypical lipomatous tumour/ well-differentiated liposarcoma.

Cytogenetics Aberra nt karyotypes, the vast majority of which are pseudodiploid or near-diploid, have been reported for close to 500 lipo­ mas, most of which were deep-seated. Four major cytogenetic subgroups have emerged: (1) structural rearrangements of chromosome bands 12q13-q15 (two thirds of abnormal cases), (2) loss of material from chromosome arm 13q (15%), (3) struc­ tural rearrangements of band 6p21 (5%), and (4) supernumerary ring chromosomes (5%); about 5% of the cases display vari­ ous combi nations of these aberrati ons {2926,230}. Structural rearrangements involving 12q13-q15 are usually translocations, the most common of which is t(3;12)(q27-q28;q13-q15). Lipo­ mas with ring chromosomes and amplified sequences from 12q most likely represent well-differentiated subtypes of atypical lipomatous tumour; lipomas with ring chromosomes are more often deep-seated, are larger, occur in older patients, and relapse more often than lipomas with other aberrations {230, 319}.

first three AT-hook-e ncoding exons in -frame or out-of-frame with ectopic sequences or simply removing regulatory sequences from the 3' untranslated region {177,2776,2503,1819}. The most comm on chimeric tran script is HMGA2-LPP, resulting from a t(3;12), but seven other fusion partners to HMGA2 have been reported {309,2418}. The HMGA2 protein is important during embryogenesis, particularly in the development of the mesoder­ mal lineage, but it is usually not expressed in differentiated adult tissues. The finding that reactivated expression of full-length, truncated, or fused HMGA2 is essential for lipoma development has bee n dem on strated not only through studies of lipo­ mas, showing near-universal upregulation, but also by studies on mice and men with constitutional HMGA2 rearrangements, as well as by the lack of other somatic mutations in lipomas {169,1858,1388}. The deletions affecting chromosome 13, with a minimal deleted region in 13q14, overlap with those in spindle cell lipoma, but the molecular outcome remains unclear {231}. Rearrangements of 6p21 affect HMGA1, a gene closely related to HMGA2 {230,309}.

Molecular genetics Chromosomal rearrangements of 12q target the HMGA2 gene, encoding an architectural transcription factor. Typically, the break in HMGA2 occurs in the large intron 3, either fusing the

、

Macroscopic appearance Lipomas, including intramuscular lipomas, are well-circum­ scribed tumours with a uniform glistening yellow to pale-tan cut surface. Superficial lipomas are typically < 5 cm, whereas those that are deep-seated may reach sizes > 20 cm. Osteolipomas and chondrolipomas harbour areas of grossly identifiable bone and cartilage, respectively. Chalky white foci of fat necrosis and dystrophic calcification, especially in large deep-seated tumours, may be present.

Histopathology

Fig. 1.04 Osteolipoma. These tumours contain nodules of metaplastic bone and car­ tilage.

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Soft tissue tumours

Histological exami nation r eveals a well-differentiated lipoma­ tous proliferation composed of mature adipocytes. Variably sized paucicellular fibrous septa may be present, but cyto­ logical atypia (atypical hyperchromatic stromal cells) is absent. Areas of fat necrosis are not un comm on, especially in larger or deep-seated lipomas. Intramuscular lipomas may show infiltration into surrounding skeletal muscle, and this finding has no clinical significanee. However, atrophic skeletal muscle cells, a potential mimic of the atypical hyperchromatic stromal cells characteristic of atypical lipomatous tumour / well-differentiated liposarcoma, are often seen in these areas. Lipomas containing

nodules of metaplastic bone or cartilage are termed osteolipoma or chondrolipoma {1076).

Cytology Aspiration specimens show adipocytes containing a single large lipid droplet with a compressed rim of cytoplasm and a flattened inconspicuous nucleus.

L

paybal：https://www.paypal.me/andy19801210 Essential and desirable diagnostic criteria Essential: circumscribed yellowish-tan mass; uniform proliferation of mature adipose tissue without atypical hyperchromatic stromal cells. Desirable (in selected cases): absence of giant marker/ring chromosomes / MD/W2amplification.

Staging Diagnostic molecular pathology Diagnostic molecular pathology is not usually required, with the exception of retroperitoneal tumours and deep-seated fatty tumours > 10 cm, in which the exclusion of /WD/W2amplification is required.

Not clin ically releva nt

Prognosis and prediction The recurrenee rate of lipomas is < 5%. Deep-seated lipomas are more difficult to completely excise, leading to a higher rate of local recurrence.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Lipomatosis

Rosenberg AE Nielsen GP

Definition Lipomatosis is diffuse overgrowth of adipose tissue. Subclassification is based on clinical findings and anatomical distribution.

ICD-0 coding None

ICD-11 coding EF02.1 Subcutaneous lipomatosis

Related terminology Not recommended: Madelung disease; Launois-Bensaude syn drome.

Subtype(s) Diffuse lipomatosis; multiple symmetrical lipomatosis; pelvic lipomatosis; steroid lipomatosis; HIV lipodystrophy

Localization Diffuse lipomatosis invoIves the trunk, a large portion of an extremity, head and neck, abdomen, pelvis, or intestines. Macrodactyly or gigantism of a digit may be present {1217,2026}. Symmetrical lipomatosis manifests as symmetrical deposition of fat in the upper body, particularly the neck. In pelvic lipomatosis there is diffuse overgrowth of fat in the perivesical and perirec­ tal areas. Steroid lipomatosis is characterized by accumulation of fat in the face, sternal region, or upper-middle back (buffalo hump). HIV lipodystrophy shows accumulation of visceral fat, breast adiposity, and cervical fat pads {2147,661}.

Fig. 1.05 Multiple symmetrical lipomatosis. Clinical photograph of an adult male pa­ tient with multiple symmetrical lipomatosis.

Clinical features Patients present with massive accumulation of fat in affected areas that may mimic a neoplasm. Patients with symmetrical lipomatosis can have neuropathy and involvement of the CNS {2259,2524}. Accumulation of fat in the lower neck can cause laryngeal obstruction and compression of the vena cava. Pelvic lipomatosis causes urinary frequency, perineal pain, constipation, and abdominal and back pain. Bowel obstruction and hydronephrosis can develop. Imaging in lipomatosis shows the extent of fat accumulation and excludes other processes. Patients with HIV treated with antiretroviral medications may develop hyperlipidaemia, in suli n resista nee, and fat wasti ng in the face and limbs {1005}.

Epidemiology Lipomatosis is rare. Diffuse lipomatosis usually occurs in chil­ dren aged < 2 years, but it may affect adults. Pelvic lipomato­ sis often affects black males aged 9-80 years; the incidence

16

Soft tissue tumours

is 0.6-1.7 cases per 100 000 hospital admissions in the USA {3351}. Multiple symmetrical lipomatosis develops in middleaged men (M:F ratio: 15:1) of Mediterranean descent, and the incidenee is 1 case per 25 000 person-years {1350}. Patients have a history of liver disease or excessive alcohol consumption. Steroid lipomatosis manifests in patients on hormone therapy or who have inc reased en doge nous producti on of ad re noc ortical steroids. Lipodystrophy is seen in HIV-positive patients treated with antiretroviral therapy.

Etiology Multiple symmetrical lipomatosis is associated with liver disease or excessive alcohol consumption. Steroid lipomatosis mani­ fests in patie nts on horm one therapy or who have in creased en doge nous production of ad re no cortical steroids. HIV-i nfected patients treated with nueleoside reverse transcriptase inhibitors and protease inhibitors often develop lipodystrophy {1005}.

paybal：https://www.paypal.me/andy19801210 Pathogenesis Patients with multiple symmetrical lipomatosis have mutations in mitochondrial DNA genes; familial subtypes are recognized {2230,2489}.

Macroscopic appearance Grossly, lipomatosis appears as poorly circumscribed, soft, yel­ low fat identical to normal fat. The differences are the site and distribution of the fat.

Histopathology ,|| of the different types of lipomatosis have identical morpho­ logical features, consisting of lobules and sheets of mature adipocytes that may in filtrate other structures such as skeletal muscle.

Cytology Not clinically relevant

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: diffuse overgrowth of mature adipose tissue.

Staging Not clinically relevant

Prognosis and prediction Idiopathic forms of lipomatosis tend to recur after surgery. Treatment is palliative surgical removal of excess fat. Massive accumulation of fat in the neck region may cause death due to laryngeal obstruction. Fat in steroid lipomatosis regresses after steroid levels are lowered. Patients with HIV treated with antiret­ roviral medications may experienee metabolic disturbsnces.

Fig. 1.06 Lipomatosis. A Adipose tissue infiltrating and replacing much of the in­ volved skeletal muscle. B Mature white fat infiltrating skeletal muscle in diffuse lipo­ matosis.

Soft tissue tumours

17

paybal：https://www.paypal.me/andy19801210 Lipomatosis of nerve

Giannini C

Definition

Subtype(s)

Lipomatosis of nerve is a tumour characterized by overgrowth of mature fibroadipose tissue within the epineurium, surrounding and separating nerve fascicles.

None

Lipomatosis of nerve occurs more frequently in the upper extremities (74%) than in the lower extremities (17%). The peripheral nerves most frequently affected include the median nerve (> 60%), ulnar nerve (7%), and plantar nerve (11%) {3022, 1977,1976}. Occasionally lipomatosis of nerve can be bilateral, affect multiple terminal nerves, or be restricted to the plexuses.

ICD-0 coding None

ICD-11 coding 2E80.0Y Lipoma, other specified site

Related terminology Acceptable: fibrolipomatous hamartoma; hamartoma; macrodystrophia lipomatosa.

Localization

Clinical features lipofibromatous

Sen sory loss and paraesthesias are the most comm on symp­ toms (accounting for nearly half of patients' reported symptoms),

Fig. 1.07 Lipomatosis of nerve. A MRI. Left ulnar-sided fourth digital nerve (arrow) is enlarged (6 mm) and shows a coaxial cable-like appearance. B Intraoperative appear­ ance. The fourth digital nerve is enlarged (6 mm) and shows a yellow lobulated appearance over a 2 cm length, typical of lipomatosis of nerve. C MRI. The sciatic nerve (arrow) is markedly enlarged (4 cm) and shows a typical coaxial cable-like appearance in this cross-section at the level of the thigh. D Longitudinal MRI. The sciatic nerve (arrow) is markedly enlarged (4 cm) and shows a typical spaghetti-like appearance in this longitudinal section at the level of the thigh.

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Soft tissue tumours

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Fig, 1.08 Lipomatosis of nerve. A The endoneurium is expanded by mature fibroadipose tissue, which separates nerve fascicles. Inset: The perineurium of small nerve fasci­

cles is markedly thickened. B Endoneurial pseudo-onion bulb-like hypertrophic change.

followed by pain and muscle weakness {1977}. Median nerve entrapment at the carpal tunnel most commonly accounts for neurological symptoms in median nerve lipomatosis of nerve. Overgrowth in the nerve distribution territory has been reported in > 60% of cases, especially in the upper extremities, with digi­ tal enlargement due to increase of soft tissue and skin and frequently true macrodactyly with enlargement of bone {1977}. On MRI, characteristic imaging features include a so-called coaxial cable-like appearanee on the cross-sectional and spaghetti­ like appears nee on the longitudi nal plane.

Histopathology On transverse section, the epineurium is markedly expanded by mature adipose tissue and to a lesser extent by fibrous tis­ sue; the nerve fascicles are widely spaced. Fascicles show frequently perineurial thickening and at times endoneurial septation with pseudo—onion bulb-like hypertrophic change mimicking intraneural perineurioma and probably representing reactive changes to nerve compression. Moderate to severe nerve fibre loss may be present. Immunohistochemical studies for EMA, S100, and NFP may help in characterizing nerve fibre pathology.

Epidemiology A recent literature review identified 618 definite cases of lipo­ matosis of nerve {1977}. Patients typically present in the first decade of life (> 60%), with only 10% of cases coming to clinical attention after the fourth decade. Sex distribution was balaneed between male (49%) and female (51%).

Cytology

Etiology

Essential and desirable diagnostic criteria

Thought to represent a hamartomatous fibroadipose tissue over­ growth, lipomatosis of nerve is often progressive and behaves in a benign tumour-like fas hi on. It is sporadic. There are no syndromic associations except rare cases reported in association with Klippel-Trenaunay syndrome {89,2011} and Proteus syndrome {584}. Associated nerve-territory overgrowth seems to occur most frequently when lipomatosis of nerve occurs in motor and sensory nerve territory, suggesting that distal over­ growth may be in flue need by the type of axons carried by the nerve {1976}.

Essential: coaxial cable-like appearanee on cross-sectional imaging; epineurial expansion by mature adipose tissue with widely spaced nerve fascicles; perineurial thickening and pseudo-onion bulb-like hypertrophic change.

Pathogenesis PIK3CA mutations have been reported in patients with lipomato­ sis of nerve-associated macrodactyly {2637,3316}.

Not clin ically re leva nt

Diagnostic molecular pathology Not clinically relevant

Staging Not clinically relevant

Prognosis and prediction A benign condition ‘lipomatosis of nerve may require sympto­ matic treatment, including nerve decompression (e.g. carpal tunnel release for distal median nerve lipomatosis of nerve) or variable degrees of excision, balancing preservation of nerve function and soft tissue debulking and/or bony procedures to address functional and cosmetic issues.

Macroscopic appearance Lipomatosis of nerve causes a yellow lobulated fusiform enlargement of a peripheral nerve and at times its branches.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Lipoblastoma and lipoblastomatosis

Black JO Bridge JA Pedeutour F

Definition

Localization

Lipoblastoma is a benign neoplasm of embryonal white fat, which may be a localized or diffuse tumour with a tendency for local recurre nee if in completely excised.

The trunk and extremities are the most common sites {629,3000, 1288}. Lipoblastoma may arise in the abdomen, mesentery, retroperitoneum, pelvis, inguinoscrotal or labial region, perineum, mediastinum, and head/neck (including the retropharynx and oral submucosa) {953,1288}. Lung, heart, colon, and parotid gland lipoblastoma have also been described {828,1556,1572, 2010,2828,1288}.

ICD-0 coding 8881/0 Lipoblastomatosis

ICD-11 coding 2E80.1 & XH8L55 Lipoblastoma & Lipoblastomatosis

Related terminology Not recommended: fetal lipoma; fetal fat tumour; fetocellular lipoma; embryonal lipoma; congenital lipomatoid tumour; lipoblastic tumour of childhood.

Subtype(s) Localized (lipoblastoma); diffuse (lipoblastomatosis)

Clinical features Superficial circumscribed lipoblastoma simulates lipoma or occasi on ally a vascular malformati on. Lipoblastomatosis originates in deep soft tissue and is more infiltrative. Truncal tumours may infiltrate through the chest wall into the thoracic cavity from extrathoracic locations, or into the spine, with reports of neuroforaminal or intraspinal invasion requiring laminectomy for com­ plete excision {2471,2439,2498,1258,1288}. Since both types recur, the distinotion between circumscribed and infiltrative

Fig. 1.09 Lipoblastoma. A This circumscribed, lobulated mass shows internal fibrous septa with a mixture of peripheral myxoid mesenchymal tissue in transition with adipocytic tissue, containing lipoblasts in various stages of maturation. B A myxoid area of lipoblastoma highlighting the delicate vasculature, myxoid matrix, and mesenchymal spindle cell component, which may occasionally include mild to moderate nuclear atypia. C Lipoblasts display a range of maturation, from multivacuolated lipoblasts to small signet-ring lipoblasts to mature adipocytes. D Mature lipoblastoma resembles fibrolipoma, with delicate internal fibrous septa, mostly mature adipocytes, and rare lipoblasts, most readily

identified at the edges of the lobules, adjacent to foci of myxoid stroma.

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Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 be difficult to detect by FISH with this fusi on eve nt {3375}. It is unknown whether the excess copies of chromosome 8 that represe nt a pote ntial alter native mecha nism of tumorige nesis are wildtype or not {763,1158}. Lipoblastoma PLAG1 fusion partners are disti net from those reported in pleomorphic ade no ma; how­ ever, RAD51B-PLAG1 has been identified in a subset of uterine myxoid leiomyosarcomas {166}.

Macroscopic appearance Lipoblastomas are typically 2-5 cm in diameter, although they can exceed 10 cm {600,629,646,1288}. The soft; lobulated; yellow, white, or tan mass may display myxoid nodules, cystic spaces, or fat nodules separated by fine white fibrous trabecu­ lae on the cut surface. Fig. 1.10 Lipoblastoma. R-banded karyotype of a lipoblastoma showing polysomy of

chromosome 8.

forms is not clinically relevant. Lipoblastoma can compress adjacent structures and interfere with function, particularly in large abdominal tumours, mediastinal tumours, or cervical tumours with stridor as a presenting symptom {629,2507,1501, 1923}. Colonic and mesenteric occurrences have been associ­ ated with intussusception and volvulus {439,2237}. Ultrasonography can detect tumours with high fluid content and vascularity in superficial tissues {1288}. MRI reveals a nodular mass with in tensity similar to (or I owe r tha n) that of lipoma or subcutane­ ous fat on T1-weighted images {552,2440,2597,1288}. A subset of patients with lipoblastoma have developmental delays or abnormalities, seizures, congenital malformations, or familial lipomas, potentially related to larger chromosome 8q alterations that include the PLAG1 gene {629,646,1368}.

Epidemiology

Histopathology Lipoblastoma characteristically dem on strates lobular architec­ ture with sheets of adipocytes separated by fibrovascular septa {357,600,629,646}. Myxoid areas display a plexiform vascular pattern with primitive mesenchymal cells. The fat cells show a spectrum of maturation, ranging from primitive stellate or spin­ bed mesenchymal cells, to multivacuolated or small signetring lipoblasts, to mature adipocytes. The proportion of these cell types varies from case to case and from lobule to lobule. The fat lobule itself can occasi on ally exhibit a zonal patter n of maturation, with more immature myxoid cells at the periphery and adjace nt to fibrous septa, with mature adipocytes in the centre of the lobule. The myxoid regi ons can occasi on ally show pooling of matrix similar to myxoid liposarcoma. Mature areas resemble lipoma or fibrolipoma with sparse lipoblasts {629, 646,2191}. Tumour maturation is documented, supported by reports of cases diagnosed by biopsy as lipoblastoma with later resection showing a fibrolipomatous appearance without

Lipoblastoma occurs predominantly in infancy and early child­ hood, with 75-90% of cases occurring before the age of 3 years {600,629,763,2919,1288}. Lipoblastoma is seen less frequently in older children and adolescents and rarely in adults. There is a slightly higher incidence in males {629,646,2078,3185,1288}.

Etiology Unknown

Pathogenesis Lipoblastomas typically exhibit simple, pseudodiploid, or hyper­ diploid karyotypes that feature a structural alteration (translocation, inversion, insertion, or ring chromosome) of 8q11-q13 leading to rearrangement of PLAG1, a developmentally regulated zinc fin ger tran scripti on factor gene, as characteristic {229,629,1158,958,704,2690}. The most comm on numerical change is one or more extra copies of chromosome 8, with or without concurrent rearrangement of 8q11-q13 {763,2070}. Reported PLAG1 fusi on gene part ners in lipoblastoma in elude H4S2(8q24.13), C0LW2 (7q21.3), RAD51B (14q24.1), COL3A1 (2q32.2), ff/\B2/\(8q12.1-q12.2), and BOC(3q13.2) {1362,2192, 428,771,3375,3248,2311}. PLAG1 transcriptional upregulation leading to ectopic PLAG1 expression is the result of replacement of the PLAG1 promoter element by constitutively active pro­ moter regions from one of the partner genes. PLAG1 rearrange­ ments may be cytogenetically cryptic {2192}. Due to the close proximity of RAB2A and PLAG1, rearrangement of PLAG1 may

Fig. 1.11 Lipoblastoma. FISH analysis performed on metaphase cells of this case us­ ing a PLAG1 break-apart probe set revealed the presence of two abnormal chromo­

some 8 homologues with a cytogenetically cryptic paracentric inversion resulting in PLAG1 rearrangement (arrows). Normal chromosome 8 with juxtaposed orange/green signals (arrowhead).

Soft tissue tumours

21

paybal：https://www.paypal.me/andy19801210 lipoblasts {2831}. Mast cells are comm on. Other histological findings include fibroblastic proliferation with collagen deposition, chon droid metaplasia, extramedullary haematopoiesis, chronic in flammatio n, and sparse multi nucleated or floret cells {629,646,675}. Hyperchromasia and mild nuclear atypia may be observed {2848}. Mitoses are very rare, and abnormal mitoses are absent. The adipocytes of lipoblastoma demonstrate reactivity for S100, CD56, and CD34 {2164}. Nuclear p16 expression, which is frequently seen in liposarcoma, is observed in only a small subset of lipoblastomas, without correlation to macroscopic appearance or clinical behaviour {478}. The primitive mesen­ chymal cells are often reactive for desmin {629}.

Cytology Cytological material from lipoblastoma varies according to the cellularity and the extent of the immature adipocyte, mature adi­ pocyte, and myxoid matrix components {990,43,178}. Variation in adipocyte size is usually observed. Lipoblasts, fibrovascular net­ work, and primitive spin died mese nchymal cells are also seen.

22

Soft tissue tumours

Diagnostic molecular pathology In selected cases, the fin ding of PLAG1 rearrangeme nts / copynumber gain can support the diagnosis {704}.

Essential and desirable diagnostic criteria Essential: lobulated mass formed of sheets of adipocytes with variable maturation separated by fibrovascular septa.

Staging Not clin ically re leva nt

Prognosis and prediction Lipoblastoma is benign, with an excelle nt prog nosis after excision {600,3185,629,2919,1288,3000}. The recurrenee rate of 13-46% is usually due to incomplete excision, and recurrenee can occur as late as 6 years after primary resec­ tion, supporting the practice of long-term follow-up, best eval­ uated with MRI or ultrasound for superficial tumours {2805}. Locally aggressive behaviour with multiple recurrences has been described, but re-excision is effective {1288}. There is no risk of metastasis.

paybal：https://www.paypal.me/andy19801210 Sciot R Nielsen GP

An giolipoma

Definition An giolipoma is a subcutaneous tumour con sisti ng of mature fat cells intermingled with small and thin-walled vessels, a number of which contain fibrin thrombi.

ICD-0 coding 8861/0 Angiolipoma NOS

ICD-11 coding 2E80.0Y & XH3C77 Other specified lipoma & Angiolipoma NOS

Related terminology None

Subtype(s) Cellular an giolipoma

Localization The extremities (usually the forearm) are the most comm on site, followed by the trunk. Intramuscular haemangiomas and the socalled an giolipomas of pare nchymal organs or of the CNS are different lesions, in that they contain larger vessels {2829,185}.

Fig. 1.12 AngiolipoThe lesion consists of mature adipocytes and capillaries, some of which contain microthrombi.

Clinical features An giolipomas most freque ntly prese nt as multiple subcutane­ ous small nodules, usually tender to painful. There is no correlation between the intensity/occurrence of pain and the degree of vascularity {831}.

Epidemiology An giolipomas are r elatively common and usually appear in the late second decade or early third decade of life. There is a male predomina nee, and an in creased familial in cide nee has been described (5% of all cases) {1,831}. The mode of inheritanee is autosomal dominant.

Etiology Unknown

Pathogenesis The vast majority of an giolipomas show a no rmal karyotype {2796,1965}, but rare cases have been reported to show rearrangements of chromosome 13 {2414}. The majority (80%) have been reported to have low-frequency PRKD2 mutations {1388}.

Macroscopic appearance An giolipomas appea r as enc apsulated yellowish to reddish nodules.

Fig. 1.13 Angiolipoma. Cellular angiolipoma, in which the vessels predominate.

Histopathology Angiolipomas typically consist of two elements: mature adi­ pocytes and branching capillary-sized vessels, which often contain fibrin thrombi. The vascularity is more prominent in the periphery {831}. The relative proportion of adipocytes and ves­ sels varies, and some lesions are almost completely composed of vascular cha nnels. These cellular an giolipomas should be disti nguished from an giosarcoma and Kaposi sarcoma {1443}.

Soft tissue tumours

23

paybal：https://www.paypal.me/andy19801210 Cytology

Staging

Not clinically relevant

Not clin ically re leva nt

Diagnostic molecular pathology

Prognosis and predict!on

Not clinically re leva nt

An giolipomas are always benig n and show no tendency to recur.

Essential and desirable diagnostic criteria Essential: tender, often multiple subcutaneous nodules; mature fat with a variable amount of capillary vessels; fibrin micro­ thrombi.

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Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 Fukushima M

Myolipoma of soft tissue to

Definition

Localization

Myolipoma of soft tissue is a benign extrauterine tumour com­ posed of mature adipose tissue and well-differentiated smooth muscle cells.

Myolipoma usually presents as a deeply situated mass within the retroperitoneum, abdominal cavity, pelvic cavity, or inguinal region. Less commonly it occurs in the trunk wall or extremities {1093,2059,2108}.

ICD-0 coding 8890/0 Myolipoma

Clinical features

Acceptable: extrauterine lipoleiomyoma.

Lesions within the abdominal cavity are often found incidentally, whereas those involving the trunk or extremities are palpable (1093,2059). MRI shows a fatty mass with associated signal­ rich areas (corresponding to the smooth muscle component) that are heterogeneous on T1 postcontrast fat-suppressed images {3183}.

Subtype(s)

Epidemiology

None

Myolipoma is a rare tumour occurring chiefly in adult women. It is not associated with tuberous sclerosis {1093,2059,2108}.

ICD-11 coding 2E80.01 & XH4VB4 Deep subfascial lipoma & Angiomyolipoma

Related terminology

Fig. 1.14 Myolipoma. A The tumour is composed of an intimate admixture of adipocytes and smooth muscle cells. B No atypia or mitotic activity is observed in either adipocytes or smooth muscle cells.

Fig. 1.15 Myolipoma. A Smooth muscle cells within the tumour show diffuse positivity for desmin. B Both smooth muscle cells and adipocytes often show nuclear positivity for HMGA2.

Soft tissue tumours

25

paybal：https://www.paypal.me/andy19801210 Etiology Unknown

Pathogenesis Cytogenetic alterations of the HMGA2gene have been reported in two cases {2413,1380}. Fusion of the HMGA2 and C9orf92 genes resulting from a t(9;12)(p22;q14) has been reported in one case of myolipoma {2413}.

suggest atypical lipomatous tumour / well-differentiated liposarcoma (e.g. enlarged atypical nuclei, fibrous septation, lipo­ blasts) {1093,2059,2108}. The lesions usually contain variable numbers of small blood vessels and uterine thick-walled ves­ sels {1093}. Immunohistochemically, desmin, caldesmon, and SMA positivity con firms smooth muscle differe ntiation. Nuclear positivity for HMGA2 is identified in 60% of cases. ER and PR are often positive. MDM2, CDK4, and HMB45 are negative {1093,2059,266,2464,3025}.

Macroscopic appearanee Deep myolipomas are frequently large, often reaching 10-25 cm in size. Superficial lesions are smaller. The tumour is well circumscribed and usually surrounded by a thin cap­ sule. The cut surface shows an admixture of yellowish adi­ pose tissue and tan-whitish whorled nodules, depending on the amount and distribution of the smooth muscle component {1093,2059,2108}.

Histopathology The lesions are composed of an intimate admixture of mature fat cells and spin died cells, in variable proportio ns. The spin died areas consist of well-differentiated smooth muscle, with intersecting fascicles of amitotic, cytologically bland cells having eosinophilic cytoplasm, cigar-shaped nuelei, and perinuclear vacuoles. The adipocytic component lacks any features to

26

Soft tissue tumours

Cytology Not clinically re leva nt

Diagnostic molecular pathology Not clin ically re leva nt

Essential and desirable diagnostic criteria Essential: extrauterine location; admixture of well-differentiated, cytologically bland smooth muscle and mature fat.

Staging Not clinically relevant

Prognosis and prediction Complete resection is curative.

paybal：https://www.paypal.me/andy19801210 Bridge JA Flucke U

Chon droid lipoma

Definition Chon droid lipoma is a benign adipose tissue tumour composed of lipoblasts that intermingle with mature adipocytes in a myxohyali ne chon droid matrix.

arise in the proximal extremities and limb girdles {2057}. Less common sites include distal extremities, trunk, and head and neck (including the oral cavity) {1095}.

Clinical features

ICD-0 coding 8862/0 Chon droid lipoma

ICD-11 coding 2E80.0Z & XH7WX8 Lipoma, unspecified & Chondroid lipoma

Most patients present with a painless mass of variable duration, with some reporting a recent increase in size {2057}. Imaging studies typically show a well-defined, heterogeneous fatty and myxoid lesi on, deviati ng from the appears nee of lipoma but oth­ erwise non-disti nctive {1889}. Calcificati on is comm only prese nt {2219}.

Related terminology None

Epidemiology

Subtype(s)

Chon droid lipoma is a rare tumour that primarily affects adult women.

None

Etiology Localization

Unknown

Tumours are typically deep-seated, involving skeletal muscle, deep fibrous connective tissue, or deep subcutaneous fat. Most

Fig. 1.16 Chondroid lipoma. A These tumours present as small, well-circumscribed or even encapsulated masses. B The tumour consists of a moderately cellular proliferation of epithelioid cells, lipoblasts, and mature fat, in a hyalinized, vaguely chondroid matrix. C Focally, chondroid lipomas can show arborizing capillaries, simulating myxoid liposarcoma. D High-power view of lipoblasts, mature fat, and hyalinized stroma in chondroid lipoma.

Soft tissue tumours

27

paybal：https://www.paypal.me/andy19801210 The tumour size ranges from 2 to 7 cm; those complicated by haemorrhage are usually larger {2057}. t(11;16)(q13;p13)

三 一

・

■ ■ ■ -

a A

11

Histopathology

16

K r n n B ■ 气 p r

t(11;16)(q13;p13)

MRTFB

16

breakpoint at 578 n

C11orf95 exon breakpoint

B

mu

4

1 2

c

8

iiimnk 12

17

MRTFB exon

CTG GCC ACG CTC AAGjCTC AGC ACC ATC L A T L K ： L S T I

C11orf95

CTG GCC ACG CTC AAG：GTA TCA GAA CTG L A T L K ： V S E L

C11orf95-MRTFB

AGC CTG GAT GAC TTAAAG：GTA TCA GAA CTG S L D D L K ： V S E L

MRTFB

SAP domain, DNA/RNA binding

DUF2130 C11orf95-MRTFB cDNA

578

1

1625 n

Fig. 1.17 Genetics of chondroid lipoma. A Partial karyotype and schematic illus­ trating the characteristic 11;16 translocation. B Schematic of C11orf95 and MRTFB showing corresponding breakpoints associated with the C11orf95-MRTFB fusion gene. C Nucleotide and amino acid sequences around the fusion point are present­ ed. D The coding region of the fusion cDNA demonstrating the boundaries of exons

Encapsulation and occasional lobulation may be seen. There are variable proportions of mature adipose tissue intermingled with nests and cords of small round vacuolated cells embed­ ded in a myxoid-ch on droid matrix. The small cells display a range of lipoblastic differentiation, consisting of undifferenti­ ated bland cells with minimal cytoplasm to small univacuolated and multivacuolated lipoblasts with fat droplets scalLoping bland nuelei. Cells with granular, eosinophilic cytoplasm may also be seen. PAS staining accentuates intracytoplasmic glycogen. Toluidine and Alcian blue staining at low pH indi­ cates the presenee of chondroitin sulfate. Owing to high vas­ cularity, haemorrhage and fibrosis are common {1636,2057, 2284}; occasi on ally calcificati on or metaplastic bone forma­ tion is seen {1382}. Imm uno histochemistry for S100 is strongly positive in the mature fatty component, weaker in the lipoblastic elements, and usually negative in cells without apparent lipoblastic differentiation. Keratins may be detected rarely, and EMA is negative {1636}. Ultrastructurai study confirms the presence of mature fat, as well as small embryonal cells with features of lipoblasts, chon droblasts, or both. The surrounding matrix con si sts of a n etwork of thin filaments, thin collagen fibres, and abundant proteoglycan particles {1636,2284}.

Cytology Cytologically, chon droid lipoma is composed of relatively cohe­ sive clusters of mature adipocytes and variably sized lipoblasts in a chondromyxoid matrix {1157,3355}.

Diagnostic molecular pathology

and the position of conserved domains.

Not clinically relevant

Pathogenesis

Essential and desirable diagnostic criteria

Chon droid lipoma is characterized by a recurrent t(11;16) (q13;p13) chromosomal translocation that results in fusion of the C11orf95 (11q13.1) and MRTFB (previous alias MKL2; 16p13.12) genes {1425,1037}. MRTFB functions as a coactivator of the transcription factor SRF, which regulates a broad range of cellular processes such as organization of the cytoskeleton, cell migration, cell growth, and differentiation {2515}. C11orf95 encodes for a hypothetical protein of unknown function.

Essential: lobulated, circumscribed mass with variable admix­ ture of mature adipocytes and lipoblasts embedded in a myxohyaline chondroid matrix.

Macroscopic appeara nee Chon droid lipomas are well deli neated, with yellowish-tan, gelatinous cut surfaces suggesting a mature fat component.

28

Soft tissue tumours

Staging Not clinically r eleva nt

Prognosis and prediction Surgical excision is usually curative and local recurrences are rare.

paybal：https://www.paypal.me/andy19801210 Billings SD Ud Din N

Spindle cell lipoma and pleomorphic lipoma

Definition

Epidemiology

Spindle cell lipomas and pleomorphic lipomas (SCL/PLs) represent the morphological spectrum of a single neoplasm. Spindle cell lipoma (SCL) is a benign adipocytic tumour composed of variable amounts of mature adipocytes, bland spindle cells, and ropy collagen {916}. Pleomorphic lipoma (PL) in addition contains pleomorphic and multinucleated floret-like giant cells.

SCL/PLs most comm only affect men aged 45-60 years; < 10% of cases occur in females {916,2851,117,1025}. These tumours are relatively uncommon compared with conventional lipomas (ratio: 1:60) and account for approximately 1.5% of adipocytic neoplasms {1025}.

Etiology ICD-0 coding

Unknown

8857/0 Spindle cell lipoma

Pathogenesis

ICD-11 coding 2E80.0Z & XH30M7 Lipoma, unspecified & Pleomorphic lipoma 2E80.0Z & XH4E98 Lipoma, unspecified & Spindle cell lipoma

Related terminology Not recommended: dendritic fibromyxolipoma.

Subtype(s) None

SCL/PL is characterized by partial or whole chromosome 13 and/or 16 deletions {722,709,1019}. Breakpoints in 13q deletions cluster around the region 13q14, where the RB1 gene resides {709}. Loss of 13q14, including FIB1, is characteristic of mammary and soft tissue myofibroblastomas, as well as of spin­ dle cell / pleomorphic lipoma and cellular an giofibroma. In addition, the overlapping morphological and immunohistochemical features support the hypothesis that these tumours represent variations along a spectrum of genetically related lesions, the so-called 13q//?B7 family of tumours {1941,1422,1040,26}.

Localization Approximately 80% of SCL/PLs arise within the subcutis of the posterior neck, back, and shoulders {916,2851}. The remaining 20% involve differe nt sites, in eluding the face, scalp, oral cav­ ity, upper and lower limbs, and trunk {2851,117,1025,548,3122}. Cases in women are more likely to arise outside the typical locations {1659}. Rarely, intramuscular lesions and dermal-based lesions are seen {3122,1070}.

Macroscopic appearanee Grossly, SCL appears as an oval or discoid mass. The cut sur­ face is variably yellow, greyish-white, and myxoid, depending on the proportion of the constituent elements. The texture is often firmer than ordinary lipoma, but it can be gelati nous in extensively myxoid tumours.

Histopathology

Clinical features SCL/PLs typically prese nt as a pain less, slow-growing, solitary, mobile mass of the subcutis, often of several years' duration. Most tumours measure < 5 cm. Occasi on ally, multiple lesi ons are seen, and these cases may be familial {964,1309}.

SCL is usually well circumscribed and often encapsulated. Der­ mal and intramuscular tumours may have an infiltrative appear­ ance. All are characterized by a triad of variable amounts of bland spindle cells, mature adipocytes, and ropy collagen (thick, r efractile, eosi nophilic) bun dies. These comp onents

Fig.1;18 Spindle cell lipoma. A This example contains bland spindle cells, ropy collagen, and mature adipocytes. B Some examples have prominent myxoid stroma. C Fatfree subtype of spindle cell lipoma with bland spindle cells and ropy collagen.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210

Fig. 1.19 Spindle cell lipoma. Pseudoangiomatous subtype of spindle cell lipoma.

are usually seen in a fibromyxoid stroma {916,117,1025}. Mast cells are a consistent finding. The adipocytes are variable in size, and occasional lipoblasts can be identified in as many as 50% of cases {2113}. The spindle cells are bland and randomly placed or arranged in short fascicles in a school-of-fish pattern, sometimes with nuclear palisading. Nuclei are uniform and elon­ gated, with bipolar eosinophilic cytoplasmic processes. Some spindle cells may show small cytoplasmic vacuoles. Mitoses are rare and necrosis is absent. Some tumours may exhibit a vas­ cular network composed of small to medium-sized thick-walled blood vessels, which may be hyalinized. PL in addition contains pleomorphic spindle cells and multinucleated floret-like giant cells. The latter cells have a ring of peripherally radially placed, hyperchromatic nuclei around central deeply eosinophilic cyto­ plasm (flower-petal arrangement) {2851,191}. Morphological subtypes include fat-poor SCL, with little to no fat {320,2703}; the myxoid subtype, with abundant myxoid stroma {3306}; the (pseudo)angiomatous subtype, with branching and dilated vascular-1 ike spaces that separate the spindle cells and stroma to form pseudopapillary projections {1326, 3385}; plexiform SCL {3391}; SCL with focal cartilaginous and osseous metaplasia {1025}; and SCL with extramedullary haematopoiesis {2797}. The spindle, pleomorphic, and floret-like giant cells characteristically stain for CD34 {3059,3001}, with loss of nuclear RB1 protein expression {550}.

30

Soft tissue tumours

Fig. 1.20 Pleomorphic lipoma. Typical example with floret-like giant cells admixed with bland spindle cells, ropy collagen, and mature adipocytes.

Cytology The smears show a mixture of adipocytes and clusters of or dispersed uniform spindle cells, often set in a myxoid stroma, which may contain mast cells. Fragments of brightly eosino­ philic collagen fibres are also seen. PL, on the other hand, shows multinucleated giant cells with hyperchromatic nuclei and a moderate amount of cytoplasm {832}.

Diagnostic molecular pathology Demon strati on of loss of the RB1 locus can be helpful in selected cases {709,231}.

Essential and desirable diagnostic criteria Essential: bland spindle cells arranged in small, aligned groups; myxoid matrix; mature fat; ropy collagen; floret-like multinucleated giant cells in PL.

Staging Not clin ically re leva nt

Prognosis and prediction SCL/PL is a benign tumour that is adequately treated with con­ servative excision. Local recurrence is rare, even with incom­ plete resection {916,2851,117}.

paybal：https://www.paypal.me/andy19801210 Fanburg-Smith JC Nord KH

Hibernoma

Definition Hibernoma is a rare, benign adipocytic tumour showing brown fat differentiation.

ICD-0 coding 8880/0 Hibernoma

ICD-11 coding 2E80.0Z & XH1054 Lipoma, unspecified & Hibernoma

Related terminology None

Subtype(s) None

Fig. 1.22 Hibernoma. Multiple hibernomas (yellow ovals), in this instance arising in a patient with documented multiple endocrine neoplasia type 1.

Localization Hiber no mas are most often located in the thigh, trunk, chest, upper extremity, and head and neck. Myxoid and spindle cell

subtypes often involve the posterior neck and shoulder {1096}. Fewer than 10% of cases occur in intra-abdominal, retroperiton eal, or thoracic locati ons. Very rare primary hiber no mas of bone chiefly involve the axial skeleton {2906}.

Clinical features Hiber no mas typically present in you ng adults (mean age: 38 years; range: 2-75 years), as small, slow-growing, pain­ less, mobile, subcutaneous masses {1096}. Fewer than 20% are in tramuscular. They are slightly more comm on in males. On MRI, they are isointense or hypointense to fat on T1, isointense to hyperintense to fat on T2, and isointense to hyperintense to muscle on short-tau inversion recovery (STIR). They often contain low-signal internal strands and may be more heterogeneous, deperiding on their composition. Enhancement is common and more avid in lesions with a greater percentage of brow n fat. Hiber no mas are highly metabolically active and are frequently detected incidentally during FDG PET performed for the staging of various malignancies. There are two reports of hiber no mas arisi ng in patie nts with multiple endocri ne n eoplasia type 1 {1339,1974}.

Epidemiology Hiber no mas accou nt for < 2% of benign and 1% of all adipo­ cytic tumours.

Etiology There is an association with multiple endocrine neoplasiatype 1 {1339}.

Pathogenesis Fig. 1.21 Hibernoma. Tumour of the abdominal wall, visualized on T2-weighted MRI (top image) and FDG PET (bottom image). Hibernomas are very metabolically active and are often identified incidentally on FDG PET performed for the detection of metastatic disease in patients with known malignancies.

Cytoge netically, almost all hiber no mas have breakpoints in chromosome arm 11q, with a distinctive clustering to 11q13 {1159,1945,2098,2319}. FISH, SNP array, and multiplex ligationdependent probe amplification analyses have revealed complex Soft tissue tumours

31

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Fig. 1.24 Hibernoma. A Spindle cell subtype of hibernoma, with short spindled cells, wiry collagen, and scattered brown fat cells. B Rare hibernomas occur in an intramuscular location. C An example with stromal myxoid change and modestly atypical stromal cells. Such tumours are easily mistaken for atypical lipomatous tumour.

genomic rearrangements, with translocations and interstitial deletions that affect both homologues of chromosome 11 {1159, 1945,2319}. The ultimate consequenee of these rearrangeinents is a set of deletions that cluster to a 3 Mb region in 11q13, with a prefere ntial localizati on to regi ons coveri ng the tumour suppressor genes MEN1 and AIP. Somatic single-nucleotide variants in MEN1 and AIP have not been detected in hibernoma {1938}. Hiber no mas strongly express the brown fat marker gene UCP1; rearrangeme nt, amplificati on, or in creased expressi on of HMGA2, CDK4, or MDM2 is not detected {232,67}.

Macroscopic appearance Grossly, hiber no mas are typically well circumscribed, vaguely lobular, and brown to yellow in appearance {1096}.

Histopathology

Fig. 1.25 Hibernoma. FISH analysis with a whole-chromosome paint probe specific for chromosome 11 reveals complex structural rearrangements involving this chromo­

some.

32

Soft tissue tumours

Hibernomas have a rich capillary network and are composed of eosinophilic and pale, polygonal, multivacuolated, granular, brown fat cells, with a variable comp orient of un ivacuolated white fat. The nuelei of the brown fat cells are small, round, and centrally located, with small nu cleoli. Classic hiber no mas contain > 70% brown fat, with lipoma-like subtypes containing more white fat. Stromal myxoid change and an increased num­ ber of stromal spindled cells resembling those of spindle cell lipoma may be seen {1096}. Nuclear atypia and mitotic activity are absent {67}.

paybal：https://www.paypal.me/andy19801210 Cytology

0.5 -

Cytology reveals uniform small multivacuolated brown fat cells with finely granular cytoplasm, bland round nuclei, and branching capillaries {1827}.

Diagnostic molecular pathology Not clin ically releva nt

Essential and desirable diagnostic criteria ...........

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Essential: tumour composed of multivacuolated brown fat cells with small, normochromatic, centrally located nuclei.

Position (Mbp)

Chromosome 11

Staging Not clin ically re leva nt

Fig, 1,26 Hibernoma. SNP array analysis shows hemizygous and homozygous dele­

tions in chromosome band 11q13. The homozygous deletions contain the genes MEN1

(64.3 Mb) and AIP (67.0 Mb).

Prognosis and prediction Hiber no mas are entirely benign and typically do not recur after local excision {1096}.

Soft tissue tumours

33

paybal：https://www.paypal.me/andy19801210 Atypical spindle cell / pleomorphic lipomatous tumour

Creytens D Marino-En riquez A

Definition

Related terminology

Atypical spindle cell / pleomorphic lipomatous tumour is a benign adipocytic neoplasm, characterized by ill-defined tumour margins and the presenee of variable proportions of mild to moderately atypical spindle cells, adipocytes, lipo­ blasts, pleomorphic cells, multinueleated giant cells, and a myxoid or collage nous extracellular matrix. It has a low tendency for local recurre nee if in completely excised. Un like conventional atypical lipomatous tumours, there is no risk for dediffere ntiation.

Acceptable: atypical spindle cell lipoma. Not recommended: spindle cell liposarcoma; fibrosarcoma-like lipomatous neoplasm.

ICD-0 coding 8857/0 Atypical spindle cell / pleomorphic lipomatous tumour

ICD-11 coding 2E80 & XH4E98 Benign lipomatous neoplasm & Spindle cell lipoma

Subtype(s) None

Localization Atypical spindle cell / pleomorphic lipomatous tumours arise in the subcutis slightly more frequently than in deep (subfas­ cial) somatic soft tissues, and they only occasi on ally arise in intracavitary or visceral locations. The anatomical distribution is wide, predominating in the limbs and limb girdles {1983,678, 683}. The most common locations are the hand and foot and the thigh, followed by the shoulder and buttock, forearm, knee, lower leg, and upper arm. Less common locations are the head and neck, genital area, trunk, and back {1983,678,200}. Rare

Fig. 1.27 Atypical spindle cell / pleomorphic lipomatous tumour. A Moderately cellular example showing spindle cells irregularly admixed with adipocytic cells. The atypical

spindle tumour cells show an ill-defined, pale eosinophilic cytoplasm with hyperchromatic nuclei, set in a collagenous and myxoid stroma. B Area composed of atypical hyperchromatic spindle cells, adipocytes, multinucleated (floret-like) cells, and a collagenous extracellular matrix. C Bizarre pleomorphic cells and atypical spindle cells with enlarged, irregular, and hyperchromatic nuclei, irregularly admixed with lipoblasts. D Cellular example composed of moderately atypical hyperchromatic spindle cells.

34

Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 sites of invoIvement include the larynx, mediastinum, retroperitoneum, trachea, and appendix {1983}.

Clinical features The tumour manifests as a persistent or enlarging soft tissue mass, no dule, or swelli ng, sometimes with ten dem ess {1983}.

Epidemiology

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Atypical spindle cell / pleomorphic lipomatous tumour occurs predominantly in middle-aged adults, with a peak incidenee in the sixth decade of life, but it can affect patients of any age (cases have been described in patients aged 6-87 years {1983, 678,200}). The large majority of patients are > 30 years old. There is a slight male predominance.

Etiology

Fig. 1.28 Atypical spindle cell/ pleomorphic lipomatous tumour. Neoplastic cells lack expression of RB1, while non-neoplastic endothelial cells and macrophages show in­ tact nuclear RB1 expression.

Unknown

Pathogenesis Deletions or losses of 13q14, including RB1 and its flanking genes RCBTB2, DLEU1, and ITM2B, have been identified in a substan­ tial subset of cases {1983,678,683,200,677,2088}. In addition, monosomy 7 has been reported in some cases {1983,1487}.

Macroscopic appearance Grossly, atypical spindle cell / pleomorphic lipomatous tumours are unencapsulated, show a nodular or multinodular growth patter n, and dem on strate ill-defi ned tumou r margins. Tumou r size is variable (range: 0.5-28 cm; median: 5-8.5 cm) {1983, 678}.

Histopathology A wide range of microscopic appearances can be observed, even regionally within the same lesion, depending on the rela­ tive proportions of atypical spindle cells, adipocytes, lipoblasts, and pleomorphic (multinucleated) cells, as well as the vari­ able amou nt of collage nous an d/or myxoid extracellular matrix (1983,678}. The adipocytic component has a predominantly mature morphology, with variation in adipocytic size and shape. Patchy, often mild to moderate adipocytic atypia with chroma­ tin coarsening, nuelear enlargement, and focal binucleation or multinueleation can be observed {21,679}. Morphologically, the lipoblasts can vary from small and univacuolated or bivacu­ olated to larger and multivacuolated (pleomorphic). Bizarre, hyperchromatic, and sometimes pleomorphic multinucleated cells are often scattered within the spindle cell or adipocytic components. Mitotic figures are often present but mostly scarce {678,680,681}. Tumour necrosis is absent. The morphology of these tumours can best be described as a broad spectrum defined by two morphological extremes {1983}. At one extreme, these tumours can be paucicellular, with few, cytologically bland spindle cells with minimal nuelear atypia set in a promi­ nent extracellular matrix (the low-cellularity end of the spectrum, often described as atypical spindle cell lipoma morphology). These spindle cell-poor subtypes of atypical spindle cell / pleo­ morphic lipomatous tumour, which can have abundant myxoid matrix, tend to occur in the hands and feet and morphologically may resemble myxoid spindle cell lipoma, except for the presence of nu clea r atypia / hyperchromasia and the an atomical location {1983,678,683,679,676}. At the other extreme, at the

high-cellularity end of the spectrum, atypical spindle cell / pleo­ morphic lipomatous tumours may be quite cellular, composed of numerous spindle cells showing diffuse, mild to moderate cytonuelear atypia, with easily identified lipoblasts and less extracellular matrix (spindle cell-rich subtypes, also described as fibrosarcoma-like lipomatous neoplasm morphology) {1983, 678,810,676}. A rare finding is heterologous (metaplastic) differentiation, including the presenee of smooth muscle, cartilaginous, and/or osseous elements {1983,677}. The tumour cells show variable expression of CD34, S100, and desmin {1983,678}. Weak and/or focal expression of MDM2 or CDK4 can be rarely seen {1983,683,2088}. The combination of MDM2 and CDK4 expression is not encountered {1983}. Loss of nuclear RB1 expression is observed in about 50-70% of cases {1983,678,200,683}.

Cytology There are few reports, but FNA may show cells similar to those seen histologically {3366}.

Diagnostic molecular pathology Molecular studies have shown a consistent absenee of MDM2 or CDK4 amplification.

Essential and desirable diagnostic criteria Essential: variable proportions of atypical spindle cells, adipo­ cytes, univacuolated or bivacuolated to multivacuolated lipo­ blasts, pleomorphic (multinucleated) cells, and a myxoid to collage nous extracellular matrix. Desirable (in selected cases): in a substantial subset of cases, RB1 expression is lost, correlating with RB1 deletion; lack of MDM2 or CDK4 amplification.

Staging Not clinically relevant

Prognosis and prediction Atypical spindle cell / pleomorphic lipomatous tumour has a low rate of local recurre nee (10-15%) for in completely removed lesions. There is no documented risk for metastasis. Most patients will have an excellent prog nosis if the lesion is com­ pletely excised {1983,678,200,2025,679}.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Atypical lipomatous tumour / well-differentiated liposarcoma

Sbaraglia M Dei Tos AP Pedeutour F

Definition

Clinical features

Atypical lipomatous tumour / well-differentiated liposarcoma (ALT/WDLPS) is a locally aggressive mesenchymal neoplasm composed either entirely or partly of an adipocytic proliferation showing at least focal nuclear atypia in both adipocytes and stromal cells. "Atypical lipomatous tumour" and "well-differentiated liposarcoma" are synonyms describing lesions that are morphologically and genetically identical. Amplification of MDM2 and/or CDK4 is almost always present.

ALT usually presents as a deep-seated, pain less mass that can slowly attain a very large size, particularly in the retrop.eritoneum. Retroperitoneal lesions are often asymptomatic until the tumour has exceeded 20 cm in diameter.

Epidemiology

ICD-11 coding

ALT/WDLPS represents the largest subgroup of adipocytic malignancies, accounting for approximately 40-45% of all liposarcomas. These lesions occur predominantly in middleaged adults, with peak incidenee between the fourth and fifth decades of life. Convincing examples in childhood are extremely rare but may be associated with Li-Fraumeni syndrome. Males and females are equally affected, with the obvious exception of those lesions affecting the spermatic cord {919,3312}.

2F7C & XH0RW4 Neoplasms of uncertain behaviour of connective or other soft tissue & Atypical lipomatous turn our 2B5H & XH7Y61 Well-differentiated lipomatous tumour, primary site & Liposarcoma, well-differentiated

ALT/WDLPS may be associated with Li-Fraumeni syndrome, but nearly all cases are sporadic, and the etiology of these is unknown.

ICD-0 coding 8850/1 Atypical lipomatous tumour 8851/3 Liposarcoma, well-differentiated, NOS

Etiology

Related terminology

Pathogenesis

Not recommended: atypical lipoma.

ALT is characterized by supernumerary ring and giant marker chromosomes, typically as the sole change or concomitant with a few other numerical or structural abnormalities {2728}. Telomeric associations are frequently observed and may give a false impression of complexity to ALT karyotypes {1966}. Both supernumerary rings and giant markers invariably contain amplified sequences originating from the 12q14-q15 region. /WD/W2(12q15) being the main driver gene. Several other genes located in the 12q14-q15 region, including TSPAN31, CDK4 (12q14.1), HMGA2 (12q14.3), YEATS4 {224,1485,1486}, CPM {925}, and FFIS2 (12q15) {3245}, are frequently coamplified with MD/W2 {1530,1797,1570}. In addition to 12q14-q15-amplified sequences, they always contain coamplification of at least one other genomic segment {2472}. The chromosomal origin of these coamplified regions varies. The most frequent is 1q21q25. Another striking feature of ALT supernumerary chromo­ somes is that they consistently contain a neocentromere {1491, 1119}. Although generation of a neocentromere is a very rare eve nt in tumour cells, it is a specific hallmark of ALT ring and marker chromosomes. The mechanism of formation of these peculiar chromosomes is not elucidated. They might be gener­ ated by chromothripsis {1119}. Overexpression of MDM2 protein resulting from genomic amplification inactivates p53; MDM2 targets p53 degradation towards the proteasome and inhibits p53-mediated transactivation.

Subtype(s) Lipoma-like liposarcoma; inflammatory liposarcoma; sclerosing liposarcoma

Localization ALT most frequently occurs in deep soft tissue of proximal extremi­ ties (thigh and buttock) and trunk (back and shoulder). The retroperitoneum and the paratesticular area are also comm only involved {919}. Rarer sites include the head and neck region, mediastinum, distal extremities, and skin {2253,1270,458,779}.

Macroscopic appearance

Fig. 1.29 Atypical lipomatous tumour/well-differentiated liposarcom a. Surgical spec­ imen showing a well-circumscribed, lobulated, yellow mass.

36

Soft tissue tumours

ALT usually con si sts of a large, well-circumscri bed, lobulated mass. Variable consistencies are present, from firm grey to gelati nous areas, depe nding on the proportio n of fibrous and myxoid components. Larger retroperitoneal tumours appear

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Fig. 1.30 Atypical lipomatous tumour / well-differentiated liposarcoma. A Striking variation in adipocytic size is a typical feature. B The presence of atypical, hyperchromatic stromal cells is an essential diagnostic feature. C A variable number of lipoblasts can be seen in atypical lipomatous.tumour/ well-differentiated liposarcoma; however, their pres­ ence neither makes nor is required for a diagnosis of liposarcoma. D The presence of scattered bizarre stromal cells exhibiting marked nuclear hyperchromasia set in a fibrillary collagenous background represents an important diagnostic feature of the sclerosing subtype.

A

Fig. 1.31 Atypical lipomatous tumour/ well-differentiated liposarcoma. A In the inflammatory subtype, an abundant chronic inflammatory infiltrate may predominate. Scattered bi­ zarre stromal cells are present. B If the inflammatory component predominates, the identification of hyperchromatic, atypical stromal cells represents the most useful diagnostic clue.

more heterogeneous, often containing foci of fat necrosis and punctate haemorrhages.

Histopathology ALi; vVDLPS can be subdivided morphologically into three main subtypes: adipocytic (lipoma-like), sclerosing, and inflammatory {940}. The presenee of more than one morphological pattern in the same lesion is common, particularly in retroperitoneal tumours. Lipoma-like ALT/WDLPS is composed of mature adipocytes in which, unlike in benign lipoma, substantial variation in cell size is appreciated alongside nuelear atypia in fat cells or stromal spindle cells. Scattered hyperchromatic stromal spindle cells

are easily identified within fibrous septa or blood vessel walls. Occasi on ally, fat cells assume hiber no ma-like features {1276}. A varying number of lipoblasts (from many to none) may be found. Importantly, the mere presenee of lipoblasts neither makes nor is required for a diagnosis of liposarcoma. Sclerosing ALT/WDLPS ranks second in frequency. This pattern is most often seen in retroperitoneum or spermatic cord. The main histological find­ ing is the presenee of scattered bizarre stromal cells, exhibiting marked nuclear hyperchromasia and set in an extensive fibrillary collagenous stroma. Multivacuolated lipoblasts can be observed. The fibrous component may overshadow lipogenic areas, which can therefore be easily missed in a small sample. Inflammatory

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Cytology Cytology is not clin ically r eleva nt in most cases, with reported appearances in keeping with histology in 85% in one series {889}.

Diagnostic molecular pathology Detection of MDM2 (and/or CDK4) amplification {2875,684, 3047} serves to distinguish ALT from benign adipose tumours.

4d 13

19

Ao

QU 14

16

15

20

21

“ 22

17

JL X

18

~~Y

Fig. 1.32 Atypical lipomatous tumour / well-differentiated liposarcoma. RHG-banded near-diploid karyotype. The sole chromosomal anomaly is the presence of a supernu­ merary ring chromosome (arrow).

Essential and desirable diagnostic criteria Essential: lipoma-like ALT/WDLPS: variation in adipocytic size associated with nuelear atypia in stromal and/or adipocytic cells; sclerosing ALT/WDLPS: hyperchromatic bizarre stro­ mal cells set in a fibrillary sclerotic background; inflammatory ALT/WDLPS: scattered atypical stromal cells scattered in a chronic inflammatory background; lipoblasts are not required for diagnosis. Desirable (in selected or challenging cases): MDM2 and/or CDK4 nuclear expression or evidence of MDM2 and心 CDK4 gene amplification.

Staging Not clinically re leva nt

Prog nosis and prediction

Fig. 1.33 Atypical lipomatous tumour / well-differentiated liposarcoma. Interphase

FISH using probes for MDM2 (green signal) and centromere of chromosome 12 (red signal) showing high-level amplification of MDM2 grouped in clusters.

ALT/WDLPS represents the rarest subtype, occurring most often in retroperitoneum. A chronic inflammatory infiltrate predominates to the extent that the adipocytic nature of the neoplasm can be obscured {157,1697}. When dealing with cases in which the adipocytic comp on ent is scarce, the prese nee of bizarre multin ueleated stromal cells represents a useful diagnostic clue. A rare finding in ALT/WDLPS is the presenee of mature heterologous differentiation, which can be osseous or myogenic, but does not of itself imply dedifferentiation {3374,940,3003}. MDM2 and/or CDK4 nuclear immunopositivity is present in most cases {327,1485, 2875}. In lipoma-like ALT/WDLPS, MDM2 and CDK4 expression may prove difficult to evaluate, making FISH a valid alternative {611}. A major pitfall is represented by MDM2 nuclear positivity in histiocytes in fat necrosis. ALT/WDLPSs associated with Li-Fraumeni syndrome are MDM2-negative; however, they express p53.

WDLPS shows no potential for metastasis unless it undergoes dedifferentiation, therefore justifying the introduction of the term "atypical lipomatous tumour" for lesions arising at ana­ tomical sites for which complete surgical resection is curative. For lesi ons arising in an atomical sites such as retroperiton eum, spermatic cord, and mediastinum, which have shown greater potential for disease progression, retention of the term '"welldifferentiated liposarcoma" can be readily justified. The most important prog no stic factor is an atomical locati on. Lesions located in surgically amenable anatomical regions do not recur after complete excision. Tumours occurring in deep an atomical sites such as r etroperit on eum, spe rmatic cord, or mediastinum tend to recur repeatedly and eventually cause death as a result of uncontrolled local effects or less often as a result of systemic spread subsequent to dedifferentiation. In retroperitoneum, multivisceral resections may increase relapse-free survival {366}. The ultimate risk of dedifferentiation varies according to site and lesional duration and is prob­ ably > 20% in the retroperitoneum but < 2% in the limbs. Over­ all, 10-year to 20-year mortality rates range from essentially 0% for ALT of the extremities to > 80% for WDLPS occurring in the retroperitoneum. The median time to death is 6-11 years {1904,3270}.

Fig. 1.34 Atypical lipomatous tumour/ well-differentiated liposarcoma. Genomic quantitative profile obtained by array comparative genomic hybridization. The profile is simple showing the characteristic 12q14-q15 amplification including MDM2 (black arrow). Amplification of 1q23-q24 and 2q11-q13 is also observed in this case (blue arrows).

38

Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 Dei Tos AP Marino-Enriquez A Pedeutour F

Dedifferentiated liposarcoma

Definition Dedifferentiated liposarcoma (DDLPS) is an atypical lipomatous tumour / well-differentiated liposarcoma (ALT/WDLPS) showing progression, either in the primary or in a recurrenee, to (usually non-lipogenic) sarcoma of variable histological grade. In most cases, there is amplification of MDM2 and CDK4. A well-differentiated component may not be identifiable.

ICD-0 coding 8858/3 Dedifferentiated liposarcoma

ICD-11 coding 2B59 & XH1C03 Liposarcoma, primary site & Dedifferentiated liposarcoma

Related terminology None

Subtype(s) None

Localization Retroperitoneum is the most common location, outnumbering somatic soft tissue by at least 10:1. Other locations in elude the spermatic cord and (more rarely) mediastinum, head and neck, and trunk. Occurrence in subcutaneous tissue is extremely rare {778}. Recent molecular data suggest that the incidenee of DDLPS at non-retroperitoneal sites may be underestimated (1782).

Clinical features DDLPS usually prese nts as a large pain less mass, which may be found by chanee (in particular in the retroperitoneum). In the limbs, a history of a Iongstanding mass exhibiting recent

Fig. 1.35 Dedifferentiated liposarcoma. Multivisceral resection gross specimen fea­ turing a large lipomatous mass associated with solid nodules representing the dedif­ ferentiated component.

increase in size often indicates dedifferentiation. Radiological imaging often shows the coexistenee of lipomatous and nonlipomatous solid comp on ents.

Epidemiology DDLPS is a comm on form of liposarcoma, acc ounting for most pleomorphic sarcomas in the retroperitoneum. Dedifferentia­ tion occurs in as many as 10% of WDLPSs, although the risk is higherfor deep-seated (particularly retroperitoneal) lesions and significantly lower in the limbs. This is likely to represent a timedependent more than a site-dependent phenomenon {3270}.

Fig. 1.36 Dedifferentiated liposarcoma. A Abrupt transition from well-differentiated liposarcoma to high-grade non-lipogenic pleomorphic sarcoma is seen. B The morphology of the dedifferentiated component most often overlaps with that of undifferentiated pleomorphic sarcoma. C The morphology of the dedifferentiated component may be identical to that of myxofibrosarcoma.

Soft tissue tumours

39

paybal：https://www.paypal.me/andy19801210 Macroscopic appearanee DDLPS usually consists of large multi no dular yellow masses containing discrete, solid, often tan-grey non-lipomatous (dedifferentiated) areas. Dedifferentiated areas may show necrosis. The transition between the lipomatous and the dedifferentiated areas may sometimes be gradual.

Histopathology

Fig. 1.37 Dedifferentiated liposarcoma. Low-grade dedifferentiation is characterized

most often by the presence of uniform fibroblastic spindle cells with mild nuclear atypia.

DDLPS affects the same patient population as ALT/WDLPS and is equally frequent in males and females. About 90% of cases arise de novo, and 10% develop in recurrences {778}.

Etiology Unknown

Pathogenesis DDLPS genetically overlaps with ALT/WDLPS: both entities are characterized by consistent amplification of MDM2 and CDK4 (12q14-q15) {2702,1485}. As in ALT/WDLPS, many other genes from the 12q13-q21 region, as well as other chromosomal regions, are variably coamplified with MDM2. The amplicons are located in supernumerary ring or giant marker chromosomes with neocentromeres. Some genomic features appear to be more often related to DDLPS histology, although not restricted to DDLPS: amplification of JUA/(1p32.1) {2899}, TEA?T(5p15.33), CPM {925}, MAP3K5, and other genes from the 6q21-q24 region {472,1978,1570}. Karyotypes and quantitative genomic profiles of DDLPS are often more complex than those of ALT/WDLPS. DDLPS shows ATRXdeletion in 30% of cases {472}. In DDLPS, loss of 11q22-q24 (carrying several genes, e.g. ATM, CHEK1, ZBTB16, PPP2R1B, and El24) is associated with genomic com­ plexity {672}. In contrast to their high copy-number variations, DDLPSs present a low rate of mutations {1570,1391}.

The histological hallmark of DDLPS is transition from ALT/ WDLPS to non-lipogenic sarcoma, which in most cases is of high grade. The exte nt of dediffere ntiatio n is variable. Tran sition is usually abrupt; however, in some cases it can be more grad­ ual and, excepti on ally, low- and high-grade areas appear to be intermingled. In some cases, a well-differentiated lipomatous comp orient is hard to ide ntify. Dedifferentiated areas exhibit a variable histological picture but most frequently resemble undif­ ferentiated pleomorphic sarcoma or intermediate- to high-grade myxofibrosarcoma {2035,3270}. Although dedifferentiation was originally defined by high-grade morphology {942}, cases with low-grade dedifferentiation have increasingly been recognized {894,1349}. Low-grade dedifferentiation is characterized most often by the presenee of uniform fibroblastic spindle cells with mild nuelear atypia, often organized in a fascicular pattern and exhibiti ng cellularity in termediate betwee n well-differe ntiated sclerosing liposarcoma and usual high-grade areas. Lowgrade DDLPS should not be con fused with atypical spindle cell lipomatous tumours; the latter contain atypical adipocytes or lipoblasts, whereas dedifferentiated areas, both low- and high-grade, are generally non-lipogenic. Low-grade DDLPS is virtually indistinguishable from cellular WDLPS {940}. DDLPS may exhibit heterologous differentiation in about 5-10% of cases {948}. Most often the line of heterologous differentiation is myogenic or osteosarcomatous/chondrosarcomatous {3341}, but angiosarcomatous elements have also been reported. A peculiar neural-like or meningothelial-like whorling pattern of dedifferentiation has been described, which is often associ­ ated with ossification {969,2255}. Local recurrences of DDLPS may be entirely well differentiated {2035,3270}. Occasionally, the high-grade comp orient may exhibit overt lipoblastic differentiation, either in the form of isolated lipoblasts scattered throughout the high-grade component or as sheets of atypical pleomorphic adipocytic cells resulting in areas morphologically

Fig. 1.38 Dedifferentiated liposarcoma. A Rhabdomyoblastic differentiation represents the most common type of heterologous differentiation in dedifferentiated liposarco­ ma. B Rarely, dedifferentiated liposarcoma may feature a distinctive whorled pattern reminiscent of neural or meningothelial structures. C Rarely, the dedifferentiated compo­ nent exhibits striking lipogenic differentiation.

40

Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 Cytology There are few reports, but cytology is likely to be challenging {889}.

Diagnostic molecular pathology Detection of MDM2 amplification by FISH {2875}, multiplex ligation-dependent probe amplification {684}, and array com­ parative genomic hybrid'ization {3047} is helpful to distinguish DDLPS from other undifferentiated sarcomas in the appropriate clin ical con text.

Essential and desirable diagnostic criteria Fig. 1 >39 Dedifferentiated liposarcoma. Diffuse nuclear expression of MDM2 is con­

sistently observed in dedifferentiated liposarcoma.

Essential: transition (abrupt or gradual) from WDLPS (of any type) to spindle cell and pleomorphic non-lipogenic (rarely lipogenic) tumour (of low grade or high grade). Desirable (in selected cases): expression of MDM2 or demonstration of MDM2 gene amplification.

Staging The American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) TNM systems can be applied.

Prognosis and prediction

Fig. 1.40 Dedifferentiated liposarcoma. Interphase FISH analysis using probes for MDM2 (green signals) and centromere 12 (red signals) showing high-level amplifica­ tion of MDM2. The amplified signals are grouped in a large cluster, representative of the presence of a supernumerary ring or giant marker chromosome. The three coupled red-green signals indicate trisomy 12.

indistinguishable from pleomorphic liposarcoma. This phenomenon has been referred to as homologous lipoblastic differentiation or pleomorphic liposarcoma-like features {356,1349,1981}. Solitary fibrous tumour-like and inflammatory myofibroblastic tumour-like morphology can be rarely observed {1906}. The main role of immunohistochemistry is in the confirmation of diverge nt differe ntiatio n and exclusi on of other tumour types. Diffuse nuclear expression of MDM2 and/or CDK4 is almost in variably observed {774} and also allows separati on of homolo­ gous DDLPS from pleomorphic liposarcoma {2875,1981}.

DDLPS is characterized by local recurrenee in at least 40% of cases. However, almost all retroperitoneal examples seem to recur locally if patients are followed for 10-20 years. Distant metastases are observed in 15-20% of cases, with an overall mortality rate of 28-30% at 5-year follow-up, although this figure is undoubtedly much higher at 10-20 years {1349,2035,3270}. The most important prog no stic factor is anatomical locati on, with retroperitoneal lesions exhibiting the worst clinical behaviour. The extent of dedifferentiated areas does not seem to predict outcome. DDLPS, despite its high-grade morphology, exhibits a less aggressive clinical course than other types of high-grade pleomorphic sarcoma, and an accelerated clinical course is observed in only a minority of patients. Recent data would indi­ cate that a prognostic differenee does exist based on grading when the French Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system is used {1226). Moreover, in contrast with previous observation {326}, myogenic (in particular rhabdomyoblastic) differentiation appears to be associated with worse outcome {1226}. Multivisceral resections appear to in crease relapse-free survival {1230,366}.

Fig. 1.41 Dedifferentiated liposarcoma. Array comparative genomic hybridization. Relatively simple quantitative genomic profile, showing characteristic high-level 12q amplifica­ tion (black arrow) including MD/W2(12q15). The 12q amplicon is large (from 12q12 upto q21) and discontinuous. It contains several genes frequently coamplified with MDM2, such as CDK4, HMGA2, and FRS2. A few other imbalanced alterations are also observed: amplification of 1q24, 2p11, 2q11, and 6p11-q16 regions (blue arrows), as well as gains and losses on chromosomes 1,16, and 20.

Soft tissue tumours

41

paybal：https://www.paypal.me/andy19801210 Myxoid liposarcoma

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Definition Myxoid liposarcoma (MLPS) is a malignant tumour composed of uniform, round to ovoid cells with variable numbers of small lipoblasts, set in a myxoid stroma with a branching capillary vasculature. Translocations producing FUS-DDIT3 or rarely EWSR1-DDIT3 fusion transcripts are pathognomonic. Included in this category are more-cellular, high-grade tumours formerly known as round cell liposarcoma.

ICD-0 coding 8852/3 Myxoid liposarcoma

ICD-11 coding 2B59.Y & XH3EL0 Liposarcoma, other specified primary site & Myxoid liposarcoma

Related termi no logy Not recommended: round cell liposarcoma.

Fig. 1.42 Myxoid liposarcoma. Macroscopically, the tumour, present here within sub­ cutaneous fat, has a soft, glistening reddish cut surface, due to old and recent haem­

Subtype(s)

orrhage.

None

Localization MLPSs typically present within deep soft tissues of the extremi­ ties, most often the thigh {1624,1387}. Very rarely they arise as primary neoplasms of the subcutis or retroperitoneum {2816, 766}.

Clinical features MLPSs typically present as large, pain less masses. Ret­ roperitoneal MLPS most often represents a metastasis {2816, 766}. Multifocal disease, either synchronous or metachronous, represents distant soft tissue metastases of monoclonal origin {130}. Surgical wide excision is the current treatment mainstay

{1008}. MLPS is extremely radiosensitive {241} and relatively sensitive to anthracyclines and trabectedin compared with other sarcomas {1546,1236}.

Epidemiology MLPS accounts for approximately 20-30% of liposarcomas {2389} and 5% of adult soft tissue sarcomas, without significant sex predilection. Although peak incidenee is in the fourth to fifth decades, MLPS is the most comm on liposarcoma subtype of children and adolescents {1438,58}.

Etiology Un know n

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Fig. 1.43 Myxoid liposarcoma. A Low-grade myxoid liposarcoma, with abundant myxoid matrix, and lymphangioma-like cystic spaces. B Higher-power magnification of lowgrade myxoid liposarcoma, illustrating the characteristic elaborate capillary vasculature of this tumour. The neoplastic cells are small, round to ovoid, and bland. Lipoblasts were very difficult to find in this particular tumour and are not required for diagnosis.

42

Soft tissue tumours

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Fig. 1.44 Myxoid liposarcoma. A Differentiating myxoid liposarcoma, with a component of mature white fat. On occasion, myxoid liposarcomas may contain abundant mature fat. mimicking lipoma with myxoid change. B Myxoid liposarcomas typically show increased cellularity at the periphery of lobules. This should not be interpreted as round cell change, for purposes of grading.

Fig. 1.45 High-grade myxoid liposarcoma. A This lesion shows an abrupt transition between typical low-grade histology (bottom) and high-grade, round cell morphology (top

idigh-powerview showing cellular overlap, elevated nuclear grade, mitotic activity, and obscuring of the underlying vascular pattern.

Pathogenesis MLPS and its hypercellular subtype (formerly, round cell liposar­ coma) harbour the same genetic abnormality. Most are character­ ized by the t(12;16)(q13;p11) translocation generating FUS-DDIT3 fusion tran scripts, tran slated into a chimeric on coprotein that alters transcription and differentiation. DDIT3 (CHOP, GADD153) is a DNA-binding transcription factor normally induced under cell stress, which blocks adipocytic terminal differentiation {1287, 409j. Fusi on tran scripts always in elude the full codi ng seque nee. In the fusion, FUS, a gene widely expressed in normal tissues, provides promoter sequences and its first 3-13 exons {2531}. Fusion protein variants consistently retain the FUS N-terminal transcriptional activation domain that is largely conserved across FET protein family members, including EWSR1 {2790}. EWSFI1 substitutes for FUS in about 3% of MLPSs, generating EWSR1DDIT3 oneoproteins {2531}, without proven histological or prog­ nostic differences. The net result is a block to terminal fatty differ­ entiation {2490}. The genomic background shows a low mutation burden, with wildtype 7P53{1550}. More than 50% of cases carry TERT promoter mutations {1667}, and about 25% have mutations activating PI3K/mTOR {3098}, but no other genetic events occur consistently at frequencies > 20%.

Macroscopic appearance MLPSs are typically large (> 10 cm), circumscribed, multinodular intramuscular neoplasms {140}. The cut surface is smooth, gelatinous, and glistening. Higher-grade tumours show a firmer, fleshy

tan surface. Macroscopic necrosis is uncommon. Adequate sampling to estimate the amount of hypercellularity is essential, because this is a major prog no stic determi nant {935,2922}.

Histopathology At low magnification, MLPSs are moderately cellular, lobulated tumours with increased peripheral cellularity, comprising pattemless arrays of uniform, small, ovoid cells without morpho­ logical adipocytic differentiation, with variable numbers of small lipoblasts. The tumours contain abundant, lightly basophilic, myxoid stroma with a striking plexiform, delicately arborizing, capillary network (chicken wire) {2389}, around which neoplas­ tic cells often cluster. Paucicellular extracellular mucin pools may be present, imparting a microcystic / pulmonary oedema­ like pattern. MLPS typically lacks atypia, substantial mitotic activity, or spindling. The lipoblasts are smaller than in other liposarcomas, and predominantly univacuolated/bivacuolated. Lipoblasts may be rare or even absent. A variable percentage of mature fat may be prese nt. Chon droid and osseous elements are rare and are thought to be metaplastic in nature {3265}. High-grade MLPSs show > 5% of the tumour to have cellular overlap, diminished myxoid matrix, less-apparent capillary vas­ culature, elevated n uelear grade, and in creased mitotic activity. A corded or trabecular pattern is often present. Pure high-grade MLPS may be indistinguishable from other round cell sarcomas, requiring molecular genetic studies for diagnosis. The presence of > 5% hypercellularity is associated with signifiesntly

Soft tissue tumours

43

paybal：https://www.paypal.me/andy19801210 poorer prog nosis (Fre nch Federati on Nationale des Centres de Lutte Contre le Cancer [FNCLCC] grading system differentiation score of 3). The presenee and percentage of hypercellular areas should be recorded. Some cases show so-called transi­ tional areas with modestly increased cellularity without elevated nuelear grade and mitotic activity {2898}. Immunohistochemistry plays little role in the diagnosis of MLPS, but it may be of some value in the distinotion of high­ grade tumours from other round cell sarcomas. MLPSs treated with either preoperative chemotherapy or radiotherapy often show a marked decrease in cellularity, with only scattered ovoid cells, extensive stromal hyalinization, and sometimes maturation into white adipose tissue.

Cytology Fig. 1.46 Metastatic myxoid liposarcoma. This lesion is a metastasis from the surface of the spleen. Essentially all intra-abdominal and retroperitoneal myxoid liposarcomas

Cytological appearances consist of variable proportions of small round cells in myxoid matrix containing thin-walled branching vessels.

represent metastases.

Diagnostic molecular pathology Demonstration of the translocation/fusion transcript may be helpful in distinguishing MLPS from other myxoid sarcomas, and high-grade MLPS from various round cell sarcomas {1489}. FUS and EWSR1 can substitute for each other and occur in other sarcomas, whereas DDIT3 is unique to MLPS. Thus, FISH break-apart probes directed at DDIT3 are a sensitive, spe­ cific strategy {2248}. Alternative diag no stic methods in elude RT-PCR with primers designed to cover all common fusion variants {2531}, massively parallel sequencing {3016}, and multi­ plexed colour-coded probe pair technologies {538}.

Essential and desirable diagnostic criteria

22

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The American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) TNM systems can be applied.

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Essential: myxoid matrix containing delicately arborizing capil­ laries; bland round to ovoid cells; variable number of small non-pleomorphic lipoblasts, often adjacent to capillaries; hypercellularity, diminished myxoid matrix, obscured capillar­ ies, and elevated nuclear grade and mitotic activity in high­ grade MLPS. Desirable: dem on stratio n of DDIT3 rearrangement (FUS-DDIT3 or EWSR1-DDIT3 fusion genes).

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Fig. 1.47 Myxoid liposarcoma. A Schematic illustration of the breakpoints involved in the translocations t(12;16)(q13.3;p11.2) and t(12;22)(q13.3;q12.2) resulting in FUSDDIT3 and EWSR1-DDIT3 fusions, respectively. B The N-terminal transcriptional ac­ tivation domain of FUS or EWSR1 is retained in the fusion to the entire coding region of DDIT3, which encodes an apparent DNA-binding and dimerization domain. There are at least 11 different isoforms of the FUS-DDIT3 fusion transcript (with types 1-3 being most common) and 4 of EWSR1-DDIT3 (with type 1 being most common in this rare molecular subtype).

44

Soft tissue tumours

Local recurrence occurs in 12-25% of cases {1293,1008}. Distant metastases develop in approximately 30-60%, sometimes years after initial diag no sis, and may progress slowly {2922}. Unlike most sarcomas, MLPSs often metastasize to other soft tissue sites and can metastasize to bone (particularly spine) {2189}, in preference to lung {2922,935}. Histologically high­ grade tumours (> 5% hypercellularity) have a statistically signifi­ cant higher rate of metastasis or death from disease {2898,140, 1387,1008,2922,2189). Necrosis a nd TP53ar\d CDKN2A alterations have bee n associated with adverse prog nosis {1008,140, 1293,2349}. The prognostic significance of transitional areas with more-limited hypercellularity is less certain. There is no association between different FUS-DDIT3 transcript isoforms and grade or prog nosis {140,347}.

paybal：https://www.paypal.me/andy19801210 Pedeutour F Montgomery EA

Pleomorphic liposarcoma

Definition

Localization

Pleomorphic liposarcoma is a pleomorphic, high-grade sar­ coma containing variable numbers of pleomorphic lipoblasts. Ng areas of atypical lipomatous tumour / well-differentiated lipo­ sarcoma or other lines of differentiation are present.

ICD-11 coding

Pleomorphic liposarcoma occurs on the extremities in two thirds of cases (more comm only in the lower tha n the upper limbs); the trunk wall, retroperitoneum, and spermatic cord are less frequently affected {848,1404,1126,2117}. Rare sites of invo Iveme nt in elude the mediasti num, heart, pleura, breast, scalp, colon, and orbit {458,1126,1404}. Most cases arise in deep soft tissue, but about 25% develop in subcutaneous fat {1126,1404}; purely dermal cases are very rare {779, 848,1404,1126}.

2B59.Y & XH25R1 Liposarcoma, other specified primary site & Pleomorphic liposarcoma

Clinical features

ICD-0 coding 8854/3 Pleomorphic liposarcoma

Related terminology None

Most patie nts r eport a rapidly growi ng pain less mass, usually with a short preoperative du rati on (media n: 3-6 months); a sub­ set of patients report pain, and some patients have symptoms related to tumour location {1126,1404}.

Subtype(s) Epithelioid liposarcoma

Fig. 1.48 Pleomorphic liposarcoma. A Note that most of the lesion shows spindle cells and such foci cannot be diagnosed as pleomorphic liposarcoma. Pleomorphic liposarcoma is diagnosed on H&E staining by identifying pleomorphic lipoblasts, as in the 叩per left of the image, in which lipid droplets crisply indent the pleomorphic nucleus. Sometimes

examination of multiple tissue blocks is required to identify the diagnostic areas, which can be missed on needle biopsies. B This field shows numerous pleomorphic lipoblasts, each with nuclear indentations by cytoplasmic lipid droplets. C These neoplasms feature some of the most bizarre nuclei in human neoplasia and lack characteristic translocations and gene fusions. D This epithelioid pleomorphic liposarcoma shows lipid droplets but also shows many epithelioid cells with round nuclei and a rich vascular network.

Soft tissue tumours

45

paybal：https://www.paypal.me/andy19801210 sectioning, most tumours are white to yellow, Myxoid changes and foci of necrosis are often observed.

Histopathology

Fig. 1.49 Pleomorphic liposarcoma. Metaphase cell (RHG-banding) showing numer­ ous quantitative and structural chromosomal alterations: near-tetraploidy and complex

marker chromosomes.

Epidemiology Pleomorphic liposarcoma is a rare subtype of liposarcoma, accounting for < 5% of all liposarcomas {1403,110}. Most cases occur in adults in later life, with peak incidenee in the seventh decade of life and a slightly higher incidence in males than females. Paediatric cases are excepti on al {58}.

Histologically, most cases have infiltrative margins, and a tumours contain a varying proportion of pleomorphic lipoblasts in a background of a high-grade, usually pleomorphic, undifferentiated sarcoma {501,778}. The presence of lipoblasts is n ecessary for the diag no sis, but their number varies consid­ erably between cases and between areas within the same tumour, emphasizi ng the imports nee of adequate samp.li ng In most cases, the n on-lipoge nic comp orient resembles undifferentiated pleomorphic sarcoma with spindle and multinucleated giant cells arran ged in short fascicles, with some notable features: namely, the presenee of extremely large tumour cells often show,ng clear or vacuolated cytoplasm, and the presenee of extracellula r and occasi on ally intracellular eosi nophilic hya line droplets. Almost half of cases contain at least focal areas similar to intermediate- to high-grade myxofibrosarcoma-like zones associated with pleomorphic lipoblasts. This myxofibro sarcoma-like component is predominant in some cases. Epi thelioid morphology is seen in about one quarter of cases witt areas resembli ng poorly differe ntiated carci no ma, renal clear cell carcino ma, ad re no cortical carci no ma, or melanoma {1126 ■ 1404,2117,455,1426}. Necrosis is present in more than half of cases. Unlike in dedifferentiated liposarcoma with homologous dif­ fere ntiation, staining for MDM2 and CDK4 is typically nega tive in pleomorphic liposarcoma {858,1126,1404,1981}. The epithelioid subtype may be positive for keratins and melan-A {110}.

Cytology

Etiology Unknown

There are few reports, but cytology is likely to be challenging {889}.

Pathoge nesis

Diagnostic molecular pathology

The molecular profiles of pleomorphic liposarcomas more closely resemble those of other pleomorphic sarcomas than those of atypical lipomatous tumour / well-differentiated lipo­ sarcoma, dedifferentiated liposarcoma, or myxoid liposarcoma {472,1078}. Metaphase cells show high chromosomal counts and complex structural rearrangements. This complexity is rep­ resented by unidentifiable marker chromosomes, non-clonal aberrations, polyploidy, and intercellular heterogeneity. No pathognomonic structural rearrangement, such as recurrent translocation or consistent presenee of supernumerary ring chromosomes, has been identified. Studies using array com­ parative genomic hybridization have shown complex profiles with numerous chromosomal imbalances {1078,1460,2623, 2768,3057}. The most frequent mutations involve TP53 and NF1 {224,2774,3057}. It has been noted that the genomic profiles of pleomorphic liposarcoma and myxofibrosarcoma are similar {224,1460}. Amplification of the 12q14-q15 region is absent in pleomorphic liposarcoma {1078,2869,3232}.

Absence of amplification of MDM2 can help distinguish pleo­ morphic liposarcoma from dedifferentiated liposarcoma.

Macroscopic appearance Most tumours are large, with a median size of 8-10 cm {1126, 1404}. They are well demarcated but non-encapsulated, or ill-defi ned and in filtrative and sometimes multi no dular. On

46

Soft tissue tumours

Essential and desirable diagnostic criteria Essential: pleomorphic spindle cell sarcoma containing a varia­ ble number of pleomorphic lipoblasts; myxofibrosarcoma-like morphology with pleomorphic lipoblasts; epithelioid subtype with sheets of carci no ma-like epithelioid cells with pleomor­ phic lipoblasts; tumours may consist only of pleomorphic lipoblasts.

Staging The American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) TNM systems can be applied.

Prognosis and prediction Pleomorphic liposarcomas are aggressive sarcomas exhibiting local recurrenee and metastatic rates of 30-50%, with an over­ all 5-year survival rate of about 60%. Metastases occur mostly in the lungs and pleura. Central locati on, in creased tumour depth, greater size, and higher mitotic count have been associ-j ated with a worse prognosis {1126,1404}.

paybal：https://www.paypal.me/andy19801210 Alaggio R Creytens D

nges| Myxoid pleomorphic liposarcoma d all lasts indif- f its is nsidDefinition ;ame Myxoid pleomorphic liposarcoma is an exceptionally rare, )ling. aggressive adipocytic neoplasm, typically occurring in chilindif- I dren and adolescents. Myxoid pleomorphic liposarcoma shows uclemixed histological features of conventional myxoid liposarcoma table and pleomorphic liposarcoma and lacks the gene fusions and cells amplifications of myxoid liposarcoma, atypical lipomatous ence tumour, and dedifferentiated liposarcoma. hya-l

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Etiology Unknown

ICD-0 coding

Pathogenesis Myxoid pleomorphic liposarcoma has been associated with Li-Fraumeni syndrome {2866}, numerical chromosomal aberrations, and inactivation of the RB1 tumour suppressor gene {1389,676,110,2554,785}.

ICD-11 coding 2B59.Y & XH3EL0 & XH25R1 Liposarcoma, other specified primary site & Myxoid liposarcoma & Pleomorphic liposar­ coma

Related terminology s difAcceptable: pleomorphic myxoid liposarcoma. ega- (■ The Subtype(s) an-A None

Localization

pleo-

Myxoid pleomorphic liposarcoma occurs predominantly in childre n and you ng adults. Patie nt age in the large majority of published cases is < 30 years {58,682,1389,2866}. There is a female predominanee {58}.

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Epidemiology

Myxoid pleomorphic liposarcoma has a predilection for the mediastinum {58,623,352}. Other reported locations include the thigh, head and neck, perineum, abdomen, and back {58,682, 1389,2866}.

Clinical features Myxoid pleomorphic liposarcoma gen erally manifests as a large, deep-seated soft tissue mass {682,1389}.

Macroscopic appearance Grossly, myxoid pleomorphic liposarcomas are non-encapsulated tumours with ill-defined margins {682).

Histopathology Histologically, the tumours show variable proportions of myxoid liposarcoma-like areas, characterized by abundant myxoid matrix, scattered lipoblasts, relatively bland primitive round to oval cells, and a delicate curvilinear to plexiform capillary network {58,682}. Lymphangioma-like myxoid pools can be observed {682}. Pleomorphic spindle or ovoid cells with hyperchromatic nuclei may be scattered within the myxoid component, with a progressive transition into more-cellular, high-grade pleomorphic liposarcoma-like areas displaying severe cytologi­ cal atypia, increased mitotic activity, atypical mitoses, pleomor­ phic lipoblasts, and occasional necrosis {58,682}. Myxoid pleo­ morphic liposarcomas have a non specific immu nophe notype.

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Fig. 1.50 Myxoid pleomorphic liposarcoma. A A fibrous, densely cellular area with pleomorphism is adjacent to a myxoid liposarcoma-like component. B Pseudocystic changes in myxoid areas with associated classic monovacuolated and multivacuolated lipoblasts. An isolated pleomorphic cell is seen.

Soft tissue tumours

47

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Fig. 1.51 Myxoid pleomorphic liposarcoma. A Delicate vaguely plexiform vascular pattern in the context of a myxoid background. Primitive cells and isolated cells with a hyperchromatic nucleus are seen. B Myxoid pleomorphic liposarcoma showing a myxoid liposarcoma-like arborizing capillary vasculature, marked nuclear atypia, and pleomorphic lipoblasts.

Cytology

Staging

Not clinically re leva nt

The American Joint Committee on Cancer (AJCC) and Union for Intemational Cancer Control (UICC) TNM systems can be applied.

Diagnostic molecular pathology FISH studies have shown that myxoid pleomorphic liposarcoma lacks the FUS/EWSFI1-DDIT3 gene fusions seen in conventional myxoid liposarcoma, as well as the /WD/W2amplification present in well-differentiated/dedifferentiated liposarcoma {58,682}.

Essential and desirable diagnostic criteria Essential: distinctive admixture of relatively bland zones resembling conventional myxoid liposarcoma and much more cellu­ lar and atypical areas, resembling pleomorphic liposarcoma. Desirable (in selected cases): absence of FUS/EWSFI1-DDIT3 gene fusions and /WD/W2amplifications.

48

Soft tissue tumours

Prog nosis and prediction Myxoid pleomorphic liposarcoma is an extremely aggressive tumour type with a high recurrenee rate; metastasis to lung, bone, and soft tissue; and poor overall survival {58,623}.

paybal：https://www.paypal.me/andy19801210 Oliveira AM Wang J Wang WL

Nodular fasciitis

Definition Nodular fasciitis is a self-limiting mesenchymal neoplasm that usually occurs in subcutaneous tissue. It is composed of plump, uniform fibroblastic/myofibroblastic cells displaying a tissue culture-like architectural pattern, and it usually harbours USP6 rearrangement.

fasciitis occur equally frequently in males and females, but cranial fasciitis is more comm on in boys.

Etiology Unknown

Pathogenesis

ICD-0 coding 8828/0 Nodular fasciitis

ICD-11 coding FB51.2 & XH5LM1 Pseudosarcomatous fibromatosis & Nodular fasciitis

Related terminology Not recommended: pseudosarcomatous fasciitis.

Subtype(s) Intravascular fasciitis; cranial fasciitis

The identification of recurrent USP6 gene rearrangements in nodular fasciitis has firmly established its previously disputed clonal neoplastic nature {329,838,924,1679,2749,3184,3262, 2461). USP6 (17p13.2) is a deubiquitinating protease involved in cell trafficking, protein degradation, signalling, and inflammation. Multiple promoter partners have been described {924, 2461,1254}; the most frequent partner is MYH9 (22q12.3), which encodes non-muscular myosin heavy chain 9 (MYH9), which is involved in cell-shape maintenance, cell motility, adhe­ sion, differentiation, and development {2370,2461}. The USP6 fusion causes transcriptional upregulation of the entire coding sequenee of USP6 driven by the active (usually MYH9) promoter in a classic promoter-swapping mechanism. As an example of

Localization Nodular fasciitis typically develops on the surface of fascia and extends into subcutis, although occasional cases are intramuscular {2066}. Dermal localization is rare {773,1707}. Any ana­ tomical site can be invoIved, but the upper extremities, trunk, and head and neck are most frequently affected. Intra-articular involvement has been described {1410}. Intravascular fasciitis is usually subcutaneous. It occurs in small to medium-sized vessels, predominantly veins but occasionally arteries {2458}. Cranial fasciitis typically involves the outer table of the skull and contiguous soft tissue of the scalp and may extend downwards through the inner table into the meninges {1773}.

Clinical features Nodular fasciitis typically grows rapidly and has a preoperative durati on in most cases of not more tha n 2-3 mon ths. Sore ness or tendemess may be present. It usually measures < 2 cm and almost always < 5 cm. Intravascular fasciitis may enlarge more slowly but is also normally not more than 2 cm. Cranial fas­ ciitis expands quickly, like nodular fasciitis, and may become somewhat larger than the usual example of the latter. When the skull is invoIved, X-ray imaging shows a lytic defect, often with a sclerotic rim. In contrast, nodular fasciitis presents as a nondistinctive soft tissue mass on imaging studies.

Epidemiology Nodular fasciitis is relatively common {76,280,1446,1683,2847, 2914,2543}. It occurs in all age groups but more often in you ng adults. Intravascular fasciitis {2458} and cranial fasciitis {1773} are rare. Intravascular fasciitis is found mostly in people aged < 30 years, whereas cranial fasciitis develops predominantly in infants aged < 2 years. Nodular fasciitis and intravascular

Fig. 1.52 Nodular fasciitis. A Nodularity, vague irregular borders, myxoid and cystic changes, and haemorrhagic areas are readily observed at low power in this typical example. B Occasional cases are intravascular.

Soft tissue tumours

49

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Fig. 1.53 Nodular fasciitis. A At medium power, the characteristic tissue culture-like appearance and cystic myxoid changes are virtually diagnostic. B Hyalinized areas are commonly encountered. C The tumour cells contain ovoid to tapering nuclei, fine chromatin, small nucleoli, and amphophilic cytoplasm. Note the loose fascicular architecture and prominent mitotic activity.

a consistently self-limited and regressing lesion with a recurrent fusion gene, the term "transient neoplasia" has been suggested (924). USP6 rearrangements are also found in aneurysmal bone cyst, myositis ossificans, cellular fibroma of tendon sheath, and fibro-osseous pseudotumour of digits, which share some his­ tological features with nodular fasciitis, suggesting a possible biological relati on ship among these tumour types {2371,2375, 2373,1036,2980,496}. Recent mechanistic studies have identi­ fied the NF-kB and JAK-1/STAT3 pathways as critical mediators of tumorigenesis by USP6 {2560,2546}. Few cases of cranial fasciitis have been reported to have USP6 rearrangement {2723}.

Macroscopic appearance Macroscopically, nodular fasciitis may appear circumscribed or infiltrative, but it is not encapsulated. The cut surface varies from myxoid to fibrous, and occasi on ally there is central cystic change. Intravascular fasciitis ranges from nodular to plexiform, the latter con tour resulti ng when there is exte nsive intra­ vascular growth. Cranial fasciitis is typically circumscribed and rubbery to firm, and it may be focally myxoid or cystic in its centre.

Intravascular fasciitis and cranial fasciitis are similar to nodu-| lar fasciitis histologically, although intravascular fasciitis often displays a greater number of osteoclast-like giant cells. Intravascular fasciitis ranges from predominantly extravascular, withi only a minor in travascula r comp orient, to predomi nantly intra­ vascular. Osseous metaplasia is occasi on ally see n in nodular fasciitis (fasciitis ossificans) and cranial fasciitis {734,1724}. By immunohistochemistry, the neoplastic cells express SMA and MSA in a typical myofibroblastic (tram-track) pattern; desmi n positivity is occasi on ally fou nd, usually focally {2180}. Nuclear 卩-catenin may be seen in cranial fasciitis {2569}.

50

Soft tissue tumours

Si ! L F1

Cytology

e

Cytology preparations reveal bland spindle cells with unipolar curved to bipolar processes, round to oval elongated nucle「 and occasional small nueleoli. A tissue culture-like appearanee and myxoid stroma can be appreciated {81,283}.

e

Diagnostic molecular pathology

C

Molecular testing is usually unnecessary in clinically and histo­ logically typical cases. However, in challenging cases, breakapart USP6 FISH or next-generation sequencing techniques may be used to confirm the diagnosis {2461,923,1739}.

E

Histopathology Nodular fasciitis is composed of plump spindle-shaped cells lacking nuclear hyperchromasia or pleomorphism. Mitotic fig­ ures may be plentiful, but atypical forms are not observed. The lesion may be highly cellular, but typically it is partly discohesive and myxoid, with a tom, feathery, or tissue culture­ like character. In more-cellular areas, there is often growth in S-shaped or C-shaped fascicles, or sometimes in a storiform pattern. There is normally little collagen, but collagen may be inc reased focally, and keloidal collage n bun dies may be present and occasi on ally promi nent. Microcystic stromal cha nges are also typical. Extravasated erythrocytes, lymphocytes, and osteoclast-like giant cells are frequently identified. The lesional border is typically infiltrative (at least focally), although it may be well delineated; peripheral extension is often seen between fat cells in the subcutis and between muscle cells in intramuscular locations. Small vessels are numerous, which may occasionally result in a resemblanee to granulation tissue.

R(

Essential and desirable diagnostic criteria Essential: bland, typically cellular myofibroblastic proliferation with a tissue culture-like growth pattern; variably myxoid stroma with microcystic changes; extravasated red blood cells. Desirable: assessment of USP6 rearrangement can be helpful in selected cases.

Staging Not clin ically re leva nt

Prognosis and prediction Recurrenee of nodular fasciitis after excision is rare, but occasional in stances have bee n observed. An excepti onal case of malignant nodular fasciitis harbouring the fusion transcript PPP6R3-USP6 has been described in a patient with long-term recurrences and multiple metastases {1254.3061A}.

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paybal：https://www.paypal.me/andy19801210 Wang WL Lazar AJ

Proliferative fasciitis and proliferative myositis

Definition Proliferative fasciitis is a mass-forming subcutaneous prolifera­ tion characterized by large ganglion-like cells and plump myofibroblastic/fibroblastic cells. Proliferative myositis has the same cellular composition but occurs within skeletal muscle. reas are litecture

n oduoften Intra.r, with intra□dular ;SMA attern; 2180).

ICD-0 coding 8828/0 Proliferative fasciitis 8828/0 Proliferative myositis

histoliques

Proliferative fasciitis and proliferative myositis are much less comm on than no dular fasciitis. Both occur predomi nantly in middle-aged or older adults, i.e. in an older age group than nodular fasciitis {606,915,1613}. A rare subtype of proliferative fasciitis is described in children {2060}.

ICD-11 coding

Etiology

Related termi no logy

Pathogenesis

None

Unlike in nodular fasciitis, a recurrent genomic abnormality or translocation has yet to be firmly established in proliferative fasciitis/myositis.

Subtype(s)

Unknown

None

Macroscopic appearance Proliferative fasciitis develops most frequently in the upper extremities, particularly the forearms, followed by the lower extrem and trunk. Proliferative myositis arises predominantly in the trunk, shoulder girdles, and upper arms, and less often in the thighs. By definition, proliferative fasciitis is subcutaneous and proliferative myositis is intramuscular.

Clinical features

)reak-

Epidemiology

FB51.Y Other specified fibroblastic disorders (index term Fas­ ciitis NOS)

Localizati on

bipolar luclei, 〔rance

imaging characteristics of proliferative myositis can be sugges­ tive of the diagnosis; those of proliferative fasciitis are less well studied {2409}.

Both proliferative fasciitis and proliferative myositis character­ istically grow rapidly and are usually excised within 2 months from the time they are first no ted. Proliferative fasciitis almost always measures < 5 cm and is most often < 3 cm. Prolifera­ tive myositis may be slightly larger. Either lesion may be painful or ten der; this is more comm on with proliferative fasciitis. The

Proliferative fasciitis typically forms a poorly circumscribed mass in the subcuta neous tissue and may exte nd horizon tally along fascia. The rare childhood subtype is often better circum­ scribed. Proliferative myositis is also poorly marginated and invoIves a variable proportion of the muscle.

Histopathology Both proliferative fasciitis and myositis contain plump myofibroblastic/fibroblastic spindle cells similar to those seen in no dula r fasciitis but also dem on strate large ganglion-like cells with roun ded n uclei, promine nt n ucleoli, and abunda nt ampho­ philic to basophilic cytoplasm {606}. These cells usually have one nucleus but may have two or three. They may be evenly or irregularly distributed. Mitotic figures are found in both the spindle cells and the ganglion-like cells and may be relatively

nation lyxoid blood

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Soft tissue tumours

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Fig. 1.55 Proliferative myositis. A Note the spindle cells. Ganglion-like cells sporting amphophilic cytoplasm are admixed. B Details of the cytological features of the ganglion­ like cells with prominent nucleoli.

numerous but are not atypical. The stroma varies from myxoid to collage no us. The lesi onal borders are typically infiltrative or even ill defined. Proliferative fasciitis may grow laterally along fascial planes, whereas proliferative myositis extends between in dividual muscle fibres, creating the characteristic checker­ board pattern. The childhood subtype of proliferative fasciitis gen erally has better-deli nested borders tha n the adult form, as well as greater cellularity, a predominance of ganglion-like cells, and more mitoses. Focal necrosis and acute inflammation may also be present. Proliferative myositis may contain metaplastic bone, dem on strating possible kin ship to myositis ossifica ns. The immunohistochemical profile is similar to that of nodular fasciitis; the spindle cells usually express SMA and MSA and are negative for desmin {895,1914}. The ganglion-like cells are often negative for actins.

numbers of large ganglion-like cells with prominent nucleoli, smooth nuclear membranes, and fine chromatin. Admixed skel­ etal muscle cells can be seen in proliferative myositis {3305}. I

Diagnostic molecular pathology Not clin ically releva nt

Essential and desirable diagnostic criteria Essential: myofibroblastic/fibroblastic proliferation with ganglion-like cells; variable collagenous/myxoid stroma; subcutaneous/fascial invoIvement (proliferative fasciitis); intramuscular checkerboard growth pattern (proliferative myositis).

Staging Not clin ically releva nt

Cytology

Prognosis and prediction

On cytology, spindle cells with long cytoplasmic processes and round or oval nuclei can be appreciated in addition to variable

Both proliferative fasciitis and proliferative myositis rarely recur after conservative local excision, but they do not metastasize.

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Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 Myositis ossificans and fibro-osseous pseudotumour of digits

Oliveira AM Rosenberg AE

Definition Myositis ossificans and fibro-osseous pseudotumour of digits (FP) are self-limited benign neoplasms composed of spindle cells and osteoblasts. Myositis ossificans, FP, and soft tissue aneurysmal bone cyst belong to the same neoplastic spectrum.

ICD-0 coding None

ICD-11 coding FB31.Y Myositis ossificans FB51.Y Fibro-osseous pseudotumour of digits

Related terminology Not recommended: pseudomalignant osseous tumour of soft tissue; myositis ossificans circumscripta; myositis ossificans traumatica.

Subtype(s) None

Localization Myositis ossifica ns can develop any where in the body {12,802, 2116.2335,2658,2987}. Comm on locations are those suscepti­ ble to trauma, such as the elbow, thigh, buttock, and shoulder. Typically it develops within skeletal muscle, but similar lesions occur in the subcutis and in the tendons/fascia and are known as panniculitis ossificans and fasciitis ossificans, respectively. FP affects the subcutaneous tissues of the proximal phalanx of the fin gers and less freque ntly the toes {545,2187}. Myositis ossificans—like lesions have also been reported in the mesen­ tery {3388}.

Clinical features The lesions grow rapidly and the clinical and radiological fea­ tures evolve over time. In the early phase (1-2 weeks), there is swelling and pain. Soft tissue fullness and oedema are present on radiographs and CT; MRI reveals signal heterogeneity, with high signal intensity on T2-weighted images. Flocculent mineialization becomes evident at the periphery of the mass 2-6 weeks afte r on set of symptoms; it evolves into an eggshell­ like layer of bone, and the centre is radiolucent. The mineralization is randomly distributed in FP. Over time, myositis ossificans and FP become hard and well demarcated and pain diminishes {12,802,2116,2335,2658,2987}.

Fig. 1.56 Myositis ossificans. A Radiograph of a round mass in the soft tissues of the wrist showing a fine cloud-like pattern of mineralization, densest at the periph­

ery. B Well-circumscribed tan haemorrhagic mass.

Epidemiology Myositis ossificans and FP develop from infancy to late adult­ hood; they usually occur in physically active young adults (mean age: 32 years) {12,802,2116,2335,2658,2987,2817,3218}. The M:F ratio is 1.5:1 for myositis ossificans; females are more com­ monly affected by FP.

Fig. 1.57 Fibro-osseous pseudotumour of digits. The lesion presents as a well-cir­ cumscribed subcuticular mass.

Soft tissue tumours

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c Fig. 1.58 Myositis ossificans. A Zonation pattern with focally cystic hypercellular centre surrounded by progressively maturing woven bone. B Poorly formed woven bone as­ sociated with osteoblasts merges with matrix that is well formed and trabecular in architecture. C Hypercellular hyaline cartilage undergoing enchondral ossification. D Fascicles of plump spindle cells with elongate nuclei that are mitotically active. The stroma is myxocollagenous with scattered extravasated red blood cells. Histological resemblance to nodular fasciitis is evident.

is extraskeletal osteosarcoma, which lacks zonation and shows maligna nt cytology.

Essential and desirable diagnostic criteria

Cytology

Essential: hypercellular fascicles of uniform spindle cells; admixed woven bone with zonation, being most mature at the periphery.

Cytology features a dual cell population of spindle cells and large ganglion-like cells set in a myxoid stroma {1649}.

Staging Not clin ically re leva nt

Diagnostic molecular pathology Molecular studies for USP6 rearrangement may be useful in the appropriate clinicopathological con text.

54

Soft tissue tumours

Prognosis and prediction Treatment of myositis ossificans and FP is usually simple excision. Prog nosis is excel le nt; recurre nee is un comm on.

paybal：https://www.paypal.me/andy19801210 Liegl-Atzwanger B

Ischaemic fasciitis

Definition

Localization

Ischaemic fasciitis is a reactive pseudosarcomatous fibroblas­ tic/myofibroblastic proliferation, sometimes associated with physical immobility.

Ischaemic fasciitis usually arises around the limb girdles, sacral region, and greater trochanter; the chest wall and back may also be affected. Ischaemic fasciitis usually develops in the deep subcutis, but invoIvement of the deep dermis, skeletal muscle, and tendinous tissue can also occur {1855}.

ICD-0 coding None

Clinical features ICD-11 coding FB51.2 Ischaemic fasciitis

This lesi on occurs as a pain less mass with a media n size of 4.7 cm. Ischaemic fasciitis may be associated with immobility or debilitation in some cases {1855}.

Related terminology Not recommended: atypical decubital fibroplasia; pseudosar­ comatous fibromatosis.

Subtype(s) None

Epidemiology Ischaemic fasciitis mainly affects elderly patients, with a peak incidenee between the seventh and ninth decades of life, although the age range is wide. Males are affected slightly more often than females {2181,2491,1855}.

Fig. 1.59 Ischaemic fasciitis. A Scanning magnification showing a distinct zonal appearance with central area of fibrinoid degeneration/necrosis with pseudocystic changes, surrounded by granulation tissue-like vascular proliferation. B Ischaemic fasciitis with a vascular proliferation showing endothelial cells with reactive hyperchromatic nuclei (no endothelial multilayering), admixed with a reactive fibroblastic/myofibroblastic proliferation with extravasated erythrocytes. C Ischaemic fasciitis with focally myxoid stroma, infarcted fat, hyalinized vessel walls, and reactive fibroblasts/myofibroblasts with a ganglion cell-like appearance. D Ischaemic fasciitis with polygonal fibroblasts showing enlarged nuclei, prominent nucleoli, and amphophilic cytoplasm, similar to ganglion-like cells in proliferative fasciitis.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Etiology Ischaemia caused by constant pressure or trauma to a pre­ disposed regio n may con tribute to the pathoge nesis in some patients {2181,2491,3328}.

can be seen, mainly in the granulation tissue-like areas, but is inconspicuous overall {2181,2491,1855}. By immunohisto­ chemistry, variable expression of SMA, desmin, and CD34 may be observed {1855}.

Pathogenesis

Cytology

Unknown

Not clin ically re leva nt

Macroscopic appearance

Diagnostic molecular pathology

Ischaemic fasciitis presents as a white fibrous to tan-yellow lesion with central necrosis or occasionally cystic change {1855}.

Not clin ically re leva nt

Essential and desirable diagnostic criteria Histopathology The histological hallmark of ischaemic fasciitis is a distinet zonal appearanee. The central part of the lesion is character­ ized by a hypocellular area of fibrinoid degeneration/necrosis with or without pseudocystic degeneration or infarcted fat. The central area is surrounded by a granulation tissue-like vascular proliferation mixed with fibroblasts and myofibroblasts, some polygonal with amphophilic cytoplasm and a ganglion cell-like appearance, similar to proliferative fasciitis. The fibroblastic/myofibroblastic cells vary in size and shape. Fibrosis/ fibrohyalinosis or myxoid stromal change, hyalinosis of vessel walls, vessels with fibrin thrombi, an inflammatory infiltrate, and extravasated erythrocytes may be observed. Mitotic activity

56

Soft tissue tumours

Essential: mass-forming lesion mainly in the deep subcutis; zonal appearance with central fibrinoid degeneration/necro­ sis and cystic changes; periphery with granulation tissue-like vascular comp on ent; admixed plump activated fibroblasts/ myofibroblasts (ganglion-like cells).

Staging Not clin ically releva nt

Prognosis and prediction Patients are usually cured by local excision even if incomplete. Recurrences may rarely develop in immobilized patients, due to persistence of the underlying cause.

paybal：https://www.paypal.me/andy19801210 Hisaoka M Nishio J

Elastofibroma

Definition Elastofibroma is a benign, ill-defined proliferation of fibroelastic tissue with excessive abnormal elastic fibres.

ICD-0 coding 8820/0 Elastofibroma

ICD-11 coding FB51.Y & XH3BQ8 Other specified fibroblastic disorders & Elastofibroma

Related terminology Acceptable: elastofibroma dorsi.

Subtype(s) None

Localization Elastofibroma most often arises in the deep soft tissue between the lower scapula and the thoracic wall. It may rarely occur in extrascapular locatio ns, in eluding other parts of the thoracic wall, extremities, limb girdles, neck, eyes, and gastrointestinal tract or other viscera. Although elastofibroma is usually a uni­ lateral and solitary mass, bilateral or multiple lesions have been reported.

Clinical features Elastofibroma occurs almost exclusively in the elderly, with a peak incidenee between the seventh and eighth decades of life. There is a striking female predominance (M:F ratio: -0.08:1) (2236}. The lesion usually presents as a slow-growing asymp­ tomatic mass or rarely causes pain, stiffness, scapular snapping, and impingement. CT and MRI show a poorly defined, heterogeneous soft tissue mass with tissue attenuation similar to that of skeletal muscle in terlaced with fat strands {2261}. The lesion may be hypermetabolic on FDG PET-CT {2385}.

Epidemiology Although elastofibroma was previously considered to be rare, its exact prevale nee is unknow n. The lesions are detectable in 2% of adults aged > 60 years by CT and in 16% of autopsy cases from adults aged > 55 years {400,1514}.

Fig. 1.60 Elastofibroma. A Axial T1-weighted MRI showing an inhomogeneous le­ sion with low and streaky high signal intensities (arrows) in the back. B An ill-defined mass comprising an admixture of greyish-white fibrous tissue and intervening yellow fat.

including gains of 6p25-q25 and Xq12-q22 and losses of 1p, 13q, 19p, and 22q {2310,1352}. Deletions of CASH (3q13.33q21.1), GSTP1 (11q13.2), and BRCA2 (13q13.1), as well as gains of APC (5q22.2) and B4A7 (12q23.2), have also been described {1352}.

Macroscopic appearanee

Unknown

The lesion is poorly defined and rubbery, composed of grey or whitish fibrous tissue with variable intervening streaks of yellow fatty tissue. The diameter ranges from 2 to 15 cm.

Pathogenesis

Histopathology

Elastotic degeneration of collagen or abnormal elastotic fibrogenesis may underlie the pathogenesis of elastofibroma {2942, 1713,1089}, and active neovascularization or endothelial-mesenchymal transition plays a potential pathogenetic role {1561, 816}. Elastofibroma ofte n exhibits chromosomal in stability

Elastofibroma is composed predominantly of fibrocollagenous tissue containing a large number of abnormal elastic fibres and dispersed, bland-appearing spindle cells, admixed with a variable amount of adipose tissue and small blood vessels. A focally myxoid matrix is comm on. The elastic fibres are typically

Etiology

Soft tissue tumours

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Fig. 1.61 Elastofibroma. A Hypocellular fibrocollagenous tissue with mature adipose tissue. B Thick or coarse, deeply eosinophilic elastic fibres arranged in beaded strings or

globules. C Elastic-Masson staining highlights the abnormal elastic fibres.

thick or coarse, deeply eosi nophilic, and frag me nted into lin­ early arranged globular or serrated disc-like structures, simulat­ ing beads on a string, which are highlighted using elastic stains.

Essential and desirable diagnostic criteria

Cytology

Staging

Linear (braid-like), globular, or stellate structures of degenerated elastic fibres are cytological features in elastofibroma {833}.

Not clin ically re leva nt

Essential: a bland-appearing, hypocellular fibrofatty tumour with I excessive abnormal elastic fibres.

Prognosis and prediction

Diagnostic molecular pathology Not clin ically re leva nt

58

Soft tissue tumours

Elastofibroma is a benign lesion and is cured by simple exci-， sion. Local recurrenee is exceptional.

paybal：https://www.paypal.me/andy19801210 Al-lbraheemi A Folpe AL

Fibrous hamartoma of infancy

Definition

Localization

Fibrous hamartoma of in fancy is a benign soft tissue neoplasm of infants and young children, showing organoid, triphasic morphology with bundles of bland fibroblastic/myofibroblastic cells; nodules of primitive, rounded °r stellate cells with myxoid stroma, and mature adipose tissue.

Fibrous hamartoma of infancy commonly invoIves the axilla, trunk, upper extremities, and genital regions. This lesion has also been described in other locations, including scalp, foot, hand, orbit, and buttock {72,2701}.

Clinical features

LC2Y Other specified hamartomata derived from dermal conn ective tissue

Fibrous hamartoma of infancy typically prese nts as pain less solitary subcutaneous masses, sometimes with overlying skin discolouration, oedema, hypertrichosis, and tethering {72}. There are rare reports of this tumour type presenting as multiple lesions in the same patient and in patients with tuberous sclero­ sis and Williams syndrome {72,1286,3080}.

Related terminology

Epidemiology

Not recommended: subdermal fibromatous tumour of infancy,

Fibrous hamartoma of infancy is rare and most often occurs in children aged < 2 years, with a male predominance. However, it can occur in older children {72}. About 15-25% of cases are congenital {2701}.

ICD-0 coding 8992/0 Fibrous hamartoma of infancy

ICD-11 coding

Subtype(s) None

Fig-1.62 Fibrous hamartoma of infancy. A Low-power view showing the triphasic organoid pattern with bundles of fibroblastic spindle cells, mature adipose tissue, and nodules of primitive mesenchyme. B Fibrous hamartoma of infancy with sarcomatous features. Typical triphasic fibrous hamartoma of infancy showing an abrupt transition to a highly cellular, sarcomatous spindle cell neoplasm. C Medium-power view showing the triphasic organoid pattern with bundles of fibroblastic spindle cells, mature adipose tissue, and nodules of primitive mesenchyme. 0 Fibrous hamartoma of infancy with sarcomatous features. High-power view of the sarcomatous area showing spindled to round cells with hyperchromatic nuclei and brisk mitotic activity.

Soft tissue tumours

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Fig. 1.63 Fibrous hamartoma of infancy. Giant cell fibroblastoma-like areas with abundant collagen with cracking artefact forming slit-like spaces lined by flattened

tumour cells.

fibroblastic/myofibroblastic cells, admixed with mature adipose tissue and myxoid nodules containing primitive mesenchymal cells with rounded to stellate nuclei. One quarter of cases show areas resembling giant cell fibroblastoma, composed of hyaliriized zones containing collagen with cracking artefact forming slit-like spaces lined by flattened tumour cells. Mitotic figures are infrequent, and necrosis is typically absent. Interspersed inflammatory cells can be seen. Very recently, two tumours showing both typical and sarcomatous morphology were reported as part of a larger series {72}. By immunohistochemis­ try, fibrous hamartoma of infancy shows variable expression of SMA in the fibroblastic areas and occasionally in the primitive mesenchyme. CD34 is expressed within the primitive meseni chyme and in areas with giant cell fibroblastoma-like morphol­ ogy.

Cytology

Unknown

FNA shows blan d-appearing fibroblasts in a collage nous matrix and mature fat without substantial n uclear atypia or mitoses {2818}.

Pathoge nesis

Diagnostic molecular pathology

Although fibrous hamartoma of infancy was historically con­ sidered a hamartoma, the recent discovery of recurrent EGFR exon 20 insertion/duplication mutations in this lesion indicates a neoplastic process {2444}. Minimal to moderate EGFR (HER1) protein expression has been reported, mostly in the primitive mesenchyme {2444}.

Not clin ically r eleva nt

Etiology

Essential and desirable diagnostic criteria Essential: organoid, triphasic morphology; variable prominence of bun dies of bland fibroblastic/myofibroblastic cells, no dules of primitive mesenchyme, and mature adipose tissue.

Macroscopic appearance

Staging

The excised lesions are poorly circumscribed and of varying size (mean: 3 cm). The cut surfaces have a variable amount of adipose tissue and greyish-tan fibrous tissue.

Not clinically r eleva nt

Histopathology Fibrous hamartoma of infancy has a triphasic organoid pattern with haphazardly arranged fascicles of cytologically bland

60

Soft tissue tumours

Prognosis and prediction Most patients are cured with simple excision, although roughly 15% of cases have been reported to locally recur if incompletely excised. The clinical significanee of sarcoma-like foci within fibrous hamartoma of infancy is unclear {72}.

paybal：https://www.paypal.me/andy19801210 ipose iymal show yalin■ming gures srsed aours were smison of nitive 2se nphol-

Davis JL

Fibromatosis colli

Definition Fibromatosis colli is a benign, self-limited fibrous proliferati°n occurring in the sternocleidomastoid muscle of infants. Some casef orogress to shortening of the muscle, resulting in torticol­

lis.

ICD-0 coding

towards the contralateral shoulder. Plagiocephaly may also occur. Fibromatosis colli is associated with other musculoskel­ etal con genital ano malies, including hip dysplasia, metatarsus adductus, talipes equi no varus, and promi nent ears {2528,566, 567}. Ultrasound is the preferred imagi ng method, dem on strating an isoechoic to hypoechoic solid, well-defined ovoid mass in continuity with the sternocleidomastoid muscle {246,7}.

None

Epidemiology natrix toses

Related terminology

Fibromatosis colli is uncomm on; however, it is the most common cause of a n eck mass in the peri natal period. The reported incidence is 0.3-2.0% of live births {568}. There is a slight male predominance (M:F ratio: 1.5:1) {566,1706}.

Not /ecommended: sternocleidomastoid tumour of infancy; pseudotumour of infancy; con genital muscula r torticollis.

Etiology

ICD-11 coding FB51.Y Other specified fibroblastic disorders

Un know n

Subtype(s) ence Jules

None

Fibromatosis colli affects the sternocleidomastoid muscle, with a predilection for the right over the left. Most commonly the mid­ dle or distal third of the muscle body is involved; however, about 15% of cases involve the entire muscle {567,566}.

Clinical features

Macroscopic appearance

Fibromatosis colli presents as a mass within the sternocleido­ mastoid muscle, most often congenitally or within the first 2-4 weeks of life. Continued growth may occur over several weeks, followed by stabilization and then spontaneous resolution in the majority of cases {2528,566,567}. Approximately 10-20% of patients develop congenital muscular torticollis {2528,566}. These patie nts dem on strate head tilt towards the invoIved sternocleidomastoid muscle, with the chin directed

If fibromatosis colli is excised, the gross appears nee is that of a firm to hard, tan-white mass with associated skeletal muscle.

Localization

jghly etely vithin

Pathogenesis The pathogenesis is uncertain; however, a scar-like/reactive process due to injury of the sternocleidomastoid muscle is most likely, acquired either in utero or at the time of delivery {2298, 739,1706}. Possible mechanisms include fetal malposition/ crowding, birth trauma, vascular compromise, and infection {1706,739,2528}.

Histopathology Surgical specimens are infrequent, obtained only in the minority of patients requiring tenotomy for persistent torticollis. When his­ tology is obtained, secti ons dem on strate a paucicellular, scar­ like fibroblastic proliferation entrapping skeletal muscle {1706}.

Fig. 1.64 Fibromatosis colli. A,B Paucicellular, scar-like fibroblastic proliferation entrapping atrophic skeletal muscle.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Cytology

Staging

FNA is a potential means of tissue diagnosis {3215,1706,1720, 1618}. Smears are typically sea nt to mildly cellular, composed of spin died to plump fibroblasts with associated collage n fibres and atrophic/degenerating skeletal muscle. The fibroblastic cells are singly or loosely cohesive, with bland oval to elongated nuelei and unipolar or bipolar tails of cytoplasm; bare nuclei may also be present. Atrophic, multinucleated myocytes are often admixed {3215,1706,1720,1618}.

Not clinically relevant

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: infant with a fusiform mass associated with the sternocleidomastoid muscle; bland fibroblastic proliferation with associated atrophic skeletal muscle. Desirable: clinical torticollis is variably present.

62

Soft tissue tumours

I j

Prognosis and prediction The majority of fibromatosis colli lesions are self-limited, with resolution within the first 6 months of life; however, a subset of cases progress with continued tumour growth and/or the devel-l opment of torticollis. If untreated, torticollis will worsen with I

patient growth and development {2528,568}. Within the first year of life, passive manual stretching/manipulations or phys-1 iotherapy is effective in about 95% of cases. However, in those I cases that do not resolve by stretching/physiotherapy (< 10% | of cases), operative management may be required {568,567,■ 1896}. Patients who present at an age > 1 year are more likely! to require surgical intervention {566,1896,568}.

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paybal：https://www.paypal.me/andy19801210 Davis JL

Juvenile hyaline fibromatosis I, with >set of devel】with e first physthose :10% 3,567, likely

Definition

Subtype(s)

Juvenile hyaline fibromatosis / hyaline fibromatosis syndrome is an extremely rare autosomal recessive syndrome that typically presents in infancy. It is characterized by painful, disfiguring, abnormal deposits of hyalinized fibrous material (extracellular matrix) in the dermis, sub cutaneous soft tissues, and gin giva.

None

Local izati on Hyaline fibromatosis syndrome is a multisystem disease (see below).

Clinical features

ICD-0 coding None

ICD-11 coding EE6Y Other specified fibromatous disorders of skin and soft tissue

Related terminology Acceptable: hyaline fibromatosis syndrome; infantile systemic hyali no sis.

Hyaline fibromatosis syndrome typically presents in infancy but can occur later in childhood; more-severe cases present earlier {507,792}. The most common clinical manifestations are subcutaneous / soft tissue nodules and papules, gingival hypertrophy, and joint contractures (85-95% of cases), followed by other cutaneous and bone manifestations. Systemic/visceral invoIvement leading to failure to thrive, intractable diarrhoea (50% of cases), and recurrent infections (30% of cases) is defined as severe dis­ ease and is associated with early mortality {507,792,2313}.

Fig. 1.65 Juvenile hyaline fibromatosis. A Dermal-based band-like deposits of hyaline matrix with obliteration of normal adnexal structures. B Dermal-based band-like and sub­

cutaneous nodular deposits of avidly PAS-positive hyaline material (PASD staining). C Cords of fibroblasts in a background of abundant amorphous hyaline material. D Cords of fibroblasts in a background of abundant amorphous hyaline material (PASD staining).

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Epidemiology

Cytology

Hyaline fibromatosis syndrome demonstrates no sex predilection, following an autosomal recessive inheritance pattern.

Not clin ically re leva nt

Diagnostic molecular pathology

Etiology Juvenile hyaline fibromatosis is an autosomal recessive syn­ drome resulting from loss-of-function mutations, including inactivating homozygous or compound heterozygous mutations in the ANTXR2 (CMG2) gene {3380,507}.

Pathogenesis The ANTXR2 gene encodes for a transmembrane protein that binds the extracellular proteins laminin and collagen VI; it also serves as a receptor for the anthrax toxin {806}. The nodules in hyaline fibromatosis syndrome patients are reported to contain collagen VI, suggesting that ANTXR2 may mediate its degradation. Therefore, in hyaline fibromatosis syndrome, given the loss of ANTXR2 function, collagen VI would accumulate in the extracellular matrix {447}.

Macroscopic appearance The nodules are solid and homogeneous.

Histopathology Hyaline fibromatosis syndrome is characterized by hyaline-like extracellular matrix deposits. The lesions show variable cellularity and are composed of plump to spin died un iform fibroblasts, often arranged in cords simulating vascular spaces, admixed with abundant extracellular eosinophilic non-fibrillar hyaline material, obliterating normal structures {792,3137}. The hyaline material stains strongly with PAS and is diastase-resistant {792,3137}.

64

Soft tissue tumours

Germline sequencing of ANTXR2 (4q21.21) can confirm the diagnosis.

Essential and desirable diagnostic criteria Essential: subcutaneous nodules and gingival hypertrophy with abundant hyaline-like material. Desirable: confirmation by germline sequencing of the ANTXR2 gene.

Staging Not clinically re leva nt

Prognosis and prediction Age at presentatio n is a predictor of prog no sis, with earlier presentation associated with more-severe disease. In systemic/ severe disease, the median age at death is 15 months {507, 2313,792}. For patients with milder forms, wheelchair use may become n ecessary because of joint con fractures. Phe notype-ge no type correlati ons have dem on strated that ANTXFI2 missense mutations in exons 1-12 and mutations leading to a premature stop cod on more comm only lead to severe disease, whereas missense mutations in exons 13-17 lead to a mild form of disease {507,3380,806,896}. Treatment is largely support­ ive. Surgical excision of subcutaneous nodules and/or gingivectomy for gingival hypertrophy is often performed; however, recurre nces are comm on {507,792}.

paybal：https://www.paypal.me/andy19801210 Laskin WB

Inclusion body fibromatosis ■m the

iy with

Definition

7TXR2

Inclusion body fibromatosis is a benign, sometimes multicentric, myofibroblastic tumour with characteristic eosinophilic intracytoplasmic in elusions and poten tial for local recurr ence,

sr pretemic/ ；{507, e may 'henoQTXR2 g to a 3ease, d form pportgingiyvever,

ICD-0 coding None

ICD-11 coding EE6Y Other specified fibromatous disorders of skin and soft tissue

Related terminology Acceptable: infantile digital fibroma/fibromatosis; recurring digi­ tal fibrous tumour(s) of childhood; recurring digital fibroma(s) of childhood/i nfan cy.

Subtype(s) None

Localization The classic subtype involves the dorsal or dorsolateral aspect of the distal or middle portion of the second, third, and fourth digits, followed by the fifth digit, while typically sparing the first digit, hand, and foot {245,599,1760}. Extradigital examples are reported on the extremities, tongue, and breast {1760}.

Fig. 1.67 Inclusion body fibromatosis. Spindled cells in short fascicles and whorls surrounding adnexa are a characteristic growth pattern.

Epidemiology

Clinical features The classic subtype presents as an asymptomatic dome­ shaped or polypoid cutaneous nodule, typically no larger than 2 cm {245,2700,1760}. Synchronous and/or metachronous lesions (sometimes affecting multiple digits) occur, but simults neous invo Iveme nt of both fin gers and toes is rare {77, 245,2700}. Non-classic examples typically present as solitary masses or nodules {1760}.

The classic subtype accounts for 0.1% of registered soft tissue tumours {77} and 2% of paediatric fibroblastic tumours {625}. Nearly all cases are reported before the age of 5 years {599}. Most tumours are documented during the first year of life, with about 30% present at birth {599,245,2700}. Rare cases occur in adults {3200,2743,2522}. No sex predilection exists.

Etiology Unknown

Pathogenesis Unknown

Macroscopic appearanee Tumours are firm or rubbery, ill-defined protuberant or polypoid dermal nodules. The cut surface is fibrous and off-white to grey in colour.

Histopathology

Fig. 1-66 Inclusion body fibromatosis. A single protuberant nodule with an erythema-

tous surface on the lateral aspect of the distal toe.

Spindle cells have lightly eosinophilic cytoplasm and an elon­ gated, cytologically bland nucleus, and they exhibit low mitotic activity. Cells proliferate in whorls, interlacing short fascicles, or storiform arrays within a variably collage nous dermis, and they characteristically grow perpendicular to the epidermis, surrou nd adnexa, and occasionally in filtrate deeper tissues {77,599}. Cells harbour a 1.5-24 pm, rounded, pale-pink to red

Soft tissue tumours

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Fig. 1.68 Inclusion body fibromatosis. A High-power view demonstrates spindle cells with elongated, cytologically bland nuclei and rounded, eosinophilic, intracytoplasmic inclusions, some indenting the nucleus. B Gomori trichrome staining highlights intracytoplasmic inclusions (red). C Immunostaining for SMA demonstrates a peripheral (tram­ track) pattern of expression. D Ultrastructurally, myofilamentous bundles at the periphery of a tumour cell merge with a dense intracytoplasmic inclusion.

in tracytoplasmic inclusion, which is freque ntly para nuclear, indentingthe nucleus {2618,599}, and is highlighted by trichrome (red), phosphotungstic acid-haematoxylin (dark purple), and Movat (pink) stains {1760}. Ultrastructurally, tumour cells contain intracytoplasmic bun dies of actin-rich myofilaments with dense bodies, which are in continuity with a non—membrane-bound, rounded inclusion consisting of a dense core of tightly packed myofilaments {2211,306,1497}. The inclusions commonly mark with actin {2210} and calponin-1 {1348}, and occasionally with caldesmon {1760}.

Cytology There are abundant plump spindle cells and few polygonal cells with a moderate cytoplasm set in a collage nous backgro und. Scattered prominent intracytoplasmic inclusions are present {2362}.

Diagnostic molecular pathology Not clinically re leva nt

66

Soft tissue tumours

Essential and desirable diagnostic criteria Essential: dermal-based and cytologically bland myofibroblastic proliferation; eosi nophilic in tracytoplasmic and paranu­ clear in clusi ons.

Staging Not clinically relevant

Prog nosis and prediction Recurrence rates between 61% and 75% are reported in large series and reviews for the classic subtype (2660,599,1760). Lower recurrenee rates are achievable with initial complete (preferably wide) excision {955,2633,3031}. Current treatment recommendations include function-preserving excision or intra lesional steroid injection for symptomatic lesions and clinica observation after diagnosis for asymptomatic tumours {1985 952}, because lesions may spontaneously regress {2274| Approximately 25% of non-classic tumours recur {1760}.

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paybal：https://www.paypal.me/andy19801210 Sciot R Cunha IW

Fibroma of tendon sheath

Definition

Pathogenesis

Fibroma of tendon sheath is a benign fibroblastic/myofibroblastic nodular proliferation, usually attached to a tendon (sheath).

A clonal chromosomal abnormality, t(2;11)(q31-q32;q12), has been described in two classic cases {720,2307}. Notably, an apparently identical translocation has also been observed in desmoplastic fibroblastoma, which can show morphological overlap with fibroma of tendon sheath {1926,277,2306}. Diffuse and strong nuclear FOSL1 expression seems to be character­ istic of desmoplastic fibroblastoma and absent in fibroma of ten don sheath {1592,1926}. Some cellula r subtypes of fibroma of tendon sheath are characterized by USP6 rearrangement, as seen in nodular fasciitis {496}. In view of the similar morphologi­ cal and molecular genetic features, some lesions diagnosed as cellular fibroma of tendon sheath are probably in fact tenosyno­ vial nodular fasciitis {1410}.

ICD-0 coding 8813/0 Fibroma of tendon sheath

ICD-11 coding EE6Y & XH0WB3 Other specified fibromatous disorders of skin and soft tissue & Fibroma of tend on sheath

Related terminology Not recommended: tenosynovial fibroma.

Subtype(s) None

Localization The lesi on typically occurs on the fin ger tendons. The thumb, index fin ger, and middle fin ger are the digits most freque ntly invoIved. Intra-articular locations (knee, elbow, wrist) have rarely been described {2446,1714,608}.

Macroscopic appearance Fibroma of tendon sheath has a lobular fibrous appearance, reminiscent of a localized tenosynovial giant cell tumour, except for the pigment, which is absent in fibroma of tendon sheath.

Histopathology

Fibroma of tend on sheath is rare and typically occurs in patie nts aged 20-50 years {2549,84}.

The lesion is well circumscribed and contains bland spindle cells in a collage nous backgrou nd. The cellularity is usually low but can be variable and is often higher at the turn our edge. There are characteristic slit-like thin-walled vessels. Degenerative features such as myxoid/cystic cha nges, chon droid or osseous metaplasia, and bizarre pleomorphic cells can be seen. The morphological features of the cellular subtype are identical to those of nodular fasciitis.

Etiology

Cytology

Unknown

Not clinically relevant

Clinical features The tumour presents as a firm, small (< 3 cm), slow-growing nodule.

Epidemiology

i large 1760). nplete itment -intra;linical (1985, 2274).

Fig. 1.69 Fibroma of tendon sheath. A Intraoperative photo showing the smooth nodular surface and attachment to a tendon. B This lower-power view shows characteristic variation in cellularity.

Soft tissue tumours

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Fig. 1.70 Fibroma of tendon sheath. A Low-power view showing the highly sclerotic and hypocellular appearances. Note the small vessels and clefts. B Some cases can show increased cellularity, which is most obvious at the edge. C The tumour is well circumscribed and is composed of bland spindle cells with a prominent collagenous stroma and slit-like, thin-walled blood vessels. 0 The tumour cells contain fine chromatin and indistinct pale cytoplasm. Note the collagenous stroma and thin-walled blood vessel.

Diagnostic molecular pathology

Staging

Not clinically re leva nt

Not clinically re leva nt

Essential and desirable diagnostic criteria

Prognosis and prediction

Essential: benign firm nodule most often on the finger tendons; usually a paucicellular collagen-rich lesion with slit-like vessels.

Fibroma of tendon sheath is benign but can recur in 5-10% ol cases.

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Soft tissue tumours

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Desmoplastic fibroblastoma

Definition Desmoplastic fibroblastoma is a benign, paucicellular, soft tissue tumour with abundant collagenous or myxocollagenous matrix; low vascularity; and scattered, bland, stellate-shaped and spindled fibroblastic cells.

ICD-0 coding 8810/0 Desmoplastic fibroblastoma

ICD-11 coding EE6Y & XH2ZF3 Other specified fibromatous disorders of skin and soft tissue & Desmoplastic fibroblastoma

Related terminology Acceptable: collagenous fibroma.

Subtype(s) None

Localizati on The most comm on sites are the upper arm, shoulder, lower limb, back, forearm, hand, and foot {941,2285,2120}.

Fig. 1.72 Desmoplastic fibroblastoma. The lesion is well circumscribed with a smooth rounded border.

Clinical features

Pathogenesis

The tumour typically presents as an asymptomatic, slowgrowing subcutaneous mass, but fascial and skeletal muscle invo Iveme nt is relatively comm on.

Most of the karyotypic studies of desmoplastic fibroblastoma have demonstrated a recurrent t(2;11)(q31;q12) {277,2306, 2715}. Deregulated expression of FOSL1 appears to be the functional outcome of 11q12 rearrangements in desmoplas­ tic fibroblastoma, based on global gene expression profiling and quantitative real-time PCR {1926}. Notably, diffuse, strong FOSL1 nuclear immunoreactivity is seen in desmoplastic fibroblastomas with 11q12 rearrangement, in contrast to the absence of overexpression in 11q12-rearranged fibromas of tendon sheath {1592}.

Epidemiology Desmoplastic fibroblastoma is a rare tumour that predominantly affects adults, with a median age of 50-60 years.

Etiology Unknown

Desmoplastic fibroblastoma. A,B The tumour is paucicellular and composed of uniform, often stellate-shaped, fibroblasts.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Macroscopic appearance Desmoplastic fibroblastomas are usually relatively small, often measuring 1-4 cm in greatest dimension, but examples > 10 cm and as large as 20 cm have occurred. Grossly, the lesions appear well circumscribed and form oval, fusiform, or discoid masses. Some examples have an externally lobulated, cobblestone-like surface. The tumours have a firm, cartilage­ like consistency, and on cut section they have a homogeneous pearl-grey colour.

intravascular growth. The tumour cells may be focally positive for SMA.

Cytology Not clinically relevant

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Histopathology Although often well demarcated grossly, most tumours micro­ scopically in filtrate into subcutaneous fat, and approximately 25% extend into skeletal muscle {941,2285,2120}. Rare exam­ ples are purely intramuscular. The lesions have abundant col­ lage nous or myxocollagenous matrix with low vascularity. Cellularity ranges from low to moderate, and the neoplastic cells tend to be uniformly distributed within the extracellular matrix. The lesional cells are stellate-shaped, bipolar, and spin died, and they have uniform, bland nuclei with distinet small nucleoli. Mitotic figures are un comm on. Rare examples have focal

70

Soft tissue tumours

Essential: hypocellular with abundant collagenous or myxocollagenous matrix; stellate, bipolar, and spindle cells with small n ueleoli.

Staging Not clinically re leva nt

Prognosis and prediction The behaviour of this tumour is benign, and none of the pub­ lished clinicopathological series have documented any recurrenc es.

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paybal：https://www.paypal.me/andy19801210 Magro G Howitt BE Liegl-Atzwanger B McMenamin ME

Myofibroblastoma

Definition

Localization

Myofibroblastoma of soft tissue is a benign neoplasm comparable to myofibroblastoma of breast, composed of myofibroblastic cells, bands of hyalinized collagen, and usually an adipocytic component.

Approximately 50% of cases occur in the inguinal/groin area, including in the vulva/vagina, perineum, and scrotum; however, there is a wide an atomical distribution, including trun k/axilla, breast, extremities, abdominal cavity, retroperitoneum, and viscera {2047,1422}. The majority are superficial/subcutaneous. The remainder are deep-seated; intramuscular; or in the pelvis, abdomen, or retroperitoneum {1422}.

ICD-0 coding 8825/0 Myofibroblastoma

ICD-11 coding

Clinical features

EE6Y & XH3NQ0 Other specified fibromatous disorders of skin and soft tissue & Myofibroblastoma

Tumours gen erally present as either pain less masses or inci­ dental lesions; occasional lesions are painful. Tumours may be present for > 20 years before clinical presentation {1422}.

Related terminology Acceptable: mammary-type myofibroblastoma.

Epidemiology

Subtype(s)

Lesions arise predominantly in adults in the fifth and sixth decades of life, but there is a wide age range (4-96 years; median age: 54 years) and a male predominance (M:F ratio: 2:1).

None

Fig. 1.73 Myofibroblastoma. A Proliferation of bland spindle cells with interspersed bands of hyalinized collagen. B Neoplastic cells may exhibit epithelioid cell morphology with a pseudoinfiltrative growth pattern. C Neoplastic cells showing round cell morphology: the presence of bands of hyalinized collagen and the absence of mitoses and nuclear

atypia are helpful diagnostic features. D This tumour shows degenerative features, exhibiting cells with moderate nuclear atypia. Mitoses and necrosis are absent.

Soft tissue tumours

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Fig. 1.74 Myofibroblastoma. A This tumour contains a lipomatous component. Low magnification showing well-circumscribed borders. B A fibrofatty tumour with spindle cell lipoma-like morphology: adm仪ture of mature adipocytes with bland spindle cells set in a fibrous stroma. C Proliferation of spindle cells with formation of Verocay-like bodies, mimicking schwannoma.

Fig. 1.75 Myofibroblastoma. A Diffuse expression of CD34 by neoplastic cells (immunoperoxidase staining). B Neoplastic cells showing multifocal staining for desmin (immu­ noperoxidase staining). C Loss of nuclear RB1, maintained in endothelial and inflammatory cells.

Etiology

Size ranges from < 1 cm to 22 cm (median: 6.6 cm). The tumours are gen erally well circumscribed, mobile, and r ubbery to gelati no us. The colour can be variable (white/yellow/pi nk, grey, or tan). The cut surface may be whorled or nodular and variably fatty.

cytoplasmic processes. They are gen erally arran ged in vari­ ably sized short fascicles, with interspersed broad bands of hyali nized collage n or (less comm only) ropy collagen. Scat­ tered mast cells are gen erally present. Tumours may vary from markedly cellular to paucicellular and hyalinized. There is usually a variable admixture of mature adipocytes, which can range from rare to occasi on ally the domi nant compone nt. Schwannoma-like palisading, focal epithelioid or round cell morphology, or degenerative-type nuclear atypia (enlarged hyperchromatic nuclei and multinucleation) can occur {1422). The blood vessels are gen erally incon spicuous, being small and often focally hyalinized and having a perivascular lym­ phocytic infiltrate. By immunohistochemistry, myofibroblastoma typically shows diffuse coexpression of desmin and CD34 (each positive in 90% of cases). Rare cases are negative for both markers. Expression of SMA is present in one third of cases. About 90% of cases show loss of nuclear RB1 {550,1422}.

Histopathology

Cytology

Tumours are unen capsulated and gen erally well circum­ scribed. They are usually composed of spindle cells with short stubby nuclei with finely dispersed chromatin, small or inc on spicuous nu cleoli, eosinophilic to amphophilic cyto­ plasm, indistinet cell borders, and sometimes elongated

Not clin ically re leva nt

Unknown

Pathogenesis Loss of 13q14, including RB1, is characteristic of mammary and soft tissue myofibroblastomas, as well as of spindle cell / pleomorphic lipoma and cellular an giofibroma. In additi on, the overlapping morphological and immunohistochemical features support the hypothesis that these tumours represent variations along a spectrum of genetically related lesions, the so-called 13q//?B7 family of tumours {1941,1422,1040,26}.

Macroscopic appearance

72

Soft tissue tumours

Diagnostic molecular pathology Loss of RB1 can be demonstrated by FISH, although this is usu­ ally not necessary to establish the diagnosis.

Essential and desirable diagnostic criteria

Staging

Essential' haphazardly intersecting short fascicles of bland, short or elongated spindle cells; bands of hyalinized collagen; variable adipocytic component; expression of CD34 and desmin. Desirable: loss of RB1 (demonstrated by immun°hist°chemistry or FISH).

Not clin ically re leva nt

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Prognosis and prediction All tumours reported to date have followed a benign course after marginal local excision, with excepti on al local recurrences.

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Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Calcifying aponeurotic fibroma

Puls F Kilpatrick SE

Defin ition

Related terminology

Calcifying aponeurotic fibroma is a rare benign tumour with potential for local recurrenee that typically arises on the distal extremities of children and adolescents. It is characterized by bland spindle cells and less cellular zones of calcification with plump to epithelioid fibroblasts.

Acceptable: juvenile aponeurotic fibroma; aponeurotic fibroma.

Subtype(s) None

Localization

ICD-0 coding 8816/0 Calcifying aponeurotic fibroma

ICD-11 coding EE6Y & XH8ZE3 Other specified fibromatous disorders of skin and soft tissue & Calcifying aponeurotic fibroma

Calcifyi ng apon eurotic fibroma arises most comm only on the palmar surfaces of the hands and fin gers, followed by the plan­ tar surfaces of the feet and toes {79}. Wrists and an kies are less commonly involved {998}. Un usual locations are proximal extremities and trunk {998}. Rare examples have been documented in the head and neck region {3063}. Most lesions arise in the subcutis, often conn ected to ten dons and apon euroses {79,998}.

Clinical features Patie nts gen erally present with a pain less, poorly circumscribed soft tissue mass or swelli ng, often of exte nded du rati on. Radio­ graphic images often dem on strate calcificati ons.

Epidemiology Calcifying aponeurotic fibroma is a rare neoplasm. Its peak incidence is between the ages of 5 and 15 years, although well-documented examples in adults have been reported {998|. Males are more often affected than females {998}.

Etiology Unknown

Pathogenesis A recurrent FN1-EGFgene fusion has been identified {2550).

Macroscopic appearance Resected specimens are usually 1-3 cm, appearing as illdefined, greyish-white to gritty soft tissue masses.

Histopathology

Fig. 1.76 Calcifying aponeurotic fibroma. A The MRI shows a 1.6 cm solid mass on the plantar aspect of the foot in an 8-year-old boy. B A resection specimen with an ill-defined greyish-white lesion with a gritty consistency.

74

Soft tissue tumours

Calcifying aponeurotic fibroma is characterized by a fibroma­ tosis-like in filtrative comp orient and a no dula r calcified component {1603}. The former is moderately cellular, composed of uniform, plump spindle cells, without substantial nuelear atypia. The tumour often extends into adjacent soft tissues, where il may be attached to tendons or entrap peripheral nerves and blood vessels. Mitotic figures are rare. The nodular calcified areas are less cellula r and appear hyali nized to chon droid, wherein cells often appear rounded and chondrocyte-like and may encircle or radiate from the calcium deposits. Osteoclast­ type giant cells are usually present. Lesions typically contain both components to a varying degree, although non-calcified lesions showing only a fibromatosis-like pattern can be seen. There is evidenee suggest!ng that lesions may evolve from a

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bribed Radio­ Fjg, 1.77 Calcifying aponeurotic fibroma. A An infiltrative spindle cell lesion within subcutaneous fat with early matrix calcification (top left). B The infiltrative spindle cell component is reminiscent of fibromatosis. C Calcified areas contain epithelioid fibroblasts and scattered giant cells. D Chondroid areas may be present (decalcified specimen).

peak cough {998|.

spindle cell-predominant morphology to a less cellular lesion with more-exte nsive calcificati ons {79,70}. By immuno histo­ chemistry, lesional cells react with SMA, MSA, CD99, and (in the chon droid areas) S100. Nuclear staining for 卩-cate nin is not seen {480}.

Cytology Not clin ically re leva nt

50}.

Diagnostic molecular pathology

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Detection of the FN1-EGFgene fusion may be helpful in cases of calcifying aponeurotic fibroma lacking calcification {70}, although this is not r equired for routi ne diag no sis.

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Staging Not clinically re leva nt

Prognosis and predict!on Largely due to the infiltrative features of calcifying aponeurotic fibroma, local recurrenee, which may occur years after initial excision, is observed in as many as 50% of cases {79,998}. The risk of local recurrenee seems to be higher in younger children (aged < 5 years). Calcifying aponeurotic fibroma typically has a limited growth potential, and multiple recurrences are rare {2228,998}. Conservative surgical management, with preservation of function, is typically recommended.

Essential a nd desirable diagnostic criteria Essential: infiltrative lesion composed of bland, evenly spaced spindle cells lying in parallel within a collagenous matrix; islands or geographical areas of calcified matrix often sur­ rounded by palisading epithelioid fibroblasts. Desirable：. FN1-EGFgene fusion (as needed in unusual cases).

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 EWSR7-S/W/4D3-positive fibroblastic tumour (emerging)

Antonescu CR Suurmeijer AJH

Definition EI/l/S/?7-S/VMD3—positive fibroblastic tumour is a benign neo­ plasm with a strong predilection for the hands and feet. Tumour nomenclature is provisional.

ICD-0 coding None

ICD-11 coding None

Related terminology None

Subtype(s)

Fig. 1.79 EWSR1-SMAD3 fibroblastic tumour.

None

immunohistochemistry.

Diffuse nuclear staining for ERG by

Local izati on Tumours are superficially located within dermis and/or subcutaneous fat. The large majority of these lesions occur in the hands and feet {2109,1574}.

Clinical features Patients usually prese nt with a small pain less superficial tumour in acral sites.

Epidemiology There is a wide age range (1-68 years), with female predilection {2109,1574}.

Etiology Unknown

Pathogenesis The tumour is defined by a fusion of exon 7 of EWSR1 with exon 5 of SMAD3 (2109,1574). SMAD3 is an important signal transducer in the TGF-p/SMAD signalling pathway, which is invoIved in extracellular matrix synthesis by fibroblasts. By RNA sequencing, one case showed substantial upregulation of FN1, similar to other fibroblastic tumours, as well as ERG overexpression {1574}.

Macroscopic appearance The tumours are small, measuring 1-2 cm in greatest dimension, and have a nodular appearanee.

Fig. 1.78 EWSR1-SMAD3 fibroblastic tumour. A Low-power view showing the char­ acteristic zonation with an acellular hyalinized centre and peripheral areas composed of a cellular spindle cell component. Focal calcifications can also be noted. B Higher power of the peripheral area showing intersecting fascicles of monomorphic spindle cells with pale eosinophilic cytoplasm and uniform ovoid nuclei.

76

Soft tissue tumours

Histopathology The tumours are typically well demarcated but show infiltration into subcutaneous fat. In particular in adult cases, the acellular centre of the tumour appears hyalinized, whereas the peripheral zones consist of intersecting cellular fascicles of fibroblastic spindle

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cells lacking nuclear pleomorphism, hyperchromasia, prominent nucleoli, or mitotic activity. Focally stippled dystrophic calcification may be found By immunohistochemistry, the fibroblastic tumour ceils consistently show diffuse ERG nuclear expression, whereas staining for SMA and CD34 is negative.

Essential and desirable diagnostic criteria

Cytology

Staging

Not clinically relevant

Not clinically re leva nt

Diagnostic molecular pathology

Prognosis and predict!on

佻 EWSR1-SMAD3 fusion may be confirmed by molecular

EWSR1-SMAD3-pos\{\\/e fibroblastic tumour is benign. Local recurrenee may occur after incomplete excision.

methods.

Essential: small dermal and subcutaneous acral nodule; histo­ logical zonation with acellular hyalinized centre and periph­ eral fascicular spindle cell growth; immu no reactivity for ERG. Desirable: EWSR1-SMAD3 fusion (if available).

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90% of the tumour {1911}. In postmenopausal patients, the stroma is often less oedematous and more fibrous, and there may be hyalinization of vessel walls. Rare cases show morphological overlap with aggressive angiomyxoma {1208}. By immunohistochemistry, the majority of cases show strong and diffuse positive staining for desmin, whereas there is usually at most only focal positivity for SMA or pan-muscle actin {1026}. Desmin staining may be reduced or absent in postmenopausal cases. Tumour cells are consistently positive for ER and PR and occasi on ally positive for CD34.

Fig. 1.83 Angiomyofibroblastoma. Immunopositivity for desmin is a typical feature in most cases.

Cytology Not clin ically re leva nt

Diagnostic molecular pathology Not clinically re leva nt

Essential and desirable diagnostic criteria Essential: well-circumscribed, prominent stromal vessels; round to spindle-shaped cells (often multinucleated) in a perivascu­ lar distributi on. Desirable: usually desmin-positive.

Staging Not clinically re leva nt

Prognosis and prediction Angiomyofibroblastoma is benign and recurrenee appears to be rare, even after marginal local excision.

Soft tissue tumours

79

paybal：https://www.paypal.me/andy19801210 Cellular angiofibroma

Iwasa Y Fletcher CDM Flucke U

Definition Cellula r an giofibroma is a benign, cellular, and richly vascular­ ized fibroblastic neoplasm that usually arises in the superficial soft tissues of the vulva or inguinoscrotal regions.

incidenee in the fifth decade of life in women and the seventh decade in men {1040,1496,1757,2331}.

Etiology Unknown

ICD-0 coding

Pathogenesis

9160/0 Cellular angiofibroma

ICD-11 coding EE6Y & XH4E06 Other specified fibromatous disorders of skin and soft tissue & Cellula r an giofibroma

Related terminology Not recommended: male angiomyofibroblastoma-like tumour.

Subtype(s)

Partial or complete losses of chromosome 13 (including the RB1 locus) and/or 16 are found in cellular an giofibroma {1937,1040, 550,2416}. Loss of 13q14, including RB1, is characteristic ol mammary and soft tissue myofibroblastomas, as well as of spin­ dle cell / pleomorphic lipoma and cellular an giofibroma. In addi­ tion, the overlappi ng morphological and immu no histochemical features support the hypothesis that these tumours represenl variations along a spectrum of genetically related lesions, the so-called 13q/RB7 family of tumours {1941,1422,1040,26}.

None

Macroscopic appearance

Local izati on Although these tumours typically arise in the superficial soft tis­ sues of the vulvovaginal region and the inguinoscrotal or paratesticular region, rare examples have been described in other sites.

Clinical features Patients usually prese nt with a slow-growing pain less mass. The most frequent preoperative diagnosis is (Bartholin) cyst {1040, 1496,2331}. In males, the mass may be associated with hernia or hydrocoele {1496,1757}.

Epidemiology Cellular angiofibroma is a rare neoplasm arising in adults. Females and males are roughly equally affected, with a peak

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The tumours vary in size from 0.6 to 25 cm. Those in women are gen erally smalle r (media n: 2.8 cm) than those in men (median: 7.0 cm). The tumours appear as round, oval, or lobulated wellcircumscribed nodules. The consistency of the lesion varies from soft to rubbery and the cut surface is solid with a greyishpink to yellowish-brown colour {1496,1757}. Foci of haemor­ rhage or n ecrosis are excepti on al {1496}.

Histopathology The tumours are generally well circumscribed. Poorly marginated, more-infiltrative tumours occur rarely in men. Tumours are com­ posed of uniform, short spindle-shaped cells in an oedematous to fibrous stroma containing short bun dies of delicate collagen fibres and numerous small to medium-sized thick-walled blood vessels with rounded, irregularly ectatic or branching lumina.

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Fig. 1.84 Cellular angiofibroma. A Note usual circumscription, varying cellularity, and prominent vessels with hyaline walls. B About 50% of cases contain variably promineM mature adipocytes. C At high power, the spindle cells have short stubby nuclei and indistinct cytoplasm, resembling spindle cell lipoma. Note the admixed mast cells and rounded vessels.

80

Soft tissue tumours

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Fig・ 1.85 Cellular an giofibroma. A Dege nerative changes such as stromal oedema, patchy chronic inflammati °n, and mild nu clear atypia are more common in male patients. B Rare cases show small aggregates of highly atypical cells, as here, and occasional cases may show overtly sarcomatous morphology but appear to retain benign

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behaviour.

The spindle cell component is usually moderately to highly cellu­ lar and randomly distributed throughout the lesion, occasionally with a fascicular arrangement or nuclear palisading. Spindle cells have short, oval to fusiform nuclei with inconspicuous nueleoli and sea nt, palely eosi nophilic cytoplasm with ill-defi ned borders. Mitoses are gen erally sparse, but they can be more freque nt in some cases. The stroma con si sts primarily of wispy collage n, with occasi onal short bun dies of densely eosi nophilic collage n fibres. Variable stromal oedema, hyalinization, or myxoid change is often seen, especially in males. Perivascular lymphoid aggre­ gates may be present. Mast cells are frequent. Small aggregates or in dividual adipocytes are observed in close to 50% of cases. Degenerative changes of slight nuelear enlargement and hyperchromasia, intravascular thrombi, and cystic change are seen in some cases {1496,1757,2031}. Morphological sarcomatous transformation has been described rarely, mostly in the vulva {553,1040,1566}. Abrupt tran sitio n from cellular an giofibroma to a discrete sarcomatous nodule composed of multivacuolated lipoblasts, or pleomorphic and hyperchromatic spindle cells showing morphological fea­ tures of pleomorphic liposarcoma, atypical lipomatous tumour, or pleomorphic spindle cell sarcoma, has been reported. Other rare cases show severely atypical cells scattered in conven­ tional cellular an giofibroma. No n ecrosis or haemorrhage is observed. In sarcomatous areas there are few mitoses {553, 1040}. By immunohistochemistry, CD34 expression has been

documented in 30-60% of tumours. Variable expression of SMA and desmin is identified in a minority of cases. ER and PR are expressed in many cases {1496,1757,2031}. RB1 loss is frequently detected.

Cytology Not clinically r eleva nt

Diagnostic molecular pathology Deletions of RB1, located in chromosome band 13q14, can be detected but are usually not required {1937,1040,2416}.

Essential and desirable diagnostic criteria Essential: bland spindle cells, short bun dies of delicate collage n fibres, and numerous small to medium-sized thick-walled ves­ sels, with or without adipose tissue. Desirable: usually in vulvovaginal or inguinoscrotal regions; loss of RB1 may be helpful.

Staging Not clin ically re leva nt

Prognosis and prediction Local recurrenee is very infrequent {1496,1757,2031}. The rare cases with atypia or sarcomatous transformation have not developed recurrence or metastasis so far {553,1040,1566}.

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Soft tissue tumours

81

paybal：https://www.paypal.me/andy19801210 Angiofibroma of soft tissue

Marino-Enriquez A Mertens F Wang J Yamada Y

Definiti on

Localization

An giofibroma of soft tissue is a benign fibroblastic n eoplasm composed of uniform spindle cells with abundant fibromyxoid stroma and a prominent network of innumerable branching, thin-walled blood vessels.

An giofibroma of soft tissue typically arises in the extremities, mainly the legs, freque ntly invo Iving or adjace nt to large -joints such as the kn ee. Un usual an atomical locations in elude the back, abdominal wall, pelvic cavity, and breast. The tumours are often subcutaneous but may be intramuscular and deep {1980,3330,261}.

ICD-0 coding 9160/0 Angiofibroma NOS

Clinical features

ICD-11 coding EE6Y & XH1JJ2 Other specified fibromatous disorders of skin and soft tissue & An giofibroma NOS

The lesion presents most often as a slow-growing painless mass {1980,3330,261}. Preoperative duration may be long {1980|. Most lesions are sharply demarcated; however, infiltration into adjacent structures may be detected on imaging {1980,261}. I

Related terminology Epidemiology

None

An giofibroma of soft tissue affects predominantly middle-aged adults, with a peak incidenee in the sixth decade of life, but patients of any age may be affected (1980,3330,261). There is a slight female predominance (M:F ratio: -0.75:1) {1980,3330,261).

Subtype(s) None

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Fig. 1.86 Angiofibroma of soft tissue. A Characteristic alternation between collagenous and myxoid areas at low magnification. B Prominent vascular network consisting^ innumerable thin-walled branching blood vessels. C Uniform proliferation of neoplastic spindle cells with inconspicuous palely eosinophilic cytoplasm and short ovoid or tape佩 nuclei. D Partial karyogram showing the characteristic t(5;8)(p15;q13) that results in the AHRFI-NCOA2 fusion. Arrows indicate breakpoints.

82

Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 Etiology Unknown

Pathogenesis Soft tissue an giofibromas have near-diploid karyotypes with a recurrent t(5;8)(p15;q13), which results in fusion of AHRR in chromosome band 5p15 and NCOA2\n 8q13 {1529}. The AHRRNCOA2 chimera, including the basic helix-loop-helix and PAS domains of AHRR and the two transcriptional activation domains of NCOA2, is present in 60-80% of the tumours {1529,3330,261); variant GTF2l-NCOA2or GAB1-ABL1 fusions have been found in single cases {151,261}. The AHRR-NCOA2 chimera is expected to upregulate the AHRR/ARNT signalling pathway.

distributed throughout the lesion. Less prominent medium-sized or large blood vessels with variably thick walls are usually also prese nt. Common additi onal features in elude perivascular col­ lage n deposition and marked hyalinization or fibrinoid necrosis of medium-sized vessel walls. Degenerative changes may be focally present, including haemorrhage or aggregates of foamy histiocytes. A variably dense in flammatory in filtrate compris­ ing mainly small lymphocytes is usually present, sometimes in a perivascular distribution. By immunohistochemistry, the neoplastic cells variably express EMA and CD34; sometimes desmin is seen in dendritic cells {1980,261).

Cytology Not clin ically releva nt

Macroscopic appearance Most lesions are well-demarcated, nodular or multinodular solid tumours of variable size, with a white to yellow, often glisten­ ing, cut surface. Cystic or haemorrhagic areas may be present {1980,3330,261}.

Diagnostic molecular pathology

Histopathology

Essential and desirable diagnostic criteria

An giofibroma of soft tissue is composed of un iform bland spindle cells in a variably myxoid to collage nous stroma with a prominent vascular network. The lesions are well circum­ scribed. The architecture is vaguely lobulated, with alter rating myxoid and collage nous areas and regional variati on in cellularity. The neoplastic spindle cells have inconspicuous palely eosinophilic cytoplasm and short ovoid or tapering nuclei, with irregular n uclea r con tours, fine chromatin, and in disti net nucleoli. Cytological atypia and nuelear hyperchromasia are gen erally abse nt. Occasi onal cases show dege nerative nuclear atypia. The prominent vascular network is composed of innu­ merable small thin-walled branching blood vessels evenly

Essential: variably myxoid or collage nous stroma; bland and uniform short spindle cells; innumerable small thin-walled branchi ng blood vessels. Desirable: NCOA2 gene rearrangements (in selected cases).

Detection of NCOA2 rearrangement or an AHRFl-NCOA2\us\or] gene (or a varia nt fusi on) supports the diagnosis of an giofi­ broma of soft tissue, but it is generally not required.

Stagi ng Not clinically relevant

Prognosis and prediction An giofibroma of soft tissue pursues a benign clinical course, with rare local recurrences and no evident metastatic potential {1980,3330,261}.

Soft tissue tumours

83

paybal：https://www.paypal.me/andy19801210 Nuchal-type fibroma

Doyle LA

Definition

Etiology

Nuchal-type fibroma is a rare benign collagenous lesion that usually arises in the neck.

Unknown

Pathogenesis

ICD-0 coding

Unknown

8810/0 Nuchal fibroma

Macroscopic appearance ICD-11 coding EE6Y & XH0XH6 Other specified fibromatous disorders of skin and soft tissue & Nuchal fibroma

The mean tumour size is 3 cm. Nuchal-type fibroma is ill defined and has a firm consistency and a white cut surface.

Histopathology Related terminology Acceptable: nuchal fibroma. Not recommended: collage nosis n uchae.

Subtype(s) None

Localization Nuchal-type fibroma typically arises in the subcutaneous tis­ sues of the posterior neck, but it can also occur at other sites {208,2111}. Most extra nuchal tumours are located on the upper back, but tumours can also arise on the face and extremities.

Clinical features As many as 50% of patients with nuchal-type fibroma have dia­ betes mellitus {2111}.

Nuchal-type fibroma is a poorly circumscribed and paucicellular lesion composed of bland spindle cells, thick hap­ hazardly arranged collagen fibres, and entrapped subcutaneous adipose tissue. Elastic fibres and small blood vessels are present between the collagen fibres. Many nuchal-type fibromas contain a localized proliferation of small nerves, in some cases similar to those seen in traumatic neuroma. This feature is usually absent from Gardner fibroma, which is often otherwise indistinguishable from nuchal-type fibroma Compared with normal tissue from the nuchai area, nuchaltype fibroma shows similarly thick collagen fibres. However, in nuchal-type fibroma there is an expansion of collagenizec dermis with encasement of adnexa, effacement of the subcutis with entrapment of adipocytes, and (in many cases) extension into underlying skeletal muscle. By immunohistochemistry. the spindled fibroblasts are CD34-positive and negative fo( p-cateni n.

Epidemiology Nuchal-type fibroma is signifiesntly more common in men, with a peak incidenee in the fourth and fifth decades of life.

Cytology Not clinically re leva nt

Fig. 1.87 Nuchal-type fibroma. A The tumour is paucicellular and contains thick haphazardly arranged collagen fibres entrapping adipose tissue and peripheral nerves. B

lesional ceils are bland spindled fibroblasts. Extension into skeletal muscle is common.

84

Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 Diagnostic molecular pathology Not clin ically re leva nt

Staging Not clinically re leva nt

Essential and desirable diagnostic criteria Essential paucicellular collagenous lesion usually with small nerve bundles; typically arising in the neck; bland CD34positive spindle cells.

Prognosis and prediction Nuchal-type fibroma is benign. It often locally recurs but it does not metastasize.

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Soft tissue tumours

85

paybal：https://www.paypal.me/andy19801210 Acral fibromyxoma

Brenn T Agaimy A Hollmann TJ

Definition

Localization

Acral fibromyxoma is a benign fibroblastic neoplasm with a marked predilection for the subungual and periungual aspects of the digits and potential for local recurrenee.

There is a strong predilection for the periungual and subungual aspects of the fingers and toes {691,1396,2536,66,997}. Other areas of the hands and feet, an kies, wrists, lower legs, and thighs may rarely be affected {1396,26}.

ICD-0 coding 8811/0 Acral fibromyxoma

ICD-11 coding EE6Y & XH5XQ3 Other specified fibromatous disorders of skin and soft tissue & Fibromyxoma

Clinical features Acral fibromyxomas present as slowly enlarging and frequen® painful solitary tumours, typically measuring 1-2 cm {691,1396, 2536,66}. The tumours may cause nail deformity, and erosive or lytic lesions of the underlying bone may be detected radio­ graphically {1396}.

Related terminology Acceptable: superficial acral fibromyxoma; digital fibromyxoma. Not recommended: cellular digital fibroma.

Subtype(s)

Epidemiology A wide age range is affected, but most tumours present in mid­ dle-aged adults, with a median age of about 50 years. Males are more frequently affected than females {997,1396}.

None

Fig. 1.88 Acral fibromyxoma. A Lobulated tumour containing a variably myxoid and collagenous stroma. B The tumours may be predominantly myxoid and show a proliferate of small delicate vascular channels. C The bland and uniform spindled and stellate tumour cells are loosely distributed in a fibromyxoid stroma. D This cellular area is character ized by a fascicular growth of uniform spindle cells in a collagenous matrix. Note the absence of cytological atypia.

86

Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 Etiology Unknow n

Pathogenesis RB1 deletions have been reported {26}.

Macroscopic appearance

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On macroscopic examination, the tumours appear dome­ shaped, polypoid, or verrucoid, with soft to firm consistency, an often lobulated aspect, and poorly defined borders.

Histopathology Acral fibromyxomas present in dermis and subcutis as lobulated tumours, occasionally with a polypoid growth and surrounding epidermal collarette formation. The majority of tumours show an infiltrative growth pattern, with rare invasi°n of underlying bone. The tumours are composed of blandappeari ng spin died or stellate cells arranged loosely in a variably myxoid or collage nous stroma. Scattered multinucle­ ated cells may be admixed. A vaguely storiform or fascicular growth pattern may be seen, and a proliferation of small vas­ cular channels is present in the myxoid areas. Cartilaginous or osseous metaplasia is rarely observed. Nuclear pleomor­ phism and tumour necrosis are absent, and mitoses are rare. By immunohistochemistry, the tumour cells express CD34 and occasionally EMA and SMA. There is loss of RB1 expression in the majority of tumours {26}.

Essential and desirable diagnostic criteria Essential: acral, usually periungual location; dermal-based tumour with infiltration of subcutis; lobulated architecture with vaguely storiform or fascicular growth; bland spindle cells in a variably myxoid or collage nous matrix. Desirable: CD34 positivity and frequent loss of RB1 expression by immunohistochemistry.

Staging Cytology

Not clin ically re leva nt

Not clinically relevant

Prognosis and prediction Diagnostic molecular pathology The tumours show deletion of the RB1 gene {26}, but this is not required.

Acral fibromyxomas recur locally in as many as 22% of cases. Local recurrences are non-destructive and can be cured by reexcision. Metastases have not been reported {997,1396}.

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Soft tissue tumours

87

paybal：https://www.paypal.me/andy19801210 Gardner fibroma

Cates JMM Cunha IW

Definition

Epidemiology

Gardner fibroma is a benign plaque-like mass composed of thick, haphazardly arran ged collage n bun dies with sparsely interspersed fibroblasts, and it is usually associated with familial adenomatous polyposis (FAP).

Gardner fibroma is diagnosed most often in children aged < 10 years but may prese nt in you ng adults as well. There is no sex predilection {3259,627}.

ICD-0 coding 8810/0 Gardner fibroma

Approximately 80% of cases are associated with FAP, APC mutation, or familial desmoid fibromatosis {3259,627}.

ICD-11 coding

Pathoge nesis

EE6Y & XH7GT0 Other specified fibromatous disorders of skin and soft tissue & Gardner fibroma

Most cases arise in patients with germline APC mutations (see Desmoid fibromatosis, p. 93).

Related terminology

Macroscopic appearance

Acceptable: Gardner-associated fibroma. Not recommended: desmoid precursor lesion.

Gardner fibroma is a poorly circumscribed, rubbery, tan-white mass ranging in size from < 1 cm to > 10 cm {3259,627}.

Etiology

Subtype(s)

Histopathology

None

The dominant histopathological feature is the haphazaro arrangement of coarse collagen fibres with characteristic clefts or cracks and few inc on spicuous spindle cells {3259,627}. A helpful diagnostic feature is entrapme nt of adjace nt adipose tissue and n eurovascula r bun dies at the edge of the lesion By immunohistochemistry, CD34 is almost always positive whereas SMA is negative {3259,627}. Nuclear accumulation of p-catenin is often observed, particularly in cases associated with FAP {627,708}.

Localization Gardner fibromas commonly arise in the superficial and deep soft tissues of the torso (usually the back or paraspinal region) or head/neck region, but almost any non-visceral anatomical site can be involved, including the mesentery {3259,627}.

Clinical features These tumours typically present as painless masses {3259,627}.

Fig. 1.90 Gardner fibroma. A Small bland spindle cells are dispersed in cracks between collagen fibres. B Entrapped mature adipose tissue and benign nerve fibres

frequently seen in Gardner fibroma.

88

Soft tissue tumours

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Cytology

l s d e u o

Staging

Not clinically relevant

Not clinically re leva nt

Diagnostic molecular pathology

Prognosis and prediction

Not clinically relevant

Gar&ner fibroma is benign but is associated with concurrent or subsequent development of desmoid fibromatosis in approxi­ mately 20% of cases {627,610}. Conversely, an associated Gardner fibroma or an area in the desmoid tumour resembling Gardner fibroma can be identified in as many as 37% of patients with desmoid fibromatosis {515,3408}. Given the close association between Gardner fibroma and FAP, a diagnosis of Gardner fibroma should prompt screening of the family for FAP.

Essential and desirable diagnostic criteria

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Soft tissue tumours

89

paybal：https://www.paypal.me/andy19801210 Palmar fibromatosis and planta r fibromatosis

Definition Palmar and plantar fibromatoses are benign nodular fibroblastic/myofibroblastic proliferations typically arising in the volar aspect of the hands and fin gers or involving planta r apon euroses, respectively.

ICD-0 coding 8813/1 Palmar/plantar-type fibromatosis

ICD-11 coding FB51.Y & XH75J5 Other specified fibroblastic disorders & Pal­ mar/pla ntar-type fibromatosis

Related terminology Palmar fibromatosis

Thway K Nascimento AF

{3139}, and it is bilateral in as many as 35% of cases. Paediatric cases of plantar fibromatosis typically involve the anteromedial portion of the heel pad. - I

Clinical features Palmar fibromatosis typically has an insidious on set, with devel­ opment of small, pain less n odules that slowly evolve to form cords or band-like in durations between nodules in the subcutis and underlying fascia, leading to digit contractures and puckering of overlying skin. In contrast, plantar fibromatosis does not typically cause contractures and is often asymptomatic, although mild pain may develop after prolonged standing or walking.

Epidemiology

Acceptable: Dupuytren disease/contracture.

Plantar fibromatosis Acceptable: Ledderhose disease.

Subtype(s) None

Localization Palma r fibromatosis prefere ntially involves the volar or flexor aspect of the hands and is bilateral in as many as 50% of cases. Plantar fibromatosis is typically located in non-weight-bearing areas, such as the aponeurosis of the medial plantar arch, from the region of the navicular bone to the base of the first metatarsal

Palmar fibromatosis predominantly affects adults, with a male predomi nance (M:F ratio: 3:1) and highest prevale nee in white people (2664). Its incidenee increases with age, and it is rare among individuals aged < 30 years. Plantar fibromatosis is more comm on in you nger patie nts (including those as young as 9 mon ths), with almost half of all patie nts aged < 30 years {1170,996}. In paediatric cases, plantar fibromatosis shows a female predominance {996}. Palmar or plantar fibromatosis can be associated with synchronous or metachronous development of the other form (with 5-20% of patients developing both), but not desmoid fibromatosis {996,3139}. Associations with epi­ lepsy and phenobarbital therapy, diabetes mellitus, cigarette smoking, and alcoholism with cirrhosis are reported but have not been widely validated {451}.

衍磁磔強罗綴曲‘ B贸 Fig. 1.91 Palmar fibromatosis. A In the early (proliferative) phase, palmar fascial or aponeurotic tissue is expanded by hypercellular spindle cell nodules. B This early-st29 lesion is cellular and shows loose fascicles of uniform spindle cells within prominent collagenous stroma.

90

Soft tissue tumours

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Fig. 1.92 Plantar fibromatosis. A Low-power view showing typically multinodular growth pattern (within tendoaponeurotic fibrous tissue), as is usually seen in plantar le­ sions. B Intimate association of the cellular, proliferative-phase lesional spindle cells with native fibrotendinous tissue is seen. C Spindle cells arranged in long, parallel fascicles in more-densely collagenous matrix. The cells are uniform and lack discernible atypia. There are associated mild chronic inflammation and rare mitotic figures. D In the prolifera­ tive phase, plump, bland-appearing spindle cells with elongated nuclei with vesicular chromatin and inconspicuous nucleoli are predominant.

Etiology Unknown

Pathogenesis Although still driven at least in part by the WNT/p-catenin signal­ ing pathway, this tumour lacks the CTNNB1 and APC mutations characteristic of desmoid fibromatosis {2178,3378,491}.

often perivascular chronic inflammation and occasional typical mitotic figures, especially in early lesions. Mitotic activity may be particularly prominent in paediatric patients. Occasional, particularly plantar lesions show interspersed multinucle­ ated cells. Late-stage histology is associated with in creased

Macroscopic appeara nee Tumours are small, poorly defined 0.5-3.0 cm nodules, inti­ mately associated with a tendon or aponeurosis and extending into subcutaneous tissue. The cut surface is firm, greyish-yel­ low or white (depending on the collagen content), and slightly whorled.

Histopathology

y-stage

Typically, tumours involve a thickened palmar/plantar aponeurosis and form single to multiple discontinuous, moderately cellular spindle cell nodules in collagenous stroma {996}. Mor­ phologically, there are three phases of growth (proliferative, involutional, and late-stage). The proliferative phase comprises cellular, parallel fascicles of bland, plump, relatively uniform spin died fibroblasts with taperi ng n uelei, vesicular chromati n, and small or inconspicuous nucleoli, with minimal stromal collagen. Some plantar lesions are hypercellular and can mimic spindle cell sarcomas, but they lack atypia. There may be scattered,

Fig. 1.93 Plantar fibromatosis. This lesion shows small numbers of osteoclast-type, multinucleated giant cells, interspersed among the plump, cellular fibroblastic cells.

Soft tissue tumours

91

paybal：https://www.paypal.me/andy19801210 collage nous matrix and decreased cellularity. Rarely, there is osseous or cartilaginous metaplasia. By immunohistochemistry, tumour cells are variably positive for SMA and occasi on ally for desmin. A subset show nuclear 卩-catenin expression, despite the absence of CTNNB1 or APCgene mutations {2178,480}.

Essential and desirable diagnostic criteria Essential: blan d, variably cellular proliferati on of spin died fibrob I asts/my of i b ro b I asts; collage nous stroma; in volveme nt of aponeurosis and variably subcutis and dermis.

Staging Cytology

Not clinically relevant

Not clin ically re leva nt

Prognosis and prediction

Diagnostic molecular pathology Not clinically relevant

92

Soft tissue tumours

The risk of local recurrenee is mostly dependent on the extent of surgical resection, although this is reserved for patients.wM have failed conservative management {3378}.

paybal：https://www.paypal.me/andy19801210 Fritchie KJ Crago AM van de Rijn M

Desmoid fibromatosis

Definition Desmoid fibromatosis is a locally aggressive but non-metastasjzing deep-seated (myo)fibroblastic neoplasm with infiltrative growth and propensity for local recurrence.

ICD-0 coding 8821/1 Desmoid-type fibromatosis

ICD-11 coding 2F7C & XH13Z3 Neoplasms of uncertain behaviour of connective or other soft tissue & Desmoid-type fibromatosis (aggressive fibromatosis) 2F7C&XH6116 Neoplasms of uncertain behaviour .of connective or other soft tissue & Abdominal (mesenteric) fibromatosis

Related termi no logy Acceptable: aggressive fibromatosis; desmoid tumour. Not recommended: musculoaponeurotic fibromatosis.

Fig. 1.95 Desmoid fibromatosis. A Low-power examination reveals an infiltrative le­ sion extending into surrounding adipose tissue with lymphoid aggregates at the ad­

vancing edge. B There is infiltration of adjacent skeletal muscle.

Subtype(s) Extra-abdominal desmoid; abdominal fibromatosis

Localization Desmoid fibromatosis is most commonly diagnosed in the extremities (30-40% of cases). Lesions also occur in the retroperitoneum or abdominal cavity (15%), abdominal wall (20%), and chest wall (10-15%). Less comnnon sites in elude head and neck, paraspinal region, and flank {671,2719,1831}.

Clinical features

Fig. 1.94 Desmoid fibromatosis. A Axial T2-weighted MRI of the abdomen shows a mass within the rectus abdominis with mixed internal heterogeneity. Areas of low signal (arrow) correspond to fibrosis, whereas areas of high T2 signal (arrowheads) correspond to areas of increased cellularity. B Gross examination reveals a firm, tan surface with infiltration into surrounding fat and skeletal muscle.

Desmoid fibromatosis generally prese nts as a pain less mass localized to the deep compartments that is fixed on physi­ cal exami nation. Approximately 10% of patie nts r eport prior trauma or surgery in the region of the desmoid tumour, and 15% have a history of recent or current pregnancy (abdominal wall desmoids) within 5 years of diagnosis {3160}. Patients with familial adenomatous polyposis most often present with intra-abdominal tumours after abdominal surgery. MRI showing mixed hyperintense and isointense signals is suggestive of

Soft tissue tumours

93

paybal：https://www.paypal.me/andy19801210

Fig. 1.96 Desmoid fibromatosis. A The fascicles of desmoid fibromatosis are long and sweeping. B Hyalinized area of a

vessels.

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Desmoid fibromatosis. A High-power examination reveals bland fibroblasts and myofibroblasts without cytological atypia or nuclear hyperchromasia. B Occasional! desmoid tumours, especially those arising in the abdominal cavity, may show areas with keloid-type collagen deposition.

desmoid fibromatosis; this finding reflects variable content of tumour cellularity and fibrous stroma {3172,2992}. Site-specific complications can occur due to local progression. Intra-abdominal lesions can cause intestinal obstruction or fistulization with infectious symptoms or gastrointestinal bleeding; in these cases, the tumour comm only in volves the root of the mesentery. Extremity lesions can be multifocal (particularly in paediatric and young adult patients) and extensive, causing limb contracture and chronic pain. A small subset of desmoid tumours occur in the con text of familial ade no matous polypo­ sis (Gardner syndrome); in this setting, lesions are frequently intra-abdominal, multifocal, and diagnosed in children or young adults {2292}.

Epidemiology Desmoid fibromatosis is estimated to affect < 4 patients per 1 million populatio n per year {2598}. Patie nts tend to be you ng, with a median age of 37-39 years. The disease is more common in women than men (M:F ratio: 0.5:1), although in paediatric patients and patients past childbearing age, the disease shows an equal sex distribution {2598,671,2719}.

Etiology The etiology of desmoid fibromatosis is multifactorial and includes gen etic factors (most comm only sporadic somatic CTNNB1 mutations and less freque ntly germli ne A PC mutations

94

Soft tissue tumours

in Gardner syndrome) and physical factors (trauma, surge。 pregnancy) {1590}. Surgery increases the risk of tumour devel opment {1200}.

Pathogenesis The majority (90-95%) of sporadic desmoid tumours resul from three d if fere nt point mutations in two codo ns (41 anc 45) of exon 3 of the gene that encodes p-catenin (CTNNBM p.Thr41Ala, p.Ser45Pro, and p.Ser45Phe {98,1781,652,834,670 p.Thr41Ala and p.Ser45Phe are the most comm on mutation {834,1781,98}. A smaller percentage of desmoid tumours arid in the setting of Gardner syndrome; affected patients harboi germline mutations in the APC tumour suppressor gene, spf cifically mutations at or beyond codon 1444, with subsequei loss of heterozygosity of the wildtype allele, and rare case of desmoid tumours with sporadic APC mutations have als been described {1148,285,1259,1872,22 93,1515,2969,229 508,3242}. The activating mutations in CTNNB1 or inactivatir mutations in APC interfere with p-catenin proteasomal degrade tion, leading to nuclear 卩-catenin accumulation (219). Becaus p-catenin functions as part of the transcription apparatus in tr nucleus, this increased activation of the WNT/p-catenin pathw； is thought to ultimately promote cell proliferation and surviv and appears to drive tumorigenesis {1780,2336,1687}. A subs of the neoplastic population of desmoid fibromatosis may " bour trisomies for chromosomes 8 and/or 20; however, the

paybal：https://www.paypal.me/andy19801210 berrations are unlikely to play a substantial role in pathogen-

；sis or behaviour {419,767,1028,2100,2718}. Macroscopic appearance

Gross exami nation r eveals a solid mass with a wide size range and a whitish-tan, coarsely trabecular or whorled cut surface. Most lesions appear poorly circumscribed with ill-defined margins and infiltration into adjacent tissues. Intra-abdominal desmoid fibromatosis tends to present as a large mass, often as large as 10 cm in diameter, with a whorled cut surface.

Histopathology Desmoid fibromatosis is characterized by long, sweeping fascicles of bland fibroblasts and myofibroblasts with infiltration into surrounding soft tissues. The fascicles often span an entire 10x objective field, and lymphoid aggregates are often appre­ ciated at the advancing edge of the lesion. The tumour cells dem on strate pale eosinophilic cytoplasm and lack n uclear hyperchromasia or cytological atypia. Thin-walled blood ves­ sels, occasionally with a gaping or staghorn appearanee, are often prominent with variable perivascular oedema. Mitotic fig­ ures are typically absent or rare, and atypical mitoses are lack­ ing. A subset of tumours harbour densely eosinophilic stromal keloidal-type collage n, a finding most comm on in in tra-abdominal tumours. Othe r morphological patter ns include myxoid change, paucicellular hyalinized areas, and zones resembling nodular fasciitis {3408,449}. By immunohistochemistry, the lesional cells are positive for SMA and MSA. The majority of tumours (-80%) show nuclear 卩-catenin expression, although definite nuclear reactivity can be difficult to appreciate {305, 480,2271}.

Cytology FNA specimens are variably cellular and typically show loose clusters of bland or reactive-appearing fibroblasts and myofi­ broblasts without substantial cytological atypia or nuclear hyperchromasia {2564}. The relatively non specific findings make desmoid tumours difficult to diagnose by FNA.

Diagnostic molecular pathology CTNNB1 mutation analysis may be helpful in small biopsy specimens, when diagnostic morphological features are not readily apparent, and/or when 卩-catenin immunostaining is equivocal or challenging to interpret {650,1785}.

Essential and desirable diagnostic criteria Essential: Iong, sweeping fascicles of bland fibroblasts and myofibroblasts without substantial cytological atypia; infiltra­ tive growth. Desirable: nuclear p-catenin expression; characteristic CTNNB1 mutation (in challenging cases or small biopsies).

Staging Not clin ically r eleva nt

Prog nosis and prediction The n atural course of desmoid fibromatosis in in dividual patients is variable, with unpredictable growth, stabilization, and regression. Tumour-related deaths are rare but seem to be more common in patients with familial adenomatous polyposis {804}. Although primary surgery with negative surgical margins was classically considered to be the standard of care, local recurrenee does not consistently correlate with margin status {2719,651}. Approximately one third of patients experienee recurrenee after resection; extensive surgery can be morbid; and spontaneous regression has been observed in a subset of advaneed, unresectable tumours. For these reasons, a watchful waiting approach with a period of initial observation has been advocated for asymptomatic patients {1590}. When surgery is considered for patients with desmoid tumours, higher rates of local recurrence are associated with extra-abdominal location, younger age, larger tumour size, and mutation status {2719, 671,1831}. Studies have suggested that tumours harbouring CTNNB1 p.Ser45Phe mutations have a greater risk for local recurrence {346,652,834,1781}. It is unclear whether similar molecular or clinicopathological factors predict progression during active observation.

Soft tissue tumours

95

paybal：https://www.paypal.me/andy19801210 Lipofibromatosis

Miettinen M Al-lbraheemi A Zambrano E

Definition

Epidemiology

Lipofibromatosis is a rare, frequently recurring paediatric soft tissue tumour with a predilection for the hands and feet. It is composed of a distinctive admixture of mature fat, short fasci­ cles of bland spindle cells, and lipoblast-like cells in the inter­ face between the spindle cell and lipomatous components.

Lipofibromatosis occurs in children from birth to early in the sec­ ond decade of life, with an M:F ratio of 2:1. Half of the cases are diag no sed by the age of 1 year, and 20% are con genital {1000 70}.

Etiology

ICD-0 coding

Unknown

8851/1 Lipofibromatosis

Pathogenesis ICD-11 coding FB51.Y & XH4QB6 Other specified fibroblastic disorders & Lipofibromatosis

Related terminology Not recommended: inf a ntile/juve nile fibromatosis varia nt (nondesmoid type).

Subtype(s) None

Localization Lipofibromatosis prefere ntially involves the hands and feet, although it can also occur at other locations such as the trunk and the head and neck {1000}.

Clinical features Lipofibromatosis typically presents as a slow-growing, poorly demarcated subcutaneous mass, which can also involve skel­ etal muscle {1000}.

Identification of fusions involving ligands (EGF, HBEGF, TGF-a| to EGFR (HER1) or EGFR itself, or other receptor tyrosine kinases (ROS1, RET, PDGFRB), suggests that activation of tha PI3K/AKT/mTOR pathway might be implicated in the pathogen-i esis of lipofibromatosis {70}.

Macroscopic appearance The firm, rubbery, poorly demarcated mass has a white or yel­ low cut surface; margins are difficult to discern. Most lesions are 1-7 cm in diameter, although larger tumours have beer reported, with some involving the entire extremity {1000,70 1215}.

Histopathology Lipofibromatosis is composed of mature adipose tissue tra­ versed by cellular fascicles of spindle cells with bland, uniform] elongated nuclei. Fat usually forms a major proportion of the lesion. In newborn patients, the fat lobules may have an immaj

ture appearanee with myxoid matrix. Small collections of uni­ vacuolated cells may be present in the fibroblastic component

Fig. 1.98 Lipofibromatosis. A The tumour, involving subcutaneous fat and skeletal muscle, is composed of mature-appearing adipose tissue and cellular fibrous septa 皿加 atypia or mitotic activity, imparting a fibromatosis-like appearance. B The fibroblasts show a uniform appearance and are embedded in an abundant collagenous matrix.

96

Soft tissue tumours

where melanin-laden cells have occasionally been documented. Lipofibromatosis entraps subcutaneous tissue and sometimes skeletal muscle. Mitotic activity is rare and necrosis absent. Occasional recurrent lesions are indistinguishable from calcifyi ng apon eurotic fibroma {70}. By immu no histochemistry, the fibroblasts show variable expression of CD34 and SMA. The spindle cells are negative for desmin, in contrast to the spindle cells in Iipoblastoma.

)e sec-

Cytology

$es are {1000,1

FNA smears show bland-appearing fibroblasts and mature fat.

Diagnostic molecular pathology Not clinically relevant

L-ladeLIO

paybal：https://www.paypal.me/andy19801210 Essential and desirable diagnostic criteria Essential: pain less subcuta neous mass; most often in the hands and feet of you ng childre n; admixture of mature fat, short fas­ cicles of bland spindle cells, and lipoblast-like cells; infiltrative margins.

Staging Not clin ically releva nt

Prognosis and prediction Lipofibromatosis has a 70% local recurrenee rate but no meta­ static potential. Congen ital on set, male sex, acral locati on, mitotic activity in the fibroblastic comp onent, and in complete excision may be risk factors for recurrenee {1000}.

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or yellesions )been )00,70.!

je traniform.' of the immaof uni-

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Soft tissue tumours

97

paybal：https://www.paypal.me/andy19801210 Giant cell fibroblastoma

Mentzel TDW Pedeutour F

Definition Giant cell fibroblastoma is a locally aggressive fibroblastic neoplasm, closely related to dermatofibrosarcoma protuberans (DFSP), arising primarily in children and characterized by the presenee of multinueleated giant cells, pseudovascular spaces, and a C0L1A1-PDGFB fusion.

ICD-0 coding 8834/1 Giant cell fibroblastoma

ICD-11 coding FB51.Y & XH9AV8 Other specified fibroblastic disorders & Giant cell fibroblastoma

Related termi no logy None

Subtype(s) None

Fig. 1.100 Giant cell fibroblastoma. Low-power view shows a hypocellular derma neoplasm with irregularly branching pseudovascular spaces.

Localization

Etiology

The majority of cases of giant cell fibroblastoma arise in super­ ficial soft tissues of the trunk, the groin and axillary region, and (more rarely) the extremities and the head and neck region {876, 1526,2852,3062}.

Unknown

Clinical features The affected patie nts usually report a slow-growi ng, pain less cutaneous lesion that is most often plaque-like {1526,2852}.

Epidemiology Giant cell fibroblastoma is a rare neoplasm arising predominantly but not exclusively in children, with a mean age of 6 years and a male predominance {1526,2852}.

Pathogenesis Giant cell fibroblastoma and DFSP share chromosomal anc molecular features, consisting of rearrangements of chromo­ somes 17 and 22 and formation of a chimeric gene that fuses COL1A1 at 17q21.33 with PDGFB at 22q13.1 {2864}. The breakpoint in COL1A1 is variable between patients (from exon 6 up to exon 49), whereas the breakpoint in PDGFB is consistentli located in intron 1 {2876}. There is no evidenee of a correla tion between a specific breakpoint within COL1A1 and eithei giant cell fibroblastoma or classic DFSP (or other DFSP-relatec tumours) {1143}. Giant cell fibroblastoma more frequently shows

Fig. 1.99 Giant cell fibroblastoma. A The neoplasms are composed of spindle cells and scattered multinucleated giant cells that also line pseudovascular spaces. B Hyt tumour with features of giant cell fibroblastoma (top) and dermatofibrosarcoma protuberans (bottom).

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Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 balaneed translocation without amplification than does DFSP (see Dermatofibrosarcoma protuberans, p. 100).

tumour progression) {1526}. By immunohistochemistry, spin­ dle-shaped cells and multinucleated tumour giant cells are positive for CD34 {1526,3062}.

Macroscopic appearance Grossly giant cell fibroblastoma is an ill-defined, infiltrative lesion with greyish-yellow and mucoid cut surfaces. The size of 阮 lesions ranges from 0.6 to 8 cm, with a mean of 3-4 cm {1526,2852,3062}.

Histopathology Giant cell fibroblastoma is a mainly subcutaneous neoplasm with infiltration of the dermis and (more rarely) superficial skeletal muscle. Typical cases of giant cell fibroblastoma infiltrate 惟 subcutis in honeycomb or parallel growth patterns, spare cutaneous adnexal structures, and show variable cellularity； however, hypocellular areas with myxoid or collagenous stroma often predominate. The neoplasms are composed of bland spin died and stellate tumour cells and scattered multinucleated giant cells with a wreath-like arrangement of nuclei, which also line irregularly branching pseudovascular spaces. Mitoses are rare, and areas of tumour necrosis are usually absent. In about 15% of cases, areas of conventional DFSP are present (hybrid cases) {1526,2852,3062}. Rarely, cases contain pigmented tumour cells, show prominent myx­ oid change, or contain fibrosarcomatous areas (representing

Cytology Not clinically re leva nt

Diagnostic molecular pathology COL1A1-PDGFB fusion may be detected by various molecular approaches but is not gen erally r equired.

Essential and desirable diagnostic criteria Essential: infiltrative margins within dermis and subcutis; hypocellula r lesi on with myxoid or collage nous stroma; bland spin died and stellate cells and scattered multinu cleated giant cells, often lining pseudovascular spaces. Desirable: COL1A1-PDGFB fusion (in selected cases).

Staging Not clin ically re leva nt

Prog nosis and predictio n A local recurrenee rate of about 50% has been reported {2852}; however, if widely excised, giant cell fibroblastoma locally recurs only rarely {3062}.

Soft tissue tumours

99

paybal：https://www.paypal.me/andy19801210 Dermatofibrosarcoma protuberans

Mentzel TDW Pedeutour F

Definition Dermatofibrosarcoma protuberans (DFSP) is a superficial, locally aggressive fibroblastic neoplasm, having a cellular storiform appearance and carrying a COL1A1-PDGFB or related fusion.

ICD-0 coding 8832/1 Dermatofibrosarcoma protuberans NOS

ICD-11 coding 2B53.Y & XH4QZ8 Other specified fibroblastic or myofibroblastic tumour, primary site & Dermatofibrosarcoma NOS 2B53.Y & XH5CT4 Other specified fibroblastic or myofibroblastic tumour, primary site & Pigmented dermatofibrosarcoma protubera ns

Related terminology Not recommended: Bednar tumour.

Subtype(s) Pigmented dermatofibrosarcoma protuberans; dermatofibro­ sarcoma protuberans, fibrosarcomatous; myxoid dermatofibro­ sarcoma protuberans; dermatofibrosarcoma protuberans with myoid differentiation; plaque-like dermatofibrosarcoma protu­ bera ns

Localization These n eoplasms occur most comm only on the trunk and the proximal extremities, followed by the head and neck region. A subset of cases are seen in the genital area, the breast, and at acral sites {1792,823,2821}.

Fig. 1.101 Dermatofibrosarcoma protuberans. A Giant dermatofibrosarcoma proli berans presenting clinically as a huge exophytic, multinodular mass with focal ulcer tion. B A case containing numerous blood vessels mimicking a vascular lesion.

Clinical features DFSP typically presents as a nodular or multinodular cutaneous mass, often with a history of slow but persistent growth. Early lesions may show a plaque-like growth with peripheral red discolouration. These neoplasms may show rapid enlargement during preqnancy or due to tumour progression to fibrosarcomatous DFSP.

Epidemiology DFSP usually prese nts in you ng to middle-aged adults, with a slight male predominance. However, a substantial number of cases are seen in children (ineluding congenital presentations) {1478,3062} and in the elderly. Although it represents a rare neoplasm (< 1 case per 100 000 person-years), DFSP is one of the most comm on dermal sarcomas. Fig. 1.102 Dermatofibrosarcoma protuberans. Cross-sectioning reveals a firm 伽

Etiology

tumour.

Most of these tumours occur sporadically. DFSP with unique features, such as multicentricity, small size, and occurrenee at early age, has been shown in children affected with adenosine

deami nase-deficie nt {1616}.

100

Soft tissue tumours

severe

combi ned

immunodeficien

paybal：https://www.paypal.me/andy19801210 pathogenesis DFSP is characterized by the presenee of supernumerary ring chromosomes {2876,2729} that contain the centromere of chromosome 22 and comprise interspersed sequences from chromosomes 17 and 22 {2473}. Additional aberrations, such as trisomy 5 and trisomy 8, are also observed {2876,2729}. Unbalanced t(17;22)(q21.3;q13.1) translocations are present in most children and rarely in adults {2876,2729}. Most DFSP cells harbour not only a structural rearrangement but also a gain of 17q21.3-17qter and 22q10-q31 sequences {1870,1593}. Both ring and der(22)t(17;22) chromosomes contain a chimeric gene fusing COL1A1 at 17q21.33 with PDGFB at 22q13.1 {2864}. The breakpoint in COL1A1 is variable: the chimeric gene is com­ posed of at least the first 6 exons up to exon 49 of COL1A1 and a consistent fragment retaining all but exon 1 of the PDGFB gene. Fewer than 5% of typical DFSP cases are negative for the COL1A1-PDGFB fusion gene by routine molecular testing; alter­ native COL6A3-PDGFD and EMILIN2-PDGFD fusion genes have been identified {705,823}, and in some cases, COL1A1PDGFB rearrangement is cryptic {705}. The COL1A1-PDGFB fusion gene encodes a fusion protein that is proteolytically pro­ cessed to normal PDGFB ligand. Because tumour cells express the PDGFRB receptor on their cell surfaces, autocrine stimulation of neoplastic cells drives tumorigenesis. This molecular pathway provides a rationale for targeted therapy with tyrosine kinase inhibitors for unresectable DFSP or metastatic fibrosarcomatous DFSP {2340,1885,2460,2694,3125,1082,2706}. Alteration of the PDGFRB/AKT/mTOR pathway is seen in fibrosarcomatous DFSP {1370}.

Fig. 1.104 Dermatofibrosarcoma protuberans. Tumour fills the dermis and expands into the subcutis, often along fibrous septa.

u ■< -c . n i cvtahciul atvoia and increased proliferative activity are seen in fibrosarcomatous areas.DA® B Pigmented cells鬭 are 隙豐豐 XZSX肌 a监 常酬爲髯常曽恤碍 dggseem 叩讪

myoid differentiation, showing a proliferation of eosinophilic spindled tumour cells set in a hyalinized stroma.

Soft tissue tumours

101

paybal：https://www.paypal.me/andy19801210

Fig. 1.105 Dermatofibrosarcoma protuberans. A A 4-year-old boy with known adenosine deaminase-deficient severe combined immunodeficiency developed multiple flj dermatofibrosarcoma protuberans. B Flat, plaque-like dermatofibrosarcoma protuberans mimicking a benign dermal neoplasm. C A hypocellular example of flat dermatofibre sarcoma protuberans is seen in this young patient with known adenosine deaminase-deficient severe combined immunodeficiency.

Macroscopic appearanee DFSP lesi ons are in du rated plaques with one or multiple nod­ ules. Multiple protuberant tumours are often seen in recurrent lesions. These ill-defined and infiltrative neoplasms have firm, greyish-white cut surfaces with occasi onal gelati nous areas, whereas areas of tumour necrosis are only rarely observed.

Histopathology Classic DFSP DFSP is characterized by a diffuse infiltration of dermis and subcutis. The n eoplastic cells in filtrate the subcuta neous fat, resulting in a typical honeycomb appearanee. The epidermis is usually uninvolved and tumour cells encase skin appendages without destroying them. DFSP is composed of cytologically un iform spin died tumour cells contai ning plump or elon gated wavy nuelei arranged in storiform, whorled, or cartwheel growth patter ns. Cytological atypia is min imal and mitotic activity is low. The collage nous stroma contains small blood vessels. The superficial portion of the neoplasm may be less cellular, causing considerable challenges in the d if fere ntial diag nosis on small biopsies. Rarely, cases of DFSP present as a subcutaneous mass with infiltration of deep soft tissues {1886,199}. Rare cases

may show prominent vessels, granular cell change, promine nuclear palisading, and Verocay body formation {3046,3260)

Pigmented DFSP (also known as Bednar tumour) Some cases of DFSP contain a variable number of pigmented dendritic melanocytic cells {874}.

Myxoid DFSP Rarely, DFSP may show prominent myxoid stroma with a mor nodular growth and numerous vessels with slightly fibrotic ves sei walls, often producing a more variable architecture, whic may mimic other myxoid mesenchymal neoplasms {1072,2595

DFSP with myoid differentiation In addition to a myointimal, non-neoplastic proliferation『 en trapped vessels, bundles and n ests of spin died myofibroblastic tumour cells are rarely observed {461}, more often in the fibrosarcomatous subtype {2077}.

Plaque-like DFSP In rare cases, DFSP may show a flat, plaque-like growth resell bling benign plaque-like CD34-positive dermal fibroma (1723)

Fig. 1.106 Dermatofibrosarcoma protuberans. A The classic G-banded karyotype shows two supernumerary chromosomes (arrows). B Multiplexed spectral in situ hybridl

tion of a chromosomal spread shows supernumerary chromosomes pseudocoloured to demonstrate material from both 22 and 17, in pink and blue, respectively (asterisks).

102

Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 pibrosarcomatous DFSP Fibrosarcomatous DFSP represents morphological progress!on to a usually fascicular pattern, with acquisition of metastatic notential. Fibrosarcomatous changes occur de novo or less ,ommonly in local recurrences and either abrupt or more-grad-

ual transformation can be encountered. The fibrosarcomatous component often shows a nodular, rather well-circumscribed growth and is composed of cellular spindle cell fascicles with a herringbone appearanee. The neoplastic cells in fibrosarcomatous areas are characterized by increased atypia and proliferative activity {2077,1178,2}. Very rarely, transformation to pleomorphic sarcomatous areas has been reported {2077,3009}.

Immunohistochemistry By immunohistochemistry, tumour cells stain positively for CD34 and may show expression of EMA {3386,3276}. Importantly, fibrosarcomatous DFSP can show loss of CD34 expression in about half of the cases {2077}. Tumour cells in myoid nodules and bun dies stain strongly for SMA.

Cytology Not clinically relevant

Diagnostic molecular pathology For histologically challenging cases and for tumours composed entirely of fibrosarcomatous DFSP without a conventional com­ ponent, detection of COL1A1-PDGFB can be used to confirm the diagnosis {1586,1489}. However, the COL1A1-PDGFBfusion

may be cryptic in about 2% of cases, and another 2% of cases harbour alter native fusi ons involving PDGFD {705,823}.

Essential and desirable diagnostic criteria Essential: a storiform architecture and uniform spindle cell mor­ phology; diffusely infiltrative growth with a honeycomb pattern in the subcutis; expression of CD34; fibrosarcomatous DFSP: fascicular architecture with increased mitotic activity. Desirable: COL1A1-PDGFB gene fusion or rarely alter native PDGFD rearrangements (in selected cases).

Staging The American Joint Committee on Cancer (AJCC) or Union for International Cancer Control (UICC) TNM system can be applied for fibrosarcomatous DFSP.

Prog nosis and prediction DFSP is characterized by locally aggressive growth and frequent, often repeated local recurrences unless widely excised. The rate of local recurrences varies from 20% to 50% in the setti ng of in adequate margins {1178,2072,1299}. In con trast, ordinary DFSP almost never metastasizes. Higher-grade fibrosarcomatous progression is seen in 5% of cases. Fibro­ sarcomatous DFSP exhibits more-aggressive behaviour than ordinary DFSP, and 10-15% of patients develop distant metas­ tases, most often to the lungs {390,1884,3208,1386,1848}. Histological grading has not been shown to be prognostic in fibrosarcomatous DFSP.

Soft tissue tumours

103

paybal：https://www.paypal.me/andy19801210 Solitary fibrous tumour

Demicco EG Fritchie KJ Han A

Definition Solitary fibrous tumour (SFT) is a fibroblastic tumour character­ ized by a prominent, branching, thin-walled, dilated (staghorn) vasculature and NAB2-STAT6 gene rearrangement.

ICD-0 coding 8815/0 Solitary fibrous tumour, benign 8815/1 Solitary fibrous tumour NOS 8815/3 Solitary fibrous tumour, malignant

ICD-11 coding 2F7C & XH7E62 Neoplasms of uncertain behaviour of connective or other soft tissue & Solitary fibrous tumour NOS 2B5Y & XH1HP3 Other specified malignant mesenchymal neoplasms & Solitary fibrous tumour, malignant

Related terminology Not recommended: haema ngiopericytoma; giant cell an giofi­ broma; benign solitary fibrous tumour.

Subtype(s) Fat-forming (lipomatous) solitary fibrous tumour; giant cell-rich solitary fibrous tumour

Localization SFTs may occur at any anato mical site, in eluding superficial and deep soft tissues and within visceral organs and bone, and they are more common at extrapleural locations. About 30-40% of extrapleural SFTs arise in the extremities; 30-40% arise in deep soft tissues, the abdominal cavity, the pelvis, or the retroperitoneum; 10-15% arise in the head and neck; and 10-15% arise in the trunk {1140,2456,2720,788,790, 1074,2784}. Deep tumours are more common than superfi­ cial tumours, accounting for 70-90% of cases {1140,2456}. In the head and neck, the sinonasal tract and orbit are the most common sites, followed by the oral cavity and salivary glands {2897}.

Fig. 1.107 Solitary fibrous tumour. A Axial contrast-enhanced CT shows a large, left-sided, peripherally enhancing retroperitoneal mass. Large feeding vessels (arroware seen anteriorly. B Axial contrast-enhanced CT shows a large central abdomin mass. Large feeding vessels (arrow) are seen anteriorly.

Clinical features Most tumours prese nt as slow-growi ng, pain less masses. Abdominopelvic tumours may present with distention, constipation, urinary retention, or early satiety, whereas head and neck SFTs may present with nasal obstruction, voice changes, or bleeding {2270,1600}. Large SFTs may cause para neoplastic syn dromes such as Doege-Potter syn drome, with the induction of severe hypoglycaemia or (more rarely) acromegaloid changes due to tumour production of IGF2 {760,559}. The radiographic features of SFT are largely non specific. CT dem on strates a well-defined, occasi on ally lobulated mass that is isodense to skeletal muscle, with heterogeneous contrast enhancement due to the extensive tumour vasculature {3363,1611}. MRI shows intermediate

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Soft tissue tumours

Fig. 1.108 Solitary fibrous tumour. Grossly, the tumour is well circumscribed, with

tan, fleshy, multilobular cut surface.

paybal：https://www.paypal.me/andy19801210

Fig. 1.109 Solitary fibrous tumour. A Tumours often have variable cellularity and a prominent ectatic, branching vasculature. B Hypocellular tumours often have a dense hyalinized collagenous stroma. Note the patternless architecture. C Cellular tumours may have little intervening stromal collagen, and the vascular network may be obscured by tumour cells. D Tumour cells may be spindled or ovoid, as in this example. E Tumour cells typically display scant to moderate amounts of indistinct, palely eosinophilic cytoplasm and bland nuclei with fine pale chromatin and inconspicuous nucleoli.

intensity on T1-weighted images and variable hypointensity to hyperintensity on T2-weighted images, corresponding to fibrous and cellular or myxoid areas, respectively [304,1611, 986}. Larger or aggressive cases may display in creased heterogeneity due to fibrosis, haemorrhage, necrosis, myxoid and cystic degeneration, or calcifications {1611}.

Epidemiology SFTs affect men and wome n equally and are most comm on in adults, with a peak incidenee between 40 and 70 years {2720, 1140,788,790,1074,2784}.

Etiology Unknown

Fig. 1.110 Giant cell-rich solitary fibrous tumour. This lesion shows scattered multi­

nucleated giant cells lining cystic spaces.

Fig. 1.111 Dedifferentiated solitary fibrous tumour. This field shows an abrupt transi­ tion from typical solitary fibrous tumour (right) to an undifferentiated sarcoma (left; this example shows a pleomorphic myxoid sarcoma).

Soft tissue tumours

105

paybal：https://www.paypal.me/andy19801210

心 、、

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Fig. 1.112 Solitary fibrous tumour. A Some tumours may have a predominantly collagenous appearance with few cellular areas. B Myxoid change is comm on and may pre­ dominate in tumours that have received neoadjuvant radiation. C Stromal and perivascular hyalinization is common. D Fat-forming (lipomatous) solitary fibrous tumour show typical features of solitary fibrous tumour with areas of mature adipose tissue or scattered adipocytes.

Pathogenesis The genetic hallmark of SFT is a paracentric inversion invoIving chromosome 12q, resulting in the fusion of the nd STAT6 genes {577,2167,2640}. Some studies have shown a correlation between fusion types and histological features {52,227,1075}. The NAB2-STAT6 fusion is thought to convert wildtype NAB2 from a transcriptional repressor of EGR1-mediated signalling into a transcriptional activator via replacement of the C-terminal

repression domain by the transcriptional activation domain c STAT6, thereby resulting in a feedforward loop of constitutivi EGR1-mediated transactivation of proliferation and survival associated growth factors, including IGF2 and FGFR1 {2640 Overexpression of ALDH1A1 (ALDH1), EGFR, JAK2, histom deacetylases, and retinoic acid receptor may also contributi to tumorigenesis {1274,299}. Other alterations associated will aggressive behaviour and dedifferentiation in elude TERT pro moter mutations {791,205,1868,52} and deletions or mutation: of TP55 {1716,707,52,2972}.

Macroscopic appearance SFTs are well-circumscribed masses that typically measui 5-10 cm, although some lesions may exceed 25 cm in greate dimension. The cut surface is nodular and tan to reddish-browi and it occasi on ally shows haemorrhage, myxoid cha nge, t cystic degeneration {1091,1312}.

Histopathology

Fig. 1.113 Solitary fibrous tumour. Immunohistochemical expression of STAT6 is characteristic of the neoplastic cells of solitary fibrous tumour. Only strong and diffuse nuclear staining should be considered positive.

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Soft tissue tumours

SFTs are composed of haphazardly arran ged spin died to ovoi cells with indistinet, pale eosinophilic cytoplasm within a variab collage nous stroma, admixed with branching and hyalinize staghorn-shaped (haemangiopericytomatous) blood vessel! There is a wide histological spectrum, ranging from paucicellul? lesions with abundant stromal keloidal-type collagen to high cellular tumours consisting of closely spaced cells with little intervening stroma. Myxoid change may be present {796}. Sr most often have low mitotic counts, without substantial nucle pleomorphism or necrosis. Tumours demonstrating a high mito

paybal：https://www.paypal.me/andy19801210 OJ

Chr12(q13.3)

[

Fig.1.114 Schematic NAB2-STAT6 gene fusion in solitary fibrous tumour. The NAB2 and STAT6genes are adjacent genes on chromosome 12q13 that are transcribed in opposite directions. This intrachromosomal fusion results from a genomic inversion at the 12q13 locus, fusing NAB2 and STAT6 in a common direction of transcription. The fusion transcript

illustrated includes NAB2 exon 6 fused to STAT6 exon 16.

count with or without in creased cellularity, atypia, n ecrosis, and infiltrative growth have traditionally been termed malignant, but new risk stratification models more accurately predict prognosis. Fat-forming (lipomatous) SFT harbours a component of mature adipose tissue {1047,1247,2281,563}. Giant cell-rich SFT, formerly known as giant cell an giofibroma, shows features of conventional SFT with an admixed populati on of multi nucle­ ated giant cells within the stroma and lining pseudovascular spaces {777,1248}. Dedifferentiated (anaplastic) SFTs show transition to high-grade sarcoma with or without heterologous elements such as rhabdomyosarcoma or osteosarcoma {1939, 2008,2972,52,3071,2205,644,3048}. By immunohistochemis­ try, SFT typically shows strong and diffuse expression of CD34 and nuclear STAT6 {2793,854,787}, but expression may be lost in dedifferentiated SFT {644,2205,707,2771}.

Cytology Cytological exami nation r eveals oval, elon gated, or roun ded cells with wispy cytoplasm and eosi nophilic collage nous stroma {3044}.

Diagnostic molecular pathology NAB2-STAT6 gene fusions are pathognomonic for SFT. How­ ever, because NAB2and STAT6 are in close proximity on chro­ mosome 12q, detection of their fusion is difficult by conventional cytogenetic methods, and the diversity of breakpoints occurring in both exons and introns makes PCR-based detection of fusion variants difficult without multiplexed sequencing assays. STAT6 immunohistochemistry is a sensitive and specific surrogate for all fusions {854,1668,2793}.

Table 1.02 Three-variable and modified four-variable risk models for the prediction of metastatic risk in solitary fibrous tumours {788,790}

Points assigned

Risk fac

Patient age in years

Mitoses/ im2 (mitoses per 10 HPFs)

Tumour size in cm

Tumour necrosis

Risk

Cut-off 3-variable model

4-variable model

55

0 1

0 1

0(0) 0.5-1.5 (1-3) n 2 (n 4)

0 1 2

0 1 2

(M.9 5-9.9 10-14.9 >15

0 1 2 3

0 1 2

10%

n/a n/a

0 1

Low Intermediate

0-2 points 3-4 points 5-6 points

45 points 6-7 points

High

3

0-3 points

HPF, high-power field; n/a, not applicable.

Soft tissue tumours

107

paybal：https://www.paypal.me/andy19801210 Essential and desirable diagnostic criteria Essential: spin died to ovoid cells arran ged arou nd a branching and hyalinized vasculature; variable stromal collagen deposition; CD34 and/or STAT6 expression by immunohistochermistry. Desirable (in selected cases): dem on strati on of NAB2-STAT6 gene fusi on.

Staging Risk stratification models are preferred over anatomical staging.

Prognosis and prediction Recurrence (distant or local) occurs in 10-30% of SFTs {788, 1140,2720,2456,1074}, with 10-40% of recurrences reported after 5 years {2041,3144} and rare recurrences seen after 15 years {1140}. TERT promoter mutations are more common in tumours with aggressive features, but they may also be seen in low-risk SFT {791,205,52}. Various single clinical or histologi­ cal features have been reported to correlate with metastatic or local recurrence potential in large series, including high mitotic count (> 2 mitoses/mm2, equating to > 4 mitoses per 10 highpower fields of 0.5 mm in diameter and 0.2 mm2 in area) {788, 3161,2456,2720}, tumour size {31-61,788,1140}, necrosis {788,

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Soft tissue tumours

2456}, patient age {788,2720}, tumour cellularity and nuclear pleomorphism {2456}, and tumour site {1140,2720}. However, I in dividual studies con tradict one another regardi ng which spe-l cific features are important. The development of multivariate risk models has resulted in improved prog no stication over the traditi onal benign/malig nant distinction. Of these models, the one most similar to the traditional definition of malignant SFT stratifies tumours into four risk tiers based on mitotic count, pleomorphism, and tumour cel­ lularity {2456}. A set of risk calculators proposed by the French Sarcoma Group (FSG) incorporates clinical data (patient age, tumour site), pathological features (mitotic count), and history of radiotherapy to variously predict overall survival, local recurrence, and distant metastatic risk {2720}. The most widely used model for metastatic risk (see Table 1.02, p. 107) in corporates mitotic count (> 2 mitoses/mm2), patient age (> 55 years), and tumour size stratified by 5 cm tiers to classify tumours into low, intermediate, and high risk groups {788}. This model has been validated for both thoracic and extrathoracic SFTs {788,790, 1074,2596}; a subseque nt refinement in eludes n ecrosis as a fourth variable, resulting in higher numbers of cases being clas­ sified as low-risk {790,2596}.

paybal：https://www.paypal.me/andy19801210 uclear ^/vever, J sp® Ited in ignant tradiur risk ir cel:rench t age, listory recur'used □rates ),and o low, been 3,790, as a I clas-

Inflammatory myofibroblastic tumour

Yamamoto H

Definition Inflammatory myofibroblastic tumour (IMT) is a distinctive, rarely metastasizing neoplasm composed of myofibroblastic and fibroblastic spindle cells accompanied by an inflammatory in filtrate of plasma cells, lymphocytes, and/or eosi nophils.

ICD-0 coding 8825/1 Inflammatory myofibroblastic tumour

ICD-11 coding 2B53.Y & XH66Z0 Other specified fibroblastic or myofibroblas­ tic tumour, primary site & Myofibroblastic tumour NOS

Related terminology Not recommended: plasma cell granuloma; inflammatory pseu­ dotumour; inflammatory myofibrohistiocytic proliferation; omental-mesenteric myxoid hamartoma; inflammatory fibro­ sarcoma.

Fig. 1.115 Inflammatory myofibroblastic tumour. The tumour presented as a circum­ scribed, solid mass in the lung.

Subtype(s) Epithelioid inflammatory myofibroblastic sarcoma

ig，1.116 Inflammatory myofibroblastic tumour. A The myxoid pattern displays spindled myofibroblasts dispersed in a myxoid background with lymphocytes and plasma cells. B The hypercellular pattern shows a fascicular spindle cell proliferation intermingled with inflammatory cells. C The hypocellular fibrous pattern is characterized by hyalinized collagenous stroma with sparse spindle cells and lymphoplasmacytic inflammation. Focal calcification is noted. D The spindled myofibroblasts show vesicular nuclei, small nucleoli, and eosinophilic cytoplasm.

Soft tissue tumours

109

paybal：https://www.paypal.me/andy19801210 Localization IMT shows a wide anatomical distribution, most frequently arising in the abdominal soft tissues, including the mesentery, omentum, retroperitoneum, and pelvis, followed by the lung, mediastinum, head and neck, gastrointestinal tract, and genitourinary tract (ineluding the bladder and uterus) {631,1167,1588, 3116}. Unusual locations include somatic soft tissues, pancreas, liver, and CNS {631,1167,2570}.

Clinical features The site of origin determines symptoms {631,1167,1588}. Abdominal tumours may cause gastrointestinal obstruction or bleeding. Pulmonary IMT is sometimes associated with chest pain and dyspnoea {2505}. As many as one third of patients have a clinical syndrome, possibly cytokine-mediated, of fever, malaise, weight loss, and laboratory abnormalities including microcytic hypochromic anaemia, thrombocytosis, polyclonal hypergammaglobuli naemia, elevated ESR, and elevated C-reactive protein {597,631,3042}. Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is predominantly intra-abdominal and associated with a more aggressive course. Radiological imaging studies reveal a lobulated heterogeneous solid mass with or without calcification {1588}.

Fig. 1.118 Inflammatory myofibroblastic tumour. Ganglion-like polygonal cells shot

large rounded nuclei and prominent nucleoli.

IMT primarily affects childre n and you ng adults, although the age range extends throughout adulthood {626,631,1167}. There is a slight female predominance.

and overexpression of the ALK C-terminal kinase region, whic is r estricted to the n eoplastic myofibroblastic comp orient (413 630,656,1220,1778}. ROS1 and NTRK3 gene rearrangements are each found r 5-10% of IMTs; TFG-ROS1, YWHAE-ROS1, and ETV6-NTRK、 gene fusions have been reported [1895,1415,62,139,3339) Very rare cases have RET or PDGFRB gene rearrangemenb {139,1895}. In contrast, such rearrangements are uncommor in IMTs diagnosed in adults aged > 40 years {534,1778,3338 1895,139}.

Etiology

Macroscopic appearance

Un know n

IMT is a nodular, circumscribed, or multinodular mass with t tan, whorled, fleshy, or myxoid cut surface and variable haem­ orrhage, necrosis, and calcification {626,631,1167}. The diarr eter of the lesion ranges from 1 to 20 cm or more, with a mediar size of 5-6 cm.

Epidemiology

Pathogenesis IMTs are genetically heterogeneous. In 50-60% of cases of IMT in children and you ng adults, the tumours harbour clonal cytogenetic rearrangements, involving chromosome band 2p23, that fuse the 3' kinase region of the ALK gene with vari­ ous partner genes, including TPM3, TPM4, CLTC, CARS, ATIC, SEC31L1, PPFIBP1, DCTN1, EML4, PRKAR1A, LMNA, TFG, FN1, HNRNPA1, and others in a growing list {413,560,769,1220, 1778,3029,3338,1468,1895}. EIMS is often associated with RANBP2-ALK or RRBP1-ALK gene rearrangements {560,1984, 1804}. IMT with ALKgenomic rearrangement features activation

Histopathology The spin died fibrob lastic-myofibr ob lastic cells and inflarr matory cells form three basic histological patter ns {626,631 1167}. The first is a myxoid patter n, which con si sts of loosel) arran ged plump or spin died myofibroblasts in an oedematou myxoid background with abundant blood vessels and an infil­ trate of plasma cells, lymphocytes, and eosinophils, mimickinc

Fig. 1.117 Epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK rearrangement. A Plump polygonal and epithelioid tumour cells with prominent nucleoli

characteristic. The neutrophilic infiltration seen here is often present. B Distinctive nuclear membranous immunoreactivity for ALK is seen.

110

Soft tissue tumours

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Fig. 1*119 Inflammatory myofibroblastic tumour with TPM3-ALK gene fusion. Dif­ fuse cytoplasmic staining for ALKis seen.

f 0尸

」

p23

«r

* IT

=

■

q23

t(2；17)(p23;q23)

“ (CLTC)

see n. One or more patter ns are ofte n see n within a single tumour. Myofibroblasts with vesicular nuelei, 1-3 small nueleoli, and eosinophilic cytoplasm are typical and sometimes show a ganglion-like appears nee. Necrosis is uncommon. Mitotic activ­ ity varies but is generally low. EIMS is an aggressive IMT subtype with plump epithelioid or histiocytoid tumour cells with vesicular chromatin, prominent nueleoli, and amphophilic or eosinophilic cytoplasm, often admixed with neutrophils in an abundant myxoid stroma {560,1984}. By immunohistochemistry,丨MT displays variable staining for SMA, MSA, calpo nin, and desmi n. Focal kerati n immuno reactiv­ ity can be see n in as many as 30% of cases. Imm uno reactiv­ ity for ALK is detectable in 50-60% of cases and correlates well with the presence of ALK gene rearrangement {526,534, 630,656,1167}. Of note, the ALK immunostaining pattern varies depending on the ALK fusion partner; for example, RANBP2ALK\s associated with a nu clea r membra nous patter n, RRBP1ALK with a peri nuclear acce ntuated cytoplasmic patter n, and CLTC-ALK with a granular cytoplasmic pattern; many other ALK fusion variants show a diffuse cytoplasmic pattern (most commonly seen in IMT) {413,1984,1804}. Highly sensitive ALK antibody clones (5A4, D5F3) may improve detection of the ALK protein in IMT {3029,3339}. ROS7-rearranged IMT typically shows cytoplasmic expression of ROS1 (3339,1415).

Cytology The cytology of IMT consists of bland spindle cells with oval nuelei and small distinet nucleoli in a background of lympho­ cytes and plasma cells. Atypical ganglion-like polygonal cells can be seen {2956}.

17

P23|

Diagnostic molecular pathology ■

ql3

t(2;2)(p23;ql3)

0(RANBP2)

B 2

2

Fig. 1.120 Inflammatory myofibroblastic tumour karyotypes. A Left to right: the 2;17 translocation resulting in CLTC-ALK fusion (schematic and partial G-banded karyo­ type) with corresponding /4/.K breakpoint-spanning probe FISH demonstrating a sig­ nal split; the white arrow indicates der⑵ and the yellow arrow der(17). ALK granular cytoplasmic immunostaining is seen with CLTC partnership; CLTC encodes a protein

component of the cytoplasmic face of intracellular organelles (coated vesicles and coated pits). B Left to right: schematic, partial G-banded karyotype and differentially labelled, dual-spanning RANBP2 and ALK FISH illustrating the RANBP2-ALK fusion;

both chrome： ome 2 homologues involved in the translocation in this fusion example and juxtaposed orange/green signals indicate fusion (white arrows). Nuclear membrane ALK immunostaining is featured when the ALK fusion partner is FIANBP2, be-

In addition to immunohistochemical detection of ALK protein, molecular assays for ALK may be used to con firm the diag nosis but are gen erally not required {630}. Exceptio nal situations such as inversion of ALK on the same chromosome arm may lead to a false-negative FISH result {1273}. In ALK-negative cases, immunohistochemistry for ROS1 and/or molecular tests for nonALK gene fusions (e.g. NTRK3) may be useful {3339,1895,62, 139}.

Essential and desirable diagnostic criteria Essential: loose or compact fascicles of spindle cells with a prominent in flammatory in filtrate and a variable fibrous or myxoid stroma; expression of ALK (seen in as many as 60% of cases). Desirable: ALKor other gene rearrangements (in selected cases).

Staging Not clin ically re leva nt

cause RANBP2 encodes a large nucleopore protein localized at the cytoplasmic side of the nuclear pore complex.

Prognosis and prediction

granulation tissue or a reactive process. The second is a hypercellular pattern, which is characterized by a compact fascicular spindle cell proliferation with variable myxoid and collagenous stroma and inflammatory infiltrate. The third is a hypocellular fibrous patter n, which features hyali nized collage nous stroma with lower cellularity of spindle cells and a relatively sparse lnflammatory infiltrate, mimicking desmoid fibromatosis. Dystrophic calcifications and osseous metaplasia are occasionally

Approximately 25% of extrapulmonary IMTs recur, in part depending on anatomical site and resectability {57,631,1167}. ALK-negative IMTs may have a higher likelihood of metastasis, but ALK immu no reactivity does not appear to correlate with recurrence {626,597,630}. Distant metastases are rare (< 5%) and involve the lungs, brain, liver, and bone. However, reliable prog no stic in dicators have not bee n developed for conventional IMT {626,1445}. Intra-abdominal EIMS behaves much more aggressively {560,1984}. Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Low-grade myofibroblastic sarcoma

Mentzel TDW

Definition

Epidemiology

Low-grade myofibroblastic sarcoma is a rarely metastasizing mesenchymal neoplasm, often having fibromatosis-like fea­ tures, which tends to arise in the head and neck region.

Low-grade myofibroblastic sarcoma occurs predominan$ in adults, with a slight male predominanee; children are more rarely affected {2083,2177,2892}.

ICD-0 coding

Etiology

8825/3 Myofibroblastic sarcoma

Unknown

ICD-11 coding

Pathogenesis

2B53.Y & XH2668 Other specified fibroblastic or myofibroblas­ tic tumour, primary site & Low-grade myofibroblastic sarcoma

Un know n

Related terminology

Grossly, the tumour is usually a firm mass with pale, fibrous cc surfaces and ill-defined margins {2083}; a minority are well cir cumscribed with pushing margins {2177}.

Macroscopic appearance Acceptable: myofibrosarcoma.

Subtype(s) Histopathology

None

Localization Low-grade myofibroblastic sarcoma shows a wide an atomi­ cal distribution; extremities and the head and neck region, especially the tongue and oral cavity, are preferred locations, whereas the skin and gastrointestinal tract are rarely affected {2083,2177,29,535}. These neoplasms arise predominantly in subcutaneous and deeper soft tissues; dermal presentation is very uncommon {539}. Rare cases involving salivary gland and n asal cavity / paranasal sin uses have bee n reported {331,1680}.

Clinical features Most patie nts report a pain less swelli ng or an en larging mass. Pain or related symptoms have more rarely been reported. Radiologically, these lesions have a destructive growth pattern.

112

Soft tissue tumours

Histologically, low-grade myofibroblastic sarcomas are charac terized by a diffusely infiltrative growth pattern, and (in deepl located neoplasms) tumour cells often grow between individua skeletal muscle fibres. Most cases are composed of spindleshaped tumour cells arranged in cellular fascicles or shows storiform growth pattern. Neoplastic cells have ill-defined palel： eosinophilic cytoplasm and fusiform nuelei that are either elon­ gated and wavy with evenly distributed chromatin or plumper more rounded, and vesicular with small nucleoli. Rarely, hypoed lular neoplasms with a more prominent collagenous (some times hyalinized) stroma have been described. Importantly neoplastic cells show, at least focally, moderate nuelear atypia with enlarged, hyperchromatic, and irregular nuelei and slightl. increased proliferative activity. These neoplasms may contair numerous thin-walled capillaries. The tumours may progress!'： morphologically higher-grade myofibroblastic sarcomas [2177!

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Fig・ *1.122 Low-grade myofibroblastic sarcoma. A Some tumours contain more-abundant, palely eosinophilic cytoplasm. Note enlarged, hyperchromatic nuclei and scattered mitotic figures. E Tumour cells are often positive for desmin.

■OUS Cf well cii

By immunohistochemistry, neoplastic cells in low-grade myofi­ broblastic sarcoma show variable positivity for SMA and/or desmin. A subset show nuclear 卩-catenin staining {480}.

Not clin ically re leva nt

Prognosis and prediction

Cytology Not clinically relevant charac-

Diagnostic molecular pathology

deepl dividue -pindi­

Not clin ically re leva nt

sh ow t

Essential: diffusely infiltrative growth, often between skeletal muscle fibres; cellular fascicles of spindle cells with pale eosi nophih： cytoplasm; at least focal ly mode rate n uclear atypia; variable expression of SMA and/or desmin.

d palel er elon ilumpei

Staging

Low-grade myofibroblastic sarcoma often recurs locally, but metastases are rare, most often occurring after a proIonged time interval {2083}.

Essential and desirable diagnostic criteria

i/poc-

(some ortantlj

tr atypi: I slightl; contar gresstc

> {2177!

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Soft tissue tumours

113

paybal：https://www.paypal.me/andy19801210 Superficial CD34-positive fibroblastic tumour

Rekhi B Folpe AL Yu L

Definition

Subtype(s)

Superficial CD34-positive fibroblastic tumour is a distinctive low-grade neoplasm of the skin and subcutis, characterized by a fascicular to sheet-like proliferation of spindled cells with abundant, eosinophilic, granular to glassy cytoplasm, marked nuclear pleomorphism, a low mitotic count, diffuse CD34 expression, and frequent aberrant keratin immunore­ activity.

None

This tumour most frequently occurs in the lower extremitie; especially thigh, followed by arm, buttock, shoulder, and (rareh vulva {497,3212,1747,2601}. Tumour size varies from 1.5 to 10 cr but is usually < 5 cm {497,1747,2910}.

ICD-0 coding

Clinical features

8810/1 Superficial CD34-positive fibroblastic tumour

ICD-11 coding

This tumour typically presents as a slow-growing, painles mass of the superficial soft tissues. A long pre-biopsy duratio(> 5 years) is often noted {497}.

2B53.Y Other specified fibroblastic or myofibroblastic tumour, primary site

Epidemiology

Related terminology Acceptable: PRDM10-feawanged soft tissue tumour.

Localization

Fewer than 40 cases have been reported. Most have occurre in middle-aged adults (median age: 37 years), with a slight maipredominance {497,1747}.

D〜 Fig. 1.123 CD34-positive fibroblastic tumour. A The tumour presents as a circumscribed subcutaneous mass. B The tumour displays a fascicular to sheet-like prolife叫 pleomorphic spindle cells with abundant, granular to glassy eosinophilic cytoplasm. C Superficial CD34-positive fibroblastic tumour. The tumour shows vague nuclear palisa1

nuclear pleomorphism, and a mixed inflammatory infiltrate, including eosinophils. D Superficial CD34-positive fibroblastic tumour. The cells show marked nuclear enlarge and pleomorphism, with frequent intranuclear pseudoinclusions; mitotic activity is extremely low.

114

Soft tissue tumours

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Fig. 1.124 Superficial CD34-positive fibroblastic tumour. A Diffuse CD34 expression is invariably present. B Patchy keratin expression, most often with the AE1/AE3 clones,

is typically present.

Etiology Unknown

CD34-positive fibroblastic tumours invariably express CD34 and are focally immu no reactive for kerati ns in close to 70% of cases (most often with the AE1/AE3 ciones).

Pathogenesis PFIDM10 rearrangements have been reported in 3 cases previ­ ously classified as superficial CD34-positive fibroblastic tumour |2553}.

Cytology

Macroscopic appearance

Diagnostic molecular pathology

The tumours are circumscribed, firm, yellow to tan soft tissue masses with a variably gelatinous appears nee {497,1747,2910}.

Not clinically relevant

Cytology shows cellular smears composed of large, pleomor­ phic cells with granular to glassy cytoplasm {1844}.

Essential and desirable diagnostic criteria

Histopathology The lesions grow in a relatively circumscribed, but at least partially infiltrative, fashion and are composed of highly cellular fascicles and sheets of spin died to epithelioid cells with abunda nt eosi nophilic cytoplasm, often having a granular or glassy appearanee. Lipidized turn our cells are commonly prese nt. The n eoplastic cells show moderate to marked nuclear pleomorphism, often with bizarre, hyperchromatic nuelei containing prominent nucleoli and intranuelear cytoplasmic pseudoinclusions. Despite these alarming nuclear features, mitotic activity is very low and necrosis is rarely seen {497,1747,3212,2601}. A mixed inflam­ matory cell infiltrate is often present. There is morphological overlap with tumours reported as PRDM10-feawanged soft tis­ sue tumours {2553,1390}. By immunohistochemistry, superficial

Essential: superficial location; large eosinophilic cells with gran­ ular to glassy cytoplasm; marked nuclear pleomorphism but a very low mitotic count; diffuse CD34 expression and frequent keratin immunoreactivity.

Staging Not clin ically re leva nt

Prognosis and prediction The prognosis for patients with this tumour is excellent, with only a single reported case with lymph node metastasis and no local recurrences in 30 cases with follow-up. All patients with this dis­ ease have been reported to be alive and disease-free at the time of last follow-up {497,1747}.

Soft tissue tumours

115

paybal：https://www.paypal.me/andy19801210 Myxoinflammatory fibroblastic sarcoma

Montgomery EA Antonescu CR Folpe AL

Definition Myxoinflammatory fibroblastic sarcoma (MIFS) is an infiltrative, locally aggressive fibroblastic neoplasm that typically arises in the distal extremities. It is characterized by pleomorphic fibro­ blastic cells with macronucleoli in a myxohyaline background with a variably prominent inflammatory cell infiltrate.

ICD-0 coding 8811/1 Myxoinflammatory fibroblastic sarcoma

ICD-11 coding 2B5F.2 & XH2D15 Sarcoma, not elsewhere classified of other specified sites & Myxoinflammatory fibroblastic sarcoma

Related terminology Not recommended: in flammatory myxohyali ne turn our of the distal extremities with virocyte-like or Reed-Sternberg-like cells; acral myxoinflammatory fibroblastic sarcoma; inflam­ matory myxoid tumour of the soft parts with bizarre giant cells.

Subtype(s)

Fig. 1.126 Myxoinflammatory fibroblastic sarcoma. These tumours most common arise in the subcutaneous tissue of the distal extremities. In this image, the lesion seen in the adipose tissue at the bottom of the image. Note the lymphoid aggrega

in the deep dermis.

None

Clinical features Local izati on MIFS usually affects the acral dorsal extremities, particularly the hands {2179,2063}, but occasional proximal examples have been highlighted {1557} and accounted for about 5% of cases in the largest series to date {1755}. The hand, fin ger, and wrist account for about 60% of cases, and the foot and ankle for about 20% {1755}.

These n eoplasms prese nt as solitary pain less masses, typ cally of the distal extremities. Most examples measure aboi 3 cm, but the size range is wide. On imaging, they are centra in the subcutis (about two thirds) or deeper and typically displs infiltration into adjoining tissues such that they mimic infectior tenosynovial giant cell tumour, or ganglion cysts {1712,2249 3053}.

Fig. 1.125 Myxoinflammatory fibroblastic sarcoma. A Note the myxoid background, scattered inflammation, and spindle cells in this BFMF-mutated case. B This ex] shows haemosiderin and scattered large cells with macronucleoli.

116

Soft tissue tumours

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Fig. 1-127 Myxoinflammatory fibroblastic sarcoma. A In some examples, the atypical cells are more numerous. Note the macronucleoli. This case showed a BR/lFfusion. B The cell'in the centre is reminiscent of a Hodgkin cell. The presence of the eosinophil beneath it and scattered lymphocytes adds to the mimicry. C Note the binucleated cell in the

centre of the field, with macronucleoli.

Epidemiology These are rare neoplasms. The reported age range is 4-91 years (median: ~40 years), with no sex predilection {1755,1691,2063, 2179,2107).

Etiology Unknown

Pathogenesis Tumours showing histological overlap with MIFS and haemosiderotic fibrolipomatous tumour (HFLT) have been reported (353,3407,495,1877,144}, suggesting a link between these two tumour types, but this link remains incompletely understood and con troversial. MIFSs have also bee n r eported to coexist with pleomorphic hyalinizing angiectatic tumour {353,495,1279}, but the precise classificati on of these unusual turn ours r emai ns the subject of debate. A complex karyotype including a reciprocal t(1;10)(p22;q24) was initially reported in MIFS {1740}, followed by a report of a reciprocal t(1;10) in a case of HFLT {3279} and a hybrid

MIFS/HFLT with der(10)t(1;10) {892}. The breakpoints in chro­ mosomes 1 and 10 cluster in TGFBR3 and in or near OGA (MGEA5), respectively, but do not result in an expressed fusion gene {1279}. The t(1;10) has been detected in most HFLT cases and appears much more comm on in hybrid HFLT-MIFS tumours than in classic MIFS {2179,144}. Although these findings resulted in the proposal of an initial pathogenetic link between MIFS and HFLT, suggesting that they represent a morphological continuum or pathological spectrum {144}, later studies have questioned this hypothesis, postulating that these two entities are unrelated and that hybrid HFLT-MIFS tumours more likely represent sarcomatous progression in HFLT, rather than true MIFS {2179,3407}. Additionally, one third of MIFSs demonstrate B/?Z\ F-re I ate d fusi ons, which were not detected in any of the HFLTs tested {1577}. Another comm on gen etic eve nt in both MIFS and HFLT is the presenee of a 3p11.1-p12.1 amplicon, including the VGLL3 gene {1279,144,1577}.

Macroscopic appearance Tumours are lobulated and variably gelati nous, fleshy, or firm, typically attaining a size of roughly 3 cm.

Histopathology

快■1.128

Myxoinflammatory fibroblastic sarcoma. Multiple green signals depict the U3amplification at 3p12.1; the red signal is the reference probe on 3q12.1-q12.2.

These tumours are infiltrative and multi no dular, being cen tred in the subcutaneous tissue in most cases. They are characterized histologically by dense inflammation merging with stroma varying from myxoid to hyalinized and containing sheets and small foci of epithelioid and spin died cells. Some lesions contain foamy histiocytes, giant cells, and haemosiderin. The cellularity is quite variable between lesions. Amid the inflammatory background, scattered bizarre cells with large vesicular nuelei and macronucleoli reminiscent of Reed-Sternberg cells or virocytes are present. Many cells show degenerated smudged chromatin. Pseu­ dolipoblasts akin to those encountered in myxofibrosarcoma with cytoplasmic mucopolysaccharide matrix compressing nuelei may be seen. The spindle cells erften coalesce at the periphery of myxoid lobules to form a reticular pattern as they merge with myxoid tissue. The inflammatory infiltrate is mixed, consisting of lymphocytes, plasma cells, histiocytes, and eosinophils in vary­ ing proportions. Emperipolesis may be present. Despite the cyto­ logical atypia, mitotic activity is minimal. Immunohistochemistry is unhelpful {1755,1691,2063,2179}.

Soft tissue tumours

117

paybal：https://www.paypal.me/andy19801210 Cytology

Staging

Cytological preparations show large epithelioid cells with macronucleoli and lipoblast-like features enmeshed in myxoid stroma with prominent inflammation and spindle cells {3086}.

Not clinically relevant

Diagnostic molecular pathology Not clin ically re leva nt

Essential and desirable diagnostic criteria Essential: typical distal extremity location; atypical fibroblas­ tic cells with macronucleoli; variably myxoid and hyalinized matrix with a mixed inflammatory infiltrate. Desirable: pseudolipoblasts.

■

“

Prognosis and prediction Local recurrences are common and often repeated. Metastases are rare, occurring in < 1% of cases after multiple recurrences' In itial complete excisi on is the best predictor of a favourable I outcome {1755}. D(

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by

IC 8E

IC 2E

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15 cm) {2915,743}. Grossly, they are typi­ cally poorly circumscribed, with in filtrative borders in to surrounding structures; some tumours may have a thin pseudocapsule.

Histopathology Histologically, IFS can display a broad morphological spec­ trum. Most comm only, it is a cellula r neoplasm composed of mono morphic spindled to ovoid cells with sea nt cytoplasm and

Clinical features IFS typically manifests as a localized, rapidly enlarging, pain less mass or swelling, or as an exophytic nodule {603}. One third of cases are found at birth {603} and 14% are detected at prenatal ultrasound {2386}. IFS may ulcerate the skin surface and resemble vascular tumours {3345}. Intratumoural haemorrhage in utero or in neonates may lead to anaemia or haemorrhagic shock {869,2760}. Imaging shows a heterogeneously enhancing mass with nonspecific characteristics that sometimes contains haemorrhage {49}.

Epidemiology More than 75% of cases occur in the first year of life, 15% in the second year, and < 10% in older children {603,2386}. Some of the tumours with alternative kinase fusions have been reported in older children {1573,743}. IFS has a slight male predominance 1603,2386}.

Etiology Unknow n

Pathogenesis IFS is driven by oncogenic activation of kinase signalling, mostly

as a result of in-frame fusions upstream of the kinase domains

Fig. 1.129 Infantile fibrosarcoma. Clinical photograph. Large soft tissue forearm mass.

Soft tissue tumours

119

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Fig. 1.130 Infantile fibrosarcoma. A Low-magnification view of infantile fibrosarcoma with numerous dilated, irregularly branching blood vessels (with ETV6-NTRK3 f sion). B Long intersecting fascicles or herringbone pattern of growth (with TPR-NTRK1 fusion). C Poorly formed fascicular growth pattern (with LMNA-NTRK1 fusion). D Cellul ovoid to round cell pattern (with ETV6-NTRK3 fusion).

slightly angulated nuclei. The cells may be arranged in ran­ domly oriented compact sheets or in herringbone fascicles. The backgrou nd stroma can range from collage nous to myxoid. A prominent haemangiopericytoma-like vascular pattern is often prese nt. Tumours with decreased cellularity and promine nt col­ lage n resembling fibromatosis or myofibromatosis can also be

see n {624,743}. A rich mixed chronic in flammatory in filtrate ma be present. Infiltrative growth into and entrapping adipose tis sue, skeletal muscle, and other structures is comm on. Mitose range from in freque nt to n umerous, without prog no stic signil cance; no atypical mitoses are seen. Patchy necrosis may b prese nt. The immu no histochemical profile is non specific, wi' variable expression of SMA, CD34, S100, and desmin {62, 743}. IFSs with NTRK gene rearrangements are often posith by immunohistochemistry using a pan-TRK antibody {144 2688}.

Cytology Not clinically re leva nt

Diagnostic molecular pathology ETV6-NTRK3 or other gene fusions/rearrangements can be de【 onstrated by a variety of molecular approaches {377,158,743).

Essential and desirable diagnostic criteria Essential: the majority of patients are aged < 2 years; spind to primitive ovoid/round cell tumour; often arranged in a fa cicular/herringbone pattern; staghom vasculature and rrixf inflammati on. Desirable: ETV6-NTRK3 fusion or other rearrangements invol ing NTRK1, BRAF, and MET. Fig. 1.131 Infantile fibrosarcoma. Primitive stellate cells in a predominantly myxoid

Staging

stroma (with E7V6-N7BK3fusion).

Not clinically re leva nt

120

Soft tissue tumours

Edello

L

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Fig. 1.132 Infantile fibrosarcoma. A Immunohistochemistry with pan-TRK antibody. Nuclear expression in a tumour with ETV6-NTFIK3 fusion. B Immunohistochemistry with

pan-TRK antibody. Cytoplasmic expression in a tumour with TPM3-NTRK1 fusion.

Prognosis and prediction IFS is locally aggressive but with relatively infrequent metas­ tases and an overall favourable outcome. The overall 10-year survival rate for IFS with stan dard treatment regime ns (various combinations of surgery and/or standard chemotherapy) is about 90% {603,2915,2386}. Reported local recurrence rates are 25-40%, with recurre nee highly associated with in complete resection {2386,743}. However, for many tumours, complete

surgical resection would result in substantial morbidity and is therefore not the ideal management. The rate of metastasis is 8-15% {743,2386,2915}. Rare cases of spontaneous tumour regression have been observed {2707}. The advent of targeted tyrosi ne kin ase inhibitors may alter the prog nosis and clinical management of this disease in advaneed or intractable disease {1733,862}.

Soft tissue tumours

121

paybal：https://www.paypal.me/andy19801210 Adult fibrosarcoma

Yoshida A Folpe AL

Definition

Epidemiology

Adult fibrosarcoma is a rare sarcoma composed of relatively monomorphic fibroblastic tumour cells with variable collagen production and often herringbone architecture. It is a diagnosis of exclusion.

Once considered the most common soft tissue sarcoma『 adults {1495}, adult fibrosarcoma has become exceedingly rare due to cha nges in diag no stic criteria and adva nces in an ciliary testing {203}. Most cases previously classified as adult fibro­ sarcoma are currently best classified as another type of spin­ dle cell sarcoma or a specific fibrosarcoma subtype. Strictly defined, adult fibrosarcomas probably account for < 1% 0; adult soft tissue sarcomas. These tumours most often occur in] middle-aged and older adults (median age: 50 years), with a slight male predominance {203}.

ICD-0 coding 8810/3 Fibrosarcoma NOS

ICD-11 coding 2B5F.2 & XH4EP1 Sarcoma, not elsewhere classified of other specified sites & Fibrosarcoma NOS

Etiology

Related terminology None

Some arise in the field of previous irradiation and rarely in association with implanted foreign material {203}.

Subtype(s)

Pathogenesis

None

Adult fibrosarcoma has been reported to show multiple numeri­ cal and structural chromosomal abnormalities {718,3150,18621 although older data should be interpreted with caution. A recen： report of an STRN3-NTRK3 fusion in a strictly defined adul1 fibrosarcoma suggests a possible link to other NTRK-rearranged mesenchymal neoplasms {3344}.

Localization Adult fibrosarcoma most often invoIves the deep soft tissues of the extremities, trunk, and head and neck.

Clinical features Adult fibrosarcoma presents as a mass with or without pain.

Fig. 1.133 Adult fibrosarcoma. A Low-power view shows a long fascicular growth with a focal classic herringbone pattern. B This high-grade tumour shows fascicular gro1' and necrosis. C The tumour consists of monomorphic spindle cells with nuclear atypia. D Radiation-induced adult fibrosarcoma showing monomorphic nuclear features.

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Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 Macroscopic appearance

Cytology

/\dult fibrosarcoma is a circumscribed, firm, white or tan mass. Haemorrhage and necrosis can be seen in high-grade tumours.

Not clin ically re leva nt

Diagnostic molecular pathology Histopathology Adult fibrosarcoma is composed of relatively monomorphic spindle cells, showing no more than a moderate degree of pleomorphism. The tumour cells are characteristically arranged in long, sweeping fascicles that may be angled in a chevron-like or herringbone pattern, Storiform areas can be focally present. The cells have tapering hyperchromatic nu clei with variably promi nent n ucleoli and sea nt cytoplasm. Mitotic activity is almost always present but variable. The stroma has variable collagen, from a delicate intercellular network to paucicellular areas with diffuse or keloid-like sclerosis or hyalinization. Some adult fibrosarcomas may contain relatively bland zones mimicking fibromatosis. By immuno­ histochemistry, adult fibrosarcomas may occasi on ally show limited expression of SMA or calponin, representing focal myofibroblastic differentiation. CD34-positive tumours show­ ing fibrosarcoma morphology typically represent fibrosarcomatous dermatofibrosarcoma protuberans or high-risk solitary fibrous tumours.

Not clinically re leva nt

Essential and desirable diagnostic criteria Essential: relatively monomorphic spindle cells showing no more than moderate nuclear pleomorphism; fascicular, herringbone architecture with variable collagen production; an immunohistochemical and molecular genetic diagnosis of exclusion.

Staging Union for International Cancer Control (UICC) or American Joint Committee on Cancer (AJCC) staging would be appropriate.

Prognosis and prediction More than 80% of strictly defined adult fibrosarcomas are high­ grade {203}, with an overall survival rate of < 70% at 2 years and < 55% at 5 years. These sarcomas metastasize to lungs and bone, especially the axial skeleton, and rarely to lymph nodes. It is likely that behaviour is related to grade, tumour size, and depth, although data are limited {203}. The probability of local recurrenee relates to completeness of excision.

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paybal：https://www.paypal.me/andy19801210 Myxofibrosarcoma

Huang HY Mentzel TDW Shibata T

Definiti on Myxofibrosarcoma comprises a spectrum of malignant fibro­ blastic neoplasms with variably myxoid stroma, pleomorphism, and a distinctive curvilinear vascular pattern.

ICD-0 coding 8811/3 Myxofibrosarcoma

ICD-11 coding 2B53.0 Myxofibrosarcoma, primary site

Related terminology Not recommended: myxoid malignant fibrous histiocytoma.

Subtype(s) Epithelioid myxofibrosarcoma

Localization The majority of myxofibrosarcomas arise in the limbs, including the limb girdles (in the I owe r extremities more commonly than in the upper extremities), whereas they are seen only rarely on the trunk, in the head and neck area, and on the hands and feet. Notably, more than half of cases occur in dermal/subcutaneous tissues, with the remainder involving the underlying fascia and skeletal muscle {2080,1428}. Origin in the retroperitoneum and in the abdominal cavity is extremely un comm on, and most lesions with myxofibrosarcoma-like features in these locations represent dedifferentiated liposarcomas {1427,2873}.

Clinical features Most patie nts prese nt with a slowly enlarging and pain less mass.

Epidemiology Myxofibrosarcoma is one of the most comm on sarcomas of elderly patients, with a slight male predominance. Although the overall age range is wide, these neoplasms mainly affect patients in the sixth to eighth decades of life, whereas they only exceptionally rarely arise in patients aged < 30 years {2080,2731,1798).

Etiology Unknown

Pathogenesis Karyotypes are highly complex, with intratumoural heterogeneity and chromosome numbers in the triploid or tetrapioid range in most cases, including even grade 1 neoplasms {2080}. Progressi on in grade is accompa nied by an in crease in cytogenetic aberrations. Local recurrences may show more complex cytogenetic aberrations than the primary neoplasms, suggesting tumour progression {3293}. Rece nt in teg rated genomic studies in dicate a predomi nance of somatic copy-number alterations in myxofibrosarcoma, with

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Soft tissue tumours

Fig. 1.134 Myxofibrosarcoma. A Subcutaneous myxofibrosarcoma. Superficial!) located, high-grade myxofibrosarcoma with a multinodular growth pattern and a soli gelatinous, myxoid cut surface. B A low-grade myxofibrosarcoma showing multinodu­ lar and highly infiltrative growth with a prominent myxoid matrix (shown here) is charac­ terized by the following features: a hypocellular appearance with atypical fibroblastic

cells with hyperchromatic, pleomorphic nuclei and elongated, curvilinear blood ves

seis (shown in Fig. 1.135A) and pseudolipoblasts (shown in Fig. 1.135B).

comparatively lower mutation burdens than many other pleomorphicsarcomatypes {224,472,2357}. These includefrequent gains of chromosome 5p, where several oneogenes {TRIO, RICTOR SKP2, and AMACR) are variably coamplified and potentially associated with increased grade {1838,1837,1343,23661 Occurring almost mutually exclusively, genetic aberrations in p53 signalling and the cell-cycle G1/S checkpoint collectively play a central pathogenetic role in half of myxofibrosarcomas TP53 (46%; most frequently mutated), FIB1 (18%), and CDKN2A CDKN2B (16%) tumour suppressor gene mutations are more common than CDK6, CCND1, and /WD/W2amplifications {2357L Components of driver regulomic pathways also harbour recurrently altered targets, such as missense mutation and amplified tion of NTRK1 and loss-of-function mutations and homozygous deletion of NF1 in the RTK/RAS/MAPK pathway and ampliM tion of VGLL3 in the Hippo pathway {224,472,2357}, as well® amplifications of TRIO and RICTOR that activate the RAC/PAK

and AKT/mTOR pathways, respectively {1343,2366}.

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L sdello

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Fjg」.135 myxofibrosarcoma, low-grade. A low-grade myxofibrosarcoma showing multinodular and highly infiltrative growth with a prominent myxoid matrix (shown in Fig‘1.134B) is characterized by the following features: a hypocellular appearance with atypical fibroblastic cells with hyperchromatic, pleomorphic nuclei and elongated, curvi­ linear blood vessels (A) and pseudolipoblasts (B).

Macroscopic appearance Superficially located neoplasms typically consist of multiple, variably gelati nous or firmer nodules, whereas deep-seated neoplasms often form a single mass with an infiltrative margin. In high-grade lesions, areas of tumour necrosis are often founcL

Histopathology Myxofibrosarcoma shows a broad spectrum of cellularity, pleo­ morphism, and proliferative activity; however, all cases share distinet morphological features, particularly multinodular growth with in complete fibrous septa and myxoid stroma. Subcuta neous examples commonly have very infiltrative margins, often extending beyond what is detected clinically {2080,1428}. The low-grade end of the morphological spectrum is characterized by hypocellular neoplasms composed of only a few, non-cohesive, plump spin died or stellate tumour cells with ill-defined, slightly eosinophilic cytoplasm and atypical, enlarged, hyperchromatic nuelei. Mitotic figures are infrequent in low-grade lesions. A characteristic finding is the presenee of prominent elongated, curvilinear, thin-walled blood vessels with a perivas­ cular condensation of tumour cells and/or inflammatory cells (mainly lymphocytes and plasma cells). Frequently, so-called pseudolipoblasts containing cytoplasmic mucin are noted in the form of vacuolated neoplastic fibroblastic cells. In contrast, high-grade neoplasms are composed partly of solid sheets and cellular fascicles of spin died and pleomorphic tumour cells with numerous, often atypical mitoses, areas of haemorrhage, and necrosis. In many cases, bizarre, multinueleated giant cells with abundant eosinophilic cytoplasm (resembling myoid cells) and irregularly shaped n uelei are no ted. However, high-grade lesions also focally show features of a lower-grade neoplasm, with a prominent myxoid matrix and numerous elongated cap川aries. The intermediate-grade lesions are more cellular and pleomorphic relative to purely low-grade neoplasms, but they lack well-developed solid areas, pronounced cellular pleomor­ phism, and necrosis. The rare epithelioid subtype of myxofibrosarcoma is comPosed predominantly of atypical epithelioid tumour cells with abundant eosinophilic cytoplasm and round vesicular nuelei arranged in small cohesive clusters in the myxoid areas or forming sheets in the hypercellular areas, mimicking metastatic

Fig. 1.136 Myxofibrosarcoma, intermediate-grade. Intermediate-grade myxofibrosar­ comas retain myxoid stroma and the characteristic vascular pattern, but they are more cellular and pleomorphic than low-grade lesions.

carcinoma or melanoma {2250}. By immunohistochemistry, focal SMA and/or CD34 reactivity is occasionally seen in myxofibrosarcoma, whereas desmin and S100 are negative.

Cytology Not clin ically re leva nt

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: multinodular architecture with infiltrative margins; myxoid stroma; variably prominent pleomorphic cells; distinctive curvilinear vessels; hypercellular areas in higher-grade tumours.

Staging The Union for International Cancer Control (UICC) or American Joint Committee on Cancer (AJCC) TNM system is applicable.

Soft tissue tumours

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Fig. 1.137 Myxofibrosarcoma, high-grade. A A component of the tumour with myxoid stroma and the typical vasculature is required to differentiate high-grade myxofibrosar­ coma from undifferentiated pleomorphic sarcoma. B A high-grade solid component resembling undifferentiated pleomorphic sarcoma is seen (bottom), juxtaposed to a myxoid

area exhibiting typical features of myxofibrosarcoma (top). C Frequent pleomorphic giant cells with eosinophilic cytoplasm are present in the high-grade component, mimicking high-grade undifferentiated pleomorphic sarcoma.

Prog nosis and prediction Local, often repeated recurrences, unrelated to histologi­ cal grade, occur in 30-40% of cases, usually as a result of in adequate surgery, sometimes eve n in experie need hands.

Fig. 1.138 Epithelioid myxofibrosarcoma, high-grade. Note the large, somewhat dis-

cohesive epithelioid cells with copious eosinophilic cytoplasm.

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Soft tissue tumours

Metastases and tumour-related mortality are closely related I to tumour grade. The overall 5-year mortality rate is 30-35%. I Although none of the low-grade neoplasms metastasize, high-1 grade tumours develop metastases in 20-35% of cases. In I addition to pulmonary and osseous metastases, lymph node I metastases are sometimes seen {1428,2731,1798}. Local recurrence within 12 months in creases tumour-associated mortality I {2080}. Given the propensity for relentless local recurrence associated with highly infiltrative growth, aggressive surgery combined with radiotherapy is advised for myxofibrosarcoma I in order to achieve improved local control, which may translate I into survival ben efits {375}. Compared with other high-grade I

pleomorphic sarcomas of somatic soft tissue, in termediategrade and high-grade myxofibrosarcomas have a I owe r meta­ static rate {1428,2731,1798}. Tumour size, morphological grade | (in versely related to the perce ntage of the myxoid comp on ent), I and surgical margins are significant predictors of survival {2731 j 1798}. The epithelioid subtype of myxofibrosarcoma behaves I more aggressively, with an in creased risk of metastasis (> 50%) I {2250}. °

paybal：https://www.paypal.me/andy19801210 Doyle LA Mertens F

Low-grade fibromyxoid sarcoma

Definition

Localization

Low-grade fibromyxoid sarcoma is a malignant fibroblastic neo­ plasm characterized by alternating collagenous and myxoid areas, deceptively bland spindle cells with a whorling growth pattern and arcades of small blood vessels. These tumours consistently have either FUS-CREB3L2or FUS-CREB3L1 gene fusions.

The most comm on sites of involvement are the proximal extrem­ ities and trunk, usually subfascial in depth {945,1245,2602}. Less common locations include central body sites (abdominal cavity, retroperitoneum, mediastinum) and superficial soft tis­ sues, with the latter being affected relatively more comm only in children {1510,1776,3121,323}. Origin at other anatomical sites is rare.

ICD-0 coding 8840/3 Low-grade fibromyxoid sarcoma

Clinical features

ICD-11 coding 2B5F.2 & XH4V76 Sarcoma, not elsewhere classified of other specified sites & Low-grade fibromyxoid sarcoma

Presentatio n is typically with a pain less mass. In many cases, the mass has reportedly been present for > 5 years.

Epidemiology Related terminology Not recommended: hyalinizing spindle cell tumour with giant rosettes.

Subtype(s) None

Although relatively rare among sarcomas, the true incidenee of low-grade fibromyxoid sarcoma may have been underestimated before the availability of an ciliary diag no stic markers and due to its propensity to mimic other soft tissue neoplasms histologi­ cally. There is a slight male predilection, and tumours typically arise in you ng adults, but the overall age range is wide, and as

Fi9-1.139 Low-grade fibromyxoid sarcoma. A Low-grade fibromyxoid sarcoma is usually hypocellular and composed of areas with myxoid and fibrous stroma, often with an abrupt transition between the two areas. B Higher power showing the distinct fibrous and myxoid areas. C The tumour cells are spindled and cytologically bland and grow in short fascicles or in a storiform pattern. 0 Areas of hypercellularity.

Soft tissue tumours

127

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Macroscopic appearance Grossly, low-grade fibromyxoid sarcomas are well-circurr scribed, fibrous, and often focally mucoid. Tumour size range from 1 to > 20 cm in greatest dimension.

Histopathology

Fig. 1.141 Low-grade fibromyxoid sarcoma. Diffuse strong cytoplasmic expression ofMUC4.

many as 20% of cases occur in patients aged < 18 years {323, 945,1055,1245,1189}.

Etiology Unknown

Pathoge nesis The cytogenetic hallmark of low-grade fibromyxoid sarcoma is the t(7;16)(q33;p11), which is present, often as the sole change, in two thirds of cases. Another 25% show supernumerary ring chromosomes {2592,2426,2094}. Both aberrations result in fusion of the 5' part of the FUS gene in 16p11 with the 3' part of CREB3L2 in 7q33; a chimeric FUS-CREB3L2 transcript is seen in > 90% of cases {2094,2018,1245,2170}. Rare cases have one of the fusion variants FUS-CREB3L1 or EWSR1-CREB3L1 {2094,1770,2684}. Apart from recurrent microdeletions in association with the t(7;16) chromosomal breakpoints and gain of 7q in cases with ring chromosomes, no recurrent genomic imbalances or single-nucleotide variants have been found in low-grade fibromyxoid sarcoma {2170,152}. The chimeric FUSCREB3L2 protein functions as an aberrant transcription factor, causing deregulated expression of CREB3L2 target genes {2170}. Many of these target genes, such as CD24 and MUC4, are shared with sclerosing epithelioid fibrosarcoma, with which low-grade fibromyxoid sarcoma overlaps with regard to underlying gene fusions but differs with regard to additional genomic imbalances {152}.

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Soft tissue tumours

Low-grade fibromyxoid sarcoma is composed of collager ous hypocellular areas and more-cellular myxoid nodules. A abrupt transition between these two areas is typical. The tumoi cells are bland, spindled, and sometimes plump, and they gro? in short fascicles or in a whorling pattern. Mitotic activity is ger erally inconspicuous. Arcades of small vessels and arteriole sized vessels with perivascular sclerosis are seen. Occasior ally, the vessels have a haemangiopericytoma-like patter {852}. Approximately 30% of cases contain collagen rosettesa central core of hyalinized collagen surrounded by a cuff(, epithelioid tumour cells {1055,1743}. In some cases, areas c sclerosing epithelioid fibrosarcoma are present, reflecting the overlap between these two entities {852,945,1245,2602,3240 Un usual features (< 10% of cases) in elude the presence of foce pleomorphism or nuelear atypia, hypercellularity, epithelioid c round cell features, and heterotopic ossification {852,945,1245 By immunohistochemistry, tumour cells show strong, diffuse cytoplasmic expression of MUC4, an epithelial glycoprote『 in approximately 99% of cases {852}. MUC4 is highly sensitive and specific for low-grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma among fibroblastic and neut tumours. Expression of EMA is present in 80% of cases anc focal expression of SMA in approximately 30% {852,1245,1055)

Cytology Not clinically relevant

Diagnostic molecular pathology If MUC4 is negative or not available to confirm the diagnosis identification of FUS-CREB3L2 (or other rare variants) o阿 molecular genetic support for the diagnosis.

Essential and desirable diagnostic criteria Essential: alternating fibrous and myxoid areas; bland spM cells in a whorled or short fascicular growth pattern; di# *

strong MUC4 expression (in nearly all cases). Desirable: FUS gene rearrangement (in selected cases).

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American Joint Committee on Cancer (AJCC) eighth-edition staging is appropriate

Prognosis and prediction Although low-grade fibromyxoid sarcoma shows low rates of recurrence and metastasis in the first 5 years after excision of the primary tumour (10% and 5%, respectively), rates are much higher with long-term follow-up {323,944,943,945,1055,1189, 1245}. A large study with long follow-up showed recurrences,

metastases, and death from disease in 64%, 45%, and 42% of patients, respectively {945}. Metastases occurred as long as 45 years after primary excision (median: 5 years), and the median interval to tumour-related death was 15 years {945}. The most common metastatic sites are lung and pleura. Histologi­ cal features generally do not correlate with clinical behaviour {945,1055}, although tumours with areas of sclerosing epithe­ lioid fibrosarcoma or round cell morphology tend to pursue a more aggressive clinical course {945}, similar to that expected for sclerosing epithelioid fibrosarcoma.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Sclerosing epithelioid fibrosarcoma

Doyle LA Mertens F

Definition Sclerosing epithelioid fibrosarcoma is a rare malignantfibroblas­ tic neoplasm characterized by epithelioid fibroblasts arranged in cords and nests and embedded in a dense sclerotic hyalinized stroma. A subset of sclerosing epithelioid fibrosarcomas are related morphologically and molecularly to low-grade fibromyxoid sarcoma.

ICD-0 coding 8840/3 Sclerosing epithelioid fibrosarcoma

ICD-11 coding 2B5F.2 & XH4BT2 Sarcoma, not elsewhere classified of other specified sites & Sclerosing epithelioid fibrosarcoma

Related terminology None

Subtype(s) None Fig. 1.142 Sclerosing epithelioid fibrosarcoma. Deep, large sclerosing epithelioid li

Localization Tumours are deep-seated and arise most often in the upper or lower extremities or limb girdle, followed by the trunk and the head and neck {136,2065,1042}. Rarely, tumours arise in the pelvis, retroperitoneum, viscera, or bone {3251,3302,161}.

Clinical features Most patients present with a mass of variable duration, with one third reporting recent enlargement or pain {2065}.

Epidemiology Sclerosing epithelioid fibrosarcoma usually arises in middleaged and elderly adults, with an equal sex distribution {2065}.

brosarcoma of the upper arm.

low-grade fibromyxoid sarcoma also have overlapping gene expression profiles, for example, with high expression of MUC4 and CD24 in both tumours {2170,152}. In contrast to low-grade fibromyxoid sarcoma, however, both pure and hybrid sclerosing epithelioid fibrosarcoma cases typically have complex genomic profiles, in eluding deleti ons / copy-neutral loss of heterozy­ gosity at chromosome arm 11 p, loss of chromosome 22, and intragenic deletions of the DMD gene {152}. No recurrent singl& nucleotide variant has been detected {152}. A small subset of sclerosing epithelioid fibrosarcomas do not have MUC4 expres­ sion or harbour any of the above fusion genes; little is known about the molecular pathogenesis of this group.

Etiology Un known

Pathogenesis Sclerosing epithelioid fibrosarcoma usually displays a near­ diploid karyotype with multiple chromosomal rearrangements. Tumours consistently harbour translocations resulting in gene fusions, the most frequent (> 60%) of which is EWSR1-CREB3L1 {855,153,2952,2544,850}. In rare cases, EWSFH is exchanged for FUS or PAX5 and/or CREB3L1 for CREB3L2, CREB3L3, or CREM {809,152}. The most comm on of these varia nt fusi on partners is FUS, which is involved in 10% of cases with pure sclerosing epithelioid fibrosarcoma morphology {1245,3240,2544}. Furthermore, most so-called hybrid sclerosing epithelioid fibro­ sarcomas / low-grade fibromyxoid sarcomas display a FUSCREB3L2 chimera, identical to that seen in most low-grade fibromyxoid sarcomas. Sclerosing epithelioid fibrosarcoma and 130

Soft tissue tumours

Macroscopic appearance Sclerosing epithelioid fibrosarcoma is usually well circum­ scribed, is lobular or multilobulated, and invoIves deep muscu­ lature and fascia. Periosteal adhere nee is common, and there is occasionally erosion of underlying bone. The cut surface is firm and white. Areas of calcification may be present. Most tumours are < 10 cm, but occasional cases measure > 20 cm {136,2065}.

Histopathology The margins of sclerosing epithelioid fibrosarcoma are typically infiltrative into muscle, fascia, or periosteum. A characteristic feature is a promine nt hyali nized sclerotic collage nous stroma, within which relatively bland and monomorphic epithelioid cells are arranged in cords, nests, or occasionally sheets. Some tumours contain more cellular fascicular areas. PseudoalveoM

L-lsdello

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Fig. 1.143 Sclerosing epithelioid fibrosarcoma. A Low power shows small nests and cords of epithelioid cells in a dense sclerotic stroma. B Sclerosing epithelioid fibrosar­ coma with areas of solid growth and less-dense stroma. C Classic growth pattern of sclerosing epithelioid fibrosarcoma. This image shows cords and strands of epithelioid cells with pale cytoplasm and round to oval nuclei. D Classic growth pattern of sclerosing epithelioid fibrosarcoma. This image shows epithelioid cells arranged in trabeculae with a

pseudoalveolar pattern.

or acinar growth patter ns are occasionally see n. Hypocellular areas with myxoid or fibrous stroma are common. The tumour cells usually have clear cytoplasm and inconspicuous nucleoli. Un usual features in elude marked pleomorphism, n ecrosis, prominent mitotic activity, and haemangiopericytoma-like ves­ sels {136,2065,951,855}. Calcifications or chondro-osseous differe ntiati on may be see n. Areas of conv enti on al low-grade fibromyxoid sarcoma may be present {2544,855}. Rarely, the sclerotic stroma is absent in large areas of the tumour in either sclerosing epithelioid fibrosarcoma or low-grade fibromyxoid

Fig. 1.144 Sclerosing epithelioid fibrosarcoma. Sclerosing epithelioid fibrosarcoma

owing abrupt transition to areas of low-grade fibromyxoid sarcoma.

sarcoma, making recog nition difficult {2551,945}. Clues to the diagnosis in such cases include the relatively monomorphic appearance of the tumour cells and the presenee of MUC4 expression in the absenee of keratin expression, which would be unusual for carcinoma. MUC4 expression is present in 80-90% of cases and is strong, diffuse, and cytoplasmic {855}. Expression of EMA and SMA is present in approximately 40% of cases. Keratins are typically negative, which is helpful in the differential diagnosis with carcinoma {136,1042}.

Fig. 1.145 Sclerosing epithelioid fibrosarcoma. Diffuse strong cytoplasmic expres­ sion of MUC4 in sclerosing epithelioid fibrosarcoma.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Cytology

Staging

Not clin ically re leva nt

Union for International Cancer Control (UICC) or American Join, Committee on Cancer (AJCC) staging is appropriate.

Diagnostic molecular pathology Demonstration of EWSR1-CREB3L1 or other rearrangements can help confirm the diagnosis. For cases with characteristic morphology and MUC4 expression, additional molecular stud­ ies are not needed.

Essential and desirable diagnostic criteria Essential: epithelioid cells arranged in cords, nests, or trabecu­ lae and embedded in a dense sclerotic hyalinized stroma; diffuse strong MUC4 expression (in most cases); keratinn egative. Desirable: EWSR1-CREB3L1 or other rearrangements (in selected cases).

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Soft tissue tumours

Prognosis and prediction Sclerosing epithelioid fibrosarcoma pursues a more aggre& sive clinical course than the related low-grade fibromyxoid sar­ coma, with recurrences (often multiple) in about 50% of cases Metastases are common, occurring in 40-50% of cases to lung pleura, bone, and brain. Poor prog no stic features in elude large tumour size and proximal location {136,2065}. Whether scleros­ ing epithelioid fibrosarcoma that arises in the con text of lowgrade fibromyxoid sarcoma has the same prog nosis has no tye; been established.

paybal：https://www.paypal.me/andy19801210 de Saint Aubain Somerhausen N van de Rijn M

Teno synovial giant cell tumour

Definition The term "ienosynovial giant cell tumour" encompasses a group of lesions most often arising from the synovium of joints, bursae, and ten don sheaths and showi ng synovial differe ntiation. The very uncommon malignant tenosynovial giant cell tumour is defined by the coexistence of a benign tenosynovial giant cell tumour with overtly malignant areas or by recurrence of a typical giant cell tumour as a sarcoma.

2D4Y & XH5AQ9 Other specified malignant neoplasms of illdefined or unspecified primary sites & Malignant tenosynovial giant cell tumour

Related termi no logy Acceptable: giant cell tumour of tendon sheath. Not recommended: pigmented villonodular synovitis.

Subtype(s)

ICD-0 coding 9252/0 Tenosynovial giant cell tumour NOS

Tenosynovial giant cell tumour, diffuse; malignant tenosynovial giant cell tumour

ICD-11 coding

Localization

2F7Z & XH0HZ1 Neoplasms of uncertain behaviour of unspeci­ fied site & Tenosynovial giant cell tumour NOS 2F7Z & XH6911 Neoplasms of uncertain behaviour of unspeci­ fied site & Tenosynovial giant cell tumour, localized 2F7Z & XH52J9 Neoplasms of uncertain behaviour of unspeci­ fied site 3 Tenosynovial giant cell tumour, diffuse

Localized giant cell tumours occur predominantly in the hand. Approximately 85% of the tumours occur in the fin gers, in close proximity to the synovium of the tendon sheath or interphalangeal joint. The lesions may rarely erode bone or involve the skin. Other sites include the wrist, ankle, foot, knee, and rarely the elbow and hip. Rarely, localized lesions may be found in large joints {2173,2005,3138}. Intra-articular diffuse-type giant cell

F.ig. 1.146 Tenosynovial giant cell tumour, localized type. A Tumours are composed 也of an admixture of small histiocyte-like cells, larger epithelioid cells, and osteoclast-like g；：nt cells. B The cytoplasm of larger mononuclear cells often contains a peripheral rim of haemosiderin. C The stroma shows variable degrees of hyalinization. D Collections 0 "my histiocytes are common.

Soft tissue tumours

133

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ce tid Fig. 1.147 Tenosynovial giant cell tumour, diffuse type. A Villous appearance of an intra-articular tumour. B Purely extra-articular tumour infiltrating muscular and adiposes

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sue. C Pseudosynovial clefts are common. D Osteoclast-like giant cells may be absent or extremely rare in the diffuse type.

134

Soft tissue tumours

Epidemiology The estimated incidenee rates in digits, localized-extremity.ait diffuse tenosynovial giant cell tumours are 29, 10, and 4 case, per 1 million person-years, respectively {2005}. The localize： form is more comm on tha n the diffuse form of tenosynovial g% cell tumour. Tumours may occur at any age, but they usual occur in patients aged 30-50 years, with a female predo] nance (M:F ratio: 0.5:1) {15,2005,3138}. The diffuse type usj

affects young adults (< 40 years of age). There is a slight fem * predominance {2904,2399,2231}. Malignant tenosynovial g® cell tumour is exceedingly uncommon, with only 50 reporl cases. Most patients are adults aged 50-60 years {69帘

297,1839}.

Etiology Unknown

Pathogenesis Cytogenetic studies have dem on strated relatively simple s tural changes that most often involve a translocation of the q gene, encoding colony stimulating factor 1 (CSF1). Cels, this translocation synthesize large amounts of the CSF1 p]

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Clinical features These tumours are usually divided according to their site (intraor extra-articular) and growth pattern (localized or diffuse) into two main subtypes, which differ in their clinical features and biological behaviour but appea r to share a comm on pathogen­ esis. Localized-type giant cell tumours prese nt as a pain less mass that develops gradually over a long period; a preoperative du rati on of several years is ofte n menti on ed. Diffuse-type giant cell tumours are associated with pain, tenderness, swelling, or limitation of motion. Haemorrhagic joint effusions are common. The symptoms are usually of relatively long duration (often sev­ eral years) {2904,2459,2399}. Repeated local recurrences can be destructive, leading to major functional loss {2629}. Radio­ graphically, most tumours present as ill-defined periarticular masses, frequently associated with degenerative joint disease and cystic lesions in the adjacent bone (often on both sides of

the joint). On MRI, giant cell tumours show decreased sigM intensity in both T1- and T2-weighted images, with artefac from haemosiderin deposition {2224,1921}. Malignanttenosym vial giant cell tumours can arise de novo or occur after multip? recurrences of a conventional tenosynovial giant cell tumo. {2004,69,2243,297,1839}.

“

tumours most comm only affect the knee (75% of cases), fol­ lowed by the hip (15%), ankle, elbow, and shoulder {2787,2399, 3323,2005}. Rare cases are reported in the temporomandibular and spinal facet joints {481}. Extra-articular tumours most comm only in volve the knee regi on, thigh, and foot. Un common locati ons in elude the fin ger, wrist, groin, elbow, and toe. Most extra-articular tumours are located in periarticular soft tissues, but these lesions can be purely intramuscular or subcutaneous {2904}. Most maligna nt tenosynovial giant cell tumours in volve the lower limbs, with a strong predilection for the knee. Other locati ons in elude the hip, an kle, fin gers, wrist, and pelvic area {69,2243,297,1839}.

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paybal：https://www.paypal.me/andy19801210 Wthin tumours that have this translocation, only a small subset f cells actually harbour the translocation, with the majority of ° cells that make up the tumour mass consisting of macrohaaes that are apparently there as a result of the high CSF1

：vels {693,3277,2003}.

Macroscopic appearance Grossly, most tenosynovial giant cell tumours of localized type are small (0.5-4 cm), although lesions of greater size may be found in large joints. Tumours are well circumscribed and typically lobulated and white to grey with yellowish and brown areas. Diffuse-type tenosynovial giant cell tumours are usually large (often > 5 cm), firm, or sponge-like. The villous pattern is usually present in intra-articular tumours, whereas extra-articuiar tumours have a multinodular appearance and a variegated colour, with alter nation of white, yellowish, and brow nish areas {2224}. Malignant tenosynovial giant cell tumours are usually large, fleshy, and poorly circumscribed, with areas of haemor­ rhage and necrosis {1839,69}.

Fig. 1.148 Malignant tenosynovial giant cell tumour. Sheets of large mononuclear cells, with enlarged nuclei and increased mitotic activity.

Histopathology The microscopic appearanee of tenosynovial giant cell tumours iS variable, depe nding on the proporti ons of mono nuclear cells, multinucleated giant cells, foamy macrophages, inflammatory cells, and haemosiderin, as well as the degree of collagenization of the stroma. Two principal cell types are identified within the mononuclear component: small histiocyte-like cells, with pale cytoplasm and round or reniform nuelei, and larger epithe­ lioid cells, with amphophilic cytoplasm and rounded vesicular nuclei. These larger cells often contain a peripheral rim of hae­ mosideri n granules. Most tumours contain a majority of small histiocyte-like cells, but larger cells may predominate. In both types, mitotic activity may be brisk. Necrosis can be present. Chon droid metaplasia can be see n in tenosynovial giant cell tumours of the temporomandibular joint {2346,1383}. Localized-type tenosynovial giant cell tumours are lobulated and well circumscribed. Osteoclast-like giant cells are usu­ ally readily appare nt, but they may be in conspicuous in some tumours. Xanthoma cells are frequent, tend to aggregate locally near the periphery of nodules, and may be associated with cholesterol clefts. Haemosiderin deposits are virtually always identified. The stroma shows variable degrees of hyalinization 12173,1543,3138}. Diffuse-type tenosynovial giant cell tumours are infiltrative and grow as diffuse, expansile sheets. Osteoclast-like giant cells are less comm on in the diffuse form tha n in the localized form, and they may be absent or extremely rare in as many as 20% of cases. Cleft-like spaces are comm on and appea r either as artefactual tears or as synovial-lined spaces. Blood-filled pseudoalveolar spaces are seen in approximately 10% of cases 12904,3138,2224}. Most malignant tenosynovial giant cell tumours are composed of sheets and nodules of enlarged mononuclear cells. These n eoplasms tend to show sign ifica ntly in creased mitotic

count, including atypical mitoses, necrosis, enlarged nuclei with nueleoli, spindling of mononucleated cells, and myxoid changes. Less comm only, these tumours contain areas resembln9 undifferentiated pleomorphic sarcoma or myxofibrosarcoma {69,2243,297,1839}.

Fig. 1.149 Tenosynovial giant cell tumour, localized type. Some cases of both local­ ized and diffuse types contain numerous desmin-positive mononuclear cells, often with dendritic processes.

The larger mononuelear cells express clusterin, and in 45-80% of cases a small subset of these cells stain for desmin, which highlights their dendritic processes. The smaller histio­ cyte-like cells are positive for CD68, CD163, and CD45. Multin ucleated giant cells display an osteoclastic phe notype {354, 2342}.

Cytology The presenee of large mononuelear cells with eccentric nuclei, finely granulated cytoplasm, and a cytoplasmic rim of haemosiderin is distinctive {3400}.

Diagnostic molecular pathology Not clin ically re leva nt

Essential and desirable diagnostic criteria Essential: \ntra- or extra-articular location; varying proportions of small histiocytic cells, large amphophilic cells, foam cells, multinucleated giant cells. Desirable: dem on stration of CSF1 rearra ngement (selected cases).

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Staging Not clinically re leva nt

Prognosis and prediction Tenosynovial giant cell tumour of localized type is a benign lesion with a capacity for local recurrenee. Although 4-30% of cases recur, these recurrences are usually non-destructive and are controlled by surgical re-excision {2005,3138,2173,1543}. Recurrences are more common in diffuse-type tumours, and repeated recurrences may severely compromise joint function. The recurrence rate has been estimated at 40-60% {2004}. In

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Soft tissue tumours

addition, rare cases with benign histology may develop meta, static disease (in the lungs or lymph nodes) {2005,2904,239g 2459). Malignant tenosynovial giant cell tumour is an agg© sive neoplasm, with substantial mortality (roughly one thirc of cases). Approximately 50% of cases metastasize to lymy nodes (inguinal and pelvic) and the lungs {69,2243,297,1831 Surgery is the main stay of the treatme nt of tenosynovial tumour^ Molecular targeted therapy targeting the CSF1/CSF1R pathwa, has shown promising results for unresectable or metastasizin〔 tumours {339,510,511}.

paybal：https://www.paypal.me/andy19801210 Jo VY

Deep fibrous histiocytoma

Definition

Epidemiology

Deep fibrous histiocytoma is a morphologically benign fibrous histiocytoma that arises entirely within subcutaneous or deep soft tissue and that may occasi on ally metastasize.

Deep-seated fibrous histiocytomas are rare, accounting for < 1% of fibrohistiocytic tumours {1015}. Patients are affected over a wide age range (6-84 years; median age: 37 years). There is a slight predominance in males.

ICD-0 coding 8831/0 Deep benign fibrous histiocytoma

Etiology Unknown

ICD-11 coding 2F7C & XH5DP4 Neoplasms of uncertain behaviour of connective or other soft tissue & Deep benign fibrous histiocytoma 2F23.0 Dermatofibroma

Related terminology None

Subtype(s)

Pathogenesis Rearrangements involving either PRKCB or PRKCD (members of the gene family encoding PKC) have been identified in all mor­ phological subtypes of benign fibrous histiocytoma, including deep fibrous histiocytoma {2521,3223}. Known fusion partners are genes encoding membrane-associated proteins (PDPN, CD63, and LAMTOR1), resulting in chimeric proteins localizing the catalytic domain of PKC to the cell membrane {2521}.

None

Macroscopic appearance

Localization The most common site is the extremities, representing more than half of cases, followed by the head and neck region. Most deep fibrous histiocytomas are subcutaneous, but nearly 10% arise in visceral soft tissue (e.g. retroperitoneum, mediastinum, pelvis) {1015,1165}. Intramuscular tumours are uncommon, and tumours arising in visceral organs are exceedingly rare {2709).

Clinical features Most lesi ons prese nt as a pain less, slowly enlarging mass 11165).

These tumours form well-circumscribed nodules, with a median size of 2.5 cm for subcutaneous lesions. Subcutaneous tumours may be observed intraoperatively to be attached to fascia or tendon. Deep-seated lesions may be larger {1165}.

Histopathology Un like their cuta neous cou nterparts, deep fibrous histiocytomas are well circumscribed. The lesions are more cellular than typi­ cal cutaneous fibrous histiocytomas, but they share a storiform architecture. A minority of tumours have a predominantly short fascicular pattern 一 similar to that seen in cellular fibrous histio­ cytoma in skin - with only focal storiform areas. A branching,

Soft tissue tumours

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Fig. 1.151 Deep fibrous histiocytoma. A Monomorphic storiform pattern is typical. B Tumour cells are generally uniform, with less cytological pleomorphism than their derm

counterparts.

haema ngiopericytoma-like vascular patter n is comm on, which may cause confusion with solitary fibrous tumour, particularly when CD34 is expressed. Gen erally, deep fibrous histiocytoma can be distinguished by its uniform cellularity and storiform architecture. The tumour cells are spin died, with plump, ovoid to elongated vesicular nuclei and indistinet, palely eosinophilic cytoplasm. Nearly half of all deep fibrous histiocytomas are cytologically monomorphic, lacking the foamy histiocytes and giant cells that are often seen in cutaneous lesions. Stromal hyalinizati on is relatively comm on; less freque nt findi ngs inc lude haemorrhage, myxoid change, cystic degeneration, central in farcti on, and a peripheral lymphoid in filtrate. There is gener­ ally no nuelear pleomorphism or hyperchromasia, although rare examples of atypical deep fibrous histiocytoma (akin to atypi­ cal cutaneous fibrous histiocytoma) have been reported {1165}. Tumour necrosis is rare. CD34 positivity is far more comm on in deep fibrous histiocy­ tomas than in those in the skin, with 40% of the former expressing this marker, sometimes diffusely {1165}. Such examples may be difficult to distinguish from solitary fibrous tumour; however, deep fibrous histiocytomas are negative for STAT6 {3371,854}. A similar number of cases express SMA, usually focally.

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Soft tissue tumours

Cytology Not clinically relevant

Diagnostic molecular pathology Not clin ically re leva nt

Essential and desirable diagnostic criteria Essential: well-circumscribed lesion located in subcutaneousc deep/visceral tissue; mixed fascicular and storiform grow? pattern; monomorphic population of spindled or histiocytoii cells; branching vessels.

Staging Not clin ically re leva nt

Prognosis and prediction Deep fibrous histiocytomas recur locally in approximately 20'： of cases, usually if incompletely or marginally excised (1015 1165}. Metastasis is rare, reported to occur in 5% of cases in a series of 69 cases {1165}, possibly reflecting referral bias.

paybal：https://www.paypal.me/andy19801210 Brenn T

plexiform fibrohistiocytic tumour

Definition plexiform fibrohistiocytic tumour is a rare dermal and subcutae0US neoplasm showing plexiform architecture and biphasic morphology, composed of nodules of histiocytoid cells and bun dies of myofibroblastic spindle cells.

ICD-0 coding 8835/1 Plexiform fibrohistiocytic tumour

ICD-11 coding 2F7C & XH4GL1 Neoplasms of uncertain behaviour of connective or other soft tissue & Plexiform fibrohistiocytic tumour

Related terminology None

Subtype(s) None

Localization There is a strong predilection for the upper limbs followed by the lower limbs. The trunk and the head and neck area are less often affected {2186,920,1397}.

Clinical features The tumours present as slow-growing, ill-defined plaques and nodules, typically measuring 1-3 cm in diameter {920}.

Epidemiology The age range is wide, but children and young adults are typi­ cally affected, with a median age of 14.5-20 years and an equal sex distribution {2186,920,1397,2610}.

Etiology Unknown

Fig. 1.152 Plexiform fibrohistiocytic tumour. The tumour shows a plexiform growth in deep dermis and subcutaneous adipose tissue.

Pathogenesis Unknow n

Macroscopic appearance These tumours form a non descript mass at the dermal-subcu­ taneous junction, usually < 3 cm in size.

be haemorrhage, haemosiderin deposition, and a chronic inflammatory infiltrate. Lymphovascular invasion can rarely be seen. Additional rare findings include myxoid or hyalinized stro­ mal changes and metaplastic bone formation. By immunohisto­ chemistry, the spindle cells express SMA {1065}.

Histopathology Plexiform fibrohistiocytic tumours are centred at the dermalsubcutaneous junction. They show an infiltrative architecture with overall plexiform outlines and may extend into skeletal muscle- The tumours are composed of small nodules of histiocytoid cells and osteoclast-like multinucleated giant cells, surrounded 切 fascicles of spindle cells in varying proportions. There may

Cytology Not clin ically r eleva nt

Diagnostic molecular pathology Not clin ically re leva nt

Soft tissue tumours

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Fig. 1.153 Plexiform fibrohistiocytic tumour. A Note the infiltrative tumour growth within subcutaneous adipose tissue and extension into skeletal muscle. B Bland-appearinc spindle cells are arranged in intersecting fascicles. C The distinctive nodules are distributed within adipose tissue in a plexiform distribution. D The nodules are composed o

bland and uniform epithelioid cells with admixed osteoclast-like multinucleated giant cells.

Essential and desirable diagnostic criteria

Prognosis and predict!on

Essential: plexiform architecture; involvement of dermis and/or subcutaneous adipose tissue; nodules composed of histiocytoid epithelioid cells and osteoclast-like giant cells; fascicles of myofibroblastic spindle cells.

Plexiform fibrohistiocytic tumour is associated with a risk for local recurrence ranging from 12.5% to 37.5% and rare lympl' node metastasis {2186,920,1397,2610}. Distant metastasis to the lung is exceptional {2725,2610}.

Staging Not clin ically re leva nt

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Soft tissue tumours

1

paybal：https://www.paypal.me/andy19801210 Oliveira AM Lee JC

Giant cell tumour of soft tissue

Definition

Epidemiology

Giant cell tumour of soft tissue is morphologically similar to but genetically unrelated to giant cell tumour of bone.

9251/1 Giant cell tumour of soft parts NOS

Giant cell tumour of soft tissue occurs predominantly in the fifth decade of life, but it can affect patients ranging in age from 5 to 89 years. Giant cell tumour of soft tissue shows no apparent differenee in incidenee with regard to sex or ethnicity {1058, 2345,2372}.

ICD-11 coding

Etiology

2F7C & XH81M1 Neoplasms of uncertain behaviour of connective or other soft tissue & Giant cell tumour of soft parts NOS

Unknown

ICD-0 coding

Pathogenesis

Related terminology Not recommended: giant cell tumour of low maligna nt potential.

Subtype(s)

Giant cell tumour of soft tissue lacks the mutations of the H3-3A (H3F3A) gene that are present in the vast majority of giant cell tumours of bone, suggesting a different pathogenesis {1805, 1961}.

None

Macroscopic appearance Giant cell tumour of soft tissue usually occurs in superficial soft tissues of the upper and lower extremities (70% of tumours). Affected less frequently are the trunk (20%) and head and neck (7%) regions {1058,2345,2372,2488,2643}. Occasional cases have been reported in other anatomical locations (1176,2158, 1645).

Tumours range in size from 0.7 to 10 cm (mean: 3 cm) {1058, 2345,2372}. Subcutaneous adipose tissue or dermis is invoIved in 70% of tumours; 30% are situated deep to superficial fascia. Giant cell tumour of soft tissue is a well-circumscribed, mostly solid, nodular mass with a fleshy, reddish-brown or grey cut sur­ face. Gritty regions of mineralized bone are frequently present at the periphery {2345}.

Clinical features

Histopathology

The tumours usually present as pain less growing masses {2345, 2372), with an average duration of 6 months {2372}. Peripheral mineralization is common.

Giant cell tumour of soft tissue displays a multinodular archi­ tecture (85%). Cellular nodules are separated by fibrous septa of varying thickness, containing haemosiderin-laden macrophages {2345}. The nodules are composed of a mixture of round to oval mononuelear cells and osteoclast-like multinucleated giant cells, with both cell types immersed in a richly

Localization

Fig. 1.154 Giant cell tumour of soft tissue. A Giant cell tumour of soft tissue is composed of nodules of osteoclast-like multinucleated giant cells intermixed with ovoid mononuclear cells. ■ The cellular nodules contain a mixture of round/oval mononuclear and multinucleated osteoclast-like giant cells.

Soft tissue tumours

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-

鹫VW.砖七瑤

A

B

Fig. 1.155 Giant cell tumour of soft tissue. A Giant cell tumour of soft tissue shows a characteristic multinodular architecture where clusters of osteoclast-like multinucleate, giant cells are often separated by fibrous septa. Metaplastic bone formation is also commonly observed (bottom). B Aneurysmal bone cyst-like changes can occur in giant ce tumour of soft tissue.

vascularized stroma. Mitotic activity is readily seen in giant cell tumour of soft tissue {1058,2345,2372}. Nuclear pleomor­ phism and bizarre giant cells are absent, and necrosis is rarely found {1058,2345,2372}. Metaplastic bone formation is present in approximately 50% of tumours, most often in the form of a peripheral shell of woven bone. Aneurysmal bone cyst-like changes may be seen. Vascular invasion is identified in about 30% of tumours {1058,2372}. Additional histological features include stromal haemorrhage (50%) and regressive changes in the form of marked stromal fibrosis and clusters of foamy macrophages (70%). Immunohistochemistry is not helpful.

Cytology Not clinically relevant

Diagnostic molecular pathology Not clinically relevant

142

Soft tissue tumours

Essential and desirable diagnostic criteria Essential: multi no dular superficial soft tissue neoplasm; hi tiocytoid mononuclear cell population with osteoclastic gia cells; haemosiderin deposition and metaplastic bone form tion are commonly observed.

Staging Not clin ically re leva nt

Prognosis and predict!on Giant cell tumour of soft tissue is associated with a local recur­ rence rate of 12%, with very rare metastasis {1058,2345,2372(

paybal：https://www.paypal.me/andy19801210 Calonje JE

Synovial haemangioma

Definition Synovial haemangioma is a benign proliferation of blood vessels arising in a synovium-lined surface, including the intra-articular gpaCe Or a bursa. Similar lesions occurring within the tendon sheath do not fall into this category.

ICD-O coding 9120/0 Haemangioma NOS

ICD-11 coding 2E81.0Y Other specified neoplastic haemangioma

Related termi no logy None

Subtype(s) None

Localization The most common site is the knee, followed much less commonly by the elbow and hand. Involvement of hip or other joints is exceptional {784}.

Clinical features The tumour presents as a slow-growing lesion, often associated with swelling and joint effusion {807}. Recurrent haemarthrosis has been reported {490,1864} and recurrent pain is a frequent symptom. Delayed diagnosis causes osteoarthritic damage. In about one third of cases, the lesion is pain less. Rarely, destruc­ tive growth may be see n {3142}, excepti on ally with extra-artic­ ular extension, bone involvement, and pathological fracture of bone {5,1399}. MRI is the best radiological technique for diag­ nosis and for determining the extent of invoIvement.

Epidemiology Synovial haemangioma is very rare. Most patients are children or adolesce nts, and males are affected more comm only tha n females {807,2217).

Fig. 1.156 Synovial haemangioma. A mixture of cavernous and capillary vascular channels underlies the synovium.

Macroscopic appearance

a diffuse growth pattern. It often has the appearanee of a cavernous haemangioma with multiple dilated thin-walled vascular channels; a smaller percentage of cases have the appearanee of either a capillary or an arteriovenous haemangioma. The vascular channels are located beneath the synovial membrane and are surrounded by myxoid or fibrotic stroma. Haemosiderin depositi on in lining synov iocytes and in histiocytes can be promine nt. Villous hyperplasia of the synovium is present in some cases.

Numerous congested, variably dilated vessels of different calibre can be see n,an dthetumourcanbefairlycircumscribedordiffuse.

Cytology

Etiology Unknown

Pathogenesis Unknow n

Not clinically relevant

Histopathology Thetumour is composed of numerouscongested, variably dilated vessels of different calibre, with either a fairly circumscribed or

Diagnostic molecular pathology Not clin ically releva nt

Soft tissue tumours

143

paybal：https://www.paypal.me/andy19801210 Essential and desirable diagnostic criteria

Prognosis and prediction

Essential: a turn our composed of nu merous con gested, variably dilated vessels of d if fere nt calibre; origin from a syno viumlined space.

Small lesions are usually easy to remove completely by syn. ovectomy with no risk of local recurrenee {2217}. When morediffuse involvement of the joint is present, complete excision can be difficult to achieve and may predispose to recurrence.

Staging Not clin ically re leva nt

144

Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 Calonje JE

Intramuscular angioma

Definition Intramuscular angioma is a proliferation of benign vascular channels within skeletal muscle, associated in most instances with variable amounts of mature adipose tissue.

ICD-0 coding g-|32/0 Intramuscular haemangioma

ICD-11 coding 2E81.0Y & XH0553 Other specified neoplastic haemangioma & Intramuscular haemangioma

Related terminology Acceptable: intramuscular haemangioma. Not recommended: intramuscular-i nfiitrating an giolipoma.

Subtype(s) None

Fig. 1.157 Intramuscular angioma. This lesion was excised from the rectus abdominis muscle of a young woman. Note the poorly circumscribed margins and prominent fatty stroma.

Localization

Epidemiology

Intramuscular angioma most commonly affects the lower limbs, particularly the thigh and calf, followed by the head and neck, upper limbs, and trunk. Cases can present rarely in the mediastinum and retroperiton eum and excepti on ally within cardiac muscle (2913).

Although relatively un comm on, intramuscular an gioma is one of the most frequent deep-seated soft tissue tumours. The age range is wide, but adolesce nts and you ng adults are most commonly affected (as many as 90% of cases) {78,254,983}, with equal sex distribution. Lesions have often been present for many years and it is therefore likely that many examples are congen ital.

Clinical features Typical presentation is of a slow-growing mass that is often painful, particularly after exercise. Pain is mainly present in tumours located in the limbs. Giant lesi ons may excepti on ally induce osteolysis {2015}. Radiological examination often reveals the presenee of calcification due to phleboliths or metaplastic ossification. MRI is the most important radiological technique to establish the diagnosis {2216}.

鳥y

Intramuscular angioma. A Extensive replacement of the muscle by

Etiology Un know n

Pathogenesis Un know n

vascular channels with focal thrombosis. There is a prominent adipocytic compo-

n' 8 Predominance of cavernous-like vascular spaces.

Soft tissue tumours

145

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Fig. 1.159 Intramuscular angiom& A Extensive adipocytic component with muscle atrophy. B Entrapped muscle fibres with hyperchromatic, reactive nuclei.

Macroscopic appearance

Cytology

Tumours are often large and there is diffuse infiltration of the invoIved muscle. Variably sized vascular channels with thrombosis and haemorrhage are usually readily seen. The appearance of the tumour can be solid .and yellowish as a result of the presence of adipose tissue. Lesions also appear solid when capillaries predominate.

Not clin ically r eleva nt

Histopathology Intramuscular angiomas are mostly composed of mixed ves­ sel types, including lymphatics {78}, large thick-walled veins, a mixture of caver no us-like vascular spaces and capillaries, or a prominent arteriovenous component. Tumours purely com­ posed of capillaries are more common in the head and neck area, and those with a predomi nant caver nous lymphatic component are seen mainly on the trunk, proximal upper limb, and head. Variable amounts of mature adipose tissue are almost always present and may be very prominent. This explains why in tramuscular an gioma was sometimes in appropriately known in the past as deep or infiltrating angiolipoma {1867}. Atrophy of muscle fibres because of tumour infiltration often results in degenerative/reactive sarcolemmal changes with hyperchromatic nu clei. Peri neural inv olveme nt may be prese nt.

146

Soft tissue tumours

h： (R p

K 9

Diagnostic molecular pathology Not clinically re leva nt

l(

L

Essential and desirable diagnostic criteria Essential: mass composed of mixed vessel types including lym­ phatics; situated within muscle and often presents with pain (worse on exercise).

R

Staging

S

Not clin ically re leva nt

卜

Prognosis and prediction The rate of local recurrence is high (30-50%) and wide local excision is therefore recommended. Local recurrenee seems to be determined only by size of the tumour and excision margins {263}.

b

paybal：https://www.paypal.me/andy19801210 Arteriovenous malformation/haemangioma

Calonje JE

Definition Arteriovenous malformation/haemangioma (AVM/H) is a fastflow mostly congenital vascular anomaly characterized by 怅 presenee of arteriovenous shunts. There are two distinctive forms: deep-seated and cutane°us (cirsoid aneurysm °r acral arteriovenous tumour). Most cases of extracranial AVM/H harbour MAP2K1 mutations, resulting in upregulated MAP2K1 (MEK1) activity. When these lesions involve multiple tissue planes, they are termed angiomatosis.

ICD-0 coding 9123/0 Arteriovenous haemangioma

ICD-11 coding LA90.3Y Other specified peripheral arteriovenous malforma­ tions

Related terminology None

Subtype(s) None

Localization AVM/H affects predominantly the head and neck (including the brain), followed by the limbs. Internal organs, including the lungs and uterus, may be involved {732}.

Clinical features Angiography is an essential tool to confirm the diagnosis and establish the extent of disease. Lesions are often associated with a variable degree of arteriovenous shunting, and this can be severe enough to induce limb hypertrophy, heart failure, and consumption coagulopathy (Kasabach-Merritt syndrome). Pain is also a frequent symptom, and superficial cutaneous changes mimicking Kaposi sarcoma clinically and histologically can be seen (pseudo-Kaposi sarcoma or acroangiodermatitis) {2967}. The prese nee of shu nting can be con firmed clin ically by auscul­ tation. AVM/H should not be confused with juvenile, cutaneous (cellular) haemangiomas because they do not usually regress spontaneously. Spontaneous regression of AVM/H is excep­ tional {2786}.

Epidemiology Deep-seated AVM/H is uncommon and affects children and young adults. AVM/H represents about 14.3% of all vascular anomalies in children {1216}. Although a large proportion of lesions (particularly those that are deep-seated) are congenital, acquired lesions are increasingly being recognized {1942}.

Etiology Unknow n

Fig. 1.160 Arteriovenous malformation/haemangioma. A In some cases, cavernous vascular spaces predominate. B There is extensive infiltration of the subcutaneous tissue by large vessels.

Pathogenesis Unknown

Macroscopic appearanee Tumours are ill defined and contain variable numbers of small and large blood vessels, many of which are dilated.

Histopathology This diagnosis always requires clinicopathological and radio­ logical correlation. AVM/H is characterized by large numbers of vessels of different sizes, including veins and arteries, with the former largely outnumbering the latter. Areas resembling a caver nous or capillary haema ngioma are freque nt, as are thrombosis and calcification. Lymphatic vessels may be present. Recog nition of arteriove nous shu nts is difficult and r equires examination of numerous serial sections. Fibrointimal thickening in veins is a useful diagnostic clue. Elastic stains are helpful in distinguishing between arteries and veins. True arteriovenous shu nts are sometimes impossible to dem on strate in superficial Soft tissue tumours

147

paybal：https://www.paypal.me/andy19801210 Cytology Not clinically relevant

Diagnostic molecular pathology Not clinically re leva nt

Essential and desirable diagnostic criteria Essential: radiological (angiographic) or auscultatory evidenee of an arteriovenous shunt within an ill-defined vascular lesion. Desirable: histology showing vessels of different sizes, including both arteries and veins; fibrointimal thickening in veins. ■

Staging Not clinically relevant

Prognosis and prediction Fig. 1.161 Arteriovenous malformation/haemangioma. An elastic stain (elastic Van Gieson) is useful to determine the type of vessels involved.

lesions. Some malformations may be purely venous (see Venous haemangioma, p. 149). Negative staining for GLUT1 may facilitate distinotion from juvenile haemangioma {2327}. WT1 protein, a marker that is usually positive in haemangiomas, tends to be negative or focally positive in other vascular malformations {55}. However, this marker has recently been reported to be positive in AVM/H {3101}.

148

Soft tissue tumours

Treatment is sometimes difficult because of the extent of tumour in volveme nt, which must be determi ned by an giographic examination. Local recurrenee is common because of difficulty in achieving complete excision.

paybal：https://www.paypal.me/andy19801210 Calonje JE

Venous haemangioma

Definition Venous haemangioma is composed of veins of variable size, often having thick muscular walls. Intramuscular angiomas and angiomatosis, which are described separately, can be composed almost exclusively of veins but are usually in termixed with other vessel typss.

ICD-0 coding 9122/0 Venous haemangioma

ICD-11 coding 2E81.0Y Other specified neoplastic haemangioma

Related terminology None

Subtype(s)

Fig. 1.162 Venous haemangioma. Venous haemangioma with typically numerous

None

prominent thick-walled veins.

Localization

Histopathology

Tumours present in the subcutaneous or deeper soft tissues and are commonly located in the limbs. Rarely, lesions have been described elsewhere, including the mandibular division of the trigeminal nerve {2048}, the orbit {1704}, the superior sulcus of the lung {3379}, the mediastinum {1369}, the retroperitoneum (1660}, the breast {1634}, the brain {1251}, and the parapharyn­ geal space {578}.

Venous haemangioma typically consists of large thick-walled muscular vessels, which are variably dilated and comm only display thrombosis, with occasional formation of phleboliths. Widely dilated vessels can show attenuation of their walls, mimicki ng a caver nous haema ngioma. Elastic stains r eveal the absenee of an internal elastic lamina. This aids in the distinction from an arteriovenous haemangioma.

Clinical features

Cytology

Venous haemangioma often presents as a Iongstanding slowgrowing tumour. Radiological exami nation often shows the presence of calcification due to phleboliths.

Not clinically re leva nt

Diagnostic molecular pathology Not clin ically re leva nt

Epidemiology Venous haemangioma is rare and data are limited, but these lesions occur mainly in adults.

Essential and desirable diagnostic criteria

The clinical evolution and clinicopathological features suggest that these lesions represent vascular malformations.

Essential: ill-defined lesion with thick-walled muscular vessels, variable dilation, and area of thrombosis; absence of internal elastic lamina. Desirable: Iongstanding, slow-growing tumour, often with calcifications (phleboliths).

Pathogenesis

Staging

Unknow n

Not clinically relevant

Macroscopic appearance

Prognosis and prediction

Venous haemangioma is ill defined and consists of dilated con­ gested vascular spaces with areas of haemorrhage.

Deep-seated tumours are difficult to excise and can recur locally, but subcutaneous tumours do not usually recur.

Etiology

Soft tissue tumours

149

paybal：https://www.paypal.me/andy19801210 Anastomosing haemangioma

Montgomery EA Umetsu SE

Definition Anastomosing haemangioma is a benign vascular neoplasm that is poorly margin ated and con si sts of thin-walled anastomosing vessels lined by a mono layer of en dothelial cells with somewhat protuberant nuclei.

ICD-0 coding 9120/0 Haemangioma NOS

ICD-11 coding 2E81.0Z Neoplastic haemangioma, unspecified

Related terminology None

Subtype(s) None

Fig. 1.163 Anastomosing haemangioma. The lesion is well marginated, which Is ger erally the case.

Localization Anastomosing haemangiotna was initially reported in the male genital tract {2176}, and the most common site is the kidney and retroperitoneal adipose tissue {2383,435}, but this type of haemangioma has been reported in multiple sites, including the female genital tract {1702,871}, gastrointestinal tract and liver {1551,1865}, soft tissue {1539}, and skin {3095}.

lesion that is mildly hyperdense with heterogeneous attenuation that is inconclusive for malignancy {2383,1539}. Multifocalit, has been documented {3}. Most lesions are 1-2 cm, but large， examples (as large as 7.5 cm in soft tissue {1539}) are known Hepatic examples can not only appear infiltrative but can alsc be as large as 16 cm {1154,3217}.

Clinical features

Epidemiology

Because many cases arise in the viscera, they may be incidental findings on imaging studies, although some patients with renal lesions present with haematuria {2176}; patients with superficial examples present with palpable masses or with pain {1539}. Colorectal lesions can manifest as polyps {1865}, and hepatic lesions often present during the evaluation of another process {1865,1154,1551}. Imaging studies often show a well-marginated

Patients are predominantly adults (mean age in the initial series ~60 years {2176}), but lesions in the paediatric age group have been reported {454}. There does not appear to be a sex predilection overall.

Etiology Unknown

Fig. 1.164 Anastomosing haemangioma. A This renal lesion is rather sclerotic and infiltrated the renal pelvic adipose tissue. However, note that the tumour is arranged in 恤 ules. B The lesion is composed of vascular spaces that are cuffed by supporting cells. Note the extramedullary haematopoiesis (erythropoiesis) in the upper-central partoM： image. C Note the anastomosing growth pattern and tiny hobnail endothelial cells.

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Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 pathogenesis Th© vast majority of cases contain an activating hotspot mutatjon 和 gNAQ or GNA14; similar mutations have been identified in hepatic small vessel neoplasms {243,242,1551}. No other molecular alterations have been identified.

Macroscopic appearance Anastomosing haemangiomas have a haemorrhagic, mahog­ any-coloured, spongy appearance.

Histopathology These lesions have a loosely lobulated architecture at low magnification and can be associated with a medium-calibre vessel. There is often focal infiltration into adjoining tissue. The neoplasms consist of anastomosing sinusoidal capillarysized vessels with scattered hob nail en dothelial cells {1748}. There may be a lymphocytic infiltrate. Mitoses are absent or rare Mild cytological atypia can be present, but no multilayering of endothelial cells is seen. Vascular thrombi are typical, and zones of central sclerosis with focal necrosis are common. Extramedullary haematopoiesis can be a prominent feature, and some examples have striking hyaline globules. Immuno­ histochemistry shows labelling with CD34, CD31, and ERG in the endothelial cells.

Fig. 1.165 Anastomosing haemangioma. Both hyaline globules and a megakaryocyte are seen.

Essential and desirable diagnostic criteria Essential: an astomosi ng vessels lined by hob nail endothelial cells. Desirable: hyaline globules and extramedullary haematopoiesis are comm on.

Cytology

Staging

Not clinically relevant

Not clin ically re leva nt

Diagnostic molecular pathology

Prognosis and prediction

Not clinically re leva nt

Anastomosing haemangiomas, even when multicentric or infil­ trative, are benign.

Soft tissue tumours

151

paybal：https://www.paypal.me/andy19801210 Bovee JVMG Huang SC Wang J

Epithelioid haemangioma

Definition Epithelioid haemangioma is a benign vascular neoplasm com­ posed of well-formed blood vessels lined by plump, epithelioid (histiocytoid) endothelial cells, with abundant eosinophilic cyto­ plasm and a variable eosi no philic in filtrate. As many as half of the cases show recurrent gene fusions in the FOS and FOSB genes.

with multiple (sometimes numerous) lesions, usually within the same anatomical region {1883}.

Epidemiology Epithelioid haemangioma occurs over a wide age range, with peak incidenee in the fourth decade of life and no sex predilec­ tion {1432}.

ICD-0 coding 9125/0 Epithelioid haemangioma

Etiology Unknown

ICD-11 coding 2E81.0Y & XH10T4 Other specified neoplastic haemangioma & Epithelioid haemangioma

Related termi no logy Not recommended: an giolymphoid hyperplasia with eosi nophilia; histiocytoid haemangioma.

Subtype(s) Cellular epithelioid haemangioma; atypical epithelioid haemangioma

Localization Cutaneous and soft tissue lesions are most commonly located in the head and neck region, especially the forehead, preauricular region, and scalp, followed by the distal extremities and trunk {2380,1432}. The penis is uncommonly involved {1001}. Visceral occurrences are exceedingly rare {2188}. Some arise in large vessels.

Clinical features The most common presentation is a single cutaneous erythema­ tous-violaceous papule or angiomatoid nodule, asymptomatic or slightly painful. Approximately 10-20% of patients present

Pathogenesis Epithelioid haemangioma is characterized by recurrent fusion genes involving the FOS or FOSB gene in as many as half of the cases. The fusion-positive tumours are more often in the extremities/trunk, non-cutaneous, and of the cellular/atypical subtypes {1432}. The gene partners for FOS are variable, including LMNA. MBNL1, VIM, and lincRNA {3162,1432}, whereas FOSB is often fused to ZFP36 or very rarely to WWTFI1 or ACTB {128,36| Dysregulation of the FOS family of transcription factors through chromosomal tran slocati on is the key eve nt. The FOS family includes FOS, FOSB, FOSL1, and FOSL2, which encode leucine zipper proteins that can dimerize with proteins of the JUN family there by forming the tran scripti on factor complex AP-1. FOS pro­ teins regulate cell proliferation, differentiation, angiogenesis, and survival. In the FOS fusions, the various fusion partners are at the C-terminal end of the protein and cause loss of the transactivating domain {3162}. The C-terminal part is essential for fast, ubiquitinin dependent FOS degradati on via the 20S proteasome. Loss ol the C-terminal part prevents the normal rapid degradation ol FOS, resulting in prolonged FOS activation {3163}. The FOSB fusions occur at the N-terminal part of the protein and are most likely activating promoter-swap events causing upregulation ol FOSB {3177}. Recent data suggest that cutaneous epithelioid

Fig. 1.166 Epithelioid haemangioma. A Epithelioid haemangioma shows a multilobular growth pattern. B High-power view details the endothelial cells, which have glassy apeosinophilic cytoplasm and central enlarged nuclei with prominent nucleoli. C Exuberant or cellular examples of epithelioid haemangioma exhibit high cellularity and sheet」* areas with inconspicuous or slit-like vascular lumina and scant intervening stroma. These lesions usually have a conventional vasoformative pattern and peripheral maturation，

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Fig. 1.168 Epithelioid haemangioma. There is strong nuclear staining for FOSBinthis cellular example of epithelioid haemangioma.

haemangioma (angiolymphoid hyperplasia with eosinophilia type) may be non-neoplastic, lacking abnormalities in the FOS or FOSB gene {1432}.

especially for head and neck cases. Dermal cases usually have less demarcation, more well-canalized lumina, and less plump endothelial cells. A subset of cases, referred to as atypical epi­ thelioid haemangiomas, can display more-solid growth, exuber­ ant and compact proliferation with increased cellularity, nuclear pleomorphism with sheet-like appearanee with inconspicuous or slit-like spaces and little intervening stroma, and necrosis {128}. These cases more often have FOSB fusions and are more often localized in the penis, with more infiltrative growth. Tumour cells express the endothelial markers CD31, FLI1, and ERG, and CD34 is expressed to a lesser extent. Many cases are also positive for keratin and EMA {2343,3190}. SMA highlights the pericytic lining and therefore the vasoformative architecture. FOSB was shown to be positive in 54% of epithelioid haemangi­ omas {1440}. The an giolymphoid hyperplasia with eosi nophilia subtype is also positive for FOSB, although gene fusions are absent {1440,2387,3162,1432}.

Cytology Not clin ically re leva nt

Macroscopic appearance Superficial epithelioid haemangiomas are usually 0.5-2.0 cm in size, only rarely exceedi ng 5 cm {2380}. Most have a non spe­ cific nodular appearance.

Diagnostic molecular pathology

Histopathology

Essential and desirable diagnostic criteria

Epithelioid haemangioma typically exhibits a proliferation of well-formed small blood vessels lined by plump and epithelioid endothelial cells with abundant eosinophilic cytoplasm and enlarged round nuclei. The tumour is typically well demarcated and has a distinctive lobulated growth at low power. Moreover, it shows increased maturation of the vascular lumina at the periphery of the lesion. These vessels are lined by a monolayered en dothelium and an in tact pericytic layer in a loose stroma. The endothelial cells may show intracytoplasmic vacuoles (socalled blister cells). Tumour cells have vesicular or fine chromatin, with only mild cytological atypia and mostly low mitotic activity. The stromal comp orient is ofte n oedematous, and the tumour may show haemorrhagic changes within the solid component. A subset of cases may display centrifugal growth around a central small artery and evenly complete intravascular growth. Marked lymphoplasmacytic in filtrates, promi nent lymPhoid follicles, and abundant eosinophils are not uncommon,

Essential: lobular architecture with vasoformation; lining endothelial cells are epithelioid, with eosinophilic cytoplasm and enlarged round nuclei; loose haemorrhagic stroma, often with eosinophils. Desirable: dem on strati on of FOS/FOSB rearra ngements or expression may be helpful in selected cases.

Rearrangement of the FOS or FOSB gene can be detected by molecular methods if required {1440,2387}.

Staging Not clin ically releva nt

Prog nosis and prediction As many as one third of patients experienee local recurrence, related to incomplete excision or multicentricity. Most of the recurre nces are in dole nt and can be cured by re-excisi on, although very rare recurrences can be locally aggressive. Rare lymph node metastasis may occur. To date, no patients have developed distant metastases. Soft tissue tumours

153

paybal：https://www.paypal.me/andy19801210 Lymphangioma and lymphangiomatosis

Thway K Doyle LA

Definition Lymphangioma is a benign vascular lesion composed of a local­ ized collection of dilated lymphatic channels. Lymphangiomatosis is multicentric or extensively infiltrating lymphangioma, and it typically invoIves multiple tissue planes or more than one organ.

ICD-0 coding 9170/0 Lymphangioma NOS 9173/0 Cystic lymphangioma

ICD-11 coding LA90.12 & XH9MR8 Lymphatic malformations of certain speci­ fied sites & Lymphangioma 2E81.10 Disseminated lymphangiomatosis

Related terminology Acceptable: cystic hygroma; lymphatic malformation; lymphan gioma circumscriptum; caver nous lympha ngioma; intraabdominal cystic lymphangioma; haemangiolymphangioma.

Subtype(s) Lympha ngiomatosis

Localization Lymphangiomas may be superficial or deep, or they may involve both superficial and deep tissue planes. Superficial lesions are often referred to as lymphangioma circumscriptum, and deep lesi ons as caver nous lympha ngioma {3280,2469,1013}. Most cases of superficial lymphangioma / lymphangioma cir­ cumscriptum arise on the skin of proximal extremities and limb girdles. Cavernous lymphangiomas most commonly involve the head and neck, followed by the extremities, axilla, groin, and abdominal sites, including the gastrointestinal tract, mesentery, and retroperitoneum {83,1409}. Cystic hygroma (cystic lymphangioma) presents as a large mass in the neck, axilla, or groin of infants. Lymphangiomatosis can involve either a single anatomical structure/organ or multiple structures (e.g. skeletal muscle, liver, spleen, lungs, and bones) {1184,2783,87}.

Fig. 1.169 Lymphangioma. Lymphangioma of the small intestine involving mucosa and submucosa. The lymphatic channels are dilated and lined by inconspicuous en­ dothelium, and they contain lymphatic fluid and occasional lipid-laden macrophages.

syndromes {264,453,569}. Head and neck lymphangiomas represent the most frequent subtype. Although lymphangiomas primarily occur in children and young adults, there is a wide age range including older adults, particularly for mesenteric lesions {3030,2624,2199}, and an overall slight male predominance.

Clinical features

Etiology

Superficial lymphangioma appears as pale or pink vesicles involving skin. Deeper lesions may present as circumscribed, soft, and fluctua nt pain less swelli ngs. Deep lesi ons may dis­ place surrounding organs at mediastinal sites (compression of trachea and oesophagus) or intra-abdominal sites (intestinal obstruction).

Early or congenital lesions favour developmental malformations, with genetic abnormalities playing an additional role {3288}. Somatic mutations in PIK3CA have been reported to be involved {1912}.

Epidemiology Lymphangiomas are common paediatric lesions, presenting most often at birth or during early life {83}. Some are identi­ fied in the con text of Turner syn drome or other malformative

154

Soft tissue tumours

Pathogenesis Lymphangiomas are thought to arise from abnormal lymphatic system development. PIK3CA and other mutations are likely drive this process through endothelial growth receptor path ways {1912,3024}.

paybal：https://www.paypal.me/andy19801210

Hg. 1.170 Lymphangioma of the mesentery. A Present within the bowel muscularis propria, this lymphangioma shows well-formed, dilated lymphatic channels that contain lymphocytes and are lined by flattened endothelial cells lacking any atypia. B Showing multiple, markedly ectatic lymphatic channels containing lymph and lined by small bland

endothelial cells.

Macroscopic appearanee Lymphangiomas are multicystic and spongy, with cavities containing watery/milky chylous fluid.

Histopathology Cutaneous lesions consist of dilated thin-walled lymphatics in superficial dermis that connect with thick-walled, often mus­ cular, lymphatic channels in deep dermis, often with overlying epidermal hyperplasia. Cavernous lymphangiomas contain variably sized thin-walled, dilated lymphatic vessels lined by flattened endothelium, frequently surrounded by lymphocytic aggregates. Lumina may be empty or may contain proteinaceous fluid, lymphocytes, and sometimes erythrocytes. Larger vessels can be surrounded by a smooth muscle layer, and longstanding lesions may show interstitial fibrosis and stromal inflammation. Stromal mast cells and haemosiderin deposition are common. Xanthogranulomatous inflammation with florid cellular reactive myofibroblastic proliferations can obscure the underlying lymphatic abnormality, particularly in mesenteric or retroperitoneal lesions {1409}. In lymphangiomatosis, the ves­ sels are similarly thin-walled and variably dilated, but they usu­ ally also show an anastomosing growth pattern and may dissect around normal structures. The endothelium expresses podoplanin (D2-40) and PROX1 {2138}, as well as CD31 (consistently) and CD34 (variably) {1409}. SMA is positive in smooth muscle cells surrounding the cysts.

Cytology Not clinically relevant

Diagnostic molecular pathology Not clinically relevant

Fig. 1.171 Lymphangiomatosis, mucosal. This example of lymphangiomatosis is seen within bowel mucosa. The ectatic lymphatic channels are lined by small, almost im­ perceptible spindle cells and contain prominent cloudy lymph as well as numerous lymphocytes.

Staging Not clin ically releva nt

Prognosis and prediction Lymphangiomas are benign, but because of their propensity for invoIvement of deeper tissue planes, recurrences occur in as many as 20% of patients after removal of apparently super­ ficial lesions {1290,83}. In general, the recurrence rate varies depending on lesion size and depth. However, lymphangiomatosis has a much higher recurrenee rate, and diffuse lymphangi­ omatosis with visceral involvement can be fatal.

Essential and desirable diagnostic criteria Essential: tumour composed of thin-walled vascular spaces. Desirable： immunohistochemical expression of CD31 and D2-40, with variable CD34 expression.

Soft tissue tumours

155

paybal：https://www.paypal.me/andy19801210 Tufted angioma and kaposiform haemangioendothelioma

le af

C C m in

Definition

ICD-11 coding

Kaposiform haemangioendothelioma (KHE) is a rare, often deep-seated, vascular neoplasm usually presenting in children, characterized by lobular in filtrates of capillaries and spindled endothelial cells associated with lymphatic vessels. Tufted angioma (TA), a more superficial lesion, is otherwise essentially identical to KHE. Together, KHE and TA are responsible for virtually all instances of the platelet-trapping syndrome Kasabach-Merritt phenomenon (KMP).

2F2Y & XH6PA4 Other specified benign cutaneous neoplasms & Kaposiform haemangioendothelioma

ICD-0 coding 9161/0 Acquired tufted haemangioma 9130/1 Kaposiform haemangioendothelioma

Related terminology

w ni

T2 El

M

Not recommended: Kaposi-like inf a ntile haema ngioe ndotheli. oma; haemangioma with Kaposi-like features; angioblastome of Nakagawa.

KI

Subtype(s)

Et

None

U

Localization TA and KHE most comm only affect the skin and deep soft tissues of the extremities, head and neck, trunk, and retroperitoneum

P?

S( 2 pl

pl (3 Vc

A m

M M

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C of

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er

Fig. 1.172 Tufted angioma / kaposiform haemangioendothelioma. A Kaposiform haemangioendothelioma lesions with both superficial and deep components show transition fro" smaller superficial tumour nodules with subtle endothelial spindling (tufted angioma pattern) to deeper coalescent nodules with more prominent spindling and platelet-trapping ©as， sic kaposiform haemangioendothelioma pattern). B This lesion shows the typical superficial (tufted angioma) pattern. Higher magnification reveals pinpoint lumina and relatively subtle endothelial cell spindling without nuclear pleomorphism. Mitotic activity is very low. C This lesion with a superficial (tufted angioma) pattern shows focal strong positivity® podoplanin within tumour nodules, sharply sparing other areas within the same nodule. A matching pattern of positivity is seen for other lymphatic endothelial markers, inclucW PR0X1 and LYVE1, as well as for CD34 (which is normally expressed preferentially in blood vascular endothelial cells). D Within tumour nodules of kaposiform haemangioendothe­ lioma, an alternating pattern of strong positivity and negativity for podoplanin is striking. Note the presence of abnormal lymphatic vasculature in adjacent stroma, a common finding

156

Soft tissue tumours

Fi

cc la

paybal：https://www.paypal.me/andy19801210 comm only, the mediasti num, splee n, bone, and testis are Reeled {1922,3410,908,3291,2325,663}.

Clinical features Cutaneous forms are violaceous, infiltrative patches/plaques that may develop nodularity. Deeper soft tissue lesions are bulging indurated masses. Congenital/early infantile cases, especially when large, commonly present with profound thrombocytopenia (KMP) {1922}. MRI shows an ill-defined, diffusely enhancing T2-hyperi ntense mass in vol ving multiple tissue layers.

Epidemiology Most cases present in children aged < 5 years; some are con­ genital. Congenital/early infantile tumours cause most KMP cases. Rare cases present in older children and adults, without KMP {2087,657,663}. There is no sex or racial predilection.

Etiology Unknow n

Pathogenesis Somatic activating GNA14 mutations have been reported in 2 cases {I860}. KMP can be attributed to histologically observed platelet-trapping within tumoural vascular beds, because podoplanin is the natural ligand of CLEC2, a platelet-bound receptor (3007}. Platelet transfusions may worsen KMP by stimulating vascular proliferation by intratumoural platelet activation {13}. A self-sustaining cycle of platelet-trapping and tumour growth may drive tumour progression and KMP development.

Macroscopic appearance Macroscopically, TA and KHE appear as multiple grey to red infiltrative nodules, encased in fibrous tissue.

Histopathology Classic KHEs are composed of ill-defined, coalescing nodules of spindled endothelial cells forming elongated slit-like lumina containing erythrocytes, curving around epithelioid nodules enriched in pericytes surrounding platelet-rich microthrombi.

Fig. 1.174 Kaposiform haemangioendothelioma, classic pattern. Classic histological manifestations of kaposiform haemangioendothelioma, such as prominent endothelial spindling and numerous platelet-rich microthrombi, are best developed in larger, more deeply seated lesions, as shown in this example from the lateral neck of an 8-day-old girl. Platelet-trapping within compressed spaces is highlighted by CD61 immunostain­ ing (not shown) and is the presumed histological correlate of Kasabach-Merritt phe­ nomenon. Note the presence of abnormal lymphatic vasculature in adjacent stroma, a common finding.

Mitoses are in freque nt. Variably promine nt areas show more typical capillary formation. Dilated crescentic lymphatic ves­ sels surrou nd and in termi ngle with n odules, most promi nently at peripheral margins. Peripheral fibrosis is common around en dothelial cell n odules. Peri neural invasion may be prese nt. Residua after medical treatment or spontaneous regression are sclerotic versi ons of the original. Spin died endothelial cells of KHE are positive for CD31, CD34, and ERG, as well as strongly positive for the lymphatic markers podoplanin, LYVE1, and PROX1 {2324,1787}. TAs are less extensively posi­ tive for lymphatic markers, seemingly correlated with reduced endothelial spindling {1787}. Expression of the infantile haemangioma-associated marker GLUT1 is absent in KHE/TA {2327, 2326,1922}. CD31/CD61 immunostaining highlights platelet-rich microthrombi.

Fig，1.173 I'ufted angioma / kaposiform haemangioendothelioma. A A lesion from the knee in a 5-month-old girl. This kaposiform haemangioendothelioma shows solid growth

composed of nests of ovoid cells, forming siit-like lumina. Perineurial invasion is present. B This lesion from the buttock of a 5-year-old girl shows tightly packed lobules of capillaries involving subcutis.

Soft tissue tumours

157

paybal：https://www.paypal.me/andy19801210 Cytology

Staging

Not clin ically releva nt

Not clinically releva nt

Diagnostic molecular pathology

Prognosis and prediction

Not clinically releva nt

Un treated lesi ons may partially un dergo fibrosis and regress but they in variably recur. Large lesi ons are associated with high mortality due to thrombocytopenia or tumour infiltration. Wide local excision, when feasible, can be curative. Medical thera­ pies (e.g. vincristine arid steroids) are the first line for high-risk patients with KMP; mTOR inhibition (e.g. sirolimus) is also prom， ising {13,14}. No distant metastases have been reported; lymph node invoIvement is rarely seen {1922,1736}. This may represent multifocal lymphatic chain invoIvement rather than true metas­ tasis.

Essential and desirable diagnostic criteria Essential: superficial dermal lesions (TA pattern): discrete lob­ ules of capillaries in can nonball patter n within dermal col­ lage n; deeper lesions (KHE pattern): ill-defined, coalescing no dules composed of fascicles of plump spin died en dothelial cells that form slit-like lumina that contain erythrocytes - a prominent component of dilated lymphatic vessels is seen at the periphery and in surrounding fibrotic stroma; the spindled cells are positive for CD31, ERG, CD34, and lymphatic mark­ ers (podoplanin, LYVE1, PROX1).

158

Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 Retiform haemangioendothelioma

Definition Retiform haemangioendothelioma is a locally aggressive, rarely metastasizing vascular lesion, characterized by distinctive arborizing blood vessels lined by endothelial cells with charac­ teristic hobnail morphology.

Calonje JE

Localization The turn our in volves predomi nantly the skin and subcuta neous tissue and is most commonly found in the distal extremities, par­ ticularly the lower limb.

Clinical features

ICD-0 coding 9136/1 Retiform haemangioendothelioma

ICD-11 coding 2B56.1 & XH64U8 An giosarcoma of skin & Retiform haemangioe ndothelioma

Retiform haemangioendothelioma presents as a red/bluish slow-growing plaque or nodule, usually < 3 cm in maximum dimension. A case with multiple lesions has been described {868}. Exceptional cases occur in the setting of previous radio­ therapy {462} or pre-existing lymphoedema {462} (including Milroy disease {173}), as well as in association with a cystic lymphangioma {65}.

Related terminology Acceptable: hob nail haemangioe ndothelioma,

Subtype(s) None

Epidemiology Retiform haema ngioe ndothelioma is un comm on. Since its original description in 1994, only about 40 cases have been reported {65,462,1090,2092,3036}. The age range is wide, but this lesion usually affects you ng adults or children; males and females are affected equally frequently.

Fig，1.175 Retiform haemangioendothelioma. A A cutaneous example showing an infiltrative growth of well-formed elongated vessels reminiscent of rete testis pattern' B Branching vessels within a sclerotic stroma with associated lymphocytic infiltrate. Dabska-like intravascular papillary structures are present. C High-power view showing vascular structures lined by monomorphic hobnail endothelial cells, lacking nuclear pleomorphism or increased mitotic activity. D Diffuse podoplanin expression, confirming Emphatic endothelial phenotype.

Soft tissue tumours

159

paybal：https://www.paypal.me/andy19801210 Etiology Unknown

Pathogenesis Unknown

Macroscopic appearance Macroscopic exami nation reveals diffuse, sometimes discol­ oured induration of the dermis, with frequent involvement of the underlying subcutaneous tissue.

Histopathology Seanning magnification reveals characteristic elongated and narrow arborizing vascular channels with a striking resemblance to normal rete testis. Although this pattern is usually readily apparent, if the vascular channels are small or col­ lapsed, then the retiform architecture may be difficult to recognize. Monomorphic hyperchromatic endothelial cells with prominent protuberant nuelei having a characteristic tombstone or hob nail appeara nee line the blood vessels. These cells have sea nt cytoplasm, which seems to blend with the un derlyi ng stroma. Pleomorphism is absent and mitotic figures are rare. A prominent stromal and often intravascular lymphocytic infiltrate is present in about half of the cases. The stroma surrounding the tumour tends to be sclerotic. Focal solid areas composed of sheets of endothelial cells are often identified. Vacuolated cells are un comm only see n. Mono morphic en dothelial spin dleshaped cells are also a rare feature and were described in a case of metastatic disease in a lymph node {462}. In some cases, there are in travascular papillae with hyaline collage nous cores similar to those see n in papillary in tralymphatic an gioen­ dothelioma {65}. Retiform haemangioendothelioma can be one

of the comp on ents of a composite haemangioendothelioma The neoplastic cells in retiform haemangioendothelioma stain for vascular markers, including CD31, CD34, and ERG. Stain， ing for CD34 is often stronger than for other vascular markers Although the lymphatic marker PROX1 is positive in retiform haemangioendothelioma, other lymphatic markers, includinc podoplanin (D2-40) and the less specific VEGFR3, are usua"； (but not always) negative {900,2138,2453}. These lesions a』

Pa am

negative for HHV8.

Defini

Cytology

Papill； mon,

Not clin ically releva nt

tumou

within

Diagnostic molecular pathology

vascul

Not clin ically re leva nt ICD-C

Essential and desirable diagnostic criteria

9135/1

Essential: arborizing branching vascular channels; blanc en dothelial cells with hob nail morphology and no or very n mitotic activity.

2F72.Y

ICD-11

beha

Staging Not clin ically re leva nt

Relate(

Not re
40% of retroperitoneal leiomyomas were reported in patients who had con current uteri ne leiomyomas or had un dergone previous hysterectomy for uterine leiomyomas may support a theory of multifocal origin {579,1402,321,2407}.

Related terminology

Pathoge nesis

None

Retroperitoneal / abdominal cavity leiomyomas carry some ol the same genetic changes as uterine leiomyomas {2417,2415 2419}. Genetic analysis of 8 leiomyomas of the retroperitoneumabdomi nal cavity showed 3 tumours with 12q rearrangements. 3 with 8q rearrangements, 1 with deletion of 7q, and 1 with aberrations of chromosome bands 3q21-q23 and 11q21-q22 The target genes of the 12q and 8q aberrations were HMGA2 and PLAG1, respectively {2419}. In other studies, mutations in exon 2 of MED 12 were reported in retroperitoneal leiomyomas {2586,2794}. KAT6B-KANSL1 and EWSR1-PBX3 fusion genes were found in retroperitoneal leiomyomas with t(10;17)(q22;q21) and t(9;22)(q33;q12) chromosomal translocations, respectively {2417,2415}.

8890/0 Leiomyoma NOS

ICD-11 coding

Subtype(s) None

Localization Leiomyomas of somatic soft tissue mostly occur in extremi­ ties and arise in deep subcutis or skeletal muscle {321,1627}. Although the retroperit on eum is the most comm on location in the other group, they may also occur in abdominal wall, omentum, mesentery, and peritoneal surface {321,2407}. In the inguinal region, leiomyomas may arise from the round ligament {2463}.

Clinical features Although usually solitary, retroperitoneal tumours may be multi­ ple {321}. Somatic tumours often have calcification and may be detected radiographically {1627,321,2145,2674}. No recurrence has been reported for somatic leiomyomas {1627,321}. Recurrence was reported in < 10% of leiomyomas of retroperitoneumabdominal cavity {321,2407}.

Epidemiology Leiomyomas of somatic soft tissue occur primarily in middleaged adults, with no sex differenee {1627,321}. Leiomyomas of

Macroscopic appearance Somatic leiomyomas are circumscribed masses that are tan­ grey to white in colour and often have a rubbery texture and a whorled cut surface. Degenerative mucoid-cystic change is occasionally present {1627,321}. The size ranges from < 1 to 15 cm {321}. Leiomyomas of retroperitoneum-abdominal cavity are reddish-tan, greyish-tan, or white circumscribed masses, often having a trabecular surface resembling that commonly seen in uterine leiomyomas {321,2407}. They range in size from 2.5 to 37 cm {321,2407}.

Fig. 1.211 Leiomyoma. A Low-power view shows clear distinction from surrounding tissue and broad interlacing fascicles of smooth muscle cells. B Higher magnification oi

leiomyoma of somatic soft tissue, showing fascicles of smooth muscle cells.

188

Soft tissue tumours

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Fig. 1-212

siomyoma. A Retroperitoneal leiomyoma with myxoid change. B Retroperitoneal leiomyoma with hyalinization.

Histopathology

Cytology

Leiomyomas of deep soft tissue are composed of cells that closely resemble normal smooth muscle cells with eosinophilic cytoplasm and uniform blunt-ended, cigar-shaped nuclei. They are arranged in orderly intersecting fascicles. They are highly differentiated, have little or no nuclear atypia, and have at most an extremely low level of mitotic activity. Limb lesions and intra-abdominal lesions in males show almost no mitoses. In peritoneal/retroperitoneal lesions in females (showing positivity for hormonal receptors), there may be a few mitoses visible. Necrosis is not found in deep leiomyoma. Most lesions are paucicellular, and degenerative or regressive changes, such as fibrosis, hyalinization, calcification, and myxoid change, are common in large tumours. Leiomyomas of retroperitoneum-abdominal cavity display a spectrum of pat­ terns similar to those of uterine leiomyomas. They show macrotrabecular and microtrabecular organization, hyalinization, and focal myxoid or cystic change. Focal epithelioid change, clear cell change, metaplastic bone, and fatty differentiation are also occasionally seen {2059}. Focal degenerative nuclear atypia should always prompt a careful search for mitoses and additional sampling, because some leiomyosarcomas may have only focal atypia and very low mitotic activity. Tumour cells are positive for SMA, desmin, and h-caldesmon, at least focally, but they are negative for S100. Leiomyomas of retroperitoneum-abdominal cavity are almost always positive for ER, PR, and WT1 {321,2407,2463}. Leiomyomas of somatic soft tissue do not express ER or PR {1627,2407}.

Large mass-forming leiomyomas may be sampled by EUSguided FNA. Fragments of spindle cells with bland cytology are noted in adequate samples. Confirmatory immunohistochemical staining can be performed on cell block material {2939}.

Fig. 1.213 Retroperitoneal leiomyoma with hydropic change. Retroperitoneal leiomy°ma composed of thin fascicles of bland smooth muscle separated by an oedematous stroma. Hydropic change is often seen in retroperitoneal leiomyomas.

Diagnostic molecular pathology Not clin ically re leva nt

Essential and desirable diagnostic criteria Essential: intersecting fascicles of benign smooth muscle. Desirable (in selected cases): expression of SMA and desmin.

Staging Not clinically relevant

Prognosis and prediction These tumours are benign, and patients are cured by complete excision. There is no metastatic risk, but local recurrences have been reported in some patients with retroperitoneal tumours {321,2407}. None of the patients with recurrenee have demonstrated disease progression or metastasis in follow-up.

Fig. 1.214 Retroperitoneal leiomyoma. The tumour nuclei are diffusely positive for ER, typical of retroperitoneal leiomyomas.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 EBV-associated smooth muscle tumour

Watanabe R Schafernak KT Soares FA

Defin ition EBV-associated smooth muscle tumour is a smooth muscle tumour associated with EBV infection, usually in the setting of immu nosuppressi on.

ICD-0 coding 8897/1 Smooth muscle tumour of uncertain malignant potential

ICD-11 coding 2F7Y & XH00B4 Neoplasms of uncertain behaviour of other specified site & Smooth muscle tumour NOS

Related terminology Not recommended: AIDS-associated EBV-positive smooth muscle tumour; EBV-associated posttransplant smooth mus­ cle tumour; smooth muscle tumour in immunocompromised patient.

Subtype(s) None

Localization EBV-associated smooth muscle tumours can occur any where in the body, in eluding sites un usual for sporadic leiomyomas and leiomyosarcomas. HIV-associated smooth muscle tumours have a particular predilection for the intra-axial or extra-axial CNS (41% of cases), whereas posttransplant smooth muscle tumours most commonly involve the liver (56%; the donor liver in liver transplant recipients and the native liver in recipients of other solid organs), followed by the lungs (31%) and gastrointestinal tract (15%); they have also been reported in kidney, lung, and heart allografts. Tumours are multicentric in 71%, 54%, and 29% of primary immunodeficiency, posttransplant, and HIV­ positive patients, respectively.

Fig. 1.215 EBV-associated smooth muscle tumour. Gross autopsy photograph( multiple splenic tumours in a child who underwent haematopoietic stem cell trans plantation for a primary immune disorder 10 months earlier; a monomorphic B-ce posttransplant lymphoproliferative disorder was found concurrently in the liver.

Clinical features Prese nting features may be non specific (pai n) or related to the site of invoIvement: neurological symptoms with intra-axial or extra-axial CNS tumours; bleeding, abdominal pain, obstruction, and perforation when involving the gastrointestinal tract; and cyanosis, fever, and lung infections with endobronchial lesions.

Epidemiology Occurring over a wide age range (1-66 years) and with a slight female predominance, most cases occur in one of three main settings: immunodeficiency due to HIV/AIDS, immunodeficiency after transplantation of a solid organ (63% kidney, 15% heart, 12% liver) or haematopoietic stem cells, and (least comm only) congen ital or primary immunodeficie ncy. Most pri­ mary immunodeficiency patients (88%) with EBV-associated smooth muscle tumours have been children {1936}; reported 190

Soft tissue tumours

Fig.1.216 EBV-associated smooth muscle tumour. Whole-mount section of EB* associated smooth muscle tumour developing in penile skin.

paybal：https://www.paypal.me/andy19801210 ,lt primary immunodeficiency patients had GATA2 deficiency ^32) In contrast, 68% of posttransplant and 72% of HIV/AIDS atients are adults. Tumours are found several months to years ；fter the on set of the patient's immu no deficie ncy syn drome or ransplantation. The epidemiology is similar to that of the immunodeficiency-associated lymphoproliferative disorders, which are frequently EBV-positive, although they tend to occur as a later consequenee than the EBV-positive lymphoproliferative disorders observed in a subset of smooth muscle tumour patients (particularly in children in the posttransplant and primary immunodeficiency settings). Rarely, these tumours are associated with iatrogenic immunosuppression for autoimmune disease {2183}. If these tumours are encountered outside of any of these settings, a thorough immunological work-up and close follow-up for opportunistic infections are warranted.

Etiology

Pathoge nesis During latent infection, as many as 10 of the nearly 100 genes in the EBV genome are expressed, another mechanism to evade T-cell immune surveillanee. The latency pattern remains contro­ versial and is perhaps unique to this entity, although many authors describe a type Ill-like pattern with positivity for EBV-encoded small RNA (EBER), EBNA2, and LMP1 despite somewhat incon­ sistent EBNA2 results and absenee of LMP1 from most posttransplant and some HIV-associated cases. MYC overexpression and AKT/mTOR pathway activation appear to be main mediators of EBV-induced smooth muscle tumour proliferation {2384,3035}. Tumour multicentricity is related to multiple infection events, with viral episomal analysis showing independent viral clones rather than dissemination or metastasis of a single clone, which is far less common {811}. Furthermore, short tan dem repeat (STR) analysis has revealed that posttransplant smooth muscle tumours can be derived from either recipie nt or donor {1548}.

The etiology involves EBV infection in the setting of T-lympho­ cyte immunosuppression.

Fig. 1.217 EBV-associated smooth muscle tumour. A Intersecting fascicles of spindled cells with ample eosinophilic cytoplasm and elongated nuclei. B Round cells with a more primitive appearance accompany the spindled cells in about one half of cases.

?g. 1.218 EBV-associated smooth muscle tumour. A The nuclei are positive with in situ hybridization for EBV-encoded small RNA (EBER). B T cells are commonly found within the tumour, although they are usually sparse.

Soft tissue tumours

191

paybal：https://www.paypal.me/andy19801210 Macroscopic appearance

Essential and desirable diagnostic criteria

Tumours range from subcentimetre to > 20 cm {1444,1548}, with white to grey cut surfaces, a firm to rubbery consistency, and well-circumscribed to infiltrative borders.

Essential: clinical history of immunosuppression; neoplasm with smooth muscle d if fere ntiati on; positivity for EBER tran scrips by in situ hybridization.

Histopathology

Staging

The tumou r is composed of in tersecti ng fascicles of spin died cells with ample eosinophilic cytoplasm and elongated nuclei; in about half of cases, a second population of round, more primitive-appearing smooth muscle cells is seen. A subset of these tumours exhibit a haemangiopericytoma-like pattern. Cytologi­ cal atypia is usually mild to moderate but can be marked in HIV­ positive patients, whose tumours also show higher mitotic activ­ ity and/or necrosis. An intratumoural T-lymphocytic infiltrate is common and usually sparse but can be more pronouneed {811}. Neoplastic cells are diffusely positive for SMA and h-caldesmon. Desmin is sometimes positive but expression is usually focal. EBER is consistently positive {1444}.Cytology Not clin ically re leva nt

Not clin ically re leva nt

Diagnostic molecular pathology Diag no stic molecula r pathology involves dem on strati on of EBV, usually by in situ hybridization for EBER.

192

Soft tissue tumours

Prognosis and prediction Prog nosis is mainly depe ndent on the con dition of the in dividual patient's immune system. Most of these tumours do not metas­ tasize. Intracranial posttransplant smooth muscle tumours (but not HIV/AIDS-associated or primary immunodeficiency-assa ciated smooth muscle tumours) have an adverse prognosis Some posttransplant cases respond to reduced immunosup. pression, which partially restores immune function, and com­ plete resolution of EBV-associated smooth muscle tumours has been reported in a patient with GATA2 deficiency after hae­ matopoietic stem cell transplantation {2454}.

paybal：https://www.paypal.me/andy19801210 Fletcher CDM Mertens F

Inflammatory leiomyosarcoma

Definition Inflammatory leiomyosarcoma (LMS) is a malignant neoplasm showing smooth muscle d if fere ntiation, a prominent inflammatory infiltrate, and near-haploidization.

ICD-0 coding 8890/3 Leiomyosarcoma NOS

ICD-11 coding 2858 & XH7ED4 Leiomyosarcoma, primary site & Leiomyosar­ coma NOS

Related terminology None

Fig. 1.220 Inflammatory leiomyosarcoma. Between numerous lymphohistiocytic cells, the spindled tumour cells are highlighted by immunopositivity for desmin.

Subtype(s) None

Etiology Unknown

Localization Most inflammatory LMSs arise in deep soft tissue, most com­ monly in the lower limb, followed by the trunk and retroperitoneum. Isolated cases have arisen at visceral locations {536, 2321).

Clinical features Most cases present as an enlarging deep soft tissue mass of variable du rati on and with no specific features. Isolated cases have been associated with inflammatory-type symptoms {536}.

Epidemiology Inflammatory LMS is very rare. The majority of cases occur in adults (with a median age of 35-40 years and an age range of 12-64 years in published cases) {2093,536,2321,150). There is a relative male predominance.

Pathogenesis The pathogenesis is not fully understood, but these tumours have a distinctive near-haploid genotype, with or without subsequent whole-genome doubling, and they are associated with striking myogenic gene expression. The near-haploidization is thought to be pathoge netically imports nt {150}. Whe n an alysed by chromosome banding or genomic arrays, 10 of 11 inflamma­ tory LMSs displayed near-haploidization, with or without subse­ quent whole-genome doubling(s) {721,536,2321,150}. Although most chromosomes thus showed loss of heterozygosity, there was always retained heterozygosity for chromosomes 5 and 22, and often for chromosomes 18, 20, and 21. Apart from mutation of the NF1 gene in a subset of the cases, no additional somatic variants that could serve as driver mutations have been detected {150}. Gene expression profiling has shown prominent

1.219 Inflammatory leiomyosarcoma. A In this tumour there is a mixed lymphohistiocytic infiltrate with prominent xanthomatous cells. B Tumour cells are largely obscured by the prominent lymphoid infiltrate.

Soft tissue tumours

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Fig. 1.221 Inflammatory leiomyosarcoma. Genomic array findings in an inflammatory leiomyosarcoma showing relative copy-number gain of chromosomes 5,and 20-Q (top, red) and loss of heterozygosity for all other chromosomes (bottom, grey).

differential expression of genes involved in muscle development and function {150}.

Cytology

Macroscopic appearanee

Diagnostic molecular pathology

Most tumours appear well circumscribed, with a maximum diameter of 3-12 cm. Cut surfaces are tan -yellow or red and soft/fleshy.

Not clinically re leva nt

Histopathology These tumours consist of eosinophilic spindle cells with bluntended elongated nuelei, arranged in fascicles or sometimes in a storiform fashion. The degree of nuclear atypia and pleomor­ phism varies, as does mitotic count, depending on histological grade. However, most cases appear to be low-grade. The striking and characteristic feature is the presenee of a prominent, usually diffuse, inflammatory in filtrate, which ofte n obscures the neoplastic cell population. The inflammatory component is usually dominated by small lymphocytes, sometimes admixed with plasma cells. Histiocytes are also often prominent and may have a xanthomatous appearanee. In a minority of cases, the inflammatory infiltrate may consist mainly of neutrophils or eosinophils. Calcospherites (psammomatous calcifications) are a striking feature in some cases. Virtually all cases show immu nopositivity for some combi nation of SMA, desmi n, and caldesm on.

Not clin ically releva nt

2

Essential and desirable diagnostic criteria Essential: fascicular proliferation of variably atypical eosinophilic spindle cells, which show mitotic activity; dense inflammatory in filtrate, most ofte n lymphoid or histiocytic/xa nthomatous, but the composition is variable; immunopositivity for smooth muscle antigens.

R N

S

Staging

L(

The America n Joint Committee on Cancer (AJCC) or Un ion for International Cancer Control (UICC) TNM system is appropriate.

S( tic Vi!

Prognosis and prediction Published follow-up data in inflammatory LMS are limited due to its rarity. Among 20 cases with follow-up, only 4 have been reported to metastasize, but du rati on of follow-up is < 5 years in most cases. Of the cases in which a near-haploid genotype has bee n well docume nted, the prog nosis seems gen erally to be very good {150}.

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194

Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 Dry SM Frohling S

Leiomyosarcoma

Definition Leiomyosarcoma (LMS) is a malignant neoplasm composed of ceils showi ng smooth muscle d if fere ntiation.

ICD-O coding 8890/3 Leiomyosarcoma NOS

ICD-11 coding 2858.0 & XH7ED4 Leiomyosarcoma of retroperitoneum or peri­ toneum & Leiomyosarcoma NOS 2B58.Y & XH7ED4 Leiomyosarcoma, other specified primary site & Leiomyosarcoma NOS 2B58.Z & XH7ED4 Leiomyosarcoma, unspecified primary site & Leiomyosarcoma NOS

Related terminology None

Subtype(s) None

Localization Soft tissue LMSs most comm only arise in the extremities (par­ ticularly the lower extremities), retroperitoneum, abdomen/pelvis, and trunk {1164,3290}. A distinctive subgroup originates in large blood vessels, most commonly the inferior vena cava, its major tributaries, and the large veins of the lower extremity. Tumours occur at intramuscular and subcutaneous localiza­ tions in approximately equal proportions, and many originate from a small to medium-sized vein {1829,972}.

Clinical features Soft tissue LMS gen erally prese nts as a mass lesion that is often associated with non specific symptoms caused by the displacement of structures rather than invasion. The symptoms produced by inferior vena cava LMS depend on location. In the upper por­ tion, it obstructs the hepatic veins and can evince Budd-Chiari syndrome with hepatomegaly, jaundice, and ascites. Tumours of the middle portion may block the renal veins. Involvement of the lower portion may cause leg oedema. Imaging studies of LMS (MRI and contrast-enhanced CT) are nonspecific but helpful in deli neating the relati on ship to adjacent structures, particularly in the retroperitoneum.

Fig. 1.222 Leiomyosarcoma. A Axial contrast-enhanced CT shows a right-sided retroperitoneal mass (solid arrow), which is clearly arising from the inferior vena cava. The lumen of the inferior vena cava is partially occluded (slit-like residual lumen indi­ cated by dashed arrow). B Leiomyosarcoma arising from the inferior vena cava.

since 2000 {2133,2134,2124,2136,3336,1366}. LMS accounts for 10-15% of limb sarcomas, with prefere nee for the thigh {2001}. Women constitute the clear majority of patients with retroperitoneal and inferior vena cava LMSs, but not among patients with tumours at other sites.

Etiology Predisposing factors recognized for LMS include Li-Fraumeni syndrome, hereditary retinoblastoma, and radiation exposure {3187,2354,426,1133}.

Epidemiology The incidence of soft tissue LMS in creases with age and peaks in the seventh decade of life, although this neoplasm may develop in young adults and children {795}. LMS accounts for about 11% of all newly diagnosed soft tissue sarcomas {865}. h is the predominant sarcoma arising from larger blood ves­ sels {3182,1829,1617,275,1754}. Gastrointestinal LMSs are very 「are, with < 80 cases reported in the English-language literature

Pathogenesis Cytogenetic, molecular cytogenetic, and next-generation sequencing studies show that LMSs display extensive genomic in stability, including chromothripsis and whole-ge nome dupli­ cation in subsets of cases {594}. Recurrent DNA copy-number alterations include losses involving tumour suppressors PTEN (10q23.31), RB1 (13q14.2), and TP53 (17p13.1), as well as

Soft tissue tumours

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Fig. 1.223 Leiomyosarcoma. A Intermediate-grade leiomyosarcoma, arising from the wall of a vein. Many soft tissue leiomyosarcomas arise from vascular smooth muscle and such tumours may be deceptively well circumscribed. B Low-grade leiomyosarcoma, composed of well-differentiated smooth muscle, with nuclear hyperchromatism anc

identifiable mitotic activity. C Intermediate-grade leiomyosarcoma. The tumour cells show classic features of smooth muscle differentiation, with variably pleomorphic, elongated nuclei; perinuclear vacuoles; and distinctly eosinophilic cytoplasm. D Low-grade leiomyosarcoma with granular cell change. Leiomyosarcomas with this unusual morphological feature may be confused with granular cell tumours.

amplification of MYOCD at 17p12, which encodes a smooth muscle-specific transcriptional coactivator {899,1962,3238, 1657,3348,1150,472,594}. Whole-exome/genome and RNA sequencing studies have dem on strated that LMSs are characterized by a modest burde n of somatic mutations and substantial mutational heterogeneity {472,594}. TP53 is mutated in as many as 50% of sporadic LMSs; approximately 90% of samples present with biallelic TP53 inactivation through mutations, deletions, chromosomal rearrangements, or protein-damaging microalterations {2525, 2492,1493,37,3346,472,594}. Similarly, the function of RB1 is disrupted in nearly all cases of soft tissue LMS by diverse mechanisms that either target RB1 itself or result in altered expression of CDKN2A, CCND1, CCND2, or CDK4 {775,1595, 2963,472,594}. Potentially deleterious ATRX alterations have bee n observed in 16—49% of cases and probably con tribute to the high prevale nee of alter native len gthe ning of telomeres in LMS {3346,1812,472,594}. ALK rearrangements have been identified in a small subset of LMSs (9 of 377 cases; 2.4%) aris­ ing in males and females (soft tissue and uterine), imparting potential for clinically actionable opportunities {744}. Gene expression studies suggest that there are multiple subgroups of LMS, including a muscle-enriched subtype and less-differentiated groupings, with indications of differing freque ncies of specific genomic changes and varying prog no ses {2291,244,575,1150,1257,1256,1818,594,1490}. Interestingly, some tumours classified as undifferentiated pleomorphic

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Soft tissue tumours

sarcoma cluster closely with a subset of LMSs {794,2291,1817 2804,1751,244,1150,2150}.

Macroscopic appearance LMS of soft tissue typically forms a fleshy, grey to white to tan mass. A whorled appearanee may be evident. Larger examples often display haemorrhage, necrosis, or cystic change. The tumour border frequently appears well circumscribed, although grossly infiltrative tumours are also seen.

Histopathology Typical LMS shows spindle-shaped cells with plump, bluntended nuclei and moderate to abundant, pale to brightly eosin­ ophilic fibrillary cytoplasm. The cells are set in long intersecting fascicles parallel and perpendicular to the plane of section, although this pattern may be ill defined or subtle; some tumours show areas with storiform or palisaded patter ns {3290}. Mod­ erate nuelear pleomorphism is usually noted, although pleo­ morphism may be focal, mild, or occasi on ally abse nt. Mitotic figures, including atypical ones, are typically easy to find. LMS usually shows diffuse hypercellularity, although focal fibrosis, myxoid change, and hyalinized hypocellular areas can be seen. Tumour cell necrosis is often present in larger tumours {3290|. The majority of LMSs are high-grade {1164,921}. Unusual features in soft tissue LMS in elude myxoid stroma, multin ueleated osteoclast-like giant cells, and granular cytoplasmic change {3290,2682}. Epithelioid morphology is exceedingly rare.

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Fig. 1-224 Leiomyosarcoma. Leiomyosarcoma showing fascicles of spindle cells with hyperchromatic nuclei with scattered moderate pleomorphism and abundant eosino­

Fig. 1.226 Leiomyosarcoma with myxoid matrix. Myxoid change in soft tissue leio­ myosarcomas is unusual but may be seen.

philic cytoplasm.

Osseous or chondro-osseous areas are rarely reported in pleomorphic/dedifferentiated LMS {554}. Lymph node metastases are very rare {860,921}. By immunohistochemistry, at least one myogenic marker (i.e. SMA, desmin, or h-caldesmon) is positive in 100% of cases, and > 70% of cases are positive for more than one of these markers. None of these is absolutely specific for smooth mus­ cle, and positivity for two myogenic markers is more supportive. Other markers, such as keratin, EMA, and CD34, may also be positive, often focally. In general, the diagnosis of LMS should not be made on the basis of immunohistochemical stains alone in the absenee of appropriate morphological features. As many as 8% of soft tissue LMSs exhibit a non specific, poorly differentiated, pleomorphic appearanee in addition to typical areas. These tumours are called pleomorphic LMS or dedifferentiated LMS {2280,2347,1016,554}. For this diagno­ sis to be established, morphological features characteristic of classic LMS must be present, or the patient must have a prior history of LMS. The area of typical LMS may be exceedingly focal, constituting far less than 5% of the tumour. The typical and pleomorphic components may form discrete areas or may comingle. Pleomorphic LMSs most often show polygonal cells, but spindled, epithelioid, and rhabdoid cells may also be seen, and multiple cell types may be present. Pleomorphic areas usu­ ally have higher mitotic counts. By immu no histochemistry, about

50-75% of pleomorphic LMSs are positive for at least one myogenic marker, although staining is often weaker and more focal than in the typical leiomyosarcomatous areas {2280,2347}. The term '"dedifferentiated" has been used for pleomorphic LMSs that lack immunohistochemical staining for myogenic markers in the pleomorphic areas {2280,2347,554}. Dedifferentiation is often seen in the primary tumour, but some cases present in recurrent or metastatic disease.

Cytology Not clinically relevant

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: fascicles of eosi nophilic spin died cells with bluntended nuclei showing variable pleomorphism; immunolabelling for SMA, desmin, and/or caldesmon.

Staging LMS should be staged using the sarcoma staging information from the eighth edition (2017) of the Union for Intemational Can­ cer Control (UICC) TNM classification {423}.

Prognosis and prediction

,ig」・225 Leiomyosarcoma. Dedifferentiated leiomyosarcoma, showing an abrupt "ansition from conventional grade 2 leiomyosarcoma to an essentially undifferentiat-

严appearing pleomorphic sarcoma. These undifferentiated areas lacked expression

LMSs are clinically aggressive neoplasms with frequent local recurrences and distant metastases. The most important prognostic factors are histological grade and tumour location and size {642,2518}. Retroperitoneal LMSs are very often fatal; they are typically large (> 10 cm), often difficult or impossible to excise with clear margins, and prone to both local recurrenee and metastasis {1933,2585,3290,1164}. LMSs of large vessels also tend to have a poor prog no sis, although local control rates are higher. Non-retroperiton eal LMSs are gen erally smalle rthan those in the retroperitoneum, are more amenable to local con­ trol, and have a better prog no sis. In some studies, in tramuscular rather than subcutaneous location {1316} and larger tumour size {972,2163,1164} were related to increased metastasis and poore r survival. Metastases most comm only occur in lun g, liver, and soft tissue, and more rarely in bone {3290,1164}. LMS is the most comm on sarcoma to produce skin metastases {3239}.

01 muscle markers.

Soft tissue tumours

197

paybal：https://www.paypal.me/andy19801210 Rhabdomyoma

Parham DM

Definition Rhabdomyoma is a benign soft tissue neoplasm showing skel­ etal muscle differentiation.

ICD-0 coding 8900/0 Rhabdomyoma NOS

ICD-11 coding 2E86.2 2E86.2 2E86.2 2E86.2

& & & &

XH8WG9 Rhabdomyoma & Rhabdomyoma NOS XH4729 Rhabdomyoma & Fetal rhabdomyoma XH4BG5 Rhabdomyoma & Adult rhabdomyoina XH5AF2 Rhabdomyoma & Genital rhabdomyoma

Related terminology Not recommended: extracardiac rhabdomyoma; rhabdomyomatous hamartoma.

Subtype(s) Fetal rhabdomyoma; adult rhabdomyoma; genital rhabdomyoma

Fig. 1.228 Vaginal rhabdomyoma. Whole mount shows a polypoid configuration anc fibrous stroma.

Localization Most adult and fetal rhabdomyomas arise in the head and neck (e.g. in the parapharyngeal space, salivary glands, larynx, mouth, and soft tissue) {80,1583}. Rarely, they arise from other locations, such as bladder {1188} and extremities {3006}. Fetal rhabdo­ myomas have a postauricular predilection. By definition, genital rhabdomyomas arise from the genitalia, predominantly the vagina {2779}, but paratesticular tumours are also described {3402}.

hoarseness, obstructive sleep apnoea, hearing loss, and dys­ phagia. Rare tumours are mistaken for parathyroid adenomas {1807,2144}. Adult rhabdomyomas arise as unifocal or multifo­ cal lesions {805}, whereas fetal rhabdomyomas are usually soli­ tary. Genital rhabdomyomas may present with menorrhagia, as vaginal polyps, or as scrotal masses.

Epidemiology

Clinical features Rhabdomyomas usually prese nt as slow-growi ng, pain less masses, but some grow rapidly. Other symptoms in elude

Rhabdomyomas are distinctly rare lesions; relatively few series exist. Adult rhabdomyomas are the most comm on {805} a nd occur in patients with a median age of 60 years (range: 33-80 years).

Fig. 1.227 Fetal rhabdomyoma. A Intermediate juvenile rhabdomyoma with increased cellularity and a mixture of mature rhabdomyoblasts and cells with smooth muscle fea­ tures, lacking a myxoid component. B Fetal rhabdomyoma containing alternating bands of myotubes and loose myxoid stroma.

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Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 jth an M:F ratio of 3:1. The mean age for fetal rhabdomyomas

，s g 1 years, and the M:F ratio is about 1.7:1. Genital rhabdovomas have been described in women with a mean age of 50 years and in males aged 8 months to 67 years {2766}.

Etiology Fetal rhabdomyoma occurs in association with basal cell naevus syndrome, caused by loss-of-funotion mutations in the tumour suppressor gene PTCH1 {1357}. Several cases have been reported with Birt-Hogg-Dube syndrome {209}, caused by F/-C/V mutation.

pathogenesis PTCH1 encodes an inhibitory receptor in the sonic hedgehog signalling pathway .In activati on of the sec ond PTCH1 allele in syndromic fetal rhabdomyoma may fully in activate PTCH1 func­ tion and thereby activate hedgehog signalling, Non-syndromic fetal rhabdomyomas reveal evidence of hedgehog pathway activation by an unknown mechanism {1357}. Although adult rhabdomyomas are not associated with basal cell naevus syn­ drome, a few tumours show evidenee of activation of the sonic hedgehog pathway {3093}. Cytogenetic analysis of one case revealed a t(15;17)(q24;p13) {1149}. SNP microarray has failed to reveal copy-number aberrations, including PTCH1 deletion or loss of heterozygosity, in genital rhabdomyoma {2779}.

Macroscopic appearance Adult rhabdomyomas form well-circumscribed, soft, nodular or lobular, deep-tan to reddish-brown masses. Tumour sizes range from 1.5 to 7.5 cm (median: 3 cm). Fetal rhabdomyomas may form sessile or pedunculated polyps on mucosal surfaces. Tumour sizes range from 1.0 to 12.5 cm (median: 3.0 cm). Geni­ tal rhabdomyomas in females form small, firm, lobulated, poly­ poid, non-uIcerated, epithelium-covered masses measuring 1-3 cm. Paratesticular rhabdomyomas may partially encase the testis and spermatic cord and have a pale, glistening sur­ face.

Histopathology Rhabdomyomas form unencapsulated, lobular masses. Adult rhabdomyomas consist of large polygonal cells with abundant granular eosinophilic cytoplasm, small round vesicular nuclei, and well-defined cellular borders. The cytoplasm may be vacu­ olated (spider cells) or may contain rod-like inclusions or cross­ striations. Mitoses are rare. Classic fetal rhabdomyomas contain irregular bundles of immature skeletal muscle fibres within a myxoid background. Cells have features of fetal myotubes, i.e. spindly contours, cen­ tal oblong nuclei, and eosinophilic cytoplasm. An intermediate (iuvenile) subset of cases show greater cellularity, less myxoid stroma, cells with a smooth muscle phenotype, and differenti­ ated rhabdomyoblasts {1583}. The fetal cellular subtype contains a more uniform population of differentiating myoblasts. The myxoid subtype shows a predominance of stroma. Mitoses can be relatively frequent (as many as 5 per 50 mm2), but tumours bek substantial nuelear atypia, infiltrative margins, atypical mitoses, and necrosis {1583}. Genital rhabdomyomas in females are relatively small lesions k 2 cm) that contain loose fibrous connective tissue with differentiated spin died, polyg onal, or elon gated rhabdomyoblasts.

Fig. 1.229 Adult rhabdomyoma. A Adult rhabdomyoma showing mature rhabdomyo­ blasts with abundant eosinophilic cytoplasm. Scattered spider cells with cytoplasmic clearing are present. B Adult rhabdomyoma with strong, diffuse desmin expres­ sion. C Adult rhabdomyomas typically show variable degrees of myogenin expres­ sion.

Many contain eosinophilic cytoplasm with cross-striations. The cells gen erally appear bland and lack mitoses, but some degree of cytological atypia may be present {2779}. Vaginal lesions are polypoid in configuration but contain no cambium layer. Male genital tumours have features of adult or fetal rhab­ domyomas. Immunohistochemical stains used for an ciliary diag nosis of rhabdomyoma include desmin, MSA, MYOD1, and myogenin. Desmin expression is generally strong and diffuse, whereas myogenin expression may be focal {2033}.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Cytology

Staging

Not clinically relevant

Not clinically re leva nt

Diagnostic molecular pathology

Prognosis and prediction

Not clinically re leva nt

Recurre nces may occur in in adequately excised lesi ons par ticularly with adult rhabdomyomas. Multifocal adult rhabdomJ mas are seen in 3-10% of patients.

Essential and desirable diagnostic criteria Essential: a well-circumscribed mass with no invasion of adjacent tissues; in the case of vaginal rhabdomyomas, small size (< 2 cm) and lack of cambium layer; mature rhabdomyoblasts lacking substantial atypia, mitotic activity, or necrosis; mitotic activity may be more prominent in fetal rhabdomyoma.

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Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 Rudzinski ER

Embryonal rhabdomyosarcoma

Definitio n Embryonal rhabdomyosarcoma (ERMS) is a malignant soft tis­ suetumour with morphological and immunophenotypic features of grnbryonic skeletal muscls.

ICD-0 coding 89io/3 Embryonal rhabdomyosarcoma NOS

ICD-11 coding 2B55.Z & XH83G1 Rhabdomyosarcoma & Embryonal rhabdo­ myosarcoma NOS

Related terminology Not recommended: sarcoma botryoides; mixed embryonal and alveolar rhabdomyosarcoma.

Subtype(s)

Fig. 1.230 Botryoid embryonal rhabdomyosarcoma. Gross photograph of a botryoid embryonal rhabdomyosarcoma showing multiple polypoid clusters of tumour.

Embryonal rhabdomyosarcoma, pleomorphic

Localization Approximately one half of ERMSs occur within the head and neck region (including the orbit), and one half within the geni­ tourinary system {3222,1324}. Less frequently, ERMS arises in the biliary tract, retroperitoneum, or abdomen. In contrast to alveolar rhabdomyosarcoma (ARMS), ERMS rarely involves the soft tissues of the extremities.

Clinical features ERMS prese nts with a variety of clinical symptoms, gen erally related to mass effects, or it may be in dole nt. Head and neck lesions can cause proptosis, diplopia, or sinusitis; genitourinary lesions may produce a scrotal mass or urinary retention; biliary tumours may cause jaundice.

Epidemiology Rhabdomyosarcoma is the most comm on soft tissue sarcoma in children and adolescents, with 4.5 cases per 1 million people aged 0-20 years {2885}. ERMS is the most comm on subtype, with one third of cases occurring in children aged < 5 years. About 4% of ERMSs affect infants. ERMSs also constitute 20% °f all adult rhabdomyosarcomas. ERMS is slightly more common in males than females (M:F ratio: 1.5:1). About 80% of rhabdomyosarcomas in North America occur in white people, compared with 15% in African-Americans {2353}.

Etiology ERMS is associated with several syndromes involving alterations of the RAS signalling pathway, for example, Costello syndrome (HRAS gene mutations), neurofibromatosis type 1 (A/F7 gene mutations), and Noonan syndrome (mutations in several genes). A few cases are reported in association with Beckwith-Wiedemann syndrome (dysregulation of imprinting in the

Fig. 1.231 Orbital embryonal rhabdomyosarcoma. An orbital embryonal rhabdomyo­ sarcoma with a fleshy, pale-tan cut surface that resulted in proptosis of the overlying globe.

11p15.5 region). Uterine ERMSs occur in DICER1 syndrome, and rhabdomyosarcoma of unclassified histology occurs in LiFraumeni syndrome (7P53 mutations) {2885}.

Pathogenesis Sporadic cases of ERMS are aneuploid with whole-chromosome gains including polysomy 8, followed by extra copies of chro­ mosomes 2, 11, 12, 13, and/or 20. Whole-chromosome losses in elude monosomy 10 and 15. In most ERMSs, a genomic eve nt such as chromosome loss, deletion, or uniparental disomy results in loss of one of the two alleles at many chromosome 11 loci. This loss of heterozygosity invoIves chromosomal region 11p15.5, which contains imprinted genes that encode a growth factor (JGF2) and growth suppressors (H19 and CDKN1C)

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Fig. 1.232 Embryonal rhabdomyosarcoma, botryoid subtype. A Low-power microscopy. Histologically, the botryoid pattern of embryonal rhabdomyosarcoma shows a variat cellular tumour with a myxoid background and condensation of nuclei beneath an epithelial surface. B This tumour presented as a polypoid submucosal mass in the bladder a boy. C Primitive round to slightly spindled cells with several differentiating rhabdomyoblasts.

{2835}. Genomic amplification in the form of double minutes or as ascertained by comparative genomic hybridization is fre­ quent in ERMS with anaplasia {414,2558}. Genomic studies of ERMS have identified somatic driver mutations involving the RAS pathway (NRAS, KRAS, HRAS, NF1, FGFR4), involving effectors of PI3K (PTEN, PIK3CA), or in genes that control the cell cycle {FBXW7, CTNNB1) {2834,2885}. Mutation of a RAS isoform occurs in one third of ERMSs, and mutation of a RAS pathway member has been found in < 50% of ERMSs. Within this group, HRAS mutations are enriched in the infant population (70% of infants aged < 1 year had HRAS

or KRAS mutations), and NFIAS mutations are enriched in ado­ lesce nts. NF1 mutations occur in 10% of cases. Epigenetic modifications may also play a role, and BCOR point mutations or focal homozygous deletions are described in 15% of ERMSs Mutations in TP53 occur in approximately 10% of ERMSs and may be associated with anaplasia {1356}. About 30% of ERMSs harbour more than one driver mutation, whereas one quarter have no driver mutation identified. Expression studies have identified markers that distinguish FOXO1 fusion—negative rhab­ domyosarcoma (HMGA2 and EGFR [HER1] overexpression)

Fig. 1.233 Embryonal rhabdomyosarcoma. A The typical histological pattern of embryonal rhabdomyosarcomas recapitulates skeletal muscle development, with altern呷 areas of loose and dense cellularity. B Embryonal rhabdomyosarcoma in this example is composed of short, irregular fascicles of ovoid to spindled cells with focal myot啦

formation. C Cartilaginous differentiation - a rare but well-recognized phenomenon. D Myogenin staining confirms skeletal muscle differentiation.

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Fig. 1-234 Dense embryonal rhabdomyosarcoma. A This pattern with sheets of round cells may show similarity to the solid pattern of alveolar rhabdomyosarcoma. B Myogenin expression confirms the diagnosis of rhabdomyosarcoma, although nuclear staining in 50-90% of tumour cells may be seen in either embryonal or alveolar rhabdomyosarcoma.

from FOXO1 fusion—positive rhabdomyosarcoma (AP-20 and p-cadherin overexpression) {1210,2687}.

Macroscopic appearance ERMS forms poorly circumscribed, fleshy, pale-tan masses that impinge upon neighbouring structures. Botryoid tumours have a characteristic polypoid appearance with clusters of small, ses­ sile or pedunculated nodules that abut an epithelial surface.

Histopathology Analogous to embryonic skeletal muscle, ERMS contains primi­ tive mesenchymal cells in various stages of myogenesis. Stel­ late cells with sparse, amphophilic cytoplasm represent the most primitive end of this spectrum. Differentiating rhabdomyoblasts acquire more cytoplasmic eosinophilia and elongation, man ifested by tadpole or spider cells. Terminal d if fere ntiatio n with cross-striations or myotube formation may be evident. Differentiation often becomes more evident after therapy {170}. Typical ERMSs are composed of variably differentiated rhabdomyoblasts within a loose, myxoid mesenchyme, with alternat­ ing areas of dense and loose cellularity. The relative amount of myxoid matrix and spin died cells is highly variable. Occasi onal poorly differentiated ERMSs consist largely of primitive round cells, simulating ARMS (so-called dense pattern) {2689}. Botryoid ERMS contains linea r aggregates of turn our cells (the cambium layer) that tightly abut an epithelial surface, along with hypocellular polypoid nodules that may appear deceptively benign. FERMS may also have prominent spindle cell morphol­ ogy, particularly in paratesticular tumours, although small foci of more-typical ERMS are usually present as well {2267}. Very rare tumours display mixed embryonal and alveolar morphologies; however, these cases typically lack the FOXO1 gene rearrangements {2689}. Heterologous cartilaginous differentiation is occasionally present. Anaplastic ERMS is defined by the presence of markedly enlarged, atypical cells with hyperchromatic nuclei, often with bizarre, multipolar mitotic figures {2558}. Anaplastic features may be focal or diffuse. By immunohistochemistry, ERMSs are essentially always positive for desmi n, although the exte nt of immuno reactivity is variable. The skeletal muscle-specific nuclear regulatory proteins myogenin (MYF4) and MYOD1 are also positive in essentially all cases, although the number of positive nuclei may be highly

Fig. 1.235 Anaplastic embryonal rhabdomyosarcoma. Poorly differentiated appear­

ance with a large, atypical mitotic figure.

Fig. 1.236 Posttherapy differentiation in embryonal rhabdomyosarcoma. After chem­ otherapy, embryonal rhabdomyosarcoma may show extensive differentiation.

variable {2198}. MSA and SMA are frequently positive. Aberrant expression of keratins, S100, and NFP may be seen {638}.

Cytology Cytological preparati ons dem on strate primitive rou nd, spindled and stellate cells with scattered rhabdomyoblasts.

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paybal：https://www.paypal.me/andy19801210 Diagnostic molecular pathology Lack of F0X01 gene fusion distinguishes ERMS from ARMS {737}.

Essential and desirable diagnostic criteria Essential: primitive round and spindle cell morphology with scattered differentiated rhabdomyoblasts; positivity for desmin and heterogeneous nuclear staining for myogenin and/or MY0D1. Desirable (in selected cases): lack of F0X01 gene rearrangements to distinguish poorly differentiated ERMS from solid ARMS.

Staging Rhabdomyosarcoma may be staged based on site of origin using the American Joint Committee on Cancer (AJCC) / Union for International Cancer Control (UICC) system for soft tissue

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sarcomas, with the exception of head and neck tumours, wh詁 are excluded from this system {101}. In children, a modified TNh stagi ng system is used (the In tergroup Rhabdomyosarcom Study Group [IRSG] grouping system). This system is heavh reliant on site of origin, with risk stratification based on favo] able site (e.g. bile ducts, orbit, head and neck, or genitourinarv [excluding bladder, prostate, and parameningeal]) or unfavour able (other) site. The IRSG grouping system is used for surgiCo. pathological evaluation, including assessment of margins and residual disease {2105}.

Prognosis and prediction Age and tumour stage are the most important risk factors m ERMS. Patients aged 1-9 years have better outcomes than infa nts or adolesce nts {1363}. Similarly, childre n have a better outcome than adults.

paybal：https://www.paypal.me/andy19801210 Alveolar rhabdomyosarcoma

Kohashi K Bode-Lesniewska B

Definition Areolar rhabdomyosarcoma (ARMS) is a malignant neoplasm composed of a monomorphic population of primitive round cells showing skeletal muscle differentiation. The presenee of either a PAX3-FOXO1 or a PAX7-FOXO1 fusion gene is detected in the majority of cases.

ICD-O coding 8920/3 Alveolar rhabdomyosarcoma

ICD-11 coding 2855.Z & XH7099 Rhabdomyosarcoma & Alveolar rhabdomyo­ sarcoma

Related terminology Not recommended: mixed embryonal and alveolar rhabdomyo­ sarcoma; fusion-negative alveolar rhabdomyosarcoma.

Subtype (s) None

Fig. 1.237 Alveolar rhabdomyosarcoma. CT of a maxillary sinus alveolar rhabdomyo­ sarcoma (arrows).

J9-1.238 Alveolar rhabdomyosarcoma. A A proliferation of tumour cells with the characteristic alveolar growth pattern. B A single layer of tumour cells adheres to fibrovascu'ar septa. C Solid subtype shows a proliferation of small round tumour cells arranged in a sheet-like pattern without fibrovascular septa. D Multinucleated giant cells with

multiple and peripherally placed nuclei.

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Fig. 1.239 Rhabdomyosarcoma with embryonal and alveolar components. Foci of small round tumour cells and differentiating rhabdomyoblasts. Most of these tumours lack the presence of a F0X01-re\a[ed fusion and probably represent embryonal rhab­ domyosarcoma.

Fig. 1.240 Alveolar rhabdomyosarcoma. Diffuse and strong immunoexpression myogenin.

Localization

PAX-FOXO1 fusion proteins function as oncoproteins affecting growth, survival, differentiation, and other pathways through activati on of numerous down stream target genes such as MET ALK, FGFR4, MYCN, IGF1R, and MYOD1 {270,252,476,1239 2885}. Less comm on fusi on gene variants in elude the fusion c PAX3 to FOXO4, NCOA1, or INO80D and the fusion of FOXOl to FGFR1 {223,2986,1878,2834}. Amplification of genomic regions 2p24 (containing the MYCh oneogene) and 12q13-q14 (including CDK4) occur most ofter in PAX3-FOXO1 ARMSs, and amplification of regions 1p36 (which encompasses the PAX7 locus) and 13q31 (whicr includes MIR17HG) are associated specifically with PAX7FOXO1 tumours {1266,106,221,2591,1192,2885}. Analyses ol in dividual genes in sporadic ARMS have implicated several important oneogenetic pathways. Inactivating mutationsof TP5一 and CD KN2A/CDKN2B and activating mutations of FGFR4 are present in a small subset {1475,3026,3058}. ALK gene copynumber gain and cytoplasmic overexpression of ALK protein

ARMS most commonly arises in the deep soft tissue of the extremities {1303}. Other sites include the head and neck, paraspinal region, and perineal region {1329,2576,3358,171}.

Clinical features ARMS is a highly aggressive and rapidly growing malignant soft tissue tumour, presenting at diagnosis with distant or locoregional metastases via lymphatic or haematogenous spread in 25-30% of patients {2339,1953,2686}. Symptoms are typically related to turn our location and size. Head and n eck tumours with meningeal extension often cause cranial nerve deficits {3120}, paraspinal tumours may result in spinal nerve compression {1882,3067}, and perirectal or pelvic tumours may lead to constipation or symptoms of bowel obstruction {1084}. Primary disseminated tumours resembling leukaemia may rarely occur {1612,1467}.

Epidemiology ARMS is the sec ond most comm on type of r habdomyosarcoma, constituting about 25% of these tumours. ARMS occurs in a slightly older population than embryonal rhabdomyosarcoma (ERMS), with a peak incidence among individuals aged 10-25 years and roughly equal incidenee in male and female patients {2686,3152,1953,361}. A subset of cases have also been observed in adults aged > 40 years {3358,870}.

Etiology Unknown

Pathogenesis A t(2;13)(q36;q14) translocation is found in the majority of ARMSs, and a t(1;13)(p36;q14) is seen in a smaller subset. These translocations juxtapose PAX3 (at 2q36.1) or PAX7 (at 1p36.13) with the FOXO1 gene at 13q14.11, to generate chimeric genes that encode PAX3-FOXO1 and PAX7-FOXO1 fusion proteins {222,746,1106}. PAX3 and PAX7 represent transcription factors that play essential roles in myogenesis {442}. The 206

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Fig. 1.241 Alveolar rhabdomyosarcoma. Cytologically, tumour cells form dyscow sive clusters, with comparatively monomorphous round nuclei and scant cytoplasm、

paybal：https://www.paypal.me/andy19801210 ① House keeping gene PGK (189bp)

② Positive control PAX3-FOXO1 ③ Case, PAX3-FOXO1 (+) PAX3 50

Fig. 1.242 Alveolar rhabdomyosarcoma. Interphase FISH analysis showing amplification of the PAX7-FOXO1 fusion gene (juxtaposed red and green signals) by 1;13

FOXO160

I

Fig. 1.243 Alveolar rhabdomyosarcoma. Detection of PAX3-FOXO1 fusion gene by

RT-PCR and direct sequencing.

translocation breakpoint-flanking probes.

occur in the vast majority of ARMSs; however, targeting this kinase in vivo does not yield therapeutic efficacy {3158,3289}. The presenee of recurrent somatic mutations (fusion-positive ARMSs have few to none) and distinet gene expression and DNA methylation profiles characterize fusion-positive and fusion-negative rhabdomyosarcomas (fusion-negative ARMS profiles are similar to those of ERMS) {223,738,1732,3298,2989, 1944,2809,3364,2273,2988}.

Macroscopic appearance ARMS is soft, fleshy, and grey, with variable amounts of fibrous tissue and occasional necrotic areas and haemorrhage. Deepseated tumours involving the musculature commonly infiltrate surrounding tissues.

Histopathology ARMS is highly cellular and composed of primitive round cells with sea nt cytoplasm and hyperchromatic n uelei. Tumou r cells are arranged in nests separated by fibrovascular septa, which frequently exhibit loss of cellular cohesion in the centre, confer­ ring a pattern of irregular alveolar spaces and a varying degree of cystic change {2686,2438}. The solid subtype of ARMS is composed of sheets of neoplastic cells that have cytomorphological features of ARMS but lack septa or discohesion. Mitotic activity is ofte n brisk. Occasi on ally, recog nizable rhabdomyoblastic differentiation can be discerned. Multinucleated tumour giant cells are a common feature of ARMS. Rare cases may show clear cell morphology, with pale-staining and glycogencontaining cytoplasm. Tumours with mixed embryonal and alveolar features were previously considered to be a subtype of ARMS, but most such cases lack PAX-FOXO7 fusions, thus appearing to be clinically and biologically more akin to ERMS. However, fusion genes have been detected in rare cases of socalled mixed ERMS/ARMS, which therefore represent examples of ARMS {2689,171}. Rhabdomyoblastic differentiation of ARMS is shown immunohistochemically with positive reactions to desmin, myogenin, and MYOD1. The nuelear expression of myogenin is strong and diffuse, unlike in ERMS and other rhabdomyosarcoma subtypes

in which the staining pattern is focal {818,1418,2604}. MYOD1 expression may be focal. Occasional expression of keratin or neuroendocrine markers (CD56, synaptophysin, and chromogranin) may also be observed.

Cytology Fine-needle biopsies are highly cellular and consist of uniform rou nd cells with sea nt cytoplasm and variable r habdomyoblastic differentiation. Wreath-like multinucleated giant cells are a common feature {1654,1066,2333,3216}.

Diagnostic molecular pathology Approximately 85% of histologically diagnosed ARMSs contain characteristic fusion genes. In fusion-positive ARMSs, PAX3FOXO1 and PAX7-FOXO1 account for about 70-90% and 10-30% of the fusions, respectively {2686,861}. Rare cases show alter native novel gene fusi ons (see Pathogenesis, above), which can be detected by various molecular strategies. The

DBD

TAD

Fig. 1.244 Wildtype and fusion products associated with 2;13 and 1;13 translocations. The paired box (PB), octapeptide, homeobox domain (HD), and forkhead domain (FD) are shown as grey boxes. Transcriptional domains (DNA-binding domain [DBD] and transcriptional activation domain [TAD]) are indicated as solid horizontal bars. The translocation fusion point is shown as a vertical dashed line.

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paybal：https://www.paypal.me/andy19801210 absenee of one of these gene fusions suggests a diagnosis of ERMS with a primitive phe notype (formerly known as fusi onnegative ARMS or mixed ERMS-ARMS).

Essential and desirable diagnostic criteria Essential: uniform primitive round cell morphology with features of arrested myogenesis; an alveolar growth pattern is common but not required; strong, homogeneous nuelear immunoexpression for myogenin; heterogeneous staining for desmin and/or MY0D1; detection of PAX3/7-FOXO1 fusion genes by molecular analysis.

Prognosis and prediction Risk stratification predictive of outcome has been address^ with surgicopathological staging and fusion-based classified tion (the Intergroup Rhabdomyosarcoma Study Group ［用® grouping system) {1325,2885,2273}. The prognosis for patie^ with fusion-positive ARMS is worse than for those with fusij negative rhabdomyosarcoma a nd ERMS, and the prog nosis fo, patients with PAX3-F0X01 ARMS is inferior to that for patient: with PAX7-F0X01 ARMS {2884,3298,2159,861,2813}. Amp} cation of MYCN, CDK4, and MIFI17HG has also been correlate with poor outcomes {414,221,2591}.

Definiti Pleomc sarcorr ophilic

Staging

muscle

See Embryonal rhabdomyosarcoma (p. 201).

ICD-O 8901/3

ICD-11 2B55.2 morp

Relatei None

Subtyp None

Fig. 1.24

the cells an atypic

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paybal：https://www.paypal.me/andy19801210 Montgomery EA Dry SM

pleomorphic rhabdomyosarcoma

Definition Pleomorphic rhabdomyosarcoma is a high-grade pleomorphic sarcoma, usually of adults, composed of bizarre brightly eosinophilic polygonal, round, and spindle cells that display skeletal muscle differentiation.

ICD-O coding 8901/3 Pleomorphic rhabdomyosarcoma NOS

ICD-11 coding 2B55.Z & XH5SX9 Rhabdomyosarcoma, primary site & Pleo­ morphic rhabdomyosarcoma NOS

Related terminology None

Subtype(s)

Fig. 1.245 Pleomorphic rhabdomyosarcoma. In this gross image, a firm and centrally necrotic tumour is present in the subcutaneous adipose tissue, although such lesions

None

are frequently deep.

Fig. 1.246 Pleomorphic rhabdomyosarcoma. A This needle biopsy specimen from a de即 thigh mass shows striking nuclear pleomorphism at low magnification. B Several of 腕 cells in this image feature macronucleoli. C Note the nuclear pleomorphism. A malignant cell in the centre of the image appears to have cannibalized another cell. There is

an atypical mitosis at the upper right. D There is striking variability in the sizes and shapes of the nuclei, and many feature macronucleoli.

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Fig. 1.247 Pleomorphic rhabdomyosarcoma. A Myogenin immunostaining. Not every cell is immunolabelled, but the pattern depicted here is sufficient to confirm the diagno sis. B These tumours are generally diffusely reactive with desmin antibodies.

Localization

Histopathology

These tumours arise in the deep soft tissue, with occasional exceptions {2329}, most often in the lower extremity but also in the chest/abdominal wall, upper extremity, abdomen/retroperitoneum, and head and neck {2329,1097,1104}.

The tumours are composed of sheets of large, atypical, anc freque ntly multinucleated polygo nal, spin died, or rhabdoid cells with eosinophilic cytoplasm. Tumours typically display strong desmin expression and often limited expression of MYOD1 and myoge nin.

Clinical features Patients present with rapidly growing, usually deep, variably painful soft tissue swelling {1097}.

Cytology

Epidemiology

Diagnostic molecular pathology

These are tumours of adults and are most comm on in the sixth to seventh decades of life (mean age: ~72 years), occurring more frequently in men than in women, with an M:F ratio of 1.8:1 {2329}.

Not clinically releva nt

Not clin ically re leva nt

Essential and desirable diagnostic criteria Essential: pleomorphic cells with copious brightly eosinophilic cytoplasm; immu no labelling for desmin and myoge nin.

Etiology Unknown

Staging See Embryonal rhabdomyosarcoma (p. 201).

Pathogenesis Pleomorphic rhabdomyosarcomas have complex karyotypes with numerical and unbalanced structural changes but no recurrent structural alterations {1843}. Genome-wide surveys have identified recurrent losses of DNA (e.g. 10q23), gains (e.g. 1p22-p23), and amplifications {1191}. This copy-number pattern differs from that found in either alveolar or embryonal rhabdo­ myosarcoma. The genetic profiles of pleomorphic rhabdomyo­ sarcomas are indistinguishable from those of undifferentiated pleomorphic sarcomas {501).

Macroscopic appearanee Pleomorphic rhabdomyosarcomas are usually large, well-marginated tumours {2329}, with a pseudocapsule and a whitish or fleshy cut surface, often with necrosis.

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Prognosis and predict!on These are highly aggressive sarcomas. The median survival was 7.3 months in the largest study to date, and about 80°： of patients died of disease {2329}. Patients with superficia1 tumours (-20%) had a favourable outcome. Metastases to lungs are comm on {2329,1097,1104}.

paybal：https://www.paypal.me/andy19801210 Agaram NP Szuhai K

gpindle cell / sclerosing rhabdomyosarcoma

Qefinition Spindle cell / sclerosing rhabdomyosarcoma is a type of rhab­ domyosarcoma that has fascicular spindle cell and/or sclerosing morphology.

ICD-O coding 8912/3 Spindle cell rhabdomyosarcoma

ICD-11 coding 2B55.Z & XH7NM2 Rhabdomyosarcoma, primary site & Spin­ dle cell rhabdomyosarcoma

Related terminology None

Subtype(s) Congenital spindle cell rhabdomyosarcoma with VGLL2/ NC0A2/CITED2 rearrangements; /WYOD7-mutant spindle cell / sclerosing rhabdomyosarcoma; intraosseous spindle cell rhab­ domyosarcoma (with TFCP2/NCOA2 rearrangements)

Localization The head and neck region is the most common site of involvement, followed by the extremities. In the paediatric population, spindle cell / sclerosing rhabdomyosarcoma arises most often in the paratesticular region, followed by the head and neck and other regions. Rarely, other locations including viscera (uterus, prostate), retroperitoneum, or bone are affected {2251,518,1241, 1629,2032,38,1056,3253,175,1767,735,2172,2085,3401}.

Clinical features Spindle cell / sclerosing rhabdomyosarcoma presents as a rap­ idly growi ng, pain less soft tissue mass with symptoms related to local compression at the tumour site.

Fig. 1.248 Spindle cell rhabdomyosarcoma. Gross image showing a well-circum­ scribed tumour with tan-yellow cut surface with central necrosis, involving soft tissue and abutting the bone.

61}. The second group, which comprises most spindle cell / sclerosi ng rhabdomyosarcomas in adolesce nts and you ng adults, as well as a subset of tumours in older adults, shows the presenee of MYOD1 p.Leu122Arg gene mutation. The mutation, which occurs in the DNA-binding domain of MYOD1, leads to blocking of the wildtype MYOD1 function and imparts a MYCbinding capability {3012,1677,30,61,32,3147}. The third group of spindle cell / sclerosing rhabdomyosarcoma shows no recurrent identifiable genetic alterations. The recently described intraosseous spindle cell rhabdomyosarcoma shows two gene fusions, one involving either the EWSR1 or the FUS gene being fused to the TFCP2 gene. The other is the MEIS1-NCOA2 gene fusion {3253,735,38}.

Macroscopic appeara nee Epidemiology Spindle cell / sclerosing rhabdomyosarcoma accounts for 3-10% of rhabdomyosarcomas. It affects infants, children, and adults. Although it affects both sexes overall, there is a decreased M:F ratio for the /WyOD7-mutant genetic subtype 132,2251,518}.

Etiology Unknow n

Pathogenesis The genetic abnormalities identified in spindle cell / sclerosing [habdomyosarcoma can be categorized into three groups. The first group, congenital/infantile spindle cell rhabdomyosarcoma, shows gene fusions involving the VGLL2, SRF, TEAD1, NCOA2, and CITED2 genes. The gene fusions include SFIF-NCOA2, TEAD1-NCOA2, VGLL2/NCOA2, and VGLL2-CITED2 {2207,

Spindle cell / sclerosing rhabdomyosarcomas present as variably circumscribed tumours, with sizes ranging from 1.5 to 35 cm. They show a white to tan cut surface with a whorled appearanee. Necrosis and cystic degeneration may be present.

Histopathology Spindle cell / sclerosing rhabdomyosarcoma shows variable morphology. Spindle cell rhabdomyosarcoma is character­ ized by cellular fascicles of spindle cells with an intersecting or herringbone growth pattern, resembling leiomyosarcoma or fibrosarcoma. The spindled neoplastic cells have pale eosinophilic cytoplasm and blunted, ovoid or fusiform, cen­ trally located nuelei with small inconspicuous nueleoli. Mitotic figures, nuelear atypia, and hyperchromatic nuclei are often present. Primitive undifferentiated areas with round cells and hyperchromatic nuelei may also be present focally. Tadpole or strap cells, rhabdomyoblasts with elongated eosinophilic tails

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Fig. 1.249 Spindle cell rhabdomyosarcoma composed of uniform spindle cells in a fascicular pattern (A). Immunohistochemistry for desmin (B) shows diffuse positivity in the

tumour cells. Myogenin staining (C) shows focal positivity, and MYOD1 staining (D) shows diffuse positivity.

with cross-striations, can be observed in some cases. Sclerosing rhabdomyosarcomas show prominent hyalinization/sclerosis, with tumour cells arranged in cords, nests, microalveoli, or trabeculae in a pseudovascular growth pattern. Prominent in terveni ng sclerosis is noted. Sclerosi ng areas may mimic osteosarcoma due to the extensive matrix formation {32,2251, 518,1830,2085}. The recently described intraosseous spindle cell rhabdomyosarcomas show, apart from the typical spindle cell morphology, areas of distinctly epithelioid cells arranged in sheets and fascicles {3253,735,38}.

Immunohistochemically, spindle cell / sclerosing rhabdomyo­ sarcoma is characterized by diffuse expression of desmin in all cases, with only focal expression of myogenin (MYF4) in most cases. MYOD1 staining can be focal or diffuse in the spindle cell tumours, but it is usually present in a diffuse pattern in the sclerosing cases. Staining for SMA and MSA is usually not present. A subset of the recently described intraosseous spindle cell rhabdomyosarcoma can also show positivity for cytokeratin ano ALK.

Fig. 1.250 Sclerosing rhabdomyosarcoma. A Clusters of tumour cells in a sclerotic collagenous background. B Pseudovascular pattern of arrangement of the tumour cells.

issue tumours

paybal：https://www.paypal.me/andy19801210 ACC ATG C G C G A GCGGCGC CGC CGGAIJCAAAGTAAATGAGGC C T TG A

ACCATGCGCGAGCGGCGCCGCCTGAGCAAAGTAAATGAGGCCTTTG

Fig. 1.251 Spindle cell rhabdomyosarcoma. MYOD1 p.Leu122Arg homozygous mutation represented on direct sequencing.

・

/ in the

>myoin all most )indle n the presecell n and

Cytology

Staging

Not clinically relevant

See Embryonal rhabdomyosarcoma (p. 201).

Diagnostic molecular pathology

Prognosis and prediction

VGLL2, CITED2, NCOA2, MEIS1, EWSR1, and TFCP2 gene rearrangements can be detected by FISH studies, using breakapart probes or fusi on probes. Alter natively, the gene fusion can be detected by targeted RNA sequencing using next-generation sequencing platforms. MY0D1 mutations can be identified by PCR and San ger seque ncing of the hotspots or by targeted DNA sequencing on next-generation sequencing platforms.

Congenital / infantile spindle cell / sclerosing rhabdomyosarco­ mas with gene fusions show a favourable clinical course {61}. /WyOD^-mutant spindle cell / sclerosing rhabdomyosarcomas fol­ low an aggressive course despite multimodality therapy and have a poor prog nosis in childre n and adults, with 3-year and 4-year survival rates of 36% and 18%, respectively {30,61,2608,32}.

Essential and desirable diagnostic criteria Essential: cellular spindle cell fascicles or tumour cells in a vari­ ably sclerotic collage nous backgrou nd; positivity for desmi n, myogenin (focal), and MY0D1. Desirable in selected cases: MY0D1 mutations and/or various gene rearrangements (see above).

cells.

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paybal：https://www.paypal.me/andy19801210 Ectomese nchymoma

Definition Ectomesenchymoma is an exceedingly rare multiphenotypic sarcoma consisting of both mesenchymal and neuroectodermal lines of differentiation. This biphasic neoplasm is composed of areas resembling rhabdomyosarcoma intermixed with variable neuronal/neuroblastic components.

Huang SC Antonescu CR

< 5 years, and there is a slight male prep on dera nee (M：F ra』 1.38:1) {1596,372,731,1430}.

Etiology Unknown

Pathogenesis ICD-0 coding 8921/3 Ectomesenchymoma

ICD-11 coding 2F7C & XH0S12 Neoplasms of uncertain behaviour of connective or other soft tissue & Ectomesenchymoma

Related terminology

Cytogenetic and array comparative genomic hybridizatior findings of ectomesenchymoma show overlap with those of embry onal rhabdomyosarcoma, with comm on trisomies o! chromosomes 2, 8, and 11 {1424}. Frequent HRAS mutations at cod on 13 o r 61 and upregulated myoge nesis-related gens such as MYOG, CHRND, and MFILN, have been demonstrated further underscoring the shared alterations seen in embryona rhabdomyosarcoma {1430}.

Not recommended: gangliorhabdomyosarcoma.

Macroscopic appearance Subtype(s) None

Localization The comm on sites inc lude pelvis/peri neum, uroge nital organs, and intra-abdominal or retroperitoneal soft tissue; less commonly, the head and neck, extremities, and mediastinum are affected {1596,372,731,1430}.

Clinical features Tumours present as a superficial or deep soft tissue mass.

Epidemiology Ectomesenchymomas are exceedingly rare, with approxi­ mately 50 cases reported to date if only composite rhabdo­ myosarcomas and neuroblastic tumours are included {1596, 372,731,1430}. Most patients are infants or children in the first two decades of life (range: birth to 15 years), frequently aged

The masses are multilobulated and thinly encapsulated, with8 tan cut surface and variable necrosis and haemorrhage (372| The tumours can vary widely in size (range: 3-18 cm), with most being > 5 cm in diameter {372}.

Histopathology The prototypical morphology is that of an embryonal rhabdomyo­ sarcoma with intermixed neuroectodermal elements. The latter cover the entire spectrum of neuroblastic phenotype, ranging from scattered gan glio n cells to mature gangli on euroma, inter­ mediate ganglion euroblastoma, and primitive n euroblastoma The appearances of embryonal rhabdomyosarcoma vary, spanning botryoid, classic fascicular spindle cell with alternating myx­ oid-cellular areas, and the so-called dense pattern of primitive round cells {372,1424,1430}. Immunophenotypically, ectomesen­ chymoma is a multiphenotypic tumour, with the rhabdomyosarcomatous component expressing MSA, desmin, MYOD1, and myogeni n, whereas the n euroblastic comp on ent is highlighted

Fig. 1.252 Ectomesenchymoma. A Intimate and composite growth of embryonal rhabdomyosarcoma and ganglioneuroblastoma is seen in this ectomesenchymoma. former is evident by myogenin immunoreactivity (shown in Fig. 1.253). B This example shows rhabdomyosarcoma of spindle cell morphology with scattered neurons.

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paybal：https://www.paypal.me/andy19801210 Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: composite morphology with areas mostly resembling embry onal rhabdomyosarcoma, in termixed with unequivocal neuroblastic elements (neurons, ganglion euroma, ganglioneuroblastoma, or neuroblastoma); immunoprofile high­ lighting the two components, with positivity for desmin/myogenin and synaptophysin, respectively.

Staging

Fig. 1.253 Ectomesenchymom& Intimate and composite growth of embryonal rhab­ domyosarcoma and ganglioneuroblastoma is seen in this ectomesenchymoma (shown m Fig. 1.252A). The former is evident by myogenin immunoreactivity (shown here).

by NSE, synaptophysin, and chromogranin A, and the Schwannian or satellite cells by S1OO {372,1430}. Pure rhabdomyosar­ coma cases with aberrant expression of neuroendocrine markers should not be considered ectomesenchymomas {372,204}.

Cytology

Ectomesenchymoma is staged according to the American Joint Committee on Cancer (AJCC) staging system for rhabdomyo­ sarcoma or the Union for International Cancer Control (UICC) TNM system.

Prognosis and prediction Patients treated with multimodality strategies including rhabdo­ myosarcoma-based protocols have a comparable outcome to patients with embryonal rhabdomyosarcoma {372,731}. Favour­ able prog no stic factors inc lude age < 3 years, size < 10 cm, and superficial location. Localized stage and the presenee of a primitive neuroblastic element do not appear to have a substantial impact on outcome {372}.

Not clinically relevant

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Gastrointestinal stromal tumour

Dei Tos AP Hornick JL Miettinen M Wanless IR Wardelmann E

Definiti on

Subtype(s)

Gastrointestinal stromal tumour (GIST) is a mesenchymal neoplasm with variable behaviour, characterized by d if fere ntiati on towards the interstitial cells of Cajal.

Suecinate dehydrogenase—deficient gastrointestinal stro【 tumour

Localization

ICD-0 coding 8936/3 Gastrointestinal stromal tumour

ICD-11 coding 2B5B & XH9HQ1 Gastrointestinal stromal tumour, primary site & Gastrointestinal stromal sarcoma

Related terminology Not recommended: leiomyoblastoma; gastrointestinal autonomic nerve sheath tumour (GANT); gastrointestinal pace­ maker cell tumour (GIPACT).

GIST can occur any where in the gastr oin testi nal tract; howev」 approximately 54% of all GISTs arise in the stomach, 30% the small bowel (i ncludi ng the duode num), 5% in the colon ai rectum, and about 1% in the oesophagus {2669}. Rarely, GIS arise in the appendix. About 10% of cases are primarily d seminated, and the site of origin cannot be established w certainty. Extragastrointestinal GISTs occur predominantly the mesentery, omentum, and retroperitoneum; they most pro ably represent a metastasis from an unrecognized primary oi detached mass from the gastrointestinal tract.

Clinical features The most comm on presentati ons in elude vague abdomin symptoms, as well as symptoms related to mucosal ulceratio acute and chronic bleeding, an abdominal mass, and tumoi perforation. Smaller GISTs are detected incidentally dunr endoscopy, surgery, or CT. Advaneed GISTs spread into peritoneal cavity and retroperitoneal space and often metasL size to the liver. Bone, skin, and soft tissue metastases are infri quently observed, whereas lung metastases are exceeding rare. Systemic spread can occur years after detection of primary tumour. Gastric GISTs exhibit a higher local recurrei rate than do small bowel GISTs, but the latter have a higher r of abdominal dissemination and metastasis.

Epidemiology Population-based studies in Seandinavia indicate an incident of 1.1-1.5 cases per 100 000 person-years {2299}. Howevf incidental subcentimetre GISTs (called microGISTs) seem be remarkably common. A frequency of 10% was reported in study of oesophagogastric junction carcinoma resection spec卜 mens {8}, and even higher frequencies in autopsy and entirely embedded gastrectomy series (22.5% and 35%, respectively) {28,1598}. Approximately 25% of GISTs (excluding microGISTs1 are clinically malignant. SEER Program data (interpolated from data on leiomyosarcomas) indicate that GISTs account for 2.2% of all malignant gastric tumours {3065}. Sporadic GISTs can occur at any age, with a peak incidence in the sixth decade of life (median age: 60-65 years) and asligM male predominance {2135}. A small fraction of GISTs affed children and adolescents; such tumours are usually succinate dehydrogenase (SDH)-deficient (and K/77PDGF朋-wildtype] SDH-deficient GISTs arise in the stomach, are more common]

females, and affect younger patients {2126,1513}. Fig. 1.254 Gastrointestinal stromal tumour (GIST). A Gross image of localized gas­ tric GIST. Ulceration of the gastric mucosa is present. B Gross image of metastatic GIST to the liver. The cut surface features areas of haemorrhage and necrosis.

:issue tumours

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Etiology

r. t GISTs are sporadic; 5-10% occur in association with a ariety of syndromes. Most syndromic GISTs are SDH-deficient, ‘nciuding those associated with the non-hereditary Carney triad (GIST, pulmonary chondroma, paraganglioma) {483} and the autosomal dominant Carney-Stratakis syndrome (GIST and oaraga nglioma in the con text of SDH germli ne mutations) $455,2962}.

Rarely, GISTs are associated with neurofibromatosis type 1

(Np|)； such cases are often multifocal, and most are located in the small bowel {2122,1121}. The extremely rare familial GISTs re caused by germline mutations of KIT or (far more rarely) PDGFRA {249,1840,1972}. Patients with these tumours tend to develop multiple GISTs, throughout the gastrointestinal tract, that can behave aggressively.

Pathogenesis Most GISTs harbour gain-of-function mutations of the KIT or PDGFRA oncogene and progress by the stepwise inactivation of tumour suppress or genes. See Diagnostic molecular pathology, below, for full details, which are of clinical significanee.

Macroscopic appearanee Localized GIST presents as a well-circumscribed mass of highly variable size (ranging from in cidental, submillimetre lesi ons to > 20 cm). In larger lesions, the cut surface may show foci of haemorrhage, cystic change, and/or necrosis. Gastric GISTs often feature an intraluminal comp on ent and may produce umbilicated mucosal ulcers. In the small bowel, GISTs more frequently present as external masses. Some GISTs feature a narrow pedicle linked to the serosal surface, the interruption of which may contribute to the generation of extragastrointestinal GISTs {2135,2130,2119}. Advaneed disease most often presents as a main lesion associated with multiple smaller nodules that may extend from the diaphragm to the pelvis. Invasion of surrounding organs such as the spleen and pancreas can be observed in aggres­ sive tumours. SDH-deficient GISTs are often associated with a distinctive multinodular pattern of growth.

Histopathology Microscopically, GISTs exhibit a broad morphological spectrum. Anatomical location (gastric vs small bowel) seems to influence

A，

Fig. 1.256 Succinate dehydrogenase-deficient gastrointestinal stromal tu­ mour. A The tumour shows a multinodular growth pattern through the wall of the stom­ ach. B Muscularis propria separates tumour nodules.

B

[g・ 1.255 Succinate dehydrogenase-deficient gastrointestinal stromal tumour. A The tumour shows epithelioid morphology. Note the uniform nuclei and cytoplasmic vacu-

〜％ B The tumour cells show loss of staining for SDHB. Endothelial cells serve as an internal positive control.

Soft tissue tumours

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Fig. 1.257 Gastrointestinal stromal tumour (GIST), epithelioid type. A This tumour harbours a PDGFRA mutation. Note the round nuclei and abundant eosinophilic cy plasm. B PDGFf?/4-mutant GISTs often show limited expression of KIT by immunohistochemistry (or are entirely KIT-negative). C Immunohistochemistry for AN01/D0G1 helpful to confirm the diagnosis of PDGFR/l-mutant GIST. D PDGffl/4-mutant GISTs typically show strong and diffuse expression of PDGFRA.

the histological appearanee. Most gastric GISTs are spindle cell tumours, with epithelioid morphology seen in approximately 20-25% of cases. Some cases feature a combi nation of spindle cell and epithelioid histology. Nuclear pleomorphism is uncom­ mon. Disti nctive histological patter ns among spindle cell GISTs exist. One example is the sclerosing type, seen especially in small tumours that often contain calcifications. The palisadedvacuolated sub type is one of the most common, whereas some examples show a diffuse hypercellular pattern. Very rarely, sarcomatoid features with substantial nuclear atypia and high mitotic activity can be observed. Epithelioid GISTs may show sclerosing, discohesive, hypercellular (sometimes with a pseudopapillary pattern), or sarcomatous morphology with sub­ stantial atypia but low mitotic activity. Myxoid stroma is rarely observed {2135}. Small intestinal and colonic GISTs are usually spindle cell tumours with diffuse sheets or vague storiform arrangements of tumour cells. Tumours with low biological potential often con­ tain extracellular collagen globules (skeinoid fibres). Intestinal GISTs may feature anuclear areas (somewhat mimicking Verocay bodies or neuropil) composed of cell processes. Nuclear palisading, perivascular hyalinization, and regressive vascular changes (e.g. dilated and thrombosed vessels, haemosiderin deposition, and fibrosis) similar to those in schwannomas can be seen. Rectal GISTs most often feature spindle cell morphol­ ogy {1177,397,2124,2135,2130}.

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Soft tissue tumours

SDH-deficient GISTs characteristically show epithelioid mor­ phology and are typically multi no dular with plexiform mural invo Iveme nt. Un like in conventional GISTs, lymphovascular invasion and lymph node metastases are common {2141,853). Extremely rarely, morphological progression to high-grade (KIT-negative) sarcomatous morphology can be observeo either de novo or after therapy with imatinib (dedifferentiated GIST). Dedifferentiation can also be associated with heterolo­ gous epithelial, myogenic, or angiosarcomatous differentiation {1856,135}. Immu nophe notypically, most GISTs show strong and diffuse expression of KIT (CD117), which appears as cytoplasmic membrane-associated, or sometimes perinuclear dot-like stain ing. However, a small minority (< 5%), especially GISTs witl PDGFRA mutations, may lack KIT expression or show very linited staining {2050}. The chloride-channel protein ANO1/D0G is an equally sensitive and specific marker and may rescu diagnostically as many as 50% of KIT-negative GISTs {327E 934,2139,2330}. KIT and DOG1 are also expressed in the intei stitial cells of Cajal, whose precursors are believed to be 枷 histogenetic origin of GISTs. Most spindle cell GISTs (especial! gastric tumours) are positive for CD34, whereas epithelioii examples are less consistently positive. Some GISTs express h-caldesmon; a minority express SMA; and rare examples show positivity for desmin, keratins (CK18), or S100 {2130}. SDH-de卜 cient GISTs exhibit loss of SDHB protein expression irrespective of which SDH gene is mutated {1152,2141,1100}. SDHA loss i

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1 258 Gastrointestinal stromal tumour (GIST). A GISTs are often composed of cytologically bland spindle cells that may feature distinctive perinuclear vacuolization. B Rare­ ly

gist may feature a high-grade morphology that is associated with high mitotic count. C The presence of myxoid change of the stroma is seen in this example of epithelioid GIST.

Specific for SDHA-mutant tumours {3213}. Loss of expression of neurofibromin (NF1; using an antibody specific to the C-termi個 may help in identifying NF1-associated GISTs {2667}.

Cytology Not clinically relevant

Diagnostic molecular pathology About 85% of GISTs harbour gain-of-function mutations of the KIT or PDGFRA oncogene located on chromosome 4 (4q12), encoding for type III receptor tyrosine kinases {1374,1637, 1342,1535}. With exceedingly rare exceptions, they are mutu­ ally exclusive and result in the constitutive activation of either KIT or PDGFRA. Normally, KIT and PDGFRA are activated by the binding of their respective ligands (i.e. stem cell factor and PDGFA). Downstream oneogenic signalling invoIves the RAS/ MAPK and PI3K/AKT/mT0R pathways {659,1534,2755}. About 75% of GISTs harbour activating mutations of KIT, most often in exon 11 (66% overall) or exon 9 (6%); mutations in exons 13 and 17 are rare (-1% each) {1374,2683,902,1535}. Even more un comm on are mutations in exon 8 {1443A.1493A}. KIT exon 11 mutations include deletions (45%), substitution mutations (30%), and insertion/deletion (indel) mutations (15%) including duplications. Nearly all KIT exon 9 mutations are

duplications (p.Ala502_Tyr503); 80% of GISTs with such mutations arise in the small intestine. KIT exon 13 and 17 mutations are most often p.Lys642Glu and p.Asn822Lys, respectively {1641,1763}. About 10% of GISTs harbour PDGFRA activating mutations (most often in the stomach), usually in exon 18 (8% overall); mutations in exons 12 and 14 are rare {1342,660}. The most comm on PDGFRA mutations are p.Asp842Val (55%) and p.Val561Asp (10%). Patients with PDGFRAmutant tumours have a lower risk of metastasis than patients with K/Tmutant tumours {1535}. Given these differences in metastatic risk, nearly 85% of advaneed GISTs harbour KITmutations and only 2% harbour PDGFRA mutations {902}. Many GISTs that are wildtype for KIT and PDGFRA harbour alterations in SDH subunit genes (5-10% overall) {1513,351}; 60% harbour inactivating mutations (nearly always germline); and 40% harbour SDHC promoter methylation (epimutation) {2141,1623}, leading to SDH dysfunction (SDH-deficient GIST). Patients with SDH-deficient GISTs are younger than those with tyrosine kinase receptor gene-mutant tumours; nearly all paedi­ atric GISTs are SDH-deficient {351}. Tumours from patients with Carney triad usually show SDHC epimutation {1623}. SDHA is the most comm only mutated subunit gene (-35% of SDH-deficient GISTs) {3213}, followed by SDHB, SDHC, and SDHD. Rare

Hg.1.259 Gastrointestinal stromal tumour (GIST). A Small bowel GISTs most often feature a spindle cell morphology that may be associated with the presence of skeinoid fi-

"es. B GISTs sometimes appear microscopically hypocellular with neoplastic cells embedded in abundant fibrous stroma. C The presence of nuclear pleomorphism represents a rare morphological feature of GIST.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Table 1.03 Relationship of mitotic count and tumour size to prognosis of gastrointestinal stromal tumour (GIST), based on large follow-up studies conducted by the US Armed Fo Institute of Pathology (AFIP)

Category

1

Size (cm)

% progression3

Mitotic count (mitoses/5 mm2) 5 to < 10

>5

55

85

6b

>10

>5

86

90

2

> 2 to

叮he given numbers for GISTs of each size indicate the percentages of progressive disease (metastasis or death due to disease) observed in the patient cohorts during a long佃” follow-up. Prognostic assessment of GISTs of all non-gastric sites follows the criteria for small bowel GISTs. Data based on Miettinen and Lasota, 2006 {2125}.

GISTs are associated with mutations of NF1 (which are usually germline alterations in patients with NF1 or rarely somatic muta­ tions), BRAF, or {2153,262,1121}. Like KIT and PDGFRA mutations, these alterations also result in RAS/RAF/MEK path­ way activati on. Most GISTs (with the exception of SDH-deficient tumours) progress through a stepwise acquisition of chromosomal alterations, each of which probably in activates tumour suppressor genes: loss of 14q (as many as 70%), followed by loss of 22q (-50%), 1p (-50%), and 15q (-40%) {2755}. MAX is the 14q GIST tumour suppress or gene, in activated early (in micro­ scopic and low-risk tumours) {2757}. Inactivating mutations in CDKN2A, TP53, and RB1 are found in GISTs of higher-risk categories {2773}. DMD inactivati on is a late eve nt in GIST progression, identified in nearly all metastatic GISTs {3247}. Very rare GISTs harbour NTRK3 or FGFR1 gene fusions {406,2838}.

Fig. 1.260 KIT (CD117)-positive gastrointestinal stromal tumour. Cytoplasmic immu­ nopositivity is associated with perinuclear dot-like accentuation.

220

Soft tissue tumours

Essential and desirable diagnostic criteria Essential: an intramural, submucosal, or subserosal mass; spin­ dle cell, epithelioid, or mixed morphology; KIT and/or DOG" immunopositivity; SDHB loss in SDH-deficient GISTs. Desirable: KIT or PDGFRA gene mutations in approximately 85% of tumours.

Staging Risk stratificati on is prefe rred to an atomical staging.

Prognosis and prediction The best-docume nted prog no stic parameters for GIST are mitotic activity, tumour size, and anatomical site (see Table 1.03). Mitotic counting is for an area of 5 mm2, which in most modern microscopes corresponds to 20-25 fields with the 40x objec­ tive and standard eyepiece diameter {2125}. This prognostic assessment applies best to KIT/PDGFF)A-rc\niar\i GISTs. In general, intestinal GISTs and SDH-deficient GISTs are more unpredictable {3395,1998}. Tumours with low mitotic counts can metastasize, whereas tumours with higher mitotic counts may remain indolent for extended periods. Many patients with SDH-deficient GISTs with liver metastases can survive for years or decades without specific treatment, in contrast to patients with KEPDGFRA-mutant GISTs, which are rapidly progressive when metastatic. Tumour rupture is an additional adverse factor in GIST {1394}. The grading principles for soft tissue sarcomas do not apply to GIST. In order to refine risk assessment for consideration of adjuvant therapy, it has been suggested to include size and mitotic counts as continuous variables to be incorporated along with anato mical site into prog no stic tools such as no mograms {2669} or prog no stic con tour maps {1536}. Mutation status represents a prognostic as well as predictive factor {1765}. In general, Wmutant tumours tend to behave more aggressively than PDGFR/\-mutant or triple-negative (KITI PDGFRAJBRAF-w\\dtype) tumours. The best outcome seems to be associated with PDGFRA exon 12, BFIAF, and KIT exon 12 mutations. An in termediate risk seems to be associated with KIT] PDGFRAI BRAF-w\\6type status and with KIT exon 17, PD& FRA exon 18 (p.Asp842Val), and PDGFRA exon 14 mutations.

paybal：https://www.paypal.me/andy19801210 The worst outcome seems to be associated with KIT exon 9 and 卄 and PDGFRA exon 18 (non-p.Asp842Val) mutations {2668}. Mutation status also predicts response to imatinib, with M ex on 11-muta nt tumou rs exhibiti ng the highest rate of response and PDGFRA exon 18 (p.Asp842Val) mutants showing primary resista nee {1537}. Molecular status also in fluences imatinib dose selection, with KIT exon 9 mutants benefiting from a higher dose (800 mg instead of 400 mg) {770}.

Subsequent mutations are associated with acquired resistance to imati nib. Sec on dary KIT gene mutati ons are most often found in the ATP-binding pocket of the kinase domain (exons 13 and 14) or in the kinase activation loop (exons 17 and 18) {127,1199}. Both KITlPDGFRAIBRAFISDH-wWdtype and NF1-associated GISTs are also characterized by a lack of sensitivity to imatinib {503}.

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paybal：https://www.paypal.me/andy19801210 Soft tissue chondroma

Rosenberg AE

Definition Soft tissue chondroma is a benign neoplasm composed of chondrocytes that produce hyaline or myxoid cartilage that arises in the extraosseous and extrasynovial soft tissues.

ICD-0 coding 9220/0 Chondroma NOS

ICD-11 coding 2E89.1 & XH0NS4 Benign tumours of uncertain differentiation, soft tissue & Chondroma NOS

Related terminology Acceptable: chondroma of soft parts; extraskeletal chondroma.

Subtype(s) Chondroblastoma-like soft tissue chondroma

Localization Approximately 80% of cases occur in the regi on of the fin gers {580,2334}. The remai nder of cases arise most comm only in the han ds, followed by the toes and feet, with origi n in the trunk and the head and neck region {957} being uncommon. Rare examples have been described in the skin {235}, lip {1816}, dura {2977}, and tongue {827}.

Fig. 1.261 Soft tissue chondroma. Small oval mineralized mass in soft tissues sepa­ rate from the phalange.

Etiology Unknown

Clinical features

Pathoge nesis

The turn our is solitary and prese nts as a pain less, firm, slowly enlarging mass {580}. Radiographically, it is well demarcated, is separated from bone, and has spiculated or ring-like calcifications. The cartilage is bright on T2-weighted MRI.

Cytogenetic analyses of limited numbers of soft tissue chondro­ mas reveal several d iffere nt aberrati ons, including rearrangements of 12q13-q15 and trisomy 5, and in a set of tumours with rearrangements of 12q13-q15, a truncated orfull-length HMGA2 transcript was found {410,2820,3033,710,2977}. In about 50% of the cases, FN1 gene rearrangements were reported, with FGFR1 and FGFR2 as fusion partners {92}.

Epidemiology Patients are usually middle-aged (average: 34.5 years), and males are affected more frequently than females (M:F ratio: 1.5:1) {601}.

Fig. 1.262 Soft tissue chondroma. A Mass is well circumscribed by fibrous pseudocapsule. B Chondrocytes in lacunae and surrounded by abundant well-formed hyaline ma"

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Soft tissue tumours

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Macroscopic appearance

Differential diagnosis

Soft tissue chondroma is a well-circumscribed, n°dular, solid mass that is greyish-bluish-white and sometimes focally myx­ oid. Most tumours are solid and 1-2 cm in size.

The tumour is distinguished from synovial chondromatosis because it lacks an association with synovium. It is separated from juxtacortical chondroma because it lacks attachment to bone. Soft tissue chondrosarcoma exhibits greater cellularity, cytological atypia, and mitotic atypia.

Histopathology The tumour is composed of lobules of well-formed hyaline and/ or myxoid cartilage that are delineated by fibrous septa {601}. The cartilage is often hypercellular and the chondrocytes are arranged in clusters and reside within lacunar spaces or float in a flocculent myxoid matrix. The nuclei are usually small, round, and dark, but they may be large with fine or coarse chromatin and small nucleoli and exhibit mild to moderate pleomorphism. Coarse calcifications and endochondral ossification may be present. The chondrocytes in the mineralized areas undergo necrosis, and heavily calcified tumours may have an in filtrate of histiocytes that may obscure the nature of the lesion. The chondroblastoma-like subtype is hypercellular and con tains chondrocytes with nuclei that are often grooved or cleaved and have moderate amounts of eosinophilic cytoplasm; the matrix contai ns calcificati ons that sur round in dividual chon drocytes, thereby mimicking chondroblastoma {514}. Regardless of the morphology, mitotic activity is limited and abnormal mitotic fig­ ures are not observed.

Cytology Not clinically re leva nt

Diagnostic molecular pathology Not clinically re leva nt

Essential and desirable diagnostic criteria Essential: a soft tissue mass composed of nodules of well-delin­ eated cartilage; matrix is hyaline or myxoid and may calcify; chondrocytes show limited atypia and little mitotic activity.

Staging Not clin ically re leva nt

Prognosis and prediction Treatment is marginal excision, and the recurrenee rate is 15-20% {601}.

Soft tissue tumours

223

paybal：https://www.paypal.me/andy19801210 Extraskeletal osteosarcoma

Yamashita K Hameed M

Definition Extraskeletal osteosarcoma is a malignant tumour character­ ized by the production of osteoid or bone matrix by neoplastic cells, and it arises without connection to the skeletal system.

ICD-0 coding 9180/3 Osteosarcoma, extraskeletal

ICD-11 coding 2B5F.2 & XH2CD6 Sarcoma, not elsewhere classified of other specified sites & Osteosarcoma, extraskeletal

Related terminology Acceptable: extraosseous osteosarcoma; soft tissue osteosar­ coma.

Subtype(s) None

Fig. 1.264 Extraskeletal osteosarcoma. Axial contrast-enhanced CT of the pe shows a subcutaneous soft tissue mass superficial to the right gluteal musculati Dense mineralization is seen centrally.

Localization The majority of the tumours present as deep-seated soft tis­ sue masses, but occasionally they originate in the dermis or subcutis. The lower extremity is commonly invoIved, with thigh as the most common location (27—52%); other frequent sites include the buttock, shoulder, trunk, and retroperitoneum {602, 217,1808,1851}.

Clinical features Most patients present with a progressively enlarging mass that may be associated with pain. Some patients present with lung metastases. Plain radiographs, CT, and MRI usually reveal a large deep-seated soft tissue mass with variable mineralization. By definition these tumours do not arise from bone, but they may subsequently involve osseous structures.

Epidemiology Extraskeletal osteosarcoma accounts for < 1% of all soft tissue sarcomas and approximately 4% of all osteosarcomas {2911, 2024,583,3318,2582}. It typically arises during midlife and late adulthood, with most patients being in the fifth to seventh decades of life at diagnosis; occurrence in children is uncom­ mon. Males may be affected more frequently than females (M:F ratio: 0.8-19:1) {602,1808,1891,3064}.

Etiology Most cases develop de novo, but approximately 5-10% of cases are associated with previous exposure to radiation {602, 1808,583}.

Pathogenesis Conventional karyotyping has shown clonal chromosomal and highly complex aberrations {2095,1964,2168}. Recurrent

224

Soft tissue tumours

Fig. 1.265 Extraskeletal osteosarcoma. Gross photograph showing a large heteroge­ neous tan-white fleshy tumour with haemorrhagic and cystic spaces.

copy-number losses in tumour suppressor genes (CDKN2A, TP53, RB1, PTEN, NF1, LSAMP); gains and amplifications M oncogenes (RUNX2, CDC5L, COPS3, EGFR, MDM2, CD組 PMP22\, mutations involving tumour suppress or genes (TP53. PTEN, RB1, NF1, SMARCA4), chromatin-remodelling genes (ATRX, DAXX, BRCA1, DAXX2, CHEK2, ARID5B), histone methylation and demethylation genes (BCOR, DNMT3A, MKK3 [MAP2K3]), and WNT/|3-catenin and sonic hedgehog pathway genes (AMER1, AXIN2, GSK3B, GLI1, NOTCH3); and in some cases TERT promoter mutation and PIK3CA mutations have been reported. The genomic signature of this tumour shows fea­ tures overlapping those of conventional skeletal osteosarco^ {1554}.

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Fig. 1.266 Extraskeletal osteosarcoma. A The bone is more prominent in the centre of the tumour. B Osteoblastic type with tumour cells producing lace-like neoplastic bone. C Chondroblastic type. Condensation and spindling of the tumour cells are shown at the periphery of the cartilaginous area. D Fibroblastic type composed of intersecting fascicles of tumour cells with focus of neoplastic bone.

Macroscopic appearance These tumours range in size from 1 to 50 cm (mean: 8-10 cm) and vary considerably in gross appears nee; many tumours are circumscribed, tan-white, haemorrhagic, and focally necrotic gritty masses {602,217). Extensive haemorrhagic cystic change is present in a minority of cases.

Histopathology Extraskeletal osteosarcoma shows an extremely broad spec­ trum of morphology, and all the major histological patter ns of osteosarcoma in bone can be seen. The osteoblastic type is the most common {602,217,1808,1851,1554}. In general, the tumours are composed of spindle or polygonal cells that are variously pleomorphic, cytologically atypical, and mitotically active and freque ntly dem on strate atypical mitotic figures. Tumour necrosis is also a common feature. Identification of the neoplastic bone intimately associated with tumour cells, which may be deposited in lace-like, trabecular, or sheet-like patter ns, is necessary for diag no sis. SATB2 immuno reactivity could be useful to detect osteoblastic differ­ entiation when immature osteoid is difficult to distinguish from collagenous stroma {654,3342). The amount and distribution °Hhe neoplastic bone vary from tumour to tumour and even betwee n d if fere nt porti ons of the same tumour. The bone is sometimes more prominent in the centre of the tumour, with the more densely cellular areas located in the periphery, a pattern that is the reverse of myositis ossificans. The rare well-differentiated subtype contains abundant bone deposited in well-formed trabeculae, surrounded by a minimally

atypical spindle cell component similar to parosteal osteosar­ coma; high-grade transformation or dedifferentiation has been reported in several cases {3361,9}.

Cytology Cytologically, a hypercellula r smear con si sts of mostly in dividually dispersed and small clusters of atypical cells. Most cases could be recognized as malignant, and fragments of osteoid­ like matrix material might be observed in association with the in dividual cells and cell clusters {2278,2238}.

Diagnostic molecular pathology Not clinically r eleva nt

Essential and desirable diagnostic criteria Essential: no connection to the skeletal system; identification of neoplastic bone/osteoid in association with malignant cells in otherwise unclassified soft tissue sarcoma.

Staging Union for In ternational Can cer Con trol (UICC) and America n Joint Committee on Cancer (AJCC) TNM staging can be applied.

Prognosis and prediction The prog nosis is usually poor, and rece nt large series reported the 5-year overall survival rate to be 37-52% {1891,2872,3064}. Distant metastasis, old age (> 60 years), large tumour size (> 10 cm), and positive margin status were associated with poor prog nosis in more than one study {2872,3064,1891,1554}.

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paybal：https://www.paypal.me/andy19801210 Schwan noma

Perry A Jo VY

Defin ition Schwannoma is a nerve sheath tumour composed entirely or nearly entirely of differentiated neoplastic Schwann cells.

ICD-0 coding 9560/0 Schwannoma NOS

ICD-11 coding 2F38 & XH98Z3 Benign neoplasm of other or unspecified sites & Schwannoma (neurilemmoma)

Related terminology Acceptable: neurilemmoma.

Subtype(s) Ancient schwa nno ma; cellula r schwan no ma; plexiform schwa nnoma; epithelioid schwannoma; microcystic/reticular schwannorna

Fig. 1.267 Schwannoma. Cut surface showing an encapsulated tan-grey tumour wiin foci of haemorrhage, yellowish-white foci of xanthic change, and cystic degeneration

Localization

Clinical features

Comm on sites of origi n are peripheral nerves in the skin and subcutaneous tissues of the head and neck or along the flexor surfaces of the extremities. Spinal intradural extramedullary examples are also comm on and form so-called dumbbell tumours when growing through neural foramina, with multiple paraspi nal schwa nno mas being common place in n eurofibroma­ tosis type 2 (NF2). Cranial n erve in volveme nt is not un comm on, with cerebellopontine angle tumours emanating from the ves­ tibular division of the eighth cranial nerve encountered most often and bilateral involvement being a definitional criterion for NF2 {937}. Spinal intramedullary and CNS sites are rare {502}, as are those involving viscera (such as the gastrointestinal tract) and bone {3205}.

Schwannomas are slow-growing tumours. They often preseni as asymptomatic masses or incidental findings on imaging studies, and they may be painful, particularly in the setting of schwannomatosis. Spinal schwannomas may elicit sensory symptoms such as radicular pain and motor signs if growing intraspinally. Vestibular schwannomas often present with hearing loss and vertigo.

Epidemiology More than 90% of these lesions are solitary and sporadic and may affect all ages but have a peak incidenee in the fourth Io sixth decades of life. There is no known predisposition with regard to race or sex.

Fig. 1.268 Schwannoma. A Alternating compact Antoni A (periphery) and loose Antoni B (centre) areas. Nuclear palisades, known as Verocay bodies, are noted in the Ai>

A area on the right. B The formation of Schwannian whorls can raise the differential with meningioma.

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Soft tissue tumours

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Fig. 1 >269 Ancient schwannoma. A The presence of scattered bizarre or atypical nuclei is often considered a degenerative phenomenon, which does not impact the prognosjs B Despite the nuclear atypia, the Ki-67 proliferation index is low, with the majority of bizarre nuclei being negative.

Etiology The etiology of most sporadic schwannomas is not known, although there is an established increased incidenee associ­ ated with prior irradiation {2654,2540}. There is an associa­ tion with neurofibromatosis in some cases (see Pathogenesis, below).

Pathogenesis A causal relationship exists between schwannoma tumorigenesis and loss of expression of merlin (NF2, schwannomin), the growth inhibitory protein product of the A/ES'tumou r suppress or

gene located at 22q12.2 {2943}. /VF^-inactivating mutations have been detected in approximately 50-75% of sporadic cases {1503,1766,2360,1323}. Underlying genetic events are predominantly frameshift and nonsense mutations, with loss of the remaining wildtype allele on chromosome 22. Other com­ mon mutations involve the LATS1, LATS2, ARID1A, ARID1B, and DDR1 genes, whereas a recurrent in-frame SH3PXD2AHTRA1 fusion is found in roughly 10% of cases {2360,42}. Multiple schwannomas are a feature of NF2 and schwannomatosis, both of which can also occur in mosaic or segmental forms {337,1607}. NF2-associated schwa nno mas comm only

ig，h270 Cellular schwannoma. A The marked hypercellularity and compact arrangement may be alarming, warranting consideration of a sarcoma in the differential diagno-

严 B Mitotic figures are common, but the mitotic count is 5 cm at the time of diagnosis and have a tanwhite, fleshy cut surface, often with areas of haemorrhage and necrosis.

Fig. 1.302 Malignant triton tumour. Malignant peripheral nerve sheath tumour with extensive rhabdomyoblastic differentiation (malignant triton tumour).

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Fig. 1.303 Malignant peripheral nerve sheath tumour with angiosarcoma. High-grade angiosarcomatous component in a malignant peripheral nerve sheath tumour arising in a patient with neurofibromatosis type 1.

Fig. 1.304 Malignant peripheral nerve sheath tumour with glands. Malignant pei eral nerve sheath tumour with glandular differentiation.

d if fere ntiation, such as skeletal muscle, bone, cartilage, and blood vessels, is seen in about 15% of tumours. A malignant triton tumour is an MPNST with skeletal muscle differentiation. Giandular differentiation, with or without mucin production, is rarely seen (glandular MPNST); almost all of these tumours arise in patients with NF1. When involving a large nerve, the neoplastic cells may track along the n erve bund les. In NF1-related MPNST arising in a pre-existent neurofibroma, the distinotion between a low-grade MPNST and an atypical neurofibroma / atypical neurofibromatous neoplasm of uncertain biological potential is often problematic, especially on small biopsies. Recently, diagnostic criteria to distinguish these tumours from other types of NF1-associated nerve sheath tumours have been established (see Table 1.04) {2142}. Epithelioid MPNST is a rare subtype of MPNST (< 5% of the tumours) that is composed of plump, epithelioid cells with abundant eosinophilic cytoplasm, sometimes embedded in an abundant extracellular myxoid or hyalinized matrix and typi­ cally dem on strati ng a lobulated growth pattern {1762}. Although rare, this subtype of MPNST is the most comm on type to arise

ex-schwannoma {2751}. Epithelioid MPNST is not associati with NF1. Immunohistochemically, MPNST may be positive for ST (< 50% of tumours), SOX10 (< 70%), and GFAP (20-30 {1569}. Importantly, staining for S100 and SOX10 is patchy focal. Diffuse staining for S100 or SOX10 is not usually coi patible with the diagnosis of conventional MPNST. Comple loss of staining for H3K27me3 may be helpful in the diagn sis of MPNST, with high-grade tumours (and radiati on-in duct MPNST) showing more-frequent loss than low-grade tumou {2475,2545,2754,2397}. The heterologous components (e. skeletal muscle differentiation or angiosarcomatous area stain for appropriate markers. The glands in glandular MPNJ show positive staining for keratin and CEA and may be po; tive for neuroendocrine markers. Unlike conventional MPNS1 epithelioid MPNSTs show strong and diffuse staining for S1C and SOX10, in the absenee of melanoma markers. They reta expression of H3K27me3 and most show loss of SMARCE expression {2751}. Epithelioid MPNST may also be positive f keratin.

Table 1.04 Proposed nomenclature for the spectrum of neurofibromatosis type 1-associated nerve sheath tumours Diagnosis

Proposed definition

Neurofibroma

Benign Schwann cell neoplasm with thin (often wavy) nuclei, wispy cell processes, and a myxoid to collagenous (shredded carrots) matrix; immunohistochemistry includes extensive but not diffuse S100 and SOX10 positivity and a lattice-like CD34+ fibroblastic network

Plexiform neurofibroma

Neurofibroma diffusely enlarging and replacing a nerve, often involving multiple nerve fascicles, delineated by EMA+ perineurial cells

Neurofibroma with atypia (ancient neurofibroma)

Neurofibroma with atypia alone, most commonly manifesting as scattered bizarre nuclei

Cellular neurofibroma

Neurofibroma with hypercellularity but retained neurofibroma architecture and no mitoses

Schwann cell neoplasm with > 2 of the following 4 features: cytological atypia, loss of neurofibroma architecture, hypercellularity, and

ANNUBP

< 1.5 mitoses/mm2 (< 3 mitotic figures per 10 HPFsa)

MPNST, low-grade

Features of ANNUBP, but with a mitotic count of 1.5-4.5 mitoses/mm2 (3-9 mitotic figures per 10 HPFsa) and no necrosis

MPNST with > 5 mitoses/mm2 (> 10 mitotic figures per 10 HPFsa) or 1.5-4.5 mitoses/mm2 (3-9 mitotic figures per 10 HPFsa) combined

MPNST, high-grade

with necrosis

ANNUBP, atypical neurofibromatous neoplasm of uncertain biological potential; HPF, high-power field; MPNST, malignant peripheral nerve sheath tumour. a1 mm2 = approximately 5 HPFs of field diameter 0.51 mm.

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Fig. 1.305 Epithelioid malignant peripheral nerve sheath tumour. A The neoplastic cells are epithelioid, with eosinophilic cytoplasm and nuclei with prominent nucleoli. B EpiIhelioid malignant peripheral nerve sheath tumour showing loss of SMARCB1 (INI1) staining. Normal cells in the background show nuclear staining.

Cytology

Stagi ng

Not clinically relevant

Not clin ically releva nt

Diagnostic molecular pathology

Prognosis and prediction

Not clinically r eleva nt

MPNST is an aggressive tumou r with a poor prog no sis. Truncal location, tumour size > 5 cm, local recurrenee, and high-grade morphology are all adverse prognostic factors; patients with NF1-associated MPNST appea r to have a worse prog nosis than patients with sporadic tumours {1783}. Malignanttriton tumours are particularly aggressive.

Essential and desirable diagnostic criteria Essential: sarcoma arising from a nerve or pre-existing nerve sheath tumour or in a patient with NF1; tumours with a spindle fascicular growth, geographical necrosis, and often a limited degree of nuclear pleomorphism; in the sporadic setting, diagnosis is most often based on the identification of Schwann cell differentiation (S100/SOX10 focal positivity) and/or loss of H3K27me3 expression in a soft tissue mass; heterologous elements in a sarcoma should suggest MPNST; epithelioid MPNSTs occur outside the NF1 setting and often show diffuse S100 and SOX10 positivity and loss of SMARCB1 expression.

Soft tissue tumours

257

paybal：https://www.paypal.me/andy19801210 Malignant melanotic nerve sheath tumour

Folpe AL Hameed M

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Definition Malignant melanotic nerve sheath tumour (MMNST) is a rare peripheral nerve sheath tumour composed uniformly of Schwann cells showing melanocytic differentiation, usually arising in association with spinal or autonomic nerves. It is variably associated with Carney complex and frequently shows aggressive clin ical behaviour. PFlKA Fl 1A mutations and loss of PRKAR1A protein expression are seen in the overwhelming majority of cases.

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ICD-0 coding 9540/3 Melanotic maligna nt peripheral nerve sheath tumour

ICD-11 coding 2B5E & XH2XP8 Malignant nerve sheath tumour of peripheral nerves or autonomic nervous system, primary site & Malignant peripheral nerve sheath tumour

Related terminology Acceptable:me\anotic schwannoma; psammomatous melanotic schwannoma; malignant melanotic Schwannian tumour.

Subtype(s) None

Fig. 1.306 Melanotic schwannoma. Malignant tumour arising in a thoracic nerve root The sectioned tumour had the appearance and texture of dried tar, and it was circum­ scribed except for a portion (left) that invaded nearby soft tissues and vertebral bone

Clinical features Prese nting symptoms in elude pain, sen sory abnormalities, and mass effect. Bone erosion may be seen in spinal nerve root tumours. Parenchymal symptoms, such as respiratory and liver failure, may be seen in patients with metastatic disease.

Localization MMNST most often arises from the spinal or autonomic nerves near the midline. However, cases have been reported in the gastrointestinal tract {564,571}, as well as in bone, soft tissues, heart, bronchus, liver, and skin.

Epidemiology MMNST is rare and occurs chiefly in adults. The tumour typi­ cally develops at an earlier age (average: 22.5 years) in patients with Carney complex than in those without this complex (aver­ age: 33.2 years) {484,3091}. Multiple tumours are seen in about

Fig. 1.307 Malignant melanotic nerve sheath tumour. A Malignant melanotic nerve sheath tumour presenting as an encapsulated posterior mediastinal mass in a 31-year-old

woman. B Higher-power view showing heavily pigmented, vaguely syncytial epithelioid cells with visible nucleoli.

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Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 m% of patients; in such patients, there is a higher probability that other manifestations of Carney complex will also be present (484,3091}.

Etiology

In some series, > 50% of patients with MMNSTs have evidenee of the Carney complex, an autosomal dominant, sometimes familial multiple neoplasia syndrome {484}. However, other series have noted an association with Carney complex in < 5% of affected patients {3145,3091,3393,3233}.

pathogenesis Two genetic loci have been identified in Carney complex: PrKAR1A(CNC1) and CNC2, mapping to 17q22-q24 and 2p16, respectively. PRKAR1A inactivation is seen in roughly 50% of Carney complex kindreds {2020,1643}. PRKAR1A encodes a tumour suppressor; PRKAR1A mutations and loss of PRKAR1A protein expression are seen in the overwhelming majority of studied MMNSTs, almost all of which have occurred in patients lacking other stigmata of Carney complex {3091,3233}. SNP arrays typically show hypodiploidy, with monosomies of chro­ mosomes 1, 2, and 17. Inactivation of both alleles of PRKAR1A through mutations and/or loss of heterozygosity of 17q has been reported {3233}. Gene expression analyses show MMNST to clearly segregate from conventional schwannomas and mela­ nomas {3091}.

Macroscopic appearance Most MMNSTs are solitary, although multiple and multicentric tumours may be seen in patients with Carney complex. Grossly, the tumours appear circumscribed or partially encapsulated, and they are frequently heavily pigmented, with the appearance of dried tar.

Histopathology The neoplastic cells grow in short fascicles or sheets, vary in shape from polyg onal to spin died, and ofte n have a sync ytial appears nee. Vague palisadi ng or formation of whorled struc­ tures may be present. Cellular detail is often difficult to discern,

Fig. 1.309 Malignant melanotic nerve sheath tumour. Although this patient was not known to have Carney complex, there was complete loss of PRKAR1A expression.

owing to the heavy pigment deposits. The melanin pigment may be coarsely clumped or finely granular and varies from area to area. It stains positively with the Fontana stain and negatively for iron and PAS. In less pigmented areas, the tumour cells have eosinophilic to amphophilic cytoplasm, round to ovoid nuelei (often with nuelear grooves and pseudoiinclusions), and usu­ ally small nueleoli. Occasional tumours show marked nuelear hyperchromatism with prominent macronueleoli. Mitoses and necrosis can be present, but they are not clearly associated with outcome. Psammoma bodies are present in roughly 50% of cases, although extensive sampling may be required to identify them. There are no clinical differences between psammoma­ tous and non-psammomatous MMNSTs, with both showing a variable association with Carney complex, loss of PRKAR1A expression, and similar clinical behaviour {3091,3233}. Immunohistochemically, MMNSTs strongly express S100; SOX10; and various melanocytic markers, including HMB45, melan-A, and tyrosinase. PRKAR1A expression is typically lost {3091, 3233}. Ultrastructurally, the cells resemble Schwann cells with elaborate cytoplasmic processes that interdigitate or spiral in

Fig. 1.308 Malignant melanotic nerve sheath tumour. A Malignant melanotic nerve sheath tumour presenting as a perigastric mass in a 45-year-old woman. Portions of this bmour showed pigmented spindle cell morphology. B Other areas in this tumour had a trabecular, epithelioid appearance, with scattered psammoma bodies.

Soft tissue tumours

259

paybal：https://www.paypal.me/andy19801210 the manner of mesaxons; premelanosomes and melanoso are routinely present {3393,1429}.

Cytology Not clinically re leva nt

Diagnostic molecular pathology PRKAR1A expression is typically lost, corresponding to mlt tions of the gene {3091,3233}.

Essential and desirable diagnostic criteria Essential: frequent origin from paraspinal or visceral autonom nerves; fascicular to sheet-like proliferation of heavily 小① men ted, relatively un iform plump spin died cells; coexpre： Fig. 1.310 Malignant melanotic nerve sheath tumour. Cervical lymph node metasta­ sis in a 46-year-old man with malignant melanotic nerve sheath tumour. Neither the primary tumour nor the metastasis showed features that might have suggested an increased risk of metastasis.

sion of S100/SOX10 and melanocytic markers (e.g. HMB45 melan-A). Desirable: loss of PRKAR1A expression.

Staging Not clin ically re leva nt

Prognosis and prediction

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Fig. 1.311 Malignant melanotic nerve sheath tumour. SNP array (OncoScan) analysis demonstrating copy-neutral loss of heterozygosity of the long arm of chromosome 17; PFIKAR1A is localized to 17q24.2.

260

Soft tissue tumours

The behaviour of MMNST is difficult to predict, and metasta­ ses can occur in the absenee of morphologically malignant features. In the past, it was thought that most of these lesions had a benign, in dole nt course, with a < 15% metastatic risk {484}. However, more-recent reports have shown frequently aggressive behaviour, with a local recurrenee rate and meta­ static risk of 26-44% {3145,3091,3233,1620}. Additionally, only 53% of patients followed for > 5 years have been reported lo be disease-free, suggesting that Iong-term follow-up is required to fully judge metastatic risk. In general, histopathological fea­ tures are not predictive of outcome, although there are limited data suggesting more-aggressive behaviour in mitotically active tumours {3091}.

paybal：https://www.paypal.me/andy19801210 Intramuscular myxoma

Liegl-Atzwanger B Hogendoorn PCW Nielsen GP

Qefinition Intramuscular myxoma is a benign hypocellular soft tissue tumour composed of bland spindle-shaped cells embedded in a usually abundant myxoid and hypovascular stroma.

ICD-O coding 8840/0 Myxoma NOS

ICD-11 coding 2E84.Z & XH6Q84 Benign fibrogenic or myofibrogenic tumour, site unknown & Myxoma NOS

Related terminology Acceptable: cellular myxoma.

Subtype(s) Cellular myxoma

Fig. 1.313 Intramuscular myxoma. T2-weighted MRI shows a well-circumscribed, hyperintense tumour.

Localization The most comm on locati ons are the large muscles of the thigh, shoulder, buttock, and upper arm {914,1479,2286,3179}.

Clinical features Intramuscular myxoma is a slow-growing painless mass {914, 1479,2286,3179}. On MRI, it is bright in T2-weighted images and shows low signal intensity compared with skeletal muscle in T1-weighted images {2788}. Intramuscular myxomas are mainly sporadic but may occur in combi nation with fibrous dysplasia, a condition called Mazabraud syndrome {1479}.

Epidemiology Intramuscular myxoma usually affects middle-aged individuals (40-70 years) and is more common in females (M:F ratio: -0.3:1)

{914,1479,2286,3179}. Most lesions are sporadic but a minor­ ity are associated with fibrous dysplasia, which is most often polyostotic (Mazabraud syndrome) {1479,1947}. In Mazabraud syndrome, myxomas are often multiple.

Etiology Unknown

Pathogenesis Activating point mutation in GNAS (exons 8 and 9) is detected in > 90% of sporadic intramuscular and cellular myxomas {2996, 781}, as well as in cases of Mazabraud syndrome {2368}. Mutations in GNAS lead to downstream activation of FOS (c-FOS) {3294}.

Fig，1.312 Mazabraud syndrome. A Intramuscular myxomas are seen in the proximal muscles of the lower extremities (stars). B Fibrous dysplasia is present in the proximal 師 ur (arrow).

Soft tissue tumours

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circumscribed, close exami nation can demon strate 川佻打 borders where the tumour merges with the surrounding ske|p3 muscle. The cut surface is gelati nous and lobulated and 时

have cystic, fluid-filled areas.

Histopathology Classic intramuscular myxoma is a cytologically bland, hypOcJ lular lesion composed of uniform spindle to stellate-shaped ceil' with uniform small oval' nuclei and indistinet palely eosinopQ

Fig. 1.314 Intramuscular myxoma. Intramuscular myxoma composed of a gelatinous

mass with internal septa. The tumour is well circumscribed overall but shows some infiltration of the surrounding skeletal muscle (left of tumour).

Macroscopic appearance On gross exami nation, the tumou r size ran ges from 5 to 10 cm {914,1479,2286,3179}; however, examples as large as 20 cm have been documented. The larger ones are usually cellu­ lar myxomas {1317}. Although these tumours appear well

cytoplasm embedded in an abundant extracellular myxoid stroma. Only sparse capillary-sized blood vessels are seen. Cystic change and vacuolation may be seen in the stroma Necrosis and mitotic figures are not seen. At the edge of lesion, infiltration of the tumour between and around individj skeletal muscle cells is often observed. A subset of tumours show hypercellular areas occupying 10-90% of the tumour. These tumours show an increasea number of cells and a more prominent vascular pattern with capillary-sized, occasionally thick-walled vessels, sometimes focally in a more collage nous backgrou nd {2286,3179,2996； Mitoses are very rare and pleomorphism or necrosis is absent There may sometimes be morphological overlap between cel­ lular myxoma and low-grade myxofibrosarcoma (also on immunohistochemistry) {2996,3294}, although nuelear atypia anc hyperchromasia usually exclude the former. Immunohistochemically, the tumour cells are commonly posi­ tive for CD34 and rarely stain for SMA. Desmin and S100 are

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Fig. 1.315 Intramuscular myxoma. A Scanning magnification of an intramuscular myxoma. B Intramuscular myxoma with entrapment of skeletal muscle fibres in the p肌： sllular and more coll< collagen ery. C Intramuscular myxoma with extracellular matrix with frothy appearance, mimicking lipoblasts. D Cellular intramuscular myxoma is a more cellular

neoplasm, with bland uniform spindle cells lacking nuclear pleomorphism.

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paybal：https://www.paypal.me/andy19801210 aative. There are often multifocally scattered muciphages for CD163.

爲unopositive

Cytology Not clinically relevant

Diagnostic molecular pathology GnaSeutation analysis may be a useful tool to differentiate cellular myxoma from a low-grade myxofibrosarcoma in diagnostically challenging cases or on limited biopsy material.

Essential and desirable diagnostic criteria Essential: intramuscular mass in middle-aged predominantly female adults; hypocellular myxoid tumour composed of bland spindle cells; in conspicuous vessels; focal n on-destructive

infiltratio n of adjace nt skeletal muscle; n uclear atypia, mitoses, and necrosis are absent; the cellular subtype is more cellular with areas of more-collagenous stroma and increased vasculature. Desirable: detection of GNAS mutations (in selected cases).

Staging Not clin ically re leva nt

Prognosis and prediction Classic intramuscular myxoma is typically a non-recurrent tumour, whereas the cellular subtype has a small risk for local non-destructive recurrence {3179,1947}. Malignant transforma­ tion does not occur.

Soft tissue turn ours

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paybal：https://www.paypal.me/andy19801210 Juxta-articular myxoma

Liegl-Atzwanger B Hogendoom PCW Nielsen GP

Definition Juxta-articular myxoma is a rare, benign myxoid soft tissue tumour morphologically similar to intramuscular/cellular myx­ oma (but lacking GNAS mutation), typically arising in the vicinity of large joints.

ICD-0 coding 8840/0 Myxoma NOS

ICD-11 coding 2E84.Z & XH6Q84 Benign fibrogenic or myofibrogenic tumour, site unknown & Myxoma NOS

Related termi no logy Acceptable: periarticular myxoma.

Subtype(s) None

Fig. 1.316 Juxta-articular myxoma. MRI of a tumour located adjacent to the kn joint, showing a homogeneous bright signal, similar to intramuscular myxoma.

Localization

Epidemiology

Juxta-articular myxoma usually arises adjace nt to large joints, with the knee joint being the most comm only affected site (> 85%). Other locations affected are the shoulder, elbow, hip, and ankle {2058}, and rare locati ons in elude the temporoma ndibular joint {3360}.

These lesions occur over a wide age range, including rarely in children, but they typically affect patients in the fifth and sixt decades of life, with a male predominance {2058}.

Clinical features Patients usually present with a swelling or a mass that may be associated with tenderness or pain in the vicinity of large joints. Duration of symptoms ranges from weeks to years. Imaging studies are similar to those of intramuscular myxoma {1638}.

Etiology In most patients, the etiology is unknown. A minority of patient have a history of trauma or osteoarthritis, which may be coinci dental.

Pathogenesis Unknown

Fig.1.317 Juxta-articular myxoma. A Cystic area filled with myxoid material surrounded by a more cellular proliferation. B Myxoid stroma with bland spindle cells resemblin?

areas of cellular myxoma.

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Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 Macroscopic appearance

Cytology

The tumour usually ranges in size between 2 and 6 cm, but amours as large as 13 cm have been described {2058}. The cUt surface is gelatinous and myxoid. Cystic degeneration is commonly seen.

Not clinically releva nt

Diagnostic molecular pathology Un like in tramuscular myxomas, juxta-articular myxomas do not demonstrate GNAS mutations {2368}.

Histopathology The tumour is generally hypocellular and composed of bland spindle-shaped cells with uniform ovoid nuclei, inconspicuoUS nuclei, and palely eosinophilic cytoplasm embedded in a hypovascular myxoid stroma. In creased cellularity can be see n (similar to in cellular myxoma); however, mitoses are scarce. In the majority of cases, cyst-1 ike spaces lined by a delicate fibri n layer or a thicker layer composed of collagen may be seen. The tumour is poorly circumscribed, dem on strati ng in filtrati on into the surrounding adipose or tendinous tissue. In a subset of cases, haemorrhage, chronic in flammation, and haemosideri n/ fibrin deposition may be seen, probably due to trauma. These reactive changes may also be seen in recurrent tumours. Immunohistochemically, the lesional cells may express CD34 and/or SMA. S100 is negative. CD163-positive muciphages may be present.

Essential and desirable diagnostic criteria Essential: affects soft tissue arou nd large joints, most comm only the knee (> 85%); hypocellular myxoid cytologically bland tumour; infiltrative growth pattern. Desirable: lacks GNAS mutations (in selected cases).

Staging Not clin ically r eleva nt

Prognosis and prediction Local recurrenee occurs in as many as one third of patients, sometimes more than once {2058). Malignant transformation does not occur.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Deep (aggressive) angiomyxo

icci MR dge JA

Definition

Etiology

Deep (aggressive) an giomyxoma is an in filtrative, benig n, myx­ oid spindle cell neoplasm that occurs in the deep soft tissue of the pelviperineal region.

Unknown

Pathogenesis

ICD-0 coding

Karyotypic aberrations involving chromosome region l2qiM q15 predomi nate in aggressive an giomyxoma (2587) cj

8841/0 Aggressive an giomyxoma

ICD-11 coding 2F7C & XH9HK9 Neoplasms of uncertain behaviour of connective or other soft tissue & An giomyxoma

Related terminology Acceptable: deep an giomyxoma; aggressive an giomyxoma.

Subtype(s) None

Localization Deep an giomyxoma typically occurs in the deep soft tissue of the pelvis and perineal region, including in the vulvovaginal and ingui no scrotal soft tissue in wome n {2937,250,994,1208} and men {3108,1463}, respectively.

Clinical features Patients typically present with a slow-growing, deep-seated pain less mass. Lesi ons may sometimes be associated with vague discomfort, pain, or mass effect on adjacent organs with associated symptoms. MRI may reveal an internal laminated appearanee to the mass (the so-called swirl sign) {2998,2927}.

Epidemiology

respondingly, rearrangements of the HMGA2 (12q14.3)locui have been identified by FISH, with associated HMGA2 tram scriptional upregulation and aberrant expression confirmed by RT-PCR and immunostaining in some studies {1602,2332 2106,2051}. The target gene has been shown to be HMGA2 (previously designated HMGIC), which is a DNA architectural factor important in transcriptional regulation that is not typically expressed in non-n eoplastic adult tissues. Aberra nt expression of HMGA2 protein is also seen in other mesenchymal tumours such as lipoma, pulm onary chon droid hamartoma, and uter­ ine leiomyoma, with similar chromosomal aberrations {2332}. The molecular mechanism for aberrant expression appears multifactorial and tumour dependent; in some instances, deep (aggressive) an giomyxoma is due to fusi on tran script production, whereas in others the gene is in tact but shows deregulated expression via alterations affecting the 5' regulatory region or the untranslated 3' region. It is not clear how HMGA2 expres­ sion leads to tumour development, but presumably altered transcription of target genes is a potential mechanism.

Macroscopic appearance Deep an giomyxomas are variably described as tan -yellow soft or gelati nous masses with ill-defi ned margins. The tumours can vary in size, but most are > 10 cm. Recurrent tumours may have a more fibrous appearanee because they may be associated with scar tissue.

Deep an giomyxoma occurs over a wide age ran ge, with a peak in the fourth to fifth decades of life. It is much more comm on in women.

Fig. 1.318 Deep (aggressive) angiomyxoma. A This tumour is characteristically paucicellular and composed of bland spindle cells set within an abundant myxoid matrix inte；

spersed with prominent vessels. B Medium-sized to large vessels can be seen, with thickened walls. Note the presence of particularly distinct myoid bundles wrapping vessels of various calibres. C A higher-power view.

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Fig. 1・319 Deep (aggressive) angiomyxoma. A The spindle-shaped cells have delicate cytoplasmic processes and ovoid bland nuclei. The myoid bundles are typically arranged in loose clusters or tight whorls around the vascular component. B When present, aberrant HMGA2 expression is a useful diagnostic marker for deep (aggressive) an giomyxoma. II js particularly helpful in defining the margin of the tumour, because non-neoplastic mesenchyme lacks expression.

Histopathology Deep an giomyxoma is composed of spin died stromal cells and a prominent vascular component set within a copious myxoid matrix. On low-power exami nation, it is relatively hypocellular, and the vessels, which are characteristically medium-sized to large, are most often evenly dispersed throughout the tumour. Lesional spindle cells have delicate eosinophilic bipolar cell processes, and the nuclei are bland and ovoid or rounded. The vessel walls may be hyali nized and show perivascular con cen­ tric condensation of collagen fibres. In addition, collect!ons of more eosinophilic smooth muscle cells (so-called myoid bun­ dles) are comm only see n in stroma arou nd the vessels. The tumour is infiltrative and the border may be difficult to delineate from surrounding non-neoplastic soft tissue. The spindle cells are typically positive for desmin (more often diffusely than focally), and they may be positive for CD34 and SMA; SMA, whe n positive, is more comm only seen in the myoid bundles {1208,3168}. The spindle cells are also often positive for ER and PR (usually with moderate to strong positivity, > 50% nuclei) {316}. HMGA2 is a sensitive but not entirely specific marker for deep an giomyxoma {2030}. Positivity for CDK4 but not MDM2 has been described {3168}; of note, CDK4 is in the same region as HMGA2 on 12q.

Cytology

Fig. 1.320 Deep (aggressive) angiomyxoma. HMGA2 (12q14.3) rearrangement. A Partial G-banded karyotype exhibiting a t(12;21)(q15;q21.1) in an aggressive angio­ myxoma. B,C Dual-colour FISH with a probe set flanking HMGA2 demonstrates the presence of a rearrangement of this locus in tumour interphase nuclei (split red and

green signals).

Not clinically relevant

Prognosis and prediction

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: poorly marginated lesion; relatively hypocellular with copious myxoid matrix; bland spindle-shaped stromal cells with eosinophilic processes; medium-sized to large vessels, often with hyalinized walls; collections of smooth muscle cells (myoid bun dies) nea r vessels; desmi n positivity. Desirable: HMGA2 is often positive.

Invasive local recurrenee may occur, although this happens much less commonly than originally thought, which is reflected by the terminology change from "aggressive" to "deep" angiomyxoma, with the latter desig nation chose n to reflect lesi onal depth. Recur­ rence rates vary (ranging from 9% to 50%) {3168,1083,2990}; this wide range may reflect uncertainty regarding margin status, because the border of the tumour can be difficult to delineate. More than one recurre nee is very un comm on. HMGA2 staining may be useful in determining margin status. Recurrent tumours that express hormone receptors have been successfully treated with surgery and adjuvant GnRH analogues {2791,44}.

Staging Not clinically relevant

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Mentzel TDW Brenn T

Atypical fibroxanthoma

Definiti on Atypical fibroxanthoma (AFX) is a dermal-based mesenchymal neoplasm of uncertain differentiation, in a disease spec­ trum with pleomorphic dermal sarcoma in sun-damaged skin. Tumours that meet strict diag no stic criteria gen erally behave in a benign fashion.

ICD-0 coding 8830/1 Atypical fibroxanthoma

ICD-11 coding 2F72.Y Other specified neoplasms of uncertain behaviour of skin (atypical fibroxanthoma)

Related terminology None

Fig. 1.321 Atypical fibroxanthoma. Clinically, atypical fibroxanthoma presents small, exophytic, often ulcerated dermal neoplasm.

Subtype(s) Epidemiology

None

Localizati on AFX arises predominantly in sun-damaged skin of the head and neck region, whereas the extremities are rarely affected {1476, 2090,247,1916}.

AFX represents a rare mesenchymal neoplasm that occur most commonly in sun-damaged skin of elderly white patient; males are affected more often than females {1476,2090,24； 1916,2157}. Exceptionally rarely, AFXs have been reported i you ng patie nts with germline mutatio n of TP53 or with xero derma pigmentosum {541,1814}.

Clinical features AFX presents as a solitary, fast-growing, exophytic, dome­ shaped nodule that is usually < 2 cm and often ulcerated. The neoplasms are red, flesh-coloured, or bluish-brown {1476,2090, 247,1916}.

Etiology Ultraviolet (UV) radiation plays a central role in the development of AFX, and UV radiation signature mutations in TP53 have been found {776}. Rarely, AFX is seen in the field of prior radiation therapy and in patients with immunosuppression.

Fig. 1.322 Atypical fibroxanthoma. A Low-power view shows a nodular, well-circumscribed, dermal neoplasm with collarette formation of the hyperplastic epidermis. B CeM^1

neoplasm composed of atypical spindled, round, polygonal, and pleomorphic tumour cells; numerous mitoses are present.

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Fig」.323 Spindle cell atypical fibroxanthoma. Cellular bundles and fascicles composed of atypical spindled cells with numerous mitoses are noted.

Fig. 1.325 Osteoclast-like giant cell-rich atypical fibroxanthoma. Numerous osteo­ clast-like giant cells with small, bland nuclei are admixed.

Fig. 1.324 Keloidal atypical fibroxanthoma. Thick bundles of hyalinized collagen

Fig. 1.326 Granular cell atypical fibroxanthoma. Tumour cells contain abundant gran­ ular cytoplasm and enlarged nuclei.

masking nuclear atypia.

Pathogenesis TP53 mutation due to UV irradiation is believed to be pathogenetically important. AFX shows abnormal accumulation of p53 and a characteristic TP53 mutation pattern. Many AFXs show deletions but lack HFIAS, KRAS, and NFIAS gene mutations, in contrast to un d if fere ntiated pleomorphic sarcoma {776,2711, 2143,2712}. Otherwise, activating mutations in the promoter region of the TERT gene, frequent N0TCH1 and FAT1 mutations, and a similar DNA methylation profile in AFX and pleomorphic dermal sarcoma suggest a close relationship {1218,1219,1669}.

Macroscopic appearance AFXs are well-circumscribed nodular or polypoid tumours of the dermis. Ulceratio n of the epidermis is a comm on feature.

of atypical multinucleated tumour giant cells. Neoplastic cells contain enlarged atypical, vesicular, or hyperchromatic nuclei, and numerous mitoses (including atypical mitoses) are present. By definition, tumour necrosis, lymphovascular and/or perineu­ ral invasion, and subcutaneous invasion are absent. Scattered inflammatory cells, numerous vessels, and areas of haemor­ rhage may be present {247,1916,2090,2157}. A number of histo­ logical subtypes are described, as follows.

Spindle cell, non-pleomorphic AFX Spindle cell AFX shows usual features of AFX but is composed of relatively monomorphic, eosinophilic, spindled tumour cells arran ged in bun dies and fascicles {463}.

Clear cell AFX Histopathology The histopathological criteria for the diagnosis of AFX must be used strictly, and the diagnosis of AFX should never be made On a biopsy only, or without the use of a panel of immunohistochemical antibodies. AFX represents an intradermal, usually symmetrical and well-circumscribed cellular neoplasm without involvement of the subcutis. Ulceration and collarette formation "the lateral hyperplastic epidermis are frequent. These cellular neoplasms are composed of sheets and fascicles of most often highly pleomorphic polygonal or histiocytoid cells, enlarged and atypical spin died and epithelioid cells, and variable nu mbers

Clear cell AFX is rare and composed of pleomorphic tumour cells with foamy or clear cytoplasm and hyperchromatic nuclei; it must be disti nguished from ballo on cell mela no ma, seba­ ceous or clear cell carcinoma, and siqnet-rinq anqiosarcoma {688,3049}.

Pigmented (haemosiderotic) AFX Pigmented AFX may resemble melanoma and is character­ ized by abundant intratumoural haemorrhage with blood-filled, pseudovascular spaces. A variable number of osteoclast-like

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 giant cells are present and abundant haemosiderin deposition is noted {819,3069}.

neoplasms. Tumour cells in AFX usually stain positivel vimentin, CD10, and p53, and often for SMA, but these areJ specific. AFX is consistently negative for keratins, S100 SoE

Myxoid AFX

CD34, ERG, and desmin. Cases of AFX occasionally may at least focal non specific expressi on of mela n-A, HMB45 Mn EMA, p63, CD99, CD68, and CD31 {247,3034,1916,30681

Promine nt myxoid stromal cha nge is very rarely seen in AFXs. Such lesions must be distinguished from myxofibrosarcoma or myxoid leiomyosarcoma {2466}.

Cytology

Osteoclast-like giant cell-rich AFX AFX may contain numerous bland osteoclast-like giant cells and must be distinguished from giant cell tumour of soft tissue, as well as from leiomyosarcoma with osteoclast-like giant cells {3087}.

Not clinically relevant

Diagnostic molecular pathology Not clin ically re leva nt

Essential and desirable diagnostic criteria Keloidal AFX AFX may rarely show thick bun dies of hyali nized collage n, masking the nuclear atypia and worrisome morphology, mim­ icking keloid or keloidal dermatofibroma {1631}.

Essential: usually pleomorphic (but variable) morphology； $曲& confinement to the dermis; immunonegativity for keratins S100, and SOX10.

Staging Granular cell AFX Rarely, AFX is composed of atypical and pleomorphic tumour cells with abundant granular cytoplasm staining positively for CD68 and NKI/C3 {2685}. Granular cell tumour, non-neural granular cell tumour, and other neoplasms with prominent granular cell features must be distinguished.

Immunohistochemistry No specific immuno histochemical marker for AFX is known, and a broad panel of antibodies must be used to exclude other

270

Soft tissue tumours

Not clin ically re leva nt

Prognosis and prediction When strict diagnostic criteria are applied, the vast majority AFXs show benign behaviour after complete surgical excisio Local recurrence is rare and distant metastases exception {3244}. Cases with tumour necrosis, invasion into subcuti and/or lymphovascular invasion have metastatic potential ar should therefore be regarded as pleomorphic dermal sarcom

paybal：https://www.paypal.me/andy19801210 Rekhi B Antonescu CR Chen G

Angiomatoid fibrous histiocytoma

pefinition Angiomatoid fibrous histiocytoma (AFH) is a rare neoplasm of •ntermediate (rarely metastasizing) maligna nt potential, mostly occurring in subcutis and characterized by varying proportions of epithelioid, ovoid, or spindle cells arranged in a nodular and often syncytial growth pattern, with haemorrhagic pseudovas小切 spaces and frequently a peripheral fibrous pseudocapsule with a prominent lymphoplasmacytic cuff.

ICD-0 coding 8836/1 Angiomatoid fibrous histiocytoma

ICD-11 coding 2F7C & XH9362 Neoplasms of uncertain behaviour of connective or other soft tissue & Angiomatoid fibrous histiocytoma

Related terminology Acceptable: angiomatoid malignant fibrous histiocytoma.

Subtype(s) None

Localization Tumours occur as subcutaneous lesions, most frequently in the extremities, followed by the trunk and the head and neck. Nearly two thirds of cases occur in areas where lymph no des are normally found (e.g. the antecubital fossa, popliteal fossa, axilla, inguinal area, and neck). These tumours are increasingly recognized in non-somatic sites, such as the ovary, vulva, lung, brain, bone, mediastinum, and retroperitoneum {555,872,1971}.

Fig. 1.328 Angiomatoid fibrous histiocytoma. A well-circumscribed tumour displaying multinodular fibrohistiocytic proliferation, pseudocystic spaces filled with blood, and a peripheral rim of lymphoid tissue, simulating a metastatic lymph node.

Clinical features Patients typically present with a slow-growing, superficial, pain less soft tissue mass, which may simulate a haematoma or a haemangioma {665,912}. Rarely, patients present with pyrexia, anaemia, malaise, and weight loss {665,912,1014}.

Fig」.327 Angiomatoid fibrous histiocytoma. A Tumour nodule surrounded by a characteristic lymphoplasmacytic cuff. B In this case from the retroperitoneum, tumour cells within a prominent myxoid stroma are surrounded by a lymphoplasmacytic cuff.

Soft tissue tumours

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Fig. 1.329 Angiomatoid fibrous histiocytoma. A More-pleomorphic tumour cells containing a moderate amount of cytoplasm, vesicular nuclei, and focal intranuclear elusions along with interspersed lymphocytes and plasma cells. B Mitoses are generally infrequent.

Epidemiology AFH is a rare soft tissue neoplasm, accounting for 0.3% of all soft tissue tumours. There is no significant sex predilection. A wide age range is reported, from birth {165} to the ninth decade of life, with a peak incidence in the first two decades of life {665,129,2600}.

Etiology

Macroscopic appearance These tumours appear as small, firm, nodular to cystic mass， with a wide size range (0.7-12 cm) and a median size of 2i {912,665}. The cut surface often shows multilocular haem rhagic areas, simulating a haematoma, to a yellowish-tan white fleshy appearance {912,665,3070}.

Unknown

Histopathology Pathogenesis The most frequent genetic abnormality is the t(2;22)(q33;q12) translocation, resulting in an EWSFI1-CFIEB1 fusion, in > 90% of cases {129,2671,2600}. Less commonly, t(12;22)(q12;q12) translocation is detected, resulting in an EWSR1-ATF1 fusion {1278}. Few cases harbouring a FUS-ATF1 fusion have been reported {2565,3252}. EWSR1-ATF1 is more frequently associ­ ated with AFH of extrasomatic soft tissues {555}. EI/l/S刖-CREB family gene fusions have been recently reported in a subset of intracranial myxoid mesenchymal tumours that lack features typical of AFH, and thus it remains uncertain whether these rep­ resent a myxoid subtype of AFH or a novel entity {213,1580}.

Tumours are circumscribed, lobulated, and characterized four key morphological components, found in varying prop， tions: (1) solid nodules of epithelioid to spindle cells arranged a syncytial pattern with moderate amounts of eosinophilic cy plasm and mildly atypical vesicular nuclei; (2) pseudoangiom tous spaces containing blood and surrounded by tumour cellb (3) a thick fibrous pseudocapsule with haemosiderin deposi tion; and (4) a pericapsular rim of lymphoplasmacytic cells wil germinal centres, simulating lymph node metastasis. Near one third of tumours lack cystic haemorrhagic spaces and sho a completely solid appearanee. Some cases lack any inflan matory comp orient. Mitotic figures are gen erally few, althouc atypical mitotic figures may be present. A variable number i pleomorphic cells may be noted in some cases {3070,2601 1575}. A subtype of AFH is characterized by small blue round cells with hyperchromatic nu clei and sea nt eosi nophilic cyto plasm, which can mimic an undifferentiated round cell sarcom; or epithelioid sarcoma {968,1314}. Myxoid forms have also beei described, containing at least focal components of classic AFh {2753,555}. Approximately 50% of cases are immunoreactive for desmin, which may be focal or diffuse. However, tumour cells are con­ sistently negative for MYOD1 and myogenin. EMA, CD99, and CD68 are variably immunopositive in as many as 50% of cases {968}.

Cytology

Fig. 1.330 Angiomatoid fibrous histiocytoma. Substantial desmin immunoreactivity in a case of angiomatoid fibrous histiocytoma.

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Soft tissue tumours

The cytomorphological features of AFH are non-distinctive. Cel­ lular smears show ovoid to spindled cells with moderate nuclei pleomorphism, arranged in loose clusters, containing moderate

paybal：https://www.paypal.me/andy19801210 'abundant cytoplasm. Interspersed are blood products and a 爲able number of inflammatory cells {2557,1826}.

Diagnostic molecular pathology 粘e

presence of EWSR1-CFIEB1 or alternative gene fusions can

oe diagnostically helpful.

Essential and desirable diagnostic criteria Essential： clinical presentation as a small subcutaneous pain[ess less nodule; nodules of epithelioid to ovoid cells arranged in syncytial-like sheets; pseudoangiomatoid spaces; peripheral in eluding germinal centres; rims of lymphoplasmacytic cells, including jmmunohistochemistry: variable desmin, CD99, and EMA immunoreactivity. Desirable (in selected cases): molecular studies confirming EWSR1 gene rearrangement.

Staging

Fig. 1.331 Angiomatoid fibrous histiocytoma. EWSFI1 gene rearrangement detected, in the form of single red-green split signals, identified in the various tumour cells.

Not clinically relevant

Prognosis and prediction Most tumours follow an in dole nt course, with local recurre nee in nearly 15% of cases and metastasis in < 2-5% of cases, predomi nantly to locoregi on al lymph no des and r arely to lungs, liver, and brain {665,590,968}. Rare deaths have been reported from metastasis, although Iong-term survival after resection

is reported in some metastatic cases {912,665}. There are no clinicopathological factors that correlate reliably with clinical outcome. However, cases with in complete surgical cleara nee and those occurring in deeper locations and extrasomatic sites have been observed to show higher rates of recurrenee and metastasis {665,555}.

Soft tissue tumours

273

paybal：https://www.paypal.me/andy19801210 Ossifying fibromyxoid tumour

Definition Ossifying fibromyxoid tumour (OFMT) is a rare mesenchymal neoplasm of uncertain differentiation, with cords and trabecu­ lae of ovoid cells embedded in a fibromyxoid matrix, often surroun ded by a complete or in complete peripheral shell of lamel­ lar bone, having potential for local recurrenee and metastasis (especially when showing malignant features).

ICD-0 coding

Endo M Mertens F Miettinen M

well-circumscribed, lobulated mass, occasionally surround by a partial peripheral calcification {905}. Intralesional minerzation may be present in some cases (918,1059,2123).

Epidemiology Tumours occur over a wide age range (5-88 years), with median age of about 50 years {918,1205,1059,3387,182), T| M:F ratio is 1.5:1 {2123}. The malignant subtype shows the san epidemiological features as typical OFMT.

8842/0 Ossifying fibromyxoid tumour NOS

Etiology ICD-11 coding 2F7C & XH1DA7 Neoplasms of uncertain behaviour of connective or other soft tissue & Ossifying fibromyxoid tumour

Unknown

Pathoge nesis

Lesions most frequently arise in the subcutis, but also not uncommonly within skeletal muscle of the extremities {1059,182}. Tumours may occur in all parts of the body; however, the relatively common sites are the thigh, head and neck, and trunk wall {918, 1059,2123}. More than 40% of cases arise in the lower extremity.

At least 85% of OFMTs, including typical, atypical, and malignant lesi ons, display a gene fusion, most comm only (in ~50% of cases) involving the PHF1 gene; the most prevale nt variants are EP400-PHF1, MEAF6-PHF1, EPC1-PHF1, and PHF1-TFE3 {1127,1206,137,3005}. In addition, rare fusions involving BCOFI BCORL1, CREBBP, and/or KDM2A have been described, espe­ cially in malignant OFMT; the proteins encoded by these genes share with PHF1 direct or in direct invo Iveme nt in processes affecting histone modification {1581}. Little is known abou' other genetic changes affecting the clinical behaviour of OFMT but FISH studies have suggested that loss of chromosome 22 material might be more common in the malignant subgroup {1127}.

Clinical features

Macroscopic appearance

The tumour usually prese nts as a pain less, slow-grow­ ing, elastic, hard mass. Radiologically, OFMT is usually a

Grossly, lesions range from 0.5 to 21 cm in greatest diameter, with a median of about 4 cm {1059,1205,3387}. OFMTs are

Related terminology None

Subtype(s) Ossifying fibromyxoid tumour, malignant

Localization

Fig. 1.332 Ossifying fibromyxoid tumour. A A well-demarcated tumour in the subcutis, whitish and translucent in gross appearance. B Low magnification reveals a partial 皿

of metaplastic bone.

274

Soft tissue tumours

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usually well circumscribed and no dular or multi nodular, and they are gen erally covered by a thick fibrous pseudocapsule with or without a shell of bone {918,2123,1059,3387}. The cut surface of the tumour is often glistening; white to tan in colour; and firm, hard, or rubbery in texture {1059,3387}.

Histopathology jter, are

Microscopically, OFMTs are gen erally well circumscribed, with a thick fibrous capsule or pseudocapsule {918,2123,1059}. Dense fibrous septa often extend into the tumour, producing

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a multino dular appears nee. A complete or incomplete periph­ eral shell of metaplastic woven or lamellar bone is present in many cases {1059}. Bone may also be present in fibrous septa. Despite apparent circumscription at low power, tumour may invade through the capsule and form extracapsular nodules in adjace nt tissue {2123}. The tumou r is composed of lobules of uniform, round to spindle-shaped cells with bland round to ovoid n uelei and sea nt, pale eosi nophilic cytoplasm {1059}. Tumour cells are usually arranged in cords, nests, or sheets, surrounded by variably fibrous or myxoid stroma. Cellularity

Fig，1.334 Ossifying fibromyxoid tumour. A,B The characteristic architectural and cytological features of ossifying fibromyxoid tumour. Note the varying trabecular and solid Patterns, delicate nucleoli, and mitotic figures.

Soft tissue tumours

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varies from low to moderate to high {2770}. Mitotic activity is usually low in typical OFMTs {2770}. About two thirds of OFMTs are positive for S100, although immu no reactivity is rarely diffuse {1206}. Desmin expression is observed in almost half of OFMTs. The lesions may also express MUC4, EMA, keratins, and SMA {1205}. SMARCB1 (INI1) expression is lost in a mosaic pattern in about three quarters of OFMTs {905,1206}. A malignant subtype has been proposed by some, as defined by cases with high nuclear grade or high cellularity and > 2 mitoses per 10 mm2 (equating to ~50 high-power fields of 0.5 mm in diameter and 0.2 mm2 in area) {1059,730}. In clinically malignant lesions, bone or osteoid deposition within tumour cell nodules may also be identified. OFMTs with histological findings deviating a little from typical OFMT, but not fulfilling these criteria for the malignant subtype, can be classified pragmatically as atypical OFMT.

Cytology Not clinically relevant

Diagnostic molecular pathology Demon strati on of PHF1 an d/or TFE3 gene rearra ngeme nt can be helpful.

276

Soft tissue tumours

Essential and desirable diagnostic criteria Essential: lobulated growth pattern with frequent capsular ossi­ fication; usually very bland cytology with uniform round tn ovoid nu clei; freque nt (but not in variable) positivity for S100 and/or desmin. Desirable: PHF1 gene rearrangement (in selected cases).

Staging American Joint Committee on Cane er (AJCC) or Union for International Cancer Control (UICC) TNM staging can be applied to the malignant subtype.

Prognosis and prediction Follow-up data indicate that even typical OFMT has the unpre­ dictable potential for recurrenee and metastasis. This is often delayed and may occur 10-20 years or more after the primary excision. The local recurrenee rates for typical, atypical, and malignant OFMTs, respectively, are reported as 0-12%, 0-13%. and 0-60% {1059,182,730,1205}. The common metastatic sites are lung and soft tissue. The metastasis rates for typical, atypi­ cal, and malignant OFMTs, respectively, are reported as 0-4%. 0-6%, and 20-60% {1059,182,730,1205}.

paybal：https://www.paypal.me/andy19801210 Myoepithelioma, myoepithelial carcinoma, and mixed tumour

Jo VY Antonescu CR Hornick JL Patel RM

pefinition

Subtype(s)

Myoepithelioma, myoepithelial carcinoma, and mixed tumour are myoepithelial tumours of soft tissue - a group of uncommon neoplasms that share morphological, immunophenotypic, and oenetic features with their counterparts in salivary gland and skin Benign myoepithelial tumours of soft tissue include myo­ epithelioma and mixed tumour. Malignant myoepithelial tumours of soft tissue are desig nated myoepithelial carci no mas.

Myoepithelial carci no ma; mixed tumour, malig nant, NOS

Localization

ICD-O coding

Most myoepithelial tumours of soft tissue (75%) arise on the limbs and limb girdles (lower more frequently than upper); oth­ ers arise on the trunk and less often the head and neck {1411, 1166,143}. Rarely, tumours arise in bone or visceral organs {143, 1790,1721}. Tumours may also arise primarily in the skin {1408, 1035,1531}.

8982/0 Myoepithelioma NOS 8940/0 Mixed tumour NOS

Clinical features

ICD-11 coding 2F7C & XH3CQ8 Neoplasms of uncertain behaviour of connec­ tive or other soft tissue & Myoepithelioma

Most patients present with a palpable mass, which is usually pain less {1625,1411,1166}. Tumours arise in subcuta neous tis­ sue somewhat more often than in deep soft tissue {2114,1411}.

Epidemiology

Related terminology Not recommended: parachordoma.

Myoepithelial tumours of soft tissue show equal distribution between the sexes and a wide age range, with peak incidence

Fig. 1.336 Myoepithelial tumour of soft tissue. A Lobulated growth with reticular and trabecular patterns and myxoid stroma. B Epithelioid and spindle cells with eosinophilic cytoplasm arranged in trabeculae.

Fig，1.337 Myoepithelioma. A Bland-appearing ovoid and epithelioid cells with uniform nuclei and eosinophilic cytoplasm. B Tumour cells may show clear cell change.

Soft tissue tumours

277

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in you ng to middle-aged adults (media n age: 40 years) {1625, 2114,1411,1166). About 20% of tumours, most of which are myo­ epithelial carcinomas, arise in the paediatric population {1166}.

Etiology Un known

Pathogenesis EWSR1 gene rearrangements are common in myoepithelial tumours of soft tissue (as well as in those of skin and bone) {143}. The largest study to date reported EWSFI1 gene rearrangements in half of the soft tissue lesions tested, with the common fusion partners POU5F1 and PBX1 identified in 16% of cases each {143}. Rare fusion partners include ZNF444, KLF17, ATF1, and PBX3, and occasional cases show alternative FUS gene rearrangements with similar partner genes {143,1431,31,1034}. These studies have suggested some associations between genotype and phenotype. Most EWSR1-POU5F1-pos\\.\\/e tumours present in deep soft tissues of the extremities in young patients and are composed of nests of epithelioid cells with clear cytoplasm; a subset of EWSFH-PBX1-pos\i\\/e tumours showed a deceptively bland and sclerotic appearanee {143}. A

Fig. 1.339 Myoepithelial carcinoma. Nuclei show appreciable atypia and readily iden­ tifiable nucleoli.

278

Soft tissue tumours

subset of myoepithelial carcinomas have homozygous deletions of SMARCB1 {1790}. Mixed tumours with ductal differentiation have PLAG1 gene rearra ngeme nts (occasi on ally with LIFR as the fusion partner) {202,145}. The presence of rearrangements of PLAG1 {1995} and EWSFI1 {2883}, respectively, in salivary gland pleomorphic adenoma and myoepithelial carcinoma emphasizes that soft tissue myoepithelial neoplasms are geneti­ cally related to their salivary gland counterparts.

Macroscopic appearanee Most benign myoepithelial tumours are grossly well circum­ scribed and nodular, whereas malignant tumours typically have in filtrative margins. The cut surface ran ges from gelati nous and glistening to firm or fleshy. Tumour size range is broad (1-20 cm in greatest dimension), with a mean size of 4—6 cm {1166,1411 2114}.

va SP 1

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Histopathology Myoepithelial tumours show a wide morphological spectrum o: architectural and cytological heterogeneity, similar to their sali­ vary gland and skin counterparts. Many show a predominantly reticular or trabecular growth pattern with prominent myxoio stroma; areas of more nested or solid growth and hyalinizec stroma are commonly observed and occasionally predominate {1411,1166,143}. Tumour cells range from spindled to epithelioio with uniform nuclei and eosinophilic to clear cytoplasm. Studies have suggested some associations between genotype and phenotype (see Pathogenesis, above). Some tumours have large epithelioid cells showing prominent cytoplasmic vacuolatic (and were classified as parachordoma in the past {700,1044ft whereas others may show predominantly spindled morphology including the cutaneous syncytial subtype {1531}. Plasmacytoid cells with hyaline cytoplasmic inclusions may be prominent {991 1625,1411}. Osseous or cartilaginous differentiation is observec in 10-15% of cases, whereas squamous or adipocytic metapla­ sia is more rare {1411}. Mixed tumours show a ductal compone" and account for approximately 10% of all myoepithelial lesions Myoepithelial carcinomas are defined as having nuclear atypf with easily discerned nucleoli, often together with a high mito count and necrosis. Some such tumours (especially in childr； may show undifferentiated round cell morphology

；； Di
f S100 and CD34, in the absence of SOX10 reactivity (40,743； whereas H3K27me3 expression is retained. The majority of tumours with NTRK fusions are reactive with an anti-pan-TRK monoclonal antibody {1442}; the staining can be either cyto­ plasmic or nuelear {1338,1442}. TRK-A immunohistochemistr/ is useful for the detection of NTRK1-rearranged tumours {2688| Importa ntly, pan -TRK and TRK-A immu no reactivity is n ot com­ pletely specific, and additional molecular genetic testing is often required for a conelusive diagnosis. Tumours with similar morphology but alternative RAF1 or BRAF]us\ons share a simi­ lar S100 and CD34 immunoprofile {743}.

Cytology Not clin ically re leva nt

Diagnostic molecular pathology Molecular detection of NTRK fusions can be useful {743,3004..

Essential and desirable diagnostic criteria Essential: tumours span a wide spectrum of morphologies anc histological grades; characterized by haphazardly arrangeo monomorphic spindle cells; infiltrative growth within fat resembling lipofibromatosis; distinctive stromal and perivas­ cular keloid collagen; immunohistochemically tumours positive for S100 and CD34 in many cases, whereas SOXW is negative; tumours with NTRK1 fusions will show NTRKJ immu no reactivity. Desirable: detection of NTRK fusions is usually required

determi nation of therapy.

伽

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fading is on" applicable to the malignant subset. The Ameri5 joint Committee on Cancer (AJCC) or Union for Interna曽伺 Cancer Control (UICC) TNM system may be used.

prognosis and prediction The prog nosis of NTRK-rearra nged adult tumours appears to oe related to histological grade. Due to their infiltrative growth attern, the benign lipofibromatosis-like neural tumours have

a propensity for local recurrenee if incompletely excised, but none were shown to metastasize {40}. Tumours with high-grade morphological features may show aggressive clinical behaviour, with metastatic spread to lungs and other organs. Importantly, the aberrantly expressed oncogenic receptor tyrosine kinases TRK-A, TRK-B, and TRK-C in NTRK-rearranged sarcomas have proven to be therapeutically targetable, which may potentially improve patient outcome.

Soft tissue tumours

289

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Synovial sarcoma

Definition

Pathogenesis

Synovial sarcoma (SS) is a monomorphic blue spindle cell sar­ coma showing variable epithelial differentiation. SS is character­ ized by a specific SS18-SSX1/2/4 fusion gene.

SS cells are dependent on SS18-SSX expression to maint 'I their transtormed phenotype {557}. Conditional expression^ SS18-SSX induces SSs in genetically engineered mouse moJ

ICD-0 coding 9040/3 Synovial sarcoma NOS

ICD-11 coding 2B5A.Y & XH9B22 Synovial sarcoma, other specified primary site & Synovial sarcoma NOS

Related terminology Not recommended: synoviosarcoma.

Subtype(s) Synovial sarcoma, spindle cell; synovial sarcoma, biphasic; synovial sarcoma, poorly differentiated

els, supporti ng its function as an on cogene when expressed permissive mesenchymal progenitor cells {1544,225}. Addition ally, SS18-SSX1 has been shown to transform primary cell {2235}. Recent evidence suggests that the SS18-SSX fusion pro tein disrupts epigenetic control and blocks mesenchymal diffj entiation by complementary mechanisms including competitiva1 binding with, and displacement of, native SS18 in the SW|/snc chromatin-remodelling complex {1559}, inducing dependence on BRD9-Containing alternative SWI/SNF complexes (ncBAF complexes) {2115,422} and colocalizing with factors such as the ATF2 transcription factor, TLE1 to repress ATF2 target genes {2290}, and the KDM2B lysine demethylase at unmethylated CpG islands to reactivate repressed genes {218,2022}.

Macroscopic appearance

Localization The majority (70%) of SSs arise in the deep soft tissue of the lower and upper extremities, often in juxta-articular locations. About 15% arise in the trunk and 7% in the head and neck regio n {2984}. Un usual sites of invo Iveme nt inc lude male and female external and internal reproductive organs, kidney, adrenal gland, retroperitoneum, stomach, small bowel, lung, heart, mediastinum, bone, CNS, and peripheral nerve (1010,251, 2762}.

Clinical features SS usually presents as a swelling (sometimes Iongstanding), which may be painful. The initial growth of SS is often slow, and a small circumscribed tumour may give the wrong impression of a benig n lesi on by clin ical exami nation and imaging {333}. SS may have radiologically detectable stippled or spiculated forms of calcification {3292}. SS with aggressive growth may erode or inv ade adjace nt bone.

Epidemiology SS may occur at any age and is equally distributed between the sexes {2984}. More than half of the patients are adolescents or young adults, and 77% of cases occur before the age of 50 years. The relative frequency of SS compared with other soft tissue sarcomas is age-dependent, ranging from 15% in patients aged 10-18 years to 1.6% in patients aged > 50 years {2984}.

Etiology There are no known predisposing factors. Exceptionally, SS is associated with a history of previous radiotherapy {1353}. SS bears a unique chromosomal translocation that results in the formation of an oncogenic SS18-SSX1/2/4 fusion gene. Otherwise, SSs have a very low mutation burden relative to other sarcomas {472}. 290

Soft tissue tumours

Most SSs are 3-10 cm in diamete r at diag no sis. Minute lesions < 1 cm occur especially in hands and feet {2110}. On cut surface, tumour colour and consistency are proportionate to cellularity, collagenization, and myxoid change or haemorrhage. Areas may be tan or grey, yellowish or pink, and soft or firm (946|. SS is frequently multinodular and can be multicystic. Calcification, metaplastic ossification, and necrosis may be present.

Histopathology Histologically, SSs are classified as biphasic (in approximately one quarter to one third of cases) or monophasic (in the majority). Biphasic SS has epithelial and spindle cell components, in vary­ ing proportions. The epithelial cells are arranged in solid nests or cords, or in glands with a tubular or sometimes alveolar or papil­ lary architecture. Inglandular areas, epithelial cells are cuboidalor columnar and have ovoid vesicular nuclei, and they typically have more-abundant palely eosinophilic cytoplasm than in the dark­ blue spindle cell component. Glandular lumina contain epithelia mucin. Focally, the glandular component can predominate, and it may be confused with adenocarcinoma; however, a scant spindle cell component is virtually always found. Rarely, epithelial cells show (keratinizing) squamous metaplasia or granular cell change The spindle cells in biphasic SS resemble the spindle cells found in monophasic SS. These delicate spindle cells are fair • uniform and relatively small, with sparse cytoplasm and ovoio. hyperchromatic nuclei with regular granular chromatin ano inconspicuous nucleoli. The N:C ratio is so high that the nude can appea r to overlap. Typically, in both mono phasic and bipha­ sic SSs, the spindle cells are arranged in dense cellular sheets or vague fascicles, with occasi on al tigroid n uclear palisading [ a herringbone architectural pattern. The amount of collagen " variable and usually scant, but SS may contain strands of ropy or wiry collagen, bands of hyalinized collagen, or (especia y

paybal：https://www.paypal.me/andy19801210 Her irradiation) foci of dense fibrosis. Myxoid change is usu-

；ly only focally present and rarely predominates, with alternating

hypocellular and more-cellular areas, as well as retiform cords or 爲ocysts {1694}. Many SSs focally display a staghorn-shaped vascular pattern, reminiscent of solitary fibrous tumour / haemangiopericytoma. Mast cells are variably present. In as many as one third of SSs, areas with calcification and/or ossification are found, which are sometimes abundant. In areas with ossification, the osteoid has a lace-like pattern mimicking osteosarcoma, and bone tissue can mature to the point of being lamellar and trabecular {2146}. Metaplastic cartilage is rarely seen. In otherwise typical biphasic or monophasic SS, poorly differentiated areas with increased cellularity, greater nuclear atypia, and high mitotic activity (> 6 mitoses/mm2 or > 10 mitoses per 10 high-power fields of 0.17 mm2) may be found {1244}. Poorly differentiated areas may be composed of fascicular spindle cells (reminiscent of malignant peripheral nerve sheath tumour), small round hyperchromatic tumour cells (reminiscent of Ewing sarcoma), or epithelioid cells {273}. Compared with typical biphasic or monophasic SS, poorly differentiated areas more often contain areas of necrosis, a branching vascular pattern, and thin ribrovascular septa separating groups of tumour cells |765}. Poorly differentiated lesions are disproportionately more comm on in elderly patie nts {533}.

Immunohistochemistry By immunohistochemistry, EMA is expressed more often and more widely in SS than cytokeratins, especially in the monophasic and poorly differentiated subtypes {2480}. Epithelial cells in biphasic SSs consistently express EMA and cytokeratins and

Fig. 1.355 Biphasic synovial sarcoma. Tumour with glandular epithelial component and spindle cell component.

may contain almost any cytokeratin subtype {2128}. Poorly differentiated areas of SS nearly always contain focal EMA, whereas cytokeratin expression is seen in only about 50% of these tumours {2128,2480}. Focal S100 expression may be detectable in as many as 40% of SSs {2480}. a-SMA is present in less than half of tumours, whereas focal desmin staining is exceptional and h-caldesmon is always negative {2480}. CD34 immunostaining is rare in monophasic SS {2480}. The large majority of SSs are positive for BCL2 and CD99 (which may show membra nous staining like in Ewing sarcoma {2379}), but these markers are not specific. Moderate or strong nuclear

Fig.1,354 Monophasic synovial sarcoma. A Tumour with fascicles of monomorphic blue spindle cells. B Tumour area with wiry collagen. C Tumour area with calcificatlOns' D Tumour area with myxoid change.

Soft tissue tumours

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Fig. 1.356 Poorly differentiated synovial sarcoma. A Hypercellular fascicular tumour resembling malignant peripheral nerve sheath tumour. B Round cell tumour resembk Ewing sarcoma.

Fig. 1.357 Synovial sarcoma. A Immunohistochemistry: diffuse and strong TLE1 nuclear staining. B Immunohistochemistry: multifocal EMA expression.

staining for the transcriptional corepressor TLE1 is found in the large majority of biphasic, monophasic, and poorly differenti­ ated SSs {1062}. However, TLE1 staining is not specific for SS, because it may also occur in histological mimics of SS, in particular malignant peripheral nerve sheath tumour and solitary fibrous tumour {2480,1062}.

Cytology For FNA material, preparation of a cell block is advocated because a conclusive diagnosis of SS heavily relies on diagnostic molecular studies (e.g. FISH) {3176}.

Diagnostic molecular pathology SS harbours a unique t(X;18)(p11;q11) translocation {1729|, by which SS18 on chromosome 18 is fused to one of the SSX genes (SSX7, SSX2, or SSX4) on the X chromosome |842| Although there is some variability, the most common fusion tran­ script links exon 10 of SS18 with exon 6 of the partner SSX gene {94}. Approximately two thirds of SS cases carry an SS78-SSX1 fusion, one third carry SS18-SSX2, and only rare cases carry SS18-SSX4 {842,94} or SS18L1-SSX1 - the latter arising from a t(X:20) {2959}. SS18-SSX1 SSs show an approximately even sex ratio, whereas SS18-SSX2 SSs are significantly more common in women {1544,1729}. Moreover, almost all SS18-SSX2 cases show monophasic histology, whereas SS18-SSX1 cases show an approximate 2:1 ratio of monophasic to biphasic histology {1544,132}. For optimal diagnostic accuracy, molecular confirmation (where available) of an SS18-SSX1/2/4 fusion should ide­ ally be performed {1489}.

Fig. 1.358 Synovia! sarcoma. Graphical representation of interrelationships of fusion type to tumour histology and patient sex in synovial sarcoma. Most synovial sarcomas are monophasic, and the SS18-SSX1 fusion type is more common than SS18-SSX2. Men and women are affected in approximately even proportions, but men show a 3:2 ratio of SS18-SSX1 to SS18-SSX2, whereas in women the ratio is close to 1:1. The vast majority of SS18-SSX2cases show monophasic histology, whereas most biphasic cas­ es show SS18-SSX1. Biphasic synovial sarcomas harbouring the SS18-SSX2 fusion are uncommon, and the diagnosis of such cases should therefore be well supported.

292

Soft tissue tumours

Essential and desirable diagnostic criteria Essential: monomorphic blue spindle cell sarcoma showing variable epithelial differentiation; diffuse and strong nuclear immunostaining for TLE1. Desirable (in selected cases): dem on strati on of SS78-SSX7/2" gene fusion.

paybal：https://www.paypal.me/andy19801210 ^American Joint Committee on Cancer (AJCC) or Union for international Cancer Control (UICC) TNM system may be used.

prognosis and prediction SS has a variable prognosis. Metastatic disease commonly occurs in lungs and bone, but also in regi onal lymph no des. Most distant tumour recurrences develop within a few years after initial diag no sis, but late r ecurre nces do occur, even after 10 years {1700}. Major prognostic determinants are tumour stage at presentation, tumour size, and French Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) tumour grade {1244,3060,1700}. Tumours with > 20% poorly differentiated areas show more aggressive behaviour {3149, 1932,273}. The best outcomes are seen with tumours that are

< 5 cm in diameter or that have < 6 mitoses/mm2 (10 mitoses in 1.7 mm2), with no necrosis {273,1244}. Minute SSs (< 1 cm) have an excelle nt prog nosis {2110}. Childre n fare better tha n adults {2984}, and extremity-based SSs have a better prog nosis than SSs involving the trunk or the head and neck area {2984,473}. A prog nostic no mogram based on data available preoperatively in patients with SS has been developed {473}. Studies of the prog no stic sign ifica nee of SS18-SSX1/2/4 fusi on type have yielded inconsistent results, either positive for modest effects or negative {1703,473}; therefore, fusion type is not regarded as being prog no stically useful. Un ited States populatio n-based SEER Program data indicate that the 5-year and 10-year dis­ ease-specific survival rates, respectively, are 83% and 75% in children and adolescents (age < 19 years) and 62% and 52% in adults {2984}.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Epithelioid sarcoma

Oda Y Dal Cin P Le Loarer F Nielsen TO

Defin ition Epithelioid sarcoma (ES) is a malignant mesenchymal neoplasm that exhibits partial or complete epithelioid cytomorphology and immu nophe no type. Two clin icopathological subtypes are recognized: the classic (or distal) form, characterized by its proclivity for acral sites and pseudogranulomatous growth pattern, and the proximal-type (large cell) subtype, which arises mainly in proximal/truncal regions and consists of nests and sheets of large epithelioid cells.

ICD-0 coding 8804/3 Epithelioid sarcoma

ICD-11 coding 2B5F.2 & XH4F96 Sarcoma, not elsewhere classified of other specified sites & Epithelioid sarcoma

Related terminology

Fig. 1.359 Classic (distal-type) epithelioid sarcoma. Multiple ulcerating lesions onto sole of the foot.

subtype tends to affect a somewhat older population - youngf middle-aged adults {3072}.

None

Etiology

Subtype(s) Proximal or large cell epithelioid sarcoma; classic epithelioid sar­ coma (also known as conventional or distal epithelioid sarcoma)

The etiology is unknown. Three studies report (probably coin­ cidental) antecedent trauma in 20% {544}, 27% (2535), and 73% {701} of patients. There is no recurrent genetic predispositio n.

Localization The classic subtype most commonly occurs in the distal upper extremity, predominantly arising in the fingers and hand {544, 3072}. Tumours of the foot and hand affect mainly volar surfaces. Proximal extremities and trunk are less frequent locations. The proximal-type subtype tends to arise in deep soft tissue, and it most often affects truncal (pelviperineal, genital, and inguinal) tissue, buttock, or hip {1249,1313}.

Clinical features Superficially located examples of classic ES present as soli­ tary or multiple, slow-growi ng, usually pain less, firm no dules. Lesions often result in non-healing skin ulcers that can clinically mimic other ulcerative dermal processes. In comparison, clas­ sic and proximal-type tumours located in deep soft tissue are usually larger in size and more infiltrative {1249,1313}. This is one of the few sarcomas that regularly metastasize to lymph n odes.

Epidemiology ES represents < 1% of all adult soft tissue sarcomas {1516} and between 4% and 8% of childhood non-rhabdomyosarcomatous soft tissue sarcomas {506}. The classic subtype is reported nearly twice as often as the proximal-type subtype {547,2603}. The M:F ratio is 2:1 for the classic subtype {3072} and 1.6:1 for the proximal-type subtype {1249,1313}. Both tumours affect patients over a wide age range. The classic subtype presents mainly in adolesce nts and you ng adults, whereas the proximal-type 294

Soft tissue tumours

Pathogenesis Both classic and proximal-type ESs are associated with almost complete loss of SMARCB1 (INI1) nuclear protein expression, except for extremely rare SMARCB1-retained tumours. Thi SMARCB1 gene (also called BAF47, IN 11, or SNF5), located on 22q11.23, encodes a protein that is part of the SWI/SNF chromatin-remodelling complex present in normal cells. SWI/ SNF has ATPase activity and functions to shift the position of nucleosomes, thereby modulating transcription of a large class of genes invoIved in stem cell biology and differentiation {2244! By immunohistochemistry, recurrent loss of SMARCB1 (INI1)' seen in a limited variety of tumour types {3246,1672,23,109(. within which the mechanisms of protein loss can be distinc' In ES, SMARCB1 biallelic deletions have been demonstratec by FISH analysis; less frequently, monoallelic deletions ari heterogeneous FISH patter ns have also bee n detected {2981, 1790,2739}. In some cases, decreased SMARCB1 (INI1) Pr0' tein expression has been associated with negative regulation of SMARCB1 transcripts by microRNAs (2434,1675,2739). An extreme minority of ESs retain SMARCB1 (INI1) protein expre-; sion, in stead exhibiti ng abno rmal expressi on of other SWI/SN chromatin-remodelling complex members, such as SMARCA(BRG1), SMARCC1 (BAF155), or SMARCC2 (BAF170); su" cases have been correlated with rhabdoid morphology a； with adverse prog no sis, especially among proximal-type 平 {1676}. Unlike in many sarcomas that affect younger patient (especially malignant rhabdoid tumours {1538,595}), genome

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Fig. 1.360 Classic (distal-type) epithelioid sarcoma. A Low-power magnification of a nodular lesion centred in the dermis composed of tumour cells surrounding an area 0, necrosis (pseudogranulomatous growth pattern). B Epithelioid tumour cells with abundant eosinophilic cytoplasm. C Cells with a plump spindle-shaped morphology.

analysis of ESs by next-generation sequencing has revealed complex copy-number aberrations (with 22q11.2 and 12p13 being the most frequent losses) and a high overall mutation burden {1512}, findings that support the differential diagnosis between ES and malignant rhabdoid tumour. SMARCB1 is the most frequently mutated gene, with or without inactivation of its second allele. By RNA sequencing, the transcriptome shows a unique profile that does not cluster with any particular tisSue type or with other SWI/SNF-aberrant model systems {1512, 1789).

Fig. 1.361 Proximal-type (large cell) epithelioid sarcoma. A Low-power magnifica­ tion shows a multinodular growth pattern of epithelioid cells with foci of tumour necro­ sis. B Pleomorphic epithelioid tumour cells with abundant, deeply eosinophilic cytoplasm and enlarged vesicular nuclei with prominent nucleoli. C Aggregates of rhabdoid cells with glassy intracytoplasmic hyaline inclusions and eccentrically located, vesicular nuclei.

Macroscopic appearance The classic subtype usually presents as one or more indurated, ill-defined, dermal or subcutaneous nodules measuring a few millimetres to 5 cm. Deep-seated tumours are multinodular masses that extend along nerves and fascial planes. The cut surface is glistening, with a greyish-white or greyish-tan colour punctuated by yellow and brown foci representing necrosis and haemorrhage, respectively. The proximal-type subtype presents as solitary or multiple whitish nodules ranging from 1 to 20 cm, with areas of haemorrhage and necrosis {1249,1313}. Soft tissue tumours

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Fig. 1.362 Classic (distal-type) epithelioid sarcoma. A Diffuse expression of keratin (CAM5.2). B Strong membranous immunopositivity for CD34. C Complete io< SMARCB1 (INI1) protein expression in the tumour cells (blood vessels being internal positive controls).

Histopathology Classic ES con si sts of cellular no dules of epithelioid and spindied tumour cells with central degeneration and/or necrosis 一 a growth pattern that imparts a vaguely granulomatous appearance to the process {1340}. Fusion of necrotizing nodules results in a serpiginous mass with central geographical necro­ sis. Deep-situated lesions spread along the fascia as undulating bands of cells punctuated by foci of necrosis. Both types typi­ cally have in filtrative margins, and skip lesi ons are comm on in the classic type. Tumour nodules are composed of large ovoid or polygonal epithelioid cells and plump spindle-shaped cells with deeply eosinophilic cytoplasm and mildly atypical nuclei possessing vesicular chromatin and small nucleoli. The epithe­ lioid cells, which are gen erally concen trated towards the centre of the n odule, gradually tran sition with the spin died eleme nt. Epithelioid cells may exhibit cytoplasmic vacuoles, mimicking a vascular tumour. Some cases have predomi nantly spin died morphology. Mitotic activity is usually low. Dystrophic calcification and metaplastic bone formation are detected in 20% of cases {544}, and aggregates of chronic inflammatory cells are usually present at the periphery of the tumour nodules. The proximal type is characterized by a multinodular and sheet-like growth of large and sometimes pleomorphic epithe­ lioid (carci no ma-1 ike) cells with en larged vesicular n uclei and prominent nucleoli {1249,1313}. Spotty foci of tumour necrosis are frequently encountered, but this feature does not gener­ ally result in a pseudogranulomatous pattern typical of classic ES. Cells with rhabdoid features occur in both forms, but they are more frequently observed in the proximal-type subtype, in which differentiation from extrarenal rhabdoid tumour becomes challenging when the rhabdoid cell is the predominant cell type {1249}. Occasional cases may have a prominent myxoid stroma {1033}. Additi on ally, rare cases of ES dem on strate hybrid histo­ logical features of both the classic and proximal types. Both classic and proximal-type ESs show immu no reactivity for epithelial markers, including low- and high-molecular-weight cytokeratins and EMA {2118}. More specifically, most cases express CK8 and CK19 {2118) but are typically negative or only focally positive for CK5/6 {1759}. Unlike in carcinoma, CD34 is expressed in > 50% of cases. Loss of nuclear expression of SMARCB1 protein occurs in the vast majority of cases of both types {1406,1670,2716}. ERG expression is observed in 40-67%

296

Soft tissue tumours

of ESs, predominantly in classic-type cases, which can cauj confusion with endothelial tumours {2137,2953,1674}.

Cytology Not clinically re leva nt

Diagnostic molecular pathology Not clin ically re leva nt

Essential and desirable diagnostic criteria Essential: tumour presenting as a soft tissue mass (so-callel distal or proximal presentations); epithelioid to spindled cyt| morphology with infiltrative growth; diffuse loss of SMARCB (INI1, BAF47) and staining for EMA and keratin.

Staging The America n Joint Committee on Cancer (AJCC) or Un ion f< International Cancer Control (UICC) TNM system may be use(

Prognosis and prediction Clinical series of ES patients have reported 5-year and 10-ye; overall survival rates of 45-70% and 45-66%, respectively {183 176,2533,2400). Overall survival rates drop to 24% in patient with metastatic ES, whereas localized ES patients fare bette with an overall survival rate of 62-88% when patients are treatei with R0 surgery {1313,1833,2533}. On multivariate analysis, dee location correlates with lower overall survival, accounting for th poorer survival associated with proximal-type ES, which is b definition deep-seated {1833,2533,2400}. Conversely, locatio in the hand correlates with good outcome in localized ES patient treated with R0 surgery {2533}. The rates of local recurrenc lymph node dissemination, and metastasis for localized ES ar 14-25%, 34-52%, and 33%, respectively {1833,2533,2400}. reported 22-30% of cases are metastatic at the time of diagnos {1833,176,2533}. Multimodal management of localized ES is sai to be associated with better local control rates when surgery combined with isolated limb perfusion chemotherapy {1833)( neoadjuvant radiotherapy {2533}. Other adverse prognostic fao tors that have been reported include older age, high grade / hie mitotic activity {1500,547,1120,1833}, nodal involvement {17 2400,881}, tumour size > 5 cm {547,2603,1500}, and proxima type histology with the presence of rhabdoid cells {1120,2603(.

paybal：https://www.paypal.me/andy19801210 Jambhekar NA Ladanyi M

Alveolar soft part sarcoma

pefinition Alveolar soft part sarcoma (ASPS) is a rare tumour of uncertain histogenesis predominantly affecting the deep soft tissues of the extremities, featuring variably discohesive epithelioid cells arranged in nests, resulting in a distinet alveolar appearance. K |S characterized by a specific translocation, der(17)t(X;17) /p11.2；q25), which results in ASPSCFI1-TFE3 gene fusion.

ICD-O coding 9581/3 Alveolar soft part sarcoma

ICD-11 coding 2B5F.2 & XH8V95 Sarcoma, not elsewhere classified of other specified sites & Alveolar soft part sarcoma

Related terminology None

Subtype(s) None

Localization ASPS comm only involves deep soft tissues of the extremities (61%; predominantly the lower extremity [51%]), trunk (20%), internal organs (8%), and head and neck (9%) {3228}. Primaries in the head and neck region, particularly in the orbit and tongue, are see n in childre n {1061,970}. Un comm on locati ons include the female genital tract {2287}, bone {2450}, urinary bladder |102), mediastinum {1030}, and spine {3399}.

Clinical features ASPS prese nts as a slow-growi ng pain less mass {581}. Propto­ sis or vaginal bleeding is seen with orbital or female genital tract tumours, respectively. At presentation the disease can be local­ ized (38%), regional (11%), or metastatic (43%) {3228}. ASPS is isodense or hypodense on CT {3073}. MRI reveals flow voids, large vessels, moderate to intense postcontrast enhancement, and central necrosis {2029}. The vascular pattern is helpful for diagnosis {690}.

Epidemiology ASPS accounts for < 1% of all soft tissue sarcomas. In a SEER Program data analysis, the patient age range was 1-78 years (median: 25 years); 72% of patients were aged < 30 years, and 58% were females {3228}. This female preponderance is well documented {591,1852,2356} but is less marked in patients aged > 30 years and in children {2529,2435,970}.

Etiology The ASPSCFI1-TFE3 translocation appears to be the initiating

genetic event in ASPS {1731}, but why the translocation occurs

Fig. 1.363 Alveolar soft part sarcoma. Tumour involving fibula and calf muscles of

a 13-year-old girl; postcontrast T1-weighted MRI images reveal a solid tumour with lobulated margins displaying inhomogeneous intense enhancement and a central non­ enhancing component A Axial view. B Coronal view.

is unknown. There have been no cases reported in association with a history of irradiation or a germline cancer predisposition syndrome.

Pathogenesis The ASPSCR1-TFE3 fusion protein localizes to the nucleus, where it functions as an aberrant transcription factor, causing c-Met overexpression and activation of c-Met signalling, rendering ASPS cells sensitive to c-Met inhibition in vitro {3109,1661} and in vivo {2212}. A recent clinical trial of the c-Met inhibitor crizotinib in ASPS reported disease stabilization in most patie nts, but tumour shri nkage was un comm on {2777}. Finally, a mouse model of ASPS driven by conditional expression of an ASPSCR1-TFE3 transgene highlighted the exquisite depen­ dence of ASPS on lactate for growth {1190}, which may be linked to its frequent occurrenee in muscle and its high expression of the lactate transporter MCT1 and its associated protein, CD147 {1728}. Cytogenetically, ASPS is defined by a specific alteration, der(17)t(X;17)(p11；q25). Because the der(X) resulting

Soft tissue tumours

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D〕 Fig. 1.364 Alveolar soft part sarcoma. A Typical organoid nests of eosinophilic tumour cells with abundant cytoplasm. B Compact cell nests outlined by sinusoidal' seis. C Alveolar-like structures, discohesive cells, and central or eccentric nuclei with prominent nucleoli. D PASD staining. A large centrally placed cell shows elongated rodintracytoplasmic crystals in a sheaf-like arrangement; numerous surrounding cells show intracytoplasmic PAS-positive, diastase-resistant granules.

from the t(X;17)(p11;q25) is rarely retained {3135}, the der(17) t(X;17) may be described in some cases as add(17)(q25), if the quality of the banding is not sufficient to allow for positive identification of the additional material as coming from the short arm of chromosome X. This translocation results in the fusion of the TFE3 transcription factor gene (from Xp11) with ASPSCFI1 (also known as ASPL) at 17q25.3 {1731}. Depending on the TFE3 intron invoIved in the genomic rearrangement, ASPSCR1-TFE3 fusion transcripts can differ by the presenee or absenee of one additional exon of TFE3.

Macroscopic appearanee Tumours vary from 1.2 to 24 cm (median: 6.5 cm) {2529}. Th are partially circumscribed and consist of multiple soft flesl n odules and fibrotic ban ds. The centre of larger lesi ons ofte shows haemorrhage or necrosis.

Histopathology ASPS is composed of large polygonal cells with well-define cell borders, eosinophilic granular cytoplasm, a rounde

J

Fig. 1.365 Alveolar soft part sarcoma. A CD34 immunohistochemistry highlights the delicate capillaries surrounding the pseudoalveolar structures. B Nuclear staining «lln TFE3 is characteristic.

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Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 ntral/eccentric vesicular nucleus, and a prominent nucleolus. cells are arranged in a uniform organoid or nest-like pat-

爲e

showing central discohesion resulting in the characteristic ive'olar pattern. A rich sinusoidal capillary vasculature is seen Toughout； this often encircles tumour nests and imparts a haemangiopericytomatous appearanee focally. Vascular invasjon is very comm on. Cytoplasmic cleari ng, rhabdoid cells, a oseudoglandular pattern, or cystic change with myxoid material 爲y be seen {2605,1547}. Nuclear pleomorphism, hyperchromasia, giant cells, mitosis, necrosis {939,970}, calcification, ivmphocytic infiltrate, and xanthomatous features are uncom­ mon (1048,2605,3315}. Small cells, non-alveolar growth, and nconspicuous vessels are particularly seen in lingual tumours 1570] Many tumours show intracytoplasmic rod-like/rhomboid crystalline structures, focally or diffusely, in a sheaf-like or stacked configuration {970,1048,2605}. These crystals and the intracytoplasmic granules are PAS-positive/diastase-resistant and are immunoreactive for MCT1 and CD147 {1728,3111}. ASPS shows nuelear immunoreactivity for TFE3 {160,2427, 3297). Immunopositivity for cathepsin K (100%) is also typical. Calretinin (46%) {1989,531} and focally desmin (50%) can be detected {1048}.

Cytology In cytological preparations, smears reveal large cells, mainly distributed singly, with granularity or vacuoles {3214,2819}.

Diagnostic molecular pathology Demonstration of 7FE3 rearrangement {1214} or ASPSCR1-TFE3 fusion transcripts {1739,3405} may be diagnostically helpful. Although the presenee of the ASPSCR1-TFE3 fusion appears to be highly specific and sensitive for ASPS among sarcomas, the same gene fusion is also found in a small but unique subset of renal cell carcinomas, often affecting young patients {154}.

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Fig. 1.366 Alveolar soft part sarcoma. Partial karyotype of alveolar soft part sarcoma showing the characteristic alteration, der(17)t(X;17)(p11,2;q25).

Staging The Union for International Cancer Control (UICC) or American Joint Committee on Cancer (AJCC) TNM system can be used.

Prognosis and prediction ASPS is not formally graded but is regarded as high-grade by definition. Local recurrenee occurs in 11—50% of cases {3228}. Metastases involve the lungs, liver, bone, brain, and (rarely) lymph nodes, often > 10 years after diagnosis {1031,2487,2529, 1852}. The overall survival rate is 82% at 2 years and 56% at 5 years {3228}. Negative prog nostic factors in elude older age, tumour size > 10 cm, distant metastasis at diag no sis, and a primary site in the trunk {3228}. Tumours detected early, at a completely resectable stage, such as lingual ASPS, have a bet­ ter prog nosis {2435,970}.

Essential and desirable diagnostic criteria Essential： eosinophilic polygonal cells in an organoid/nested pattern; rich sinusoidal capillaries and intracytoplasmic crys­ tals (in some cases); TFE3 nuclear expression by immunohistochemistry (strong and diffuse). Desirable: dem on strati on of TFE3 gene rearra ngeme nt or ASPSCR1-TFE3 \\js\on (in selected cases).

Soft tissue tumours

299

paybal：https://www.paypal.me/andy19801210 Clear cell sarcoma of soft tissue

Fritchie KJ van de Rijn M

Definition Clear cell sarcoma (CCS) of soft tissue is a malignant mesenchymal neoplasm, typically involving deep soft tissue and most often characterized by EWSR1-ATF1 fusion, harbouring a distinctive nested growth pattern and melanocytic differentiation.

ICD-0 coding 9044/3 Clear cell sarcoma NOS

ICD-11 coding 2B5F.2 & XH77N6 Sarcoma, not elsewhere classified of other specified sites & Clear cell sarcoma

Related terminology Not recommended: malignant melanoma of soft parts.

Fig. 1.367 Clear cell sarcoma. This well-circumscribed tumour arose in the plan曲 tendon of an 18-year-old woman. Despite the small size of the tumour, she died fro disseminated metastases 4 years later.

Subtype(s) None

Epidemiology

Localization

CCS mainly affects you ng adults, with a peak in cide nee in th third and fourth decades of life {605,772,880,1905(. There is slight female predominance {880,913,605,1905}.

CCS occurs most commonly at deep-seated sites in the extrem­ ity, with almost 50% of cases arising in the distal lower extrem­ ity, ankle, or foot, where they can be associated with tendons or aponeuroses {605,772,880,1905}. CCS has also been reported in the head/neck, trunk, and viscera including the lung and gas­ trointestinal tract {11,1919,605,1905,1174}. Lesions arising in skin and oral mucosa are recognized. CCS-like tumour of the gas­ trointestinal tract (malignant gastrointestinal neuroectodermal tumour) most likely represents a distinct entity from CCS and is discussed in the Digestive system tumours volume {3282}.

Clinical features Almost all patients present with a palpable mass of months' to years' du rati on. Pain and ten dem ess are reported in approxi­ mately one third to one half of cases {605,772,880,1905}.

Etiology Unknown

Pathogenesis The genetic hallmark of CCS is the reciprocal translocation t(12;22)(q13;q12), present in 70-90% of cases, which fuses EWSR1 with ATF1 {417,29 45,25 90,30 9 9,2479,1746,2423, 1203,3350}. Exon 8 of EWSFI1 fuses with exon 4 of ATF1 most frequently, and this has been designated as the type 1 fusion {3409,141,3241}. In the resultant EWSR1-ATF1 chimeric fusion protein, the N-terminus of EWSR1 and the basic leucine zipper (bZIP) domain of ATF1 are linked. Consequently, ATF1. a transcription factor normally regulated by cAMP, becomes

Fig. 1.368 Clear cell sarcoma. A Tumour cells have pale eosinophilic cytoplasm with prominent nucleoli. B Wreath-like multinucleated giant cells are a common finding.

300

Soft tissue tumours

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Fig」.369 Clear cell sarcoma. A subset of clear cell sarcomas have necrosis, which is an unfavourable prognostic factor.

Fig. 1.371 Tumour with CRTC1-TFIIM11. Newly recognized melanocytic neoplasms with CRTC1-TFIIM11 fusions exhibit morphological overlap with clear cell sarcoma.

12

Fig. 1.370 Clear cell sarcoma. Tumour cells show strong and diffuse expression of S100.

t(12;22)(q13;q12)

22

Fig. 1.372 Clear cell sarcoma of soft tissue. Schematic and partial G-banded karyo­ type of the 12;22 translocation in clear cell sarcoma.

a cAMP-independent transcriptional activator and constitutively activates the promoter for MITF, a target of the MSH pathway {741}. This activation is responsible for melanocytic differentiation and growth of CCS {741,434,1085}. ATF and CREB protei ns are function ally similar, and a smaller subset of cases harbour a variant translocation, t(2;22)(q34;q12), resulting in an EWSR1-CREB1 fusion {1378,3241}. An intra­ dermal melanocytic neoplasm with a novel CRTC1-TRIM" fusion, substantial morphological overlap with CCS, and metastatic pote ntial, provisi on ally ter med cutaneous melanocytoma, was recently described {365,522}. Additional work is necessary to determine whether this tumour represents CCS with a novel fusion or a distinet entity. Although the majority of CCSs investigated have failed to show BRAF or NRAS muta­ tions, BRAF p.Val600Glu mutations have been identified in a small subset of molecularly confirmed tumours {2424,1381, 3350,22 62).

Macroscopic appearance Most CCSs measure 2-5 cm, but tumours > 15 cm have been ©ported {605,1905}. Gross examination reveals a circumscribed mass with a lobulated tan to greyish-white appearanee, some"mes with a coarse or gritty texture {913}. A subset of CCSs may show melanin pigmentation, necrosis, or cystic change.

Histopathology On low-power exami nation, CCS exhibits a characteristic nested or fascicular architecture with epithelioid to plump spindied cells partitioned by thin fibrous septa. Tumours typically show notably infiltrative growth through dense fibrous tissue. Despite its name, CCS typically has tumour cells with palely eosinophilic cytoplasm and vesicular nuelei with macronueleoli, with only rare examples showing true cytoplasmic clearing. Substa ntial n uelear pleomorphism is gen erally abse nt, although scattered wreath-like multinucleated giant cells are relatively common. Melanin pigment is present in more than half of cases but is difficult to appreciate on H&E staining. Rare cases may show junctional tumour nests at the dermoepidermal inter­ face {1647,1098}. The mitotic count of CCS is frequently low (< 3 mitoses/mm2, equating to < 5 mitoses per 10 high-power fields of 0.17 mm2), and necrosis is identified in roughly one third of cases {880,1905,913}. CCS shows consistent expression of S100, SOX10, melan-A, HMB45, and MITF {1378,1209,1381}.

Cytology The cytological features of CCS are similar to those of melanoma, with aspiration specimens showing single or small clus­ ters of round to polygonal cells with pale cytoplasm and promi­ nent nucleoli {479,1498}. Pleomorphism is not prominent.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Diagnostic molecular pathology

Prognosis and prediction

Demonstration of EWSR1 gene rearrangement or EWSR1-ATF1 gene fusion may be helpful.

CCS is an aggressive malignancy with recurrenee rate； approaching 40% and pulmonary or lymph node metast in at least 30-50% of patients {880,772,1905,1378,118613^

Essential and desirable diagnostic criteria

Metastasis often occurs more than a decade after initial dia sis. Survival rates at 5, 10, and 20 years are approximately 壯

Essential: characteristic nested or fascicular low-power archi­ tecture; plump spindle or ovoid cells with palely eosinophilic cytoplasm and prominent nucleoli; multinucleated wreath-like giant cells are common; expression of melanocytic markers, including S100, SOX10, melan-A, and HMB45; 70-90% of cases harbour EWSR1-ATF1 fusions, helping to differentiate these neoplasms from melanoma.

Staging The American Joint Committee on Cancer (AJCC) or Union for International Cancer Control (UICC) TNM system may be used.

302

Soft tissue tumours

35%, and 10%, respectively {1381,1378,1905,1186}. TumJ size > 5 cm, n ecrosis, and regi on al lymph node involvem, are unfavourable prog nostic factors {1905,772,1381,880 2749]

Fusion variant and transcript type have not been found to ha prognostic significanee {640}.

paybal：https://www.paypal.me/andy19801210 ^xtraskeletal myxoid chondrosarcoma

Horvai AE Agaram NP Lucas DR

Definition Fxtraskeletal myxoid chondrosarcoma (EMC) is a malignant mesenchymal neoplasm of uncertain differentiation characterized by abundant myxoid matrix, multilobular architecture, and uniform cells arranged in cords, clusters, and reticular networks. These tumours are characterized by NR4A3 gene rearrangement. Despite the name, there is no evidenee of cartilaginous differentiation.

ICD-O coding 9231/3 Extraskeletal myxoid chondrosarcoma

ICD-11 coding 2B5F.2 & XH9344 Sarcoma, not elsewhere classified of other specified sites & Myxoid chondrosarcoma

Related terminology Acceptable: NR4A3-(eawa nged myxoid sarcoma (provisi on al).

Subtype(s) None

Localizatio n Most EMCs arise in the deep soft tissues of the proximal extrem­ ities and limb girdles, with the thigh being the most comm on site {917,2062}. Less common sites include the trunk, head and neck, paraspinal soft tissue, abdomen, pelvis, and foot. Rare tumours have also bee n reported in the fin ger {2367}, cranium |2745), retroperitoneum {1087}, and pleura {1173}. Despite the current nomen clature, rare genetically con firmed cases of EMC have been described in bone {1626,1006}.

Fig. 1.373 Extraskeletal myxoid chondrosarcoma. T2-weighted axial MRI highlights the hyperintense signalling and pronounced lobular architecture in an extraskeletal myxoid chondrosarcoma of the thigh.

tumours may mimic a haematoma. Tumours around joints can restrict range of motion.

Epidemiology EMC is rare, accounting for < 1% of soft tissue sarcomas. It usually occurs in adults, with a median age of 50 years {859, 2062}. Only rare cases in childhood or adolescence have been reported {1267}. The M:F ratio is 2:1.

Clinical features Patients most often present with an enlarging, deep-seated soft tissue mass, often accompanied by pain and tendemess. Some

Etiology Unknown

1.374 Extraskeletal myxoid chondrosarcoma. A Grossly, these tumours are well demarcated, are contained by a pseudocapsule, and have a lobular architecture defined by brous septa. B Cystic cavities, haemorrhage, and necrosis are often found on the cut surface. Note the well-defined lobular architecture and thick fibrous septa.

Soft tissue tumours

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Fig. 1.375 Extraskeletal myxoid chondrosarcoma. A Nodular architecture; thick fibrous bands separate pools of myxoid stroma containing tumour cells. Chronic inflammation and focal haemorrhage may be seen. B The tumour is characterized by abundant myxoid matrix and interconnecting cords of uniform cells, often with long, delicate process es. C Spindle cell differentiation is common and when present can be either focal or diffuse. Note the interconnecting growth pattern. D The cells sometimes form cohesive clusters and ring-forms mimicking an epithelial neoplasm, most importantly a myoepithelial tumour.

Pathogenesis Molecular characterization of the t(9;22) and subsequently also of the t(9;17) variant translocation has shown that they result in gene fusions in which the NF14A3 gene is fused with either EWSR1 at 22q12.2 or TAF15 at 17q12 {183,1726,2422,2878}. The /V/?4A3fusions, which are present in > 90% of EMCs {1376, 2425,2879}, have not been found in any other sarcoma and may therefore be considered a hallmark of this disease. NF14A3 (also known as TEC, CHN, and NOR" encodes an orphan nuclear receptor belonging to the steroid/thyroid receptor gene family, whereas EWSR1 and TAF15 - also known as TAF2N, RBP56, and TAF(II)68 一 belong to the TET family of multifunctional pro­ teins that bind both RNA and DNA. Two additi on al ge ne fusi ons, TCF12-NR4A3 and TFG-NR4A3, have also been identified in isolated cases of EMC {1377,2881,39}. The molecular con sequences of the NR4A3 gene fusions in EMC have only been partially elucidated. The EWSR1-NR4A3 and TAF15-NR4A3 fusion proteins are strong transcriptional activators {1633,1725}. There is evidence suggesting that coex­ pression of native NR4A3 and its coactivator SIX3 may be an alter native mechanism to gene fusi on {1379). The orpha n recep­ tor NR4A3 is a tran scripti onal target of p53 and in teracts with the antiapoptotic BCL2 protein, presumably promoting apop­ tosis {978}. Cytogenetically, EMC is characterized by a t(9;22)(q22;q12) translocation or less frequently a t(9;17)(q22;q11) or t(9;15) (q22;q21) translocation {183,2422,2798,2878,2879,2881,2944}. Although the t(9;22) has been found as the sole anomaly, most 304

Soft tissue tumours

cases also show other chromosome changes, including trisomy for 1q25-qter, 7, 8, 12, and 19 {2425,2879}.

Macroscopic appearance EMCs form large, well-demarcated tumours. Tumour size is variable and some very large tumours can reach 30 cm {2062| On cut surface, EMC has a well-defined multinodular archi­ tecture comprising gliste ning, gelati nous areas separated by fibrous septa. Intratumoural haemorrhage, cystic cavities, and geographical areas of n ecrosis are comm on. Highly cellular tumours are fleshy.

Histopathology EMC has a multinodular architecture defined by fibrous septa that divide the turn our into hypocellular lobules with abundan: pale-blue myxoid or chondromyxoid matrix. Well-formed hyaline cartilage is virtually never seen. The stroma is strikingly hypovascular. The cells characteristically interconnect wit「 one another to form cords, small clusters, and complex tra­ becular or cribriform arrays. The cells have a modest amount of deeply eosinophilic to vacuolated cytoplasm, as well as uni­ form round to oval nuelei, and delicate elongated cytoplasmic processes are common. The chromatin is evenly distributed, often with a small, inc on spicuous n ueleolus. Mitotic activity is usually low. Some tumours have prominent rhabdoid cytopla5mic inclusions. Rare cases are hypercellular with decreased myxoid matrix and have higher-grade, often epithelioid cy® morphology.

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Fig. 1.376 Extraskeletal myxoid chondrosarcoma. The cellular subtype of extraskel泅 myxoid chondrosarcoma is characterized by sheets and cords of cells with little intervening myxoid matrix. The cells frequently have an epithelioid morphology and large vesicular nuclei, prominent nucleoli, and brisk mitotic activity.

S1OO is positive in as many as 20% of cases, and KIT (CD117, is positive in as many as 30%. Expression of synaptophysin and NSE has been demonstrated in some tumours {1305, 2367,2376). Tumours with rhabdoid features are often nega­ tive for SMARCB1 (INI1). Notably, tumour cells only very rarely express keratins or GFAP, and muscle markers are negative. c-KIT)

Fig. 1.377 Extraskeletal myxoid chondrosarcoma. Rhabdoid cells with eccentric eo­ sinophilic cytoplasm and perinuclear hyaline globules are seen in some extraskeletal myxoid chondrosarcomas. These cells are frequently negative for SMARCB1 (INI1) by immunohistochemistry.

NR4A3

]9q22

Cytology Not clinically releva nt

Diagnostic molecular pathology Identification of NR4A3 gene rearrangement is diagnostically helpful.

Fig. 1.378 Extraskeletal myxoid chondrosarcoma. Schematic of the four known NR4A3 gene fusions and their respective chromosomal locations.

Essential and desirable diagnostic criteria Essential: generally bland cells with eosinophilic cytoplasm dis­ posed in strands or cords in a predominantly myxoid stroma. Desirable: NH4A3 rearrangement (in selected cases).

Staging The American Joint Committee on Cancer (AJCC) or Union for International Cancer Control (UICC) TNM system may be used.

Prognosis and prediction Although often associated with proIonged survival, EMC has high rates of distant recurrenee and disease-associated death 1859,20 62,2721}. Metastases are usually pulm on ary; however, extrapulmonary and disseminated metastases also occur

{2721}. Interestingly, proIonged survival even in the face of metastatic disease is not uncommon. Two large retrospective series {859,2062} report 5-year, 10-year, and 15-year over­ all survival rates of 82-90%, 65-70%, and 58-60%, respec­ tively. Older age, large tumour size (especially > 10 cm), and proximal location are adverse prognostic factors {2062,2376}. Some studies suggest that tumours with in creased cellularity and atypia are more aggressive {126,1902,2376}. Others sug­ gest that the presenee of rhabdoid cells represents an adverse histological finding {2376,2392}. EMCs with variant non-EWSFH gene fusions tend to show a higher incidenee of rhabdoid phe­ notype, high-grade morphology, and aggressive outcome than the EWSR1 -NR4A3-pos\\.\\/e tumours {39}.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 Desmoplastic small round cell tumour

Agaram NP Antonescu CR Ladanyi M

Definition Desmoplastic small round cell tumour (DSRCT) is a malignant mesenchymal neoplasm composed of small round tumour cells associated with prominent stromal desmoplasia, polyphenotypic differentiation, and EWSFU-WTI gene fusion.

ICD-0 coding 8806/3 Desmoplastic small round cell tumour

ICD-11 coding 2B5F.2 & XH5SN6 Sarcoma, not elsewhere classified of other specified sites & Desmoplastic small round cell tumour

Related terminology Acceptable: intra-abdominal desmoplastic round cell tumour.

Subtype(s) None

Localization The vast majority of patients develop tumours in the abdominal cavity, frequently in the retroperitoneum, pelvis, omentum, and mesentery. Multiple serosal implants are comm on. Clinical presentation outside the abdominal cavity is rare and mainly restricted to the thoracic cavity and paratesticular region {692}. Very rare cases occur in the limbs, head and neck, kidney, and brain {3236}.

Clinical features Clinical symptoms are usually related to the primary site of presentation, such as pain, abdominal distention, palpable mass, acute abdomen, ascites, and organ obstruction.

Fig. 1.379 Desmoplastic small round cell tumour. A CT image of a large pelvic des moplastic small round cell tumour. B Desmoplastic small round cell tumour present­ ing as one dominant tumour mass and multiple smaller tumour nodules. The cross­ section shows a solid whitish-tan cut surface, with foci of necrosis.

Epidemiology DSRCT primarily affects children and young adults, who usu­ ally present with widespread abdominal/peritoneal involvement {1136}. There is a striking male predominance, with peak incidence in the third decade of life, although this tumour type occurs over a wide age range (first to fifth decades).

Etiology Unknown

Pathogenesis DSRCT is characterized by a recurrent chromosomal translocation t(11;22)(p13;q12) {2750,312,2645}, resulting in fusion of the EWSR1 gene on 22q12.2 and the Wilms tumour gene, WT1, on 11p13 {1730,747,1137}. The most common chimeric transcript is composed of an in-frame fusion of the first seven exons of EWSR1, encoding the potential transcription-modulating domain, and exons 8-10 of WT1, encodi ng the last three zinc fin gers of the DNA-binding domain. Rare variants including additional exons 306

Soft tissue tumours

of EWSR1 can also occur. Detection of the EWSR1-WT1 gene fusion can be especially useful in cases with unusual clinical or histological features {1135}. Studies of the EWSR1-WT1 aberrant transcription factor have revealed deregulation of several target genes {1134} and activation of neural gene expression and par­ tial neural differentiation via ASCL1 {1567}. The serosal lining of body cavities, the most comm on site c DSRCT, has high transient fetal expression of the WT1 gene WT1 is expressed in tissues derived from the intermedia^ mesoderm, primarily those undergoing transition from mesen­ chyme to epithelium {2547,2571}. This pattern recapitulates the

epithelial differentiation noted in DSRCT.

Macroscopic appearance The typical gross appeara nee con si sts of multiple tumour no duS studding the peritoneal surface. Often there is a dominant tumou mass accompanied by satellite smaller nodules. The cut surface is firm and greyish-white, with foci of haemorrhage and necrosis.

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Histopathology DSRCT is characterized by sharply outlined nests of small neoplastic rou nd (more rarely epithelioid or even spin died) cells, usually surrounded by a prominent desmoplastic stroma. The nests can vary con siderably in size ‘ranging from minute clus­ ters to large irregular con flue nt sheets. Central necrosis is com­ mon and cystic degeneration can also be seen. Some tumours focally exhibit epithelial features, with glands or a rosette pat­ tern. The tumour cells are typically uniform, with small hyperchromatic nuclei, scant cytoplasm, and indistinet cytoplasmic borders. In a subset of cases, tumour cells can show cytoplas­ mic eosinophilic rhabdoid inclusions. Some tumours have larger cells with greater pleomorphism. The chromatin is typically dis­ persed, with inconspicuous nueleoli. Mitoses are frequent and individual cell necrosis is common. The desmoplastic stroma is composed of fibroblasts or myofibroblasts embedded in a loose extracellular matrix or collagen. Prominent stromal vascularity is

also present, ranging from complex capillary tufts to larger ves­ sels with eccentric thickened walls. Immunohistochemically, DSRCT shows a distinctive and complex pattern of multiphenotypic differentiation, expressing proteins associated with epithelial, muscular, and neural dif­ fere ntiati on. Most cases are immu no reactive for cytokerati ns, EMA, and desmin. A distinctive dot-like cytoplasmic localization is seen with desmin and occasionally with other intermedi­ ate filaments. Myogenin and MYOD1 are consistently negative. Nuclear expression of WT1 (using antibodies to the C-terminus but not the N-terminus) is usually seen {220,1367}. Ultrastructurally, most tumour cells have a primitive/undifferentiated appears nee, with minimal cytoplasm and sea nt organelles. A notable feature is the prese nee of para nuclear aggregates and whorls of in termediate filame nts. Rare dense core gran ules can be also see n occasi on ally. Few cells are con nected by cell ju nction complexes, including well-formed desmosomes.

Fig，1.381 Desmoplastic small round cell tumour. A Infiltrative growth pattern and single-file appearance. B Small round cells with minimal nuclear pleomorphism. C Rosette brmation D Focal necrosis. E Glomeruloid vascular proliferation. F Epithelial features with gland formation.

Soft tissue tumours

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B Fig. 1.382 Desmoplastic small round cell tumour. A Strong immunoreactivity for keratin. B Strong immunoreactivity for desmin. C Immunodetection of EWSR1-WT1 ch protein. Strong nuclear reactivity with the WT1 (C19) antibody directed to the C-terminus of WT1.

Cytology

Essential and desirable diagnostic criteria

Cytological specimens are cellular and show cells with a high N:C ratio, having granular chromatin, nuclear moulding, and variable nuclear membranes. Pseudorosettes are common {673}.

Essential: nests of small round cells in a desmoplastic stroma immunopositivity for cytokeratin, desmin (dot-like pattern) and WT1 (antibody to C-terminus). Desirable (but often not required): molecular studies to dem­ onstrate EWSR1 gene rearrangement or EWSR1-WT1 fusion tran script.

Diagnostic molecular pathology The presenee of EWSR1 and WT1 gene rearrangements or alter natively of the EWSR1-WT1 chimeric tran script may represent a useful diagnostic tool.

Staging Not clin ically re leva nt

Prognosis and prediction The overall survival remains poor, despite multimodality ther­ apy {2508,1738,2970}. The 5-year overall survival rate is about 10-15% at most.

308

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 ytrarenal rhabdoid tumour

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Oda Y Biegel JA Pfister SM

pefinition Extrarenal rhabdoid tumour is a highly malignant soft tissue tumour, mainly affecti ng infants and childre n, that con si sts of characteristic rounded or polygonal neoplastic cells with glassy eosinophilic cytoplasm containing hyaline-like inclusion bodeccentric nuclei, and macronucleoli. Morphologically and genetically identical tumours also arise in the kidney and brain. The majority of tumours are characterized by biallelic alterations of the SMARCB1 gene leading to loss of expression of SMARCB1 (INI1).

ICD-0 coding 8963/3 Rhabdoid tumour NOS

ICD-11 coding 2B5F.2 & XH3RF3 Sarcoma, not elsewhere classified of other specified sites & Maligna nt r habdoid tumour

Related terminology Acceptable: rhabdoid tumour of soft tissue; malignant rhabdoid tumour.

Fig. 1.383 Congenital extrarenal rhabdoid tumour. In this neonatal patient, a huge paravertebral and retroperitoneal tumour is evident. Multiple metastatic lesions were also identified at birth.

None

genitourinary tracts, and gastrointestinal system. The liver appears to be the single most common visceral location (73% of all cases {408,3103}).

Localization

Clinical features

This rare tumour seems to arise most often in deep, axial loca­ tions such as the neck, paraspinal region, perineal region, abdominal cavity or retroperitoneum, and pelvic cavity {1664, 3283,965,2348}. Lesions in the extremities (especially the thigh) and cutaneous lesions are also well documented. This tumour also often affects visceral organs such as the liver, thymus,

Most cases present as a rapidly enlarging soft tissue mass 一 the associated clinical symptoms depend on the primary organ invoIvement. Occasional cases present with multiple cutaneous nodules {265}. Particularly in infants, some cases present with disseminated disease without an obvious primary tumour — such

Subtype(s)

Fi9-1.384 Extrarenal rhabdoid tumour. A Characteristic rhabdoid cells with eosinophilic cytoplasm containing glassy inclusion-like bodies, eccentric vesicular nuclei, and

Prominent nucleoli. B Rhabdoid cells show a discohesive growth pattern.

Soft tissue tumours

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paybal：https://www.paypal.me/andy19801210 mutations, which may be present in the germline tumour predisposition syndrome 2).

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Pathogenesis Extrare nal rhabdoid tumours arise as a con sequence j

homozygous inactivation of the SMARCB1 gene in chromJ some band 22q11.2. Approximately 98% of extrarenal rhabdcj tumours, maligna nt rhabdoid tumours of kidney, and「 cal teratoid/rhabdoid tumours demonstrate genomic a側 tions of both copies of the gene, including coding-sequerf mutations, partial- or whole-gene deletions, and copy-neu3

Fig. 1.385 Extrarenal rhabdoid tumour. Proliferation of undifferentiated small round

cells, which is often observed in liver tumour.

cases are often associated with rhabdoid tumour predisposition {877}.

Epidemiology Extrarenal rhabdoid tumour is exceedingly rare, and it is largely confined to infants and children. Among fetal and neonatal rhabdoid tumours, the extrarenal rhabdoid tumour is more common than those in the kidney or brain. Conversely, on average, patients with extrarenal, extracranial rhabdoid tumours tend to be older than patients with renal rhabdoid tumours {2983}.

Etiology Familial cases are typically associated with germline mutations in SMARCB1 (INI1, hSNF5, BAF47) in 22q11.23 {313,3199,877}. Germline mutations or deletions in SMARCB1 (rhabdoid tumour predisposition syndrome 1) are present in approximately 13% of patients with extrarenal rhabdoid tumours {1398}. Patients with germline alterations in SMARCB1 typically present in early childhood, but they are at increased risk for other soft tissue tumours, no tably schwan no mas, in later decades. A very small percentage of rhabdoid tumours are associated with SMARCA4

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loss-of-heterozygosity events that unmask a recessive alia on the remaining homologue {408}. There is some genotype phe no type correlation, with rhabdoid tumours demonstrat" ing truncating mutations or deletions throughout the codinti sequenee. Extrarenal rhabdoid tumours have a particularly hjnM incidence of homozygous deletions of the SMARCB1 gene. This is often a consequenee of a chromosomal translocatioii between chromosome band 22q11.2 and a variety of different partner chromosomes. The translocation is unbalaneed at the molecular level, resulting in deletion of SMARCB1. The second allele is usually lost as a result of an interstitial 22q11.2 deletion Consistent with the function of SMARCB1 as a classic tumour suppressor gene, initiating germline mutations or deletions in SMARCB1 function as the first hit in patients who have a genetic predisposition to the development of rhabdoid tumours. Such patients are also at risk for malignant rhabdoid tumour of kidney and atypical teratoid/rhabdoid tumour. In rare rhabdoid tumours with retained SMARCB1 expression, mutation and/or loss of the SMARCA4 gene in 19p13.2 has been reported {2775}, Inacti­ vation of the SWI/SNF complex by targeting either SMARCBi or SMARCA4 gives rise to both intracranial and extracranial rhabdoid tumours. The loss of this epigenetic remodeller leads to silencing of a variety of tumour suppressor and differentiation genes and pathways that are considered hallmarks in the pathogenesis of these tumours {927,2115,500}.

Macroscopic appearance Most tumours are unencapsulated and measure > 5 cm in maxi­ mum diameter. The tumours are usually soft and grey to tan in colour on cut surface, and they are frequently accompanied by foci of coagulative and haemorrhagic necrosis.

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Fig. 1.386 Extrarenal rhabdoid tumour. A Positive nuclear expression of SMARCB1 (INI1) protein is observed in the vascular endothelial cells and inflammatory cells but： completely absent in the tumour cells. B Strong positive cytoplasmic immunoreactivity for keratin CAM5.2, which is confined to the inclusions. C Focal membranous posit")

for EMA.

310

Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 Histopathology

attern. Many tumour cells have juxtanuclear eosinophilic, PASP°sitive, diastase-resistant hyaline inclusions or globules. At the Periphery, tumou r cells in filtrate surrou nding tissue. Nuclear ple仏orphism is not evident, whereas mitotic figures are frequently

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observed. The tumour often shows loss of cellular cohesion. Some cases dem on strate predomina nt proliferati on of un differentiated small round cells, with only a small number of typical rhabdoid cells {1673,3204}. Immunohistochemically, most of these tumours show expression of epithelial markers such as keratins and EMA {965,2348}. The expression of neural or neu­ roectodermal markers such as CD99 and synaptophysin is also frequently observed in soft tissue tumours. Less comm only, the ceils express MSA and focal S100 {965,1673}. SALL4 and glypican-3 (GPC3) immu no expression is freque ntly observed {3369, 1674,1671}. Characteristically, rhabdoid tumours show loss of SMARCB1 (INI1, BAF47) expression {1399A,1396A}.

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tumour is characterized by rhabdoid cells with large vesiclar roun ded to bean-shaped n uclei, promine nt n ucleoli, and 爲曲nt cytoplasm, arranged in sheets or in a solid trabecular

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Fig. 1.387 Extrarenal rhabdoid tumour. Next-generation sequencing analysis dem­ onstrating a SMARCB1 nonsense mutation (NM_003073.4:c.778C>T, p.Gln260 *) in a rhabdoid tumour with copy-neutral loss of heterozygosity of chromosome 22 (not shown). The mutant base is highlighted in yellow; sequencing reads are visualized with custom software (Genetrix).

Not clinically relevant

Diagnostic molecular pathology

Prog nosis and prediction

Not clinically relevant

Regardless of tumour location, patient outcome is dismal. Because of the entity's rarity, there are no large studies of survival analysis in uniformly treated patients with extrarenal tumours. The media n age was 28 mon ths, and the overall 5-year survival rate was < 15% {376,1934}. Patients with rhab­ doid tumours of the liver have a worse survival than patients with other extracranial and extrarenal sites {3103,407}.

Essential and desirable diagnostic criteria Essential: primitive undifferentiated or rhabdoid cell morphol­ ogy; loss of expression of SMARCB1 (INI1).

Staging Not clinically r eleva nt

Soft tissue tumours

311

paybal：https://www.paypal.me/andy19801210 Doyle LA Argani P Hornick JL

PEComa

Definition PEComas are mesenchymal neoplasms composed of perivas­ cular epithelioid cells (PECs) — distinctive epithelioid cells that are often closely associated with blood vessel walls and that express both melanocytic and smooth muscle markers.

ICD-0 coding 8714/0 Perivascular epithelioid tumour, benign

ICD-11 coding 2F7C & XH4CC6 Neoplasms of uncertain behaviour of connective or other soft tissue & Perivascular epithelioid tumour, benign 2B5F.2 & XH4CC6 Sarcoma, not elsewhere classified of other specified sites & Perivascular epithelioid tumour, malignant

Related terminology

Fig. 1.389 Sclerosing PEComa. The tumour cells are focally situated within the of a dilated blood vessel.

Acceptable: an giomyolipoma; epithelioid angiomyolipoma; lympha ngioleiomyomatosis Not recommended: clear cell myomelanocytic tumour; sugar tumour of the lung.

Subtype(s) Perivascular epithelioid tumour, malig nant; an giomyolipoma; an giomyolipoma, epithelioid

Localization PEComas show a wide anatomical distribution {1052,1057,269, 851,3175,2089,1857,3340).

Clinical features PEComas of soft tissue usually present as painless masses.

Epidemiology PEComas are rare and are more frequent in females than males (M:F ratio: -0.2:1), with a wide age range and a peak in you ng to middle-aged adults (mean age: 45 years) {1052,1057,851,1413}.

Etiology Most PEComas are sporadic; a small subset are associatec with tuberous sclerosis {364,1057,1413}.

Pathogenesis Loss of heterozygosity involving the TSC2 locus has been found {2411}. Deletion of 16p, the location of the TSC2 gene in dicates the one oge netic relati on ship of PEComas and angiomyolipomas as 7SC2-Iinked neoplasms. TP53 mutations have been identified in 63% of rSC2-mutated PEComas {35|. A small subset of PEComas harbour TFE3 gene fusions, which correlate with strong nuclear immu no reactivity for TFE3 (1551 The most common fusion partner with TFE3 is SFPQ 冋八 {2580,3038,35}. DVL2-TFE3 and NONO-TFE3 gene fusions have also been identified in PEComa arising in soft tissue 卩6匕 TFES-rearranged PEComa lacks TSC2 mutations / loss of het­ erozygosity and thus appears to be pathogenetically distinct Fig. 1.388 PEComa. This pancreatic tumour is grossly well circumscribed, with a fleshy cut surface.

312

Soft tissue tumours

{35,1956}.

paybal：https://www.paypal.me/andy19801210

he wall

Fig. 1.391 PEComa. A Note the typical nested architecture. B The epithelioid tumour cells contain abundant clear cytoplasm. C This tumour is composed of small nests of clear cells with small round nuclei and sharply defined cell borders (sugar tumour). D A tumour with a sheet-like growth pattern. Note the granular to clear cytoplasm and uniform nuclear morphology. E Some tumours show spindle cell morphology.

Macroscopic appeara nee PEComas are grossly well circumscribed, with a firm and fibrous or fleshy cut surface. Tumours show a wide size range (mean: 5-8 cm); cutaneous tumours are usually smaller than those aris­ ing at deep locations {1057,1857,1413,851,269}.

Histopathology

iated

PEComas typically show a nested architecture and are com­ posed of epithelioid cells with abundant granular eosinophilic or clear cytoplasm and round nuclei with small nucleoli. The nests or trabeculae are typically surrounded by thin-walled cap­ illary vessels. A small subset of tumours have predominantly spindle cell morphology {1057,851}. PEComa usually shows

a distinctive perivascular pattern of growth, with tumour cells radially arranged around vessels, replacing the vessel wall and approaching the endothelium. The sclerosing subtype of PEComa is composed of cords and trabeculae of epithelioid cells in a densely collage nous stroma {1413}. Epithelioid an gio­ myolipoma is synonymous with PEComa {189,427}. Typical PEComa may contain occasional multinucleated cells and show limited pleomorphism (symplastic change), but mitotic figures are usually scarce or absent. Malignant PEComas are charac­ terized by a variable combination of mitotic activity, necrosis, and pleomorphism {364,1057,851,269}. PEComas characteristically express both melanocytic mark­ ers, such as HMB45 (the most sen sitive immu no marker),

oeen jene. igiohave 5|. A /hich 155).

PSF) Mons 162|. het川net Fig，1,392 PEComa. A Malignant PEComa composed of epithelioid tumour cells with clear cytoplasm, nuclear atypia, and mitotic activity. Note the trabecular architecture. B A malignant PEComa with marked nuclear atypia and pleomorphism. Note the abundant granular eosinophilic cytoplasm.

Soft tissue tumours

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Fig.1.393 PEComa with TFE3 rearrangement. A PEComa with TFE3 rearrangement showing nested and solid alveolar growth patterns and epithelioid tumour cells with m ate amounts of granular eosinophilic cytoplasm. B Nuclear TFE3 expression in PEComa corresponding to the presence of TFE3 rearrangement.

in soft tissue {156,162} and most closely fit into the category IFES-rearranged PEComa. Sm7

D16S521

Cytology Not clinically releva nt

Diagnostic molecular pathology For cases with strong TFE3 protein expression, identification TFE3 gene rearrangement or a corresponding fusion gene c, help con firm the diag no sis. Fig. 1.394 PEComa. Loss of chromosome arm 16p demonstrated by comparative genomic hybridization and loss-of-heterozygosity analysis using microsatellite mark­ ers Sm7 and D16S521 (arrows), which flank the locus of the TSC2gene.

melan-A, and MITF, and muscle markers, such as SMA, desmin, and caldesmon {1054,1413,851,269,1949}. Expression of melano cytic markers is more common in epithelioid tha n spin died tumour cells. Desmin and h-caldesmon are often less extensively positive than SMA {1413}. Some tumours lack expression of muscle markers {1054}. Nuclear expression of S100 is gen­ erally not observed in PEComas. Approximately 15% of cases show strong nuclear staining for TFE3 {162,1057,851,155}. PEComas with TFE3 rearrangement tend to occur in younger patients, have a prominent alveolar growth pattern and epithe­ lioid morphology, and often lack expression of smooth muscle markers {162,1956,2580,35}. Occasional TF£3-rearranged epi­ thelioid but non-epithelial neoplasms contain melanin pigment; these were initially described in the kidney as melanotic Xp11 translocation renal cancer, but they have also been described

:issue tumours

Essential and desirable diagnostic criteria Essential: epithelioid and/or spindle cells with granular eosino­ philic to clear cytoplasm; nested, trabecular, or sheet-like architecture with frequent perivascular orientation; variabh coexpression of melanocytic and smooth muscle markers. Desirable: TFE3 expression if smooth muscle markers are nega tive.

Staging Not clin ically re leva nt

Prognosis and prediction Clinically malignant tumours are typically large; show mark® nuclear atypia and pleomorphism, conspicuous mitoses, necrc sis, and in filtrative margins; and tend to pur sue an aggressiv clinical course {1057,269}. Tumour size > 5 cm has also bee significantly associated with recurrenee {341}. The most common metastatic sites are the liver, lymph nodes, Iungs, and bone {1057,851,269}.

paybal：https://www.paypal.me/andy19801210 intimal sarcoma

Bode-Lesniewska B Debiec-Rychter M Tavora F

Qefinition Intimal sarcomas are malignant mesenchymal tumours arising in large blood vessels of the systemic and pulmonary circulahon and also in the heart. The defining feature is predominantly intraluminal growth with obstruction of the lumen of the vessel of origin and seeding of emboli to peripheral organs.

ICD-0 coding 9137/3 Intimal sarcoma

ICD-11 coding 2B5F.2 & XH36H7 Sarcoma, not elsewhere classified of other specified sites & Intimal sarcoma

Related terminology None

Subtype(s)

Fig. 1.395 Intimal sarcoma. CT of a patient with intima! sarcoma of the right pulmo­ nary artery demonstrating a solid intraluminal mass, which showed metabolic activity on PET-CT (not pictured).

None

Localizatio n Intimal sarcomas of the pulmonary circulation mainly involve the proximal vessels: the pulmonary trunk (80%), the right or left pulmonary arteries (50-70%), or both (40%) {450,2316}. Some tumours involve cardiac structures: the left heart, pulmonary valve, or right ventricular outflow {448,2266,1494,3156). Direct infiltration or lung metastases are observed in 40% of cases, and extrathoracic spread occurs at presentation in 20% (brain, skin, lymph nodes) {450}. Aortic intimal sarcomas mostly arise in the abdominal aorta between the celiac artery and the iliac bifurcation, and 30% are located in the thoracic aorta {2931, 450,2738,2801}.

Clinical features Clinical prese ntation is non specific and often related to tumour emboli {1628,2803,1088,3413}, with r ecurrent pulmonary embolic disease being the most comm on primary diag no sis. Proper diagnosis is often delayed or made after death. Imaging is non specific, but the n eoplastic n ature of the tissue occludi ng the lumen can be suspected on the basis of some diagnostic procedures (CT, MRI, PET) {1628,2803,2396,3299}.

Epidemiology Intimal sarcomas are very rare tumours, with major pulmonary vessel sarcomas being twice as common as aortic tumours 1349,450,80 8,2485,2801}. Intracardiac intimal sarcomas are 「are, although this is the most comm on type of heart sarcoma 12266}. Pulmonary and heart intimal sarcomas are slightly more common in females (M:F ratio: -0.7:1), whereas aortic tumours may be more comm on in males {2931}. The mean age at diagnosis is 48 years for pulmonary, 50 years for heart, and 62 years for aortic intimal sarcomas {1628,3156,2931,450}.

Fig. 1.396 Intimal sarcoma. A View of the hilum of the resected lung of a patient with obstruction of the lumen of the pulmonary artery by tumour tissue. B Endarterectomy specimen of another patient with intimal sarcoma of the pulmonary artery.

Soft tissue tumours

315

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Fig. 1.397 Intimal sarcoma. A Spreading of the tumour along the intrapulmonary branches of the pulmonary artery. B Myxoid tumour with low cellular density. C Bundles of tumour cells resembling leiomyosarcoma. D An endothelium-lined vascular cleft surrounded by pleomorphic tumour cells.

De

Etiology Unknown

Pathogenesis By comparative genomic hybridization (CGH) and array com­ parative genomic hybridization (aCGH), gains/amplifications of 12q12-q15 (CDK4, TSPAN31, MDM2, GLI1 [GLI]) and 4q 12 were reported as the most consistent aberrations {349,3392,3399A}.

In terphase FISH revealed amplificati on of PDGFFIA and KIT (CD117) and amplification/polysomy of EGFR in all and in 6 c 8 tumours, respectively {3034A}. In a recent aCGH study, 6 oi 8 tumours showed 4q12 amplification, with the common region containing only PDGFRA. Other, less consistent alterations were gains/amplifications in 7p14-p22, 8q11-q23, 12p11, and 12q13q15 (GL/7 [GLI], CDK4, DDIT3, HMGA2, BEST3, MDM2) and losses in 3q12-q21, 9p21, 10q22, 12q12, and 12q23. Frequent high-level (co)amplifications/gains of PDGFFIA (81%), EGFR (76%), and/or MDM2 (65%) were confirmed in 21 tumours by FISH {808}. Recently, based on molecular analysis, intimal sar­ coma was identified as the most frequent sarcoma histotype (42%) in a series of 100 cardiac sarcomas {2266}. With the use of FISH, quantitative PCR, and aCGH, MDM2 amplification was detected in 100% of cardiac intimal sarcomas. aCGH showed a complex profile, with recurrent 12q13-q14 amplicons contain­ ing MDM2, 7p12 gain involving EGFR, 9p21 deletion targeting CDKN2A in all cases, and KIT and PDGFRA amplification m 2 of 5 cases {2266}.

Macroscopic appearanee

Fig. 1.398 Intimal sarcoma. Nuclear immunoexpression of MDM2 protein in numer­

By definition, intimal sarcomas are mostly intravascular masses attached to the vessel wall, grossly resembling thrombi and extending distally along the branches of the involved vessels. Occasi on ally, a mucoid lume n cast can be recovered intraoperatively, or harder, bony areas corresp on ding to osteosarcomatous differentiation are found. Some of the aortic tumours may cause thinning and aneurysmal dilatation with adherent

ous tumour cells.

thrombus, suggesting atherosclerosis {2258,2303}.

316

Soft tissue tumours

St; Nc

paybal：https://www.paypal.me/andy19801210 Histopathology 'jrTial sarcomas are morphologically non-distinctive, poorly Mffere ntiated maligna nt mesen chymal tumours, con sisting of mildly to severely atypical spindle cells with varying degrees f mitotic activity, necrosis, and nuclear polymorphism. Some tumours show myxoid areas or epithelioid morphology {1179, 280儿 Prominent spindling and bundling may resemble leio­ myosarcoma. Rare cases may contain neoplastic cartilage tumour osteoid, or show focal rhabdomyosarcomatous or angiosarcomatous features {450,1179,1419,2316}. Immunohistochernically, variable positivity for SMA is found, and some tumours exhibit positivity for desmin. Rhabdomyosarcomatous Mfferentiation is accompanied by the expression of myogenin and MYOD1 {2266}. Nuclear expression of MDM2 can be observed in at least 70% of cases {349,808}.

Cytology

F(A specimens of intraluminal sarcomas contain obviously malig nant, spin died and pleomorphic mesenchymal tumou r cells.

Diagnostic molecular pathology Demon strati on of A4D/W2amplificatio n can be helpful.

Essentia; and desirable diagnostic criteria

dies ol

1 KIT i 6 of ,6of 5gion were !q13and ]uent

Essential: occurrenee within the lumen of a large vessel of the pulmonary or systemic circulation or within the heart cavities; primary high-grade sarcoma, with or without heterologous elements. Desirable: MDM2 amplification (in selected cases).

Staging Not clinically releva nt

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B

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Fig. 1.399 Intimal sarcoma. A A representative copy-number alteration profile (Agi­

lent 244K array comparative genomic hybridization) showing high-level amplification of the PDGFRA/4q12 and A4DM2/12q14-q15 regions; gain of 6q, 7, 8q, 12p, and 17q; and partial/total losses of 1p, 3q, 5q, 9p, 10, 15q, 1 & and X. The individual probes are arranged according to their genomic location (x axis) and their respective tumour/ reference log2 ratios (y axis). B Array comparative genomic hybridization profile of a selected region of chromosome band 4q12, showing high-level amplification of the genes CHIC2, PDGFRA, and KIT. C A representative example of dual-colour inter­ phase FISH images of intimal sarcoma, showing exclusive high-level amplification of PDGFRA (red signals; long arrows) or MDM2 (green signals; short arrows), intermin­ gled with cells showing separate amplicons for both genes.

Prognosis and prediction The prog nosis for patie nts with in timal sarcomas is poor, with a mean survival time of 5-9 months in patients with aortic sar­ comas and 13-18 months in patients with pulmonary sarcomas {349,450,2316,2485}.

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Soft tissue tumours

317

paybal：https://www.paypal.me/andy19801210 Undifferentiated sarcoma

Dei Tos AP Mertens F Pillay N

Definition Undifferentiated soft tissue sarcoma (USTS) shows no identifiable line of differentiation when analysed by presently available technology. At present, this is a heterogeneous group and a diagnosis of exclusion, although genetic subgroups (particu­ larly in the round cell group) have emerged. Not included are dedifferentiated types of specific soft tissue sarcomas (e.g. dedifferentiated liposarcoma), in which the high-grade component is comm only un differe ntiated.

ICD-0 coding 8805/3 Un differentiated sarcoma

ICD-11 coding 2B5F.2 & XH73J4 Sarcoma, not elsewhere classified specified sites & Giant cell sarcoma 2B5F.2 & XH0947 Sarcoma, not elsewhere classified specified sites & Malignant fibrous histiocytoma 2B5F.2 & XH6HY6 Sarcoma, not elsewhere classified specified sites & Undifferentiated sarcoma 2B5F.2 & XH85G7 Sarcoma, not elsewhere classified specified sites & Small cell sarcoma

of other

of other

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Fig. 1.400 Undifferentiated pleomorphic sarcoma. Grossly, undifferentiated pleomc phic sarcomas most often feature a fleshy appearance with areas of necrosis ar haemorrhage.

of other

Etiology

None

The etiology of most USTSs is unknown. However, at least 25% of radiati on-associated soft tissue sarcomas are un differenti­ ated {1163,1761}.

Subtype(s)

Pathogenesis

Spindle cell sarcoma, undifferentiated; pleomorphic sarcoma, undifferentiated; round cell sarcoma, undifferentiated

Undifferentiated pleomorphic sarcomas (UPSs) typically dis­ play extensive genomic rearrangements. Cytogenetic data from > 100 cases have, with few exceptions, revealed complex karyotypes with chromosome numbers ranging from near-hap­ loid to hyperoctaploid {1021,1390}. The extensive reshuffling of chromosomal material indicated by tumour karyotypes is corroborated by array-based genomic studies, showing structural rearrangements and copy-number shifts involving most if not all chromosomes {482,1699}, as well as by massively parallel sequencing studies {472,2935}. UPSs demonstrate substan­ tial copy-number heterogeneity compared with other sarcoma subtypes and do not form distinet methylation subgroups |472. 2935}. Whole-genome sequencing has revealed that punctu­ ated evolutionary events such as whole-genome duplications and chromothripsis accompanied by telomere dysfunction underpin the genomic complexity of UPS {2935}. The aberrations in telomere biology are achieved either through activation of telomerase through deregulation of TERT or through the alternative lengthening of telomeres pathway {472,2935}. There are no tumour-specific amplicons, but some 10-15% of cases show amplification of VGLL3 or YAP1, and 10% have amplification of CCNE1 {1344,472}. Targets of frequent deletions and disruptive rearrangements include CDKN2A and CDKN2B in 9p, PTENW 10q, FIB1 in 13q, and TP53 in 17p, each affected in 10-20% of cases {2865,576,2492,1150,472,2935}. RB1 and TP53, as

Related terminology

Localizati on USTS may be found at any location. Published data are lim­ ited, but overall it seems that these lesi ons are most comm on in somatic soft tissue.

Clinical features USTS has no characteristic clinical features that distinguish it from other types of sarcoma, other than a frequently rapid growth rate.

Epidemiology USTSs are uncommon mesenchymal neoplasms that are ana­ tomically ubiquitous and occur at all ages and with no differ­ ence between the sexes. USTSs account for as many as 20% of all soft tissue sarcomas. Those with round cell morphology are most freque nt in you ng patie nts and are curre ntly in large part labelled according to their main driving genetic anomaly, if known (see Chapter 2: Undifferentiated small round cell sarco­ mas of bone and soft tissue, p. 321). Those that are pleomorphic (often known as pleomorphic malignant fibrous histiocytomas in the past) occur mostly in older adults.

318

Soft tissue tumours

paybal：https://www.paypal.me/andy19801210 I，as ATFIX, are among the few genes that recurrently show * thogenetic variants at the nucleotide level (472). At the tran^iptomic level, UPS cannot be distinguished from high-grade S vxofibrosarcoma, and it is possible that these two entities

may lie on a spectrum of differentiation {472}. A small subset of UPSs with low mitotic counts show gene fusions involving the PRDM10 gene, with either MED12 or CITED2 as the 5' partner □390}. Otherwise, driver gene fusions have not been found in UPS {472}.

Macroscopic appearance USTSs are a heterogeneous group and thus have no distinctive macroscopic features, other than the frequent presence of necrosis and haemorrhage.

Histopathology USTSs may be broadly divided into pleomorphic, spindle cell, round cell, and epithelioid subsets, but none have specific defining features other than their lack of an identifiable line of (jifferentiation {1018}. Pleomorphic USTSs, which represent the largest group, closely resemble other specific types of pleomor­ phic sarcomas and are often patternless, with frequent bizarre multinucleated tumour giant cells. Spindle cell USTSs most often show a fascicular architecture with variably amphophilic or palely eosinophilic cytoplasm and tapering nuclei. Round cell USTSs consist of relatively uniform rounded or ovoid cells with a high N:C ratio, and they most often closely resemble

other specific types of round cell sarcomas, especially Ewing sarcoma. However, many cases can now probably be more precisely classified within specific molecular subsets, such as C/C-rearranged and BCOR-rearranged sarcomas, as well as within the group of round cell sarcomas associated with EWSR1 fusions involving partners unrelated to the ETS family of genes (e.g. PATZ1, NFATC2, SP3, SMARCA5, and POU5F1) - see Chapter 2: Undifferentiated small round cell sarcomas of bone and soft tissue (p. 321). USTSs with epithelioid morphology have been little studied as yet {2716}, but they are probably not rare. Morphologically, these lesions closely resemble metastatic carcinoma or melano ma, but they gen erally lack n esting and have amphophilic or palely eosinophilic cytoplasm and large vesicular nuclei. Some appear to show SMARCA4 inactivation {1789,2493}. Importantly, genomic profiling may reveal that some seemingly undifferentiated sarcomas can be classified more specifically {482,639,641,2150}.

Cytology Not clinically r eleva nt

Diagnostic molecular pathology Undifferentiated pleomorphic and epithelioid sarcomas are characterized by complex genetic aberrations not suitable for diag no stic pur poses. However, molecular gen etics plays a major role in excluding specific molecular entities, particularly when dealing with undifferentiated round cell sarcomas. UPS must be

Fig. 1.401 Undifferentiated sarcoma. A Undifferentiated pleomorphic sarcoma is composed of a spindle cell and pleomorphic cell population most often characterized by high mitotic activity. Atypical mitoses are very common. B Undifferentiated spindle cell sarcoma features a highly atypical spindle cell proliferation. Mitotic activity is most often high. C Currently, undifferentiated round cell sarcoma can be diagnosed only if distinctive gene fusions have been ruled out. D Undifferentiated epithelioid sarcoma is most often

composed of a high-grade epithelioid cell population lacking any specific line of differentiation.

Soft tissue tumours

319

paybal：https://www.paypal.me/andy19801210 separated from dedifferentiated liposarcoma, a lesion charaq ized molecularly by MDM2 and CDK4 gene amplification {5； 641}.

11705 substitutions

Essential and desirable diagnostic criteria 721 deletions and insertions

Essential: spin die, pleomorphic, epithelioid, and round cell often high-grade) morphology; absenee of any morphoi^ cal or immunohistochemical feature of specific differential

dem on strated abse nee of disti nc tive molecular aberration

Staging

copy number

The American Joint Committee on Cancer (AJCC) or Union International Cancer Control (UICC) TNM system may be us(

329 rearrangements deletion

Prognosis and prediction S

?

S

S

S

Fig. 1.402 Undifferentiated pleomorphic sarcoma. Circos plot illustrating the complex copy-number and rearrangement patterns seen in a typical undifferentiated pleomor­ phic sarcoma genome. The outer ring denotes chromosomal location, with subsequent rings representing single-nucleotide variants, insertions, deletions, and copy-number gains and losses. The arcs rep resent interchromosomal and intrachromosomal re­ arrangements.

320

Soft tissue tumours

Because of the lack of substantive studies, data are limit© The majority of USTSs are morphologically high-grade. Amon pleomorphic sarcomas in adults, those that are undifferentiate and arise in the limbs or trunk have a reported 5-year meta tasis-free survival rate of 83% {1023}. USTS with epithelioi morphology seems to be more aggressive {2716}. In childrei reported survival rates for USTS, whether of round cell or spir die cell / pleomorphic type, are 70-75% {59,2468,2905}.

paybal：https://www.paypal.me/andy19801210

yndifferentiated small round cell sarcomas of bone and soft tissue Edited by: Bridge JA

E时ing sarcoma Round cell sarcoma with EWSR7-non-ETS fusions CQ-rearranged sarcoma Sarcoma with BCOR genetic alterations

*

paybal：https://www.paypal.me/andy19801210 WHO classification of undifferentiated small round cell sarcomas of bone and soft tissue 9364/3 * 9366/3

Ewing sarcoma Round cell sarcoma with EI/l/SH7-non-ETS fusions

* 9367/3 9368/3 *

C/C-rearranged sarcoma Sarcoma with BCOF) genetic alterations

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) (1471). Behaviour is coded /0 for benign turrm J /1 for un specified, borderli ne, or uncertai n behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for maligna nt tumours, primary site; and /6 for malig n晶 t tumn metastatic site. Behaviour code /6 is not gen erally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions. * Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-0 at its meeting in January 2020.

322

Un d iff ere ntiated small rou nd cell sarcomas of bone and soft tissue

paybal：https://www.paypal.me/andy19801210 de Alava E Less nick SL Stamenkovic I

Wing sarcoma

Definition Ewing sarcoma is a small round cell sarcoma showing gene fusions involving one member of the FET family of genes (usuaily EWSR1) and a member of the ETS family of transcription factors.

ICD-O coding 9364/3 Ewing sarcoma

ICD-11 coding 2B52.3 Ewing sarcoma of soft tissue 2B52.Y Ewing sarcoma of bone and articular cartilage of other specified sites

Related terminology Not recommended: Askin tumour (for Ewing sarcoma arising in the chest wall); primitive neuroectodermal tumour. Note: Some small round cell sarcomas previously considered subtypes of Ewing sarcoma (Ewing-like sarcomas) are geneti­ cally and clinically disti net entities and in elude C/C-rearranged sarcoma and sarcoma with BCORgenetic alterations, described in separate sections.

Subtype(s) None

Localization Ewing sarcoma arises in the diaphysis and diaphyseal-me­ taphyseal portions of long bones, pelvis, and ribs, although any bone can be affected. Extraskeletal Ewing sarcoma occurs in about 12% of patients {1238} and has a wide an atomical dis­ tribution

Clinical features Ewing sarcoma often presents with locoregional pain and a palpable mass, sometimes associated with pathological frac­ ture and fever (particularly with advaneed and/or metastatic disease). Plain radiographs ofte n dem on strate poorly defi ned osteolytic-permeative lesions with a classic multilayered peri­ osteal reaction (onion-skin appearance). Additional studies including CT, MRI, and/or PET imaging are used to fully define primary lesions and soft tissue extension, as well as to evaluate for metastatic disease (present in 〜25% of patien⑸.

Fig. 2.01 Ewing sarcoma of bone. Anteroposterior radiograph of the right humerus shows an aggressive lesion in the proximal metadiaphysis, with permeative bone de­ struction, cortical lysis, and a multilamellated periosteal reaction, which is interrupted

medially and laterally.

ancestry as compared to individuals of European ancestry is probably caused by genetic rather than environmental or life­ style factors {3311}.

Etiology The majority of cases are sporadic, but germline mutations have been detected {3394}.

Epidemiology Ewing sarcoma is the sec ond most comm on malig nant bone tumour in children and young adults, after osteosarcoma {1260}, and it shows an M:F ratio of 1.4:1. Nearly 80% of patients are aged < 20 years, and the peak incidence occurs during the second decade of life. Cases in patients aged > 30 years are bss comm on, and these tumours more often arise in the soft tissue. The rarity of Ewing sarcoma among individuals of African

Pathogenesis All cases of Ewing sarcoma are associated with structural rearra ngements that gen erate FET-ETS fusi on genes (see below). Additional mutations may occur in STAG2 (15-22%), CDKN2A (12%), and TP53 (7%) {432,686,3077,3394}. FETETS fusion genes encode chimeric transcript!on factors that serve as master regulators to activate and repress thousands

Undifferentiated small round cell sarcomas of bone and soft tissue

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Fig. 2.02 Classic Ewing sarcoma. Notice the vaguely lobular pattern and cleared-out cytoplasm, due to glycogen deposits.

Fig. 2.03 Ewing sarcoma. Ewing sarcoma with extensive neuroectodermal di tiation (formerly called primitive neuroectodermal tumour) showing well-formed dorosettes, absence of nucleoli, and finely granular chromatin.

Fig. 2.04 Ewing sarcoma. A classic Ewing sarcoma (A) can be compared with atypical Ewing sarcoma (B) in terms of nuclear size, chromatin structure, and cytoplasmic cleari

of genes. Expression of these aberrant transcription factors, presumably in the correct cellular and developme ntal con text, is required for the development of Ewing sarcoma. Proteins bind both GGAA microsatellites and canonical ETS binding sites in the genome and recruit chromatin regulators. Binding of the fusion proteins to GGAA microsatellites results in the transition from a closed to an open chromatin state that establishes de novo enhancers, which activate genes. Conversely, binding to canonical ETS binding sites displaces wildtype ETS factors and represses gene expression. Together, these events establish an oneogenic gene expression programme that underlies transformation and subsequent tumour initiation.

(ill-defined groups of as many as 10 cells oriented towards a central space an d/or with a con sistent immun ophe notype) is present (historically termed primitive neuroectodermal tumour) {1887}. After in duction chemotherapy, Ewing sarcoma cells show a variable degree of necrosis and are replaced by loose connective tissue. Immunohistochemically, CD99 is a cell-surface glycoprotein and a r eleva nt diag no stic marker for Ewing sarcoma. Strong.

Macroscopic appearance The cut surface of untreated Ewing sarcoma specimens is grey­ ish-white and soft, and it frequently includes areas of haemor­ rhage and necrosis

Histopathology Most cases are composed of uniform small round cells with round nuelei containing finely stippled chromatin and incon­ spicuous nu cleoli, sea nt clear or eosi nophilic cytoplasm, and indistinet cytoplasmic membranes (classic Ewing sarcoma) {1887}. In others, the tumour cells are larger, with prominent n ueleoli and irregular c on tours (atypical Ewing sarcoma) {1930}. Sometimes, a higher degree of neuroectodermal differentiation 324

Fig. 2.05 Ewing sarcoma. Ewing sarcoma typically shows strong and diffuse mem brane staining for CD99.

Undifferentiated small round cell sarcomas of bone and soft tissue

paybal：https://www.paypal.me/andy19801210 dffuse membra nous expressi on of CD99 is evide nt in about L of Ewing sarcomas. NKX2-2 {1931} has a higher specific啊 CD99. Keratin expression is present ；［% of cases {1051}. FLI1 and ERG are often

RGG

in approximately expressed in the

RRM

RGG

RGG

breakpoints

cases with the corresp on ding gene fusions {3243}. Some cases express neuroendocrine antigens and/or S100. A distinct subset of lesions carrying the same fusions has been described, predominantly in the head and neck region, as adamantinoma-like Ewing sarcoma. This subset often expresses markers of squamous differentiation. The relation­ dip of this tumour type to classic Ewing sarcoma is uncertain (412,332}

DNABD

breakpoi nts PNT

DNABD

FLI1 protein 匚

Cytology Not clinically relevant

Diagnostic molecular pathology Genetic con firmation is often required for Ewing sarcoma diagnosis. The most comm on Ewing sarcoma tran slocati on (present in -85% of cases) is t(11;22)(q24;q12), which results in the EWSR1-FLI1 fusion transcript and protein. The second most common is t(21;22)(q22;q12), which results in EWSR1-ERG in about 10% of cases. The remai ning cases have alter native translocations that join either EWSFI1 or FUS (which, along with TAF15, form the FET family) to other ETS family members. All cases of Ewing sarcoma harbour a FET-ETS fusion.

Fig. 2.06 The EWSR1-FLI1 fusion. The most common Ewing sarcoma translocation is between the EWSR1 gene on chromosome 22 and the FU1 gene on chromosome 11. The EWSR1 protein has an N-terminal domain (NTD) that is an intrinsically disordered domain and a C-terminal region that contains RGG domains and an RNA-recognition motif (RRM). The FLI1 protein has an N-terminal domain with a pointed protein-pro­ tein interaction domain (PNT) and an ETS-type DNA-binding domain (DNABD) in its C-terminus. The resulting EWSR1-FLI1 protein retains the EWSR1 NTD and the FLI1 DNABD.

Essential and desirable diagnostic criteria Essential: small round cell morphology; CD99 membra nous expression. Desirable: FET-ETS fusion detection (in selected cases).

Staging The American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) TNM systems can be applied.

Prognosis and prediction The prognosis of Ewing sarcoma has improved considerably with curient multimodal therapy, with a 65-70% cure rate for localized disease. However, metastatic and early-relapsing tumours have a poor prog no sis, with a 5-year survival rate of < 30%. The presenee of metastases appears to be the main prog nostic factor. Other n egative prog no stic factors in elude the anatomical location of the tumour, such as the pelvis. Com­ plete pathological response to neoadjuvant chemotherapy is a favourable prognostic factor {64}. There are currently no other Prognostic markers in widespread use.

Fig. 2.07 Next-generation sequencing of EWSR1-FLI1. Next-generation RNA se­ quencing of Ewing sarcoma demonstrates in-frame fusion between EWSR1 and FU1 gene products. Next-generation sequencing is more specific than EWSR1 break-apart FISH because it provides detailed information about both translocation partners.

Undifferentiated small round cell sarcomas of bone and soft tissue

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paybal：https://www.paypal.me/andy19801210 Le Loarer F Szuhai K Tirode F

Round cell sarcoma with EI/I/SR7—non-ETS fusions

Defin ition

None

of long bones is involved in the following sites in decreasin order of frequency: femur, humerus, radius, and tibia. Soft ti sue cases involve extremities, head and neck, and chest wan {3014,633,2704}. FUS-NFATC2 tumours have been reported exclusively in long bones {3253,348,820}. EWSFI1-PATZ1 Sar comas arise in the deep soft tissue and show a predilection for the chest wall and abdomen; however, extremity and head/neck locations have also been described {589,418}. EWSR1-Patzi fusions have also been identified in CNS tumours {2556154。 418}.

Related terminology

Clinical features

Not recommended: Ewing-like sarcoma.

EWSR1-NFATC2 and FUS-NFATC2 sarcomas manifest as frequently painful, locally destructive bone lesions that may in vade surrounding soft tissue, or less comm only, as wellcircumscribed or locally invasive primary soft tissue tumours {633,820}. A subset of patients experie nee symptoms in elud­ ing a slow-growing mass for years before diagnosis {633,820| Patients with EWSR1-PATZ1 sarcomas may present with a pal­ pable soft tissue mass and/or pain related to tumour location

Round cell sarcomas with EWSR1 -non-ETS fusions are round and spindle cell sarcomas with EWSR1 or FUS fusions invoIving partners unrelated to the ETS gene family.

ICD-0 coding 9366/3 Round cell sarcoma with EI/l/S/?7-non-ETS fusions

ICD-11 coding

Subtype(s) None

Localization EWSFl1-NFATC2sarcomas are dominantly located in bones, with a 4:1 ratio over soft tissues {820). The metaphysis or diaphysis

Fig. 2.08 EWSR1-NFATC2 sarcoma. A Sarcomas with NFATC2 rearrangement infiltrating and destroying bone. B Infiltration and destruction of bone with intertrabecula;； filtration. C The tumour is composed of an undifferentiated round cell proliferation without admixed stroma and cytological features reminiscent of Ewing sarcoma. D DM us

expression of CD99.

326

Undifferentiated small round cell sarcomas of bone and soft tissue

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Fig,2.09 EWSR1-NFATC2sarcoma. A Spindled to rounded tumour cells separated by scant stroma. B Tumour cells embedded in fibrohyaline stroma. C Myxohyaline stromal changes defining a nested appearance.

Fig.2.10 EWSR1-PATZ1 sarcoma. A Small to medium-sized tumour nuclei are round to ovoid, with fine granular chromatin. B Tumour nuclei may exhibit mild atypia with size/ shape variation and coarse chromatin.

and size or extent of disease (a subset exhibit distant or locoregional metastases at time of diag no sis) {589,418}.

Epidemiology These tumours are rare. EWSR1-NFATC2 and FUS-NFATC2sar­ comas feature a strong male predominance (M:F ratio: 5:1), with presentation in children and adults (age range: 12-67 years; median age: 32.3 years) {1931,348,3227}. The age range of patients diagnosed with EWSR1-PATZ1 sarcoma in published cases is broad (1-81 years), with a mean of 42 years; sex distri­ bution is near-equivalent {418}.

Etiology Unknow n

Pathogenesis At the cytoge netic level, the translocati on eve nt r esulti ng in fusion of the EWSR1 (22q12.2) and NFATC2 (20q13.2) genes typically arises within a derivative 22 ring chromosome as unbalanced and amplified {3014,3013}. The EWSR1-NFATC2 fusion induces activation of the NFATC2 transcription factor consequent to the loss of the N-terminal regulatory domain, leading to the relocation in the nucleus of the chimeric transcription factor. Expression and methylome profiling has shown that EWSR1-NFATC2 and FUS-NFATC2 sarcomas differ from Ewing sarcomas, EWSR1-PATZ1 sarcomas, and C/C-fused and BCOfl-rearranged sarcomas {3253,1666,432,210}. In contrast

to EWSR1-NFATC2, the FUS-NFATC2 fusion gene has not dem on strated amplificatio n. Clusteri ng an alyses also suggest that FUS-NFATC2 sarcomas are tran scripti on ally disti net from EWSR1-NFATC2 sarcomas {3253}. PATZ1 enc odes a zinc fin ger protei n with a Cys2-His2 motif with tumour suppressive functions invoIved in transcriptional regulation {977,2007}. PATZ1 resides in close proximity (~2 Mb distance) to EWSR1 on chromosome 22. The EWSR1-PATZ1 fusion eve nt is most likely the result of a submicroscopic intrachromosomal paracentric inversion (as the genes are normally tran scribed in opposite di recti ons), although genesis of this fusion via more-complex structural alterations at least for some cases cannot be fully excluded {2007,589,418}. An in-frame fusion between exon 8 or 9 of EWSFI1 and exon 1 of PATZ1 results in removal of the putative transcriptional repressor domain and the AT-hook domain at the N-terminus of PATZ1 and converts a transcriptional repressor into a transcriptional activator. EWSR1-PATZ1 sarcomas possess a unique expression signature, but they have not been compared with the CNS cases {3253}. In one study, comprehensive DNA and RNA sequencing revealed loss/deletion of CDKN2A/CDKN2B in 5 of 7 EWSR1-PATZ1 sarcomas, with concurrent MDM2 amplifica­ tion in one (representing alterations that may have prognostic significanee, because these events were evideneed in the clinically most aggressive tumours for which follow-up data was available and contrasted with absence of these alterations in a surgically resected, well-encapsulated EWSR1-PATZ1 sarcoma

Un differentiated small round cell sarcomas of bone and soft tissue

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Fig.2.11 EWSFI1-NFATC2sarcoma. A Multicolour FISH of an EWSR1-NFATC2fusion-positive case exhibiting a ring chromosome derived from multiple alternating segmf of chromosomes 20 and 22 (arrow). B EWSR1 break-apart FISH demonstrates split signals with amplification of the telomeric probe (green); normal cells with colocalized sigi are seen on the left.

that dem on strated no evide nee of disease at 19 months after resection) {418}.

Macroscopic appearance Gross examination of primary soft tissue or bone EWSR1NFATC2 sarcoma reveals a solid mass with a wide size range (4-18 cm in greatest dimension) and a yellowish-tan, firm or fleshy cut surface. Most of these sarcomas are ill defined and are locally destructive or in filtrate into adjace nt tissues; however, a few primary soft tissue and bone lesions have been described as being well circumscribed or confined to the intramedullary cavity, respectively {3227,633,820}. EWSFI1-PATZ1 sarcoma is a solid-cystic mass with reported tumour sizes of 3.5 to > 10 cm in greatest dimension {589,418}.

Lane M: 100 bp ladder

■

A

Lanes 1 and 2: EWSRl-PATZl fusion transcripts detected with the same EWSR1 exon 8 primer and differing PAJ71 exon 1 primers

B

Histopathology EWSFI1-NFATC2 and FUS-NFATC2 sarcomas are compos， of small to medium-sized rou nd and/or spin died cells with lim­ ited eosinophilic or clear cytoplasm, predominantly arranged in cords, small nests, trabeculae, and pseudoacinar structures『 a fibrohyaline or myxohyaline stromal background. Less co( monly, matrix-poor sheets of cells are encountered focally diffusely {125,3359,3227}. Small round monotonous to markedly pleomorphic nuclei featuring smooth or irregular nuclear cot tours, dense hyperchromatic or vesicular chromatin, and smj or prominent nueleoli represent the morphological spectrui reported {125,3227,3359}. Tumour necrosis and mitotic acti' ity are variable. Tumour cells diffusely express CD99 in half of cases; PAX7 and NKX2-2 may be expressed {3082,543). Focal dot-like staining for keratin AE1/AE3 is possible, as is focal staining for CD138. Cases have been mainly misdiagnosed as myoepithelial tumour, plasmacytoma, and lymphoma |633. 2704,3359,2651,3191,1640,125}. The histopathological and immunophenotypic features described for EWSFI1-PATZ1 sarcomas are fairly diverse {2007. 3253,589,418}. Tumour cells are small, round, and/or spindled and are often accompanied by a fibrous stroma. Necrosis and mitotic activity may or may not be evident. Coexpression of myo­ genic markers (desmin, myogenin, MYOD1) and neurogemc markers (SIOOP, SOX10, MITF, GFAP) is seen at variable levels CD34 can be positive. CD99 is not consistently expressed.

Cytology EWSR1 exon 1

exon 7

exon 8

PATZ1

exon 1

exon 2

exon 5

Not clin ically re leva nt

fusionpoint ? SYGQ wnoctivationdoniaTn--... {fS06

Diagnostic molecular pathology 盯B/POZ

c

|

AT-hook domain

border of exon 8*

zinc finger domain

A in-frame deletion

Fig. 2.12 EWSR1-PATZ1 sarcoma. A Detection of the EWSR1-PATZ1 fusion by RT-PCR. B Direct sequencing demonstrates the nucleotide sequence and deduced amino acid sequence around the EWSFI1-PATZ1 fusion point. C Schematic represen­ tation of the EWSFI1 and PATZ1 genomic organization and fusion transcript.

328

Identification of the EWSR1-NFATC2, FUS-NFATC2, and EWSFI1-PATZ1 fusions can be attained via diverse molecular approaches {3013,3227,348,2007,589,2985,3230,418}. How­ ever, for the EWSR1-PATZ1 fusion, the sensitivity of an break-apart probe may be compromised by the short genomic distance between PATZ1 and EWSR1 on 22q12.2 and corresponding interpretive challenges in visualizing the subtle

Un d if fere ntiated small round cell sarcomas of bone and soft tissue

paybal：https://www.paypal.me/andy19801210 dissociation or breaking apart of signals in balanced alterations; additional studies would be required for identification of the PATZ1 partnership {418}.

Essential and desirable diagnostic criteria Essential: spin died to roun ded cytomorphology; mostly lowgrade features, but high-grade cases are reported; fibrohyaline stromal changes are common; EWSR1 break-apart FISH shows amplification of the 5' probe in EWSR1-NFATC2rearranged sarcomas; identification of the fusion transcript remains the gold standard. Desirable: most NFATC2-rearrartged tumours are located in long bone;刊 7Z7-rearra nged sarcomas: rou nd to spin died cells with diverge nt phe no type, both myoge nic and n eurogenic.

Staging Round cell sarcoma with EH/Sff7-non-ETS fusions is staged under the Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) TNM systems.

Prognosis and prediction The clin ical course may in elude local recurre nces an d/or metastatic disease. Disease control was achieved in 11 of the 14 EWSR1-NFATC2 patients managed with surgical resection with a media n follow-up of 45 mon ths. Lung, cuta neous, and bone metastases have been reported as long as 10.5 years after in itial diag nosis and clin ical indole nee; two patients died of disease, at 4 and 94 months {3227}. Little to no histologi­ cal response has been observed in patients treated with neoadjuvant chemotherapy {820}. Outcome data of FUS-NFATC2 sarcomas are limited, with one unfavourable outcome at 15 months reported in a congenital case that displayed high­ grade features, whereas other patients were free of disease after surgical management {348}. Evidenee of metastatic dis­ ease at the time of diag no sis, of developme nt of metastatic disease 5-24 months after diagnosis, and of patient death due to disease within 5-32 months of initial diagnosis underscores the aggressive behaviour characterizing a subset of EWSR1PATZ1 sarcomas for which follow-up data are available {2007, 589,418}. Responses to conventional systemic chemotherapies have been negligible to modest.

Undifferentiated small round cell sarcomas of bone and soft tissue

329

paybal：https://www.paypal.me/andy19801210 C/C-rearranged sarcoma

Definition

Antonescu CR Yoshida A

C/C-rearranged sarcoma is a high-grade round cell undifferentiated sarcoma defined by C/C-related gene fusions, most often CIC-DUX4.

retroperitoneum, or pelvis. About 10% of cases have a viscerpresentation, including kidney, gastrointestinal tract, and bra' {134,3370,2968}. Primary osseous involvement is rare (< 50) {134,1109}.

ICD-0 coding

Clinical features

9367/3 C/C-rearranged sarcoma

CIC sarcoma presents as a mass with or without pain. Somer the patients (16-50%) present with symptoms from their mete static disease {134,3370}.

ICD-11 coding None

Epidemiology Related termi no logy Acceptable: CIC-DUX4 sarcoma.

There is a wide age range at presentation, from children t elderly adults {134,3370}; however, there is a striking predilj

None

tion for young adults (median age: 25-35 years), and < 25%( cases present in the paediatric age group {134,3370}. There i slight male predominance.

Local izati on

Etiology

Most CIC sarcomas occur in the deep soft tissues of the limbs or trunk, and less comm only in the head and n eck,

Un know n

Subtype(s)

Fig.2.13 CIC-DUX4 sarcoma. A This sarcoma shows a lobular growth pattern divided by fibrous septa. B High power showing solid sheets of primitive round cells wit scattered larger cells and mild nuclear pleomorphism. C Solid sheets composed of relatively monomorphic epithelioid cells with moderate amount of light eosinophilic to clear cytoplasm. D Focal areas of short spindle cells arranged in a storiform pattern.

330

Undifferentiated small round cell sarcomas of bone and soft tissue

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Pig.2,14 CIC-DUX4 sarcoma. A Immunohistochemical studies show consistent strong nuclear staining for WT1. B Diffuse nuclear staining for ETV4.

Pathogenesis A CIC-DUX4 fusion is present in 95% of cases, resulting from either a t(4;19)(q35;q13) or a t(10;19)(q26;q13) translocation P5971492}； however, rare examples are associated with nonDUX4 partner genes, including F0X04, LEUTX, NUTM1, and NUTM2A {1788,2974,2975,1433}. CIC encodes a high-mobility group (HMG) box transcriptional repressor. Most CIC break­ points are located within CIC exon 20 {1578}. The DUX4 gene, encoding for a double homeobox transcription factor, is located within the D4Z4 macrosatellite repeat region of the chromo­ somes 4 and 10 subtelomeric regions (4q35 or 10q26.3). DUX4 is normally expressed in germ cells, but it is epigenetically silenced in somatic d iffere ntiated tissues. The predicted CICDUX4 chimeric protein retains the HMG box, with a large part of the N-terminal DUX4 being lost. In a subset of cases, the CICDUX4 fusion leads to a stop codon right after the breakpoint; thus, the resulting chimeric protein lacks any DUX4 sequenee, suggesting that a truncated CIC protein may be sufficient to trigger oncogenesis {1578,3368}. Trisomy 8 and MYC amplifi­ cation are some of the other common genetic changes {2896}. Concurrent CIC mutations have been described in the context of tumours with CIC-LEUTXfusion {1433}. The gene expression profile of CIC sarcoma is distinet from that of Ewing sarcoma 12917}. The CIC-DUX4 fusion markedly enhances the CIC tran­ scriptional activity, upregulating its targets, including CCND2, MUC5AC, and PEA3 family genes (e.g. ETV1, ETV4, and ETV5) 12917,1597,3377}.

Macroscopic appeara nee The tumours are gen erally large, well-circumscribed, white or tan, soft masses, with frequent haemorrhage and necrosis.

Histopathology Tumours are composed of diffuse sheets of undifferentiated round cells, displaying at least in part a lobulated growth pattem, delineated by fibrotic stroma. A minor component of spin"e or epithelioid cells may be seen in many cases. The tumour

Chromosome 19 CIC

Chromosomes 4 a nd 10 DUX4

Oncogenic function (activation)

Fig. 2.15 CIC-DUX4 sarcoma. Diagrammatic representation of CIC-DUX4 fusions, which result from either a t(4;19) or a t(10;19) translocation. The interrupted red line highlights the common breakpoints, which include most of the coding sequence of CIC and a small portion of the 3' end of DUX4. The resulting fusion protein drives the oncogenic activation of target genes, such as the PEA3 family of transcription factors (ETV1, ETV4).

cells have relatively uniform cytomorphology but often reveal a mild degree of nuclear pleomorphism, with vesicular chromatin and prominent nueleoli. The cytoplasm is lightly eosinophilic, with occasional clearing. Necrosis is common and mitotic activity is brisk. In one third of the cases, focal myxoid stromal changes are present, in which tumour cells exhibit reticular or pseudoacinar arrangements {1492,134,3370,2896}. Tumours with CiC_non-DUX4 fusion variants are associated with histo­ logical features similar to those of tumours with the canonical CIC-DUX4 {1788,2974,2975}. By immunohistochemistry, CIC sarcomas often express CD99, mostly in a patchy pattern and less commonly being diffuse and membra nous (20%) {134}. WT1 (90-95%) and ETV4 (95-100%) are frequently positive and represent useful ancillary markers {1439,1786,2917}. NKX2-2 is typically negative {3370}. Sarcomas with CIC-NUTM1 fusions express NUT protein {2968,1788}. Keratin, S100, and myogenic markers are rarely expressed. Calretinin and ERG can be posi­ tive {3370,2896,2917}.

Un differentiated small round cell sarcomas of bone and soft tissue

331

paybal：https://www.paypal.me/andy19801210 Cytology

Staging

Not clinically releva nt

C/C-rearranged sarcoma is presumably staged under Unio International Cancer Control (UICC) and American Joint c mittee on Cancer (AJCC) TNM principles.

Diagnostic molecular pathology CIC gene rearrangements can be detected by a variety of techniques {1492,1578}. However, none of these methods are highly sensitive {1578,3368}.

Essential and desirable diagnostic criteria Essential: predomina nt rou nd cell phe notype; mild nu clear pleomorphism; epithelioid and/or spindle cell components; variably myxoid stroma; immunoprofile shows variable CD99 staining, with frequent WT1 and ETV4 positivity. Desirable: CIC gene rearrangement (in selected cases).

332

J 1

Prognosis and prediction Most tumours follow a highly aggressive course with freQ metastases, most commonly to the lung. The estimated 5.「 overall survival rate is 17-43%, significantly worse than that Ewing sarcoma {134,3370}. The chemotherapy response Ewing sarcoma regime ns has bee n dismal {134}.

Undifferentiated small round cell sarcomas of bone and soft tissue

2

paybal：https://www.paypal.me/andy19801210 Sarcoma with BCOff genetic alterations

Antonescu CR Puls F Tirode F

Definition

Related terminology

Several groups of primitive round cell sarcomas show BCOR genetic alterations, resulting in oneogenic activation and BCOR overexpression. Although these pathological entities show distinct clinical presentations, there is overlap with regard to mor­ phology, immunoprofile, and gene expression, suggesting a shared pathogenesis. The first group is characterized by sarcomas with 8CO/?-related gene fusions, most frequently BCORCCNB3. The sec ond group shows in ternal tan dem duplicati on (BCOF-ITD), which has been described in infantile undifferentiated round cell sarcomas and primitive myxoid mesenchymal tumours of infancy.

Acceptable: BC0R-CCNB3 sarcoma; BCOfl-rearranged sar­ coma; infantile undifferentiated round cell sarcoma; primitive myxoid mesenchymal tumour of infancy.

ICD-O coding 9368/3 Sarcoma with BCOR genetic alterations

ICD-11 coding

Subtype(s) None

Localization BC0R-CCNB3 sarcoma occurs slightly more often in bone than in soft tissue (ratio: 1.5:1), with a predilection for pelvis, lower extremity, and paraspinal region {2510,2552}. Rare locations in elude the head and n eck region, lung, and kidney {1576,159, 2019}. Sarcomas with BCO/?-ITD and primitive myxoid mesenchymal tumour of infancy occur mainly in the soft tissues of the trunk, retroperitoneum, and head and neck, typically sparing extremities {1582}.

None

f'9-2.16 Sarcoma with BCOR-CCNB3 fusion. A A primitive round to spindle cell proliferation arranged in sheets and vague fascicles, involving the marrow spaces of a long bne. B Tumour of lower cellularity embedded in a loose fibromyxoid stroma and microcystic changes. C Solid sheets of undifferentiated round to ovoid cells with light eosino卩hilicto clear cytoplasm and round nuclei with fine chromatin and scattered mitotic figures. D Deceptively bland ovoid to short spindle cells arranged in a streaming pattern in fibrotic background with a rich vascular network.

Undifferentiated small round cell sarcomas of bone and soft tissue

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喊獵瀑糠號螂辭镰證 遨鹼 鮎蕊核 few

Fig. 2.17 Sarcoma with BCOR internal tandem duplication (BCOR-ITD). A Solid sheets of monomorphic round cells with scant eosinophilic cytoplasm and round nuclei Se rated by thin septa with delicate capillaries, from an infant patient. B Strong and diffuse nuclear staining for BCOR with immunohistochemistry. C Strong nuclear reactivitv SATB2.

chrX (p11.4)

I

昭

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~TTX^51

BCOR-CCNB3 BCOR-MAML3J

—— 十“”十一

r:~i......... r--2

知 24HV肚1

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13

|

14

|

15

(■ BCOR Exon

bcorTtd BCOR exon15 - CCNB3 exon5 CTGGGCTCCTCTGTAGAGTGGCTCCACCCCAGTGATCTGGCCICAGACAACTACTGGCATWGCTGGAAGTCACACCAGTAGTAGCCTCTACTACCGTGGTACCAAACAn BCOR exon15 - MAML3 exon2 CTGGGCTCCTCTGTAGAGTGGCTCCACCCCAGTGATCTGGCCICAGAGCTACAAGAGACTGTGAAAAGGAAGnGGAAGGAGCTCGATCACCA

BCOR exon15 ITD CTSGGCTCCTCTGTAGAGTGGCTCCACCCAGATCTGGTGGAAnCACGAACGAMnCAGACTCTGCTGGGCTCCTCTGTAGAGTGGCTCCACCC

Fig. 2.18 Sarcomas with BCOR genetic alterations. Diagrammatic representation of

BCOR genetic abnormalities, including the more common BCOR-CCNB3 intrachromosomal inversion, the rare BC0R-MAML2 interchromosomal fusion, and the BCOR internal tandem duplication (BCOR-ITD). All three of these genetic events involve the last exon (exon 15) of BCOR and result in consistent up regulation of BCOR mRNA and BCOR overexpression at the protein level.

The molecula r con sequences of the BCOR genetic abm malities remain largely unknown. BCOR is both an interac of BCL6 and a repressor of its expression {1455}. BCOR w later shown to be part of the non-canonical polycomb reps sive complex 1.1 (PRC1.1) {1125}. In high-grade neuroepithelial tumour with BCOR alteration, BCOR-ITD activates both sonic hedgehog and WNT/卩-catenin signalling pathways {2968(. Cyclin B3 (CCNB3) expression, which in normal tissues is restricted to testis, was also show n to be sufficie nt to in crease cellule proliferation in ectopic models {2510}.

Macroscopic appearance Tumours are typically large (> 5-10 cm), tan-grey, soft to flesh lesions, with areas of necrosis. Osseous lesions often show co tical destruction and extension into the soft tissues {636,2552；

Clinical features

Histopathology

Pain and swelling are the most comm on symptoms {636}.

BCOR family tumours show substantial morphological overlaf BCOR-CCNB3 sarcomas are typically composed of a uniform proliferation of primitive small round to ovoid cells arranged in solid sheets or a vague nesting pattern, surrounded by a rich capillary network {2019,1576,2552}. Other morphological patterns can occur, including less cellular areas of short spindle cells within a myxoid matrix {1576,2552} or solid areas of predominantly plump spindle cells arranged in short fascicles, remin isce nt of poorly d if fere ntiated syno vial sarcoma {1846,24991 The nuelei have finely dispersed chromatin and nucleoli are gen erally inc on spicuous. The mitotic activity is variable {1576, 636}. Metastatic/recurrent lesions occasionally display pleomor­ phic nuclei and osteoid deposition {1576,2552}. Rare tumours reported in the kidney show substantial overlap with clear cell sarcoma of the kidney {159,186}. The spectrum of tumours with BCOR-ITD abnormalities shows variable degrees of cellularity. ranging from solid sheets of small primitive cells to hypocellular areas of dispersed spindle cells, within a myxoid matrix and delicate vessels {60,2737,1582}. Immunohistochemically, a11 tumours with various BCOR gene alterations show strong and diffuse nuclear BCOR positivity and in most cases also express SATB2, TLE1, and cyclin D1. CD99 is positive in approximately 50% of cases {1576}. However, BCOR expression is not specific and, for example, is often observed in synovial sarcoma 卩579,

Epidemiology BCOR family tumours are uncommon, with a much lower inci­ dence than Ewing sarcoma {2552,1582}. BCOR-CCNB3 sar­ comas have a striking predilection for children, with > 90% of patients aged < 20 years {1576,2019}, and show a male sex predominance (M:F ratio: 4.5:1) {1909,3329,2552}. Soft tissue sarcomas with alter native BCOR gene rearra ngeme nts are seen in a wider age range {2918}. Sarcoma with BCOR-\TD and primitive myxoid mesenchymal tumour of infancy occur within the first year of life or may be present at birth {60,1582}.

Etiology Unknown

Pathogenesis Similar to clear cell sarcoma of kidney and high-grade endo­ metrial stromal sarcoma {3124,1982,1799}, infantile undifferenti­ ated round cell sarcomas are characterized either by BCORITD or in rare cases by YWHAE-NUTM2B fusions {1582}; both genotypes result in oneogenic upregulation of BCOR. BCOR family tumours share a similar gene expression signature, with strong overexpression of HOX family genes {2918,1576,3253}.

334

Undifferentiated small round cell sarcomas of bone and soft tissue

paybal：https://www.paypal.me/andy19801210 fi1gi BC0R-CCNB3 sarcomas also express cyclin B3, which

，s 訓 seen in other BCOR family tumours {2552,2019,2840}. cytology

Staging Sarcoma with BCOR genetic alterations is presumably staged under Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) TNM principles.

Not clinically relevant

Prognosis and prediction

Diagnostic molecular pathology 陆 BCOR gene rearrangements and BCOR-\7D can be

detected by various molecular approaches.

Essential and desirable diagnostic criteria Essential： primitive round to spindle cells arranged in nests, sheets, or fascicular growth; variably myxoid stroma with deli­ cate vasculature; immunohistochemical positivity for BCOR, SATB2, and cyclin D1. Desirable (in selected cases): molecular confirmation of BCOR genetic abnormality (BCOR fusion, BCOR-\1D\

Emerging data suggest that patients with BCOR-CCNB3 sar­ coma show 5-year survival rates similar to those of patients with Ewing sarcoma (72-80%) and show histological response to Ewing sarcoma-based treatme nt regime ns {636,1576,2552}. A substantial proportion of patients present with metastatic dis­ ease; the most comm on metastatic site is the lung, followed by bone, soft tissue, and visceral locations {636,1576,2552}. The outcomes of the other BCOR family tumours are not well defi ned.

Un differentiated small round cell sarcomas of bone and soft tissue

335

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Bone tumours Egted by: Bovee JVMG, Flanagan AM, Lazar AJ, Nielsen GP, Yoshida A

Chondrogenic tumours Osteogenic tumours Fibrogenic tumours Vascular tumours of bone Osteoclastic giant cell-rich tumours Notochordal tumours O^ier mesenchymal tumours of bone Haematopoietic neoplasms of bone

paybal：https://www.paypal.me/andy19801210 WHO classification of bone tumours Chondrogenic tumours

Osteoclastic giant cell-rich tumours

Benign 9213/0 9212/0 9221/0 9220/0 9210/0 9230/0 9241/0 9211/0

Benign 9260/0 8830/0

Subungual exostosis Bizarre parosteal osteochondromatous proliferation Periosteal chondroma Enchondroma Osteochondroma Chondroblastoma NOS Chondromyxoid fibroma Osteochondromyxoma

Intermediate (locally aggressive) 9220/1 Chondromatosis NOS 9222/1 Atypical cartilaginous tumour Malignant 9222/3* 9220/3 9220/3 9221/3 9242/3 9240/3 9243/3

Chondrosarcoma, grade 1 Chondrosarcoma, grade 2 Chondrosarcoma, grade 3 Periosteal chondrosarcoma Clear cell chondrosarcoma Mesenchymal chondrosarcoma Dedifferentiated chondrosarcoma

Intermediate (locally aggressive, rarely metastasizing) Giant cell tumour of bone NOS 9250/1 Malignant 9250/3 Giant cell tumour of bone, malignant

Notochordal tumours Benign 9370/0

Other mesenchymal tumours of bone Benign

8818/0

Benign 9180/0 9191/0

8850/0 8880/0

Intermediate (locally aggressive) *9200/1 Osteoblastoma NOS Malignant 9187/3 Low-grade central osteosarcoma 9180/3 Osteosarcoma NOS Conventional osteosarcoma Telangiectatic osteosarcoma Small cell osteosarcoma 9192/3 Parosteal osteosarcoma 9193/3 Periosteal osteosarcoma 9194/3 High-grade surface osteosarcoma 9184/3 Sec on dary osteosarcoma

Fibroge nic tumours Intermediate (locally aggressive) 8823/1 Desmoplastic fibroma Malignant 8810/3 Fibrosarcoma NOS

Vascular tumours of bone Benign 9120/0

Haemangioma NOS

Intermediate (locally aggressive) 9125/0 Epithelioid haemangioma Malignant 9133/3 Epithelioid haemangioendothelioma NOS 9120/3 Angiosarcoma

Benign notochordal tumour

Malignant 9370/3 Chordoma NOS Chondroid chordoma 9370/3 Poorly differentiated chordoma 9372/3 Dedifferentiated chordoma

Osteoge nic tumours Osteoma NOS Osteoid osteoma NOS

Aneurysmal bone cyst Non-ossifying fibroma

Chondromesenchymal hamartoma of chest wall Simple bone cyst Fibrous dysplasia Osteofibrous dysplasia Lipoma NOS Hibernoma

Intermediate (locally aggressive) *9261/1 Osteofibrous dysplasia-like adamantinoma 8990/1 Mesenchymoma NOS Malignant 9261/3 Adamantinoma of long bones Dedifferentiated adamantinoma 8890/3 Leiomyosarcoma NOS 8802/3 Pleomorphic sarcoma, undifferentiated Bone metastases

Haematopoietic neoplasms of bone 9731/3 9591/3 9650/3 9680/3 9690/3 9699/3 9702/3 9714/3 9727/3 9687/3 9751/1 9751/3 9749/3

Plasmacytoma of bone Malignant lymphoma, non-Hodgkin, NOS Hodgkin disease NOS Diffuse large B-cell lymphoma NOS Follicular lymphoma NOS Marginal zone B-cell lymphoma NOS T-cell lymphoma NOS Anaplastic large cell lymphoma NOS Malignant lymphoma, lymphoblastic, NOS Burkitt lymphoma NOS Langerhans cell histiocytosis NOS Langerhans cell histiocytosis, disseminated Erdheim-Chester disease Rosai-Dorfman disease

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) (1471). Behaviour is coded /0 for benign tumours. /1 for un specified, borderli ne, or uncertai n behaviour; /2 for carcinoma in situ and grade III in traepithelial n eoplasia; /3 for malig nant tumours, primary site; and /6 for malign ant tumours metastatic site. Behaviour code /6 is not gen erally used by can cer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions. * Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-0 at its meeting in January 2020.

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Bone tumours

paybal：https://www.paypal.me/andy19801210 TMN staging of tumours of bone Bone (ICD-O-3 C40,

41)

Rules for Classification The classification applies to all primary malignant bone tumours except malignant lymphoma, multiple myeloma, surface/ juxtacortical osteosarcoma, and juxtacortical chondrosarcoma. There should be histological con firmation of the disease and division of cases by histological type and grade. The following are the procedures for assessing T, N, and M categories: T categories N categories

M categories

Physical examination and imaging Physical examination and imaging Physical examination and imaging

Regional Lymph Nodes The regi on al lymph n odes are those appropriate to the site of the primary tumour. Regional node involvement is rare and cases in which no dal status is not assessed either clin ically or pathologically could be con sidered NO in stead of NX or pNX.

TNM Clinical Classification T-Primary Tumour TX TO

Primary tumour cannot be assessed No evidenee of primary tumour

Appendicular Skeleton, Trunk, Skull and Facial Bones T1 Tumour 8 cm or less in greatest dimension T2 Tumour more than 8 cm in greatest dimension T3 Disc on tinuous tumours in the primary bone site

Spine T1 Tumour con fined to a single vertebral segment or two adjacent vertebral segments T2 Tumour con fined to three adjacent vertebral segments T3 Tumour con fined to four adjace nt vertebral segme nts T4a Tumour invades into the spinal canal T4b Tumour invades the adjacent vessels or tumour thrombosis

Pelvis T1a A tumour 8 cm or less in size and con fined to a single pelvic segment with no extraosseous extension T1b A tumour greater than 8 cm in size and confined to a single pelvic segment with no extraosseous extension T2a A turn our 8 cm or less in size and confi ned to a single pelvic segment with extraosseous extension or confined to two adjacent pelvic segments without extraosseous extension T2b A tumour greater than 8 cm in size and confined to a single pelvic segment with extraosseous extension or confined to two adjacent pelvic segments without extraosseous extension T3a A tumour 8 cm or less in size and confined to two pelvic segments with extraosseous extension T3b A tumour greater than 8 cm in size and confined to two pelvic segments with extraosseous extension T4a Tumour involving three adjacent pelvic segments or crossing the sacroiliac joint to the sacral neuroforamen T4b Tumour encasing the external iliac vessels or gross tumour thrombus in major pelvic vessels Note The four pelvic segments are the: Sacrum lateral to the sacral foramen, Iliac wing, Acetabulum/periacetabulum and Pelvic rami, symphysis and ischium

N 一 Regional Lymph Nodes NX NO N1

Regional lymph nodes cannot be assessed No regional lymph node metastasis Regi on al lymph node metastasis

M 一 Distant Metastasis MO M1

No distant metastasis Distant metastasis M1a Lung M1b Other distant sites

within the adjacent vessels

pTNM Pathological Classification Note The five vertebral segments are the:

Right pedicle Right body Left body Left pedicle Posterior element

The pT and pN categories correspond to the T and N categories.

pM 一 Distant Metastasis * pM1

Distant metastasis microscopically con firmed

Note * pMO and pMX are not valid categories.

Stage - Appendicular Skeleton, Trunk, Skull and Facial Bones Stage Stage Stage Stage Stage Stage Stage

IA IB IIA IIB III IVA IVB

T1 T2.T3 T1 T2 T3 Any T Any T Any T

NO NO NO NO NO NO N1 Any N

MO MO MO MO MO M1a Any M M1b

G1,GX G1.GX G2,G3 G2.G3 G2.G3 Any G Any G Any G

Low Grade Low Grade High Grade High Grade High Grade

Stage 一 Spine and Pelvis There is no stage for bone sarcomas of the spine or pelvis.

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition {423,3126}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm-help-desk.

Bone tumours

339

paybal：https://www.paypal.me/andy19801210 Flanagan AM Blay JY Bovee JVMG Bredella MA

Bone tumours: Introduction

The ICD-0 topographical codi ng for the an atomical sites cov­ ered in this chapter is presented in Box 3.01.

Epidemiology and etiology Among the wide array of human neoplasms, primary tumours of bone are relatively common; however, clinically significant bone neoplasms are infrequent.

Incidence The true incidenee of benign bone tumours is unknown, although older radiographic studies have suggested that a substa ntial proporti on of the populati on has an in dole nt lesion. Non-ossifying fibroma is the most common bone tumour. Cartilagi nous lesi ons are relatively comm on incidental findi ngs on knee MRI and have an estimated prevale nee of 2.8% {2957}. As a result of the improved sen sitivity of radiological sea ns, the reported incidence of benign and low-grade cartilaginous tumours (atypical cartilaginous tumour / chondrosarcoma, grade 1 [ACT/CS1]) has increased overthe past decade {3167}. In contrast, bone sarcomas are rare and accounted for only 0.2% of all neoplasms in one large series {1423}. Comparison of the incidence of bone sarcomas to that of soft tissue sarcomas indicates that clinically significant osseous neoplasms occur at a rate approximately one tenth that of their soft tissue counter­ parts. The overall annual reported incidenee of bone sarcomas in both sexes in North America and Europe is about 0.75 cases per 100 000 population. Somewhat higher incidenee rates have been reported by local cancer registries in China (1.7-2.0) {401A}. The incidence rates of specific bone sarcomas are age-related. Osteosarcoma, which is the most common malignant primary bone turn our excludi ng malig nant myeloma, has a bimodal distribution. The first well-defined peak occurs during the second decade of life and the second peak occurs in peo­ ple aged > 60 years. This second peak is related to other risk factors such as radiati on treatme nt and Paget disease. Ewing sarcoma is less comm on than osteosarcoma, and most patie nts are < 30 years old. The incidence of chondrosarcoma and chor­ doma inc reases from adolesce nee on wards {2213}.

Cool P Nielsen GP Yoshida A

Box3.01 ICD-0 topographical coding for the anatomical sites covered in this ch {1077} C40 Bones, joints, and articular cartilage of limbs C40.0 Long bones of 叩per limb, scapula, and associated joints C40.1 Short bones of upper limb and associated joints C40.2 Long bones of lower limb and associated joints C40.3 Short bones of lower limb and associated joints C40.8 Overlapping lesion of bones, joints, and articular cartilage of limbs C40.9 Bone of limb NOS

C41 Bones, joints, and articular cartilage of other and unspecified sites C41.0 Bones of skull and face and associated joints C41.1 Mandible C41.2 Vertebral column C41.3 Rib, sternum, clavicle, and associated joints C41.4 Pelvic bones, sacrum, coccyx, and associated joints C41.8 Overlapping lesion of bones, joints, and articular cartilage C41.9 Bone NOS

Fig. 3.01

Age-specific incidence of primary bone sarcomas by major histopathologica

type, world data, both sexes, from Cancer Incidence in Five Continents, Volume XI {401 A；

Predisposing lesions Although most primary bone malignancies appear to arise de novo, it is increasingly apparent that some develop in associa­ tion with benign precursor lesions or in diseased bone. Paget disease of bone, radiation injury, bone infarction, chronic osteo­ myelitis, and certain pre-existing benign tumours are the most clearly established precancerous conditions {53,645,1162, 1272,1447,3284,226,1073,1108,2154,3090}. There are reported cases of bone sarcoma arising in association with implanted metallic hardware, but a causal association has not been proven {1155,1281,1604,2486,1458}.

340

Bone tumours

Genetic predisposition Constitutional genetic variants affecting the risk for bone tumour development range from mutations with high penetrance, caus­ ing disorders that typically follow traditional Mendelian patterns of inheritance, to SNPs that only mildly influence the functior of the proteins encoded by the genes involved. SNPs are by definition present in > 1% of the population, and their collec­ tive in flue nee may accou nt for a substa ntial proportion o bone tumours {268}. Individual genetic variants with high Pen' etrance for bone tumour development are rare (see Table 4.02. p. 503), but they are important to identify because they may affect response to treatment or predict an increased risk °f

paybal：https://www.paypal.me/andy19801210 .e3 0l Most-common locations of presentation for primary malignant bone tumours and overall risk of a pathological fracture at time of diagnosis, based on data from 3000 »mary malignant bone tumours seen at the Royal Orthopaedic Hospital in Birmingham, United Kingdom

Diagnosis

Osteosarcoma

Knee3

Hip and pelvisb

Shoulder girdle0

Lower leg

Upper limb

Trunk"

Risk of pathological fracture

66%

15%

10%

5%

3%

1%

9%

7%

12%

3%

6%

Chondrosarcoma

17%

48%

15%

4%

9%

Ewing sarcoma

22%

44%

11%

13%

7%

41%

29%

9%

5%

14%

2%

16%

43%

31%

11%

7%

5%

3%

10%

UPS All diagnoses

•

UPS, undifferentiated pleomorphic sarcoma. *nee includes distal femur, proximal tibia, and proximal fibula. bHip and pelvis include pelvis and proximal femur. cShoulder girdle includes proximal humerus, scapula, and clavicle. H'runk includes spine, ribs, etc.

developing other tumours. Such information can be used to provide genetic counselling or screening of at-risk individuals (3394}. important examples include mutations in TP53 (see LiFraumem syndrome, p. 510) and RB1 {793,1925}, both of which predispose to osteosarcoma. Non-inherited, postzygotic mutations result in mosaicism and can in crease the risk of tumour development in the affected parts of the body, as exemplified by IDH1 and IDH2 mutations causing enchondromatosis (see Enchondromatosis, p. 506) and GNAS mutations in polyostotic fibrous dysplasia, McCune-Albright syndrome, and Mazabraud syndrome (see McCune-Albright syndrome, p. 514).

Clinical features Bone tumours present in a n umber of differe nt ways, in elud­ ing with pain, swelling, pathological fracture, and neurovascular compromise, or as an incidental fin ding. The most common presenting symptom of a benign bone tumour is aching pain that can be intermittent. However, a previously asymptomatic individual may present with a pathological fracture (e.g. fracture through a simple bone cyst). Osteoid osteomas typically present with night pain that is relieved by anti-inflammatory agents. Less frequently, osteoid osteomas are in a periarticular location and present clinically as a monoarthritis. Osteochondromas typi­ cally prese nt as a pain less lump, whereas chon droblastomas comm only prese nt with severe pain. Clinical signs are ofte n nonspecific. Swelling and tenderness over the affected bone are the most common findings. Periarticular lesions (e.g. chon­ droblastoma and juxta-articular osteoid osteoma) can irritate the joint, with resulting joint effusion and stiffness. Malignant tumours typically present with worsening pain that is non-mechanical in nature {3287}. At the time of diag­ nosis, many patients experience night pain that interrupts sleep. Swelling usually becomes apparent once the cortex is breached and the tumour starts to grow beneath the perios­ teum or extend through it. Most malignant bone tumours arise 'n a metaphyseal location. However, Ewing sarcoma and ada­ mantinoma are usually diaphyseal. The presenee of swelling in a limb (in particular around the knee) associated with pain bparticular non-mechanical or night pain) should always lead t0 further investigation. There is a wide differential diagnosis 伽 patients presenting in this manner, with the most comm on diagnoses being metastases, malignant bone tumour, benign bone tumour, infection, and haematological disorder. A simple algorithm based on the most likely diagnosis for a patient of a

particular age has been advocated {1223}. This is based on the fact that metastatic carcinoma is uncommon in individuals aged < 35 years, whereas the likelihood of a bone tumour being a metastasis from a known or undiagnosed carcinoma increases after that age {1954}. As many as 43% of malignant bone tumours arise around the knee, but in patients aged < 20 years this rises to 56% (see Table 3.01). Therefore, for any child or adolesce nt presenting with pain and/or swelling around the knee that does not resolve, a diagnosis of a primary bone tumour should be considered and inv estigated. The sec ond most comm on site is the pelvis, which is the most comm on site for both Ewing sarcoma and chondrosarcoma. Delays in diagnosis of pelvic tumours are freque nt, because symptoms are non specific and ofte n of con­ siderable du rati on {3319}. Referred pain to the leg or knee is not infrequent and it is not unusual for patients to have been investigated before diagnosis without the possibility of a bone tumour being considered. Night pain, again, is often the key that should alert the clinician to the possibility of a bone tumour being present. Pathological fractures in malignant bone tumours are often associated with pre-existing pain or discomfort in the limb. The fracture is often caused by minimal force. Awareness of the possibility of a neoplastic cause for the fracture is essential to prevent in advertent internal fixation that jeopardizes clinical outcome {16}. Usually the imaging manifestations combined with the history are sufficient to raise suspicion for an underlying malignant primary bone tumour. Blood tests are usually not helpful in diagnosing bone tumours. An elevated alkaline phosphatase level is seen in about 46% of patients with osteo­ sarcoma and is a poor prognostic sign {196}. Raised LDH, ESR, and C-reactive protein may be seen in Ewing sarcoma, also being poor prog no stic in dicators (194).

Biopsy specimens Obtaining a diagnosis for a symptomatic patient as quickly as possible is essential, but delays in diagnosis are frequent {2893}. All patients with suspected bone tumours should be discussed at a multidisciplinary team meeting that includes the radiologist and pathologist invo Ived in the diag no sis, as well as the orthopaedic surge on and on cologist invo Ived in the patie nt's treatment {504,1221}. Local staging investigations should be completed before a biopsy. A biopsy can alter the imaging features, making interpretation and diagnosis more difficult. A Bone tumours

341

paybal：https://www.paypal.me/andy19801210 reliable histological diagnosis often cannot be made without prior correlation with radiographic imaging {749). The biopsy of a suspected tumour should be performed at a referenee centre for bone sarcomas. Planning of the surgical approach to the biopsy site, tract, and diagnosis should involve the orthopaedic surge on who will perform the surgery {504}. There is evide nee that treatment in centres with a high volume of bone tumours and the presenee of an experieneed multidisciplinary team positively affects outcome {111,340}. The pathologist must be informed of the patient's age and the exact anatomical site and size of the tumour. This in formation should be correlated with the imagi ng. Additi on ally, it is importa nt to know about the presence of other lesions, possible underlying bone disease, and family history to provide an informed diagnostic opinion.

Tissue processing All tissue, whether from a biopsy, curettage, or resection of a suspected bone turn our should be processed in a manner that allows molecular studies to be undertaken successfully. Decal­ cification can be detrimental to nucleic acid; therefore, freezing samples and/or fixing non-calcified portions of the tumour in buffered formalin alone before paraffin embedding is encour­ aged, to facilitate modern technologies (e.g. next-generation sequencing) that facilitate diag no sis. As r ecomme nded by the European Society for Medical Oncology (ESMO) guidelines, an alter native is to decalcify material in ethyle nediami netetraacetic acid (EDTA) instead of harsher acidic reagents {504}.

Use of clinical imaging Diagnosis Radiographs (of the whole bone in two planes) are the initial imagi ng exami nation in the work-up of bone tumours and are usually the most specific for establishing a diagnosis {667}. CT can be helpful in complex anatomical regions, such as the spine and pelvis, showing matrix mineralization, periosteal reaction, and cortical destruction. CT is usually used for percu­ taneous biopsy guidanee {2000}. MRI is the imaging modality of choice for local staging, treatment evaluation, and detection of recurrences. Marrow replacement typically demonstrates T1-hypointense signal (lower than surrounding muscle or disc) and hyperintense signal on fluid-sensitive sequences with avid enhancement after intravenous contrast administration {1295}. Intravenous contrast is also useful for distinguishing cystic from solid areas within tumour tissue and peritumoural oedema from viable tumour {2474}. Whole-body MRI can be used to screen the entire body for metastases or multifocal bone tumours {724, 2000}. Bone scintigraphy using methylene diphosphonate (MDP) labelled with a technetium radioisotope is used for staging and for evaluation of skip lesions, metastases, or tumour recurrence {655}. FDG PET in combination with CT (PET-CT) or MRI (PET-MRI) is primarily used for staging and has been found to be more accurate than bone scintigraphy in detecting skeletal metastases {402,537}. Important parameters in imaging evaluation of bone tumours include tumour location, matrix, margins, and periosteal reaction. Certain tumours occur in a characteristic location in the skeleton. Adamantinoma and osteofibrous dysplasia have a strong predilection for the anterior cortex of the tibia. In long bones, epiphyseal lesions include chondroblastoma, giant cell tumour, and clear cell chondrosarcoma. Several tumours have a

342

Bone tumours

predilection for sites of rapid growth and involve the metaph regions, often around the knee joints, such as osteosarc： chondrosarcoma, osteochondroma, and enchondroma § tumours have a predilection for the bone surface or cortex " as osteoid osteoma, fibrous cortical defect, osteochondro . periosteal chondroma, and parosteal and periosteal」°steosai comas {2148,2276}. Bone tumours usually produce an intern­ matrix that can be classified as bone, cartilagi no us, or fibg : The term "mineralization" refers to calcification of the mat' {2276,2148}. Margins and periosteal reaction of a bonetum ' reflect the growth rate and biological behaviour of the tumj Slow-growing tumours have circumscribed margins with ana row zone of transition and solid or thick periosteal reactio Aggressive and rapidly growing tumours have indistinet ma gins with a wide zone of transition and aggressive periosta reaction, such as onion-skin, spiculated, sun burst, or hair-o； end periosteal reaction, or a Codman triangle. Radiographs ai most useful in evaluating margins and periosteal reaction {18& 2148,2276}.

Posttreatment imaging Radiographs can be used to assess tumour recurrenee and posttreatment complications, such as fracture, prosthetic loos * ening, or non-union. MRI provides an accurate evaluation of treatment response and tumour recurrence, and facilitates differentiation of tumour recurrenee from posttreatment changes. PET-CT can be used to determine treatment response, to iden­ tify both local recurrence and metastatic disease, and to pro­ vide information on prog nosis {1118,666}.

Terminology used to reflect biological potential Bone tumours are now divided into four categories: benign, intermediate (locally aggressive), intermediate (rarely metastasizing), and malignant, which were defined in the third and fourth editions of the WHO Classification of Tumours series. The division between these categories can be somewhat arbitrary and the subject of debate, especially in regard to tumours that belong to a histological and biological spectrum of disease (e g conventional central and peripheral cartilaginous tumours). The intent of the classification is to specify which lesions would be best managed by regular surveillanee without surgical removal, which need local treatment such as curettage, and which require wide en bloc resection. The division into these categories is maintained and further defined or revised for certain tumours in the current edition. The four categories are defined along the same lines as the soft tissue tumour counterparts. Benign: Most benign bone tumours have a limited capacity for local recurrenee. Those that do recur do so in a non-destructive fas hi on and are almost always readily cured by complete local excision/curettage. In the current classification, chondroblas­ toma is no Ion ger in the intermediate (rarely metastasizing) cate­ gory. The reported rate of metastases is < 1% and con sequent chondroblastoma is better classified as benign. Likewise, chondromyxoid fibroma and aneurysmal bone cyst are now clas­ sified as benign (previously locally aggressive). Hibernoma o bone, which has been recently well characterized {362}, isa

new addition to this category.

Intermediate (locally aggressive): Bone tumours in this ca egory often recur locally and may be associated with an infi鸟 tive and locally destructive growth pattern. They do not appe

paybal：https://www.paypal.me/andy19801210 Bone sarcomas in which grade is determined by histotype

Sarcoma type Low-grade central osteosarcoma

Gradel (low-grade)

Parosteal osteosarcoma Clear cell chondrosarcoma

Grade 2 (intermediate-grade)

Periosteal osteosarcoma

Osteosarcoma (conventional, telangiectatic, small cell, secondary, high-grade surface)

Undifferentiated high-grade pleomorphic sarcoma Ewing sarcoma Dedifferentiated chondrosarcoma

Grade 3 (high-grade)

Mesenchymal chondrosarcoma Dedifferentiated chordoma

Poorly differentiated chordoma

Angiosarcoma Conventional chondrosarcoma (grade 1-3 according to Evans et al. {947})

Variable grading

Leiomyosarcoma of bone (grade 1-3, no established grading system) Low- and high-grade malignancy may occur in giant cell tumour of bone

t0 have the potential to metastasize but typically require wide excision with a margin of normal tissue or application of a local adjuvant to ensure local control. In the 2013 WHO classifica­ tion, the term "chondrosarcoma, grade 1" was replaced with the term "atypical cartilaginous tumour" - in the intermediate (locally aggressive) category 一 in order to reflect the clinical behaviour of well-differentiated/low-grade lesions. The argu­ ment is made that such lesions, especially in the long bones, oehave in a locally aggressive manner and do not metastasize; therefore they should not be classified as having full maligna nt ootential. In this edition, we propose to define the use of the terminology "atypical cartilaginous tumour" and "chondrosarcoma, grade 1". Analogous to the concept of atypical lipoma­ tous tumour (extremities) / well-differentiated liposarcoma (retroDeritoneum), cartilaginous tumours in the appendicular skeleton (long and short tubular bones) should be termed atypical car­ tilaginous tumours, and the term "chondrosarcoma, grade 1" is reserved for tumours of the axial skeleton, including the pelvis, scapula, and skull base (flat bones) - reflecting the poorer clinical outcome of these tumours at these sites {452,3167}. Using OMere nttemni no logy for tumours with ide ntical histomorphology could be con sidered cou nterin tuitive and therefore con trove rsiaL However, this terminology has the dual ben efit of being simple in application and reflecting the worse outcome for "mours at these sites, where there is a need for more-extensive surgery {452}. Synovial chondromatosis has now been placed 1 惦 intermediate (locally aggressive) category (previously enign) on the basis of the locally aggressive behaviour of this 『our, which has a high incidence of local recurrence {92}. peofibrous dysplasia-like adamantinoma is also now classi5 as an intermediate (locally aggressive) lesion, although it acknowledged that exceptional cases may transform into a fic form of adamantinoma. Unlike osteofibrous dysplasia­ fl adamantinoma, classic adamantinoma is unequivocally a ■L ?nant disease. Fibrocartilaginous mesenchymoma, which jpq., een newly added to this current classification, represents er example of a tumour in this disease category. Although 'originally described in 1984 {713}, there has been debate

as to its relati on ship with other tumours. Non etheless, it has a characteristic morphology, and recent evidenee (albeit from a small series) suggests that it lacks GNAS mutations, IDH1 and /D/-/2 mutations, and /WD/W2amplification {1113}, supporting the notion that it is a distinct entity. Of note, tumours may behave differently depending on their localization; for example, epithelioid haemangioma of bone is considered to be locally aggressive, whereas epithelioid haemangioma of soft tissue is considered a benign tumour. Intermediate (rarely metastasizing): Bone tumours categorized as intermediate are often locally aggressive (see above). How­ ever, there is well-documented evidenee of such lesions occasionally giving rise to distant metastases. Such metastases occur in < 2% of cases and are not predictable morphologically. These lesions usually metastasize to the lung. The prototypical example in this category is giant cell tumour of bone. Malignant: In addition to the potential for locally destructive growth and recurrenee, bone sarcomas have a substantial risk of distant metastasis, ranging in most instances from 20% to almost 100%, depending on histological type and, if applica­ ble, histological grade. Some (but not all) histologically lowgrade sarcomas have a metastatic risk of only 2-10%, but such lesions may advanee in grade with local recurrenee and thereby acquire a higher risk of distant spread. Examples in which progression to high-grade sarcoma can be seen include parosteal osteosarcoma and low-grade central osteosarcoma. It is impor­ tant to note that in this new biological grouping, the intermediate categories do not correspond to intermediate histological grade (grade 2) in a bone sarcoma (see below). Poorly differentiated chordoma is included as a new entity in this book; it is charac­ terized by immunoreactivity for brachyury (encoded by TBXT) and loss of SMARCB1 (INI1) expression representing a genetic eve nt. Making this specific diag nosis is warranted in view of this tumour's aggressive behaviour and poor outcome. New infor­ mation is now known about malignancy in giant cell tumours of bone. A small percentage (probably no more than 5%) of giant cell tumours of bone transform into a high-grade neoplasm, the morphology of which may be unrecognizable as being derived

Bone tumours

343

paybal：https://www.paypal.me/andy19801210 from a giant cell tumour of bone. The H3.3 p.Gly34 mutation, which is present in approximately 96% of the conventional subtype, may also be present in the frankly histologically malignant tumour. Therefore, this mutation is not helpfuI in making a diagnosis of malignancy. Complicating matters further, it has rece ntly bee n dem on strated that abse nee of immu no reactivity for the mutant histone protein may be seen in some cases of malignant transformation {3376}. In such cases, a diagnosis can only be provided when the conventional component of a giant cell tumour is also available. The underlying genetic changes that account for the transformation have not been described.

Prineiples of grading and staging Grading Bone tumours vary widely in their biological behaviour. His­ tological grading is an attempt to predict the behaviour of a malignant tumour based on histological features. There is no gen erally accepted gradi ng system for bone sarcomas, and the French Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system used in soft tissue sarcomas has never been validated for bone tumours {642,2265}. In bone sarcomas, the histological subtype often determines clinical behaviour and therefore also the grade (see Table 3.02, p. 343). For example, Ewing sarcoma, mesenchymal chondrosarcoma, and dedifferentiated chondrosarcoma are always considered high-grade, whereas clear cell chondrosarcoma and parosteal osteosarcoma are considered low-grade. The exception to this includes conventional chondrosarcoma and leiomyosarcoma of bone; in the former, the gradi ng system as proposed by Eva ns et al. {947} is widely used. Adamantinoma and conventional chordoma are malignant neoplasms but are not graded. The clinical sign ifica nee of histological gradi ng is limited by in terob­ server variability {883,2886}. Guidelines for reporting and grading of bone tumours are available from both US and European perspectives {504,2680,1969}.

Staging Enneking and coauthors {910,909} described a staging system for musculoskeletal tumours that has been adopted by the Mus­ culoskeletal Tumor Society (MSTS). It is mainly the staging for malignant tumours that has gained acceptanee by orthopaedic

:umours

Table3.03 Enneking staging for malignant bone tumours {910,909}

Stage

Grade

Site

IA

Low

Intracompartmental

IB

Low

Extracompartmental

IIA

High

Intracompartmental

IlB

High

Extracompartmental

III

Any

Any

Metastases

Regional or distant

surgeons because it helps to determine the surgical treatment The system has not been changed since its introduction in iggg (see Table 3.03). The Enneking stage is determined by tumour grade, extent beyond the surgical compartment, and the pres ence of metastases. However, there are some drawbacks to the Enn eking stagi ng system .In reality, most tumours are stage IlB limiting the system's usefulness. Furthermore, the size of the prj, mary tumour is an important prog nostic factor. However, tumour size is not part of the Enneking staging system. In addition there is no special consideration for tumours involving the spine or pelvis {1517,2938}. The TNM staging system, as described by the American Joini Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC), is based on evolving prognostic evi­ dence and is now in its eighth edition {101,423}. An 8 cm cut-oi1 point distinguishes between T1 and T2 tumours. Skip lesions are defined as T3. Most bone tumours primarily metastasize to lung and are classed as M1a (stage IVA). Metastases to bone or other sites (M1b) have a worse prog nosis (stage IVB). Metas­ tases to regi onal lymph n odes, which are un comm on, are also stage IVB. Bone tumours of the axial skeleton have a worse prognosis than those of the appendicular skeleton. Conse­ quently, the eighth edition of the TNM system in eludes a special T classification for spine and pelvic tumours. In the spine, the classification is based on five segments (see TNM staging of tumours of bone, p. 339). However, in the pelvis the T classi­ ficati on is determined by tumour size (cut-off point: 8 cm) and tumour extent into four defined segments. There is no defined stage for malignant bone tumours of the spine or pelvis.

paybal：https://www.paypal.me/andy19801210 bungual exostosis

Yoshida A Bloem JL Mertens F

npfjnition 缶ungual exostosis is a benign 當nof the distal phalangeal bone

osteocartilaginous surface underlying the nail bed.

iCD-0 coding 9213/0 Subungual exostosis

iCD-11 coding 壬13丫 &

XH1XL9 Other specified nail disorder & Subungual

exostosis 2E83 5 & XH1XL9 Osseous and chondromatous neoplasm, benign & Subungual exostosis

Related terminology Not recommended: Dupuytren exostosis. Subtype(s) None

Localization

Fig. 3.02 Subungual exostosis. A mature osseous mass, with a soft tissue mass sur­

Mearly 80% of cases affect the dorsal or medial surface of the distal phalanx of the big toe. The remaining cases involve distal ohalangeal bones of other toes or fingers.

rounding it, is attached on the cortex of the distal phalanx.

Clinical features Signs and symptoms Many patients present with painful swelling in the nail bed that lifts and deforms the nail plate. Ulceration and infection may occur. The preoperative period ranges from months to years.

Imaging On radiographs, a small bony protuberanee is attached to the dorsum or side of the phalangeal bone surface. There is no continuity between the lesion and the medullary cavity of native bone. The small fibrocartilaginous cap appears hyperintense on T2-weighted images {2214}.

Epidemiology Subungual exostosis often occurs in young patients, with > 50% aged < 18 years (average: 25.7 years). There is no sex predilec­ tion (702). Etiology

Preceding trauma and infection are reported in 29% and 14% of fases, respectively {702}, although their causal relationship to •he tumour is unknown. The clonal cytogenetic findings suggest a true neoplastic process.

Pathogenesis Wogenetically analysed cases of subungual exostosis cons’tently feature a t(X;6)(q24-q26;q15-q25), often as the sole C ange (717,3384,2960}. The breakpoints are located in the

Fig. 3.03 Subungual exostosis. Low-power view showing fibrocartilaginous cap and osseous stalk involving the nail bed.

Bone tumours

345

paybal：https://www.paypal.me/andy19801210 .4

U2

A

B

二

Fig. 3.04 Subungual exostosis. A Cartilage can be hypercellular and atypical. Note the fibrous nature of the cartilaginous matrix. B Cartilage can blend with spindle cell liferation.

Histopathology

COL12A1 gene on chromosome 6 and near the IRS4 gene, encoding an insulin receptor substrate, on the X chromo­ some. The translocation does not result in any fusion transcript; in stead, it leads to increased expressi on of IRS4 at the mRNA and protein levels {2097}. This translocation has not been found in bizarre parosteal osteochondromatous proliferation (BPOP), supporting the existenee of subungual exostosis as a distinet disease entity.

Subungual exostosis is composed of fibrocartilaginous tissue; the lesional periphery and bone trabeculae in the stalk. Cartilag can look atypical with hypercellularity and nuclear enlargemen and it can blend with spindle cell proliferation in the nail be( Mitoses can be seen. The cartilaginous cap can be tenuou or even absent. Bone forms through enchondral ossification c directly from spindle cells, and intertrabecular tissue is hype vascular and fibrous. Early lesi ons may lack attach me nt to thi subjacent bone {2149}. Subungual exostosis should be distin guished from osteochondroma, which is rare in the small bone of the hands and feet. Un like in osteoch on droma, a fibrillar

Macroscopic appearance The lesi on con si sts of small bony and cartilagi nous fragme nts.

)1 1

2

r-K 6

1

3

(C 8

9

12

Fig.3.05 Cytogenetic findings of subungual exostosis. Karyogram showing the characteristic t(X;6) that juxt即oses COL12A1 with IRS4. Arrows indicate breakpoints.

346

Bone tumours

paybal：https://www.paypal.me/andy19801210 jnous matrix with marked proliferative activity and an F I r bone-cartilage interface, as well as enlarged, bizarre, l?h'nucleatecl chondrocytes may be seen in subungual exosBj1 巳 continuity with the underlying medulla is lacking. Sub■ exostosis is also different from BPOP because it affects F. tal phalanx by definition, whereas BPOP has a wider ana輒;al distribution, often involving more-proximal bones. BPOP R; racterized by at least focal presenee of distinet blue bone, 陰 js gen erally absent in subungual exostosis.

cytology

Not clinically relevant

Essential and desirable diagnostic criteria Essential: a small osteocartilaginous lesion on the distal phalangeal bone; no continuity between the lesion and the medul­ lary cavity of native bone.

Staging Not clinically relevant

Prognosis and prediction Subungual exostosis is benign and is adequately treated with simple excision. Local rapid recurrence has been reported {2149}. Rare r ecurrences can be man aged by re-excisi on.

Diagnostic molecular pathology Not

clinically relevant

Bone tumours

347

paybal：https://www.paypal.me/andy19801210 Bizarre parosteal osteochondromatous proliferation

Defin ition Bizarre parosteal osteochondromatous proliferation (BPOP) is a benign surface lesion of bone, composed of an admixture of spindle cells, cartilage, and bone.

Yoshida A McCarthy EF

Clinical features Signs and symptoms BPOP typically prese nts as a pain less mass, which is presi for a few months to several years. Some examples grow v idly.

ICD-0 coding 9212/0 Bizarre parosteal osteochondromatous proliferation

ICD-11 coding 2E82.Z & XH23J5 Benign chondrogenic tumours, site unspeci­ fied & Bizarre parosteal osteocho ndromatous prolife ration

Imaging Radiologically, BPOP is a well-circumscribed calcified ma， plastered onto the cortical surface. The underlying cortex in tact, with no conti nuity betwee n the lesi on and the medulla cavity of affected bone. Exceptional cases are reported to di play medullary continuity {2695,2710}.

Related terminology Not recommended: Nora lesion.

Epidemiology

Subtype(s)

BPOP has a wide age range, with a peak in the third to foui decades of life. There is no sex predilection.

None

Etiology Localization BPOP typically affects small bones in the hands and feet, most comm only phala nges of the hand. Long tubular bones are also affected in as many as 27% of cases {2074}. BPOP has been rarely reported on the craniofacial bones.

BPOP is viewed by some as part of a spectrum encompassing florid reactive periostitis and turret exostosis {815}, and by oth­ ers as a neoplasm. A minority of the patients report preceding trauma.

B Fig. 3.06 Bizarre parosteal osteochondromatous proliferation. A On the dorsal surface of the middle phalanx, mature bone is seen closest to a normal underlying cortex. the periphery, more fluffy calcifications are present. A lucent demarcation line projects between cortex and the bizarre parosteal osteochondromatous proliferation. B On the

radial side of the proximal phalanx, a soft tissue swelling with some calcifications and mature bone is seen superficial and contiguous to an intact cortex. There are no signs。

osteochondroma. C CT shows a calcified mass attached to the intact cortex of the ulna.

:umours

paybal：https://www.paypal.me/andy19801210

」e 匸 e

Q. e

o

-q7 Bizarre parosteal osteochondromatous proliferation. A Gross specimen showing a bony stalk with cartilaginous surface. B Bizarre parosteal osteochondromatous 務Cation with a more disorganized mixture of mainly bone and cartilage. Pathogenesis

Histopathology

Recurrent cytogenetic abnormalities of BPOP include t(1;17) fa32;q21), inv(7), and inv(6) {2300,431}. These are different from the translocations associated with subungual exostosis {2097}, supporting the notion that BPOP is a distinet entity.

BPOP is composed of a variable mixture of cartilage, bone, and fibrous tissue. The outermost part of the lesion can be covered by hyaline cartilage. Myxoid and fibrocartilaginous tissue may also be seen. The cartilage has an increased num­ ber of chondrocytes with enlarged nuelei and binueleation, and it therefore often looks atypical (bizarre). Marked hyperchromasia or atypical mitoses are not seen. The cartilage transitions to trabeculae of bone via enchondral ossification,

Macroscopic appearance BPOP is an exophytic bony lesion with a cartilaginous surface. Most tumours measure 1-3 cm.

d *5 • 、 A

I

B

二":

Fig, t 3.08 Bizarre parosteal osteochondromatous proliferation. A Low-power view showing bony stalk covered by cartilaginous cap. B Cartilage often looks atypical with an ased number of chondrocytes with enlarged nuclei. C Spindle cell proliferation with osteoid formation. 0 So-called blue bone is characteristic.

Bone tumours

349

paybal：https://www.paypal.me/andy19801210 with an irregular in terface. Betwee n the cartilage and bone, characteristic stroma can be seen, with a basophilic tinctorial quality (so-called blue bone), even after decalcification {2074, 622). The intertrabecular space is filled with hypervascular tis­ sue without a marrow comp orient and is populated by a non­ atypical spindle cell pro life rati on.

Cytology Not clin ically re leva nt

Diagnostic molecular pathology Not clinically re leva nt

Essential and desirable diagnostic criteria Differential diagnosis The differential diagnosis includes subungual exostosis, which exclusively affects the distal phalangeal bone and lacks blue bone. Osteochondroma shows medullary continuity, cortical flari ng, and fatty in tertrabecular spaces, gen erally without cartilaginous atypia. Parosteal osteosarcoma is large and harbours intertrabecular fascicles of mildly atypical spindle cells, which are often positive for MDM2 amplification. Periosteal osteosar­ coma shows characteristic radiological findings, with prominent periosteal reaction and more atypical tumour cartilage and bone. Fibro-osseous pseudotumour of digits, which may har­ bour a USP6 rearrangement {1036}, shows a fasciitis-like background and disorganized bone {2187}.

350

Bone tumours

Essential: an exophytic bony growth with in tact cortex，a dj organized cellular lesion comprising spindle cells, atyw j chondrocytes, and bone; the presenee of blue bone is ch初 acteristic.

Staging Not clinically re leva nt

Prognosis and prediction BPOP is treated with simple excision. Recurrences occur in』 many as half of the cases, sometimes multiple times, but theJ are non-destructive and man aged by re-excisi on. BPOP has no capacity to metastasize.

paybal：https://www.paypal.me/andy19801210 periosteal chondroma

disoicai :har-

Bridge JA Cl eve n AHG Tirabosco R

pefinition Periosteal chondroma is a benign cartilaginous neoplasm that arises on the bone surface beneath the periosteum.

ICD-O coding 9221/0 Periosteal chondroma

ICD-11 coding in as they is no

2E82 & XH3BC3 Benign chondrogenic tumours & Periosteal chondroma

Related terminology Not recommended: juxtacortical chondroma.

Subtype(s) None

Localizatio n Periosteal chondroma occurs most commonly in the small bones of the hands and the long bones of the appendicular skeleton {236,421,1834}. The proximal humerus is the most fre­ quent locati on.

Clinical features Signs and symptoms Periosteal chondroma presents as a small palpable swelling, causing pain or local discomfort, especially if arising close to a joint. It is a sporadic tumour and usually solitary.

Imaging Radiographically, it appears as a well-demarcated metaphyseal and juxtacortical radiolucent neoplasm, with a variable degree of internal mineralization, ranging from punctate to diffuse. The underlying cortex is scalloped and sclerotic, and the lateral bor­ ders of the tumour are typically buttressed {236,421,1834}.

Epidemiology

Fig. 3.09 Periosteal chondroma. A This radiograph depicts a mineralized tumour (arrow) with underlying cortical sclerosis. B CT of a periosteal chondroma of the pos­ terior femur illustrates characteristic radiographic findings. The tumour is well demar­ cated, partially mineralized, and contained by a discontinuous thin layer of periosteal bone. The underlying cortex is thickened and sclerotic and there is peripheral buttress­ ing around the base of the tumour.

Periosteal chondromas most frequently affect children and young adults, with an M:F ratio of 1.5:1. They are much less common than enchondromas {236,421,1834}.

Etiology Unknow n

Pathogenesis A subset of periosteal chondromas, similar to enchondromas, are caused by mutations in one of the IDH genes. These muta­ tions were shown to promote chondrogenic differentiation in favour of osteogenic differentiation in preclinical models {1528, 2979}. Chromosomal aberrations described in periosteal chon­ droma in elude loss of chromosome 6 material rearra ngements 0f2q37, 4q21-q24, 11q13-q15, and 12q13-q15 {2421,710}.

Fig-3.10 Periosteal chondroma. Well-marginated surface cartilaginous tumour. Note the hyaline, lobulated appearance and the cortical buttressing (arrow), but no invasion.

Bone tumours

351

paybal：https://www.paypal.me/andy19801210

Fig. 3.11 Periosteal chondroma. A Low-power micrograph illustrating the classic features of periosteal chondroma. The tumour is situated beneath the periosteum (small ar rows) and erodes the underlying sclerotic cortex. Thick periosteal buttressing is present at the periphery (large arrow). B Classic features of periosteal chondroNoteihj cortical buttressing. C The tumour is arranged in hyaline lobules composed of bland chondrocytes. Note the thick periosteal layer on top, covering the tumour.

Macroscopic appearance

Cytology

The typical periosteal chon drama is a small lobulated tumour, < 5 cm in size, with a hyaline appears nee, sited on the bone sur­ face and covered by periosteum. The tumou r in duces a crisp cortical osteosclerosis with for mation of the characteristic bone buttressing at the lateral edges of the tumour.

Not clin ically re leva nt

Histopathology Periosteal chondromas are well demarcated from the underlying sclerotic cortex, which may be focally eroded but never per­ meated. The tumour has a lobulated arrangement and is cov­ ered by ac ontin uous I aye r of atten uated periosteum. In vasi on of surrounding soft tissue or medullary canal is not a feature seen in periosteal chondromas. The cellularity is variable but gener­ ally low, and the chondrocytes do not show cytological atypia. Occasi on ally, however, in comparis on with enchon dromas, per­ iosteal chondromas are more cellular and may exhibit a greater degree of nuelear pleomorphism, including cell spindling and binueleation. Focal myxoid change of the matrix, which is typi­ cally hyaline, may also occur.

Diagnostic molecular pathology Periosteal chondroma frequently harbours heterozygous mutations in IDH1, with p.Arg132Cys appearing to represent the most comm on amino acid alterati on {93,726,2421}. IDH mutation testing will not distinguish this entity from periosteal chon­ drosarcoma {93}.

Essential and desirable diagnostic criteria Essential: well-marginated, lobulated cartilaginous tumour arising on the bone surface, with elevation of periosteum; erosion but no invasion of the underlying cortex; low to moderate cel­ lularity, with relatively uniform chondrocytes. Desirable: size usually < 5 cm.

Staging Not clin ically releva nt

Prognosis and prediction Differential diagnosis Size > 5 cm favours the diagnosis of periosteal chondrosarcoma {1453}. The presence of invasion into the haversian sys­ tem allows a definitive diagnosis of periosteal chondrosarcoma.

352

Bone tumours

Periosteal chondromas are treated by curettage or simple excision. Recurrenee is rare regardless of surgery type {236,1834(

paybal：https://www.paypal.me/andy19801210 n cho ndroma

Bovee JVMG Bloem JL Flanagan AM Nielsen GP Yoshida A

pefinition Enchondroma is a benign hyaline cartilaginous neoplasm that arises within the medullary cavity of bone.

ICD-O coding 9220/0 Enchondroma

ICD-11 coding 2E83.Y & XH9SY5 Other specified benign osteogenic tumours & Enchondroma

Related terminology Not recommended: chondroma,

Subtype(s) None

Localization Enchondramas most commonly affect the short tubular bones of the hands {2509}. The long tubular bones are less frequently affected, and location in flat bones is very un comm on (< 1%).

Clinical features Signs and symptoms Most enchondromas are solitary; occasionally they are multi­ focal affecting one or multiple bones, a syndrome referred to as enchondromatosis. The size of the enchondroma is usu­ ally < 3 cm. Typically an enchondroma does not cause pain. Enchondromas in the short tubular bones of the hands and feet may cause palpable swellings, pain, and pathological fracture, whereas long bone lesions are more often asymptomatic.

Fig. 3.12 Enchondroma. A Note the popcorn-like calcifications. B Symptomatic enchondromas in small tubular bones frequently present with pathological frac­ tures. Note cortical attenuation (white arrow) and fracture (black arrow) in this expansile enchondroma, extending proximally.

Imaging Enchondromas are located in the medullary cavity, typically in the metadiaphysis {2530}. The ring and arcs matrix mineralization, seen on radiographs and CT, is typical for cartilaginous tumours but may be absent, especially in young patients and in tumours involving small bones of the hands and feet. In mature enchondroma, these may coalesce into solid areas of calcification. 1 he lobulated, non-sclerotic margin is well depicted on MRI but not on radiographs. Superficial scalloping (seen on CT and MRI) of the cortex, cortical thinning, and bone expansion (especially in phala nges) are freque ntly prese nt. Un less the tumour is completely calcified, additional MRI features are septonodular enhancement of the fibrovascular septations that enhance on late gadolinium chelate-enhanced images, small mucoid areas (high signal on T2), and fat {1128}. Over the years, enchondromas may change in size {598}. Radiological differentiation between enchondroma, atypical cartilaginous tumour, and high-grade chondrosarcoma is described in the section Central atypical cartilaginous tumour / chondrosarcoma, grade 1 (p. 370).

Fig・3・13 Enchondroma. CT of a femoral enchondroma illustrates the dense, solid calcifications.

Bone tumours

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Fig. 3.14 Enchondroma. Enchondroma showing encasement: the separate nodules are surrounded by bone, which is a sign of slow growth.

Epidemiology En chon dromas are relatively comm on, acc ounting for 10-25% of all surgically removed benign bone tumours. The exact inci­ dence is unknown because many are discovered incidentally on radiographic images taken for other reasons. The prevalence of enchondroma as an incidental finding on knee MRI is approxi­ mately 2%; 84% measure < 2 cm {2957}. Enchondromas that come to clinical attention are usually found in the third to fourth decades of life (range: 1-86 years; median: 36 years) {2509}. On average, patie nts with an ench on droma are younge r th a n those with a chondrosarcoma. The sexes are equally affected.

Etiology Enchondromas may be caused by heterozygous somatic muta­ tions in the isocitrate dehydrogenase genes IDH1 and IDH2. Mutations are found in 52% of sporadic enchondromas and in about 90% of enchondromas in patients with enchondromatosis (see Enchondromatosis, p. 506), indicating that these represent an early driver eve nt for enchon droma formation {93,2430,96}. Patients with enchondromatosis are somatic mosaic for IDH1 or IDH2.

Pathoge nesis Isocitrate dehydrogenases are enzymes involved in the conver­ sion of isocitrate to a-ketoglutarate in the tricarboxylic acid cycle, producing energy for the cell. The gain-of-function mutations give the mutant enzyme the activity to convert a-ketoglutarate into the oneometabolite D-2-HG. Indeed, increased levels of D-2-HG can be detected in cartilage tumours with an IDH1 or IDH2 mutation {96}. This causes epigenetic changes (i.e. altered histone methylation and hypermethylation) {2430,1242}. In deed, D-2-HG has bee n show n to promote chon droge nic and in hibit osteogenic d if fere ntiatio n of mese nc hymal stem cells, the presumed precursor cells of enchondroma {2979,1528}.

Macroscopic appearance If treated, the specimen is usually received in fragments (curet­ tage). These tissue fragments contain bluish-white glistening cartilage tissue admixed with medullary bone. Gritty, yellow foci are seen as a result of calcification, and red areas represent ossification or surrounding bone marrow. Resection specimens are un comm on and dem on strate a well-margi nated, ofte n 354

Bone tumours

Fig. 3.15 Enchondroma. A Enchondromas commonly have a multinodular architec­ tural pattern characterized by islands of cartilage encased by thin mantles of bone that are often separated by marrow. This pattern is more common in larger tumours. Enchondromas in small tubular bones tend to have a more confluent architec­ ture. B Some enchondromas become heavily calcified, as shown by densely stippled and solid areas of deeply basophilic staining. The chondrocytes are often necrotic in these areas, reduced to eosinophilic bodies within lacunae. C The chondrocytes are typically situated within sharp-edged lacunar spaces. The cytoplasm is frequently retracted to form vacuoles and spider-like eosinophilic extensions. Nuclei are small­ round, and hyperchromatic, although larger, vesicular nuclei can also be present. Mi­ totic figures are usually non-existent and binucleation is uncommon. Finely stippled

calcifications within the hyaline matrix are common.

multi no dular, whitish-blue glistening tumour in the medullary cavity of the bone, with intact cortex. In the short tubular bones, the lesions are less multinodular and have a more confluent

growth pattern.

paybal：https://www.paypal.me/andy19801210 Histopathology Histologically，enchondromas are hypocellular, with an abundance of hyaline cartilage matrix. The tumour cells are embedded within sharp-edged lacunar spaces and evenly dispersed. When the cytoplasm is visible, it is usually eosinophilic. The uciei are typically small and round, with condensed chromatin /lymphocyte-like). Cytological atypia and mitoses are absent. Le architecture can be multinodular or con flue nt. In cases with muitinodular growth, the lobules can be separated by delicate fibrous septa with small-calibre vessels. The separate nodules can be surrounded by bone, which is referred to as encasement and is a sign of slow growth {2155}. Normal bone marrow can be pres ent betwee n the no dules. Enchon dromas do not invade and destroy the cortex, entrap pre-existing lamellar bone, or extend into soft tissue. Degenerative features, such as ischaemic necrosis or calcification, can be prominent. ,n the small phalangeal bones, as well as in patients with enchondromatosis, enchondromas can be much more cellular; in such cases, the tumou r cells occasi on ally have more-ope n chromatin and small nucleoli. Binucleated cells can be seen. The matrix composition can be more myxoid, and then cells become more elongated or stellate in shape. Cortical destruc­ tion, soft tissue extension {387,768}, and entrapment of host lamellar bone (see Central atypical cartilaginous tumour/chon­ drosarcoma, grade 1, p. 370) are not allowed even under these circumstances, and often a diagnosis cannot be established without proper radiological correlation.

Immunohistochemistry Immunohistochemistry is usually not helpful in the diagnosis. The tumour cells are positive for S100. Approximately 24% are positive for the p.Arg132His mutation-specific IDH1 antibody, limiting its usefulness because this represents only a small percentage of the IDH mutations that can be found in cartilage tumours {93,2430,96}.

Differential diagnosis The distinotion between enchondroma and central atypical cartilaginous tumour / chondrosarcoma, grade 1 (ACT/CS1) can be difficult {1130,2155} and is subject to in terobserver variability, even among experts {883,2886}. A combination of

five parameters (high cellularity, host bone entrapment, open chromatin, mucoid matrix degeneration > 20%, and patient age > 45 years) is helpful in differentiating between enchondromas and central ACT/CS1s {883}, with mucomyxoid matrix degeneration and host bone entrapment being most discriminating. In the phalanges, enchondromas are more cellular and can have worrisome histological features that do not predict the clinical behaviour. The main discriminating factors in distinguishing enchondroma from chondrosarcoma in the phalanges are the presenee of mitoses, cortical breakthrough, soft tissue invoIvement {387}, and host lamellar bone entrapment.

Cytology Not clin ically releva nt

Diagnostic molecular pathology Molecular pathology is rarely used for diagnosis. Hotspot mutations are exclusively found at the IDH1 p.Arg132 and the IDH2 p.Arg172 positions. These mutations are specific for enchon­ dromas, periosteal chondromas, and conventional and peri­ osteal chondrosarcomas, and they are absent in other mesenchymal tumours of bone. Mutation analysis cannot be used to distinguish enchondroma from ACT/CS1.

Essential and desirable diagnostic criteria Essential: abundanee of cartilaginous matrix; absenee of cyto­ logical atypia, mitoses, cortical invasion, and soft tissue extension; tumours arising in small bones and/or in patients with enchondromatosis may show more cellularity and atypia.

Staging Not clin ically re leva nt

Prognosis and prediction Asymptomatic enchondromas can be followed clinically and do not need to be treated. In case of symptoms, curettage is usually curative. Longstanding enchondromas identified radiologically have been shown to progress. However, malignanttransformation of enchondromas is thought to be rare (< 1%) in a non-syndromic setting. Pain without the presenee of a fracture and radiological changes should raise the possibility of progression.

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paybal：https://www.paypal.me/andy19801210 Bovee JVMG Bloem JL Heymann D Wuyts W

Osteochondroma

Definition Osteochondroma is a benign cartilaginous neoplasm consisting of a bony projection covered by a cartilage cap, arising at the external surface of bone and containing a marrow cavity that is continuous with that of the underlying bone.

ICD-0 coding 9210/0 Osteochondroma

ICD-11 coding 2E83.Y & XH5Y87 Other specified benign osteogenic tumours & Osteochondroma

Clinical features Signs and symptoms Many osteochondromas, whether solitary or multiple, are asymptomatic and found incidentally. Osteochondromas develop and increase in size during the first decade of life and they stop growing around puberty, when the growth plates close. Symptoms are often related to the size and location of the lesion. The most comm on prese ntation is that of a hard, long, standing mass. Complications in elude bursa formation; arthrm； and impi ngeme nt on adjace nt tend ons, n erves, vessels, or spinal cord {3285}. Increasing pain and/or a growing mass in ar, adult patient may be a manifestation of progress!on towards a peripheral chondrosarcoma.

Related terminology Not recommended: (osteo)cartilaginous exostosis.

Subtype(s) None

Imaging

.

Osteochondromas are typically located at the transition of diaphysis to metaphysis of the bone. The radiological hallmark of osteochondroma, best seen on CT and MRI, is the continuity of bone marrow into a pedunculated (slim base) or sessile (broad

Localizati on Osteochondromas arise in bones that are formed by endochondral ossification during skeletal development, explaining their localization. The most common sites include the metaphyseal regions of the distal femur, proximal tibia, proximal humerus, and less frequently flat bon es. The cranio facial bones are gen­ erally not affected, except for the mandibular condyle.

Fig. 3.16 Osteochondroma. Axial CT of an osteochondroma demonstrating continuity of both the stalk and centre of the lesion with the tibial cortex and medullary cavity, respectively.

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Bone tumours

Fig. 3.17 Osteochondroma. A Macroscopic view showing the external cartiag®

cap. B Cut section revealing the continuity of the cortex and marrow cavity with underlying bone.

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3,18 Osteochondroma. A From left to right, the three layers can be recognized: perichondrium, cartilaginous cap, and bony stalk, with enchondral ossification at the inter(ace between cartilage and bone. Note the resemblance to the growth plate with organization of hypertrophic chondrocytes in columns. B Low-power view of osteochondroma.

base) outgrowth combined with flaring of cortical bone into the margins of the outgrowth. Osteochondromas point away from the adjace nt joint. Smooth calcificati ons can be see n. MRI may dis­ play the cause of symptoms based on mechanical compromise of neighbouring tendons, muscles, bones, vessels (including pseudoaneurysm), and nerves. A bursa can develop and must be differentiated from the cartilaginous cap. Bone deformity may be caused by the lesion itself, or by metaphyseal undertubulation. Fat, haematopoietic marrow, and cartilaginous nests may be seen on MRI in the base of the stalk. Septations in the lobulated lesion may enhance on MRI and/or may show mineralization on CT and MRI. The size of the cartilaginous cap is measured per­ pendicular to the tidemark (the bon e-cartilage in terface) and can be well established with T2-weighted MRI. The cap should be < 2 cm and display high homoge neous sign al inte nsity {1131, 279}. A bulky benign cartilaginous cap may be present in the paediatric age group, but it should decrease in size with ageing. Only in you ng childre n, active en cho ndral ossificati on may cause inhomogeneity in the cap. A cartilage cap > 2 cm in the skeletally mature is suggestive of progressive disease {2220,279}.

Epidemiology Osteochondroma is one of the most common benign bone tumours. The average age at diagnosis of solitary osteochondroma is 18 years (median: 15 years; range: 2-77 years), with a male predominance (65% vs 35%) {2509}. The reported incidenee, 35% of benign and 8% of all bone tumours, may be an underestimate because many osteochondromas are asymptomatic. Approximately 15% of osteochondroma patients have multiple lesions characteristic of the autosomal dominant hereditary multiple osteochondromas syndrome (see Multiple osteochondromas, p. 517).

Pathogenesis The finding of biallelic inactivation of the EXT1 or EXT2 gene within the cartilage cap supports the neoplastic nature of these tumours. The cell of origin is considered to be either a chondrocyte within the growth plate {1545} or a mesenchymal progenitor cell from the perichondrium {1436}. Most of the mutations found in the EXT1 or EXT2gene are predicted to result in a truncated or non-functional protein {1522}. The EXT gene products, EXT1 and EXT2, are glycosyltransferases invoIved in heparan sulfate biosynthesis. The cartilage cap of osteochondroma is composed of a mixture of wildtype (normal heparan sulfate) and mutated (heparan sulfate-deficient) cells {2012,1545,750}. Heparan sulfate proteoglycans serve as key modulators of endochondral ossification by forming an osmotic gradient around chondrocytes and by controlling signal transduction {1268}. Loss of heparan sulfate may give a proliferative advantage to the mutated chondroprogenitor cells and leads to loss of polar­ ity {612,752}. Because defective heparan sulfate mainly affects multiple sign ailing pathways, including those involving hedge­ hog {1692}, BMP {2408}, FGFR3 {2514}, and WNT/p-catenin {2514}, disturbed signalling causes EXT-mutated cells to grow out of the bone and recruit normal cells to form an osteochondroma.

Macroscopic appearance Osteochondroma may be cauliflower-like, sessile, or pedunculated {959}. Within the underlying stalk, a cortex and medul­ lary cavity can be recognized. The size of the overlying glassy bluish-white cartilaginous cap is important and should be well documented. It should be measured perpendicular to the bone-cartilage interface, at its thickest portion. The cartilage cap is usually thin (and thickness decreases with age). A thick and irregular cap (> 2 cm) may be indicative of progression.

Etiology Osteochondromas are caused by biallelic inactivation of the EXT1 or EXT2 gene. In patients with multiple osteochondromas, heterozygous germline alterations are found in the EXT1 or EXT2 gene (see Multiple osteochondromas, p. 517), combined with somatic loss of the remaining wildtype allele within the car"age cap of the osteochondromas {381,1545,278,2593,3411}. b solitary sporadic osteochondromas, homozygous deletions of EXT1 can be found in about 80% of tumours {1285,3411}. Osteochondromas have been reported to occur after total body irradiation in childhood {1639}.

Histopathology The lesion has three layers: perichondrium, cartilage, and bone. The outer layer is a fibrous perichondrium that is continuous with the periosteum of the underlying bone. Below this is a cartilage cap that mimics disorganized growth plate cartilage, with endochondral ossification: the superficial chondrocytes are clus­ tered, whereas the ones close to the transition to bone become larger, similar to the hypertrophic cells of the growth plate. With age, the cellularity is progressively reduced, sometimes with extensive coarse and irregular calcification. Binucleated cells,

Bone tumours

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calcification, focal necrosis, nodularity, and degenerative cystic/mucoid changes can be seen and do not indicate malig­ nancy {749}. Nuclear atypia and mitoses are absent.

Differential diagnosis The disti nction betwee n osteoch on droma and sec on dary peripheral atypical cartilaginous tumour / chondrosarcoma, grade 1 (ACT/CS1) is histologically difficult and should be made in a multidisciplinary team taking the radiology, especially the size of the cartilage cap, and the patient's age into account. Loss of architecture, n odularity, wide fibrous ban ds, myxoid change, binucleated cells, and in creased chon drocyte cellularity should be considered with caution. Fractures within a stalk may elicit a focal fibroblastic response. Periosteal chon­ drosarcoma differs from osteochondroma by the absenee of a stalk. Subungual exostosis can be very cellular but has a

0

0

characteristic fibrillary cartilaginous matrix, which is not see in osteochondroma. Dysplasia epiphysealis hemimelica (Trevi disease), a non-hereditary skeletal dysplasia, demonstratf cartilaginous overgrowth at the epiphysis, strongly resemblir an osteochondroma, although there is clumping of chondn cytes within a more fibrillary chon droid matrix {382}.

Immunohistochemistry Immunohistochemistry is not of help in the diagnosis of ostei chondroma.

Cytology Not clinically relevant

Diagnostic molecular pathology Molecular testing is not required for the diagnosis of osteochon droma. Chromosomal aberrations involve 8q22-q24.1, where the EXT1 gene is located {416,2099,979}, or 11p11.2, where the EXT2 gene is located {1521}. Mutations in IDH1 or IDH2aie absent in osteochondromas {93,2430}.

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f

Essential and desirable diagnostic criteria

o

Essential: cartilaginous cap, with growth plate-like architecture (in children) or extensive calcification (with increasing age), underlying stalk, with medullary and cortical bone that is continuous with that of the underlying bone; the size of the cartilaginous cap should be well documented and should be < 2 cm in the skeletally mature.

Staging Not clinically re leva nt

Prognosis and prediction

Fig. 3.20 Osteochondroma formation. A second hit in EXT in a proliferating cell of the growth plate near the bony collar underlies osteochondroma formation in patients with multiple osteochondromas. The cells lose polarity and grow out of the bone through a defective bony collar. In the cartilaginous cap, EXT-/- cells are intermingled with EXT+/- cells (mosaicism). In solitary osteochondromas, two somatic hits are required in a single chondrocyte.

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Bone tumours

Excision of the osteochondroma is usually curative, although recurrenee is seen after incomplete removal. Multiple recur­ rences or recurrenee of a well-excised lesion should raise suspicion for progression. The risk of progression to second­ ary peripheral chondrosarcoma is estimated at about 1% 瀏 solitary and as high as 5% for multiple osteochondromas {3285, 1823,2767}. In very rare instances, osteosarcomas, spindle cell sarcomas, and dedifferentiated chondrosarcomas can develop in osteochondroma {1741,385,2930}.

paybal：https://www.paypal.me/andy19801210 Amary F Bloem JL Cl eve n AHG Konishi E

Chondroblastoma

pefinition Chondroblastoma is a benign tumour of bone that has a predilection for epiphyseal or apophyseal regions, composed of chondroblastic cells and islands of eosinophilic chondroid

matrix.

ICD-O coding 9230/0 Chondroblastoma NOS

ICD-11 coding 2E82.Z & XH4NK2 Benign chondrogenic tumours, site unspeci­ fied & Chondroblastoma NOS

Related terminology None

Subtype(s) None

Localization

Fig.3.21 Chondroblastoma. A Lateral radiograph showing a lytic lesion in the distal femoral epiphysis (arrows). B Sagittal short-tau inversion recovery (STIR) MRI show­ ing a well-defined lesion of increased signal in the epiphysis, with similar, oedema-like, high signal in the adjacent marrow and soft tissues.

Approximately 75% of chondroblastomas involve the epiphy­ seal (subchondral) region of long bones, with the femur being the most commonly affected site, followed by the proximal tibia and proximal humerus {1718,343}. Other sites include the talus, calcaneus, patella, and pelvic bones (especially the acetabu­ lum). Less frequently, the ribs, vertebrae, and small bones of the hands and feet are affected. InvoIvement of craniofacial bones is excepti on al. I n adult patie nts aged > 30 years, short tubular bones and flat bones, rather than long bones, are more com­ monly affected {714,1718}.

Clinical features Signs and symptoms The clinical presentation varies with the site of disease. The most common symptom is pain. Local tenderness, joint effusion, impaired movement, and muscle atrophy may be found as presenting symptoms.

Imaging Radiographically, a well-defined, often sclerotically marginated bcent lesion is present, showing geographical bone destruc•i°n. Chondroblastoma is typically located adjacent to a growth "ate, usually in the epiphysis or in the epiphysis and meOphysis, and rarely in the metaphysis or apophysis only {2039, 343,714}. The lesions are usually < 5 cm {1718}. Mineralization, babeculation, cortical erosion, and expansion are frequently Present； expansion is more common in flat and small bones B43}. MRI characteristically exhibits reactive changes outside the tumour, which are r eflected by synovitis a nd periosteal reaction also distant from the tumour, as well as in creased signal 联ensity in bone and surrounding soft tissues on fluid-sensitive and gadolinium chelate-enhanced images {343,714,1718}. The

Fig.3.22 Chondroblastoma. Axial CT of patella showing an eccentric well-defined lytic lesion (arrow).

tumour itself is in homogeneous and has areas of low signal intensity on fluid-sensitive sequences due to mineralization and trabeculation, which are also well seen on CT {2562}. Aneurysmal bone cyst-like changes can be seen as fluid-fluid levels on MRI in areas of marked expansion {1630,1519}.

Epidemiology Chondroblastomas account for < 1% of all bone tumours. Most occur in patients with an immature skeleton in the second to Bone tumours

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B

Fig.3.23 Chondroblastoma. A Sheets of chondroblastic oval to polygonal cells, osteoclast-like giant cells, and an area of matrix calcification. B Oval to polygonal chondi blasts with well-defined cytoplasmic borders, merging with an area of eosinophilic cartilaginous matrix. C Chondroblastic cells with nuclear indentation and grooves. The top-ngr' corner shows chicken-wire pericellular calcification. D H3.3 p.Lys36Met (K36M) diffuse nuclear expression in the chondroblastic cells. Note that the osteoclast-like giant cells show no expression.

early third decades of life (10-25 years of age), although it may prese nt at any age {343,114,1718}. It is twice as prevale nt in males {3119,343,1718}.

matrix may be prominent. Blood-filled spaces may be seen in some cases with aneurysmal bone cyst change {714,2759).

Histopathology

Etiology Unknown

Pathogenesis H3.3 alterations are seen in various tumour types in eluding bone tumours like chondroblastoma and giant cell tumour of bone. Specific substitutions are associated with different tumour types: p.Lys36Met with chondroblastoma and p.Gly34Trp with giant cell tumours of bone, suggesting that specific substitutions provide a growth advantage to specific cell types {257, 237}. p.Lys36Met substitutions in chondroblastoma are more frequent in the H3-3B (H3F3B) gene on chromosome 17 {257, 2538}. The p.Lys36Met mutations inhibit the H3K36 methyltrans­ ferases NSD2 (MMSET) and SETD2, which results in reduced global H3K36 methylation {971,3352}. These epigenetic path­ way alterations probably block mesenchymal differentiation and in flue nee tumorigenesis in chon droblastoma {1897,1742,3225}.

Histologically, chondroblastomas are composed of sheets of ovoid to polygonal cells with small singular grooved nuelei ano eosinophilic cytoplasm {3146,714}. The cytoplasmic border is usually distinet. Epithelioid cells may be present. There are inter­ spersed osteoclast-like giant cells and islands of eosinophilic chon droid matrix. Basophilic hyali ne cartilage is infrequent Pericellular lace-like or chicken-wire calcification is characteris­ tic and usually noted among degenerative cells. Nuclear atypia and/or mitotic figures may be found. Aneurysmal bone cyst-like cha nge is comm on.

Immunohistochemistry

JJ

Immunohistochemistry using an antibody against H3.3B (H3F3B) p.Lys36Met (K36M) shows diffuse nuclear expressior in > 96% of the cases and is helpful in small biopsies or cases with exte nsive aneur ysmal bone cyst-1 ike cha nge |95,615|. SOX9, S100, cytokeratin, and DOG1, although not specific, may be focally positive {1681,2174,2814,614}.

Macroscopic appearance

Differential diagnosis

Macroscopically, chondroblastomas are usually well-defined eccentric lesions with a thin sclerotic rim. The features vary from soft to rubbery with gritty and haemorrhagic areas. Chon droid

The differential diagnosis includes primary aneurysmal bone cyst, giant cell tumour of bone, clear cell chondrosarcoma, chondromyxoid fibroma, Langerhans cell histiocytosis, and an

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paybal：https://www.paypal.me/andy19801210 extremely rare subtype of osteosarcoma: chondroblastoma-like osteosarcoma {192}.

cytology

Desirable: a fine network of pericellular chicken-wire calcification; presence of H3.3 mutatio n dem on strated by p.Lys36Met (K36M) expression or H3-3A (H3F3A) / H3-3B (H3F3B) mutation analysis.

Not Clinically relevant

Staging

Diagnostic molecular pathology The vast majority of chondroblastomas harbour a p.Lys36Met substitution in one of the genes that encode H3.3: H3-3B (H3F3B) (> 95%) on chromosome 17 or, less frequently, H3-3A (H3F3A) on chromosome 1 {257,95,615}. Among bone tumours, this is highly specific for chondroblastoma, although one case of clear cell chondrosarcoma was reported to harbour an H3-3B (H3F3B) p.Lys36Met mutation {257}. IDH1 and IDH2 substitu­ tions are not seen in chondroblastomas {726,93,615}.

Essential and desirable diagnostic criteria Essential: epiphyseal/apophyseal location; sheets of chondroblastic cells, island of eosinophilic chondroid matrix and osteoclast-like giant cells.

Not clin ically releva nt

Prognosis and prediction Chondroblastomas are benign tumours that in > 80% of the cases are successfully treated with surgical curettage with or without adjuvant treatment of the surgical bed {878,2994}. Radiofrequency ablation may be used {2696}. The recurrenee rates vary with site of disease, being lower in long bones and higher in flat bones and cranio facial bones, rangi ng from 10% to 18% {878,2994,295,3119}. There are no reliable histological parameters predicting local recurrenee {3119,801,1682}. In exceptional cases, so-called benign lung metastasis may develop {2406}.

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paybal：https://www.paypal.me/andy19801210 Chondromyxoid fibroma

Hogendoom PCW Bloem JL Bridge JA

Defin ition Chondromyxoid fibroma is a benign lobulated cartilaginous n eoplasm with a zonal architecture composed of chon droid, myxoid, and myofibroblastic areas.

ICD-0 coding 9241/0 Chondromyxoid fibroma

ICD-11 coding 2E82.Z & XH89S0 Benign chondrogenic tumours, site unspeci­ fied & Chondromyxoid fibroma

Related terminology None

Subtype(s) None

Localization Chondromyxoid fibroma can occur at almost any osseous site. It is most frequent in the long bones, most often the proximal tibia and distal femur. Approximately 25% of cases occur in the flat bones, mainly the ilium. When involving bones of the feet, chondromyxoid fibroma often involves metatarsals. Other sites of invo Iveme nt in elude the ribs, vertebrae, skull and facial bones, and tubular bones of the hand.

Clinical features Signs and symptoms Pain, which is the most common symptom, is usually mild and sometimes present for several years {3313}. Swelling is infre­ que nt, most commonly observed in the bones of the hands and feet.

Imaging Radiographically, chondromyxoid fibroma in a long bone is typically a well-demarcated, oval-shaped, lobulated osteolytic, eccentric, and metaphyseally located lesion, with attenuation and expansion of the cortex. Lesions of the rib or ilium may be discovered as in cidental r adiological fi ndings {3313}. Less fre­ que ntly, the tumour is juxtacortical (207}. The Iongitudinal axis of the lesion corresponds to that of the involved bone, and the average size is 3 cm (range: 1-10 cm). In the small bones, fusi­ form expansion of the entire bone is typical. Approximately 10% of cases may show focal calcified matrix, more often detectable with CT. There may be cortical destruction, but this is contained by the periosteum {2653,3313}. On MRI, chondromyxoid fibroma has an in termediate to high signal in tensity on fluid-se nsitive sequences, with a strong homogeneous or peripheral contrast enhancement {477}. Reactive high signal intensity changes may be present on fluid-sensitive sequences.

Fig. 3.24 Chondromyxoid fibroma. A Radiograph shows an eccentrically localize expansile mixed osteolytic-sclerotic tumour with a well-defined sclerotic margin in t metaphysis and proximal diaphysis of the tibia. The combination of these morph logical characteristics with the location is indicative of chondromyxoid fibroma. B T myxoid components have a high signal intensity on the T2-weighted fat-suppress images. Note the reactive high signal surrounding the tumour in the bone marrow a in the periosteum medially.

Fig.3.25 Chondromyxoid fibroma of the ilium. Note the yellowish-grey, relatively u' form lesion, with sharply demarcated borders and expansion of the bone.

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Hg,3,26 Chondromyxoid fibroma. A Stellate cells embedded in a myxoid matrix are seen on the right, with more-cellular areas containing round cells and multinucleated giant cells on the left. IB Moderate nuclear enlargement may be present. The eosinophilic cytoplasmic processes are evident. C Lobular architecture. In addition to myxoid areas, areas with more hyaline cartilaginous matrix can be seen in a subset of cases. D Focal coarse calcification.

Epidemiology Chondromyxoid fibroma is a rare tumour {2653,3151}. Although it may affect a wide age range (first to seventh decades of life), it occurs most often in the second and third decades of life and more frequently in males {1138,3313}.

Etiology Unknown

Pathoge nesis Recombination of the glutamate receptor gene GRM1 with several 5' partner genes through promoter swapping and gene fusion events leading to upregulated expression of transcripts encompassing the entire GRM1 coding region, with or with­ out n on-coding 5' partner rem nan ts, is considered the drive r event for chondromyxoid fibroma development {2318}. These canonical gene fusions were shown to be caused by complex rearrangement processes, predominantly chromoplexy, but also chromothripsis {107}. GRM1 expression is absent or very low in other cartilaginous neoplasms, emphasizing the high level of specificity of this finding in chondromyxoid fibroma {2318}. However, approximately 10% of chondromyxoid fibromas do not exhibit upregulation of GRM1 expression, suggesting that this small sub set may develop via a differe nt gen etic pathway.

Macroscopic appearance he gross features of chondromyxoid fibroma include welldefined margins, grey or white tumour, lack of obvious necrosis, cystic change, and liquefaction. The tumour is multilobulated

and well demarcated from the surrounding bone. Typically, there are scalloped margins.

Histopathology Typically, chondromyxoid fibroma is sharply demarcated from the surrounding bone. Lobules of tumour may be separate from the main lesion. A lobular pattern with stellate or spindle-shaped cells in a myxoid background is evident {3313}. Lobules demonstrate hypocellular centres with hypercellular peripheries. The centre of the lobules shows morphological features more similar to those of hyaline cartilage, in terms of both extracellular matrix and cell composition {2650,2901}. Microscopic cystic or liquefactive change is uncommon and usually focal when present. Hyaline cartilage is present in 19% of cases {3313}. Calcification, when present, is usually coarse, and it occurs more frequently in older patie nts and in flat-b one tumours {3331}. In dividual cells within lobules have oval to spin died n uclei and in disti net to densely eosinophilic cytoplasm. Cytoplasmic extensions, often bipolar or multipolar, are frequent. Enlarged, hyperchromatic and pleomorphic nuclei are noted in 20-30% of cases. Mitoses are uncommon, although atypical mitoses have been noted {3313}. Entrapment of surrounding bone trabeculae by tumour is very rare. Because of these features, differential diagnosis with high-grade central chondrosarcoma is considered. However, clinicoradiological features and histology are quite distinet; chondrosarcomas more often affect older patients and the diaphysis of long bones, with more frank atypia and mitoses. Moreover, osteoclast-like giant cells are often present at the periphery of the lobules. There may also be haemosiderin Bone tumours

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paybal：https://www.paypal.me/andy19801210 features of both chondroblastic and fibroblastic different’ {2652,2283}. Cells with the classic features of chondro "" those with myofibroblastic features, and in termediate f j have been described in chondromyxoid fibroma {2652 228；"

Cytology TBL1XR1 (3q26.32) COL72A(6q13)

BCLAF1 (6q23.3) FRMD6 (14q22.1) MXOfE (15q22.2)

MEF2A(15q26.3) Fig. 3.27 Chondromyxoid fibroma. GRM1 recombines with or has been predicted to recombine with one of the following 5' gene partners: TBL1XR1, COL12A1, BCLAF1,

Not clinically releva nt

Diagnostic molecular pathology Molecular an alysis is gen erally not n eeded for diag nosis I selected cases, identification of the exceedingly specific uprej ulation of GRM1 expression in chondromyxoid fibroma could 畫 a strong diagnostic adjunct in distinguishing this entity from ； mimics {2318}.

Essential and desirable diagnostic criteria

deposition and inflammatory cells, usually lymphocytes. Aneurysmal bone cyst-like areas are noted in approximately 10% of long- and flat-bone lesions {3313}.

Essential: lytic metaphyseal ecce ntric appears nee on convex tional radiograph with sharp margins; lobulated lesion with zonal architecture; chondroid and stellate cells embedded in chon droid and/or myxoid matrix in the centre of the lobules， spindle-shaped myofibroblast-like cells at the periphery of the lobules admixed with osteoclast-like giant cells.

Immunohistochemistry

Staging

Immunohistochemistry is not required for routine clinical prac­ tice. The cartilaginous nature of this tumour is reflected by immunopositivity for S100 [342,727,1681,3406}.

Not clin ically re leva nt

FRMD6, MYO1E, and MEF2A.

Electron microscopy Ultrastructurally, the stellate cells have irregular cell processes, scalloped cell membranes, cytoplasmic fibrils, and glycogen,

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Bone tumours

Prognosis and prediction The prog nosis is excelle nt, eve n for recurre nt tumours. Recur­ rence has been reported in approximately 9-15% of cases treated locally {303}.

paybal：https://www.paypal.me/andy19801210 Osteochondromyxoma

Bovee JVMG

Definitio n Osteochondromyxoma is an extremely rare, benign, sometimes really aggressive, chondroid and osteoid matrix-producing tumour, with extensive myxoid changes, predominantly occur“ng in patients with Carney complex.

ICD-O coding 9211/0 Osteoch on dromyxoma

ICD-11 coding 2E82.Z & XH6KR3 Benign chondrogenic tumours, site unspeci­ fied & Osteochondromyxoma

Related terminology Not recommended: Carney bone tumour.

Subtype(s) None

Localization Tumours are found in the nasal region and the diaphysis of the tibia and radius. In dividual cases have bee n reported in rib, chest wall, and spine {1180}.

Clinical features Signs and symptoms Patients present with a painless mass, usually found on screening for skeletal involvement in cases of Carney complex. Carney complex is a rare, autosomal dominant, multiple endocrine neoplasia and lentiginosis syndrome. In Carney complex, at least two of the following are found: spotty pigmentation, endocrine overactivity, osteochondromyxomas, recurrent cardiac myxo­ mas, cutaneous and bilateral breast myxomas, multiple endo­ crine neoplasms, psammomatous melanotic schwannomas,

Fig. 3.28 Tibial osteochondromyxoma. The longitudinally sectioned tibia showed a heterogeneous, elongated, oval tumour. Inferiorly, the lesion was demarcated by a zone of haemorrhage (probably biopsy-related). Superiorly, the lesion was poorly delineated. A vague cylindrical zone (arrows) had a cartilaginous appearance and con­ tained a small cyst with mucoid content.

pigmented mucosal and skin lesions, large cell calcifying Sertoli cell tumours, growth hormone-secreting pituitary ade no mas, and breast ductal ade no mas {1180}.

Imaging Osteochondromyxomas do not have a uniform radiographic appearanee and can manifest as a permeative lytic periosteal lesion with aggressive new bone formation or as an expansile bone area with sclerotic and luce nt regi ons {668,669,485}. On MRI, increased T2-weighted signalling is seen {1180}.

許3.29

Osteochondromyxoma. A A sheet of tumour cells with overall clear appearance and vague lobular pattern (right) erodes the bony cortex of the tibial lesion. The jpocellular tumour with dilated sinusoids penetrates between narrow reactive bony trabeculae just beneath the periosteum (top). B The circumscribed but unencapsulated ''ypocellular myxochondroid tumour abuts the nasal submucosa.

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Fig.3.30 Osteochondromyxoma. A The tumour is composed of a patternless sheet of cells separated by abundant basophilic mucopolysaccharide ground substance, gonal, elongated, and stellate-shaped cells are arranged in moderate-sized lobules.

Epidemiology Osteochondromyxoma is extremely rare, occurring in about 1% of patients with Carney complex {486,487}. The tumour can occur over a wide age range, but it typically presents early and can be congenital {485}. In adults, osteochondromyxoma can occur as an isolated entity {485,2208}.

Etiology Osteochondromyxoma is part of the Camey complex, a genetically heterogeneous syndrome in which the majority of patients carry inactivating mutations in PRKAR1A, the gene encoding the type IA regulatory subunit of PKA.

Pathogenesis Karyotypes were normal {485}. Carney complex is genetically heterogeneous, with two genetic loci: PRKAR1A (C/VC7) at chromosome 17 and CNC2 at chromosome 2. Most often, inactivating mutations are found in the tumour suppressor gene PRKAR1A at chromosome 17. PRKAFI1A encodes the type IA regulatory subu nit of PKA, an importa nt reg u I ator of cAMP signalling. FRKAR1A inactivation causes hyperstimulation of PKA, which r esults in in complete osteoblastic differentiati on whe n

occurring in osteoblasts {2467}. Prkarla (+/-) mice devel bone tumours with a high frequency {1643,1180,2467}.

Macroscopic appearanee The lesions are circumscribed and unencapsulated and show a lobulated growth pattern with a white and light-yellow gelatinous, cartilaginous, and haemorrhagic gross appearanee. Usu­ ally there is erosion of the cortex without penetration.

Histopathology Tumour cells are embedded in an abundant clear and basophilic myxoid matrix in a moderately cellular to hypocellular, loose mesenchyme. The cells form sheets, with or without a poorly or well-defined microlobular or macrolobular pattern. The cells are polygonal, stellate, round, and bipolar in shape; a minor­ ity are spindle-shaped. In limited areas, the cells are packed together. The nuclei are medium-sized, pale, and vesicular, with a small nucleolus. They have a uniform and bland appearanee There are occasional mitotic figures. Binucleation is very rare Chon droblast-like cells and osteoblast-like cells are found. The matrix varies from stringy, clear, and lightly basophilic to gel­ like, solid, and cartilage-like. These zones blend with areas of

Fig.3.31 Osteochondromyxoma. A Polygonal and bipolar tumour cells in a barely perceptible, weakly basophilic matrix. Nuclei are hyperchromatic as a result of decalcifica­ tion. B Spindle cells and polygonal cells in a loose matrix with round eosinophilic hyaline areas. C Osteoid formation present in an area of polygonal cells with lightly eosinophils

cytoplasm. The nuclei are round and regular, with occasional lobulation and grooving (arrows).

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paybal：https://www.paypal.me/andy19801210 Essential and desirable diagnostic criteria

mature cartilage, where well-outlined round cells occupy evenly disposed spaces. Acidophilic hyaline fibrous nodules and bands may be present, which can coalesce, trap cells, become Icified, and form osteoid and bone. Some of the mature bony trabeculae are bordered by plump osteoblasts. The cells are pAS-positive, diastase sensitive. Colloidal iron staining is posi­

Staging

tive.

Not clinically releva nt

Essentia/: variably cellular chon droid and osteoid matrix-producing tumour with extensive myxoid changes; patient has other symptoms of Carney complex.

immunohistochemistry

Prognosis and prediction

Tumour cells are occasionally S100-positive.

Complete excision is curative; however, local recurrence is comm on with in complete resecti on {485,1180}. No metastases have been reported.

Cytology Not clinically relevant

Diagnostic molecular pathology Not clinically releva nt

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paybal：https://www.paypal.me/andy19801210 Synovial chondromatosis

Flanagan AM Bloem JL Cates JMM O'Donnell PG

Definition Synovial chondromatosis is a locally aggressive neoplasm con­ sisting of multiple hyaline cartilaginous nodules involving the joint space, subsynovial tissue, or tenosynovium (extra-articular subtype). A small subset of cases are malignant.

ICD-0 coding 9220/1 Chondromatosis NOS

ICD-11 coding 2E82.Z & XH5BT0 Benign chondrogenic tumours, site unspeci­ fied & Chondromatosis NOS

Related terminology Not recommended: synovial osteochondromatosis; synovial chondrosis; Reichel syndrome; synovial chondrometaplasia.

Subtype(s) Extra-articular synovial chondromatosis (tenosynovial chondro­ matosis)

Localization Most cases involve the large joints, with approximately 60-70% of cases affecting the knee. Any joint can be affected, including the temporomandibular and intervertebral joints. Some cases are entirely extra-articular and termed tenosynovial chondroma­ tosis, typically arising in the hands and feet {1002}.

Clinical features Signs and symptoms Symptoms include pain, swelling, and mechanical symptoms (including locking, crepitus, and reduced range of movement) {2264}. Palpable n odules can be detected on exami nation. Malignant change is associated with persistent and increased pain.

Imaging Radiographs show a calcified mass in 75-90% of cases {2225}, showing either chondroid mineralization (punctate, ring and arc, so-called feathery calcification) {3300} or ossified nodules, typically of similar size and shape {2225}. The joint space is usually maintained, but pre-existent or resultant osteoarthritis may be present {2225}. Pressure erosion occurs where joint capacity is restricted, for example the hip {2323}. Although CT shows subtle calcification that can be missed on radiographs, approximately one third of patients lack calcifications on CT. Other imaging features comm on to well-differentiated cartilaginous neoplasms are shown using cross-sectional imaging {2225}. On MRI, the mass may consist of lobulated areas of low signal in tensity (calcification and ossificati on), T2 hyperi nten sity (cartilage), or fatty signal (mature bone marrow) {2225}. Septal and peripheral enhancement is seen on MRI and CT after con­ trast administration {2225}. MRI also frequently shows synovial

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Fig. 3.32 Synovial chondromatosis. Lateral radiograph of the left knee. Lobular ma at the posterior aspect of the knee with extension into the proximal calf. The ma shows diffuse punctate calcification. Small foci of calcification are also visible att anterior aspect of the knee.

thickeni ng, effusi ons, and bone erosi on. Teno synovial chondr matosis is suggested by an elongated mineralized mass with a tendon sheath, with otherwise similar imaging appearanc( to intra-articular chondromatosis and eroding the adjace bone in as many as 43% of cases {3219}. Tumours with simil imaging appearances can occur at the site of a known bur * {3219}. Multiple osteochondral loose bodies due to seve degenerative joint disease typically vary in shape and size( radiographs, but they may show similar appearances to syn vial chondromatosis.

Epidemiology Synovial chondromatosis is a rare neoplasm, with an estimate incidence of about 1.8 cases per 1 million person-years {226舟 It typically occurs in the third to fifth decades of life and is twid as common in males as in females {745,2264}.

Etiology Unknown

Pathogenesis FN1-ACVR2A and ACVFI2A-FN1 fusions, as assessed by FISH are found in at least 50% of benign synovial chondromatosis,[ well as in cases of malignant synovial chondromatosis {3091

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Fig,3.33 Synovial chondromatosis. A Composed of multiple cartilaginous nodules. The lesions are cellular and the maturity of the ossification of the nodules is variable, from osteoid deposition to mature bone. B A low-power view showing multiple cartilaginous nodules embedded in synovium. There is peripheral ossification of the nodules. C Cluslered chondrocytes in a hyaline matrix with little atypia.

92|. It is not clear whether it is the FN1 or ACVR2A altered gene that drives tumour development, because both FN1-ACVR2A and ACVR2A-FN1 are predicted to be in -frame. Both genes have been implicated in the development of other neoplasms 12420,2550,1881}.

Macroscopic appearance Synovial chondromatosis appears as multiple greyish-white, smooth or irregular, uniform or variably sized nodules, usually in the form of intra-articular loose bodies but sometimes embed­ ded within or attached to synovium.

chondromas {92}. Formati on of con centric layers of cartilage and a uniform, more orderly distribution of chondrocytes is sug­ gestive of osteochondral loose bodies. Benign lesions can exhibit atypia, and making a diagnosis of malignancy requires observation of unequivocal substantial nuclear enlargement, pleomorphism, hyperchromasia, and loss of chondrocyte clustering {296}. Permeative infiltration of adjacent cortical or cancellous bone, conspicuous and/or atypical mitotic figures, and merging with a high-grade non-chondroid sarcoma are strong indicators of malignancy {745,3300,2272}.

Cytology

Histopathology

Not clin ically re leva nt

Nodules consist of hypercellular hyaline cartilage, in which chondrocytes are typically clustered. Nodules are often surrounded by a rim of residual synovial tissue. Calcification and/or endochondral ossification may be seen in Iongstanding lesions {745}.

FISH can be used to detect FN1-ACVFI2A rearrangements but will not distinguish benign from malignant {237}. /DA77 and IDH2 mutations are absent {93,726}.

Differential diagnosis

Essential and desirable diagnostic criteria

Primary synovial chondromatosis must be distinguished from multiple osteochondral loose bodies within the synovium seen in severe degenerative joint disease, as well as from soft tissue

Essential: nodular cartilaginous tumour within synovium or loose in joint space; clustering of chondrocytes; minimal atypia and increased cellularity; malignancy is defined by unequivocal nuclear atypia, loss of chondrocyte clustering, bone invasion, conspicuous and/or atypical mitotic figures, or merging with a high-grade non-chondroid sarcoma.

Diagnostic molecular pathology

Staging Not clinically relevant

Prog nosis and predictio n The disease recurs in 15-20% of patients, with higher rates reported for tenosynovial cases {2264,1002}. Malignant transformation is un comm on, occurri ng in 5-10% of cases, usually in large tumours and in Iongstanding cases after multiple local recurrences over several years {745,950}. However, malignant cases may present de novo. Early and rapid growth of a local recurrenee after treatment should raise suspicion for malig­ nancy {2272}. Fig, 3,34 Chondrosarcoma arising in association with synovial chondromatosis. In罟ased cellularity, loss of organization, nuclear aypia, and increased mitoses suggest chondrosarcoma arising in synovial chondromatosis.

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paybal：https://www.paypal.me/andy19801210 Central atypical cartilaginous tumour / chondrosarcoma, grade 1

Bovee JVMG Bloem JL Flanagan AM Nielsen GP Yoshida A

Definition Central atypical cartilaginous tumour / chondrosarcoma, grade 1 (ACT/CS1) is a locally aggressive, hyaline cartilageproducing neoplasm arising in the medulla of bone. Tumours in the appendicular skeleton (long and short tubular bones) are termed ACTs, whereas tumours of the axial skeleton (flat bones, including the pelvis, scapula, and skull base) should be called CS1s. Primary conventional central ACT/CS1s are tumours aris­ ing centrally within bone without a benign precursor; sec on dary conventional central ACT/CS1s are tumours arising centrally in bone in association with a pre-existing enchondroma.

ICD-0 coding 9222/1 Atypical cartilaginous tumour 9222/3 Chondrosarcoma, grade 1

ICD-11 coding 2B50.Z & XHOFYO Chondrosarcoma of bone and articular car­ tilage of unspecified sites & Atypical cartilaginous tumour / chondrosarcoma, grade 1

Related terminology Acceptable: low-grade central chondrosarcoma.

Subtype(s) None

Localization Central ACT/CS1s arise in bones formed by endochondral ossificati on. The most comm on locations are the femur (31% of cases overall: 17% proximal, 2.5% midshaft, and 11% distal), the pelvic bones (22% overall, 18% in the ilium), the humerus (11%), the tibia (8%), and the ribs (6%). The short tubular bones of the hands and feet are rarely involved. Central ACT/CS1 is rare in the spine and the base of the skull.

Clinical features Signs and symptoms Patients with central ACT/CS1 can be asymptomatic or can present with pain and/or swelling. Central ACT/CS1 can also be found incidentally. Tumours in the skull base can cause neurological symptoms.

Imaging Radiographically, ACT is a lytic lesion with geographical destruction, which is ill-defined and usually contains the typi­ cal cartilaginous popcorn calcifications. Cortical scalloping without breakthrough is often present. Approximately 50% of central ACTs are located in the metaphysis of long bones, a third in the diaphysis, and the rest in the epiphysis. In the long bones, the radiographic and MRI features of ACT are different from those of grade 2 or 3 chondrosarcoma but overlap with

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Fig.3.35 Atypical cartilaginous tumour in long bone. Conventional radiograph of atypical cartilaginous tumour in long bone shows features identical to those of enchondroma, including popcorn-like calcifications.

those of enchondroma, and this distinction can be difficult |992, 685,1130}. As a rule of thumb, cartilaginous tumours in the phalanges are most often enchondromas, whereas cartilaginous tumours in the axial skeleton are probably chondrosarcomas. Enchondromas are typically < 5 cm long; > 80% of enchondromas in long bones are < 2 cm and are located close to the physis {2957}. Larger tumours with cortical remodelling, deep scalloping, and enhancement seen on dynamic gadolinium chelate-enhanced MRI within 10 seconds of the start of arte­ rial enhancement favour a diagnosis of ACT over enchondroma {2226,1130,444,1128,1131,582,758,844}. Diffusio n-weighted MRI and PET-CT do not allow reliable differentiation between enchondroma and ACT {843,2971}. The distinction between central ACT and grade 2 or 3 chondrosarcoma is more clinically relevant and also more reliable. The absence of MRI features of high-grade chondrosarcoma and the presence of trapped fat allow reliable differentiation between ACT/CS1 and grade 2 or 3

chondrosarcoma {3367}.

Epidemiology The incidence of central ACT/CS1 has increased over the years, from 1.2 cases per 1 million person-years in 1989-1996 to 6.63 cases per 1 million person-years in 2005-2013, which can

paybal：https://www.paypal.me/andy19801210 eexplained by ageing and increased use of diagnostic imagD ⑶ 67}. The estimated populati on prevale nee of enchonJfoma and ACT/CS1 is 2.8% {2957}. Conventional central ACT/ is seen mainly in adults in the third to sixth decades of He with equal sex distribution. Of the central cartilage tumours, 75% are found in patients aged 21-75 years (median: 49 years), patients with tumours arising in enchondromatosis are generEy0unger than patients with primary tumours. Central cartilaginous tumours have also been found to occur in association with the development of ER-positive breast cancer at a relatively ear” age {2351,613}. Central ACT/CS1s (85-90%) are much more comm on than peripheral ACT/CS1s (10-15%).

Etiology Patients with enchondromatosis (see Enchondromatosis, p 506), carrying a somatic mosaic mutation in IDH1 or IDH2{96, 2430}, are at in creased risk of progressi on towards central ACT/ CS1, depending on the localization of the tumours. Although the overall risk is about 40%, patients with multiple enchondromas in the hands and feet have a risk of only 15%, whereas patients pith multiple enchondramas affecting both small and Iong/flat bones have a risk of 46% {3193}. The risk of developing chon­ drosarcoma is especially in creased when enchon dromas are located in the pelvis {3193}.

Pathoge nesis Similar to enchondromas, about 50% of primary central ACT/ CS1s and as many as 78% of sec on dary central ACT/CS1s (in enchondromatosis) harbour somatic mutations in the isocitrate dehydrogenase genes IDH1 and /DH2 {93,2430,96}.

Macroscopic appearance Tissue fragments obtained from curettage are composed of translucent, bluish-grey or greyish-white tissue, usually admixed with red fragments of bone marrow. Yellowish-white chalky areas of calcification are often present. In resection specimens, the turn our is usually sharply demarcated and may dem on strate erosion of the surrounding cortex, which corresponds to the cortical scalloping seen in imaging studies. Soft tissue extension is usually not seen in central ACT/CS1. Extensive sampling is required to rule out areas of dedifferentiation.

Histopathology Central ACT/CS1 has abundant hyaline cartilage matrix. A lobulated growth pattern is often recognized, and lobules can be 『regularly shaped and vary in size. The lobules may be separated by fibrous bands containing small vessels. The lobular growth pattern can cause typical cortical thinning represented In radiographs by cortical scalloping. The typical encasement pattern (deposition of bone surrounding the tumour lobules, a sign of in dole nt growth as see n in slow-growi ng enchon dromas) ls highly un comm on {2155}. I nstead, as a sign of more-rapid growth, the tumour lobules usually permeate and entrap the Pre-existing lamellar bone trabeculae, although this may be difhcult to appreciate in fragmented curettage specimens {2155, 883}. Entrapment is defined as the presenee of tumour around three sides of a normal spicule of medullary trabecular bone. The cellularity in central ACT/CS1 is low, but slightly higher than in enchondroma. The nuelei can be small and condensed

Fig.3.36 Atypical cartilaginous tumour / chondrosarcoma, grade 1 (ACT/ CS1). A ACT/CS1 showing a lobular growth pattern, abundance of predominantly hya­ line cartilaginous matrix, and low cellularity. B ACT/CS1 demonstrating entrapment of pre-existing lamellar host bone, as well as myxoid matrix changes. These two criteria distinguish ACT/CS1 from enchondroma. C Tumours show moderate cellularity, with cells embedded in hyaline cartilaginous matrix. Nuclei usually show condensed chro­ matin. Note the presence of binucleated cells, whereas mitoses are absent.

(lymphocyte-like), although they sometimes have more-open chromatin with a visible nucleolus. The n uelei are gen erally uni­ form in size. Binucleation is frequently seen, but mitoses are absent. The surrounding matrix is predominantly hyaline, some­ times with more mucoid or myxoid changes. Necrosis may be present. Areas of a pre-existing enchondroma, with extensive calcifications, may be recognized in central ACT/CS1.

Immunohistochemistry The tumour cells strongly express S100 and are negative for brachyury. Because the p.Arg132His mutation-specific IDH1

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paybal：https://www.paypal.me/andy19801210 antibody only recognizes a small percentage of the IDH muta­ tions in central ACT/CS1, its usefulness is limited {93,2430,96}.

Differential diagnosis There is overlap between the histological features of enchondroma and those of central ACT/CS1, and the distinction is made by the higher cellularity, irregular distribution of the cells, and occurrenee of binucleated cells in central ACT/CS1. A very important criterion is the growth pattern, in which the presenee of entrapment (of pre-existing lamellar bone) and the absenee of encasement are indicative of central ACT/CS1 {2155,883}. The presenee of > 20% myxoid changes of the matrix also favours the diagnosis of ACT/CS1 over enchondroma {883}. The distinction can be extremely difficult on small biopsy specimens, and clinicoradiological correlation is essential. When these cri­ teria are used, the localization of the lesion and the age of the patie nt are imports nt {768}. With regard to localizati on, if the tumour is located in the medullary cavity of a long tubular bone, then increased cellularity with irregular distribution, more-open chromatin with visible nucleoli, and the presence of binueleated cells are indicative of central ACT/CS1, whereas if the tumour is located in the phalangeal bone, these histological features are accepted in an enchondroma because they are not indicative of more-aggressive behaviour {387}. Similarly, in patients with enchondromatosis and for tumours arising in patients before puberty (before growth plate fusion), increased cellularity, moreope n chromatin, and the presenee of binucleated cells do not exclude the diagnosis of enchondroma {749}. Thus, a multidisciplinary approach with clinicoradiological correlation is often indispensable. Grade 2 conventional central chondrosarcoma is disti nguished from ACT/CS1 on the basis of its in creased cel­ lularity, the presenee of mitoses, myxoid matrix degeneration, spindle cell changes at the periphery of the lobules, increased vascularization, and increased nuclear pleomorphism.

Cytology Not clinically r eleva nt

Diagnostic molecular pathology Hotspot mutations are exclusively found at the IDH1 p.Arg132 and the IDH2 p.Arg172 positions; the IDH1 p.Arg132Cys mutation is the most frequently found mutation. About 50% of pri­ mary central ACT/CS1s and as many as 78% of central ACT/

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CS1s occurring in enchondromatosis have IDH1 or /DH2m I tions {93,2430,96}. Mutations at the IDH1 p.Arg140 position J extremely rare {1910}. In the rare occurrence in the skull ba[ the mutation frequency is very high (85.7%), whereas mutatiol are rare to absent in the laryngeal and tracheal tumours ⑴ 8；

Essential and desirable diagnostic criteria Essential: location in the medulla of bone; abundance of CJ tilaginous matrix, often hyaline, sometimes with r-> * myxo changes; lobular growth pattern with entrapment of pre；xQ ing lamellar bone trabeculae; increased cellularity, with sma conden sed nu clei; bin ueleated cells are comm on; abse nce( mitoses, severe nu clear atypia, and en caserne nt.

Staging Staging is according to bone sarcoma protocols (see TNMstac ing of tumours of bone, p. 339). See also the information o staging in Bone tumours: Introduction (p. 340).

Prognosis and prediction Central ACT/CS1 has a locally aggressive behaviour. Loc; recurrenee is seen in 7.5-11% of the cases, compared wit 0% in enchondroma {930,436,113}. In about 10% of recurrin central ACT/CS1s, progression to a higher grade is seen |42( 1701,947). Reported 5-year overall survival rates for ACT/CS are 87-99%, and 10-year overall survival rates are 88-95c {864,113,1161,1079,947,3167}. Patients die from locally recu rent tumours that are sometimes difficult to manage surgical!' depending on the location {947,1132}. In the long bones, centr; ACT is treated with curettage and local adjuvants, giving a goo prog nosis {1132}. Overall, tumours located in the axial skeleto have a worse outcome {325,1079,3167}. Therefore, CS1s of th pelvis and spine are treated with surgical excision and negativ margins. For skull base CS1, the mortality rate is 5%. A larg proportion of the mortality of ACT/CS1 is probably caused bl intracranial or axial tumours that are difficult to treat becausi of their location. Therefore, the location determines whethe to diagnose ACT (in the appendicular skeleton) or CS1 (in th( axial skeleton and pelvis), to better reflect outcome {768}. It i： at present unclear whether the presenee of an IDH mutation i associated with prognosis {93,1910,2430,618}.

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旳ondary peripheral atypical cartilaginous mour/chondrosarcoma, grade 1

Bovee JVMG Bloem JL Flanagan AM Nielsen GP Yoshida A

Definition Secondary peripheral atypical cartilaginous tumour / chondrosarcoma, grade 1 (ACT/CS1) is a locally aggressive, hyaline cartilage—producing neoplasm arising within the cartilaginous cap of a pre-existing osteochondroma. Tumours in the appendicular skeleton can be called peripheral ACTs, whereas tumours of the axial skeleton (including the pelvis, scapula, and skull base) can be called peripheral CS1s.

ICD-O coding 9222/1 Atypical cartilaginous tumour 9222/3 Chondrosarcoma, grade 1

ICD-11 coding 2850.Z & XHOFYO Chondrosarcoma of bone and articular car­ tilage of unspecified sites & Atypical cartilaginous tumour / chondrosarcoma, grade 1

None

Fig. 3.37 Secondary peripheral atypical cartilaginous tumour / chondrosarcoma, grade 1 (ACT/CS1), two resection specimens. A Secondary peripheral ACT/CS1 aris­ ing juxtaposed to a pre-existing osteochondroma. The size of the cartilaginous cap, which should be measured perpendicular to the tidemark, exceeds 2 cm. B Large secondary peripheral ACT/CS1. Note the remnants of the stalk on the right, as well as the abundant nodular proliferation of cartilage, with areas of calcification.

Localization

Epidemiology

Localization in the flat bones (CS1) includes the ilium (19%), fol­ lowed by the scapula (15%), pubic bone (10%), and ribs (10%). In the appendicular skeleton (ACT), the tibia (12%) and femur (11%) are most often affected.

Progressi on towards sec on dary peripheral ACT/CS1 occurs predominantly in patients aged 20-40 years (in 75.2%), and 56.2% of cases occur at the pelvis and proximal femur {980}. Thus, patie nts with sec on dary peripheral chon drosarcoma are 1-2 decades younger than those with primary chondrosarcoma {45}. After progression in osteochondroma, > 90% of these neoplasms are ACT/CS1, whereas only 9% are grade 2 or 3 {45}.

Related terminology Acceptable: low-grade peripheral chondrosarcoma.

Subtype (s)

Clinical features Signs and symptoms Patients usually present with a Iongstanding mass with recent rapid enlargement or pain {45}. Tumour growth after puberty and pain should raise suspicion for malignant progression.

Imaging The radiological features of sec on dary peripheral ACT/CS1 largely overlap with those of osteochondroma. MRI is the bestvalidated method to detect ACT/CS1 arising in an osteochon­ droma. In the literature, 1.5 and 2 cm cut-off points for cartilage cap thickness are used to indicate the presence of ACT/CS1 12220,279}. The use of a 2 cm cut-off point seems the best: 18% °f osteochondromas have a cap > 1 cm and 7% have a cap > 1.5 cm, whereas a cap of > 2 cm is extremely rare for osteo­ chondroma (seen in < 1.5% of cases), and none of the chondro­ sarcomas have a cap < 2 cm {279}. The 2 cm cut-off point has a sensitivity of 100%, specificity of 98%, positive predictive value of 96%, and negative predictive value of 100% {279}.

Etiology Patients with multiple osteochondromas, carrying germline mutations in EXT1 or EXT2, are at increased risk of developing ACT/CS1 within the cartilaginous cap of an osteochondroma (see Multiple osteochondromas, p. 517). The risk is estimated to be as high as about 5% for patients with multiple osteochon­ dromas, compared with about 1% for those with solitary osteo­ chondromas {3285,1823,2767,980}.

Pathogenesis Un like in sec on dary peripheral chon drosarcoma's precursor osteoch on droma, in which EXT1 or EXT2 is biallelically in acti­ vated in at least a subset of the tumour cells {381,1545,278,2593, 3411,1285), upon progression the cartilaginous cap of secondary peripheral chondrosarcoma becomes gradually populated by cells that retain at least one functional copy of EXT1 or EXT2 {751,2229}. In secondary peripheral ACT/CS1, the propor­ tion of EXT1- or EXT2-mutated alleles among all EXT alleles is about 40%, showing that EXT-mutant alleles and EXT-wildtype

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paybal：https://www.paypal.me/andy19801210 alleles coexist {3094}. This suggests that the wildtype cells in osteochondroma are prone to undergoing progression, and that (genetic) factors other than EXT1 or EXT2 mutations are also involved. These other factors probably involve mutations in cell­ cycle regulatory genes such as CDKN2A {754}.

Macroscopic appearanee Sec on dary peripheral ACT/CS1s show a thick (> 2 cm), lobulated cartilaginous cap (mean cap thickness: 3.9 cm) {45}. Careful gross macroscopic documentation of the thickness of the cartilaginous cap is crucial, and the cap should be measured perpe ndicular to the bon e-cartilage in terface, at its thickest portion, because the thickness is one of the most important determinants for progression in an osteochondroma {749}.

Differential diagnosis The distinction between osteochondroma and second peripheral ACT/CS1 solely based on the morphology is no(' sible. It has been shown that cystic degeneration, nodul；

or necrosis does not indicate progression {749}. The distinct should be made in a multidisciplinary setting in which the th ness of the cartilaginous cap is most important. In grade 2 an sec on dary peripheral chon drosarcoma, mitoses and nuch pleomorphism are seen, both of which should be absent in $ ondary peripheral ACT/CS1.

Cytology Not clinically re leva nt

Diagnostic molecular pathology Not clin ically releva nt

Histopathology There are no generally accepted histological criteria that indi­ cate progressi on from osteoch on droma towards sec on dary peripheral ACT/CS1 {749}. Coarse and irregular calcifications are usually prominent, and evidenee of a pre-existing osteochondroma can often be seen. A lobular pattern is common, and sometimes nodules are separated from the main mass lying in the surrounding soft tissue {45). Binucleated cells, cystic changes (areas of cystic spaces containing mucoid material), and necrosis can be seen within the cartilaginous cap and should not be interpreted as evidenee of progression, because these features can also be seen in osteochondroma {749}. Increased vascularization can also be seen {753}. Correlation between clinical and radiological features combined with the thickness of the cartilaginous cap is crucial to establish a diag nosis of sec on dary peripheral ACT/CS1 {749}. Mitoses and nuclear pleomorphism are absent. Invasion in the stalk is rare and indicative of progression.

Immunohistochemistry The tumour cells strongly express S100.

Essential and desirable diagnostic criteria Essential: location at the surface of the bone; presenee of pre-existing osteochondroma; size of the cartilaginous cj exceeds 2 cm, measured perpendicular to the bone-cartilac in terface; abse nee of n uelea r pleomorphism and mitoses,'

Staging Staging is according to bone sarcoma protocols (see TNMsta ing of tumours of bone, p. 339). See also the information on sta ing in Bone tumours: Introduction (p. 340).

Prognosis and prediction The clinical course can be variable and is dependent on loca zation and operability. The 5-year and 10-year local recurrencu rates for sec on dary peripheral chon drosarcoma are 15.9% and 17.5%, respectively, and the 5-year and 10-year mortality rate： are 1.6% and 4.8% {45}. Local recurrences can occur and are usually r elated to in complete excisi on in difficult locations. In the pelvis, peripheral CS1 can become very large and thereby difficult to excise completely, eve ntually becomi ng in operable and fatal in some cases {1132,45}.

Fig. 3.38 Secondary peripheral atypical cartilaginous tumour / chondrosarcoma, grade 1 (ACT/CS1). A A lobular hyaline cartilaginous tumour is seen with nodular extension ir the surrounding soft tissues. B Tumours show moderate cellularity and an abundance of hyaline cartilaginous matrix. Areas of hypertrophic differentiation and calcification 盹 can be seen.

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paybal：https://www.paypal.me/andy19801210 Central chondrosarcoma, grades 2 and 3

Bovee JVMG Bloem JL Flanagan AM Nielsen GP Yoshida A

Definition Grade 2 and 3 central chondrosarcomas are central (intrameduHary), intermediate-grade (grade 2) and high-grade (grade 3) maiignant cartilaginous matrix-producing neoplasms.

ICD-O coding 9220/3 Chondrosarcoma, grade 2 9220/3 Chondrosarcoma, grade 3

ICD-11 coding 2B5O.Z & XH6LT5 Chondrosarcoma of bone and articular carti­ lage of unspecified sites & Chondrosarcoma, grade 2 2B5O.Z & XH0Y34 Chondrosarcoma of bone and articular carti­ lage of unspecified sites & Chondrosarcoma, grade 3

Related terminology None

Subtype(s) None

Localization The localization is similar to that of central atypical cartilaginous tumour / chondrosarcoma, grade 1 (ACT/CS1), and all parts of the skeleton arising from endochondral ossification can be affected: the long tubular bones (especially proximal femur, proximal humerus, and distal femur), the flat bones (especially pelvis [most frequently the ilium] and ribs), and occasionally the spine or base of the skull.

Clinical features Signs and symptoms Patients present with pain and/or swelling. Occasionally the lesion is found as a consequenee of a pathological fracture. Especially when arising in the pelvis, but also in the ribs, chon­ drosarcomas can grow to a large size before becoming symp­ tomatic.

Imaging ln long bones and pelvis, these tumours are normally > 5 cm and show large osteolytic areas on radiographs, with motheaten or permeative bone destruction, and often cortical destruction and soft tissue extension. MRI is the method of choice to show areas similar to that of ACT/CS1, as well as features of in termediate- to high-grade chon drosarcoma. Feahres include abundant (> 50%) mucoid areas with high signal intensity on fluid-sensitive MRI sequences and an osteolytic appearanee on CT and radiographs, cortical thickening (also well seen on radiographs and CT), bone expansion with corticalthinning, cortical destruction, soft tissue extension, perilesional inflammatory reaction in bone and soft tissue, and peri°stitis {3367,844}. On PET-CT, there is a significant difference

Fig. 3.39 High-grade central chondrosarcoma. A Radiograph showing mainly os­ teolytic, ill-defined lesion in the proximal femur (arrows). There are small calcifica­ tions centrally. B Coronal reconstruction of CT showing an osteolytic, ill-defined le­ sion in the proximal femur (arrows). Tunnelling is depicted in the cortex at the minor trochanter. C Coronal gadolinium chelate-enhanced fat-suppressed MRI. Centrally septonodular enhancement typical for cartilaginous tumour is seen. Apart from size (> 5 cm), there are several features indicating the presence of high-grade chondrosar­ coma rather than atypical cartilaginous tumour. In the periphery, enhancement is more homogeneous. Peripheral to the tumour, intraosseous and extraosseous ill-defined reactive changes are enhancing. Also, high signal in cortical bone medially and cir­ cumferential periostitis are visualized. D Whole-body maximum intensity projection of FDG PET shows markedly increased FDG uptake in the lesion, consistent with high­ grade sarcoma and not atypical cartilaginous tumour.

in the FDG uptake of grade 2 or 3 chondrosarcoma (with a maximum standardized uptake value of > 4.4 with specificity of 99%) versus that of enchondroma and ACT (with a stand­ ardized uptake value of < 2); however, 46% of tumours are in the indeterminate 聞ge, with standardized uptake values of 2-4.5 {1802}.

Bone tumours

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Fig.3.40 High-grade central chondrosarcoma. A Axial T2-weighted fat-suppressed image shows the cortical involvement and the periosteal and soft tissue reactive change： as high signal intensity. The intraosseous tumour component has an inhomogeneous mainly high signal intensity, consistent with mucoid areas (non-enhancing on gadolinium chelate images) and cellular areas (enhancing on gadolinium chelate images). B Axial gadolinium chelate-enhanced fat-suppressed MRI. Centrally septonodularenhancemec typical for cartilaginous tumour is seen. Apart from size (> 5 cm), there are several features indicating the presence of high-grade chondrosarcoma rather than atypical cartilao nous tumour. In the periphery, enhancement is more homogeneous. Peripheral to the tumour, intraosseous and extraosseous ill-defined reactive changes are enhancing. Hig「 signal in cortical bone medially and circumferential periostitis are also visualized.

Pathogenesis

Fig. 3.41 High-grade central chondrosarcoma. This tumour involves the proximal fe­ mur. Note the haemorrhagic and necrotic areas, and the cortical scalloping.

Epidemiology The incidence of grade 2 and 3 central chondrosarcoma was 0.95 cases per 1 millio n pers on -years in 1989-1996 and 1.81 cases per 1 million person-years in 2005-2013 {3167}. Adults in the third to sixth decades of life are predominantly affected, with an equal sex distribution. Patients with central chon drosarcoma in enchon dromatosis are gen erally you nger than patients with primary chondrosarcoma. In patients with enchondromatosis, the overall risk of developing chondrosar­ coma is about 40%, which is less when enchondromas are confined to the hands and feet, and in creases when the long bones or bones of the pelvis are also involved {3193}.

About half of these tumours carry IDH1 or IDH2 mutations, suggesting that they have progressed from enchondroma and ACT/ CS1. Grade 2 and 3 central chondrosarcomas are character­ ized by aneuploidy and complex karyotypes {410,1963,30331 Polyploidization of an initially hyperhaploid/hypodiploid cell population is a common mechanism of progression in a subset {1280,2382}. Alterations in the p53 and RB1 signalling pathways are involved in tumour progression; the RB1 pathway is affected in 86% of high-grade chondrosarcomas {2782,3148}, including by loss of p16 and overexpression and/or amplification of CDK4 {179,2782,2401,3051}. TP53 is mutated in 20-49% of the cases, whereas mutations in CDKN2A (encoding p16) are infrequent {179,378,1910}. For central chondrosarcoma, several active sig­ nalling pathways have been identified (384,2920), which might provide novel treatment options, such as hedgehog signalling {386,2676,3074,1284}, mTOR signalling {17}, SRC and AKT {2781}, and metabolic pathways {350,2677,2500,2501}. Mem­ bers of the BCL2 family seem to play an important role in the chemoresistanee of chondrosarcoma {3165,759}. Mutations in the COL2A1 gene were found in about 45% of central chondrosarcomas {3051,3094}. The COL2A1 gene encodes the alpha chain of type II collagen fibres, which are a major component of the cartilaginous matrix. CDKN2A copy­ number variation occurs in about 75% of high-grade central chondrosarcomas and not in enchondroma or central ACT/CS1 {99}. Additional recurrent mutations involve YEATS2 (12.3%). EGFR (19%), NRAS (p.Gln61Lys and p.Gln61His; up to 12%). and IHH signalling (18%) {3051,3094,3398,1910}.

Etiology Patients with enchondromatosis, carrying a somatic mosaic mutation in IDH1 or /D/72 {93,96,2430}, are at increased risk of progression towards chondrosarcoma, depending on the localization of the tumours (see Enchondromatosis, p. 506).

:umours

Macroscopic appearance Resection specimens reveal a translucent, often lobular, bluishgrey or white cut surface. Cystic changes can be seen, as well as areas of myxoid material. Calcification can be visibe

paybal：https://www.paypal.me/andy19801210 yellowish-white chalky areas. Erosion and destruction of the

；rtex with soft tissue extension are frequently present. Exten■ e sampling is needed to rule out areas of dedifferentiation F j chondroblastic osteosarcoma.

Histopathology

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tive changes n gadolinium nhancemeni ical cartilagiancing. High

‘The tumours are cellular with an overall lobular con figuration in which the tumour lobules permeate and entrap the pre-existing t)one trabeculae {2155}. The tumour cells are embedded within Me cartilaginous matrix, which can still be hyaline but most Mten shows myxoid changes to a variable extent. The cellularity g higher than in ACT/CS1 and mitoses are present. The nuclei can still be small and condensed, and severe condensation of 惟 nuclei may hamper the detection of mitoses. More often the nuclei vary in size, with open chromatin and a visible nucleolus. Nuclear atypia can be present but is usually not severe. Binudeation can be seen and necrosis can be present. In grade 3 chondrosarcomas, mitoses are more easily found, and the cells at the periphery of the mostly myxoid, highly cellular tumour lobules are spindled and less differentiated. These spindled cells gradually merge with the fibrous cells in the fibrous septations SUrrounding the lobules that contain numerous small vascular channels and immune cells. The tumours often destroy and grow through the cortex.

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Immunohistochemistry ons, sugand ACT/ :haracter53,3033). jloid cell a subset pathways ;affected including i of CDK4 ie cases, [frequent ctive sigich mighl signalling and AKT 1}. MemDie in the

Tumours can be positive for S100 {2853} and are negative for brachyury {3210}. The p.Arg132His mutation-specific IDH1 antibody only recognizes a small percentage of the IDH muta­ tions in chondrosarcoma, and its usefulness is therefore limited (93,2430,96}.

Grading

Fig.3.42 Central chondrosarcoma. A High-grade. A low-power view showing per­ meative growth pattern, in which the pre-existing bone trabeculae are entrapped by the tumour, filling the marrow cavities. B Grade 2. This low-power view demonstrates the typical lobular growth pattern. There are extensive myxoid matrix changes.

The tumour must be graded on the areas dem on strati ng the highest grade. It should be noted that histological grading is subject to in terobserver variability {883,2886}. Histological grading does not appear to be useful for central chondrosarcomas located in the phalanx {387}. Grade 2 chondrosarcoma is separated from ACT/CS1 predominantly on the basis of its in creased cellularity, a greater degree of n uclear atypia,

hyperchromasia, nuclear size, myxoid matrix changes, and the presenee of mitoses. Grade 3 chondrosarcoma is highly cellular and more pleomorphic, mitoses are more easily found, and the cells at the periphery of the mostly myxoid tumour lobules are spin died and less differe ntiated.

it 45% of A1 gene vhich are 2A copye cent制 ACT/CS1 (12.3%). to 12%)， Rg‘3.43 Central chondrosarcoma. A Grade 2. Cellularity is increased compared with atypical cartilaginous tumour/chondrosarcoma, grade 1 (ACT/CS1). The matrix is hyaline,

ir, bluishseen, as )e visible

岫focal myxoid changes. B Grade 2. This high-power view shows extensive myxoid matrix, increased cellularity, and more nuclear atypia compared with ACT/CS1. C Grade 'High cellularity, myxoid matrix changes, and spindle cell changes. Mitoses are easily seen.

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paybal：https://www.paypal.me/andy19801210 Differential diagnosis

Staging

Chondrosarcoma in the skull base should be distinguished from chordoma, in cludi ng the chon droid subtype. Grade 3 chon drosarcoma can resemble chondroblastic osteosarcoma.

Staging is according to bone sarcoma protocols (see TNMst J ing of tumours of bone, p. 339). See also the information °

Cytology

Prognosis and prediction

Not clinically re leva nt

Patients are usually treated with en bloc resection to obtain ne( ative margins {1132}. The reported 5-year overall survival ratefo grade 2 chondrosarcoma is 74-99% and for grade 3 tumour! 31-77% {113,1161,1079,947,3167,864,2328}. The 10-year over all survival rate for grade 2 is 58-86% and for grade 3 tumourz-^ Z-X I— L C , '~ r1 」' 1 ' 八 26-55%. Even after 10 years, deaths due to disease can stil occur {864}. Local recurrence rates are 19% for grade 2 anc 26% for grade 3 chondrosarcoma {113}; 10-30% of the grade ； tumours and 32-71% of the grade 3 tumours metastasize 1113 1079,947,334}. Chondrosarcomas with axial localization have a significantly lower survival than extremity chondrosarcomi {864,325,1079,3167}. It is unclear at present whether the IDH mutation is associated with outcome {1910,2430,618}.

Diagnostic molecular pathology Molecular analysis is not needed for diagnosis in most cases. Detection of mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 may be helpful in distinguishing these tumours from chondroblastic osteosarcoma {93}.

Essential and desirable diagnostic criteria Essential: origin in the medulla of the bone; lobulated cartilaginous tumour with entrapment of pre-existing host bone; in creased cellularity, myxoid matrix, and prese nee of mitoses; absence of osteoid deposition associated with malignant cells.

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staging in Bone tumours: Introduction (p. 340).

paybal：https://www.paypal.me/andy19801210 Secondary peripheral chondrosarcoma, grades 2 and 3

Bovee JVMG Bloem JL Flanagan AM Nielsen GP Yoshida A

Definition

Imaging

Grade 2 and 3 sec on dary peripheral chon drosarcomas are mtermediate-grade to high-grade malignant cartilaginous matrix-producing neoplasms originating at the surface of the bone in a pre-existing osteochondroma.

9220/3 Chondrosarcoma, grade 2 9220/3 Chondrosarcoma, grade 3

Because grade 2 and 3 peripheral chondrosarcomas are very rare compared with peripheral atypical cartilaginous tumour / chondrosarcoma, grade 1 (ACT/CS1), no specific radiological criteria have been validated. Radiological features in the adult population that favour the presenee of a higher-grade peripheral chondrosarcoma are solid enhancing areas, mucoid degeneration, irregular ossification, and cartilaginous cap thickness largely exceeding 2 cm.

ICD-O coding

ICD-11 coding

Epidemiology

2050.Z & XH6LT5 Chondrosarcoma of bone and articular carti­ lage of unspecified sites & Chondrosarcoma, grade 2 2B5O.Z & XH0Y34 Chondrosarcoma of bone and articular carti­ lage of unspecified sites & Chondrosarcoma, grade 3

Grade 2 or 3 sec on dary peripheral chon drosarcomas are very rare (accounting for only -9% of chondrosarcomas arising in osteochondroma) {45} and arise mainly in patients aged 20-40 years {980}.

Related terminology

Etiology

Not recommended: chondrosarcoma sec on dary to osteoch on droma.

Patients with the multiple osteochondromas syndrome are at in creased risk (-5%) of developi ng sec on dary peripheral cho ndrosarcoma within an osteochondroma {3285,1823,2767,980}. See Multiple osteochondromas (p. 517).

Subtype(s) None

Localization

Pathogenesis

These tumours most commonly arise in osteochondromas of the pelvis, trunk, and proximal femur {45}.

Whereas in sec on dary peripheral ACT/CS1, EXT-muta nt cells and EXT-wildtype cells coexist, in high-grade sec on dary peripheral chondrosarcoma, the EXT-wildtype cells predominate {751}. Similar to grade 2 and 3 central chondrosarcoma, these chon drosarcomas display chromosomal in stability and a complex karyotype that increases with increasing histological grade {378,1280}, probably caused by alterations in the p53 and RB1 pathways {1280,754,3051}.

Clinical features Signs and symptoms Enlargement or pain in a longstanding mass, especially after puberty, should raise suspicion for malignancy {45}. Neurologi­ cal symptoms and limited joint motion can be present.

Rg.3.44 Secondary peripheral chondrosarcoma arising in a patient with multiple osteochondromas. A Conventional radiograph (left) and surgical specimen (right) of the right Proximal fibula. Note the thickness of the cartilaginous cap (> 2 cm), flaring of the cortex (macro), and indistinct margins with irregular mineralization (radiograph). B Discrete

缨pheral nodules of cartilage are embedded in the soft tissue at the periphery of the lesion. These features explain the irregular margins and the possibility of local recurrence when the lesion is resected with inadequate surgical margins.

Bone tumours

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9

Fig. 3.45 Secondary peripheral chondrosarcoma. A Grade 2 chondrosarcoma with increased cellularity and myxoid matrix changes. B Grade 3 chondrosarcoma with' creased cellularity, myxoid matrix changes, and spindled cells. Mitoses are easily found.

Macroscopic appearance

Cytology

These lesions are translucent lobular bluish-white tumours in which there may be areas with myxoid material and cystic changes. The stalk of the pre-existing osteochondroma might still be recognized; the cap size exceeds 2 cm.

Not clinically relevant

Diagnostic molecular pathology Molecular analysis is rarely n eeded for diag no sis. Mutations in IDH1, IDH2, and NRAS are absent {93,2430,3398}.

Histopathology Grade 2 and 3 secondary peripheral chondrosarcomas are lob­ ular cartilaginous matrix-producing tumours that are morpho­ logically identical to grade 2 and 3 central chondrosarcomas. Sometimes areas of endochondral ossification suggestive of pre-existing osteochondroma can be seen. Nuclear pleomor­ phism and mitoses are often easily seen. At the periphery of the neoplastic cartilaginous lobules, spindle cell changes may occur. Coarse and irregular calcification, binucleated cells, cys­ tic change, and necrosis can be observed.

Essential and desirable diagnostic criteria Essential: chondrosarcoma arising in a pre-existing osteochon­ droma or with evidence of the stalk of a precursor osteochon­ droma; cartilage cap exceeds 2 cm; mitoses and nuclear pleomorphism are present.

Staging Staging is according to bone sarcoma protocols (see TNM staging of tumours of bone, p. 339). See also the information on staging in Bone tumours: Introduction (p. 340).

Immunohistochemistry These tumours can be positive for S100 {2853}.

Prognosis and prediction

Grading

Local recurre nces can occur, gen erally related to in complete excision. The majority of patients who die of their disease have local recurrenee {45}.

Criteria for histological grading are identical to those for grade 2 and 3 central chondrosarcoma {947}.

Differential diagnosis Periosteal osteosarcoma is included in the differential diagno­ sis. Peripheral chondrosarcoma is separated from central chon­ drosarcoma based on its location at the surface of the bone.

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paybal：https://www.paypal.me/andy19801210 Cl eve n AHG Bloem JL Tirabosco R

periosteal chondrosarcoma

Qefinition

Imaging

Periosteal chondrosarcoma is a malignant cartilaginous neoplasm that occurs on the surface of bone in close association with the periosteum and invades the underlying cortex or is >5 cm.

Periosteal chondrosarcoma is usually located in the metaphy­ sis, and it often shows a large lobulated mass (> 5 cm) located on the cortex {528,1172,2314}. The cortex may be thickened or thinned, but bone marrow involvement is rare. A calcified shell may be seen.

ICD-O coding 9221/3 Periosteal chondrosarcoma

ICD-11 coding 2850.Z & XH1S32 Chondrosarcoma of bone and articular carti­ lage of unspecified sites & Periosteal chondrosarcoma

Epidemiology Periosteal chondrosarcoma is a rare chondrosarcoma sub­ type, representing about 2.5% of all chondrosarcomas {2509}. Periosteal chondrosarcoma has a peak incidence in the third decade of life, with a wide age range (9-79 years) and a male predominance {616}.

Related terminology Not recommended: juxtacortical chondrosarcoma.

Etiology Unknown

Subtype(s) None

Pathoge nesis

Localization

A subset of periosteal chondrosarcomas bear the same IDH1 and IDH2 mutations as enchondroma and conventional central chondrosarcoma {93,616,2430}.

Periosteal chondrosarcoma predominantly affects the metaphy­ sis of long tubula r bon es, most comm only the distal femur, fol­ lowed by the humerus {1172}.

Clinical features Signs and symptoms Patients with periosteal chondrosarcoma frequently present with pain, with or without swelling or limitation of movement {1172}.

Macroscopic appearance A large (often > 5 cm) lobulated mass is located on the surface of the bone {2314}. On cut section, the tumour is grey and glistening and is often associated with gritty white areas of calcification. The tumour erodes or invades the cortex; the medullary canal is usually not involved.

Fig，3.46 Periosteal chondrosarcoma. A Conventional radiograph of the left humerus, with a periosteal tumour extending into the soft tissue. B Axial T1-weighted MRI (with fat

Oppression after intravenous contrast administration) showing a periosteal tumour (diameter: 5.5 cm) with septonodular enhancement typical for a cartilaginous tumour. C Gross Matures of the same periosteal chondrosarcoma show a large lobulated cartilaginous tumour (diameter: 5.5 cm) at the surface of bone, with growth into the cortex.

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paybal：https://www.paypal.me/andy19801210 Histopathology A lobular, moderately cellular cartilaginous tumour is seen with myxoid matrix. Calcification and endochondral ossification can be present {528,2314,616}. Osteoid or bone directly formed by the tumour cells is absent, although formation of metaplastic bone at the periphery of the cartilage lobules and the tumour (formation of a so-called neocortex) can be found {528,2314, 616}. The features resemble those of atypical cartilaginous tumour / chondrosarcoma, grade 1 (ACT/CS1) or grade 2 cen­ tal chondrosarcoma {528,2314,616}. There is often invasion of the underlying cortex. Intramedullary extension and subsequent host bone entrapment are seen in a subset of cases. Demarcation with the soft tissue is usually sharp {528,2314, 616}.

Differential diagnosis The d iffere ntial diag nosis also inc ludes periosteal chon droma, periosteal osteosarcoma, and parosteal osteosarcoma. The distinction between periosteal chondroma and chondrosarcoma is based on cortical invasion. In periosteal chondrosarcoma, the tumour is often > 5 cm {528,2314,616,1453}.

Grading Histological grading is not applicable {616}.

Cytology Not clinically releva nt

Diagnostic molecular pathology Although IDH1 and IDH2 mutations are found in a subset of periosteal chondrosarcomas {93,616,2430}, mutatio n analysis is rarely used in the diagnostic work-up for periosteal chondrosarcoma. It might be used to distinguish periosteal chondrosarcoma and periosteal osteosarcoma, the latter being negative. The EXT1 protein is normally expressed, whereas RB1 signalling can be deregulated by loss of p16 expression, and WNT/p-catenin signalling is lost in the majority of cases. Amplification of CDK4 or MDM2 is absent, unlike in parosteal osteosarcoma {616}.

Essential and desirable diagnostic criteria Essential: cartilaginous tumour arising on the surface of bone in close association with periosteum; invasion of the underlying cortex or size > 5.0 cm.

Fig. 3.47 Periosteal chondrosarcoma. A Cortical extension (arrowhead) of the car­ tilaginous tumour. B Occasionally, cartilage tumour lobules may be observed in the medullary bone (arrowheads). C Formation of metaplastic bone (arrowhead) on the edges of the cartilaginous lobules.

Staging The Union for International Cancer Control (UICC) TNM classifi­ cation of malignant tumours {423} does not recommend that the TNM staging system for bone tumours be applied to surface/ juxtacortical osteosarcoma or juxtacortical chondrosarcoma. However, other staging systems, such as the American Joint Committee on Cancer (AJCC) TNM system {101}, do include these tumours in the bone staging system. See also the information on staging in Bone tumours: Introduction (p. 340).

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Bone tumours

Prognosis and prediction Periosteal chondrosarcomas have a relatively low metastatic rate (5-12.2%), and metastases especially involve the lungs and rarely the lymph nodes {1172}. Histological grading does not predict outcome {616}.

paybal：https://www.paypal.me/andy19801210 Baumhoer D Bloem JL Oda Y

Qlear cell chondrosarcoma

pefinition Clear cell chondrosarcoma is a low-grade malignant cartilagin0US epiphyseal neoplasm characterized by lobules of cells with abundant clear cytoplasm.

ICD-O coding 9242/3 Clear cell chondrosarcoma

ICD-11 coding 2550.Z & XH7XB9 Chondrosarcoma of bone and articular carti­ lage of unspecified sites & Clear cell chondrosarcoma

Related terminology None

Subtype(s) None

Localization Approximately two thirds of clear cell chondrosarcomas develop in the femoral and humeral head. However, tumours have been reported in most bones of the skeleton, including in the ribs, skull, spine, han ds, and feet.

Clinical features Signs and symptoms Pain is the most common presenting symptom: 55% of patients experieneed pain for > 1 year; 18% had symptoms for > 5 years |335}.

Imaging Radiographically, clear cell chondrosarcoma presents as a well-defined, purely lytic lesion in the epiphysis of a long bone that may extend into the metaphysis. A sclerotic rim may be present. Some lesions may contain stippled radiodensities, characteristic of cartilage. On MRI, clear cell chondrosarcoma shows a specific low sign al inten sity on T1-weighted images and moderate or marked high signal on fluid-sensitive images 1647}. Clear cell chondrosarcoma and chondroblastoma can be difficult to distinguish radiologically {1562}.

Fig. 3.48 Clear cell chondrosarcoma. A Plain radiography shows a well-defined lytic lesion with calcification in the femoral head and neck. B Coronal reformatted CT high­ lights the intramedullary tumour with spotty mineralization.

Pathogenesis Cytogenetic analyses of small series have revealed clonal abnormalities, with diploid or near-diploid complements pre­ dominating and loss or structural aberrations of chromosome 9 and gain of chromosome 20 {2925,2405,1963,2880,2309}. CDKN2A alterations appear to be infrequent, although all clear cell chondrosarcomas examined lacked expression of p16 (CDKN2A) {2447,2055}. p53 overexpression is frequently found in the absenee of detectable mutations {2448}. Neither IDH1 nor IDH2 mutations are present (93,2054). One of 15 clear cell chondrosarcomas investigated for H3.3 mutations to date has shown an H3-3B (H3F3B) p.Lys36Met mutation, a highly spe­ cific driver mutation of chondroblastoma, suggesting a pathogenetic relation in at least a small subset of tumours {257}.

Macroscopic appearance Lesions range from 2 to 13 cm in maximum diameter. They contain soft but gritty material, sometimes with cystic areas. Gross features characteristic of hyaline cartilage can be focal or absent.

Epidemiology Clear cell chondrosarcomas account for approximately 2% of all chondrosarcomas {2537}. Men are almost three times as likely t0 develop clear cell chondrosarcoma as women. The reported age range is 12-84 years {335,1481), but most patients present in their third to fifth decades of life. Rarely, synchronous tumours have been reported {1967}.

Etiology Unknown

Histopathology The tumours consist of lobules of cells with abundant pale, clear or slightly eosinophilic cytoplasm, which resemble hypertrophic cells of the growth plate {48,380}. The cells have distinct cyto­ plasmic membranes and large round nuclei with only minor atypia and central nueleoli. Mitotic figures are rare. Further characteristics frequently observed in elude regularly distrib­ uted woven bone formation with intermingled osteoclast-like giant cells. Areas of conventional low-grade chondrosarcoma with minimally atypical nuclei can be observed in about half of Bone tumours

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B Fig.3.50 Clear cell chondrosarcoma. A Tumour cells stain strongly with antibodi against S100. B Tumour cells focally show positivity for pancytokeratin AE1/AE3.

Differential diagnosis The differential diagnosis includes metastatic clear cell ren： cell carcinoma, chondroblastoma, and osteosarcoma, as we as (depending on localization) a notochordal tumour.

Cytology Not clin ically releva nt

Diagnostic molecular pathology Not clinically re leva nt Fig. 3.49 Clear cell chondrosarcoma. A Low-power view of the transition to lowgrade clear cell chondrosarcomatous areas. B Round or polygonal cells with slightly eosinophilic cytoplasm are arranged in lobules and sheets, admixed with trabeculae of woven bone. C High-power view of clear cell chondrosarcoma; note the abundant cytoplasm, with the centrally placed nucleus with central nucleolus.

cases {3129}. The hyaline cartilage can become calcified and/ or ossified, which can be detected radiologically as a cartilage­ type pattern of mineralization. Areas of cystic degeneration resembling aneurysmal bone cyst can also occur. Infiltrative growth can be seen.

Essential and desirable diagnostic criteria Essential: clear cells with abundant cytoplasm and a centrally placed nucleus; presenee of woven bone and osteoclast-like giant cells. Desirable: epiphyseal location.

Staging Staging is according to bone sarcoma protocols (see TNMstag­ ing of tumours of bone, p. 339). See also the information on staging in Bone tumours: Introduction (p. 340).

Prog nosis and prediction

Immunohistochemistry Immunohistochemically, the clear cells are strongly positive for S100, as well as for collagen types II and X {48}. They also show occasional immunoreactivity for cytokeratins (AE1/AE3 and CK18) {2016}.

384

Bone tumours

En bloc resection with clear margins is usually curative. Marginal excision or curettage results in high recurrenee rates of up to 86% {2537,335}. Metastases, usually to the lungs and other skeletal sites, develop in 15-20% of cases. The overall mortality rate is 15% {1484}. Dedifferentiation to high-grade sarcoma has been reported in 3 cases {1563}.

paybal：https://www.paypal.me/andy19801210 Fanburg-Smith JC de Pinieux G Ladanyi M

Mesenchymal chondrosarcoma

Definition Mesenchymal chondrosarcoma is a high-grade, malignant, biphasic, primitive mesenchymal tumour with a well-differentiated, orga nized hyali ne cartilage comp orient.

ICD-O coding 9240/3 Mesenchymal chondrosarcoma

ICD-11 coding 2B5O.Z & XH8X47 Chondrosarcoma of bone and articular car­ tilage of unspecified sites & Mesenchymal chondrosarcoma

Related terminology None

Subtype(s) None

Localization These tumours have widespread an atomical distributio n in bone, soft tissue, and intracranial sites {962}. Intraosseous lesions are mainly in the craniofacial region (50% jaw) {3186, 525), ribs or chest wall, ilium, vertebrae (sacral/spinal), or lower extremities (especially femur) {962}. Within bone the tumour usually presents in the medulla; location on the bone surface is less comm on {1711}. Overall, approximately 40% of cases affect the somatic soft tissue {1240}. The meninges are one of the most comm on extraskeletal sites {962}. Visceral locati on is unusual and includes the kidney {963,2822,2772,1071,988}.

Clinical features Signs and symptoms The cardinal symptoms are pain and swelling {3110}. About 15% of patients present with metastasis {1071}.

Fig. 3.51 Mesenchymal chondrosarcoma involving the left pedicle of the eighth tho­ racic vertebra. A CT showing an osteolytic and destructive lesion with irregular cal­ cification accompanied by extraosseous extension into the soft tissue in the vertebral foramen and spinal canal. B T1-weighted MRI. C T1-weighted MRI with gadolinium enhancement. D T2-weighted MRI.

30 years {962,963}. There is a minimal male predilection (M:F ratio: 1.3:1) {962,963,1071,2772,3325}.

Imaging On radiological imaging, skeletal lesions are primarily lytic and destructive, with poor margins {2226}. Mottled calcification can be prominent. Some have well-defined margins with a sclerotic 「im. Expansion of the bone is frequent, and cortical destruction or cortical breakthrough with extraosseous extension into the soft tissue is common. Bone sclerosis, cortical thickening, and superficial involvement of the bone surface may be observed. 加agi ng features of extraskeletal tumours are also non specific, demon strati ng chon droid-type calcificati ons and foci of low signal intensity within enhancing lobules. This tumour takes up contrast medium on CT or MRI.

Etiology Unknown

Pathogenesis A highly specific recurrent gene fusion between HEY1 and NCOA2 occurs in almost all mesenchymal chondrosarcomas {3231}. Mesenchymal chondrosarcomas are thought to arise from early, immature cartilage cells (chondroblastsj, which dif-

ferentiate into well-differentiated hyaline cartilage and then often undergo endochondral ossification to bone {963}. The cartilage to bone production in this region invoIves the WNT/卩-catenin pathway {963}.

Epidemiology Mesenchymal chondrosarcomas account for 2-4% of all chondrosarcomas. The peak incidence is in the second and third decades of life, with a wide age range and a median age of

Macroscopic appearance The tumours are variably grey/white/pink, firm to soft, and usu­ ally circumscribed masses, 0.9-30 cm in maximum diameter. Bone tumours

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Fig. 3.52 Mesenchymal chondrosarcoma. This gross pathology picture of a bone surface tumour demonstrates a well-delineated and circumscribed tumour with zonal white cartilaginous (closer to bone surface) and tan-pink solid components.

Fig. 3.53 Mesenchymal chondrosarcoma. Mesenchymal chondrosarcoma ma\ commonly show spindle cell morphology and eosinophilic matrix resembling oste

Most lesions contain hard mineralized deposits that vary from dispersed foci to promine nt areas; often either the cartilagi nous comp on ent or the sheeted rou nd cell comp on ent with n ecrosis and haemorrhage may predominate {962,963,1450}.

well-differentiated hyaline cartilage. Spindle cell morphoh can be present. In areas, the matrix may mimic osteoid depi tion. -i

Histopathology

Tumour cells can be positive for S100, CD99, and SOX9 |963| FLU is negative {1795}. Aberrant expression of EMA, desmm myogenin (MYF4), and MYOD1 may be identified, whereas SMARCB1 (INI1) is retained {962,1053}. SMA, GFAP, and keratins are negative {962}.

Immunohistochemistry Mesenchymal chondrosarcoma is composed of small to medium-sized, poorly differentiated round cells with a high N:C ratio and a characteristic staghorn or pericytoid vascu­ lar pattern, admixed with various proportions of islands of

Fig. 3.54 Mesenchymal chondrosarcoma. A Round cells with central zonal cartilage and bone. B Staghorn or pericytoid vascular pattern present in the undifferentia area. C A round cell tumour of undifferentiated tumour cells, which may be seen in small biopsies. D Linear progression from resting chondrocytes to proliferating to hypertrop1 to endochondral ossification to bone.

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paybal：https://www.paypal.me/andy19801210 Differential diagnosis

Essential and desirable diagnostic criteria

When the undifferentiated component is biopsied alone, there ■ ay be confusion with other small cell neoplasms.

Essential: undifferentiated tumour cells with a high N:C ratio; islands of cartilage. Desirable: staghorn vascular pattern; HEY1-NCOA2fusion.

Cytology There is a biphasic appearance of medium-sized cells, oval to spindled in CNS tumours, that have a high N:C ratio and basoohilic extracellular matrix {3100,962,963}.

Staging Staging is according to bone sarcoma protocols (see TNM stag­ ing of tumours of bone, p. 339). See also the information on staging in Bone tumours: Introduction (p. 340).

Diagnostic molecular pathology Mesenchymal chondrosarcoma harbours a recurrent HEY1NC0A2 rearrangement {3231}, representing an in-frame fusion of HEY1 exon 4 to NCOA2 exon 13 at the mRNA level. This fuSion is detected in almost all well-characterized mesenchymal chondrosarcomas tested, and it is absent in other subtypes of chondrosarcomas. Given that HEY1 and NCOA2 are only approximately 10 Mb apart on chromosome 8, mapping lo 8q21.13 and 8q13.3, respectively, and that both are in the same orientation, this fusion may arise via a small interstitial deletion, del(8)(q13.3q21.1), which is difficult to detect in most conventional cytogenetic preparations. The consistent molecu­ lar detection of the HEY1-NCOA2\us\on in this sarcoma estab­ lishes it as a defining molecular diagnostic marker {891}. A recent study using genome-wide array-based methylation profiling found that mesenchymal chondrosarcomas form a very distinct methylation cluster {1665}. Finally, although > 90% have (he highly recurrent HEY1-NCOA2^s\on, there has been a sin­ gle case report of a mesenchymal chondrosarcoma bearing an IRF2BP2-CDX1 fusion gene generated by a t(1;5)(q42;q32) |2337}. Downregulation of the RB1 pathway has been reported 12054}, and IDH1 and IDH2 mutations, characteristic of conventional chondrosarcoma, are absent {93,2054}.

Prognosis and prediction Mesenchymal chondrosarcoma is an aggressive neoplasm, with estimated overall 5-year and 10-year survival rates (which range from study to study) as high as 60% and 40%, respec­ tively. Dista nt metastases are occasi on ally observed eve n after a delay of > 20 years. The clinical course is frequently protracted and relentless, requiring Iong-term follow-up. There are no histological features correlative with prog no sis. The presence of metastatic disease at initial presentation, tumour size, and (to a lesser degree) original site of the tumour, have been dem on strated to have an impact on survival in mese nc hymal chondrosarcoma {1071,2772,3325,3110,891}. Children, adolescents, and you ng adults tend to have a slightly better outcome {1102,962,963}. Craniofacial origin appears to be associated with a more in dole nt course and favourable prog no sis, whereas axial origin has worse outcome. Complete resection combined with chemotherapy should be considered the standard of care (1071,2772,3325,3110,891,2196).

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paybal：https://www.paypal.me/andy19801210 Dedifferentiated chondrosarcoma

Definition Dedifferentiated chondrosarcoma is a high-grade subtype of chondrosarcoma with the bimorphic histological appearanee of a conventional chon drosarcoma comp orient with abrupt transi­ tion to a high-grade, non-cartilaginous sarcoma.

In wards CY Bloem JL Hogendoorn PCW

invoIvement follows that of conventional chondrosarcoma pelvis, scapula, and ribs {2675,2930}.

Clinical features Signs and symptoms

9243/3 Dedifferentiated chondrosarcoma

The most common clinical presentations include pain and palpable mass. Pathological fracture is found in about 20% ； patients {1224}.

ICD-11 coding

Imaging

2B50.Z & XH6E77 Chondrosarcoma of bone and articular carti­ lage of unspecified sites & Dedifferentiated chondrosarcoma

Imaging findings are usually indicative of an aggressive destructive tumour, often with a heterogeneous radiological presentation of both conventional chondrosarcoma (the presence of ring-like densities) and lytic, permeable, destructive areas. Bimorphic features, suggesting dedifferentiation, are seen on CT in approximately 50% of histologically proven cases and on MRI and radiographs in 30%. These features in elude a dominant lytic area within, or adjacent to, a mineralized tumour on radiographs and a large unmineralized soft tissue mass {1874}. Rarely, dedifferentiation occurs in secondary periphera! chondrosarcoma {2675}. The imaging characteristics of central and peripheral dedifferentiated chondrosarcomas are similar {1347}.

ICD-0 coding

Related terminology None

Subtype(s) None

Local izatio n The most comm on sites of in volvement are the femur (46%), pelvis (28%), humerus (11%), and scapula (5%) {1224}. In dedif­ ferentiated peripheral chondrosarcoma, the preferred site of

A Fig.3.55 Dedifferentiated chondrosarcoma. Anteroposterior radiograph (A) and sagittal fat-suppressed T2-weighted MRI of the humerus (B) demonstrate imaging features of

a high-grade chondrosarcoma. The radiograph and MRI show, in the intramedullary portion of the mid- and proximal humeral diaphysis, chondroid matrix with homogeneous high signal, associated expansion, cortical permeation, irregular periosteal reaction, and soft tissue reactive oedema or even tumour extension. More proximally, the more ag­ gressive part of the tumour shows an area with more lytic destruction with an associated pathological fracture and an adjacent soft tissue mass containing amorphous osteoi

matrix. C Corresponding resection specimen of the dedifferentiated chondrosarcoma. The greyish-white hyaline cartilage component fills the medullary cavity, whereas fleshy, tan and reddish-brown high-grade sarcoma component involves surrounding soft tissue.

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Fig,3・56 Dedifferentiated chondrosarcoma. A There is an abrupt transition between the low-grade chondrosarcoma and high-grade sarcoma components. B The high-grade sarcorna in this dedifferentiated chondrosarcoma shows deposition of osteoid. C The high-grade sarcoma in this dedifferentiated chondrosarcoma is undifferentiated pleomorphic

sarcoma.

Epidemiology Dedifferentiation develops in 10-15% of central chondrosarcomas {1068,2928}. The median age of patients with dedif­ ferentiated chondrosarcoma is 59 years (range: 15-89 years), and there is a slight male predominanee {1224}. On very rare occasions, dedifferentiation of peripheral chondrosarcoma has been reported {2675}, and these patients are slightly younger (average: 46 years; range: 22-74 years) {2930}.

Etiology Unknow n

Pathogenesis The findi ng of identical TP53 a nd IDH mutati ons in the conven­ tional and dediffere ntiated comp onents in dicates a comm on origin of the components {93,379}. Potential genetic targets for treatment are under study and could be BCL2 family members and TGFB genes {3166}.

Macroscopic appearance The cartilaginous and non-cartilaginous components of the tumour are grossly evident in varying proportions. The bluishgrey, lobulated cartilage component is usually located centrally, whereas the fleshy, pale-yellow or tan-brown high-grade sar­ coma component is predominantly extraosseous or near the site of pathological fracture.

Histopathology There is an abrupt transition between the conventional hyahe cartilage and high-grade sarcoma comp on ents of dedif­ ferentiated chondrosarcoma {712}. The cartilaginous portion can range from enchondroma-like appearanee to grade 1 or grade 2 chondrosarcoma. The high-grade dedifferentiated component usually has the appearanee of a high-grade undifferentiated pleomorphic sarcoma or osteosarcoma. Less keque ntly, it dem on strates features of a high-grade an giosar-

coma, leiomyosarcoma, or rhabdomyosarcoma {2941}. Rare cases of dedifferentiated chondrosarcoma with epithelial di什erentiation, induding squamous, epithelial, and adamanGnoma-like, have been reported {3397,1552,1111}. The ratio

conventional to dedifferentiated is highly variable, and the Percentage of dedifferentiated component ranges from 2% to

98% (median: 60%) {2928}. Dedifferentiated chondrosarco­ mas usually show a poor histological response to preoperative chemotherapy.

Immunohistochemistry The immu nophe no type of the non-cartilagi nous component follows its histological line of differentiation, and keratin and desmin expression can be observed. A small subset of H3K27me3-deficient dedifferentiated chondrosarcomas histo­ logically resembling malignant peripheral nerve sheath tumour has also been described {1951}. Immunohistochemistry to detect an IDH mutation is of limited use because only a small percentage of the IDH1 mutations (< 20%) can be identified using the p.Arg132His mutation—specific IDH1 antibody {93}. p53 overexpression may be present, especially in the dedifferentiated component (59%), whereas MDM2 is overexpressed in 16% of the tumours in the dedifferentiated component {2054}. PDL1 expression has been reported in approximately 50% of dedifferentiated chondrosarcomas, a finding that may play a role in future imm unotherapeutic strategies {1686}.

Differential diagnosis It can be impossible to make a histological diagnosis of dedifferentiated chondrosarcoma on a limited amount of biopsy tis­ sue if only the high-grade sarcoma comp on ent is sampled. Correlatio n with imaging fin dings is crucial to come to the correct diagnosis. Because the characteristic IDH mutation is present in both components, mutation analysis can be helpful, although these heterozygous mutations are found in only 50-87% of cases {2054,558,93}. Cytokeratin positivity can be seen in the high-grade undifferentiated sarcoma component, making it dif­ ficult to disti nguish from metastatic sarcomatoid carci no ma. Careful review of radiological images and thorough sampling of resected tissue are helpful in ide ratifying the low-grade carti­ laginous component. Molecular studies revealing H3-3 (H3F3) mutations in dedifferentiated chondrosarcoma mimicking giant cell tumour of bone support the notion that some cases represent giant cell tumours of bone with cartilaginous differentiation {1615}.

Cytology Not clin ically releva nt

Bone tumours

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paybal：https://www.paypal.me/andy19801210 Diagnostic molecular pathology Dedifferentiated chondrosarcomas harbour complex karyo­ types {2054}. About 50-87% of dedifferentiated chondrosarcomas carry mutations in IDH1 or IDH2, which can be found in both the conventional chondrosarcoma and the dedifferentiated component {93,2430,558,2054,3397}. Because the two components share identical genetic aberrations, including the early IDH mutation, a comnnon precursor cell for the components is presumed {379,3397,2655,2054}. Additional genetic changes occur in the anaplastic component {379,2655}, indicating early diversion of the two components during the development of dedifferentiated chondrosarcoma. Mutations in TP53 are also frequently found {2054}.

Essential and desirable diagnostic criteria Essential: conventional chondrosarcoma juxtaposed to a high­ grade sarcoma, with a sharp interface. Desirable: IDH mutations present.

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Staging

Staging is according to bone sarcoma protocols (see TNM I ing of tumours of bone, p. 339). See also the informaticj8划 staging in Bone tumours: Introduction (p. 340).

Prog nosis and prediction Patients with dedifferentiated chondrosarcoma have a dism prog no sis, most often as a r esult of widespread lung metast； ses. Overall 5-year survival rates of 7-24% have been reported

(3

{821,1068,1224}. Treatment consists of surgery with wide radical margins. Poor prognostic factors include size > 8 爲 presenee of a pathological fracture, metastatic disease at diac； no sis, pelvic locati on, and inadequate surgical margi n or treat ment without surgery {1224,1835,1875,2965}. Chemother」 吒py and radiation therapy have not been shown to improve proqn, sis {821,1224,2317}.

paybal：https://www.paypal.me/andy19801210 Osteoma

Baumhoer D Bredella MA Sumathi VP

Definition Osteoma is a benign tumour arising on the surface of bone and composed primarily of lamellar/cortical-type bone. When osteoma develops within the medullary cavity, the term "bone island" is used.

ICD-0 coding 的80/0

Osteoma NOS

ICD-11 coding 2E83.Z & XH4818 Benign osteogenic tumours, unspecified & Osteoma NOS

Related terminology Osteoma Not recommended: ivory exostosis; parosteal osteoma; torus palatinus/ma ndibularis.

Bone island Not recommended: enostosis.

Subtype(s) None

Localizatio n Osteomas predominantly affect bone formed by membranous ossification, i.e. calvarial, facial, and jaw bones {1752}. They rarely occur outside the skull {298}. Intramedullary lesions gen­ erally originate in the epiphysis and metaphysis of long bones, the pelvic bones, and vertebral bodies.

Clinical features Signs and symptoms

Fig.3.57 Osteoma of the right frontal sinus. A Frontal radiograph. B Sagittal refor­ matted CT demonstrating an ossified mass arising on the surface of bone.

Osteomas are usually slow-growing and asymptomatic, but they can cause pain and headache, obstruction of the para na­ sal sinuses, and/or local swellings {1752}.

Imaging Osteomas are round, dense, well-defined ivory-like lesions, which are attached to the underlying bone without cortical invasion. The presenee of multiple osteomas suggests the diagno­ sis of Gardner syndrome {2991}. Bone islands are intramedullary lesions typically measuring < 1 cm, although larger lesions can occur (sometimes referred to as giant bone islands). Both osteomas and bone islands can grow slowly {1678}. Osteomas and bone islands may show mild radionuelide uptake on bone scan, mimicking a sclerotic metastasis. CT density measure­ ments can be used to distinguish these lesions from sclerotic metastases, using a cut-off point of > 885 Hounsfield units 曲27}. Bone islands in osteopoikilosis are usually bilateral and symmetrical in distribution, typically involving the metaphyseal Ed epiphyseal regions of tubular bone, although any bone

Fig. 3.58 Osteoma. Axial CT showing an osteoma of the right jaw angle (arrow). The tumour is arising on the surface of the bone and is homogeneously dense.

Bone tumours

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7

Fig. 3.59 Bone island. Axial CT shows an intramedullary dense bone island involving

the coracoid process.

may be affected {267}. On MRI, osteomas and bone islands are hypointense on T1- and T2-weighted images.

% Epidemiology Due to their high amount of inorganic matrix, osteomas are among the best-preserved and best-documented tumours in human history, dating back to the Late Period of ancient Egypt (664-332 BCE) {2807}. They affect men and women equally, whereas bone islands seem to be more common in males. Since osteomas commonly represent incidental findings, their actual prevale nee is difficult to determine but has bee n reported to reach 6.4% in selected case series {1800}.

Fig. 3.61 Bone island / enostosis. Low-power image of a bone island involving the medullary cavity of the proximal femur. The lesion is composed of lamellar/cortical-

type bone that merges with the surrounding trabecular bone.

Fig. 3.60 Osteoma. A Well-demarcated tumour composed of trabecular bone. B Osteoma of the frontal sinus. The tumour is composed of lamellar/cortical-type bone adjace

to sinus epithelium.

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paybal：https://www.paypal.me/andy19801210 Etiology

Histopathology

The etiology of sporadic cases is unknown. The presenee of multiple osteomas is suggestive of Gardner syndrome, a subtype of familial adenomatous polyposis {2991}; familial adenomatous polyposis is an autosomal dominant disorder caused by mutatio ns in the A PC gene. Multiple bone isla nds re observed in osteopoikilosis (spotted bone disease), an autosomal dominant disorder caused by loss-of-function mutations of the LEMD3 gene, with or without melorheostosis and/or dermatofibrosis (dermato-osteopoikilosis, BuschkeOllendorff syndrome) {446,2269,1685,2526,1345}. However, most cases of bone islands seem to represent hamartoma[ous Issions.

Osteomas are predominantly composed of mature lamellar/cortical-type bone and can be divided histologically into compact and (less frequent) spongious subtypes. In cancellous areas, a well-vascularized and moderately cellular and fibrous stroma fills the marrow spaces. Osteoblasts and osteocytes are gener­ ally inconspicuous; inflammatory infiltrates are typically absent. However, in the frontoethmoid region, conspicuous osteoblastic and osteoclastic activity may be present, mimicking osteoblas­ toma {2037,2023}.

pathogenesis

Diagnostic molecular pathology

LEMD3 encodes for an inner nuelear membrane protein that interacts with both the BMP and TGF-p signalling pathways and antagonizes both pathways in humans {446,2269,1685, 2526).

Not clinically relevant

Macroscopic appearance Osteomas arise on the surface of the bone and are typically well-circumscri bed tumours with a broad attach me nt to the underlying bone. Bone islands are intramedullary and com­ posed of compact bone that merges with the surrounding trabecular bone. Bone islands are usually small, although rare giant bone islands do occur.

Cytology Not clinically releva nt

Essential and desirable diagnostic criteria Essential: bone tumour with compatible imaging; tumour arises on the surface of bone or within the medullary cavity; tumour composed of lamellar/cortical-type bone.

Staging Not clin ically releva nt

Prognosis and prediction Asymptomatic cases generally do not require treatment and follow an in dole nt clin ical course; symptomatic cases can be conservatively excised.

Bone tumours

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paybal：https://www.paypal.me/andy19801210 Osteoid osteoma

Definition Osteoid osteoma is a benign bone-forming tumour character­ ized by small size (< 2 cm) and limited growth potential.

ICD-0 coding 9191/0 Osteoid osteoma NOS

ICD-11 coding 2E83.Z & XH61J9 Benign osteogenic tumours, unspecified & Osteoid osteoma NOS

Related terminology None

Subtype(s) None

Local izati on Long bones are affected in 50% of patients, particularly femur and tibia. Other typical locati ons in elude the small bones of the hands and feet and the spine, where the neural arch (posterior elements) are most comm only affected. Un comm on locations in elude flat bones; it is rare in the craniofacial bon es. Osteoid osteoma pref ere ntially invo Ives the cortex (75% of cases) and less frequently the medulla (25%); subperiosteal/surface lesions are rare.

Clinical features Signs and symptoms The usual prese nting symptom is pain. The pain, at first in termit­ tent and mild with nocturnal exacerbation, eventually becomes relentless to the point of interfering with sleep. In about 80% of patients, NSAIDs, even in small doses, completely, albeit tem­ porarily, relieve the pain {1336}. On physical examination, there is often an area of exquisite localized tenderness, redness, and swelli ng. Less comm on man ifestatio ns are site-depe ndent. For example, osteoid osteomas at the ends of long bones may present with swelling and effusion of the nearest joint, and intra-articular osteoid osteomas can result in osteoarthritis and ectopic ossification {1999,2322}. Patients with osteoid osteomas in the spine may present with painful scoliosis due to spasm of the paraspi nal muscles {1644}. In the fin gers, the persistent soft tissue swelling and periosteal reactions may result in functional loss that leads to numerous surgeries and large en bloc exci­ sions {2902}.

Imaging Radiographs often show only periosteal reaction with corti­ cal thickening, with or without central lucency (nidus). CT is the imaging modality of choice to detect the nidus, an ovoid lucency, < 2 cm, which can have central areas of mineralizatio n. Luce nt cha nnels represe nting vessels may be see n

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Bone tumours

Fig.3.62 Osteoid osteoma. A Frontal radiograph of the femur demonstrates corti­

cal thickening and sclerosis of the medial femoral shaft. B Axial CT showing a sma nidus with central calcification, surrounded by diffuse sclerosis and cortical thickening

paybal：https://www.paypal.me/andy19801210 ..the thickened cortex {1880,180}. MRI can be misleading, ；owing reactive oedema-like signal within the bone marow and surrounding soft tissues, without dem on strati on of 惦 nidus. Technetium scintigraphy shows intense uptake at the site of the nidus and less-marked activity in the surunding reactive bone (the double-density sign). Intramedullary lesions may incite little reactive cortical thickening but usually show surrounding medullary sclerosis. Subperiosteal lesions show little reactive sclerosis but can cause erosion of the underlying cortex. Intra-articular lesions can mimic a monoarthropathy, with joint space narrowing, joint effusion, and synovitis {2923}.

Epidemiology Osteoid osteoma represents 10-12% of primary bone tumours. U usually affects children and adolescents, although it is occa­ sionally seen in older individuals. There is a male predominance (M：F ratio: 2:1).

Fig. 3.64 Osteoid osteoma. A very sharp circumscription of nidus near the cortical surface showing dense cortex to the right and reactive neocortex to the left of the lesion.

Histopathology

Etiology Unknow n

Pathogenesis Rearrangement of FOS has been identified in both osteoblas­ tomas and osteoid osteomas, further strengthening the link between these two lesions {1012,91A}. The rearrangement is present In 91% of the cases and may be detected at the protein level using anti-FOS (c-FOS) N-terminus immu no histochem­ istry, resulting in n uclear immu no reactivity in the osteoblastic ce胎 |1012,91A,1739A}. Prostaglandins, especially PGE2, PGI2, and COX-2, have been implicated in the characteristic pain syn­ drome of osteoid osteoma and may explain the exquisite sensi­ tivity toNSAIDs {1952,2215}.

Macroscopic appearance Osteoid osteoma is a small, round, often cortically based red gritty or granular lesion surrounded by (and sharply circum­ scribed from) ivory-white sclerotic bone. The lesion seldom exceeds 1 cm in greatest diameter.

The central portion of the lesion (nidus) contains differentiated plump osteoblasts present as a single layer around trabeculae of unmineralized or mineralized woven bone {1505}. Vascular­ ized connective tissue, within which there are fibroblast-like stromal cells and cells differentiating into osteoblasts, sepa­ rates the trabeculae. The osteoid may be microscopically dis­ posed in a sheet-like configuration, but it is often organized into microtrabecular arrays. Osteoclasts may be conspicuous. Substantial nuclear pleomorphism and cartilage are absent. Hypervascular sclerotic bone with enlarged haversian canals surrounds the nidus and tends to be more pronounced as lesions become closer to the bone surface. The interface between the nidus and the surrounding reactive bone is abrupt and circumscribed, a fin ding that supports the in dole nt local behaviour of osteoid osteoma. The central area of the nidus may display intense mineralization. The nidus can be histologically indistinguishable from osteoblastoma, and the two lesions are separated by size: lesions < 2 cm are osteoid osteomas.

f'9-3.63 Osteoid osteoma. A Well-defined nidus surrounded by dense cortical / compact lamellar bone. B Anastomosing trabeculae of woven bone rimmed by plump osteo恤sts in a highly vascular background with numerous osteoclast-like giant cells.

Bone tumours

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paybal：https://www.paypal.me/andy19801210 The pathological evaluation of osteoid osteoma has undergone changes because of the increasing use of minimally invasive techniques to ablate these tumours. If the diagnosis of osteoid osteoma can be made clinically and radiographically, the tumour is sometimes ablated without prior biopsy, although a core biopsy may be obtained immediately before ablation. In other cases, fragments obtained from a drill procedure are sent for histological exami nation. Not only is the sea nt yield of diagnostic tissue in these cases lower than with resection specimens, but the histopathology may be obscured by heat or crush artefact {54,1651}.

Essential and desirable diagnostic criteria Essential: bone tumour with compatible imaging; radiograph demonstration of small (< 2 cm) central nidus, often s： rounded by sclerosis; bone-forming tumour composed Of microtrabeculae of woven bone rimmed by plump osteoblast in a vascularized stroma. Desirable: noctumal pain relieved by NSAIDs; abrupt transition between central nidus and peripheral sclerotic bone.

Staging Not clin ically re leva nt

Cytology

Prognosis and prediction

Not clinically re leva nt

The prog nosis is excelle nt. Recurrences are uncomm on. Some lesions have been reported to disappear without therapy(11171 Although traditional surgical excision is curative, it is sometimes challenging to resect small lesions, particularly when there is a great deal of reactive sclerosis. Consequently, less invasive techniques including CT-guided core drill excision, image-guided percutaneous radiofrequency ablation, cryoablation, high-inten­ sity focused ultrasound, and laser photocoagulation have largely replaced the traditional approach {474,1117,1997,2234}. Arthro­ scopic excision is used for intra-articular tumours (2921).

Diagnostic molecular pathology FOS gene rearrangement (not necessary for diagnosis) may be found in osteoid osteoma, but it can also be found in osteoblas­ tomas and epithelioid haemangiomas {1012}.

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Bone tumours

paybal：https://www.paypal.me/andy19801210 Osteoblastoma

Amary F Bredella MA Horvai AE Mahar AM

pefinition Osteoblastoma is a locally aggressive bone-forming tumour, morphologically similar to osteoid osteoma but with growth potential and generally > 2 cm in dimension.

ICD-O coding 9200/1 Osteoblastoma NOS

ICD-11 coding 2E83.Z & XH4316 Benign osteogenic tumours, unspecified & Osteoblastoma NOS

Related terminology Acceptable: epithelioid osteoblastoma. Not recommended: pseudomalignant osteoblastoma; aggres­ sive osteoblastoma.

Subtype(s) None

Localization The spine, in particular the neural arch (posterior elements), is the most frequent site, affected in more than one third of cases. Although the tumours may extend into the vertebral body, they are very rarely seen in isolation in the vertebral body {1907}. Other sites in elude the pelvis, the limbs (particularly the femur and tibia), the jaws, and other craniofacial bones {1542A}. How­ ever, any bone may be invoIved {1907}.

Clinical features Signs and symptoms The presenting symptom is frequently pain, but unlike with oste­ oid osteoma, NSAIDs usually do not provide relief {1907}. Neu­ rological symptoms may be present with spinal lesions. Rarely, there may be systemic symptoms including fever, weight loss, and hyperdynamic circulation {725}. Systemic symptoms have been attributed to an exaggerated immune response to the tumour. Excepti on ally, cases can be associated with one oge nic Phosphaturic syndrome {596}.

Imaging °n radiographs and CT, osteoblastomas present as lytic lesions > 2 cm in size, with surrounding reactive sclerosis. Vernal mineralization can be present, which may be ossified or chondral-type {1105}. Medullary lesions are associated with surrounding sclerosis and non-aggressive periosteal reaction. "the spine, osteoblastomas typically involve the posterior ele­ ments and can have an eurysmal bone cyst-1 ike cha nges. Bone scintigraphy shows non specific in creased radiotracer uptake. °n MRi, osteoblastomas can demonstrate low signal inten­ sity on T1- and T2-weighted images, corresponding to heavily

Fig.3.65 Osteoblastoma. A Axial CT shows an expansile tumour in the posterior el­ ements, with matrix mineralization. B Sagittal short-tau inversion recovery (STIR) MRI showing a well-defined lesion with hyperintense oedema-like signal in the adjacent marrow and soft tissue.

min eralized lesi ons with variable adjace nt oedema-like signal and enhancement in the marrow and surrounding soft tissues {284}. Fluid-fluid levels can be seen in lesions with aneurysmal bone cyst-like changes.

Bone tumours

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Fig. 3.66 Osteoblastoma. A Well-defined tumour borders. The tumour is focally merging with remodelled bone at the periphery (maturation). B Woven bone trabeculae lined one or more layers of plump osteoblasts, scattered osteoclast-type giant cells, and intervening vascular stroma. Anaplasia and atypical mitotic figures are absent.

Fig.3.67 Osteoblastoma. A Interconnecting trabeculae of woven bone rimmed by plump osteoblasts. Richly vascularized fibroblastic stroma. B Nuclear expression of FO! (c-FOS), highlighting the osteoblastic cells.

Epidemiology Osteoblastomas are rarer than osteoid osteomas, representing < 1% of primary bone tumours {284,1907}. The peak incidence is between the second and third decades of life. Osteoblastoma is twice as frequent in males as females {284,1907}.

diploid tumour cells with few other somatic alterations (1012| Previously, karyotypic abnormalities such as rearrangementof chromosome 13 {1146} and deletions on chromosome 22 have been reported {2320}; these activate the WNT/p-catenin signal­ ling pathway {2320,2625}.

Etiology

Macroscopic appearanee

Unknown

Macroscopically, osteoblastomas are usually red to tan lesions, reflect! ng their in tense vascularity {1907}. Bone expa nsion with marked cortical thinning or surrounding areas of sclerosis may be seen. The borders are usually well defined. Blood-filled cys­ tic spaces (aneurysmal bone cyst change) may be present.

Pathogenesis Rearrangement of FOS has been identified in both osteoblas­ tomas and osteoid osteomas, further strengthening the link between these two lesions {1012,237}. The rearrangement is present in 87% of the cases. The breakpoints in FOS cluster to exon 4, which is fused to introns of other genes or intergenic regions. The resulting transcript lacks regulatory elements, simi­ lar to the v-Fos retroviral on cogene {1012}. FOS is a member of the AP-1 family of transcriptionfactors, increased levels of which can promote cell growth. FOS rearrangements can be detected at the protein level using an antibody against the FOS N-ter­ minus, which results in n uclear immu no reactivity in the osteo­ blastic cells {237,91A,1739A}. In a smaller percentage of cases, FOSB rearrangement has been detected {1012}. Whole-genome DNA sequencing analysis performed in osteoblastomas shows

tumours

Histopathology Osteoblastomas are microscopically similar to osteoid osteo­ mas. Osteoblastomas are characterized by interconnecting, delicate, woven bone trabeculae, usually rimmed by a single layer of polygonal osteoblasts {1907}. The trabeculae may show different levels of mineralization, from osteoid to densely miner­ alized woven bone that shows multiple cement lines (pagetoi appearance) {1907}. The stroma is loose and usually richly vas­ cularized, with dilated capillary-type blood vessels. Osteoclas like giant cells are scattered throughout the tumour. Lace-liw osteoid deposition, although uncommon, can be present, *s

paybal：https://www.paypal.me/andy19801210 L cartilaginous differentiation. The borders are usually well defined, often showing peripheral bone maturation towards lamellar bone {1907}. Destructive host bone permeation should not be seen, and it is possibly the most reliable histological fea训e in differentiating osteoblastoma from osteoblastoma-like osteosarcoma {1110}. Atypical mitotic figures should be absent. 陆 diagnosis of so-called aggressive osteoblastoma is contro­ versial and not recommended. This entity was initially reported 附血 a more aggressive clinical course and morphologically characterized by the presenee of large, epithelioid osteoblasts (twice the size of normal osteoblasts) that are frequently mitotically active {841,1907}. However, the presence of epithelioid osteoblasts does not seem to predict an aggressive clinical course in osteoblastoma {1907,782}; therefore, the term "epithelioid osteoblastoma" is preferred. Rarely osteoblastomas may show degenerative atypia, which should not be mistaken for malignancy.

Fig. 3.68 Osteoblastoma. Osteoblastoma with extensive sclerosis.

Cytology Not clinically relevant

Diagnostic molecular pathology FOS gene rearrangement or rarely FOSB gene rearrangement is found in the majority of osteoblastomas {1012}.

Essential and desirable diagnostic criteria Essential： bone tumour with compatible imaging; radiologi­ cal dem on strati on of a > 2 cm lesi on; well-defi ned tumour borders, absenee of host bone permeation; bone-forming tumour composed of trabeculae of woven bone rimmed by plump osteoblasts in a vascularized stroma.

Staging Not clinically re leva nt

Fig. 3.69 Epithelioid osteoblastoma. The lesion is composed of sheets of large, epi­ thelioid osteoblasts associated with bone formation.

Prognosis and prediction The prog nosis is good, but recurre nces are described in as many as 23% of the cases {284}, more frequently in patients treated with curettage than with en bloc resection, with which a 14% recurrenee rate is reported {284}. Although osteoid osteoma and osteoblastoma may be morphologically indistinguishable, and they may in fact be different clinical manifestations of the same disease, an attempt to differentiate these tumour types is justified by the tendency for clinical progression and recurrenee seen in the latter.

Epithelioid osteoblastoma was initially reported with a more aggressive clinical course and morphologically characterized by the presenee of large, epithelioid osteoblasts that are fre­ que ntly mitotically active {841,1907}. The presenee of epithelioid osteoblasts does not consistently predict an aggressive clinical course in osteoblastoma {1907,782}. Conversely, some osteo­ blastomas > 4 cm with locally destructive features and repeated recurrences may lack epithelioid cytomorphology. Rare cases of maligna nt tran sformati on are described {840,1715}.

Bone tumours

399

paybal：https://www.paypal.me/andy19801210 Low-grade central osteosarcoma

Yoshida A Bredella MA Gambarotti M Sumathi VP

Definition Low-grade central osteosarcoma (LGCOS) is a low-grade malignant bone-forming neoplasm that originates within the in tramedullary cavity and con si sts of fibroblastic tumour cells with low-grade nuclear atypia and well-formed neoplastic bony trabeculae.

ICD-0 coding 9187/3 Low-grade central osteosarcoma

ICD-11 coding 2B51.Z & XH7N84 Osteosarcoma of bone and articular carti­ lage of unspecified sites & Low-grade central osteosarcoma

Related terminology Acceptable: well-differentiated intramedullary osteosarcoma.

Subtype(s) None

Fig. 3.72 Low-grade central osteosarcoma. Bisected resection specimen of the pro) mal femur showing a fibrous tumour with focal gritty areas and cortical expansion.

Local izati on LGCOS most often affects the metaphysis of long bones, predominantly the femur and tibia. Jaw bones, small tubular bones, and axial bones are rarely involved {786,1955,2785}.

Clinical features Signs and symptoms The tumour often presents with swelling or pain. The preoperative period tends to be longer than with conventional osteosarcoma

Fig.3.70 Low-grade central osteosarcom& Frontal radiograph of the hip demon­ strates an ill-defined lytic and sclerotic lesion with coarsened trabeculations in the proximal femoral metaphysis.

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Bone tumours

Fig. 3.71 Low-grade central osteosarcoma with focal dedifferentiation. A large lytlC and sclerotic lesion with trabeculation in the distal femoral metaphysis, extending。

the end of the bone. The tumour margin is partly well defined, and bone cortex is mi expanded. Cloud-like soft tissue density represents a dedifferentiated component

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fjg.3,73 Low-grade central osteosarcoma. A Low-power view showing a mildly cellular fascicular proliferation of spindle cells, admixed with well-formed neoplastic bone trabeculae in a parallel distribution. B Tumour spindle cells display mild nuclear atypia.

(COS) and can exceed 10 years (average: > 2 years) {1955, 587). Imaging

proxi>n.

On radiographs, LGCOSs typically present as large intramedullary expansile lytic and/or sclerotic lesions with coarsened incomplete trabeculations. Dense sclerotic lesions are less likely. LGCOS usually invoIves the metaphysis or metadiaphysis of long bones, often extending to the end of the bone {112). The tumour border may be circumscribed but often shows at least focal areas of cortical destruction {112}. Cortical disruption and/ or soft tissue extension is commonly seen on MRI and CT.

be present. Mitotic activity is low. Cartilage formation may be focally present {1717}. Some tumours focally lack bone matrix. In 10-36% of cases, LGCOS progresses to high-grade sarcoma. This phenomenon, known as dedifferentiation, may occur at presentation or in a recurrenee. High-grade areas often show high-grade osteosarcoma histology indistinguishable from that of COS, with lace-like immature osteoid formation and higher cellularity, nuelear grade, and mitotic activity. High-grade areas

Epidemiology LGCOS is rare, accounting for 1-2% of all osteosarcomas. It most commonly affects young adults, with a peak incidenee in the third decade of life {1717}. There is a mild female predilec­ tion {2785,112,3372}.

Etiology Unknow n

Pathoge nesis Amplification of 12q13-q15 involving MDM2 and CDK4 is comm on {1335,3050,867}. MDM2 amplification is maintained m high-grade progression. A subset of LGCOSs lack MDM2 amplification.

Fig.3.74 Low-grade central osteosarcoma. Some tumours produce well-formed but irregular bone trabeculae, reminiscent of fibrous dysplasia.

Macroscopic appearance LGCOS is a large, relatively well-circumscribed, white rubbery fibrous tissue mass with gritty calcification, Iocated in the med­ ullary cavity.

Histopathology

! lytic ng io nildly it，

LGCOS is composed of mildly to moderately cellular fascicles of spindle cells with mild nuclear atypia in a fibrosclerotic stroma. These are admixed with a neoplastic bone comp orient, which typically con si sts of long and thick bony trabeculae, often with parallel arrangement, resembling parosteal osteosarcoma. Boneca n be thi nn er a nd more irregular. Bone is typically woven, Mt it may be lamellar. Pagetoid bone with irregular cement lines may be present {1067}. Permeation of host bone is invariably Present. Cortical destruction with soft tissue infiltration may also

Fig. 3.75 Low-grade central osteosarcoma. Some tumours focally lack matrix pro­ duction, resembling desmoplastic fibroma.

Bone tumours

401

paybal：https://www.paypal.me/andy19801210

Fig.3.76 Dedifferentiated low-grade central osteosarcoma. Low-grade central osteo­ sarcoma (left half) progresses (dedifferentiates) to high-grade sarcoma (right half) with

Fig.3.77 Low-grade central osteosarcoma. FISH shows MDM2 amplification in mour cells. Green, MDM2] red, CEN12.

greater degrees of cellularity and nuclear atypia.

may lack osteoid formation and resemble undifferentiated pleo­ morphic sarcoma or fibrosarcoma.

Immunohistochemistry LGCOSs and the high-grade sarcomas that result from their progression express MDM2 and/or CDK4 in a high proportion of cases, and this feature can be used as a surrogate when access to MDM2 molecular testing is limited {3372,867}.

Differential diagnosis LGCOS should be distinguished from benign fibro-osseous lesions such as fibrous dysplasia. Whe n bone formati on is in ap­ parent, LGCOS can mimic desmoplastic fibroma or low-grade fibrosarcoma.

Cytology Not clinically relevant

Diagnostic molecular pathology Testing for /WD/W2 amplification is helpful to differentiate LGCOS from benign mimics. Because MDM2 amplification is rare in COS {866}, it may help separate dedifferentiated LGCOS from COS in the appropriate histological context {867,3373}. Unlike fibrous dysplasia, LGCOS lacks GNAS mutation {2724}. The lack of MDM2 amplification cannot exclude the diagnosis of LGCOS.

402

Bone tumours

Essential and desirable diagnostic criteria Essential: bone tumour with compatible imaging; intramedullar location; predominantly fibroblastic osteosarcoma with mil nuclear atypia and well-formed neoplastic bony trabeculae. Desirable: /WD/W2amplification.

Staging Staging is according to bone sarcoma protocols (see TNMstag­ ing of tumours of bone, p. 339). See also the information on staging in Bone tumours: Introduction (p. 340).

Prog nosis and prediction LGCOS has a good prog nosis when widely resected, with a metastatic rate of < 5% and 5-year and 10-year overall survival rates of 90% and > 80%, respectively {1955,587,1717], The tumour invariably recurs after curettage and incomplete exci­ sion. The presenee of dedifferentiation confers a worse progno­ sis, and detecting such areas is therefore critical. It remains to be determined whether the volume of the dedifferentiated com­ ponent may be prognostically significant {2785,2631}. Chemo­ therapy is reserved for dedifferentiated tumours.

paybal：https://www.paypal.me/andy19801210 Osteosarcoma

Baumhoer D Bohling TO Cates JMM Cleton-Jansen AM

Hogendoorn PCW O'Donnell PG Rosenberg AE

Definition Osteosarcoma is an intramedullary high-grade sarcoma in which the tumour cells produce bone.

ICD-O coding gi80/3 Osteosarcoma NOS

ICD-11 coding 2B51.Z & XH1XF3 Osteosarcoma of bone and articular cartilage of unspecified sites & Osteosarcoma NOS 2851.Z & XH5CL5 Osteosarcoma of bone and articular carti­ lage of unspecified sites & Telangiectatic osteosarcoma 2851.Z & XH4EZ4 Osteosarcoma of bone and articular carti­ lage of unspecified sites & Small cell osteosarcoma

Related terminology None

Subtype(s) Conve ntional osteosarcoma; small cell osteosarcoma

telan giectatic

osteosarcoma;

Localization Conventional osteosarcomas (COSs) can arise in any bone, but the vast majority originate in the long bones of the extremities, most commonly in the distal femur (30%), followed by the proxi­ mal tibia (15%) and the proximal humerus (15%), i.e. sites of the most proliferative growth plates. In long bones, the tumour is usually metaphyseal (90%) and only infrequently develops in the diaphysis (9%) or rarely in the epiphysis. The jaws are the fourth most comm on site of origi n {2747,238}. Inv olveme nt of the small bones of the extremities and multifocal osteosarcoma, either synchronous or metachronous, are rare, the latter representing metastatic spread rather than multiple independent primary tumours {193}. Telangiectatic osteosarcomas (TAEOSs) also frequently develop around the knee (-60%) and in the proximal humerus (-20%) (116). They occur in the metaphysis, commonly with direct extension into the adjacent epiphysis and diaphysis. Small cell osteosarcoma (SCOS) has a similar disMbution but more commonly develops in the diaphysis of long bones (10-15%) {188,2627}.

Clinical features Signs and symptoms There is usually a short history (weeks to mon ths) of a painful, enlarging mass and occasionally restricted movement at the adjacent joint. The skin overlying the tumour may be warm and

Fig. 3.78 Conventional osteosarcoma. A Anteroposterior radiograph shows scle­ rosis of proximal humerus and ossification within a large extraosseous mass (aster­ isks). B Coronal T2-weighted MRI shows hypointense tumour within the humerus and a heterogeneous circumferential mass (asterisks). Tumour extends to the humeral head and involves the shoulder joint (arrow). C Technetium radioisotope bone scan showing markedly increased uptake in the tumour in the proximal humerus but no other lesions. D Macroscopic appearance of a resected tumour of the proximal humerus.

erythematous {1652}. A minority of patients (10-15%) present with pathological fracture, most comm only see n in tumours of the femur and humerus {1507}. The clinical presentation of TAEOS and SCOS is similar to that of COS, although pathologi­ cal fracture is more comm on in TAEOS (see n in ~30% of cases) {2101,2240,116}.

Bone tumours

403

paybal：https://www.paypal.me/andy19801210 destruction and extraosseous extension and helps to 血 ti4L ossificati on in poorly min eralized tumours or those in vol/

complex an atomical sites (e.g. spine and pelvis). COS s^q a heterogeneous intermediate signal on T1-weighted MR| WS hyperintensity on fluid-sensitive sequences, with hyperinten ° haemorrhagic and hypointense mineralized areas {299別 p e

pendicular periosteal ossification may be seen as radiaf ' low-signal strands; the outer periosteum may form a low-si； |j capsule, which is often focally breached. After administratj of contrast medium, viable tumour enhances, whereas ossifj d tumour areas may remain hypointense and there may be septgj/ nodular enhancement in chondroblastic areas {1129}. The diagnosis can often be predicted from radiography appearances {1979}, but histological subtypes cannot be relia bly ide ntified. Atypical appeara nces are comm on {2662,2993! A predominantly lytic tumour suggests certain osteosarcoma subtypes (fibroblastic, small cell, tela ngiectatic, and sec on darv tumours) but may nevertheless be osteoblastic with immature and still-uncalcified matrix deposition {797}. SCOS frequently resembles COS but occasi on ally also shows a predominantlv lytic, non-mineralized appearanee that can mimic Ewing sar­ coma, particularly when occurring in the diaphysis of a Iona bone {293,2240}. TAEOS is typically associated with aggressive bone destruction, expansile remodelling, extraosseous extension, and pathological fracture {2227}. Sclerosis is rare and tumour ossification is frequently subtle, requiring CT for visu­ alization {2227}. Cortical striations suggesting hypertrophied in traosseous veins may be see n adjace nt to the tumour {3174|. MRI reveals a multicystic turn our con sisti ng largely of bloodfilled spaces and often revealing fluid-fluid levels. TAEOS can resemble aneurysmal bone cyst, but it usually presents more aggressively, with thickened septa and nodular/solid compo­ nents {2227}. Fig.3.79 Telangiectatic osteosarcoma. A Lateral radiograph of the distal femur shows a predominantly lytic lesion with a striated appearance, cortical destruction, mild expansile remodelling, and an extraosseous mass (arrows). B,C Coronal T1-

weighted MRI (B) and axial proton density MRI (C) show an elongated intramedullary tumour and a cystic, haemorrhagic extraosseous mass (asterisks) containing multiple fluid levels. D Gross appearance of telangiectatic osteosarcoma with dominant cystic architecture, incompletely filled with blood clots (a bag of blood). There is no fleshy or sclerotic tumour bone formation. The tumour permeates the surrounding medullary canal.

Imaging Imaging of COS typically shows permeative bone destruction in conjunction with tumour mineralization - a mixed lytic/sclerotic appears nee — with ill-defi ned, immature (fluffy, cloud-like) tumour ossifications {2999}. There is usually non-expansile cortical destruction and mechanical displacement of the peri­ osteum that produces reactive new bone, which is classically oriented perpendicular to the tumour but may be parallel (onion skin - like) or diverge nt (sunburst-like). The periosteal resp onse may be interrupted centrally and results in Codman triangles peripherally (1652}. An extraosseous extension is common and usually large, often eccentric and mineralized. Isotope bone sea ns show increased activity on all phases within osteoblastic tumour areas (in primary and metastatic sites), as well as an exte nded uptake in adjace nt bone, which is thought to reflect peritumoural hyperaemia {574}. CT dem on strates cortical

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Bone tumours

Epidemiology Osteosarcoma is the most common primary high-grade sar­ coma of the skeleton. It has a bimodal age distribution, with most cases developing between the ages of 14 and 18 years and a second smaller peak in older adults (30% of cases occur in individuals aged > 40 years) {2152,2398,3143}. The annual incidence rate is about 4.4 cases per 1 million population for people aged 0-24 years, about 1.7 cases per 1 million population for people aged 25-59 years, and about 4.2 cases per 1 million population for people aged > 60 years {119). Males are affected more frequently (M:F ratio: 1.3:1) {3143}. Tumours of the jaws primarily occur in the third to fourth decades of life {238}. TAEOS is a rare subtype, accounting for 2-12% of all high-grade osteosarcomas. It also commonly develops in the second decade of life and has a male predominanee similar to that of COS {116). SCOSs account for only 1.5% of all osteosar­ comas and have been observed in patients aged 5-83 years. However, they occur most frequently during the pubertal growth spurt {293,188,2240}. There is a slight female predominance (M:F ratio: 0.9:1) {293,188,1991,2240}.

Etiology Although the etiology is unknown, there is an in creased inc idence of primary osteosarcoma associated with several genetic syn­ dromes. Inactivation of the 7P53 gene due to mutations or loss of

heterozygosity / deletions occurs in individuals with Li-Fraumen

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Fig,3.80 Conventional osteosarcoma. A Pre-existing cancellous bone encased by a sclerosing osteosarcoma in a patient with Rothmund-Thomson syndrome. B Chondro-

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Mastic osteosarcoma with high-grade cartilaginous component. C Highly atypical spindle cells producing immature and lace-like bone.

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syndrome, who have an increased incidenee of osteosarcoma 11957,23 54}. Patients with hereditary retinoblastoma also have a high risk of developing osteosarcoma {856}, in particular after receiving ionizing radiation therapy. The genes causing these syndromes are also the most commonly mutated genes in sporadic osteosarcoma {JP53 in > 90% and RB1 in as many as 56% of cases) {562,2495,1690}. Germline mutations in various RECQ helicases underlie another group of rare syndromes asso­ ciated with COS, including Bloom syndrome (BLM [FIECQL3]), Werner syndrome (WRN), and Rothmund—Thomson syndrome (RECQL4) {592}. Acquiri ng chromosomal in stability is also the hallmark of sporadic COS and probably the most crucial step for initiating and driving tumour development. Syndrome-related COSs have been recognized for a long time, but the increasing use of DNA sequencing for genotyping neoplasms and also the germline of individuals has identified pathogenic germline muta­ tions in as many as 17.9% of COSs in larger studies {3394}, a figure that is likely to increase in sequencing studies to come.

Pathogenesis The pathogenesis and cell of origin of COS are unknown. Many potential driver genes in osteosarcoma have been identified; the largest sequencing study to date found 67 different driver genes in a series of 112 COSs {256}. Although these mutations certainly occur early in the course of the disease, it seems likely thatchromothripsis/chromoplexy caused by an unknown trigger

initiates chromosomal instability and subsequent tumour devel­ opme nt {256}.

Somatic genetics COS is characterized by highly complex chromosomal aneuploidy and both intertumoural and intratumoural heterogen eity due to chromosomal in stability. Somatic alterations involve various numerical and structural alterations, whereas specific point mutations are rather infrequent {256}. Specific translocations have not been identified so far. There is general consensus about recurring amplifications for some regions, such as gains of chromosome arms 6p (4050% of cases, harbouring RUNX2, VEG FA, E2F3, and CDC5L [CDC5]), 8q (45-55% of cases, harbouring MYC), and 17p, which have been detected by classic karyotyping and conventional comparative genomic hybridization, as well as deep sequencing. However, studies are difficult to compare because the definition of a recurrent alteration varies {2924,1768,1960, 2889,562,2495,1690,256}. The TP53 antagonist MDM2 is amplified in about 10% of cases, suggesting a pre-existing cen­ tral low-grade osteosarcoma that underwent dedifferentiation in at least a subset of cases {2067,2724}. FGFR1 amplifications have bee n dem on strated in 18.5% of cases; alterati ons in the IGF1R signalling pathway were observed 14% of COSs {985, 256}. Homozygous loss of CD KN2A occurs in 10% of COSs, is associated with an adverse outcome, and has been implicated

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Fig・3.81 Giant cell-rich osteosarcoma. A Highly pleomorphic sarcoma with abundant osteoclast-like giant cells. B This tumour shows numerous non-neoplastic osteoclast-

giant cells admixed with malignant tumour giant cells and filigree-pattern neoplastic bone.

Bone tumours

405

paybal：https://www.paypal.me/andy19801210 the generation of distinct cancer driver events, i.e. CDK4hz amplification {256}. ■

Kataegis, a phenomenon of localized hypermutations h been demonstrated in 50% of COSs {562}, but recurrent si'nai^i nucleotide variants are rare. Inactivation of TP53 is the common mutation in COS (> 90%) and can occur through ch ' mosomal deletion, single-nueleotide variants, and rearrano ' merits affecting the first intron of the gene, with rearrangem器；

appearing to be relatively specific for COS {562,2620}. Muta tions of IDH1 and IDH2 have not been detected in COS and can be helpful in distinguishing between chondroblastic osteosar coma and chondrosarcoma {93}. Other recurrent somatic pOinj mutations have been identified in RB1, ATRX, and NF2 {256| Fig. 3.82 Small cell osteosarcoma. Densely packed small blue round cells showing a

delicate and immature bone formation.

in osteosarcoma development from a mesenchymal progenitor {2169}. RB1 is deleted in about 50% of osteosarcomas {2495}. Other recurrently deleted genes include LSAMP, DLG2, and WWOX {2890). Distinct patterns of large-scale transitions and loss of heterozygosity reminiscent of that seen in BRCA1I BFlCA2-deV\c\ent tumours have been identified in COS, sug­ gesting a deficiency in homologous recombination repair (socalled BRCAness) {1690}. These findings indicate a potential sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors {907}. Chromothripsis and chromoplexy, subsumed under the term "chromoanagenesis", cause massive, chaotic, and complex chromosomal alterations through a single catastrophic event (2478). Sequencing studies found evidenee that chromoanagenesis is the molecular mechanism initiating the chromosomal complexity of COS in > 90% of cases {1690,256}; however, the trigger of the process itself remains unclear. Inactivating mutations of TP53 with subseque nt in ability to mediate cell-cycle arrest, apoptosis, and cellular senescenee have been proposed as the trigger, but errors in mitotic chromosome segregation producing whole chromosome-containing micronuelei might better explain the spatial distribution of chromosomal regions affected {674,2478}. A specific pattern of chromothripsis and amplification has been observed recently, which might result in

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Bone tumours

Gene expression Gene expressi on profili ng dem on strated an associati on between macrophage expression profiles and lack of metastases, suggesting a beneficial effect of macrophage infiltration. These findings have also been confirmed by immunohistochemical an alysis {443}. A nu mber of genes have bee n dem on strated to be hypermethylated in COS, affecting transcriptional activity HIC1, WIF1, PHLDA2 (TSSC3), RASSF1 (RASSF1A), GADD45. and RUNX2 {1571}. Methylation of ER (ESR1) seems particularly interesting, because this steroid receptor is involved in osteo­ blastic differentiation. Relieving ESR1 hypermethylation by DNA methyltransferases resulted in growth inhibition of tumour cells {1859}.

Tumour markers Tumour mutation burden has been shown to be relatively low, at 0.3-1.2 mutations per megabase {2495}, thereby designating osteosarcoma as a so-called cold tumour, with limited poten­ tial for immu no therapy. Indeed, only 1 of 22 COSs treated with the checkpoint inhibitor pembrolizumab (directed against PD1) showed a partial response to treatment {3055}.

Macroscopic appearance COS usually presents as a large (> 5-10 cm) intramedullary mass centred in the metaphyseal region with variable extension into the adjacent diaphysis and epiphysis. The cut surface is heterogeneous, depending on the type and degree of minerahzation of the predominant matrix. Heavily mineralized tumours

paybal：https://www.paypal.me/andy19801210 are tan-white/yellow and densely solid (resembling cortical ©one), whereas non-mineralized cartilaginous components are either grey and rubbery (if hyaline in nature) or mucoid (if the matrix has undergone myxoid degeneration). Areas of haemo“hage, tumour necrosis, and cystic cha nge are comm on. Intramedullary involvement is often considerable. When extra­ neous infiltration occurs, the tumour usually forms an eccentfic or circumferential soft tissue mass that displaces the periosteum peripherally. TAEOS shows a haemorrhagic multicystic lesion filled with blood clots, classically described as a bag of blood {2014}. Solid fleshy or sclerotic areas are usually not seen. Extensive cortical erosion or destruction associated with nearby soft tissue involvement may be seen. The gross features ofSc6s are indistinguishable from those of COS.

Histopathology COS has a broad histomorphological spectrum. Essential to the diagnosis is the identification of neoplastic bone formation. The tumour grows with a permeative pattern; replacing the marrow space and encasing and eroding pre-existing trabeculae, it fills and expands haversian systems within cortical bone. The neoplastic cells typically dem on strate severe anaplasia and pleomorphism, and they may be fusiform, plasmacytoid, or epi­ thelioid. Neoplastic cells often become small and normalized in appearanee (mimicking benign osteocytes) when surrounded by bone matrix. Mitotic activity is usually brisk, and abundant atypical mitotic figures are often present, which are useful in the d if fere ntial diag nosis of benign mimics of osteosarcoma. No minimum quantity of bone formation is required; any amount is sufficie nt to ren der the diag no sis. Characteristically, the bone is intimately associated with the tumour cells; varies in quantity; is woven in architecture; and is deposited as primitive, disorganized trabeculae that may produce fine (filigree) or coarse lace­ like patter ns, or as broad, large sheets of compact bone formed by coalescing trabeculae. Bone matrix is eosinophilic on H&E-stained sections if unmineralized and basophilic/purple if mineralized, and it may have a pagetoid appearanee imparted by haphazardly depos­ ited cement lines. Distinguishing unmineralized matrix (osteoid) from other eosinophilic extracellular materials such as collagen or compacted fibrin matrices may be difficult and subjective. Collagen tends to be less glassy and more fibrillar, and it is frequently deposited in broad aggregates or elongated fibrils compressed between lesional cells. COS may have different histological patterns. Curren tly, how­ ever, there is no relati on ship betwee n histological patter ns, treatment, and prognosis {1322}. COS commonly contains varying amounts of neoplastic cartilage and/or fibroblastic components; on the basis of the predominant matrix, they are sub­ divided into osteoblastic (76-80%), chondroblastic (10-13%), and fibroblastic (10%) types {1322,197}. In osteoblastic osteo­ sarcoma, neoplastic bone is the principal matrix and varies from 恤,lace-like trabeculae to compact bone. When the latter is Pronounced, the tumour is designated as a sclerosing type. b chondroblastic osteosarcoma, the predominant component is hyaline cartilage with severe cytological atypia, but the chondroid matrix may also appear myxoid with single cells or delicate cords of cells displaying more-subtle atypia, particuarly in tumours arising in gnathic bones. Neoplastic cartilage usually merges with areas containing neoplastic bone, often

Fig. 3.84 Conventional osteosarcoma. Fibroblastic osteosarcoma composed of in­ tersecting fascicles of pleomorphic spindle cells with central focus of neoplastic bone.

Fig. 3.85 Small cell osteosarcoma. High-power image.

with condensation and spindling of tumour cells at the periph­ ery of the chon droid no dules. In the appropriate con text, a biopsy containing only high-grade malignant cartilage should strongly raise the suspicion of chondroblastic osteosarcoma, especially in younger patients (in whom chondrosarcoma is much less comm on) and in the jaws, where chon drosarcoma practically does not occur. In fibroblastic osteosarcoma, the maligna nt cells are usually spindled and less frequently epithe­ lioid; they often, but not always, dem on strate severe cytological atypia. The tumour cells are associated with extracellular col­ lage n, which can be extensive, and they are often arranged in a storiform pattern. Non-neoplastic, osteoclast-type giant cells scattered throughout the tumour are the hallmark of the giant cell-rich sub type {288}. Some bone sarcomas without asso­ ciated giant cell tumour of bone histology harbour an H3-3A (H3F3A) or H3-3B (H3F3B) p.Gly34 mutation; these are usu­ ally sited in the epiphysis in you ng people, suggesti ng a relationship with a giant cell tumour of bone. Therefore, there is a move to expand the definition of primary malignant giant cell tumour of bone on the basis of an H3-3A (H3F3A) or H3-3B (H3F3B) p.Gly34 mutation {91}. Large polyhedral tumour cells characterize the epithelioid osteosarcoma subtype {1693}. In the osteoblastoma-like subtype, the tumour cells usually show less-pronounced atypia and rim the neoplastic bony trabeculae as typically observed in osteoblastoma. However, the tumour

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paybal：https://www.paypal.me/andy19801210 It can help to distinguish SCOS from Ewing sarcoma, beca it has been reported only rarely in the latter {654,2627,庇家

Ultrastructure Ultrastructurally, osteosarcoma cells have the features < mesenchymal cells with abundant dilated rough endoplaSmreticulum. The nuelei may be eccentric and the Golgi apparat" prominent. The matrix contains collagen fibres, which mayshQS calcium hydroxyapatite crystal deposition. These findings c be helpful in excluding Ewing sarcoma, metastatic carcinom ' melanoma, and lymphoma.

Cytology Not clinically relevant Fig. 3.86 Conventional osteosarcoma. Chemotherapy-induced change in osteosar­ coma. There is neoplastic woven bone and the area previously inhabited by tumour cells is composed of reactive fibrous tissue.

Diagnostic molecular pathology No specific diagnostic molecular pathology tests are available

Essential and desirable diagnostic criteria in filtrates and encases pre-existi ng bone trabeculae as a sign of osteodestructive growth {287,192,1110}. In TAEOS, the tumour is composed of blood-filled or empty cystic spaces closely simulating aneurysmal bone cyst. The septa show variable thickness and are populated by pleomor­ phic cells showing substantial nuclear hyperchromasia. Some maligna nt cells can be see n floating in the haemorrhagic areas. Atypical mitoses are easily identified. Osteoid formation is usu­ ally focal and con flue nt but may be abse nt in a biopsy. The septa also contain osteoclast-type giant cells. At the edges of the lesion, tumour permeation into pre-existing bone trabeculae is often observed. SCOS is composed of small cells with sea nt cytoplasm, asso­ ciated with osteoid production. Nuclei are round to oval and the chromatin may be fine to coarse; mitoses can easily be found. In the less frequent spindle cell type, nuclei are short and oval to spin die, with gra nular chromati n and inc on spicuous n ueleoli. A focal haemangiopericytoma-like pattern may be seen. Lace­ like osteoid production is always present. Particular care must be taken to distinguish osteoid from fibrin deposits that may be seen among Ewing sarcoma cells.

Immunohistochemistry COS has a broad immunoprofile that lacks diagnostic specific­ ity. Commonly expressed antigens include SATB2, osteocalcin (BGLAP), osteonectin (SPARC), osteoprotegerin (TNFRSF11B), RUNX2, S100, actins, and CD99 {1311,961,742}. Importantly (because it is a diagnostic pitfall), osteosarcomas may also express keratin and EMA {2364,1779}. Tumour cells are gener­ ally negative for CD31, CD45, and FOS, with FOS representing a relatively recent surrogate marker for the FOSgene rearrangements typically observed in osteoid osteoma and osteoblas­ toma (1012,91A,1739A). FOS immunohistochemistry might also be helpful in d if fere ntiating osteoblastoma and osteoblastoma­ like osteosarcoma. TAEOS and SCOS have an immunopheno­ type similar to that of COS. SATB2 is regarded as a very sensi­ tive marker for osteoblastic d iffere ntiatio n but lacks specificity.

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Essentia/: bone tumour with compatible imaging; bone production by turn our cells; permeative and destructive growth pat­ ter n; TAEOS: blood-filled or empty cystic spaces separated by fibrous septa; SCOS: small blue round cell morphology with focal neoplastic bone formation. Desirable: tumour cells with high-grade atypia; atypical mitotic figures frequently present.

Staging The eighth edition of the Union for International Cancer Control (UICC) TNM classification of malignant tumours stages osteo­ sarcoma of the appendicular skeleton, trunk, skull, and facial bones on the basis of the greatest tumour dimension (s 8 cm: T1 > 8 cm: T2) and discontinuous involvement of the primary bone site (T3). Staging of spinal and pelvic tumours is based on ana­ tomical intraosseous and extraosseous extension and size (423|. The eighth edition of the American Joint Committee on Cancer (AJCC) AJCC cancer staging manual stages osteosarcoma arising in the appe ndicular, trun cal, and craniofacial bones on the basis of the presence or absenee of distant metastasis, histo­ logical grade, and greatest tumour dimension (< 8 cm or > 8 cm) {101}. However, dichotomizati on of tumour size fails to con tribute prog no stically sign ifica nt information in this stagi ng system (516, 517}. Tumours of the pelvic or spinal skeleton are now substaged on the basis of the an atomical exte nt of in traosseous in vasion or presence of extraosseous invasion; prognostic stage groupings for these an atomical sites have not yet bee n developed. The Musculoskeletal Tumor Society (MSTS) staging system is arguably the more clinically useful staging system for planning optimal surgical therapy and is based on the presenee of meta­ static disease, histological grade, and local anatomical extent (defined by the presenee of extraosseous extension). However, breaking through the cortex with periosteal elevation (and intact periosteum) does not appear to be associated with worse out­ come per se. Instead, tumour extension beyond the periosteun has been shown to significantly correlate with an inferior prog­ nosis {2916,513,517}.

paybal：https://www.paypal.me/andy19801210 prognosis and prediction Aggressive local growth and rapid haematogenous systemic jissemination characterize the clinical course of COS. Pul­ monary metastases, followed by skeletal deposits (sometimes presenting as skip metastases), are the most frequent sites of gystemic disease. High-grade osteosarcoma is therefore usually treated with preoperative and postoperative chemother­ apy； local control is achieved via surgical resection with wide margins, often using limb-salvage techniques {1968}. Radia­ tion can be used for unresectable tumours {2638}. The use of multiage nt chemotherapy for COS has had a dramatic impact on outcome {119,703}. In the pre-chemotherapy era, > 80% of patients treated with surgery alone died of disease, whereas 70% of patients with localized osteosarcoma of the extremities are currently long-term survivors {2638,119,703}. Unfortunately, patients presenting with metastatic or recurrent disease have a survival rate of < 30% {1560,588}.

The histological response to neoadjuvant chemotherapy remains one of the most importa nt prog no sticators of overall and disease-free survival {119,703}. A good response is usu­ ally defined as > 90% necrosis {2726,516}. The prognosis of osteosarcoma is also influenced by tumour stage, anatomical location, and adequacy of surgical resection margins {314}. Localized distal disease, > 90% chemotherapy-induced tumour n ecrosis, and complete resecti on are positive prog no stic factors associated with a 5-year survival rate of > 80% {989}. Predictors of poor outcome include proximal extremity or axial skeleton involvement, large tumour size/volume, detectable metastases at diag no sis, and poor resp onse to preoperative chemotherapy (< 90% tumour necrosis). TAEOS is exquisitely sensitive to chemotherapy {116}, and the overall survival for these patients is similar to that seen with COS {195,3267}. SCOS has a slightly worse prog nosis tha n COS, but no particular histological, imag­ ing, or genetic findings related to prognosis have been identified to date {188,2240}.

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paybal：https://www.paypal.me/andy19801210 Wang J Nord KH O'Donnell PG Yoshida A

Parosteal osteosarcoma

Definition Parosteal osteosarcoma is a low-grade malignant bone-forming neoplasm that arises on the cortical surface of bone.

A long history, frequently over a year, is typical {2363)； the his tory is sometimes shorter with primary dedifferentiated tumours {2836}.

ICD-0 coding

Imaging

9192/3 Parosteal osteosarcoma

Radiographs show a mineralized, lobular mass at the bone surface, denser centrally than peripherally. Attachment to the bone may be slender or broad, with the remainder of the lesion separated by a luce nt cleavage plane, represe nting intact periosteum. The underlying cortex may be normal, thickened or destroyed. CT shows cortical cha nges, the luce nt cleav­ age plane, and ossified intramedullary extension (which is seen with equal frequency in low-grade and dedifferentiated tumours) {2836,1520}. The mass is usually hypointense and heterogeneous on T1- and T2-weighted MRI sequences, but appearances suggesting fatty marrow may be seen in welldifferentiated tumours {2732}. Luce nt areas on radiographs and CT, which are hyperintense on fluid-sensitive MRI, raise the pos­ sibility of focal dedifferentiation {1520}, particularly when they are large, located deeply, and enhancing {1099,837}. A thin, usually incomplete, hyperintense rim corresponding to cartilage is occasi on ally see n on the tumour surface {1520}.

ICD-11 coding 2B51.Z & XH8HG5 Osteosarcoma of bone and articular carti­ lage of unspecified sites & Parosteal osteosarcoma

Related terminology Not recommended: \\dx\acoriica\ osteosarcoma.

Subtype(s) None

Localization Approximately 70% of parosteal osteosarcomas are located at the posterior aspect of the distal femur in the metaphyseal regi on {2363,1292}; the next most comm on sites are the proxi­ mal portions of the tibia and humerus. Other less frequently involved sites in elude the cranio facial bon es, ribs, and small bones of the hands and feet {1358,556,3171}.

Clinical features Signs and symptoms Patients prese nt with a mass, which is occasi on ally painful. Dis­ tal femoral lesions are associated with restricted knee flexion.

Fig.3.87 Parosteal osteosarcoma. A Lateral radiograph shows a densely ossified mass attached to the posterior aspect of the distal femur superiorly, separated by a lu­ cent plane inferiorly (arrow). B Gross appearance (sagittal section) showing the three tumour components: a well-differentiated deep component (1); a large, mineralized overlying mass ⑵；and the layer of cartilage on the tumour surface ⑶.

Epidemiology Parosteal osteosarcoma accounts for about 4% of all osteo­ sarcomas, and it is the most common type of surface osteo­ sarcoma. It occurs in young adults, with a peak incidence in the third decade of life. There is a slight female predominance {2363}.

Fig. 3.88 Parosteal osteosarcoma. A Axial CT shows a heterogeneous ossified mass with slender attachment to the posterior cortex of the femur. A well-differentiated, relatively lucent component is seen deeply (1) and a lobular, sclerotic mass superfi­ cially (2). B Sagittal T2-weighted MRI shows a deep, well-differentiated (partially 恢的)

component (1) abutting femoral cortex, a large surrounding low-signal (ossifying) mass (2), and a thin hyperintense rim of cartilage on the surface of the tumour (3).

paybal：https://www.paypal.me/andy19801210 {2160}. The ring chromosomes contain amplified material from chromosomal region 12q13-q15 {1160,1341,3017}. Potential tar­ get genes in these amplicons include MDM2and CDK4, which are amplified in > 85% of the cases {866,867,1341,2067,3317). The same genes may be amplified in high-grade osteosarcoma with ring chromosomes, but the overall frequency of amplification is about 10% in conventional high-grade osteosarcomas, some of which may represent unrecognized dedifferentiated low-grade osteosarcomas {2067,562,256,866,3373}. Gene amplification is usually accompanied by increased expression of MDM2 and CDK4 at the RNA and protein levels {867,2067}.

Macroscopic appearance Parosteal osteosarcoma presents as an exophytic, lobulated mass, typically attached to the underlying cortex by a broad base. Large tumours may encircle the involved bone. Satellite no dules may be no ted, particularly in recurrent lesi ons. The cut surface shows a tan-white tumour with a hard gritty tex­ ture. Nodules of cartilage may be prese nt. Occasi on ally, the cartilage may form an in complete cartilage cap on the oute r surface, simulating an osteochondroma {1866}. Penetration of the underlying cortex with or without invasion into the medullary cavity may be seen. Soft and fleshy areas, if present, suggest dedifferentiation of the tumour. Focal necrosis, haemorrhage, and fluid cavities may be present.

Histopathology

Fig.3.89 Dedifferentiated parosteal osteosarcoma. The large dedifferentiated, haemorrhagic component is seen inferiorly (1); low-grade ossified tumour is present superiorly (2).

Etiology Unknow n

Pathogenesis Parosteal osteosarcomas are cytogenetically characterized by one or more supernumerary ring chromosomes, often as the sole aberration. The chromosome number is typically near-diploid, and the tumours do not show the massive chromosomal rearrangements associated with high-grade osteosarcomas

Parosteal osteosarcoma is composed of well-formed bone tra­ beculae with intervening fascicles of spindle cells. Typically, the tumour is hypocellular with minimal atypia and low mitotic activity. At the periphery of the tumour, the spindle cell component may show invasion into the adjace nt skeletal muscle. Some tumours may resemble desmoplastic fibroma because of focal lack of bone formation. In about 20% of the cases, the tumour is more cellular and the spindle cells show moderate atypia. The bone trabeculae are arranged mostly in a parallel fashion and may or may not show osteoblastic rimming. Some tumours contain irregular anastomosing and curved bone tra­ beculae, simulating woven bone in fibrous dysplasia. Approxi­ mately 50% of cases display cartilaginous differentiation, in the form of small scattered nodules or a cartilaginous cap. Progression to high-grade sarcoma, which can also be referred to as

Fig・3.90 Parosteal osteosarcoma. A Low-power image showing fascicles of spindle cells admixed with well-developed bone trabeculae arranged in a parallel pattern. B Irfgular anastomosing and curved bone trabeculae in parosteal osteosarcoma simulating fibrous dysplasia. C Higher magnification showing spindle cells with mild atypia and bone trabeculae.

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paybal：https://www.paypal.me/andy19801210

Immunohistochemistry Immunohistochemical study of MDM2 and CDK4 may provide a useful diag no stic too I in parosteal osteosarcoma, particularly in small biopsies and/or when molecular access is limited {3372. 867}. Analysis of MDM2 and CDK4 may also help identify dedif­ fere ntiated parosteal osteosarcoma with limited low-grade com­ ponents {3373}.

Differential diagnosis

Fig.3.92 Parosteal osteosarcoma. Diffuse nuclear staining for MDM2.

dedifferentiation, occurs in 15-43% of cases, either at presentation or (more often) at the time of recurrenee {2363,2836, 3303,290}. The high-grade component can be osteosarcoma or undifferentiated spindle cell sarcoma {290,190}, or very rarely rhabdomyosarcoma {2599}.

Because of its deceptively bland appears nee, parosteal osteo­ sarcoma must be differentiated from a variety of benign fibrous and fibro-osseous lesions, including florid reactive periostitis, juxtacortical myositis ossificans, desmoplastic fibroma, and fibrous dysplasia protuberans. In addition to the clinical, radio­ logical, and pathological features, MDM2 amplification assay or the surrogate immunostaining of MDM2 and CDK4 is help­ ful in the distinotion, because the above-mentioned mimics are negative for MDM2 amplificati on. Un like in osteoch on droma, the cartilage cap in some parosteal osteosarcomas is mildly hypercellular and the chondrocytes show mild atypia and lack the perpendicular columnar arrangement seen in osteochon­ dromas. Parosteal osteosarcoma can be morphologically distin­ guished from periosteal osteosarcoma and high-grade surface

Chromosome 12

Fig. 3.93 Parosteal osteosarcoma. A SNP array analysis of a parosteal osteosarcoma shows gain of genomic regions in chromosome 12, including high-level amplification of CDK4 and MDM2. B Partial metaphase spread from a parosteal osteosarcoma. FISH analysis using probes specific for MDM2 (red) and CDK4 (green) shows that the nng

chromosome contains many copies of these genes.

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paybal：https://www.paypal.me/andy19801210 osteosarcoma, the other two subtypes of surface osteosarcoma.

Staging

陆 prese nee of a focal low-grade spindle cell comp orient and/

The Union for International Cancer Control (UICC) TNM classifi­ cation of malignant tumours {423} does not recommend that the TNM staging system for bone tumours be applied to surface/ juxtacortical osteosarcoma or juxtacortical chondrosarcoma. However, other staging systems, such as the American Joint Committee on Cancer (AJCC) TNM system {101}, do include these tumours in the bone staging system. See also the information on staging in Bone tumours: Introduction (p. 340).

or MDM2 amplification suggests dedifferentiated parosteal osteosarcoma over high-grade surface osteosarcoma.

Cytology 何

clinically relevant

Diagnostic molecular pathology FISH for MD/W2amplification is more sensitive and specific than immunohistochemistry.

Essential and desirable diagnostic criteria Essential： bone tumour with compatible imaging; parosteal location; Iow-grade spindle cell tumour with woven bone for­ mation. Desirable: MDM2 amplification.

Prognosis and prediction The prog nosis is excelle nt, with a 90% overall survival rate at 5 years {2363}. For pure low-grade tumours, wide surgical excision is curative. Incomplete resection results in local recurrence. Metastasis, usually a late phenomenon, occurs rarely in low-grade tumours, whereas dedifferentiated tumours metasta­ size at a high rate, leadi ng to a poor prog no sis. Chemotherapy is reserved for dedifferentiated tumours.

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paybal：https://www.paypal.me/andy19801210 Bonar SFM Klein MJ O'Donnell PG

Periosteal osteosarcoma

Definition Periosteal osteosarcoma is a malignant, predominantly chondroblastic, intermediate-grade bone-forming sarcoma arising on the surface of the bone, typically underneath the periosteum.

ICD-0 coding 9193/3 Periosteal osteosarcoma

ICD-11 coding 2B51.Z & XH48A9 Osteosarcoma of bone and articular carti­ lage of unspecified sites & Periosteal osteosarcoma

Related termi no logy Not recommended: juxtacortical chondroblastic osteosarcoma.

Subtype(s) None

Localization Periosteal osteosarcoma usually occurs in the diaphysis of the femur and tibia {524,532,1222,1943,2221,291,697,3133}. Occasionally, cases occur in other long bones and flat bones, with rare examples arisi ng in cranio facial and acral bones {2221,532, 1222}. Rare bilateral metachronous and synchronous cases are documented {1943}, and a single case in a patient with Marfan syndrome is recorded {3324}.

Clinical features Signs and symptoms Swelli ng and/or pain of short du rati on (weeks to mon ths) is char­ acteristic {291,2221,697,3133}.

Imaging Radiographs show a luce nt, fusiform mass on the sur face of bone, with variable mineralization (usually fine perpendicular (hair-on-end) ossific striations, frequently accompanied by focal clumps of calcification). The cortex is thickened, with an adjacent solid or lamellated periosteal reaction and occasionally a Codman triangle. Although the thickened cortex is eroded by the mass, the endosteal cortex typically remains intact. CT and MRI often suggest an extensive chondroblastic component, based on low attenuation, hyperintensity on fluid-sensitive MRI sequences, and typical enhancement. Axial images show that tumour encircles at most approximately 50% of the bone circumferenee. Marrow infiltration is rare and abnormal marrow signal usually reactive {2221}.

Fig. 3.94 Periosteal osteosarcoma. A Lateral radiograph of the left femur. There is a fusiform mass on the bone surface, showing dense calcification and lobular lessmineralized tumour superficially, within which are irregular bone spicules. The cortex of the femur appears intact. B Axial T1-weighted (left) and T2-weighted (right) MRI

of the left femur. The surface mass incompletely surrounds the bone. It is hyperintense on both sequences, with homogeneous low signal at its base, indicating ossification, and slender hypointense strands, best seen on the T1-weighted image, due to fine bone spicules. The cortex is thinned laterally but not disrupted, and marrow signal is normal.

Etiology Unknown

Pathogenesis Epidemiology Periosteal osteosarcoma accounts for < 2% of all osteosarcomas {3128,2221,524,532,697,3133}. Peak incidence is in the second decade of life (range: first to seventh decade) {524,532,1222,1250}. Overall, the sexes are affected equally {524,532,1250,2221}.

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Very rare cases in large series of osteosarcomas have been genetically studied, but no consistent anomaly is documented {2404,415}. In some cases, more-complex chromosomal altera­ tions and point mutations in TP53, similar to those seen in high­ grade osteosarcoma, are recorded {256,1943,2404}.

paybal：https://www.paypal.me/andy19801210 formation. High-grade surface osteosarcoma has an aplastic high-grade features throughout, with distribution and demo­ graphic status similar to those of conventional osteosarcoma {2365,697}.

Cytology Not clinically re leva nt

Diagnostic molecular pathology MDM2/CDK4 amplification and IDH mutations have not been identified {2626,93}.

Essential and desirable diagnostic criteria Essential: bone tumour with compatible imaging; surface loca­ tion under the periosteum; intermediate-grade, largely chondroblastic osteosarcoma.

Pig,3,95 Periosteal osteosarcoma. A Gross specimen, coronal. Pale tumour with visible vertical perpendicular spiculation confined to the surface of the cortex and enilfely beneath the periosteum, lending a fusiform architecture. The cortex and meduliary cavity are unremarkable. B Gross specimen, axial. In this section, much of the bmour has a translucent, chondroid appearance. Irregular cream-coloured ossifica­

tion is visible near the cortex, whereas the spiculated linear appearance predominates atlhe perimeter. A surface rim of periosteum surrounds the tumour, and the cortex and medulla are intact.

Macroscopic appearance The tumour, in continuity with the inner periosteum, has a demarcated lobulated broad-based ovoid appearanee and is attached to the surface of the cortex, elevating the outer peri­ osteum, producing a fusiform architecture. Cortical thickening may be conspicuous, with the mass causing cortical scalloping. The tumour comprises lobulated pale glistening cartilaginous tissue. Reactive bone spicules emanating from the cortex may be visible, and a delineated surface capsule derived from the periosteum is usual {3128,291,697,3133}.

Histopathology The tumour comprises poorly delineated lobules of cytologically atypical cartilage with intervening bands of primitive sarcoma­ tous cells in which bone formation is present. Atypical fibro­ blastic areas may occur. Perpendicular periosteal reaction may be present, corresponding to the hair-on-end reaction seen on conventional radiographs. Primitive-appearing undifferentiated mesenchymal cells with nuelear atypia and mitoses prevail at the perimeter of the tumour. In cartilaginous areas, transition to osteoid matrix occurs {3128,291,697,3133}.

Immunohistochemistry SATB2 immunoexpression does not distinguish chondroblastic osteosarcoma from high-grade chon drosarcoma a nd is unhelp刨 in diagnosis {1929}.

Differential diagnosis Periosteal chondrosarcomas occur in older individuals, are

metaphyseal in distribution, have coarse calcification, and con­ tain large lobules of well-differentiated hyaline cartilage. Tumour bone is absent. Parosteal osteosarcoma exhibits a protuberant mushrooming architecture arising from outer layers of the peri°steum and is fibroblastic, with more mature appearing bone

Fig. 3.96 Periosteal osteosarcoma. A Scanning power. This composite photomicro­ graph demonstrates pale cartilaginous areas with intervening linear arrays of reactive bone coursing through the matrix towards the perimeter. The base is more densely ossified and consists of tumour bone and cartilage matrix. Note the thin layer of peri­ osteum along the surface. B Higher power of the tumour periphery demonstrates a tendency of the tumour cells to spindle. C At higher power, the linear reactive bone spicules are separated by cartilaginous tumour matrix, with focal central lace-like oste­ oid production. D Atypical nuclear morphology of the cartilaginous matrix is illustrated and central osteoid formation is present.

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paybal：https://www.paypal.me/andy19801210 Staging

Prognosis and prediction

The Union for International Cancer Control (UICC) TNM classifi­ cation of malignant tumours {423} does not recommend that the TNM staging system for bone tumours be applied to surface/ juxtacortical osteosarcoma or juxtacortical chondrosarcoma. However, other staging systems, such as the American Joint Committee on Cancer (AJCC) TNM system {101}, do include these tumours in the bone staging system. See also the informa­ tion on staging in Bone tumours: Introduction (p. 340).

Periosteal osteosarcoma has a better prognosis than Conv tional osteosarcoma, with disease-free survival rates of 89^ [ 5 years and 77-86% at 10 years. Marrow involvement 0° nally thought to preclude the diagnosis, is rare and may pred" more-aggressive behaviour: cases without marrow invoj ment show a trend towards a better outcome at 5 years {524 532,1250,2617}. Wide excision is optimal. Local recurrence metastasis, and death usually occur within 3 years of diagno, {1222,2657}. Chemotherapy, although frequently used doe；

not appear to in fluence prog nosis or survival {524,532125( 2657,2617}. Assessment of postchemotherapy necrosis is noi predictive of outcome {524,532,1222,697}. Occasional patients treated with chemotherapy developed a second malignancv {524,1222}.

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Bone tumours

paybal：https://www.paypal.me/andy19801210 High-grade surface osteosarcoma

Klein MJ Bonar SFM O'Donnell PG

Definition High-grade surface osteosarcoma is a high-grade malignant bone-forming neoplasm arising on the surface of the bone.

ICD-O coding 9194/3 High-grade surface osteosarcoma

ICD-11 coding 2B51.Z & XH6TL0 Osteosarcoma of bone and articular carti­ lage of unspecified sites & High-grade surface osteosarcoma

Related terminology None

Subtype(s) None

Localization The three most common sites, in descending frequency, are the femur, tibia, and humerus. In the long bones, high-grade surface osteosarcomas are most frequently diaphyseal or diametaphyseal.

Clinical features Signs and symptoms Swell i ng and pain of short du rati on are usual.

Imaging A radiodense mass extends into soft tissue from the bone sur­ face, usually showing fluffy, ill-defined immature ossification. Purely radiolucent lesions are rare {572,2365}. Dense ossifica­ tion may occur {3173}, and the mass may show radiati ng bone spicules similar to periosteal osteosarcoma. A cleavage plane of radiolucency representing the periosteum is unusual {3173}. Cortical erosion and medullary involvement, rare in periosteal osteosarcomas, are seen in about half of patients with high­ grade surface osteosarcomas and are best dem on strated using cross-sectional imaging {2929}. Soft tissue extension may be seen. A periosteal reaction is un comm on and variable {2365}. There is usually greater circumferential involvement than in other types of surface osteosarcomas {3357}.

Fig.3.97 High-grade surface osteosarcoma. A Lateral radiograph of the right tibia and fibula. An elliptical mass is projected adjacent to the tibial bone surface, show­ ing fairly dense lobular and punctate mineralization. No cortical destruction is identi­ fied. B Axial T1-weighted MRI of the right proximal calf. A lobular mass is located on the subcutaneous surface of the tibia. It causes cortical thinning, invades adjacent muscle, extends into the subcutaneous fat, and fungates through the skin. Lobular low

signal in the deep aspect of the mass is consistent with ossification.

Pathogenesis Epidemiology High-grade surface osteosarcomas account for < 1% of osteosarcomas. The published incidence shows a male predominance and a peak incidence in the second decade of life 12365}. However, because there are very few published cases and most of them are derived from consultation files, the statistical sign ifica nee is questi on able.

The pathogenetic mechanisms of high-grade surface osteosar­ coma are unknown. High-grade surface osteosarcomas arising in parosteal osteosarcomas (dedifferentiated parosteal osteo­ sarcomas) display amplification of MDM2 and CDK4. The single case of TSPAN31 (SAS) amplification in a high-grade surface osteosarcoma heretofore described {2616} was an example of dedifferentiated parosteal osteosarcoma because it had grade 1 foci.

Etiology Unknown

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paybal：https://www.paypal.me/andy19801210 extracellular matrix produced, as well as on tumour stroma.

Histopathology These tumours are histologically identical to high-grade conv tional osteosarcoma, with the same degree of matrix variabil'' Immu no histochemistry is not re leva nt to making the diagnosi *

Differential diagnosis The degree of cytological atypia is greater than in periost osteosarcoma. No areas of low-grade osteosarcoma should b dem on strable {2365}.

Cytology Not clin ically re leva nt

Diagnostic molecular pathology Not clin ically re leva nt

Essential and desirable diagnostic criteria Essential: bone tumour with compatible imaging; histologically high-grade osteosarcoma; arising on the surface of the bone without a substa ntial in traosseous comp orient.

Staging

Fig. 3.98 High-grade surface osteosarcoma. A Grass specimen sectioned axially demonstrates a large tumour mass extending from the bone surface to the skin. The cortex and medullary cavity are not involved. The tumour has a heterogeneous ap­ pearance, ranging from densely ossified to fleshy. B The histology is typical of high­ grade osteoblastic osteosarcoma, with malignant-appearing polyhedral and spindle cells producing an immature osteoid matrix with a lace-like pattern. Note the abundant mitoses.

Macroscopic appearance The tumour is usually well circumscribed externally and situ­ ated on the fibrous periosteal surface. It often extends through the periosteum to attach to or even erode the underlying corti­ cal surface. Endosteal extension may be present, but the bulk of the tumour is outside the bone. Its cut surface is variable because its appearance depends on the predominant type of

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The Union for International Cancer Control (UICC) TNMclassifi­ cation of malignant tumours {423} does not recommend that the TNM staging system for bone tumours be applied to surface； juxtacortical osteosarcoma or juxtacortical chondrosarcoma However, other staging systems, such as the American Joini Committee on Cancer (AJCC) TNM system {101}, do include these tumours in the bone staging system. See also the information on staging in Bone tumours: Introduction (p. 340).

Prognosis and prediction The overall 5-year survival rate of patients with high-grade surface osteosarcoma, compiled from the two studies report­ ing follow-up, is 62% {2365,2929}. Factors that favour survival include good response to neoadjuvant chemotherapy {2365I and localized disease. Poor response to chemotherapy, meta­ static disease at the time of presentation, and local recurrence are adverse factors {2365,2929}. The presence of medullary involvement does not seem to be an independent prognostic factor {2365}.

paybal：https://www.paypal.me/andy19801210 Flanagan AM Bridge JA O'Donnell PG

Secondary osteosarcoma

Definition Secondary osteosarcoma is osteosarcoma arising in abnormal bone.

ICD-O coding 9184/3 Sec on dary osteosarcoma

ICD-11 coding 2651.Z & XH06W9 Osteosarcoma of bone and articular carti­ lage of unspecified sites & Osteosarcoma in Paget disease of bone (en compasses sec on dary osteosarcoma)

Related terminology Acceptable: Paget sarcoma; osteosarcoma in Paget disease of bone (PDB); radiation-associated osteosarcoma. Not recommended: postirradiati on sarcoma; radiati on-induced sarcoma

Subtype(s) Osteosarcoma in Paget disease of bone; radiation-associated sarcoma; infarct-related osteosarcoma; osteosarcoma due to chronic osteomyelitis; implant-related osteosarcoma; osteosar­ coma sec on dary to early postzygotic disorders such as fibrous dysplasia

Localization Paget sarcoma most commonly affects the femur (34%), pel­ vis (24%), and humerus (24%) {1893}, reflecting the distribution of uncomplicated PDB, except for a disproportionately high and low incidenee in the humerus (24%) and the spine (2%) 11893}, respectively. Multifocal synchronous tumours may occur (2-17%) {3209}. Long bone lesions tend to be metaphyseal {2894}, and tumours have been noted to occur at the site of a previous fracture {2185}. Radiation-associated osteosarcoma occurs at the site of r ad iotherapy, most freque ntly in the flat bones of the chest wall and pelvis {3019}. Osteosarcoma related to premalignant bone syndromes generally affects the same locations as non-syndromic osteo­ sarcoma. However, tumours may be multifocal in Rothmund— Thomson syndrome and occur at unusual sites in Werner syn­ drome (foot and ankle, patella) {465}. Bone sarcomas outside the radiation field in hereditary reti no blastoma develop predominantly in the lower limbs {1975}.

Clinical features Signs and symptoms New pain and an enlarging mass in a patient with a history predisposing bone condition suggest the diagnosis of secondary osteosarcoma; occasi on ally, the un derlying condition is unknown. Paget sarcoma typically develops in a °ackground of polyostotic symptomatic PDB {2185}. Tumours are frequently lytic, occasionally mineralized {2185,2833}, and 劭

Fig.3.99 Paget osteosarcoma. A Axial CT shows multifocal synchronous tumour at presentation. An osteoblastic lesion is present in the right ilium (arrow). B The more inferior tumour in the acetabulum is lytic (asterisk). There is background cortical thick­

ening and trabecular coarsening in the pelvis and right proximal femur due to Paget disease.

may be multifocal {3209}. Pathological fracture is common {1893}.

Imaging Radiographs show lytic (65%) destruction of pagetic bone {2894}, and there is typically a large extraosseous mass. Lytic tumours appear photopenic on isotope scintigraphy {1893}; mineralized lesions may be difficult to distinguish from adjacent PDB {2185}. Replacement of fatty, heterogeneous pagetic mar­ row, cortical destruction, and an extraosseous mass are use­ ful MRI findings to d if fere ntiate sec on dary osteosarcoma from PDB. Radiation-associated osteosarcoma usually presents some years after treatment, with aggressive bone destruction and an extraosseous mass, superimposed on postradiotherapy bone changes {2833}. Syndromes predisposing individuals to secondary osteosarcoma may show evidenee of a bone dys­ plasia (e.g. in Rothmund-Thomson syndrome {465}) but other­ wise show similar presentation and imaging to non-syndromic

Bone tumours

419

paybal：https://www.paypal.me/andy19801210 changes, and aggressive bone destruction. Infarct-rel osteosarcoma usually occurs at the knee. The tumour usu； develops in the margin {2933} but may obliterate all evide%

of the infarct {2933}.

Epidemiology Osteosarcoma is the most common sarcoma associated w th PDB {1296}. PDB develops predominantly in populations' English descent「50% of bone sarcomas in patients aged > 50 years are sec on dary to PDB in en demic areas {1893| i areas where PDB is not found, there is no second, older peakin the bimodal incidenee of osteosarcoma {2542,1296}. The inci I

Fig. 3.100 Postirradiation osteosarcoma. A Anteroposterior radiograph of the right

hemipelvis showing lytic destruction of the right ilium (arrows) and pathological fracture of the acetabulum, with central dislocation of the right hip. Postradiotherapy sclerosis is present in the right ilium after radiotherapy 12 years previously for a gynaecological malignancy. B Coronal T2-weighted MRI of the right hemipelvis. The lytic tumour cor­ responds to a haemorrhagic mass (asterisk), which has destroyed the acetabulum and infiltrated the ilium and ischium (arrows).

dence of Paget sarcoma in PDB is 07-6.3% {1893}, but as the incidence of PDB is declining, Paget sarcoma also appears to be less frequent {1970} and is occurring at older ages [197q| | Most patients are in the sixth to seventh decades of life {吒晶 (range: 32-86 years {1212}). Radiati on-associated osteosarcoma most comm only arises in bone after treatment of tumours with long survival (breast and cervical carcinomas, Hodgkin lymphoma, retinoblastoma) {2462}. Radiati on-associated osteosarcoma is estimated to occur in 0.03% of patients receiving radiotherapy {2462}, with osteosarcoma accounting for 21-77% {396,2833}. The median latency period after radiotherapy is 10 years {2462} (range 3-55 years {1451,3254}). Most patients are in the fifth decade of life, with an earlier peak in the second decade (children treated for hereditary retinoblastoma and other malignancies) {2462| Osteosarcoma in older populations is most frequently due to Paget disease or irradiation {2815}.

Etiology Ionizing irradiation is the strongest risk factor for developing sec on dary osteosarcoma. Development of a radiati on-asso­ ciated osteosarcoma appears to be dose-dependent, with lower, potentially mutagenic doses at the edge of the radiation field {2833}. Most patie nts who develop radiati on-associated osteosarcoma have received a median of 50 Gy {2462}. Bone infarcti on is an ack no wledged cause of un differe ntiated sar­ coma, and an association between caisson disease, sickle cell disease, other biological in suits, and osteosarcoma is now rec­ ognized {1541,1094,3090}. Sarcomas, including osteosarcoma, infrequently develop adjacent to orthopaedic implants (1594). A causal link to the constituents of implanted material, which may be carcinogenic in vitro, has been suggested but not proven {1604}.

Pathogenesis

Fig. 3.101 Secondary osteosarcoma. Osteosarcoma arising in association with a to­ tal knee prosthesis. The tumour is haemorrhagic and has destroyed the bone.

osteosarcoma (465,1282,1899). Osteosarcoma at the site of a pre-existing benign bone tumour or chronic osteomyelitis may show imaging evidenee of the underlying disease, posttreatment 420

Bone tumours

The pathogenesis of secondary osteosarcoma is likely to be variable and determined by its etiology. Comparison of tran­ scriptome modification identified a signature of 135 genes discrimi nating radiati on-associated sarcomas from sporadic sarcomas; the functions of the signature genes suggest that radiati on-associated osteosarcomas were subject to chronic oxidative stress, probably as a result of mitochondrial dysfunction {1269}. Two mutation signatures of ionizing radiation, an excess of small deletions and balaneed inversions (both aberration types gen erate driver mutations), have bee n identified by paired tumour-normal tissue whole-genome sequencing in radiati on-associated malig nan cies, including radiati on-associ­ ated osteosarcoma {255}. Radiation-associated osteosarcomas

paybal：https://www.paypal.me/andy19801210 feature complex karyotypes {2096,256,255}. Unlike in primary osteosarcoma, losses are more frequent than gains; in particu应 loss at 1p is more comm on (57% vs 3%).

Macroscopic appearance The macroscopic features of sec on dary osteosarcoma are not gignifica ntly differ ent from those of primary osteosarcoma. The tumours occur at all sites in bon e: in a series of 23 radiati onassociated osteosarcomas in children/adolescents (excluding retinoblastomas), 21 were central, 1 was a high-grade surface iesion, and 1 was a periosteal osteosarcoma {3019}. When an osteosaicoma develops in association with fibrous dysplasia and is diagnosed early, the features of the fibrous dysplastic bone may be apparent, but this is rare.

Histopathology The histological features of sec on dary osteosarcoma are not distinguishable from those of primary osteosarcoma.

Fig. 3.102 Osteosarcoma in Paget disease of bone. The pre-existing bone shows fea­ tures of Paget disease: the bone is thickened with mosaic lines of mineralization and is bordered by osteoclasts. A highly pleomorphic sarcoma is present, with bizarre nuclei and atypical mitoses, adjacent to the aberrant bone.

Cytology Not clinically relevant

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essentia, bone tumour with compatible imaging; known history of previous radiati on therapy or the presence of an un derlying bone abnormality; osteosarcoma histology. Desirable: histological evidenee of underlying abnormal bone.

Staging Staging is according to bone sarcoma protocols (see TNM stag­ ing of tumours of bone, p. 339). See also the information on staging in Bone tumours: Introduction (p. 340).

Prognosis and prediction The prog nosis of Paget sarcoma and radiation-associated osteosarcoma, which are typically high-grade tumours unre­ sponsive to chemotherapy, is worse than that of conventional osteosarcoma. I n Paget sarcoma, patie nt age con tributes to poor prognosis: the 2-year survival rate is 25%; 29% of patients have pulmonary metastases at presentation {1893}. The 5-year survival rate in radiati on-associated osteosarcoma is 10-32% {2833}; 87% of tumours are high-grade {396}, and many patients die from metastatic disease within a few months 12641}. Prog nosis is better in operable extremity lesi ons {1470}.

Fig. 3.103 Osteosarcoma arising in infarct. An osteosarcoma (right) arising in a bone affected by infarction (left).

The use of alkylating agents {3117} and younger age at treat­ ment {3019} in crease the risk of radiati on-associated osteosar­ coma and may reduce the latency period {2833}. In the setting of cancer predisposition syndromes, the treatment and prog nosis of in dividual tumours are simila r to those of non-syndromic lesions; management is complicated and aims to maximize clin ical surveilla nee while minimizing radiati on exposure {465}.

Bone tumours

421

paybal：https://www.paypal.me/andy19801210 Desmoplastic fibroma of bone

Suurmeijer AJH Cleton-Jansen AM

Definition Desmoplastic fibroma of bone is an extremely rare locally aggressive bone tumour composed of bland spindle cells set in abundant collagen, with histology reminiscent of desmoid-type fibromatosis.

ICD-0 coding 8823/1 Desmoplastic fibroma

ICD-11 coding 2F7B & XH6YK5 Neoplasms of uncertain behaviour of bone and articular cartilage & Desmoplastic fibroma

Related terminology Not recommended: desmoid tumour of bone.

Subtype(s) None

Localizati on Desmoplastic fibroma may involve any bone but is most frequently found in the mandible, followed by long bones (femur, radius, tibia) and pelvic bones.

Fig. 3.104 Desmoplastic fibroma of bone with a CTNNB1 (p.Ser45Phe) mutation. Plain radiograph showing a well-demarcated lytic tumour of the distal radius with corti­ cal breakthrough, extension in surrounding soft tissue, and bowing of the ulna.

Clinical features Signs and symptoms Some tumours are found incidentally in asymptomatic patients. However, most patients have a Iongstanding history of pain or bone deformity .In about 10% of cases, a pathological fracture is the presenting symptom.

Imaging Radiographically, desmoplastic fibroma is a well-defined, lobulated, radiolucent lesion that may expand the host bone. Intralesional trabeculation is often present. Larger lesions may destroy cortical bone and extend into surrounding soft tissue, which is well appreciated by MRI. Desmoplastic fibroma has low signal intensity in both T1- and T2-weighted MRI images and may show in creased uptake with bone scin tigraphy or FDG PET.

Epidemiology Desmoplastic fibroma accounts for < 0.1% of all primary bone tumours. The tumour mainly affects adolesce nts and you ng adults, with near-equal sex distribution.

Fig. 3.105 Desmoplastic fibroma of bone. Recurrent tumour showing invasion of bone

and surrounding soft tissue. The cut surface of the tumour has a fibrous appearance.

Etiology Un know n

Macroscopic appearance

Pathogenesis Un know n

422

Bone tumours

Due to its high collagen content, desmoplastic fibroma is afire creamy-white tumour with a whorled architecture. The tumour

paybal：https://www.paypal.me/andy19801210 border is well defined and has scalloped margins, even when it extends into soft tissue.

Histopathology Desmoplastic fibroma has an infiltrative growth pattern and typically consists of a tumour of low cellularity composed of fascicles of bland non descript spindle cells set in a collage noUS matrix. Mitoses are sea nt. Necrosis is not prese nt. The fibroblastic spindle cells show variable immu no reactivity for SMA; p-catenin can be present {2908}, most commonly in the cytoplasm {1321}. The differe ntial diagnosis in eludes fibrous dysplasia, low-grade central osteosarcoma, low-grade myofibroblastic sarcoma, myoepithelial tumours, follicular dendritic cell tumours, and synovial sarcoma.

Cytology Not clinically relevant

Diagnostic molecular pathology In view of recent advances in molecular pathology allowing classification of bone tumours more objectively, the diagnosis of desmoplastic fibroma should be one of exclusion. In particular, fibrous dysplasia and low-grade central osteosarcoma should be excluded by molecular tests for GNAS single-nucleotide variants and /WDM2amplification, respectively. There are reports of two cases of desmoplastic fibroma in bone revealing a CTNNB1 mutatior ■ one p.Thr41Ala {1038} and one p.Ser45Phe alteration )2908}. Both cases exhibited nuclear p-catenin immunostaining. Previously, CTNNB1 mutations were not detected in a series of 13 cases {1321}.

Fig.3.106 Desmoplastic fibroma of bone. Tumour with fascicles of fibroblastic spin­ dle cells embedded in fibrillary collagen.

Staging Not clin ically releva nt

Prognosis and prediction Prog nosis and predict! on are difficult to predict because so few cases have been reported. Desmoplastic fibroma is a slowly progressive and locally aggressive tumour, which may recur after curettage or intralesional excision {2261A}.

Essential and desirable diagnostic criteria Essential: a bland spindle cell lesion in bone; collagenous matrix. Desirable: exclude fibrous dysplasia by showing the absenee of GNAS mutations; exclude low-grade central osteosarcoma by showing the absenee of A4D/W2amplification.

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423

paybal：https://www.paypal.me/andy19801210 Fibrosarcoma of bone

Dei Tos AP Czerniak B Inwards CY

Definition Fibrosarcoma of bone is a spindle cell malignant neoplasm of bone composed of relatively monomorphic fibroblastic tumour cells with variable collagen production and a fascicular (com­ monly herringbone) architecture. The diagnosis is one of exclu­ sion.

ICD-0 coding 8810/3 Fibrosarcoma NOS

ICD-11 coding 2B5J & XH4EP1 Malignant miscellaneous tumours of bone or articular cartilage of other or unspecified sites & Fibrosar­ coma NOS

Fig. 3.107 Fibrosarcoma. Gross specimen of primary fibrosarcoma of bone. Cut sur­ face is whitish and translucent, with more dense areas at the periphery.

Related terminology None

Subtype(s) None

Localization The distal femur is the most comm on site (21-47%), with the proximal femur (16%), distal humerus (14%), and proximal tibia (11%) also involved {1449,3021}.

Clinical features Signs and symptoms The most common clinical signs and symptoms are local pain, swelling, limitation of motion, and pathological fracture.

Imaging Typical imagi ng findings in elude ecce ntrically located, lytic lesions with a geographical, moth-eaten, or permeative pattern of destructi on and freque nt exte nsion into adjace nt soft tissues.

Fig. 3.108 Fibrosarcoma. Fibrosarcoma is composed of undifferentiated spindle cells

organized in fascicles. No specific line of differentiation is present.

Epidemiology Historically, the term "fibrosarcoma of bone" has been applied to primary malignant spindle cell neoplasms of bone in which the turn our cells are typically orga nized in a fascicular or herringbone pattern. But a variety of primary bone tumours occupying other specific diagnostic categories may also show this histological pattern; therefore, there are no properties distinctive of or specific for fibrosarcoma of bone. This term is uncommonly used as a specific diagnostic category today, particularly due to the advent of an ciliary techniques and evolving classification schemes. Therefore, the incidence is probably far less than the reported rates of as many as 5% of all primary maligna nt bone tumours. Tumours with a predominance of this fibrosarcomatous pattern, but probably representing a variety of tumour types, have been described with equal sex distribution and relatively uniform incidenee over the second to sixth decades of 424

Bone tumours

life, with occasional occurrenee in infants {276,711,1449,1753. 2651}. Fibrosarcoma of bone represents a diagnosis of exclusion once specific lines of differentiation are excluded.

Etiology Unknown

Pathogenesis There is little information in the literature regarding genetic cha nges in tumours with fibrosarcomatous d if fere ntiation {1277, 1319,2296}. The average number of imbalances, detected by high-resolution array comparative genomic hybridization, is as high as 43 per tumour {2296}. The most common losses, observed by array comparative genomic hybridization, are 6q, 8p, 9p, 10, 13, and 20p; the most common gains are 1q, 4q, 5p，

paybal：https://www.paypal.me/andy19801210 ■q, 12p, 15, 16q, 17q, 20q, 22, and Xp (2296}. CDKN2A (in 9p) I is homozygously deleted in > 60% of 17 cases, and STAFID13

W I3q) is heterozygously or homozygously deleted in 45% of cases {2296}. Recently, a novel STRN-NTRK3 gene fusion has been reported in one case of primary fibrosarcoma of the radius I {3344}. This finding, albeit rare, seems re leva nt con sidering the 」successful attempt to target NTRK with specific inhibitors {621}.

Macroscopic appearance Grossly, fibrosarcomas are collage nous, resulti ng in a firm consistency with a trabeculated, white cut surface and circum­ scribed margins. High-grade lesi ons show a fleshy appears nee.

Sclerosing epithelioid fibrosarcoma can occur as either a pri­ mary or a metastatic bone lesi on {3302,2628}. I n this con text, the presenee of striking epithelioid morphology combined with MUC4 immu nopositivity or dem on stration of a fusion betwee n FUS or EWSR1 and one of the CREB3L genes allows accurate classification. Epithelial markers (and absenee of SS18 gene rearrangements) distinguish fibrosarcoma from synovial sar­ coma. The expression of SATB2 in the absence of tumour oste­ oid visible on routine microscopy as a marker for osteosarcoma is con troversial.

Cytology Not clin ically re leva nt

Histopathology Microscopically, fibrosarcoma is composed of a uniformly cellu­ lar population of spindle-shaped cells arranged in a fascicular pattern with a variable amount of collagen production. Given that these fibrosarcomatous features can be seen in a wide vari­ ety of bone tumours, the great majority of tumours previously considered to reside in this category are probably better placed in other categories, such as leiomyosarcoma, mono phasic synovial sarcoma {3192,308,1416}, and solitary fibrous tumour )3192}. Thus, fibrosarcoma is a diagnosis of exclusion. The prese nee of osteoid and cartilagi nous d iffere ntiatio n excludes the diagnosis of fibrosarcoma.

Diagnostic molecular pathology Molecular genetics plays a major role in excluding tumour-spe­ cific aberrati ons.

Essential and desirable diagnostic criteria Essential: bone tumour with compatible imaging; monomorphic cellular spindle cells; fascicular growth pattern; diagnosis of exclusion — lack of morphological, immunohistochemical, and gen etic features suggesti ng an alter native diagnosis. Desirable: herringbone fascicles.

Staging Differential diagnosis The differential diagnosis includes solitary fibrous tumour, des­ moplastic fibroma, synovial sarcoma, low-grade leiomyosar­ coma, osteosarcoma, and dedifferentiated chondrosarcoma. Tumours with marked cytological atypia and a storiform growth pattern are best classified as undifferentiated pleomorphic sarcomas. STAT6 is of great help in excl u di ng a diag nosis of solitary fibrous tumour, and expression of desmin and h-caldesmon is helpful in making a diagnosis of leiomyosarcoma.

Staging is according to bone sarcoma protocols (see TNM stag­ ing of tumours of bone, p. 339). See also the information on staging in Bone tumours: Introduction (p. 340).

Prognosis and prediction The 5-year and 10-year survival rates are as poor as 34% and 28%, respectively, depending on patient age and tumour grade, site, and stage, with metastases to the lungs and other bones commonly noted {292,2431,1449,3021}.

Bone tumours

425

paybal：https://www.paypal.me/andy19801210 Haemangioma of bone

Hameed M Bloem JL Righi A

Definition Haemangioma of bone is a benign tumour in bone composed of vascular channels of small or large calibre. When haemangiomas involve a large localized region, or are widespread throughout the skeleton, this is known as angiomatosis.

ICD-0 coding 9120/0 Haemangioma NOS

ICD-11 coding 2E81.0Y & XH5AW4 & XA5GG8 Benign vascular neoplasms & Haemangioma NOS & Bones

Related terminology Acceptable: Gorham-Stout syndrome; massive osteolysis; cys­ tic an giomatosis.

Subtype(s) Caver nous haema ngioma; capillary haemangioma; angiomato­ sis

Localization Vertebral bodies are the most commonly affected site, followed by the craniofacial skeleton and the long bones, where haemangiomas tend to involve the metaphysis or diaphysis {20,698, 3272}. Multifocal occurrence is frequent.

Fig. 3.109 Haemangioma of bone. CT axial image demonstrates a low-density, fat­ containing lytic vertebral lesion with coarse trabeculae, known as the polka-dot pat­ tern.

Clinical features Signs and symptoms The majority of haemangiomas, especially those arising in the spine, are inc idental radiographic fin dings. However, large ver­ tebral tumours may cause cord compression, pain, and neuro­ logical symptoms. Symptomatic tumours occurring elsewhere are painful and may cause a pathological fracture. GorhamStout syndrome, a rare non-hereditary disorder, is character­ ized by diffuse angiomatosis with massive osteolysis, frequently involving contiguous bones {3221}.

Fig. 3.110 Haemangioma of bone. Portion of tibia with a well-circumscribed tumour showing a solid component and coarse trabeculations.

Imaging

Epidemiology

Haema ngioma ofte n prese nts as a well-demarcated luce nt mass containing fat and coarse primary trabeculations. These features are frequently seen as incidental findings on MRI and CT of the spine. In flat bones, such as the calvaria, the tumour is expansile and lytic, and it produces a centrally localized spoke­ wheel or sun burst patter n of reactive bone formati on. Some haemangiomas show absenee or paucity of fat and abundant vasculature, which has a high signal on fluid-sensitive and gadolinium chelate-enhanced MRI. These tumours are usu­ ally expansile, compromise neurological structures, and cause related symptoms {698,3130,2013}.

Haema ngiomas are comm on lesi ons; autopsy studies have identified them in the vertebrae of approximately 10% of the adult population {20}. However, clinically significant sympto­ matic tumours are un comm on and accou nt for < 1% of primary bone tumours {698}. Haemangiomas can occur at any age, but most are diagnosed during middle-age or late middle-age, with the peak incidenee in the fifth decade of life. The M:F ratio is about 0.7:1 {20,698,3131,3272}.

Etiology The etiology is unknown. Both developmental and neoplastic

origins have been postulated.

426

Bone tumours

paybal：https://www.paypal.me/andy19801210 pathogenesis jnknow n

Macroscopic appearance Haemangioma manifests as a soft, well-demarcated, dark-red mass. It may also have a honeycomb appearanee, with intralesional sclerotic bone trabeculae and scattered blood-filled cavities.

Histopathology Haemangiomas have variable histological features. Capillary and caver nous haema ngiomas are composed of thin-walled blood-filled vessels lined by a single layer of flat, cytologically banal endothelial cells. The vessels permeate the marrow and surround pre-existing trabeculae. In angiomatosis, a lymphangiomatous component may be seen.

Immunohistochemistry Reactive new bone formation can be prominent. The tumour cells stain for endothelial markers, such as CD31, ERG, FLI1, CD34, and factor VIIl-related antigen.

Fig.3.111 Haemangioma of bone. Cavernous haemangioma consisting of dilated blood vessels lined by flat banal endothelial cells.

Essential and desirable diagnostic criteria

Not clinically r eleva nt

Essential: bone tumour with compatible imaging; thin-walled blood vessels lined by a single layer of non-atypical endothe­ lial cells.

Diagnostic molecular pathology

Staging

Not clinically releva nt

Not clin ically re leva nt

Cytology

Prog nosis and prediction Haema ngiomas have an excelle nt prog nosis and a low rate of local recurrenee.

Bone tumours

427

paybal：https://www.paypal.me/andy19801210 Epithelioid haemangioma of bone

Bovee JVMG Rosenberg AE

Definition

Related terminology

Epithelioid haemangioma of bone is a locally aggressive vas­ cular neoplasm arising in bone, composed of cells that have an epithelioid morphology and endothelial differentiation.

Not recommended: histiocytoid haemangioma; haemorrhagic epithelioid and spindle cell haemangioma.

Subtype(s) ICD-0 coding

None

9125/0 Epithelioid haemangioma

Localization ICD-11 coding 2E81.0Y & XH10T4 Other specified neoplastic haemangioma & Epithelioid haemangioma

Tumours most commonly involve long tubular bones (~40%) followed by short tubular bones of the distal lower extremities (18%), flat bones (18%), vertebrae (16%), and small bones of the hands (8%) {2289}. Approximately 18-25% of the tumours are multifocal in a regional distribution {2289,931}.

Clinical features Signs and symptoms Patients usually present with pain localized to the invoIved ana­ tomical site; identification as an incidental finding is rare.

Imaging The tumour usually involves the metaphysis or diaphysis of the long tubular bones and manifests as a well-defined lytic, some­ times expansile, septated mass that may erode the cortex and extend into the soft tissue. In paediatric patients, epiphyseal involvement is common {2764}. On MRI, signal intensities are not specific {931}.

Epidemiology Epithelioid haema ngioma is un comm on; the true in cide nee is unknown. Patients range in age from the first to ninth decades of life, with most being adults; an average age of 35 years has been reported {2289,931}. The M:F ratio is 1.4:1 {2289}.

Etiology Unknown

Pathogenesis

Fig.3.112 Epithelioid haemangioma of bone. A Lytic and expansile mass of the distal clavicle surrounded by a thin rim of reactive bone. B Lobulated mass that is sharply demarcated and shows high signal intensity on axial proton density fatsaturated MRI.

428

Bone tumours

Epithelioid haemangioma of bone is characterized by fusion genes involving the FOS gene at 14q24.3 in 59-71% of the cases. Fusion partners for FOS are variable and include MBNL1, VIM, lincRNA {FIP11-326N17.1), and LMNA {3162,1432}. Alterna­ tively, the FOSB gene in 19q13.32 is fused to ZFP36 or (rarely) WWTR1 {128}. Dysregulation of the FOS family of transcription factors through chromosomal translocation is the key event in the majority of epithelioid haemangiomas of bone. The FOS family includes FOS, FOSB, FOSL1, and FOSL2, which encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. In this way, the FOS proteins regulate cell proliferation, dif­ ferentiation, and survival. In the FOS fusions, the various fusion partners are at the C-terminal end of the protein and cause loss of the transactivating domain {3162}. The C-terminal part

paybal：https://www.paypal.me/andy19801210

Fig. 3.114 Epithelioid haemangioma of bone. A dark-red, well-circumscribed tumour arises in the bone and extends into the soft tissue.

Histopathology

Fig,3.113 Epithelioid haemangioma of bone. Numerous round, lytic, well-defined le­ sions in distal radius and ulna.

is essential for fast, ubiquitin-independent FOS degradation via lhe 20S proteasome. Loss of the C-terminal part prevents the normal rapid degradation of FOS, and the resulting proIonged FOS activation accounts for the abnormal vessel growth in epithelioid haemangioma {3163}. The FOSB fusions occur at the N-terminal part of the protein and are most likely activating oromoter-swap events causing upregulation of FOSB {3177}.

Macroscopic appears nee The lesions range in size from several millimetres to 15 cm; most are < 7 cm and are well defined, nodular, soft, solid, red, and haemorrhagic. They may expand the bone, erode the cortex, and extend into the soft tissue.

The tumours have a lobular architecture, replace the marrow cavity, and often in filtrate pre-existi ng bony trabeculae. The centres of the lobules are the most cellular and contain epi­ thelioid cells that form vascular lumina or grow in solid sheets {2289,931,3190}. The periphery of the lobules may contain many small arteriole-like vessels lined by flat endothelial cells. In some tumours, solid cellular sheet-like areas predominate, whereas in others they account for a small portion of the neoplasm. The large and polyhedral epithelioid cells have oval or kidney-shaped nuelei, which tend to be hyperlobated or cleaved, with fine chromatin. The cytoplasm is abundant and deeply eosi no philic, occasi on ally containing one or a few clear vacuoles, which may contain in tact or fragme nted eryth­ rocytes {2289,931,3190}. Vacuolated cells may aggregate such that neighbouring vacuoles coalesce to form vascular lumina. Most tumours contain many well-formed vessels lined by the epithelioid cells that sometimes protrude into lumina in a tombstone-like fashion. Mitoses are relatively infrequent and are not atypical. Small foci of necrosis may be present. The stroma con si sts of loose con nective tissue and may con­ tain a prominent inflammatory infiltrate rich in eosinophils (angiolymphoid hyperplasia with eosinophilia—like), which may even mimic osteomyelitis. Foci of intralesional haemor­ rhage are present in some tumours, especially those involving the short tubular bones of the extremities. These areas may

加115 Epithelioid haemangioma of bone. A Lobulated architecture with a congeries of arteriole-like structures surrounding tumour. (e 愉med vascular lumina and also grow in solid clusters.

B Epithelioid endothelial cells bulge into

Bone tumours

429

paybal：https://www.paypal.me/andy19801210

/c Fig. 3.116 Epithelioid haemangioma of bone. A Intratumoural haemorrhage with spindle-shaped neoplastic cells. B Epithelioid endothelial cells with vesicular nuclei and | densely eosinophilic cytoplasm that contains vacuoles. C Numerous eosinophils are present within the tumour in a subset of cases.

also contain cytologically banal, sometimes mitotically active spindle cells that are arranged in fascicles {1605}. Infrequent findings in elude scattered in tratumoural osteoclast-type giant cells, reactive bone formation that compartmentalizes the tumour into small nodules, and a large dilated vessel lined by epithelioid endothelial cells located within the centre of the tumour. A subset of cases, referred to as atypical epithelioid haemangiomas, display more solid growth, increased cellularity, nuelear pleomorphism, and necrosis {128}. These cases more often harbour FOSB fusions.

Cytology Not clinically re leva nt

Diagnostic molecular pathology Rearrangement of FOS or FOSB can be detected in the majority of cases {3162,1432,128}.

Essential and desirable diagnostic criteria Essential: primarily located in bone; large epithelioid endothelial cells with densely eosinophilic cytoplasm. Desirable: lobular architecture with distinet vasoformation.

Immunohistochemistry Tumour cells express endothelial markers, such as CD31, CD34, FLI1, ERG, and factor VIIl-related antigen. Many cases are also positive for keratin and EMA {2343,3190}. SMA high­ lights the pericytic lining and the vasoformative architecture. FOS or FOSB can be expressed in a subset of cases {3163, 1440}.

Differential diagnosis Epithelioid haemangioma should be distinguished from angiosarcoma, which lacks the lobular architecture, displays more nuelear atypia, and has a higher mitotic activity. It should also be separated from epithelioid haemangioendothelioma, which usually shows myxohyaline stroma and no vasoformati on.

Staging Not clin ically re leva nt

Prognosis and prediction Epithelioid haemangioma is a locally aggressive lesion, and treatme nt usually con si sts of curettage and less freque ntly marginal en bloc excisi on. Radiati on has bee n used for tumours in in accessible locati ons. The prog nosis is very good, and in the largest reported series the local recurrence rate is about 10%|

regi on al lymph n odes can be inv olved and it is unclear whether this represents multicentric disease or metastatic deposits {1032,2289,931,3190,3404}. Clinicopathological features that are predictive of local recurrenee or lymph node involvemenh have not been reported.

Fig. 3.117 Epithelioid haemangioma of bone. A The epithelioid cells stain strongly with CD31 on immunohistochemistry. B The epithelioid cells can stain strongly with ker] tin. C The 即ithelioid cells stain strongly with FOSB.

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paybal：https://www.paypal.me/andy19801210 Epithelioid haemangioendothelioma of bone

Definition Epithelioid haemangioendothelioma of bone is a low- to interMediate-grade malignant neoplasm arising from the bone, composed of epithelioid endothelial cells within a distinctive myxohyaline stroma.

ICD-O coding M33/3 Epithelioid haemangioendothelioma NOS

ICD-11 coding 2B5Y& XH9GF8 Other specified malignant mesenchymal neoplasms & Epithelioid haemangioendothelioma NOS

Bovee JVMG Antonescu CR Rosenberg AE

especially in lower extremities, followed by pelvis, ribs, and spine; 50-64% are multifocal within a single bone or involving separate bones; however, they tend to cluster in an anatomical region {1650,2344,3190}.

Clinical features Signs and symptoms Comm on symptoms are localized pain and swelli ng, but some­ times the lesions are asymptomatic. Epithelioid haemangioendothelioma with YAP1-TFE3 has a clinical presentation similar to that of classic epithelioid haemangioendothelioma.

Imaging Related terminology 呵 recommended: malignant epithelioid haemangioendothelioma.

The tumours manifest as a lytic lesion with well-circumscribed or poorly circumscribed margins. They may be expansile and erode cortex. Transgression of the cortex with extension into the soft tissue is uncomm on.

Subtype(s) Epithelioid haemangioendothelioma with WWTR1-CAMTA1 iusion; epithelioid haemangioendothelioma with YAP1-TFE3 fusion

Localizatio n The skeleto n can be the only orga n involved or a comp orient of multiorgan (liver, lung, soft tissue) disease {1769}. Any bone :an be affected; 50-60% of cases arise in long tubular bones,

3,118 Epithelioid haemangioendothelioma of bone. A Expansile lytic tumour of 「distal ulna has a trabeculated pattern. B Tumour has multinodular growth pattern "dhas high signal intensity on coronal T2 fat-saturated MRI.

Epidemiology Epithelioid haemangioendothelioma is rare, and the true inci­ dence is un know n. The prevale nee for all orga n sites is < 1 case per 1 million individuals {1769}. The age range is broad (first to eighth decades of life), with most patients diagnosed during the second to third decades of life. The sexes are equally affected, although some studies have reported a male predominance {1650,2344,3190,115}.

Fig. 3.119 WP7-TFE3-positive epithelioid haemangioendothelioma of bone. A Tu­ mour replaces the marrow in multiple vertebral bodies and has high signal intensity in sagittal T2 MRI. Also note vertebral fractures and epidural extension. B FDG PET showing multiple lesions that have avid FDG uptake.

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paybal：https://www.paypal.me/andy19801210 Histopathology Epithelioid haemangioendothelioma is a solid mass that |a a lobular architecture and is composed of large epithelioid spindle cells with round or elongated vesicular nuclei, pd

Fig. 3.120 Epithelioid haemangioendothelioma of bone. Sharply demarcated tan­ white mass involving the cortex.

Etiology Unknown

Pathogenesis The overwhelming majority of epithelioid haemangioendotheliomas harbour a t(1;3)(p36;q25), resulting in a fusion of WWTR1 at 3q25.1 with CAMTA1 at 1p36.31-p36.23 {2073,932,3041). The WWTR1 (TAZ) protein is a transcriptional coactivator and effector of the Hippo pathway. The Hippo pathway phosphoryl­ ates WWTR1 (TAZ), which leads to its cytoplasmic localization and ubiquitin-dependent degradation {3040). Fusion of WWTR1 (TAZ) to CAMTA1 results in dysregulation of the Hippo path­ way, such that WWTR1-CAMTA1 constitutively localizes in the nucleus, where it acts as a neomorphic transcription factor to activate a WWTR1 (TAZ)-like transcriptional programme {3040}. The monoclonal origin of multifocal epithelioid haemangioendothelioma has also been established using WWTFI1-CAMTA1 breakpoint analysis. This indicates that multiple lesions arise from locoregional or distant metastatic spread from a single primary as opposed to multiple independent primaries {929}. A small subset of tumours (< 5%) have a YAP1-TFE3\us\on resulting in oncogenic activation of TFE3 {133).

Macroscopic appearance The tumours are ovoid, rubbery, tan or less frequently haemor­ rhagic masses that are < 1 cm to 10 cm in size.

nent nucleoli, and abundant densely eosinophilic cytop|a< Intracytoplasmic lumina appear as clear vacuoles that may。 tain intact or fragmented red blood cells (so-called blister c， or signet-ring cells). Well-formed blood vessels are not pres in the classic epithelioid haemangioendothelioma; instead tumour cells are arranged in cords and nests, which are emb ded within a myxohyaline stroma that may resemble cartilagin( matrix. Cytological atypia and mitotic activity are often limit A small subset of epithelioid haemangioendotheliomas h; atypical histological features, including nuclear pleomorphic increased mitotic activity, solid sheet-like growth, and necroj Epithelioid haemangioendothelioma with YAP1-TFE3 fusion associated with distinet morphology. The tumour cells are Ian with abundant voluminous cytoplasm that is sometimes feathi in appears nee. The n uelei can exhibit mild to moderate atyr The epithelioid cells may delineate well-formed vascular lum or grow in solid sheets; a myxohyaline stroma is usually abs「 or inc on spicuous {133}.

Immunohistochemistry The tumour cells express endothelial markers, such as CD CD34, ERG, FLI1, factor VIIl-related antigen, D2-40, a PROX1. They may be strongly positive for keratin (-40%) EMA {1650,2344,1153,1705}. Nuclear staining for CAMTA1 positive in 86-88% and is highly specific {2841,849}. TF immunohistochemistry can be used to identify epithelioid hi mangioendotheliomas with YAP1-TFE3, although positivity not always correlated with 7FE3 fusion {1041}.

Differential diagnosis Epithelioid haemangioendothelioma of bone, especially wh multifocal and positive for keratin, can be easily misdiagnos as metastatic carcinoma. Epithelioid haemangioendothelioi with atypical histological features should be distinguished fr( epithelioid an giosarcoma, which lacks the typical myxohyalii stroma and specific fusion genes of epithelioid haemangioe dothelioma. The presenee of the cord-like cellular arrangeme or characteristic stroma also helps distinguish epithelioid ha mangioendothelioma from epithelioid haemangioma.

Fig. 3.121 Epithelioid haemangioendothelioma of bone. A Tumour infiltrates the bone. The neoplastic cells are arranged in cords within a myxohyaline stroma. B The tum consists of cords of 即ithelioid cells with deeply eosinophilic cytoplasm, with some containing clear vacuoles, in a basophilic myxohyaline stroma.

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Hg,3,122 Epithelioid haemangioendothelioma of bone with /4P/-TFE3 fusion. A Tumour shows well-formed lumina and large tumour cells with abundant cytoplasm. B Large 恫our cells have voluminous eosinophilic cytoplasm.

Cytology Not clinically relevant

Diagnostic molecular pathology The WWTR1-CAMTA1 fusion can be detected in 89-100% of all epithelioid haemangioendotheliomas with classic histological features, and it is not found in epithelioid haemangioendothelioma's mimics {3041,932}. YAP1-TFE3 fusions are found in a small subset of cases.

Essential and desirable diagnostic criteria Essential: classic epithelioid haemangioendothelioma is com­ posed of cords or nests of epithelioid endothelial cells within a myxohyaline stroma; epithelioid haemangioendothelioma with YAP1-TFE3 fusion shows either solid growth or well-formed vascular channels lined by epithelioid endothelial cells with nuclear atypia and abundant pale cytoplasm. Desirable (in selected cases): CAMTA1 expression by immu­ nohistochemistry and/or WWTR1-CAMTA1 fusion; TFE3 overexpression by immunohistochemistry and/or TFE3 gene rearra ngeme nt.

Staging Staging is according to bone sarcoma protocols (see TNM stag­ ing of tumours of bone, p. 339). See also the information on staging in Bone tumours: Introduction (p. 340).

Fig. 3.123 Epithelioid haemangioendothelioma of bone. Tumour cells show strong

nuclear immunohistochemical staining for CAMTA1.

Prognosis and prediction Wide resection is the treatment of choice. The clinical course can be highly variable {2344}. The overall survival rate of patients with epithelioid haemangioendothelioma of bone is 92% at 10 years {115}. Involvement of two or more bones is associated with a worse prog nosis (74% 10-year overall survival rate), regardless of the number of organs invoIved {1769,115}. The mortality rate is about 20% {1650,1769}. One study found no correlati on betwee n histological parameters and prog nosis {1650}. Histological risk stratification systems, which were pro­ posed for soft tissue or thoracic examples {813,108}, have not been tested for bone tumours.

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paybal：https://www.paypal.me/andy19801210 Nielsen GP Bovee JVMG

Angiosarcoma of bone

Definiti on Angiosarcoma of bone is a high-grade malignant neoplasm of bone dem on strati ng en dothelial differe ntiation.

{3197}. MRI demonstrates a heterogeneous lesion, with exte sive reactive changes seen on T2-weighted images {3197}

Epidemiology ICD-0 coding 9120/3 An giosarcoma

ICD-11 coding 2B56.Y & XH6264 An giosarcoma, othe r specified primary site & Haemangiosarcoma

Related terminology None

An giosarcoma of bone is rare, accou nting for < 1% of malignant bone tumours. Patients have a broad age range, but the tumour usually arises in older individuals and is slightly more common in males {3189,800}.

Etiology The etiology is unknown for most cases. A small number ol cases are associated with previous radiati on therapy ⑵ 62 2242} or bone infarct {4,523}.

Subtype(s)

Pathogenesis

None

The tumour manifests as a single or regionally multifocal osteolytic tumour, with a well- to poorly defined margin and a geographical pattern of destruction. Most lesions show corti­ cal destruction, whereas a periosteal reaction is usually absent

Gen etic information on an giosarcoma of bone is limited. An array comparative genomic hybridization study distinguished two molecular groups: cases with few or no gross aberra­ tions and cases with numerous genetic aberrations consisting of chromosomal losses, chromosomal gains, and high-leve' amplifications or complex aberrations {3191}. The most common finding was amplification of 2q and 17q, which was also found in angiosarcoma of soft tissue, suggesting overlap in tumorigenesis irrespective of their location {3191}. One angio­ sarcoma of bone was shown to harbour a KDR mutation, while CIC abnormalities were absent {1433}. MYC overexpression can be seen in some cases {3191}. The RB1 pathway is involved in tumorigenesis in about 55% of angiosarcomas of bone (loss of p16 and/or overexpression of cyclin D1), whereas overexpression of p53 or MDM2 is absent, suggesting that the p53 pathway is less important {3188|. In additi on, TGF-卩 signalling is highly active in an giosarcoma of bon e when compared with an giosarcoma of soft tissue (3188) Although the PI3K/AKT pathway is active in angiosarcomas in

Fig.3.124 Angiosarcoma of bone. Coronal CT of an angiosarcoma producing multi­ ple lytic lesions involving the femur and pelvic bones.

and destroys several bones, extending into soft tissues.

Localization An giosarcoma shows a wide skeletal distributio n with preferen­ tial involvement of long and short tubular bones (74%), espe­ cially the femur, followed by the pelvis (15%), axial skeleton (7%), and trunk (4%). Approximately one third of cases are multifocal and affect contiguous (64%) or distant bones (36%) {3189,800}.

Clinical features Signs and symptoms Angiosarcoma most commonly presents as a painful lesion that may be associated with a palpable mass.

Imaging

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Bone tumours

Fig. 3.125 Angiosarcoma of bone. The resected large haemorrhagic tumour involves

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Fig,3.126 Angiosarcoma of bone. The tumour infiltrates bone. It forms obvious vas­ cular spaces, with some of the lumina being lined by malignant endothelial cells.

both bone and soft tissue, different mechanisms seem to be involved: 41% of an giosarcomas of bone show a decrease in eXpression of PTEN, whereas angiosarcomas of soft tissue overexpress KIT {3188}.

Macroscopic appearance Angiosarcoma is usually > 5 cm in greatest dimension, friable, haemorrhagic, and tan-red. The tumour erodes and destroys the cortex and in filtrates into the soft tissues. Areas of n ecrosis are difficult to identify because of the haemorrhagic appear­ ance of the tumour.

Fig. 3.127 Epithelioid angiosarcoma of bone. The tumour cells are 即ithelioid and form a solid growth pattern, mimicking metastatic carcinoma.

Differential diagnosis The combination of multifocality, epithelioid morphology, and expressi on of epithelial markers can lead to con fusion with metastatic carcinoma {800,2736,3197,3189}. Given its wide spectrum of morphology, an giosarcoma should be con sidered in the differential diagnosis of any high-grade (especially epithelioid) malig nancy of bone. Epithelioid an giosarcoma will stain for endothelial markers, which should be negative in metastatic carcinoma.

Cytology Not clin ically releva nt

Histopathology Angiosarcoma is characterized by cytologically malignant cells that are most often epithelioid in appearanee (> 90% of cases) and less freque ntly spin died. The nu clei are usually vesicular and contain one or several small nueleoli or a macronueleolus. The cytoplasm is deeply eosinophilic and often contains one or more vacuoles, which may be clear and empty or may hold intact or fragmented erythrocytes {3273,2344,949). Mitotic fig­ ures are often numerous, and atypical forms can be seen. The tumour cells usually grow in solid sheets; however, in approxi­ mately one half of cases, they line irregular vascular lumina 13189). Extravasated erythrocytes can be numerous, and scat­ tered deposits of haemosiderin may also be present. A variable inflammatory in filtrate is prese nt, generally con sisti ng of lym­ phocytes and neutrophilic or eosinophilic granulocytes {3189}. Reactive bone formation can sometimes be observed. In the absence of obvious vascular differentiation, abundant intratumoural haemorrhage and intratumoural neutrophils are useful morphological features that may suggest the diagnosis {800}.

Diagnostic molecular pathology Not clin ically re leva nt

Essential and desirable diagnostic criteria Essential: primary origin in bone; vasoformative architecture and/or expression of endothelial markers; prominent nuelear atypia and readily observed mitoses.

Immunohistochemistry Expression of various endothelial markers is seen; ERG, CD31, and FLU are usually positive, whereas positivity for CD34 and factor VIIl-related antigen is less common {800,3189,2129}. b addition, tumour cells may be positive for SMA and D2-40 ⑶89}. Keratin and EMA are frequently positive, particularly, but n°t exclusively, in tumour cells that have an epithelioid morphol°gy 12121,2361,3189}.

Fig. 3.128 Angiosarcoma of bone. This tumour shows spindle cell morphology and extravasation of erythrocytes.

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paybal：https://www.paypal.me/andy19801210 Staging Staging is according to bone sarcoma protocols (see TNM stag­ ing of tumours of bone, p. 339). See also the information on staging in Bone tumours: Introduction (p. 340).

Prognosis and prediction Patients are usually treated with surgery, radiation therapy, and/ or chemotherapy. The biological behaviour of in dividual cases is un predictable, although as a group an giosarcomas of bone are high-grade and clinically extremely aggressive {3304,469}.

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In a study of 31 patients, the 1-year, 2-year, and 5-year s vival rates were 55%, 43%, and 33%, respectively {3189] fL presence of a macronucleolus, > 3 mitoses per about 2 mm夕 and < 5 eosinophilic granulocytes per about 2 mm2 within a tumour has been shown to be associated with a worse survival {3189}. Lymphangiogenic differentiation as evidenced by D2-h expression also seems to predict a more aggressive course {3189}. Loss of p16 expression is also associated with a sigmf,. cantly worse prog nosis {3188}.

paybal：https://www.paypal.me/andy19801210 Aneurysmal bone cyst

Agaram NP Bredella MA

Definition Aneurysmal bone cyst (ABC) is a benign neoplasm of bone containing multiloculated blood-filled cystic spaces.

ICD-O coding 9260/0 Aneurysmal bone cyst

ICD-11 coding FB80.6 & XH23E0 Aneurysmal bone cyst & Aneurysmal bone cyst

Related terminology Not recommended: giant cell reparative granuloma of small bone; giant cell lesion of small bones.

Subtype(s) None

Localization ABC can affect any bone but usually arises in the metaphysis of long bones, especially the femur, tibia, and humerus, and the posterior elements of vertebral bodies. Rare tumours occur in the soft tissues {103,2282,2907}.

Clinical features Signs and symptoms The most common signs and symptoms are pain and swell­ ing, which are rarely due to fracture. In the vertebrae, ABC can compress nerves or the spinal cord and cause neurological symptoms.

Imaging On radiographs and CT, ABC presents as a lytic, expansile lesion with well-defined margins. Most tumours contain a thin shell of subperiosteal reactive bone. On MRI, characteristic fluid-fluid levels created by the different signal intensities of the cyst contents are present. Signal intensity can be variable on T1-and T2-weighted images, depending on the age of the blood products. Contrast administration can show septal enhance­ ment and can be helpful in detecting solid components, which suggest ABC-like changes {1695,3195}. On bone scan, ABCs show in creased peripheral radiotrace r uptake, with a central Photopenic area.

Epidemiology ABC affects all age groups but is most comm on duri ng the first two decades of life (80%). The sexes are equally affected {1994, 3195}. The estimated annual incidence is 0.15 cases per 1 milllon Population {1825}.

Etiology Unknow n

Fig. 3.129 Aneurysmal bone cyst. A Lateral radiograph demonstrates an expansile multiloculated lytic lesion in the distal tibia. B Axial fat-suppressed T2-weighted MRI of the distal tibia demonstrates multiple fluid-fluid levels.

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paybal：https://www.paypal.me/andy19801210 Macroscopic appearance Grossly, ABC is well defined, multiloculated, and compos ri of blood-filled, cystic spaces separated by tan-white, qn/l septa (sponge-like). More-solid areas can be pres ent, rep/ senting a solid portion of the ABC. The peripheral soft tissu] comp orient is surrou nded by a thin shell of reactive bone f0 mation.

Histopathology

Fig.3.130 Aneurysmal bone cyst. Gross image of a resected specimen from the pel­ vic bone showing multiple haemorrhagic cystic spaces with intervening septations.

Pathogenesis ABC contains cytogenetic rearrangements of the USP6 gene at chromosome band 17p13.2. The most comm on tran slocation, t(16;17)(q22;p13) {716,2373,2428,2506,2799}, leads to the fusion of CDH11 with USP6, with resultant upregulation of USP6 transcription {2373,2374}. USP6 rearrangements are found in approximately 70% of ABCs but not in ABC-like changes in other tumours {2375}. USP6 rearrangements do not seem to be associated with distinet biological behaviour {2375}. The most frequent USP6 fusion partner is CDH11 (30% of USP6 fusions); others include THRAP3 (TRAP150), CNBP (ZA/F9), OMD, COL1A1, CTNNB1, STAT3, FOSL2, EIF1, SPARC, PAFAH1B1, USP9X, and RUNX2 {2374,3249,2811,1261,336}. The ABC neo­ plastic component, containing the USP6 rearrangement, is a spindle cell population indistinguishable from normal fibroblasts and myofibroblasts {2375}. Other cells commonly seen in ABC, including inflammatory cells, endothelial cells, metaplastic boneassociated osteoblasts, and multinueleated osteoclast-like giant cells, do not contain a USP6 rearrangement and are presumably reactive {2375}. USP6 gene rearrangements occur in the cystic and solid ABCs of the small bones of the hands and feet, but not in the giant cell reparative granulomas in gnathic locations {33}.

ABC is well circumscribed and contains blood-filled cystic spaces separated by fibrous septa. The fibrous septa are composed of a moderately dense, cellular proliferation of bland fibroblasts, with scattered, multinucleated, osteoclast­ type giant cells and reactive woven bone rimmed by osteo­ blasts. The woven bone frequently follows the contours of the fibrous septa. In about one third of the cases, the bone is basophilic and has been termed blue bone, although its presenee is not diagnostic. Mitoses are commonly present and can be numerous; however, atypical forms are absent Necrosis is rare unless there has been a pathological frac­ ture. The solid subtype of ABC has the same comp on ents What was previously considered giant cell lesion of small bones has identical morphology to the solid subtype of ABC {286,2730}.

Immunohistochemistry Immunohistochemically, the lack of expression of H3.3 p.Gly34Trp could help to distinguish ABCs from giant cell tumours of bone with ABC-like changes.

Differential diagnosis ABC-like areas can be seen in other benign and malignant bone tumours that have undergone haemorrhagic cystic change. The term "secondary aneurysmal bone cyst" was previously used for such areas but is no longer acceptable. The majority of ABC-like changes develop in association with benign neoplasms, most commonly giant cell tumour of bone, osteoblastoma, chondroblastoma, and fibrous dyspla­ sia {1695,1994,3195}. However, ABC-like changes may also complicate sarcomas, especially osteosarcoma. The most

Fig.3.131 Aneurysmal bone cyst. A Cyst wall with multiple septations. B Cyst wall showing lack of distinctive cell lining and composed of spindle cells with scattered osteo­ clast-like giant cells, haemorrhage, and haemosiderin pigment deposition. C Aneurysmal bone cyst with areas of basophilic blue bone formation.

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B Fig,3,132 Solid aneurysmal bone cyst. A Tumour composed of fibroblast-like spindle cells, osteoclast-like giant cells, and reactive new bone formation. B FISH for USP6 gene using break-apart probe showing split green and red signals indicating rearrangement.

important differential diagnosis is telangiectatic osteosarcoma because both may have similar imaging characteristics and gross appearanee. In telangiectatic osteosarcoma, the fibrous septa contain obvious malignant neoplastic cells, which are not seen in ABC.

Essential and desirable diagnostic criteria Essential: radiology: multicystic lesion with fluid-fluid levels; his­ tology: cyst wall composed of fibroblasts, osteoclast-like giant cells, haemosiderin pigment, and new bone formation. Desirable: molecular: USP6 gene rearrangement.Staging Not clinically re leva nt

Cytology Not clinically releva nt

Diagnostic molecular pathology USP6gene rearrangement can be detected by FISH. The per­ centage of lesional cells carrying the rearrangement can some­ times be low.

Prognosis and prediction ABC is a potentially locally recurrent neoplasm. The recurrenee rate after curettage is variable (20-70%). Spontaneous regression after in complete removal is very unu sual. The prese nee or abse nee of USP6 fusion does not seem to affect prog no sis.

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paybal：https://www.paypal.me/andy19801210 Giant cell tumour of bone

Flanagan AM Larousserie F O'Donnell PG Yoshida A

Definition

Localization

Giant cell tumour of bone is a locally aggressive and rarely metastasizing neoplasm composed of neoplastic mononuclear stromal cells with a monotonous appearanee admixed with macrophages and osteoclast-like giant cells. A small subset of cases are malignant.

Giant cell tumour of bone typically affects the ends of |onn bones (distal femur, proximal tibia, distal radius, and - proxi^

ICD-0 coding 9250/1 Giant cell tumour of bone NOS

ICD-11 coding 2F7B & XH4TC2 Neoplasms of uncertain behaviour of bone or articular cartilage & Giant cell tumour of bone NOS

mal humerus) in the mature skeleton and occasionally the metaphysis {91}, particularly in skeletally immature individuals Giant cell tumours in the axial skeleton arise most commonly in the sacrum and vertebral body {2733,1990}; a tumour corn fined to the posterior elements only is not a giant cell tumour of bone. Flat bone invoIvement is rare but most frequent in the pelvis. Small numbers of giant cell tumours affect the tubular bones of the hands and feet {2377,2538}. Mutant-proven giant cell tumours are rarely reported in the gnathic bones {2538 91}. Malignant giant cell tumours affect bones similar to those invoIved in conventional giant cell tumour {289,1185,91,2538|.

Related termi no logy Not recommended: benign fibrous histiocytoma; osteoclastoma.

Clinical features Signs and symptoms

Subtype(s)

Giant cell tumour presents with pain, swelling, and occasionally restricted joint moveme nt. The du rati on of symptoms is typically weeks to months {468}. Tumours may be discovered inciden­ tally and occasionally during pregnancy {468}. A pathological

Conventional giant cell tumour of bone; giant cell tumour of bone, malignant

Fig. 3.133 Giant cell tumour of bone. A A non-mineralized, lytic lesion is seen in the left proximal tibia. No sclerosis is seen in the margin, and it extends to the articular surface The cortex is markedly thinned inferomedially. B Sagittal T2MRI. The lesion shows marked hypointensity due to haemosiderin. C The gross appearance of the giant cell tumour is shown in a coronal plane, filling and expanding the central marrow space. The tumour abuts the subarticular space but does not extend into the joint, reflecting what is seen in the radiograph and MRI. The features are typical of a giant cell tumour, showing variegated red and pale areas of tumour.

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paybal：https://www.paypal.me/andy19801210 fracture occurs in 5-12% of patients {468,3118}, most com­ monly in the distal femur {879}. Vertebral and sacral lesions cause in sidious on set of pain {3118} and freque ntly a neurologi­ cal deficit {3153}.

imaging When arising in long bones it is typically lytic and eccentric and extends to the articular cartilage {879}. Trabeculation is common, ranging from fine to coarse, and it represents endosteal ridging {2223}. The lesion shows a narrow zone of transition, with a well-defined, non-sclerotic border and no matrix mineralization. It is unusual for there to be a periosteal reaction, and its presenee may indicate a fracture {1811}. Less commonly, the tumour is centrally located {1435} and shows a poorly defined margi n {1435} or in complete marginal sclerosis {2202}. The overlying cortex may be normal, thinned to a variable degree, or breached by tumour that is contained within an attenuated periosteum; extension into soft tissue is the exception {3118}. Primary malignant giant cell tumours may show aggressive appearsnces but they are usually indistinguishable from conventi onal tumours; sec on dary maligna nt giant cell tumours resemble recurrent conventional disease but may also show postradiotherapy or postsurgical changes {289}. Giant cell tumour in the sacrum is often poorly visualized on radiographs due to its location {2403}, but it is typically located eccentrically within proximal sacral segments, causing lytic destruction )3153}, frequently involving the sacroiliac joint {3153,1990}. Ver­ tebral lesions cause lytic destruction and kyphosis. The lytic, non-mineralized nature and lack of periosteal reaction is best shown using CT {2223}. Scintigraphy most typically shows increased activity in the periphery of the lesion, with central photope nia (donut appears nee) {1435}. Intermediate to low T2 signal intensity, due to haemosiderin from chronic haemor­ rhage, is typical on MRI studies, but evidenee of recent haem­ orrhage {146,90} and fluid-fluid levels {2223} may also be seen, the latter suggesting aneurysmal changes. Denosumab-treated giant cell tumours show new bone formation in〉50% of cases, predominantly at the periphery of the tumour {2359,3362}.

Epidemiology Giant cell tumours represent 4-5% of all primary bone tumours and 20% of benign bone tumours, with an estimated incidenee rate of 1.2-1.7 cases per 1 million person-years {100,1853, 3198}. The peak incidence is between the ages of 20 and 45 years, with approximately 10% of cases occurring in the second decade of life {71}. Giant cell tumours, as defined by the H3.3 mutation, arise (although rarely) in the immature skeleton 11181,91,71}. A slight female predominance is reported, with the notable exception of a slight male predominance in a large series of subjects/patients from China {1863,2312}. Malignant giant cell tumours account for < 10% of all giant cell tumours, and the affected patients are generally the same age as those with conventional giant cell tumours {835,100,91}.

Etiology The etiology of the majority of sporadic giant cell tumours is

not known, whereas the phaeochromocytoma-paraganglioma and giant cell tumour syndrome is caused by an early postzygotic H3.3 mutation {3085,3084}. Synchronous or metachronous multicentric giant cell tumours are rare, most commonly

Fig.3.134 Giant cell tumour of bone. A 14-year-old girl with a lytic lesion in the distal radial metaphysis; note that the growth plate is open. A pathological fracture is present in the lateral cortex.

Fig.3.135 Giant cell tumour of bone. A Giant cell tumour of bone before denosumab treatment. Lytic, trabeculated tumour in the distal radius showing mild expansile remod­ elling and marked cortical thinning. B Denosumab-treated giant cell tumour of bone.

There is peripheral and internal sclerosis after 3 months of treatment with denosumab.

involving extremities in young patients {1142}. Multicentric giant cell tumours with early postzygotic H3.3 mutations are reported in the phaeochromocytoma-paraganglioma and giant cell tumour syndrome {3085}. However, many so-called multicentric giant cell tumours occur in a disease setting with known predisposing genetic alterations, such as Paget disease of bone {2614}, Gorlin-Goltz syndrome {368,2825}, and Jaffe-Campanacci syndrome {2947,239}. Osteoclast-rich tumours in these settings may also occur as single lesions. In most cases, it has not been determined whether such osteoclast-rich lesions harbour an H3.3 mutation, but they are not detected in osteoclast­ rich lesions of the severe familial form of Paget disease of bone caused by ZNF687 mutations {830}. Transformation to malignancy may occur after radiation therapy.

Pathogenesis Conventional giant cell tumour There is evidenee that the neoplastic stromal cells in giant cell tumour are of osteoblastic lineage: when treated with deno­ sumab, a RANK ligand inhibitor, the mutant cells mature and form bone, a process reversed on withdrawal of treatment. In addition, the stromal cells express (pre)osteoblast markers, including alkaline phosphatase, RUNX2, SP7 transcription Bone tumours

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Fig. 3.137 Malignant giant cell tumour in proximal femur. A destructive tumour focally destroying the articular cartilage and the cortical bone and extending into soft tissue. The tumour is nodular, has a firm rubbery texture, and shows haemorrhage and necrosis.

unknown. TP53 and HRAS mutations have bee n ide ntified in malignant giant cell tumour not associated with prior irradiation {1193}. Strong expression of p53 has been demonstrated in some (but not all) sec on dary malia nant aiant cell tumours {1185,2369}. — Fig. 3.136 Giant cell tumour of bone. A Typical features of a giant cell tumour of bone in a distal femur showing extensive cystic haemorrhagic areas. B Typical features of a giant cell tumour in the distal radius showing homogeneous pale soft tumour with focal recent haemorrhage and cyst formation.

factor (osterix), and SATB2 {1961}. Depletion of osteoclast-like cells implies that an osteoclast-like growth factor suppresses stromal cell differentiation and results in proliferation. At least 95% of giant cell tumours harbour pathogenic H3-3A (H3F3A) gene mutations, approximately 90% of which are H3.3 p.Gly34Trp, with the next most common being p.Gly34Leu; rarer variants (p.Gly34Met, p.Gly34Arg, and p.Gly34Val) have also been reported {257,91,2358,3337}. Copy-number and rearrangement analysis showed that tumours are diploid overall, with a paucity of structural changes {257,2358}. The mechanism by which the mutant H3.3 drives the neoplasm is not defined.

Malignancy in giant cell tumour The mechanism by which malignant transformation occurs is

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Bone tumours

Macroscopic appearance Conventional giant cell tumour is well defined and often lies eccentrically within the end of a long bone, which is typically asymmetrically- expanded. The surrounding cortex is often thinned and in areas may be destroyed completely, but it is gen­ erally contained by the periosteum. The subchondral bone plate can be focally eroded, but the tumour seldom penetrates the articular cavity. Viable tumour is characterized by a soft, friable, tan-red and haemorrhagic appearanee, but cream-yellow and firm white areas corresponding to xanthomatous change and fibrous tissue are comm only see n. Areas of haemorrhage and blood-filled cystic spaces corresponding to aneurysmal changes may be seen. In contrast to conventional giant cell tumour, the texture of a malign ant giant cell tumour is typically firm and fleshy.

Histopathology Giant cell tumour is a highly cellular lesion typically dominated by large n umbers of non-n eoplastic osteoclast-1 ike giant cells, between which mononuelear cells are embedded. The gia"

paybal：https://www.paypal.me/andy19801210 I cells have a variable number of nuclei, some with > 50 per cell. Mononuclear cells in giant cell tumour exhibit a variety of mor-

r ho|ogical appearances, including round to oval cells in a nonfjMotic background and spin died cells associated with fibrous matrix. The neoplastic cells have an ill-defined cell membrane with pale eosinophilic cytoplasm; their nuclei exhibit an open I chromatin pattern and contain one or two small nucleoli. How；ver, jt is difficult to distinguish the neoplastic cells from mac■ rophages (CD68-positive cells) without immunolabelling; the

former show a variable (occasionally high) mitotic count {71}. The presenee of atypical mitotic figures should raise suspicion for malignancy. The typical features of a giant cell tumour can be obscured by extensive necrosis, recent haemorrhage, haemosiderin deposition, aneurysmal change, collections of foamy macrophages, and reactive/reparative non-mutant fibrous tissue. In addition, areas of stromal overgrowth of the neoplastic mononuclear cells are un comm on. The prese nee of substa ntial depositi on of bone iS not common, although reactive/metaplastic bone formation can occasi on ally be striki ng and can be promine nt when asso­ ciated with a fracture. Excepti on ally, otherwise typical giant cell tumour contains benign-appearing hyaline cartilaginous nodules, and the differential diag nosis the n in eludes dediffere ntiated chondrosarcoma and chondroblastoma {1615,71}. Small numbers of otherwise typical giant cell tumours may contain scattered mononuelear cells with marked nuclear

Fig.3.138 Pelvic giant cell tumour of bone treated with denosumab. The tumour is composed of white nodules surrounded by pale-yellow fibrous-type tissue.

pleomorphism, en larged hyperchromatic n uclei, irregular nuclear con tours, smudged nu clear chromati n, and nu clea r pseudoinclusions. The nature of these cells is uncertain and probably represents degenerative change {2744,201}, because their scattered distribution/pattern is not suggestive of malignancy. Nevertheless, these cases can be challenging to clas­ sify, particularly on a biopsy specimen.

F'9-3.139 Giant cell tumour of bone. A The periphery of the tumour is sharply defined. The cortex is focally completely destroyed and partly surrounded by an eggshell-like rim "reactive bone. B Typical features of a giant cell tumour. The osteoclast-like giant cells dominate, between which are the mononuclear neoplastic cells. C Vascular invasion of a Writ cell tumour of bone outside the main bulk of the tumour. This is of no prognostic significance. D An area of foamy macrophages in a giant cell tumour of bone, which would

ave Previously been called a benign fibrous histiocytoma. Elsewhere in the tumour there is diffuse H3.3 p.Gly34Trp immunoreactivity (not shown).

Bone tumours

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A Fig.3.140 Giant cell tumour of bone. A Stromal overgrowth in a giant cell tumour. There is a striking lack of osteoclast-like giant cells. B The spindle cells in this area of stromal overgrowth show diffuse H3.3 p.Gly34Trp immunoreactivity.

The cortical bone surrounding the giant cell tumour is often severely eroded by osteoclasts and is commonly replaced by a reactive eggshell-like rim of new bone at the tumour periphery. In areas, the cortical bone can be completely destroyed but is gen erally contai ned by a band of fibrous tissue, which is likely to represe nt reactive periosteum; it is un comm on to see convincing soft tissue invasion. Focal incipient entrapment of host bone can be seen at the leading edge of the tumour. Vascular invasion may be present, especially after previous curettage. Giant cell tumour may metastasize to the lung, and in these cases the histological appearanee is similar to that at the

primary site {551,257,294}. Peripheral reactive bone formation can also be seen in these tumour nodules.

Malignant giant cell tumour Primary malig nancy in a giant cell tumo ur is un comm on and is typically represented by a nodule of highly pleomorphic, neo­ plastic mononuelear cells in an otherwise conventional giant cell tumour. Malignant transformation in a giant cell tumour is more common than the primary subtype and occurs after treatment of a conventional giant cell tumour, including with radio­ therapy. The conventional giant cell tumour may or may not be

Fig.3.141 Giant cell tumour of bone. A Necrosis. This is usually seen in the setting of pathological fracture. B Permeative growth at the leading edge of a giant cell tumour o bone is uncommon. C Section of a giant cell tumour showing nuclear atypia of the mutant mononuclear cells, consisting of smudgy chromatin and intranuclear pseudoinclusion. The implications of these focal changes are unknown. D H3.3 p.Gly34Trp immunoreactivity of atypical stromal cells.

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Bone tumours

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Fig.3.142 Primary malignant giant cell tumour. A Features of giant cell tumour of bone (lower right) tissue juxtaposed to a high-grade sarcoma (upper left). B H3.3 p.Gly34Trp

inniunoreactivity is seen in the giant cell tumour of bone component, whereas this is lacking in the sarcomatous component.

detectable in these cases {2644}. The ratio of the conventional to malignant components varies considerably. Some use the term "dedifferentiated giant cell tumour" to describe malignant giant cell tumours that exhibit a sharp delineation between the conventional and the malignant components {2056}. The malignant component of a giant cell tumour does not have specific histological features and may be either an undif­ ferentiated sarcoma or an osteosarcoma with telangiectatic or osteoblastic features {91,2644,2056}. In some cases of malig­ nant transformation, the H3.3 p.Gly34 mutation, as demon­ strated by immunohistochemistry, is retained in the malignant population (91,1615,2630,3337,3114), but there is also evidence that expression of the H3.3 protein is absent in at least some cases showing malignant transformation {2358,3376}. Finally, some bone sarcomas without associated giant cell tumour his­ tology harbour an H3-3A (H3F3A) or H3-3B (H3F3B) p.Gly34 mutation; these are usually sited in the epiphysis in you ng peo­ ple, suggesti ng a relati on ship with giant cell tumour. Therefore, there is a move to expand the definition of primary malignant giant cell tumour on the basis of an H3-3A (H3F3A) or H3-3B (H3F3B) p.Gly34 mutation {91}.

Changes in denosumab-treated giant cell tumour Giant cell tumours treated with denosumab for several months

show substantial new bone formation, associated with bland neoplastic mutant spindle cells and a striking depletion of osteoclast-like giant cells. However, variable amounts of conventional giant cell tumour may persist {401,1156,3337, 1591}. These features may mimic de novo osteosarcoma or sec on dary malig nant giant cell tumour. However, deno­ sumab-treated giant cell tumours gen erally lack substa ntial nuclear atypia, high mitotic activity, atypical mitotic figures, extensive necrosis, and infiltration of pre-existing bone {3301,2648}. Nevertheless, there are occasional reports of malignancy arising subsequent to denosumab-treated giant cell tumour. Further studies are needed to establish whether deno sumab might be r elated to maligna nt tran sformatio n {148,430,3113}.

Immunohistochemistry H3.3 p.Gly34Trp (G34W) immunohistochemistry is a reliable surrogate marker for molecular analysis {91,3337}.

Differential diagnosis Benign fibrous histiocytomas located in the epiphysis in the mature skeleton are now gen erally con sidered to represe nt giant cell tumour of bone and those in the metaphysis to represent non-ossifying fibroma. The differential diagnosis of malignant

F'9-3.143 Secondary malignant giant cell tumour. A A high-grade sarcoma with numerous atypical mitoses, which has developed as a local recurrence of giant cell tumour of bne about 20 years later. B High-grade sarcoma showing H3.3 p.Gly34Trp-mutant cells.

Bone tumours

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B X'X Fig. 3.144 Denosumab-treated giant cell tumour. A The right part of the figure shows spindle-shaped cells and no osteoclast・type giant cells, whereas the left side demonstrate the deposition of bone by the neoplastic cells. B H3.3 p.Gly34Trp immunohistochemistry showing numerous positive neoplastic cells and lack of osteoclast-type giant cells

giant cell tumour is undifferentiated sarcoma of bone and giant cell-rich osteosarcoma.

Cytology Not clinically relevant

Diagnostic molecular pathology An H3-3A gene mutation is detected in the neoplastic stromal cell population in as many as 96% of giant cell tumours {91, 257,2358,615,1615,3337}; 90% of these are represented by the H3.3 p.Gly34Trp mutation. The p.Gly34Leu mutation is much less frequent and is mostly found in tumours in the small bones of the hand, patella, and axial skeleton. There have also been occasional reports of p.Gly34Val, p.Gly34Arg, and p.Gly34Met {257,2358,2538}. Detection of the mutation does not distinguish between conventional and malignant giant cell tumours. Failure to detect an H3.3 mutation should prompt testing for alterations in other osteoclast-rich lesions.

Essential and desirable diagnostic criteria Essential: bone tumour with compatible imaging; an osteolytic circumscribed tumou r involving the epiphysis, gen erally in a skeletally mature in dividual; numerous large osteoclasts togethe r with a monon uclear cell n eoplastic comp orient with­ out atypia. Desirable: Detection of H3.3 p.Gly34—mutated cells.

Staging Not clin ically r eleva nt

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Bone tumours

Prognosis and prediction Between 15% and 50% of conventional giant cell tumours recur locally after curettage and usually within 2 years Between 3% and 7% of patients develop metastatic lung disease with histological features of conventional giant cell tumour {63,551,2656}. Predictors of metastatic disease in elude local recurre nee, but also possibly surgical manipulation. Vascular invasion is commonly seen in cases that metas­ tasize to the lung. The median interval between metastasis and local recurrence is 15 mon ths and most occur within 36 mon ths, but delayed metastasis (up to 10 years) has been described ,l {2656}. Pulmonary metastases are slow-growing and are j thought to represent pulmonary implants that result from |

embolization of intravascular growths of giant cell tumour.( Some conventional pulmonary implants can regress spon- * taneously. A small number exhibit progressive enlargement ! and lead to the death of the patient as a result of reduced lung volume {551,294}. Denosumab has been used with ben­ efit in the treatment of benign metastasizing disease {2410, 885). Denosumab may be used as the treatment for giant cell tumours that are unresectable or where surgical resection is likely to result in excessive morbidity. Neoadjuvant denosumab therapy can be used to facilitate surgical resection of locally advaneed tumours. However, there is no consensus J about optimal treatme nt dose, du rati on, or in terval between treatments. Furthermore, the safety of this drug when taken over long periods remai ns unknown {2410}. The prog no sis for patie nts with sec on dary maligna nt giant cell tumours is similar ■ to that of patients with a high-grade sarcoma and is reported to be worse than that for patients with primary malignant giant cell tumour {120,289,835}.

paybal：https://www.paypal.me/andy19801210 Baumhoer D Rogozhin DV

Non-ossifying fibroma

Definition Non-ossifyi ng fibroma (NOF) is a benign and gen erally self-lim■ iting storiform spindle cell tumour of bone containing osteoclastlike giant cells.

ICD-O coding 8830/0 Non-ossifying fibroma

ICD-11 coding 2E85.Y & XH06N0 Benign fibrohistiocytic tumour of other speci­ fied sites & Benign fibrous histiocytoma 2E85.Y & XA5GG8 Benign fibrohistiocytic tumour of other spec­ ified sites & Bones

Related terminology Not recommended: fibrous cortical defect (confined to the cor­ tex); metaphyseal fibrous defect; benign fibrous histiocytoma.

Subtype(s) None

Localizatio n The vast majority of NOFs arise in the metaphysis of long bones of the lower extremities, especially around the knee and in the distal tibia. Multifocal lesions may occur.

Clinical features Signs and symptoms NOF arises in skeletally immature individuals, with a peak inci­ dence in the second decade of life. It is usually asymptomatic and often discovered incidentally. Larger tumours can affect the biomechanical properties of the affected bone, become painful (probably related to microfractures), and/or cause pathological fracture {149,2714}.

Imaging The radiological features on plain radiographs are usually Pathog no monic and show a well-defi ned, lobulated lesi on cen­ tred in the cortical bone with sclerotic and scalloped borders. The tumours are aligned to the long axis of the bone. They are often ecce ntric and gen erally appear radiolucent. Sectonal images are usually not required; however, CT con firms a well-demarcated and purely lytic appearance; MRI shows low "-weighted and heteroge neous T2-weighted signal in tensity. Remarkably, (residual) NOFs are rarely seen in adults, suggestln9 spontaneous regression and resolution overtime, the cause "which is still unclear. Multiple NOFs can develop sporadically but also in patients with neurofibromatosis type 1, Jaffe-Cam-

Panacci syndrome, and the rare oculoectodermal syndrome 1470,149,2470,239}.

Fig. 3.145 Non-ossifying fibroma. A Plain radiographs of non-ossifying fibromas of the distal radius (left) and the distal tibia (right). Both lesions are lobulated and well demarcated, with a sclerotic rim. B Coronal (left) and sagittal (right) formatted CT of a non-ossifying fibroma of the distal tibia.

Epidemiology The incidenee of NOF is unknown, because most lesions will not come to clinical attention due to lack of specific symptoms. However, it has been estimated that approximately 30-40% of children have one or more occult NOFs, rendering NOF the most common tumour of bone {1958}. Radiographic studies have shown that 54% of boys and 22% of girls have NOF at the age of 4 years {1506,2909}.

Etiology The cause of sporadic NOFs is not known. However, NOFs (sin­ gle or multiple) may also occur on a background of germline Bone tumours

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Fig.3.146 Non-ossifying fibroma. A Non-ossifying fibroma composed of spindle-shaped cells arranged in a storiform growth pattern, with scattered osteoclast-type giar cells. B Non-ossifying fibroma with large collections of foamy histiocytes.

or postzygotic mosaic mutations in NF1, causing neurofibroma­ tosis type 1 and Jaffe-Campanacci syndrome, and in KRAS (oculoectodermal syndrome). Notably, in Jaffe-Campanacci syndrome and oculoectodermal syndrome, patients may develop multifocal NOFs and giant cell lesions of the jaws.

Essential and desirable diagnostic criteria Essential: bone tumour with compatible imaging findings. Desirable: storiform proliferation of plump spindle cells' metaphyseal location in long bones in skeletally immature patients;intermingled giant cells, haemosiderophages, and clusters of foamy histiocytes.

Pathogenesis In sporadic NOFs, mutually exclusive hotspot mutations in KRAS and FGFR1 have been identified in > 80% of cases, indi­ cating that NOFs represent true neoplasms driven by activated MAPK signalling {239,383}. NOFs appear to be related to giant cell lesions of the jaws, as they share histological and genetic alterations {1183}.

Macroscopic appearance Grossly, NOFs are rarely seen; they are well circumscribed, appear reddish-brown with areas of yellow discolouration, and have sclerotic borders. Cystic changes may be present, and haemorrhage and necrosis can be seen in tumours that have undergone pathological fracture.

Staging Not clinically relevant

Prognosis and prediction The prog nosis of NOF is excelle nt. Asymptomatic lesions detected inciden tally do not require biopsy con firmation in cases with typical imaging. Treatment is not necessary as long as there is biomechanical stability of the involved bone. When > 50% of the bone width is replaced or in case of pathological fracture, the lesion can be curetted. Local recurrences are rare; malignanttransformation has not been reported.

Histopathology Tumours consist of bland, spindle-shaped cells that are arranged in a storiform growth pattern. Mitotic activity is gener­ ally low. Osteoclast-type giant cells are scattered throughout the lesi on. Reactive features in elude haemosideri n deposition and collections of foamy macrophages. Reactive woven bone formation and cystic change may occur focally .In cases with pathological fracture, areas of necrosis can be present. Tumours with morphology similar to that seen in NOF but occur­ ring at sites such as pelvic bones and epiphysis of long bones, and in age groups unusual for NOF, have formerly been design ated as benign fibrous histiocytoma of bone. Curre nt cone epts indicate that benign fibrous histiocytoma probably constitutes a heterogeneous group of lesions, with the majority of cases representing giant cell tumours of bone with regressive changes (see Giant cell tumour of bone, p. 440).

Cytology Not clin ically re leva nt

Diagnostic molecular pathology KRAS a nd FGFR1 mutati on testing can be con sidered in ambig­ uous cases.

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Bone tumours

Fig. 3.147 Non-ossifying fibroma. Schema of signalling pathways involved in 惟 pathogenesis of non-ossifying fibromas.

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genign notochordal cell tumour

Definition Benign notochordal cell tumour (BNCT) is a benign tumour showing notochordal differentiation.

ICD-O coding 937O/O Benign notochordal tumour

ICD-11 coding 2E89.Z & XH7MT7 Benign mesenchymal tumours of uncertain differentiation, unspecified & Benign notochordal tumour

Related terminology ^lotrecommended: notochordal hamartoma; giant notochordal rest.

Subtype(s) None

Localization BNCTs occur in the skull base, vertebral bodies, and sacrococ­ cygeal spine. Occasi on ally they can be multiple and may be associated with chordoma {799}. Small numbers of extraskeletal BNCTs have been reported in a number of sites, including the lung {1621}. Ecchordosis physaliphora spheno-occipitalis (EPS) represents extraosseous intradural residual embryonic notochordal tissue sited in the region of the clivus.

Clinical features Signs and symptoms BNCTs are usually found in adults but have been reported in children. Most BNCTs are found incidentally on imaging, although they may be associated with pain. EPS may produce neurological deficits such as diplopia and visual field defects.

Imaging Radiographs may reveal mild sclerosis within a vertebral body or the clivus, although they usually fail to dem on strate any abnormality. CT may show an intraosseous sclerotic lesion with­ out bone destruction or extraosseous tumour extension, or it may fail to dem on strate a lesi on. MRI reveals homoge neously low signal intensity on T1-weighted imaging, homogeneously high signal intensity on T2-weighted imaging, and no contrast enhancement on gadolinium-enhanced T1-weighted imaging, h some cases, foci of T1-hyperintensity are seen within the bsion, which correspond to fatty bone marrow. Technetium bone sea ns usually do not demon strate any abno rmal uptake. °n PET-CT studies, the tumour usually shows low avidity for FD& Occasi on ally, tumours may be extremely sclerotic, showin9 the radiographic appears nee of an ivory vertebra {3333}.

Epidemiology "e incidence of BNCTs found incidentally is uncertain, though an autopsy study indicates a high incidence (-20%)

Fig.3.148 Benign notochordal cell tumour. A Sagittal T1-weigthed MRI (left) and T2-weighted MRI (right) show a well-defined, intraosseous lesion in the first coccy­ geal vertebra, containing several small foci of hyperintense T1 signal, suggesting fat (arrow). Histological diagnosis was confirmed after coccygectomy for pain. B Verte­ bral body with dense white lesion.

of microscopic BNCT among Japanese individuals aged 7-82 years {3334}. EPS is found in 0.6—2.0% of autopsy cases and in 1.7% of patients on MRI {2052}.

Etiology Unknown

Pathogenesis The embryonic protein brachyury (encoded by TBXT) is expressed in BNCTs and EPS.

Macroscopic appearance BNCTs are located within bone. The cut surfaces reveal a firm, well-demarcated but unencapsulated bright-tan tumour lacking any lobular con figurati on. EPS is a gelati nous polypoid lesi on attached to the dorsal surface of the clivus.

Bone tumours

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.___________ Fig.3.149 Benign notochordal cell tumour. A Benign notochordal cell tumour reveals scattered residual bone marrow islands within the lesion. B The affected bone trabecui * show appositional bone formation and no osteolytic process. C Benign notochordal cell tumour consists of solid sheets of vacuolated tumour cells with bland nuclei. The tumour cells mimic mature fat or brown fat cells.

Immunohistochemistry Both BNCT and EPS are immunoreactive for brachyury (encoded by TBXT), cytokeratin, EMA, and (variably) S100.

Differential diagnosis BNCT and chordoma can be difficult to distinguish, particularly on a biopsy: the juxtaposition of a chordoma with BNCT confounds the challenge {3332}. Atypical notochordal cell tumour is a recently described entity, but the criteria distinguishing it from BNCT and chordoma are ill defined. Atypical notochordal cell tumou r is considered a con troversial and challe nging diag nosis and may reflect a transition from BNCT to chordoma {498,16981

Cytology Not clinically relevant

Diagnostic molecular pathology Fig.3.150 Benign notochordal cell tumour coexisting with conventional chordoma. This tumour shows a focus of benign notochordal cell tumour (right) coexisting with

Not clinically r eleva nt

conventional chordoma (left).

Essential and desirable diagnostic criteria

Histopathology

Essential: bone tumour with compatible radiology; notochordal differentiation without atypia; brachyury (encoded by TBXT) and cytokerati n imm uno histochemistry.

BNCT consists of solid sheets of adipocyte-like vacuolated tumours cells and eosinophilic, less-vacuolated tumour cells. The nuclei are usually bland and mitotic figures are absent. Some cystic spaces filled with colloid-like eosinophilic material may be prese nt. The turn our often contains isolated isla nds of bone marrow. The involved bone trabeculae are usually viable and may be woven but show little evidenee of excessive bone resorption or formation. Unlike chordoma, BNCT lacks a lobular architecture, fibrous septa and capsule, extracellular myxoid matrix, and tumour vasculature.

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Bone tumours

Stagi ng Not clin ically re leva nt

Prognosis and prediction Prog nosis is excel le nt and BNCTs do not require any surgical procedure. Malignant transformation to chordoma is rare, but the incidenee is unknown. There is no consensus in terms of clinical surveillanee {1698}.

paybal：https://www.paypal.me/andy19801210 Tirabosco R O'Donnell PG Yamaguchi T

Conventional chordoma

Definition Conven tional chordoma is a malig nant tumou r with a phe notype that recapitulates notochord and that usually arises in bones of the axial skeleton.

ICD-O coding

being 32% skull-based, 32.8% in the mobile spine, and 29.2% in the sacrum and coccyx, according to the SEER Program {2042,2213}. Only a small n umber of extra-axial and extras ke Ietal chordomas are reported {3076,1774,2632}. Tumours in children and young adults have a greater propensity to occur in the base of the skull and upper cervical sites.

9370/3 Chordoma NOS

ICD-11 coding 2B5K & XH9GH0 Unspecified malignant soft tissue tumours or sarcomas of bone or articular cartilage of other or unspecified sites & Chordoma NOS 2B5K & XH17D8 Unspecified maligna nt soft tissue tumours or sarcomas of bone or articular cartilage of other or unspecified sites & Chon droid chordoma

Related termi no logy None

Subtype(s) Chon droid chordoma

Localizatio n Chordomas are chiefly located in the axial skeleton, involving bones from the base of the skull to the coccyx, the frequency

Clinical features Signs and symptoms Chordomas most commonly present with pain and site-related neurological symptoms.

Imaging Chordoma is typically a lytic, destructive lesion arising in the mid­ line. It grows slowly, expanding the bone, and is frequently asso­ ciated with a large mass. It is not mineralized, but bone fragments are often seen within and at the periphery of the mass {2305}. On MRI, the mass is lobular, septated, and heterogeneous, show­ ing low signal on T1-weighted images (but frequently contain­ ing high-signal foci) and hyperintensity on T2-weighted images {2995}. Enhancement after gadolinium administration is also het­ eroge neous and often septal {2995}, with myxoid areas enhanc­ ing poorly. The tumour shows low activity on technetium isotope bone sea ns {2672}, but there may be uptake at the margin and there is moderate avidity for FDG on PET studies {2445}.

Fig.3.151 Conventional chordoma. A Sagittal CT of the sacrum. There is destruction of the sacrum inferior to S1. Tumour extends proximally within the central spinal canal posterior to S1, the proximal level indicated (arrow). Bone fragments (arrowheads) remain visible anterior and posterior to tumour in the central spinal canal, which is expanded, jstally, there is an anterior extraosseous presacral mass (asterisk). B Sagittal T1 MRI shows a heterogeneous mass arising from the distal sacrum, extending within bone from .to 'he coccyx. There is a large anterior and small posterior extraosseous mass. C Sacrectomy specimen showing a large lobulated mass with a gelatinous appearance, evading and destroying the distal sacrum.

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Fig. 3.152 Chordoma. A Classic appearance of conventional chordoma showing the lobulated architecture with abundant extracellular matrix. B Tumour cells are arranged in cords and nests. Note the typical light basophilic appearance of the myxoid matrix. C Cords of tumour cells with mixed physaliphorous and epithelioid features. D Cytological atypia including multinucleated cells with bizarre nuclei and pseudonuclear inclusion.

Epidemiology The incidenee of chordoma is 0.08 cases per 100 000 personyears, with an M:F ratio of approximately 1.8:1. Chordoma rarely occurs in the black African population but appears to be represented equally in people of other ethnic groups. However, in one review African-America ns were more represented in the paediatric cohort than in the adult cohort {2802}. All ages are affected, but chordoma most comm only occurs in the fifth to seventh decades of life.

the cell cycle and extracellular matrix {2263}. Fin ally, growth arrest and senescenee upon silencing of TBXTin chordoma cell lines adds to the critical role of TBXT\n chordoma {2539}. In addition, PI3K signalling mutations have been reported in 16% of cases, and mutations (always inactivating) of LKSThave been described in 10% of cases {3052}. Phosphorylated and total EGFR (HER1) appears to play an important role in the disease, because it 厂

i

Etiology In rare cases, chordoma is associated with a germli ne tan dem duplicati on of TBXT {1609}, and rare cases of childhood chor­ doma occur in the setting of tuberous sclerosis, caused by germline loss-of-function mutations in the tumour suppressor gene TSC1 or 7SC2 {1820,2043}.

Pathogenesis The hallmark of chordoma is the expression of brachyury (encoded by TBXT) {3210,3076}: in 27% of cases, this is asso­ ciated with copy-number gain of TBXT, a transcription factor required for notochordal development {2539,3052}. This reca­ pitulates the tan dem duplicati on of TBXT that un derlies familial chordoma {3052,3354}. The strong association of rs2305089 in TBXT in patients with chordoma makes a strong case that this SNP contributes substantially to the development of chordoma {2512}. Brachyury has also been shown to act as a master regu­ lator of an elaborate oncogenic transcriptional network encompassing diverse signalling pathways, including components of 452

Bone tumours

Fig. 3.153 Chordoma. Tumour cells arranged in a pseudoalveolar pattern, mimicking renal cell carcinoma.

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pig,3,154 Chondroid chordoma. A Lobules of tumour cells within a hyaline matrix. B Small clusters and cords of cells. This feature may be helpful in cases with widespread

chondroid matrix.

is expressed in 47% and 67% of chordomas, respectively, and EGFR (HER1) inhibitors reduce cell survival {2823,2761}.

Macroscopic appearance Chordoma prese nts as a lobular solid mass with a gelati nous appearanee, destroying bone and extending into surrounding soft tissue. Sacrococcygeal tumours tend to be larger than those at other sites, most likely related to a Ion ger symptom-free period.

Essential and desirable diagnostic criteria Essential: bone tumour compatible with imaging; voluminous epi­ thelioid cells exhibiting notochordal differentiation embedded in copious myxoid matrix; brachyury and cytokeratin expression.

Staging Staging is according to bone sarcoma protocols (see TNM stag­ ing of tumours of bone, p. 339). See also the information on staging in Bone tumours: Introduction (p. 340).

Histopathology

Prognosis and prediction

Conventional chordoma is composed of large epithelioid cells with clear to light eosinophilic cytoplasm, separated into lobules by fibrous septa. The tumour cells may have bubbly cytoplasm (physaliphorous cells). They are arranged as cords and nests embedded within an abundant extracellular myxoid matrix, or as more-densely arranged epithelioid packets. Chordomas often show a substantial degree of intratumoural cytological heterogeneity, with features including nuclear atypia and pleo­ morphism ranging from minimal, usually associated with a low mitotic activity, to (less commonly) severe, in which bizarre nuclei or cell spindling can be seen. In the latter, mitotic figures can be easily detected and large areas of tumour necrosis may be prese nt. The term uch on droid chordoma" refers to chordoma m which a large area of the matrix mimics hyaline cartilaginous tumours {2659,1384}.

The overall median survival time is 7 years. As many as 40% of chordomas arising at sites other than the base of the skull metastasize. Metastatic sites include lung, bone, lymph nodes, and subcutaneous tissue. It is unclear whether chondroid chor­ domas behave differently than conventional chordomas; previ­ ous literature on the subject is no longer reliable, because data were derived from the pre-brachyury era, and therefore some cases coded as chondroid chordoma may have in fact been low-grade chondrosarcoma.

immunohistochemistry The tumour is diffusely immu no reactive for cytokerati n and EMA and shows variable S100 positivity.

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Differential diagnosis The diagnostic hallmark is the expression of brachyury, which helps to distinguish chordoma from chondrosarcoma, carcin°ma, and chordoid meningioma. The differential diagnosis includes metastatic carcinoma, chondrosarcoma, chordoid meningioma, and myoepithelial tumour of bone.

Cytology Not clinically relevant

Fig. 3.155 Chordoma. Nuclear immunoreactivity for brachyury.

^agnostic molecular pathology Nodiagnostic molecular markers have been reported.

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paybal：https://www.paypal.me/andy19801210 Dedifferentiated chordoma

Tirabosco R Hameed M

Definition Dedifferentiated chordoma is a chordoma with a biphasic appearance, characterized by conventional chordoma and high-grade sarcoma.

ICD-0 coding 9372/3 Dedifferentiated chordoma

ICD-11 coding 2B5Z & XH7303 Malignant mesenchymal neoplasm of unspeci­ fied type & Dedifferentiated chordoma

Related terminology None

Subtype(s) None

Localization The locations are similar to those of conventional chordoma, predominantly in sacrococcygeal sites {2213}.

Clinical features Signs and symptoms

Fig. 3.156 Dedifferentiated chordoma. Axial T2-weighted MRI of the pelvis shows a biphasic tumour. A large, heterogeneous, hyperintense mass has destroyed the sa­ crum (asterisk) and extended into the presacral space. Within the anterior aspect of the mass, there is a well-defined, relatively hypointense component (arrows) consistent with dedifferentiated tumour (high-grade pleomorphic spindle cell sarcoma showing smooth muscle differentiation).

The symptoms are similar to those of conventional chordoma, although progression may be more rapid. Pain and site-related n eurological symptoms are comm on. Dediffere ntiated chor­ doma may present de novo or at a location of a previously resected conventional chordoma.

Imaging Dedifferentiated chordomas show morphology similar to that of conventional tumours and can not be disti nguished on radio­ graphs or CT. A bimorphic appearanee may be appreciated on MRI, with the dediffere ntiated comp orient suggested by areas of tumour that are relatively hypointense on T2-weighted imaging /fluid-sensitive studies, distinct from the typically T2-hyperintense conventional chordoma {1294}.

Epidemiology Dedifferentiated chordoma is the rarest notochordal tumour subtype, with only case reports and small series published {1294,2061,330,2127}.

Etiology Unknown

Pathogenesis See Conventional chordoma (p. 451). Fig.3.157 Dedifferentiated chordoma. Sacrectomy specimen showing a large d学 structive tumour: the haemorrhagic area represents the conventional component, an

the more solid fleshy larger area is a dedifferentiated tumour.

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fig,3,151 Dedifferentiated chordoma. A Typical features of a chordoma (right), with an abrupt change to a high-grade pleomorphic sarcoma showing rhabdomyoblastic dif­ ferentiation (left). B Rhabdomyosarcomatous differentiation highlighted by desmin immunostain. The tumour was also positive for myogenin (not shown).

Macroscopic appearance The tumour presents as a large mass with a biphasic appear­ ance. The dediffere ntiated comp orient has the gross features of a high-grade sarcoma with a solid surface, juxtaposed to a gelati nous and myxoid conventi onal chordoma.

Histopathology The distinguishing characteristic is the simultaneous presence of a conventional chordoma and a high-grade spindle and/or pleomorphic sarcoma. Osteosarcomatous and rhabdomyosar­ comatous differentiation can be seen. The two components are usually abruptly separated, but they can be intermingled.

Immunohistochemistry The dediffere ntiated comp orient can show focal cytokeratin expression but does not express brachyury {3210}. Specific lineages, such as rhabdomyoblastic, should be supported by Immunohistochemical expression of desmin and myogenin.

Fig. 3.159 Dedifferentiated chordoma. Immunoreactivity to brachyury is lost in the dedifferentiated component (left).

Differential diagnosis The differential diagnosis includes dedifferentiated chondrosarcoma.

Cytology

Staging Staging is according to bone sarcoma protocols (see TNM stag­ ing of tumours of bone, p. 339). See also the information on staging in Bone tumours: Introduction (p. 340).

Not clinically relevant

Prognosis and prediction

Diagnostic molecular pathology No diagnostic molecular markers have been reported.

The prog nosis is poor; the metastatic rate and mortality are high. The ben efits of chemotherapy or r adiotherapy seem neg­ ligible. Surgery is the only option.

Essential and desirable diagnostic criteria Essential: bone tumour with compatible imaging; conventional chordoma (histologically or by history) plus high-grade sar­ coma.

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Poorly differentiated chordoma

Definiti on Poorly differentiated chordoma is a poorly d if fere ntiated n eoplasm with notochordal differentiation, usually arising in the axial skeleton, and characterized by loss of SMARCB1 expression.

ICD-0 coding 9370/3 Chordoma NOS

ICD-11 coding 2B5Z & XH9GH0 Malignant mesenchymal neoplasm of unspec­ ified type & Chordoma NOS

Related terminology None

Subtype(s) None

Localizati on The most common location is the skull base (clivus), followed by the cervical spine and rarely the sacrococcygeal region {2607, 2843,2166,123,441,527,2402,2612,3326,546,1384}.

Clinical features Signs and symptoms Patie nts gen erally prese nt with non specific symptoms such as headache, pain, cranial nerve symptoms, and weight loss.

Imaging On imaging, the tumours are destructive, arise in bone, and exte nd into adjace nt soft tissues. By CT, the tumours are lytic, and they are heterogeneous on T1- and T2-weighted MRI.

Epidemiology This is a rare type of chordoma, with approximately 60 cases reported in the English-language literature. Tumours typically arise in childre n and occasi onally in you ng adults; they occur in females roughly twice as frequently as in males. In the largest series to date, the age range was 1-29 years (median: 11 years) {2843}.

Fig. 3.160 Poorly differentiated chordoma. Axial T2-weighted image showing a large enhancing tumour arising in the skull base.

appear to have intact SMARCB1 and loss of SMARCB1 expression {2166}, but the mechanism by which this is brought about is prese ntly un clea r {2402}. Un supervised clusteri ng an alysis of DNA promoter methylati on profiles in di cates that the presence of SMARCB1 deletions in these tumours readily distinguishes them from conventional chordoma, as well as the atypical teratoid/rhabdoid tumour {1318}.

Macroscopic appearance

Unknown

The size of tumours gen erally ran ges from 2.0 cm to > 10 cm. although most are about 5.0 cm at presentation {123,2402. 2843}. Descriptions of the cut surface are, to date, lacking: poorly differentiated chordomas are destructive and may be well demarcated and multilobulated {2607}.

Pathogenesis

Histopathology

In most cases, cytogenetic studies have identified deletions involving SMAFICB1 {2402,1434}; these may be heterozygous or homozygous and of variable size, and they can be detected by DNA sequencing {2612,1201}. There is no evidence to date of single-nucleotide variants accounting for loss of SMARCB1 protein {2166,1318,2842). A subset of cases also show hete­ rozygous co-deletion of the EWSR1 locus, which lies in close proximity to SMARCB1 {527,2402,1434}. A minority of cases

Poorly differentiated chordoma is composed of cohesive sheets or nests of epithelioid cells, often with a focal rhab­ doid morphology. There is relatively abundant eosinophilic cytoplasm and scattered cytoplasmic vacuoles reminiscenW signet-ring cells. The nuclei are round to ovoid, with vesicular chromatin, and they reveal mild to moderate pleomorphism, mitotic activity is increased. The physaliphorous cells typi­ cal of chordoma with classic features are absent. Similarly，

Etiology

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Fig.3.161 Poorly differentiated chordoma. A The tumour is composed of sheets of poorly differentiated epithelioid cells with eosinophilic cytoplasm, irregular nuclei, and prominent nucleoli. There is a central area of necrosis, but no myxoid stroma is present. B Poorly differentiated chordoma demonstrating diffuse immunohistochemical staining for keratin. C Poorly differentiated chordoma demonstrating diffuse immunohistochemical nuclear staining for brachyury. D Poorly differentiated chordoma demonstrating lack olstaining for(i.e. loss of) SMARCB1 (INI1).

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extracellular myxoid stroma, if prese nt, is gen erally no more than focal. Geographical necrosis is often conspicuous {1384, 2402,2843}.

is gen erally un like the typical EWSR1 rearra ngeme nts and must be interpreted with caution {1434}.

Essential and desirable diagnostic criteria sut of :e 5S

Immunohistochemistry The tumours are immu no reactive for cytokeratin and brachyury (encoded by TBXT\ with variable positivity for S1OO. A diag­ nostic feature is the loss of SMARCB1 (INI1) expression {2166, 1318,2843}.

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Staging Differentiai diagnosis The differential diagnosis includes malignant rhabdoid tumour and rhabdoid meningioma.

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Staging is according to bone sarcoma protocols (see TNM stag­ ing of tumours of bone, p. 339). See also the information on staging in Bone tumours: Introduction (p. 340).

Cytology

Prognosis and prediction

Not clinically relevant

Treatment con si sts of a combi nation of surgery, r adiati on therapy, and chemotherapy. Fewer than 60 cases have been reported in the literature, but this subtype of chordoma is asso­ ciated with a poor prog nosis 一 worse tha n that of conventional chordoma {2843,2402,3326,1384,1318}.

Diagnostic molecular pathology re

Essential: bone tumour with compatible imaging; poorly dif­ fere ntiated malignant neoplasm arising in the axial skeleton; positive immunohistochemical staining for keratin and brachy­ ury; loss of SMARCB1 (INI1) expression.

FISH can be used to identify deletions in SMARCB1, and these may be associated with a co-deletion of the EWSR1 locus. FISH for EWSR1 in such tumours may exhibit a complex pattern that

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paybal：https://www.paypal.me/andy19801210 Chondromesenchymal hamartoma of chest wall

Fritchie KJ Gambarotti M

Definition Chondromesenchymal hamartoma of chest wall is a benign bone tumour arising from the ribs, composed of hyaline carti­ lage, woven bone, bland spindle cells, and blood-filled cystic spaces.

ICD-0 coding None

ICD-11 coding None

Related terminology Not recommended: chest wall hamartoma; vascular and carti­ laginous hamartoma of the chest wall; giant chondromatous hamartoma; cartilaginous hamartoma; benign mesenchymoma. Note: Nasal chondromesenchymal hamartoma most likely represents a distinet entity from chondromesenchymal hamar­ toma of the chest wall and is discussed in the head and neck volume.

Fig. 3.162 Chondromesenchymal hamartoma. Axial CT of a chondromesenchymal hamartoma shows an expansile lytic lesion involving a right posterior rib with internal chondroid matrix (arrow) and an associated extrapleural and posterior soft tissue mass (asterisks).

Subtype(s) None

Localization Lesions arise from either the medullary cavity or the surface of the rib and may extend to involve multiple ribs simultaneously {845,104,634,187,2027}. The lateral or posterior aspects of the ribs are invoIved most frequently {845}. The majority of patients present with a solitary mass, but bilateral or multicentric tumours have been reported {1235,1400,2338,2350,3106,1346}.

Clinical features Signs and symptoms Patients often present with a slow-growing palpable mass, with or without clinical symptoms {104,1235,187}. Larger lesions result in respiratory distress, scoliosis, and chest wall deformity {187}.

Imaging X-ray and CT usually show an expansile rib lesion with welldefined sclerotic margins and extrapleural extension containing mineralization and cystic regions with fluid-fluid levels {1235, 1632}. The min eralization is predominantly chon droid but may show osteoid or mixed features {1235}. MRI shows solid and cystic components, with heterogeneous signal intensities on T1and T2-weighted images {1235,1632}.

Epidemiology The reported incidence is 1 case in 3000 among primary bone tumours and < 1 case per 1 million person-years in the 458

Bone tumours

Fig. 3.163 Chondromesenchymal hamartoma. Sagittal T2-weighted MRI of a 1-yea" old girl shows a large mass arising from a posterior rib with a large heterogeneous extrapleural soft tissue mass. The mass is associated with deformity of the adjacent rib (not shown) and contains multiple internal fluid-filled spaces (arrow), some of which contain fluid-fluid levels indicative of intralesional haemorrhage.

general population, with approximately 100 cases reported in the literature {2579,395,3170}. The majority of tumours appear to arise congenitally and are noted at birth, and almost all are

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e £deuo Fig.3.164 Chonaromesenchymal hamartoma. A Low-power examination reveals a cystic lesion with nodules of hyaline cartilage. B Nodule of cartilage with an appearance similar to the epiphyseal growth plate. C The cyst walls are composed of a loose arrangement of bland spindled cells and multinucleated giant cells. D Foci of immature bony

trabeculae are also present.

diagnosed by the end of the first year of life {634,845}. Rare cases present in older children {845,3039}. There is a male pre­ dominance (M:F ratio: 2:1) {467,845}.

Cytology Not clin ically r eleva nt

Diagnostic molecular pathology

Etiology

Not clin ically re leva nt

Unknow n

Essential and desirable diagnostic criteria

Pathogenesis Unknow n

Macroscopic appearance Gross examination reveals a well-circumscribed multinodular or lobulated mass with a variably solid and cystic cut surface, typi­ cally ranging from 5 to 10 cm, although tumours > 15 cm have been reported {845,634). The cystic component often contains blood-filled spaces, and the solid areas exhibit a reddish-brown or tan appearanee with foci of cartilage.

Histopathology Histological exami nation reveals a variably cystic lesion contain­ ing nodules of hyaline cartilage, often with enchondral ossificaUon similar to the epiphyseal growth plate, surrounding bloodMled spaces. The walls and septa of the cystic component are composed of reactive-appearing bone, bland spin died cells, and multinueleated giant cells, often resembling aneurysmal bone cyst. The spindle cell comp on ent does not show substan讷 cytological atypia or nuclear hyperchromasia.

Essential: well-circumscribed mass arising from the rib; variable solid and cystic comp on ents; nodules of hyali ne cartilage admixed with blood-filled cystic spaces, reactive bone, bland spindle cells, and osteoclast-like giant cells. Desirable: paediatric presentation.

Staging Not clinically relevant

Prognosis and prediction Although chondromesenchymal hamartoma of chest wall is a benign entity, rare cases of death have resulted from respira­ tory insufficiency {2040,1346,634}. Surgical excision is typically curative, but postoperative complications may include severe scoliosis and chest wall deformity. There is some evidenee that these lesions decrease in size after the second year of life, and conservative treatment may be an option if the patient is not in dan ger of respiratory compromise and can be routi nely moni­ tored {1873,187,1614,2277}.

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Osteofibrous dysplasia

Definition Osteofibrous dysplasia (OFD) is a benign fibro-osseous tumour of long bone that typically arises in the anterior cortex of the tibia and/or fibula during childhood.

Clinical features Signs and symptoms Patients report pain, localized swelling, and bowing deformih rarely does it cause a pathological fracture. The tumour may als be discovered incidentally on X-rays taken for other reasons

ICD-0 coding

Imaging

None

ICD-11 coding 2E83.5 & XH6M86 Benign osteogenic tumours of bone or artic­ ular cartilage of limbs & Ossifying fibroma

Related terminology Not recommended: ossifyi ng fibroma of long bon es; Kemps onCampanacci lesion.

Subtype(s) None

Localization OFD typically arises in the proximal or middle third of the tibial cortex. Lesions can be bilateral with ipsilateral or contralateral involvement of the fibula. Ipsilateral involvement of the fibula is seen in approximately 20% of patients. Very rarely has it been reported to involve other long bones such as the radius, ulna, and humerus, although the documentation of these reports is not convincingly diagnostic for OFD.

OFD is typically epicentred in the cortical bone, but it may focall involve the underlying medullary cavity. Although slow growth is characteristic of OFD, some lesions may be periodically aggressive and may involve the entire bone with a substantial anterior bowing deformity. Often well demarcated, it is associated with a thinning expanding, or even missing cortex. The expanding cortex is frequently sclerotically rimmed near the medullary bone. Separate or con flue nt oval, scalloped, saw-toothed or bubbly multiloculated. lytic lesions are ofte n noted, orie nted parallel to the shaft of the bone. Perilesional sclerosis may be considerable. The interior of the lytic foci is typically more radiodense than soft tissue. Bone scans are typically hot. CT delineates the cortical epicentre of the lesion not breaking through into the soft tissue and demarcated from medul­ lary bone by sclerosis. MRI findings show intermediate to high signal intensity on T2-weighted images, with diffuse enhancement on postcontrast images and mixed signals on T1-weighted andfat-suppressed images. Radiological differentiation from adamantinoma may be difficult, but young age, presence of anterior bowing with ground-glass appearance and absenee of multilayered periostea reaction, and absence of moth-eaten destruction favour OFD |344|

Fig.3.165 Osteofibrous dysplasia. A Plain radiograph shows a mixed lytic and sclerotic lesion that is causing endosteal scalloping and cortical expansion of the proxim tibial diaphysis. B Axial CT shows that the tumour is confined to the cortex of the tibia and surrounded by a rim of bone, without involvement of the medullary cavity or soft tis­ sues. C Axial T1 MRI demonstrates an expansile intracortical tumour causing cortical thinning, without periosteal reaction. There is no infiltration of the adjacent medullary cavity.

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Fig.3-166 Osteofibrous dysplasia. A Osteofibrous dysplasia composed of trabeculae of woven bone with osteoblastic rimming and fibrous tissue. B Higher-power view of osteofibrous dysplasia demonstrating the woven bone with osteoblastic rimming, surrounded by spindle-shaped cells.

Epidemiology OFD is a very rare tumour, accounting for approximately 0.2% of all primary bone tumours. It typically develops during the first and second decades of life, which is younger than patients with adamantinoma. OFD is rare after the age of 15 years.

Etiology The etiology is unknown. Rare familial cases have been reported (1211}.

xanthomatous change, cyst formation, and foci of giant cells are rare. Cartilage is absent.

Immunohistochemistry Immunohistochemical staining for keratin shows no or only sin­ gle keratin-positive stromal cells. Clusters of keratin-positive cells as seen in OFD-like adamantinoma are not present. Typi­ cally these in dividual cells express CK14, CK19, and to a lesse r extent CK5 and CK17 {1331}. Additionally, OFD shows positive staining for p63 and occasionally S100 {2713}.

Pathogenesis Recurrent cytogenetic and FISH findings in OFD in elude trisomies of chromosomes 7, 8, and 12 that have been identified in both adamantinoma and OFD {1334}. The genetic abnormali­ ties are found in a minority (5-10%) of spindle-shaped cells and not in the osteoblasts or osteoclasts, indicating that a large portion of the tumour is non-neoplastic in nature; it has been hypothesized that the stromal cells showing epithelial differen­ tiation might be the neoplastic comp orient {1168}. Causative molecular genetic aberrations have not been identified, but the proto-on coge nes FOS and JUN are expressed. Additi on ally, GNAS mutatio ns (see n in fibrous dysplasia) are abse nt in OFD 13018}. Germline mutations involving MET(encoding a receptor lyrosine kinase) are seen in hereditary forms of OFD {1211}.

Differential diagnosis OFD should be distinguished from fibrous dysplasia. The stroma in fibrous dysplasia is more cellular and collagenous than in OFD, and the woven bone in fibrous dysplasia does not show promi nent osteoblastic rimming; additi on ally, mutatio ns in the GNAS gene are found in most cases of fibrous dysplasia but are absent in OFD. Immunohistochemically, there are no keratin-positive epithelial cells in fibrous dysplasia, and this tumour is epicentred in the medullary cavity of the bone. The distinotion from OFD-like adamantinoma, which also preferentially occurs

Macroscopic appearance OFD is a solid, white or yellow, gritty tumour. It is confined to the cortex, rarely with minimal invo Iveme nt of the adjace nt medul­ lary cavity. Although the cortex may be thinned, the overlying periosteum is intact.

Histopathology Histologically the tumour is composed of an admixture of bone and fibrous tissue. The bone is composed of trabeculae of woven bone with prominent osteoblastic rimming. The inter­ vening fibrous stroma is composed of bland-looking spindleshaped cells embedded within an extracellular collage nous or sometimes myxoid matrix. Osteoclasts may be present. Mitoses are extremely rare. Zonal architecture is delineated with thin spicules and woven bone or even fibrous tissue predominating in the centre of the lesion with more-abundant anastomosin9 and lamellar bone peripherally, the latter often blending into the surrounding host bone. Hyalinization, haemorrhage,

Fig. 3.167 Osteofibrous dysplasia. Osteofibrous dysplasia shows single scattered keratin-positive stromal cells. Clusters of keratin-positive cells (as seen in osteofibrous dysplasia-like adamantinoma) are not seen.

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paybal：https://www.paypal.me/andy19801210 in the tibia, can be difficult and depends on the extent of the epi­ thelial comp orient. Classic adama ntinoma can be disti nguished by the presenee of easily identifiable clusters of epithelial cells.

Staging

Cytology

The tumour may gradually grow during the first decade of life Most undergo spontaneous regression after puberty. It is con­ troversial whether OFD may progress into OFD-like adaman­ tinoma {2778}, and it is possible that some reported cases of this progression represent sampling issues or that series reporting the absenee of progress!on lack proIonged follow-up. Most patients can be treated conservatively with close observation, patient/parent education, and no surgery .In the prese nee of substantial deformity or pseudoarthrosis, impending or existing pathological fracture, the desire for definitive diagnosis, or severe symptoms, surgical in tervention may be warranted {3278}.

Not clinically relevant

Prognosis and prediction OFD can not and should not be diag no sed on the basis of FNA.

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: bone tumour with compatible imaging; almost exclu­ sively in the tibia and/or fibula, always involving cortex; a fibro-osseous tumour of bone in which the woven bone shows prominent osteoblastic rimming; absenee of keratin-positive clusters of cells.

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/\damantinoma of long bones

Definition Adamantinoma is a biphasic locally aggressive or malignant tumour characterized by a variety of morphological patter ns, with a variable epithelial comp on ent withi n a bland osteofibrous component.

ICD-O coding 9261/1 Osteofibrous dysplasia-like adamantinoma 9261/3 Adamantinoma of long bones

ICD-11 coding 2B5J & XH1SV4 Malignant miscellaneous tumours of bone or articular cartilage of other or unspecified sites & Ameloblas­ toma NOS

Related terminology Not recommended: well-differentiated adamantinoma.

Subtype(s) Classic adamantinoma (malignant); osteofibrous dysplasia-like adamantinoma; dedifferentiated adamantinoma

Localizatio n The tibia, in particular the anterior metaphysis or diaphysis, is involved in 85-90% of cases. Multifocal involvement of the tibia is frequently present {3155}. In as many as 10% of patients, this is combined with one or more lesions in the ipsilateral fibula. Adamantinoma involving other bones has very rarely been reported, including the radius, ulna, calcaneus, femur, humerus, olecranon, ischium, rib, spine, metatarsals, and capitate {2778, 1606}; however, one should be very careful about making the diagnosis of adamantinoma outside the tibia and fibula.

Clinical features Signs and symptoms The main symptom is painful or pain less swelli ng. Adamanti­ noma often displays a protracted clinical behaviour. Clinical symptoms such as swelling or radiographic abnormality may last for > 30 years before diagnosis, whereas local recurrences or metastases may develop years after primary, intralesional, or marginal surgical treatment {1606}.

Fig. 3.168 Osteofibrous dysplasia-like adamantinoma. A Osteofibrous dyspla­ sia-like adamantinoma presenting as numerous lytic areas involving the cortex and medullary cavity. The tumour has distorted the tibia, which demonstrates some an­ terior bowing. B In the anterior cortex of the mid-tibial shaft there is an intracortical, multiloculated lytic lesion with surrounding sclerosis. C Axial CT demonstrating lytic lesions with surrounding sclerosis involving the anterior cortex.

lesion. MRI is useful to document multicentricity, the extension of the lesion, and possible soft tissue invoIvement {3155}.

Epidemiology Imaging °n X-ray, the tumour is typically well circumscribed, cortical, multilobulated, and osteolytic (soap bubble appearance). Intralesional opacities, septation, and peripheral sclerosis may also be seen. Multifocality within the same bone is regularly observed. The lesi on comm only remai ns in tracortical and extends lon­ gitudinally along the bone, but it may also destroy the cortex and invade the medullary cavity or adjace nt soft tissue. This is usually accompanied by lamellar or solid periosteal reaction. Aggressive tumours occasionally present as a single, large, lytic

Adamantinoma accounts for about 0.4% of all primary bone tumours. Patients present with this tumour at an age of 3-86 years, with a median age of 25-35 years. The youngest age group predominantly includes patients with osteofibrous dysplasia (OFD)-like adamanti no ma, but you ng childre n with classic adamantinoma and adults with the OFD-like subtype have been reported {1333,2182,3010}. It is more comm on in males. Rarely, at middle and advaneed age, further progression into dedifferentiated adamantinoma may occur {1332, 1499}. Bone tumours

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paybal：https://www.paypal.me/andy19801210 Etiology Unknown

Pathogenesis Rare cases of OFD-like adamantinoma seem to arise from pre-existing OFD. OFD-like adamantinoma may also rarely progress into classic adamantinoma. Dedifferentiated ada­ manti noma arises in the setting of pre-existing classic ada­ mantinoma {1332}. A recurrent pattern of numerical abnormalities featuring extra copies of chromosomes 7, 8, 12, 19, and/or 21 has been detected in classic as well as OFD-like adamantinoma {1168,1565}. Extra copies of one or more of these chromo­ somes (except for chromosome 19) have also been identified in OFD, supporting a related pathogenesis {1168,411}. In addition to trisomy 19, structural abnormalities including translocations and marker chromosomes have been reported in adamantinoma, but not in OFD {1334,1565}. The progres­ sive complexity of the karyotypic aberrations observed in OFD, OFD-like adamantinoma, and classic adamantinoma may be indicative of a multistep transformation process {1168}. Trisomies 7, 8, and 12 have not been observed in osteo­ blasts or osteoclasts, suggesting that the osseous component is reactive and non-neoplastic, in contrast with the pres­ ence of these trisomies in the spindle cell stroma comp on ent of the same lesions {1168}. DNA index studies have shown

Fig. 3.169 Classic adamantinoma. A Classic adamantinoma demonstrating a large expansile osteolytic lesion with soap bubble appearance involving the distal tibia and causing cortical thinning. B A resection specimen from the tibia shows a tan mass involving the medullary cavity associated with a pathological fracture. Proximal to the main tumour there are smaller nodules of tumour associated with sclerosis.

Fig. 3.170 Classic adamantinoma. A Biopsy from the tibial lesion shows classic adamantinoma with the neoplastic 即ithelial cells forming tubular structures. B Basaloid

pattern with the peripheral palisading of the tumour cells surrounding inner spindle-shaped cells. C Squamous differentiation, where the centre of the 即ithelial islands shows obvious keratinization, is the rarest subtype of adamantinoma. D Spindle cell subtype of adamantinoma with tumour cells arranged in intersecting fascicles. This subtype must be distinguished from intraosseous synovial sarcoma.

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fjg,3,171 Osteofibrous dysplasia-like adamantinoma. A Osteofibrous dysplasia-like adamantinomatous areas that look like osteofibrous dysplasia with trabeculae of woven bone rimmed by plump osteoblasts. Within the fibrous stroma there are small nests of epithelial cells (inside circle) that are hard to see on H&E-stained slides and may mimic endothelial cells. B A keratin stain highlights the small clusters of epithelial cells.

that in aneuploid adamantinomas, the aneuploid population is always r estricted to the epithelial comp orient {1330}. TP53 aberrations are also restricted to the epithelial component.

Macroscopic appearance Classic adamantinoma usually presents as a cortical, welldemarcated, lobulated, whitish-grey gritty tumour with periph­ eral sclerosis. It may be a single lesion or occasionally multi­ focal. Small lesions remain intracortical. Larger tumours may show intramedullary extension and cortical breakthrough, with soft tissue invasion in a minority of cases. Macroscopically detectable cystic spaces are comm on, filled with straw-col­ oured or blood-like fluid. The tumour varies in size from < 1 cm to> 10 cm.

Histopathology The distinotion between OFD-like and classic adamantinomas depends on the extent of the epithelial component. OFD-like adamantinoma contains a predominance of OFD-like areas with only small nests of epithelial cells; the epithelial nests may be difficult to see or to distinguish from endothelial cells by light microscopy. In classic adamantinoma, the epithelial compo­ nent is prominent, with inconspicuous OFD-like areas. The epithelial component may be tubular, squamous, basaloid, or

spindle-shaped. The basaloid cells usually have peripheral palisading and central stellate or spindle-shaped cells {1606}. By far the rarest subtype is dedifferentiated adamantinoma. In these tumours, areas of classic adamantinoma gradually merge with a diffuse growing proliferation in which the characteristic epithelial differentiatio n is lost and in stead pleomorphic cells are prese nt, with a high mitotic cou nt. Chon droid differe ntiation, osteoid deposition, and clear cell changes can be seen {1332,1499}.

Immunohistochemistry Immunohistochemically, the fibrous tissue is positive for vimentin. The epithelial cells show coexpression of keratin, EMA, vimentin, p63, and podoplanin {822,1589}. Chain-specific keratin expression reveals a predominantly basal epithelial cell dif­ fere ntiation, regardless of subtype, with widespread presenee of basal epithelial cell keratins CK5, CK14, and CK19 {1331}. CK1, CK13, and CK17 are also variably present. CK8 and CK18 are virtually absent.

Electron microscopy Electron microscopy studies have confirmed the epithelial nature of adamantinoma, showing intracytoplasmic hemidesmosomes, tonofilaments, and microfilaments. Irrespective of histological subtype, the epithelial cells are bound by desmosomes, and

%3.172 Dedifferentiated adamantinoma. A Sarcomatous progression of the epithelial component is characteristic of dedifferentiated adamantinoma. B Keratin AE1/AE3 is

Positive in dedifferentiated adamantinoma.

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paybal：https://www.paypal.me/andy19801210 Table3.04 Adamantinomas and osteotibrous dysplasia (OFD)

OFD

OFD-like adamantinoma

Classic adamantinoma

Dedifferentiated adamantinoma

Light microscopy

Osteotibrous lesion

Osteotibrous lesion, small clusters of ep ithelial cells

Biphasic lesion, epithelial component easily identified

sarcomatoid change

Keratin staining

Single positive cells, no clusters

Small clusters of keratin-positive cells

Highlights the epithelial component a M

Sarcomatoid elements may or may not show some keratin positivity

Behaviour

Benign

Locally aggressive

Malignant

Malignant, high-grade

basement membranes have been found to surround the epithe­ lial n ests.

Differential diagnosis The main differential diagnosis includes OFD, which may be difficult to distinguish from OFD-like adamanti no ma. In OFDlike adamanti no ma, there are small n ests of epithelial cells, whereas in OFD, only single keratin-positive cells are seen. See also Table 3.04. Additionally, classic adamantinoma composed predominantly of a spindle cell epithelial comp orient must be distinguished from synovial sarcoma, because the treatment is very differe nt {1416}. Occasi on ally there is morphological and immunohistochemical overlap between Ewing sarcoma and adamantinoma, in the so-called Ewing-like adamantinoma. However, the specific gene fusions that characterize Ewing sar­ coma are absent {1320}.

Cytology Not clin ically re leva nt

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: bone tumour with compatible imaging; primary bipha­ sic fibro-osseous tumour of bone, almost exclusively of the tibia and/or fibula; always involves cortex; OFD-like adamantinoma: inconspicuous clusters of epithelial cells, embedded in the fibro-osseous stroma; classic adamantinoma: obvi­ ous epithelial elements embedded in fibro-osseous stroma; dedifferentiated adamantinoma: classic adamantinoma in which the epithelial component has progressed to high-grade sarcoma.

umours

Loss of epithelial differentiation

Stagi ng Staging is according to bone sarcoma protocols (see TNMstag ing of tumours of bone, p. 339). See also the in formation on staging in Bone tumours: Introduction (p. 340).

Prognosis and prediction Risk factors for recurrenee are intralesional or marginal surgery and extracompartmental growth. In OFD-like adamantinoma recurrenee rates are about 20% {2778}. OFD-like adamantino­ mas may rarely metastasize after recurrenee and subsequent progressi on to classic adamanti no ma. In classic adamantinoma, the recurrenee rate after non-radical surgery may be as high as 90%. Recurrenee is associated with an increase in the ratio of epithelium to stroma and with more-aggressive behav­ iour. Additionally, male sex, female sex combined with young age, pain at prese ntatio n, short du rati on of symptoms, young age (< 20 years), and lack of squamous differentiation of the tumour have bee n associated with in creased rates of recur­ rence or metastasis {1606,1333,1555,2563,1420}. Classic adamantinomas metastasize in 12-29% of patients, with compara­ ble mortality rates {1333,1606}. The tumour spreads to regional lymph no des and the lun gs, and infreque ntly to the skeleton, liver, and brain. Dedifferentiated adamantinoma has an aggres­ sive clinical course {1332,1499}.

paybal：https://www.paypal.me/andy19801210 Reith JD Bloem JL Forsyth RG

Simple bone cyst

Definition

ICD-11 coding

Simple bone cyst is an intramedullary, usually unilocular, cystic bone lesion lined by a fibrous membrane and filled with serous or Serosanguineous fluid.

FB80.5 Solitary bone cyst

Related terminology

ICD-O coding

Acceptable: solitary bone cyst. Not recommended: unicameral bone cyst.

None

Subtype(s) None

Localization Most simple bone cysts arise in the proximal humerus (50%) and proximal femur (25%), followed by the proximal tibia and other long tubular bones. The pelvic bones and calcaneus are less frequently involved, and patients with lesions in these bones are often slightly older. Rare cases have been described in other locations, including the spine and small bones of the hands and feet. Similar lesions in the jaws have been termed traumatic bone cysts.

Clinical features Signs and symptoms Patients may be asymptomatic or present with mild pain, swell­ ing, or limitation of motion. Many simple bone cysts are discov­ ered after pathological fracture {2541}.

Imaging Roentgenograms show a central, radiolucent lesion that initially abuts the growth plate. As the skeleton grows, the cyst appears to migrate away from the growth plate. The cyst is well circum­ scribed from the adjace nt bone, and it may cause mild expa nsile remodelling, thinning of the cortex, and endosteal scalloping. However, a periosteal reaction is seldom present unless a patho­ logical fracture is present. In the presenee of a fracture, fragments of cortical bone may float freely in the cyst fluid, a pathognomonic finding referred to as the fallen fragment sign {2966}. The finding of a gas bubble in the most non-dependent portion of a solitary bone cyst, referred to as the rising bubble sign {1549,1271}, has also been described as pathognomonic. MRI confirms the high water content of the cyst fluid, which shows low signal intensity on T1-weighted images and bright, homogeneous signal intensity on T2-weighted or other fluid-sensitive sequences {2982}. Repeated fractures may cause trabeculations to form or result in a multiloculated appears nee, mimicking aneurysmal bone cyst.

Epidemiology

Fig.3.173 Simple bone cyst. A Simple bone cysts may occur in the calcaneus in Mder patients. B T1 MRI highlights the circumscribed borders of the cyst and the low signal intensity of its contents. C MRI highlighting the increased signal intensity of the

W contents on T2-weighted images.

The majority of simple bone cysts are identified during the first two decades of life. Males are more commonly affected than females (M:F ratio: 2:1).

Etiology Unknown

Bone tumours

467

paybal：https://www.paypal.me/andy19801210 Histopathology The wall of a simple bone cyst is composed of a thin layer of fibrous tissue and lacks a true lining. Foci of chronic inflamma tion, multinucleated giant cells, haemosiderin, cholesterol clefts and reactive bone may be present in the wall. Commonly,打匕爪 like collagen deposits are seen on the cyst surface and within the wall {240}. These deposits may become mineralized, result ing in a cementum-like or ossified appearanee.

Differential diagnosis

Fig. 3.174 Simple bone cyst. A X-ray demonstrating the fallen leaf sign of a fractured

lesion, which when present is highly suggestive of a hollow lesion. B The contents of the cyst are bright on T2-weighted MRI.

In the presenee of a pathological fracture, multiloculated foci containing reactive bone, multinueleated giant cells, and haemosiderin may develop, which are difficult to distinguish from aneurysmal bone cyst. Simple bone cyst may also be difficult to distinguish from cystic fibrous dysplasia histologically. Calcaneal lipoma with cystic degeneration is also in the differential diag no sis.

Cytology

Pathoge nesis Unknown

Macroscopic appearance It is extremely rare to exami ne in tact simple bone cysts. The unilocular cysts are lined by a thin, smooth layer of tan fibrous tissue and contain serous or serosanguineous fluid. Small bony ridges may be present in the cyst. After pathological fracture, the cyst may contain thickened reparative foci or brownish haemorrhagic foci similar to aneurysmal bone cyst.

Aspiration generally yields a colourless to amber fluid with scant cellularity that may in elude histiocytes, chronic inflammatory cells, and giant cells {1291}. In the absence of a confirmatory curettage, if the fluid has the above characteristics and the clini­ cal and radiological features are consistent with solitary bone cyst, FNA may be considered diagnostic. However, the pres­ ence of bloody fluid man dates further inv estigati on.

Diagnostic molecular pathology Not clinically relevant

Fig. 3.175 Simple bone cyst. A The lining is composed of a thin layer of fibrous tissue containing fibroblasts and small blood vessels. B Fibrin-like deposits are commonly found in the cyst wall. C The fibrin-like deposits in the wall can calcify and ossify. D Foci of foamy histiocytes are commonly found in the cyst wall.

468

Bone tumours

paybal：https://www.paypal.me/andy19801210 Essential and desirable diagnostic criteria

Prognosis and prediction

Essential: bone tumour with compatible imaging; a simple cyst lacking a true lining. Desirable: often containing fibrin-like deposits, which may organize and mineralize, resulting in cementum-like struc­ tures.

Local recurrence rates are typically reported in the 10-20% range {3389}. Factors that in crease the likelihood of local recurrence in elude patie nt age < 5 years, large cyst size, and fracture {3061}. Spontaneous healing after pathological fracture occurs in approximately 10% of patients {1213}. Simple bone cysts have been treated with a variety of injectables, including steroids and demineralized bone marrow, decompress!on techniques, and curettage {2541}. Complications of large cysts and pathological fracture include growth arrest of the affected bone and avascu­ lar n ecrosis.

Staging Not clinically relevant

Bone tumours

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paybal：https://www.paypal.me/andy19801210 Fibrocartilaginous mesenchymoma

Gambarotti M In wards CY

Definition Fibrocartilaginous mesenchymoma is a locally aggressive neoplasm composed of spindle cells with mild cytological atypia, nodules of hyaline cartilage-containing areas resembling growth plate-like cartilage, and bone trabeculae.

ICD-0 coding 8990/1 Mesenchymoma NOS

ICD-11 coding 2F7C & XH2AD1 Neoplasms of uncertain behaviour of connective or other soft tissue & Mesenchymoma NOS 2E8A & XH7AA3 Other mixed or unspecified benign mesenchymal tumours & Mesenchymoma, benign

Related terminology Not recommended: fibrocartilaginous mesenchymoma with low-grade malignancy.

Subtype(s) None

Localizati on Fibrocartilaginous mesenchymoma most frequently occurs in the metaphysis of long tubular bones (61%), followed by the iliac-pubic bones (18%), vertebrae (15%), and metatarsus and rib (3% each) {1113,3027,445}.

Fig. 3.176 Fibrocartilaginous mesenchymoma. A Anteroposterior radiograph shows an eccentric, lytic lesion in the metadiaphysis and epiphysis of the distal right femur, containing a punctate and hazy internal matrix. B Coronal CT shows an eccentric, lytic, expansile lesion in the distal right femoral metadiaphysis with extension into the epiphysis. The lesion contains a punctate and hazy internal matrix and is associated with cortical destruction and a soft tissue mass along the proximal aspect of the lesion medially.

Pathogenesis Unknown

Macroscopic appearance

Clinical features Signs and symptoms Fibrocartilaginous mesenchymoina can be asymptomatic or can present as a painful lesion with localized swelling.

Fibrocartilaginous mesenchymoma is composed of tan-white fibrous tissue with scattered pale, bluish-grey, glistening areas corresponding to cartilaginous tissue. Resected specimens may show areas of cortical destruction.

Imaging

Histopathology

Radiologically, fibrocartilaginous mesenchymoma has the appears nee of an aggressive benign or low-grade malig nant tumour. Radiographs and CT show a lytic, expansile lesion with calcifications. Thinning of the cortex with areas of cortical destruction and soft tissue extension is common. On MRI, fibro­ cartilaginous mesenchymoma shows low signal on T1-weighted images and high signal on T2-weighted images, with very strong contrast medium uptake {1113}.

Fibrocartilaginous mesenchymoma is characterized by a popu­ lation of spindle cells, hyaline cartilage nodules, and trabeculae of bone. The hypocellular to moderately cellular spindle cell comp orient contai ns elon gated cells with slightly hyperchromatic, mildly atypical n uelei arranged in bun dies or intersect­ ing fascicles. Cellular areas may resemble a low-grade spindle cell sarcoma, but mitotic figures are rare or absent. Benignappearing cartilaginous nodules of varying size and shape are scattered throughout the tumour. They often contain zones mimicking epiphyseal growth plate characterized by chondrocytes arranged in parallel columns and areas of enchondral ossification. Bone is present as long or short trabeculae. Woven bone rimmed by osteoblasts can be seen emerging from enchondral ossification of the cartilaginous nodules. Both the spindle cel and the cartilaginous comp onents often in filtrate host bone, at times extending into surrounding soft tissues. Clusters of osteo­ clast-type giant cells may be found.

Epidemiology Fibrocartilagi nous mesenchymoma is very rare, with < 40 reported cases. It tends to affect young patients (age range: 3 months to 27 years; median: 13 years), with a slight male predominanee {1113}.

Etiology Un known

470

Bone tumours

paybal：https://www.paypal.me/andy19801210

e -lsdell 。

Fig.3.177 Fibrocartilaginous mesenchymoma. A Epiphyseal growth plate-like cartilaginous nodule in a spindle cell proliferation. B Enchondral ossification with bone forma­ lion at one edge of a cartilaginous nodule. C Long and short bony trabeculae are present. D High-power view showing a highly cellular spindle cell component that can resemble

librasarcoma.

Immunohistochemistry Immunohistochemistry is not helpful.

Diagnostic molecular pathology Mutations in GNAS, IDH1, and I6h2and amplification of MDM2 were absent in the few tumours tested {1113}.

Differential diagnosis The main differential diagnosis is with fibrous dysplasia con­ taining cartilage (fibrocartilaginous dysplasia). The cartilage in fibrous dysplasia can have a growth plate-like appears nee, but in fibrocartilaginous mesenchymoma it is a more prominent feature. Moreover, the spindle cells in fibrous dysplasia contain small bland nuclei, unlike those in fibrocartilaginous mesenchymoma with mild hyperchromasia. Desmoplastic fibroma of bone and low-grade fibrosarcoma lack cartilaginous nodules. Unlike fibrocartilaginous mesenchymoma, dedifferentiated chondrosarcoma is characterized by a high-grade sarcoma­ tous component. Chondromesenchymal hamartoma shows similar cartilaginous nodules, but these occur in the chest wall of infants and usually contain an aneurysmal bone cyst-like component.

Cytology Not clinically relevant

Essential and desirable diagnostic criteria Essential: bone tumour with compatible imaging; spindle cells with mild cytological atypia, nodules of hyaline cartilagecontaining areas resembling growth plate-like cartilage, and bone trabeculae. Desirable: you ng patie nt (aged < 30 years).

Staging Not clinically re leva nt

Prognosis and prediction No metastatic spread or tumour-related deaths have been reported {1113}. Local recurrences tend to occur after intralesional excision, although the literature describes some patients who were disease-free many years after in complete surgery {445,3027}. Surgical removal with a wide margin is gen erally the best treatment {1113}.

Bone tumours

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paybal：https://www.paypal.me/andy19801210 Fibrous dysplasia

Siegal GP Bloem JL Cates JMM Hameed M

Definition Fibrous dysplasia is a benign, medullary, fibro-osseous neoplasm that can be multifocal and is characterized by distorted, poorly orga nized and in adequately min eralized bone and inter­ vening fibrous tissue.

ICD-0 coding 8818/0 Fibrous dysplasia

ICD-11 coding FB80.0 Fibrous dysplasia of bone

Related terminology Not recommended: liposclerosing myxofibrous tumour; fibrocartilaginous dysplasia.

Subtype(s) None

Localization Craniofacial bones and the femur are the two most common sites, both in mono static and polyostotic forms, but every bone can be affected {311}. In the mono static form, a substa ntial number of cases involve the femur, skull, tibia, and ribs. In the polyostotic form, the femur, pelvis, and tibia are involved in most cases {1306}.

Fig. 3.178 Polyostotic fibrous dysplasia. Polyostotic fibrous dysplasia with localiza­ tions in proximal femur, pubic bone extending through inferior ramus to acetabulum, and left iliac bone. The lesions have sclerotic, well-defined, lobulated margins and a geographical pattern of destruction, and they exhibit a combination of osteolysis, ground-glass opacities, and sclerotic septations. Also note the varus deformation

(shepherd's crook) of the right femur, which eventually resulted in a fracture.

Clinical features Signs and symptoms Fibrous dysplasia can be monostotic or polyostotic; in the lat­ ter case it can be confined to one extremity or one side of the body, or it can be diffuse. The monostotic form is 6-10 times as comm on as the polyostotic form. Fibrous dysplasia prese nts in childhood or adolescence, but the monostotic form may remain asymptomatic until adulthood. The polyostotic form often mani­ fests earlier in life than the monostotic form {1306}. The lesion is ofte n asymptomatic, but pain and fractures are comm on presenting features {542}. Fibrous dysplasia infrequently produces excess FGF23, causing osteomalacia similar to tumour-induced osteomalacia {2449,2634}. Fibrous dysplasia occurs in association with endocrinopathies and abnormalities of cutaneous pigmentation in McCune-Albright syndrome, as well as with intramuscular myxomas in Mazabraud syndrome {954,1527}.

Fig. 3.179 Fibrous dysplasia. CT of skull with fibrous dysplasia. In flat bones the pro­ cess is often expansile.

Imaging Radiographs often show a non-aggressive geographical lesion with a ground-glass matrix. However, radiographic findings can be substantially altered by changes in Iongstanding lesions (e.g. cyst formati on and fracture). A cartilagi nous comp orient can sometimes be identified. Shepherd's crook deformity of the proximal femur is highly diagnostic when present. Gener­ ally, there is neither soft tissue extension nor periosteal reaction 472

Bone tumours

unless there is a complicating fracture. Bone scintigraphy, CT, and MRI best delineate the extent of polyostotic disease {7°6, 1518,3081}.

Epidemiology Fibrous dysplasia occurs in children and adults worldwide and affects all racial groups with an equal sex distribution.

paybal：https://www.paypal.me/andy19801210 Macroscopic appearance The bone is often expanded and the lesional tissue has a tan­ grey colour with a firm to gritty consistency. There may be cysts, which may contain some yellow-tinged fluid {2857}. When car­ nage is prese nt (a rare eve nt), it often stands out as sharply circumscribed, blue-tinged, translucent material {3132}.

Histopathology

Fig.3.1^0 Fibrous dysplasia. Fibrous dysplasia with gross cartilaginous components.

Etiology Fibrous dysplasia is caused by postzygotic activating mis­ sense mutations in the GNAS gene (20q13.32), which encodes the alpha subunit of the stimulatory G protein (Gsa) (1813,1553}.

Fibrous and osseous tissues are present in varying proportions. The fibrous tissue is composed principally of bland fibroblastic cells. Mitoses are uncomm on but are more ofte n see n in the setting of a fracture. The osseous comp onent con si sts of irregular, curvilinear trabeculae of woven (or rarely lamellar) bone in the majority of cases, but other appearances including cementumlike bone deposition, and rounded psammomatous calcification can be seen, particularly in the jaw {2877}. In some cases, the bony spicules assume a pagetoid appearanee, with intercon­ necting thickened trabeculae and intervening fibrous tissue. Nodules of benign hyaline cartilage, which undergo endochondral ossification, can be seen in rare cases. Osteoblasts are present but inconspicuous and sometimes spindle-shaped. Other changes include aneurysmal bone cyst-like changes, foam cells, multinucleated osteoclastic giant cells, and extensive myxoid change (particularly in Iongstanding cases) {839}.

Pathogenesis GNAS activating mutations are detected in 50—70% of fibrous dysplasia samples, with p.Arg201His (66%) and p.Arg201Cys (31%) as the most commonly identified mutations {1813,1553}. Gsa proteins in crease WNT/p-cateni n signalling, which inhib­ its terminal maturation/differentiation of osteoprogenitor cells {1619}. Studies of transgenic mice constitutively expressing Gsa p.Arg201Cys replicate the human disease and show that fibrous dysplasia develops through three distinet histopatho­ logical stages {2705}. However, we do not typically recognize these stages in routine histology. GNAS mutations have also been associated with McCune-Albright syndrome and nonskeletal isolated endocrine lesions, suggesting a spectrum of phenotypic expression {310).

Cytology Not clin ically releva nt

Diagnostic molecular pathology The mutation discovery rate in GNAS is dependent on the technology used and is adversely affected by sample decalcification. Somatic mosaicism may also account for the reported vari­ ability in mutation detection rates in the literature {1553}. These molecular assays are diagnostically useful, because occasionally fibrous dysplasia can be con fused histologically with lowgrade central osteosarcoma {2724}. The only recurrent clonal chromosome aberrations described to date include trisomy 2 and structural aberrations of 12p13 {719}.

^9-3.181 Fibrous dysplasia. A Typical deposition of woven bone in a background of bland spindle cell proliferation. B Higher power showinq Sharpev-like fibres, a typical fi^g in fibrous dysplasia.

Bone tumours

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paybal：https://www.paypal.me/andy19801210 Essential and desirable diagnostic criteria

Staging

Essential: bone tumour with compatible imaging; osseous component composed of irregular, curvilinear trabeculae of woven bone without conspicuous osteoblastic rimming; fibrous compone nt composed of bland fibroblastic cells. Desirable (in selected cases): activating missense mutations in GNAS (p.Arg201His, p.Arg201Cys) present.

Not clinically relevant

474

Bone tumours

Prognosis and prediction The prognosis for many patients with fibrous dysplasia is excel­ lent. However, monostotic fibrous dysplasia can cause skeletal deformities or leg-length discrepancies, or it can impinge on cranial nerves, and extensive polyostotic disease may be crip­ pling. Malignant transformation very rarely occurs {1894},

paybal：https://www.paypal.me/andy19801210 Rosenberg AE Bloem JL Sumathi VP

Lipoma and hibernoma of bone

Definition jpoma and hibernoma of bone are benign neoplasms com­ posed of white adipocytes (lipoma) or brown adipocytes (hibernoma) that arise within or on the surface of bone.

ICD-O coding 8850/0 Lipoma NOS 8880/0 Hibernoma

ICD-11 coding 2E80 & XH1PL8 Benign lipomatous neoplasm & Lipoma NOS 2E80 & XA5GG8 Benign lipomatous neoplasm & Bones 2E80 & XH1054 Benign lipomatous neoplasm & Hibernoma

Related terminology None

Subtype(s) None

Fig. 3.182 Lipoma of bone. A Radiograph shows well-circumscribed oval radiolucency, with calcifications. B Coronal T1-weighted MRI demonstrates the lipoma that has high signal intensity and is longer than appreciated on the plain film.

Localization Lipomas commonly arise in the calcaneus and metaphysis of long tubular bones, especially the femur, tibia, and humerus, and infrequently in the skull, pelvis, vertebrae, sacrum, mandible, maxilla, and ribs; approximately 70% involve the lower limb 11289,471}. Parosteal lipoma develops on the diaphysis of long tubular bones, especially the femur, radius, humerus, and tibia (234). Hibernoma often affects the axial skeleton {1710}.

Clinical features Signs and symptoms Lipoma may be asymptomatic (30%) or produce aching pain (70%) (1710}. Parosteal lipoma may be painful and can produce a palpable mass {234}. Hibernoma is usually asymptomatic and detected during evaluation for an unrelated disorder {1710}.

Imaging Intraosseous lipomas occur mainly (71%) in the lower extremity (calcaneus) and exhibit low density on plain radiographs, high signal on T1-weighted images, and low signal on fluid-sensitive fat-suppressed images {471}. Calcifications in the well-defined margin and within the lesion are seen as high density on radio­ graphs and CT, and they show signal void on MRI. Fat necrosis and cystic degeneration occur more frequently in the calcaneus and have high signal on fluid-sensitive sequences. Parosteal lipomas display the same fatty characteristics on imaging, but the lesion is superficial to and in continuity with the periosteum. Bone formation can be seen in the centre of the lesion at the surface of cortical bone {2222}. Underlying cortical bone and bone marrow are not involved. Hibernoma is characterized by a combination of imaging features: high uptake of FDG on PET-CT, uptake on bone scintigraphy, sclerotic ill-defined appearanee

Fig.3.183 Parosteal lipoma. A Juxtacortical mass is well circumscribed and bubbly in appearance. It contains linear mineralization that is most prominent at its site of at­ tachment to the bone. B Axial CT shows bone at base of parosteal lipoma surrounded by oval well-circumscribed mass of fat that is dark with low density. Cortex is intact and there is no continuity between the lesion and the bone marrow of the diaphysis.

on CT, low signal on T1, slightly increased heterogeneous signal on fluid-sensitive MRI sequences, and mild enhancement on gadolinium chelate-enhanced MRI {362}.

Epidemiology Lipoma is rare and accounts for < 0.1% of primary bone tumours. The patient age range is from the second to eighth decades of life (mean age: 50 years). Males are affected more frequently than females (M:F ratio: -1.3:1) {1568}. Parosteal Bone tumours

475

paybal：https://www.paypal.me/andy19801210

Fig. 3.185 Hibernoma of bone. A Coronal CT shows well-circumscribed hibernoma that is mineralized. B Brown fat cells of hibernoma have multiple small clear vacuoles enmeshed in eosinophilic cytoplasm.

lipoma accounts for 15% of bone lipomas and develops during the fi卄h to sixth decades of life. There is a slight male predomi­ nance (M:F ratio: -1.3:1). Hibernoma is very rare, develops in patients aged 40-80 years, and shows a female predominance {1710}.

Etiology Unknown

Pathogenesis The pathogenesis is unknown, but it is presumably related to gen etic abno rmalities and activati on of specific cell sign ailing pathways.

Macroscopic appearance Intramedullary lipoma is well defined, soft but sometimes gritty, and yellow; tumours containing brown adipocytes are yellowishbrow n in colour. Tumours are usually 3-5 cm in size; exceptional cases are > 10 cm {1568}. The bone surrounding the tumour is often sclerotic. Parosteal lipoma is 4-10 cm in greatest dimension, well defined, soft, and yellow. Some cases contain gritty spicules of bone or firm nodules of cartilage in the base or scat­ tered throughout the mass.

Histopathology

Fig. 3.186 Parosteal lipoma. Parosteal lipoma of rib composed of a juxtacortical, welldefined mass of yellowish fat.

:umours

Lipoma is composed of lobules of mature-appearing adipo­ cytes. Delicate trabeculae of woven and lamellar bone may be present throughout the tumour. The adipocytes have a single, large, clear cytoplasmic vacuole that displaces the crescent­ shaped nucleus to the periphery. Some tumours may demon­ strate necrosis with foamy macrophages and fibrosis. Parosteal lipoma is a well-defined mass of white fat. Its base, adjacent to

paybal：https://www.paypal.me/andy19801210 the cortex, may have bone trabeculae or hypocellular hyaline cartilage, which undergoes endochondral ossification. Brown fat cells in hibernoma are large, have numerous clear vacuoles Mat scallop central nuclei, and are surrounded by eosinophilic cytoplasm; the cells may be admixed with haematopoietic elennerits.

e

Immunohistochemistry

匸

Adipocytes are positive for S100 and negative for CD68. Hibernomas strongly express the brown fat marker UCP1 {2319}.

0

Differential diagnosis Bone marrow infarction with dystrophic calcification is distinguished from lipoma by the presence of pre-existing necrotic bone throughout the lesion and the lack of a discrete mass on imaging studies.

Cytology Cytology shows adipocytes with vacuolated cytoplasm; there is no cytological atypia.

Fig. 3.187 Parosteal lipoma. Woven bone with a small amount of cartilage at the base beneath lobules of white adipose tissue.

Staging Diagnostic molecular pathology

Not clin ically releva nt

Not clinically releva nt

Prognosis and prediction Essential and desirable diagnostic criteria Essential: lipoma of bone: aggregates of mature-appearing adipocytes, presenting as a bone tumour with compatible imaging; parosteal lipoma: aggregates of mature-appearing adipocytes, presenting as a bone tumour on the surface of the bone; hibernoma of bone: aggregates of brown fat cells, presenting as a bone tumour with compatible imaging.

The prog nosis is excelle nt. Symptomatic in traosseous tumours are curetted, and parosteal lipoma is marginally excised. Recurrence rates are extremely low.

Bone tumours

477

paybal：https://www.paypal.me/andy19801210 McCarthy EF Antonescu CR

Leiomyosarcoma of bone

Definition Leiomyosarcoma (LMS) of bone is a primary malignant neoplasm of bone showing smooth muscle differentiation.

ICD-0 coding 8890/3 Leiomyosarcoma NOS

ICD-11 coding 2B58 & XH7ED4 Leiomyosarcoma & Leiomyosarcoma NOS 2B58 & XA5GG8 Leiomyosarcoma & Bones

Related termi no logy None

Subtype(s) None

Localization Most lesions occur in the lower extremity around the knee (distal femoral or proximal tibial metaphysis), followed by the craniofa­ cial skeleton {131,1194,2606}.

Clinical features Signs and symptoms Patients typically report pain and occasionally present with pathological fracture. Metastatic disease from extraosseous primary lesions (uterus, bowel, soft tissue) should be excluded, because this is much more comm on tha n primary LMS of bone.

Imaging There are no specific imaging features. Radiographically, they are lytic, aggressive lesions, with a permeative growth pattern

Fig.3.188 Leiomyosarcoma. A X-ray of a tumour in the distal femur showing an ag­ gressive, permeative lytic lesion with cortical destruction. B Femoral macroscopy. Note both an intraosseous and an extraosseous component of the white fleshy tumour

and cortical destruction. MRI shows soft tissue extension, and signal inten sities are non specific {2832,181}.

Epidemiology There is a wide age distribution (9-87 years), with a peak inci­ dence in the fifth decade of life and a slight male predominance.

Etiology A small subset of LMSs of bone are associated with prior expo­ sure to radiation therapy or with bone infarcts {147,2504}. LMS of bone related to EBV in fecti on in immu no compromised patients has been reported {811}.

Fig. 3.189 Leiomyosarcoma. A Low-power image showing bundles of spindle cells. B On high power, cellular pleomorphism of the tumour cells is seen.

478

Bone tumours

paybal：https://www.paypal.me/andy19801210 pathogenesis

Diagnostic molecular pathology

gipqilar to deep soft tissue LMSs, intraosseous lesions show genomic losses and absenee of phosphorylated RB1 {3194}.

Not clinically relevant

Essential and desirable diagnostic criteria

Staging Staging is according to bone sarcoma protocols (see TNM stag­ ing of tumours of bone, p. 339). See also the information on staging in Bone tumours: Introduction (p. 340).

Prog nosis and prediction Immunohistochemistry Smooth muscle differe ntiation is dem on strated by diffuse stain­ ing with desmin and/or h-caldesmon, as well as SMA {2606}. LMP1 immu no histochemistry can be used to docume nt the EBV protein {811}. Positivity for ER or PR in female patients strongly suggests a primary uterine origin.

Histological grade correlates with clinical outcome {131}. High­ grade lesions are highly aggressive, with a high index of distant spread (often to the lung) and a 5-year disease-free survival rate of < 50% {18,2195}.

Cytology nag­ copy, nour.

Not clinically re leva nt

and

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Bone tumours

479

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Histopathology The lesions resemble LMSs from other locations, with cells arranged in long, in tersecti ng fascicles, growing in an in filtra­ te patterr\ The tumour cells have fibrillary, eosinophilic cyto­ plasm and elongated, cigar-shaped nuelei with blunted ends. The tumours are associated with variable degrees of necrosis, nuclear pleomorphism, and mitotic activity.

Essential: bone tumour with compatible imaging; exclusion of other primary sites; intersecting fascicles of fusiform cells with eosinophilic fibrillary cytoplasm and elongated cigar-shaped nuelei, with variable nuelear pleomorphism; SMA and desmin and/or h-caldesm on immu no reactivity.

ello

The lesions vary widely in size. On cut surface, they show a tan, fleshy, creamy appearance, with obvious areas of necrosis.

ee

Macroscopic appearanee

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paybal：https://www.paypal.me/andy19801210 Undifferentiated pleomorphic sarcoma

Defin iti on Undifferentiated pleomorphic sarcoma (UPS) is a pleomorphic malignant neoplasm of bone with no identifiable line of differentiation; this is a diagnosis of exclusion.

Inwards CY Czerniak B Dei Tos AP

bones of the trunk, the pelvis is most comm only affected. UPS rarely occurs in the spine.

Clinical features Signs and symptoms

1

ICD-0 coding

Symptomatic patients typically report pain and occasionall]

8802/3 Pleomorphic sarcoma, undifferentiated

swelling. Pathological fractures are common, particularly in weight-bearing long tubular bones.

ICD-11 coding 2B54 & XH0947 Un classified pleomorphic sarcoma, primary site & Maligna nt fibrous histiocytoma

Related terminology Not recommended: malignant fibrous histiocytoma of bone; pleomorphic fibrosarcoma of bone.

Subtype(s)

Imaging The r adiological features of UPSs are non specific, but the major­ ity of cases dem on strate an aggressive osteolytic n eoplasm with ill-defined margins, cortical destruction, and an associated soft tissue mass {1684}. Periosteal reaction is an infrequent find­ ing, and mineralized matrix is absent. The tumours are usually centred in the metadiaphyseal region of long bones and occasionally extend into the epiphysis.

None

Epidemiology Localization UPS has a predilection for long tubular bones, particularly around the knee {315,2302}. The most frequently involved bone is the femur, followed by the tibia and humerus. Among the

UPS of bone is rare, representing < 2% of all primary malignant bone tumours. Males are more frequently affected than females. There is a broad age distribution, from the second to

A Fig. 3.190 Undifferentiated pleomorphic sarcoma of bone. A Lateral radiograph shows a predominantly osteolytic lesion in the distal femoral diaphysis, with malignant periosteal new bone formation. B Sagittal T2-weighted fat-suppressed MRI shows a predominantly osteolytic lesion in the distal femoral diaphysis, with malignant periosteal new bone for­

mation and soft tissue mass anteriorly. C Cut surface of the resected tumour shows a yellowish-grey tumour with areas of reddish-brown haemorrhage and soft tissue extension.

480

Bone tumours

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pig,3.191 Undifferentiated pleomorphic sarcoma of bone. A Marked cytological pleomorphism characterized by giant tumour cells with large hyperchromatic nuclei. B At higher power. C Marked cytological pleomorphism characterized by giant tumour cells with large hyperchromatic nuclei and atypical mitoses.

eighth decades of life, but most patients are aged > 40 years. Only 10-15% of cases occur in patients aged < 20 years.

Etiology The etiology of primary UPS of bone is unknown. Secondary UPS, representing approximately 28% of cases, arises in association with a pre-existing bone condition or disease )2302,2432,1448}. The majority of secondary UPSs are asso­ ciated with a bone infarct, Paget disease, or prior irradiation I m the field of the affected bone {1452,836,2933}. Rare exam­

ples of UPS of bone occur at the site of a metallic orthopae­ dic prosthesis or hardware {1604,1903). Diaphyseal medul­ lary stenosis, a rare autosomal dominant bone dysplasia, is another less common setting associated with UPS of bone (172,1300}. This disorder is characterized by cortical growth abnormalities, including diffuse diaphyseal medullary stenosis with overlying endosteal cortical thickening, metaphyseal striations, and scattered infarctions {846}. Approximately 35% I of patients with this syndrome develop UPS of bone {1987, 2218,466). The disorder is caused by mutations in the gene encoding methylthioadenosine phosphorylase, MTAP {466}.

Macroscopic appearance The gross appearanee of UPS is quite variable. The cut surface texture ranges from fibrous to soft. Areas of necrosis and haem­ orrhage are frequently present. The tumours exhibit a range of colours, including greyish-white, yellow, and brownish-tan. Cor­ tical destruction and a soft tissue mass are commonly present.

Histopathology The tumour is diffusely composed of spindle-shaped and epi­ thelioid or polygonal cells with marked pleomorphism arranged in a haphazard, storiform, and fascicular growth pattern. Vari­ able numbers of large, bizarre multinucleated giant cells and numerous typical and atypical mitotic figures are readily identi­ fied. The tumour cells are often embedded within a collagenrich stroma, which may be hyalinized. A background population of scattered foamy histiocytes and inflammatory cells can be seen among the neoplastic cells. Importantly, the tumour lacks any evide nee of maligna nt osteoid or cartilage, thus n ecessitating thorough sampling in order to rule out osteosarcoma and dedifferentiated chondrosarcoma. Trabeculae of reactive wove n bone are occasi on ally prese nt, particularly at the periph­ ery or in the setting of a pathological fracture {2239}.

Pathogenesis

osteal ne lofision.

UPS of bone is highly aneuploid and shows complex chromo­ somal complements with numerous structural aberrations and marker chromosomes {2865}. These cytogenetic observations are confirmed by array hybridization studies, which reveal frequent losses of 8p, 9p, 10, 13q, and 18q and gains of 4q, ;5p, 6p, 7p, 8q, 12p, 14q, 17q, 19p, 20q, 22q, and X {2295}. Homozygous deletions of CDKN2A, RB1, TP53, and ING1 are :present in a subset of UPSs {2295}. Mutations in TP53 (-30%) and/or chromatin-remodelling genes (-40%) are most frequent I68). In general, the copy-number alterations in UPS of bone overlap with those identified in the same tumours originating in soft tissue {68,472}. UPS of bone exhibits multiple somatic gene fusions, two of which, CLTC-VMP1 and FAFIP1-STK24, appear 1 to be recurrent and were reported previously in multiple cancers {68,1145}. RNA sequencing expression data indicate that UPS has an expression profile distinet from that of its soft tissue counterpart and is characterized by activation of the FGF23 Pathway {68}.

Immunohistochemistry Immunohistochemistry is an essential part of the diagnosis because, by definition, UPS lacks an identifiable line of differentiation and is a diagnosis of exclusion. Caution is required when interpreting myogenic markers, because approximately 50% of UPSs of bone show focal positivity with a single myogenic marker {3123,2651}. SMA positivity with an additional myogenic marker (desmin or h-caldesmon) supports leiomyosarcoma in an appropriate histological con text. Desmi n, myoge nin, and MYOD1 aid in ruling out rhabdomyosarcoma. SATB2 immuno­ reactivity can be seen in UPS, a limiting factor when exploring the possibility of osteosarcoma {742}. H3.3 p.Gly34Trp (G34W) expression is occasionally seen in bone sarcomas without associated giant cell tumour histology; these are usually sited in the epiphysis in young people, suggesting a relationship with a giant cell tumour. Therefore, there is a move to expand the definition of primary malignant giant cell tumour on the basis of an H3-3A (H3F3A) or H3-3B (H3F3B) p.Gly34 mutation {2358, 2630,91,3337}. Focal cytokeratin positivity can be seen in UPS, but abundant expression should raise concern for metastatic Bone tumours

481

paybal：https://www.paypal.me/andy19801210 sarcomatoid carci no ma. Several melanocytic markers are indi­ cated in the setting of focal S100 expression in order to exclude mela noma.

Differential diagnosis The differential diagnosis is broad, including a variety of high­ grade sarcomas, metastatic carcinoma, and metastatic melanoma. When features are similar to those of high-grade myxofi­ brosarcoma of soft tissue, some pathologists favour a diagnosis of high-grade myxofibrosarcoma of bone {2651}.

Essential and desirable diagnostic criteria Essential: bone tumour with compatible imaging； pleomorphi spindle-shaped and epithelioid cells in a storiform or fascic lar growth pattern; no malignant cartilage or bone production by the tumour cells; no specific line of differentiation. Desirable: atypical mitotic figures; necrosis.

Staging Staging is according to bone sarcoma protocols (see TNMstag­ ing of tumours of bone, p. 339). See also the information on staging in Bone tumours: Introduction (p. 340).

Cytology Not clinically r eleva nt

Diagnostic molecular pathology The absenee of IDH1 or /D/72mutations in UPS of bone can be used in the differential diagnosis with dedifferentiated chondrosarcoma {558). Similarly, the presence of an H3-3A (H3F3A) or H3-3B (H3F3B) p.Gly34 mutation may suggest a relati on ship with giant cell tumour of bone, and there is a move to expand the definition of primary malignant giant cell tumour of bone on the basis of an H3-3A (H3F3A) or H3-3B (H3F3B) p.Gly34 mutation {2358,2630,91}.

482

Bone tumours

Prognosis and prediction Patients with UPS of bone are generally treated with chemother­ apy and complete en bloc resection {3365,198,1525}. Patients with localized disease and adequate therapy have a 5-year survival rate of 50-67% {399,2432,315}. Pulmonary metastases are common, occurring in approximately 35-50% of cases. Sec on dary UPS and metastatic disease are associated with a poorer prog no sis. Incomplete expressi on of myoge nic markers is not thought to affect the prognosis {2651}.

paybal：https://www.paypal.me/andy19801210 Kalil RK Bloem JL Hornick JL Righi A

Bone metastases lie 'uon

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Definition

Imaging

Bone metastases are tumours involving bone as a result of haematogenous spread from malignancies at distant sites.

None

Radiographically, metastases can be lytic, sclerotic, or mixed. Typical lytic metastases in elude primary renal cell, lung, and thyroid carcinomas. Sclerotic metastases sug­ gest primary prostate, breast, and neuroendocrine carcinomas. Bone scintigraphy has been the method of choice to detect bone metastases because of its high sensitivity to osteoblastic activity, which is almost always present to some degree. FDG PET has largely replaced bone scintigraphy because it directly shows tumour in any location rather than host bone reaction only. However, this functional technique is dependent on glucose metabolism and is only reliable if the primary tumour takes up FDG. Whole-body MRI is an alterna­ tive, depending on the morphological features of the tumour deposits.

Localization

Epidemiology

Any site can be involved. Common sites are long bones such as femur and humerus and the axial skeleton. There is a predilec­ tion for more-vascularized areas of bone like the metaphysis of long bones and vertebrae. Lung cancer is the most cominon primary malignancy that metastasizes to acral sites {2611,3264}.

Metastatic carcinoma lesi ons con stitute the more comm on type of osseous tumour in elderly patients. The more frequent pri­ mary sites are lung, breast, prostate, kidney, thyroid, panereas, and liver. Other common primary tumours are lymphoma and melanoma. Metastases in young patients are much less fre­ quent and are usually due to neural, renal, or soft tissue and bone tumours, such as neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma.

ICD-O coding ernts sar 〕es es. ia ers

None

ICD-11 coding None

Related terminology None

Subtype(s)

Clinical features Signs and symptoms Pain is usually the first symptom and is almost always present. Pathological fracture is common and may cause abrupt pain. Sometimes metastasis is the first manifestation of cancer. A primary tumour cannot always be identified (a so-called unknown primary).

Etiology Bone metastases result from metastatic spread of a primary malignancy elsewhere in the body.

fi9-3.192 Metastatic carcinoma in pelvic bone. Multiple skeletal lesions in elderly patients are suggestive of metastatic spread.

Fig. 3.193 Metastasis from renal car­ cinoma. Radiography of hip with large solitary skeletal lesion.

Bone tumours

483

paybal：https://www.paypal.me/andy19801210 Pathogenesis Involvement of bone by these tumours is the result of haematoge nous spread (metastasis) from the site of the primary malignancy

Macroscopic appearance Usually, metastases have haemorrhagic and friable tissue especially if they are from thyroid or kidney. Metastases from prostate and breast can be hard due to reactive bone sclerosis Melanoma can produce dark, pigmented metastases.

Histopathology Metastases present with histological features similar to those of the primary lesi ons, the most common being ade no carcinomas and squamous cell carci no mas. Osteoblastic metastases contain abundant reactive woven bone and must be distinguished from osteosarcoma. Haemorrhage, fibrosis, and osteoclast-like giant cell reactions are frequent and can sometimes obscure the meta­ static cells.

Immunohistochemistry Immu no histochemistry should be used to suggest or confirm a possible primary origin {3180,2940}. See Table 3.05.

Differential diagnosis Primary vascular tumours of bone can very closely simulate metastatic carcinoma on radiology and histology, and they may also be positive for epithelial markers {3189,3197}.

Cytology Not clin ically releva nt

Diagnostic molecular pathology Molecular diag no sties related to the primary tumou r may be of diag no stic or prog nostic re leva nee {3295,360}.

Essential and desirable diagnostic criteria

Fig.3.194 Metastatic carcinoma in the spine. Gross photography showing a solid vertebral lesion involving multiple levels.

Essential: malignant growth at distanee from a primary site else­ where; correlation with imaging and clinical history. Desirable (in selected cases): immunohistochemistry, as indi­ cated, is frequently necessary.

Table3.05 Immunohistochemical markers for the most common metastatic carcinomas to bone: primary site determination

Primary site

CK7 and CK20 (most-common patterns)

Other markers Cytoplasmic or membranous

Nuclear3

ER, GATA3, SOX10 (triple-negative)

Breast

CK7+, CK20-

GCDFP-15, mammaglobin

Kidney (renal cell carcinoma)

CK7-, CK20-

RCCm

PAX8

Liver (hepatocellular carcinoma)

CK7-, CK20-

Arginase-1 (ARG1), CPS1 (Hep Par-1)

Arginase-1 (ARG1)

Lung (adenocarcinoma)

CK7+, CK20-

Napsin A

Pancreas

CK7+, CK20-

Prostate

CK7-, CK20-

Small cell carcinoma13 Squamous cell carcinoma0 CK7+, CK20-

Thyroid

TTF1

SMAD4 (loss) PSA, PSAP

NKX3-1

Chromogranin, synaptophysin

TTF1.RB1 (loss)

High-molecular-weight cytokeratins (e.g. CK5)

p63, p40

Thyroglobuli n

PAX8, TTF1

aNudear markers are particularly susceptible to decalcification; the possibility of false-negative results (when relevant) should be included in a disclaimer in pathology reports, immuno­ histochemistry cannot distinguish among metastatic small cell carcinomas (i.e. pulmonary vs extrapulmonary origin). "Immunohistochemistry cannot distinguish among metastatic squa_ mous cell carcinomas (other than p16-diffuse staining suggests a high-risk HPV-associated squamous cell carcinoma, such as from the oropharynx, anal canal, or uterine cervix).

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Bone tumours

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Fig.3.195 Metastasis from breast carcinoma. A Medium-power microscopic view showing small infiltrating glands. Comparison with the specimen from the original cancer site iSoften necessary. B Staining for ER is positive.

Staging

Prognosis and prediction

Not clinically relevant

The prog nosis is predomi nantly defi ned by the primary tumour {358}. The overall median survival time for patients with spinal metastases in one series was 5.1 months {359}.

Bone tumours

485

paybal：https://www.paypal.me/andy19801210 Ferry JA Deshpande V Lorsbach RB

Solitary plasmacytoma of bone

Definition Solitary plasmacytoma of bone (SPB) is a localized, intraosse­ ous neoplasm composed of clonal plasma cells, with no evidence of other bony lesions and no evidenee of plasma cell myeloma (PCM).

ICD-0 coding 9731/3 Plasmacytoma of bone

ICD-11 coding 2A83.2 & XH4BL1 Solitary plasmacytoma & Plasmacytoma NOS

Related terminology Not recommended: osseous plasmacytoma.

Subtype(s) None

Localization The axial skeleton is affected more often than the appendicular skeleton; other bones commonly affected in elude the pelvis, ribs, skull, and long bones {3250,1656,2071,2978}.

Clinical features Signs and symptoms Patients typically present with localized pain, sometimes accompanied by fracture. Vertebral SPB with fracture can be associated with spinal cord compression {2978}. SPB may present occasi on ally as a soft tissue lesi on in cases with localized extraosseous exte nsion. Patients comm only have a serum or urine M component {2978,233}.

A

Fig. 3.197 Solitary plasmacytoma of bone. Anteroposterior radiograph of the right humerus shows geographical destruction consisting of patchy bone lysis. There is no surrounding sclerosis and the cortex is mildly thinned (arrows) but intact.

Imaging Radiographically, SPB manifests as a well-circumscribed geo­ graphical lytic bone lesion without identifiable matrix {1622, 3255).

Epidemiology SPB affects men more often than women (M:F ratio: 2-3:1) {3250,1656,1622,1139}, and its incidence is higher in black people than in white people {1622}. Most patients are middleaged and older adults (median age: 55-60 years) {1622,1139, 3255,233}. Young adults are occasionally affected {3250,1656).

B

g 2；、) in u, the u,c posterior aspect 5 ulc left 口 I ilium, iuuni. The cortex is thinned Fig. 3.196 Solitary plasmacytoma of bone. A Axial CT image of the pelvis shows a well-defined lytic lesion (asterisk) of the well-defined lytic lesion (asterisk) in the posterior aspect of the e and there is mild expansile remodelli ng. B Proto n density MRI with fat saturation image of the pelvis shows a\ , x ilium, with homogeneous, hyperintense marrow infiltration.

486

Bone tumours

paybal：https://www.paypal.me/andy19801210 Table3.06 Solitary plasmacytoma of bone: differential diagnosis

Diagnosis

Clinical features

Solitary plasmacytoma of

Isolated lytic lesion of bone, often painful, +/fracture; no association

bone

Chronic osteomyelitis

Plasmablastic lymphoma

with immunodeficiency

Fever, local pain

Immunosuppressed patient with extranodal lesion (oral cavity, gastrointestinal, others; bone involvement is uncommon), usually without lymphadenopathy

Lymphoplasmacytic

lymphoma

Symptoms usually related to anaemia and paraprotein, +/autoimmune phenomena orcryoglobulinaemia; lymphadenopathy and/or splenomegaly may be present; discrete bone lesions are rare

Morphology

Immunoglobulin (Ig) expressed

Immunophenotype, additional features

Cytogenetic/genetic features

Diffuse, destructive infiltrate of mature, immature, lymphocyte-like, plasmablast-like, or rarely anaplastic plasma cells

Monotypic cytoplasmic Ig light chain; IgG > lgA> light chain only; others rare

As for plasma cell myeloma

Similar to plasma cell myeloma, but not as extensively studied

Mature plasma cells, +/lymphocytes, granulocytes, fibrosis, and necrotic bone

Polytypic cytoplasmic Ig light chain

CD138+, CD38+, CD19+, CD56- plasma cells

No abnormalities

Monotypic cytoplasmic Ig light chain +/-

CD138+, CD38+, IRF4 (MUM1)+, MYC+, CD45+/-, CD79a+/-, CD56+/-, CD20-, PAX5-, BCL6-, ALK-, HHV8-, Ki-67 high; EBER usually positive

Diffuse infiltrate of plasmablasts +/differentiation to more-

mature plasma cells; high mitotic count; may have starry-sky appearance

Diffuse, interstitial, or patchy involvement by small lymphocytes, plasma cells, and plasmacytoid lymphocytes

Monotypic surface and cytoplasmic Ig light chain; lgM+, almost all cases

CD19+, CD20+, CD5-, CD10- BCL6-, CD23clonal B cells and clonal plasma cells

Complex karyotype; MYC

often rearranged, less often amplified

MYD88 p.Leu265Pro point mutation

Hyperdiploid cases (-45%): 48-75 chromosomes; gains of > 3 of oddnumbered chromosomes: 3, 5, 7, 9,11,15,19, 21

Most patients have symptoms related to CRAB, infections, and Plasma cell myeloma

bleeding; some are asymptomatic and may have smouldering myeloma

Diffuse, interstitial, or patchy marrow involvement by mature, immature, lymphocyte-like, plasmablast-like, or rarely anaplastic plasma cells

Monotypic cytoplasmic Ig light chain; IgG > lgA> light chain only; others rare

CD138+, CD38+, IRF4 (MUM1)+, CD45- or dim, CD19CD56+; cyclin D1+ (in cases with CCND1 rearrangement); minority: CD20+, KIT (CD117)+, CD10+; Ki-67 usually low; EBER almost always negative

Non-hyperdiploid cases (-50%): Translocation of IGH with CCND1 (most common), MAF, or FGFR3INSD2 (FGFR3/MMSET); rare IGH partners (< 2% of cases): CCND3, CCND2, MAFA, or MAFB

Other changes: Activating mutations of KRAS, NRAS, or BRAF; mutations activating NF-kB; MYC translocation; TP53 abnormalities

CRAB, hypercalcaemia, renal insufficiency, anaemia, and bone lesions. EBER, EBV-encoded small RNA.

SPB accounts for < 5% of all plasma cell neoplasms {2071, 3255}. Most cases of SPB progress to PCM, a condition that is much more comm on than SPB. In the USA, there are an estimated 22 350 new cases of PCM diagnosed per annum and 10 710 deaths each year due to PCM {2859}.

Etiology Unknow n

Pathogenesis Changes in SPB are similar to those in PCM (see the volume WHO classification of tumours of haematopoietic and lymphoid tissues {3011}. Genetic and cytogenetic abnormalities are het­ erogeneous. Immunoglobulin (Ig) heavy and light chain genes are clonally rearranged, with a heavy load of mutations in the variable region of the Ig heavy chain gene, without ongoing mutations. Complex karyotypes are common. FISH is much

Bone tumours

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Fig. 3.198 Plasmacytoma of bone. A Low power shows sheets of cells without intervening stroma. B In this case, neoplastic plasma cells are mostly small and mature, c Neo­ plastic plasma cells are CD138-positive on immunohistochemistry. They were also positive for CD56 and monotypic kappa (not shown).

more sensitive for detecting cytogenetic abnormalities than routine karyotyping. Two main groups of PCM are defined by cytogenetic abnormalities: hyperdiploid and non-hyperdiploid (see Table 3.06, p. 487) {570}.

Staging Bone marrow biopsy and radiographic studies are required Additional plasmacytoma(s) and/or > 10% clonal plasma cells in a random bone marrow biopsy is diagnostic of PCM and excludes SPB {3250}.

Macroscopic appearance SPB is a gelati nous, haemorrhagic lesion.

Histopathology SPB is composed of sheets of neoplastic plasma cells, which can be small and mature or enlarged, immature, and atypical. Infrequently, the tumour cells are large and poorly differentiated, rarely with an aplastic morphology. SPB may be associated with amyloid deposition {1139} and rarely with crystal-storing histio­ cytosis {1918}. Immunophenotyping can be performed by flow cytometry or immunohistochemistry. The immunohistochemical profile of the neoplastic cells in SPB is as follows: CD138+, CD38+, IRF4 (MUM1)+, CD45- or dim, CD19-, monotypic lg+, and usually CD56+ and CD20-. Cyclin D1 is expressed in a subset of cases. SPB may resemble large cell lymphoma, plasmablastic lymphoma, round cell sarcoma, germ cell tumour, or metastatic carcinoma or melanoma {1139,2245}. Occasional tumours are composed of small lymphocyte-like plasma cells and may mimic a low-grade lymphoma.

Cytology Not clinically relevant

Diagnostic molecular pathology There is rearrangement of Ig heavy and light chain genes.

Essential and desirable diagnostic criteria Essential: single osseous lesion on skeletal survey; diffuse, destructive infiltrate of clonal plasma cells; no evidenee of PCM on staging iliac crest bone marrow biopsy; no related end-organ damage (e.g. hypercalcaemia, renal insufficiency, anaemia, and bone lesions [CRAB]).

488

Bone tumours

Prognosis and prediction Radiati on provides excelle nt local con trol. Local recurrence is frequent without radiation {1656,2978,1622,233}. Radiation does not prevent progression to PCM {1656,2978,3255,233). Approximately two thirds of cases of SPB progress to PCM within 5 years {3250,1622}. SPB > 5-6 cm has been associated with recurrenee or local progression of disease (3255), higher risk of PCM, and worse overall survival {1656,1622,233], Pro­ gressi on to PCM is more likely among SPB patients with minimal bone marrow invoIvement by clonal plasma cells (< 10%, socalled plasmacytoma plus) than among patients with negative marrows (60% vs 10% within 3 years) {2568}. Older age and persistence of serum M component after treatment (probably representing persistent disease) are associated with higher risk of PCM {3255}. Elevated B2M is associated with worse over­ all survival {2978}. As many as one third of SPB patients have long survival (> 10 years) without progression to PCM (1622, 233}. SPB is associated with substantial morbidity {3250). Mor­ tality usually results from progression to PCM. The 5-year and 10-year overall survival rates of patients presenting with SPB (most of whom develop PCM) are in the range of 70-80% and 40-60%, respectively {1656,2978,1622,233}.

paybal：https://www.paypal.me/andy19801210 primary non-Hodgkin lymphoma of bone

Cleven AHG Ferry JA

Definition Primary non-Hodgkin lymphoma of bone is a neoplasm com­ posed of malignant lymphoid cells, producing one or more lesions within bone, with no (supraregional) lymph node involvement or other extra nodal lesi ons.

30-

ICD-0 coding

d. lls id

9591/3 Maligna nt lymphoma, non-Hodgki n, NOS 9650/3 Hodgkin disease NOS 9680/3 Diffuse large B-cell lymphoma NOS 9690/3 Follicular lymphoma NOS 9699/3 Marginal zone B-cell lymphoma NOS 9702/3 T-cell lymphoma NOS 9714/3 An aplastic large cell lymphoma NOS 9727/3 Malignant lymphoma, lymphoblastic, NOS 9687/3 Burkitt lymphoma NOS

:e 3n 3). :M

ICD-11 coding 2B33.5 & XH0L78 Maligna nt lymphoma, not elsewhere classi­ fied & Malignant lymphomas NOS or diffuse

30

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nd

Related terminology Acceptable: primary bone lymphoma.

Subtype(s) None

Localization Primary bone lymphomas most frequently occur in the femur, followed by the pelvis, vertebrae, and humerus, usually arising in the metadiaphyseal region of the bone {302}. Approximately 10-40% of cases are multifocal, producing several lesions in one bone or involving multiple bones concurrently (polyostotic).

Clinical features Signs and symptoms The majority of patients with primary bone lymphoma present with pain in the affected bone but rarely with systemic symp­ toms such as fever, weight loss, or night sweats.

Fig. 3.199 Diffuse large B-cell lymphoma of bone. A A lesion in the right clavicle (ar­ rowheads) on conventional X-ray. B MRlof the right clavicle (single arrowhead) shows soft tissue extension (double arrowhead).

extra nodal lymphomas, and < 1% of all non-Hodgki n lympho­ mas {301}. Almost 50% of patients with primary lymphoma of bone are aged > 40 years; only a minority of cases arise in children {301,1361}. Importsntly, primary nodal lymphomas fre­ quently involve the skeletal system; bone involvement is seen in as many as 20% of patients and may be in distinguishable from primary lymphoma of bone on biopsy {301}.

Imaging Although there is no specific radiological appearanee for pri­ mary bone lymphomas, imaging frequently shows a large, lytic, and destructive tumour that may erode the involved bone cortex and extend into the adjacent soft tissue {3256}. Borders of the lesion are often moth eaten or permeative, and an onion-skin periosteal reaction may be present. In some cases, the tumour may elicit extensive medullary sclerosis {259,893}.

Etiology

Epidemiology

Although the pathogenesis and role of the microenvironment in primary bone diffuse large B-cell lymphoma (DLBCL) are not fully elucidated, clinical and molecular genetic data suggest

Primary lymphomas of bone typically arise sporadically, with a few exceptions: rare HIV-positive patients with primary lym­ phoma of bone are reported {757,798}. In rare patients, lym­ phoma has arisen on a background of Iongstanding osteomy­ elitis {2394,658} or Paget disease of bone {2394}.

Pathogenesis Primary lymphoma of bone is not a common disease, constitut­ es approximately 7% of all malignant bone tumours, 5% of all

Bone tumours

489

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Fig. 3.200 Primary bone diffuse large B-cell lymphoA Pleomorphic B cells with large irregular multilobulated nuclei and prominent nucleoli. B Crush and smear artefacts are frequently observed in primary bone diffuse large B-cell lymphoma. C Extensive immunoreactivity for CD20, a pan-B-cell marker, in tumour cells of this primary bone diffuse

large B-cell lymphoma.

that primary bone DLBCL probably arises from centrocytes. Naive B cells in the bone may enter lymphoid follicles as part of an inflammatory/immu no logical resp onse and un dergo IGH somatic hypermutation to become centrocytes in the germinal centre light zone {1847}. Primary bone DLBCL may originate from these centrocytes. Alternatively, the centrocytes from which the lymphoma originates may also derive from extraosseous lymphoid tissue, migrate to the bone, and give rise to lymphoma {1847}.

Macroscopic appearance It is uncommon to see gross specimens of primary bone lym­ phomas, because diagnosis is made on biopsy material and treatment consists of chemotherapy and radiotherapy without surgery. If available, macroscopy shows a greyish-white and fleshy tumour in the bone, frequently with areas of necrosis.

Histopathology The majority (> 80%) of primary bone lymphomas are diffuse large B-cell lymphomas. Follicular lymphoma, marginal zone lymphoma, lymphoblastic lymphoma, Hodgkin lymphoma, ALK-positive and ALK-negative anaplastic large lymphomas, and other B-cell and T-cell lymphomas only rarely originate pri­ marily within the bone {1646,2103}.

DLBCL is characterized by a diffuse growth pattern of large atypical lymphoid cells filling the marrow space, some­ times with prominent fibrosis. Bony trabeculae show reac­ tive changes. Neoplastic cells have large, round or irregular nuclei, often with a cleaved or multilobated (or occasionally pleomorphic) appearanee and variably prominent nueleoli. Cytoplasm may be amphophilic but is not abundant. Crush artefact is comm on; this histological finding should raise the possibility of a lymphoma. Typically the tumour cells are accompanied in areas by many reactive, non-neoplastic lym­ phocytes and histiocytes. The crush artefact, admixture of reactive cells, and reactive bone may obscure the neoplastic population, sometimes necessitating rebiopsy to obtain diagnostic tissue. The rare cases of lymphoblastic lymphoma, ALK-positive and ALK-n egative an aplastic large cell lymphomas (ALCLs), Burkitt lymphoma, low-grade B-cell lymphomas, and other peripheral T-cell lymphomas have pathological features similar to those seen in extraosseous sites. ALCL in bone is very rare, but it is the most comm on primary T-cell lymphoma of bone. Tumour cells are large, with characteristic irregular, eccentric kidney-shaped n uelei. Un commonly, classic Hodgki n lymphoma prese ntswith bony invoIvement, probably reflecting extranodal localization of a primary no dal Hodgki n lymphoma in most cases, although

Fig.3.201 Primary bone diffuse large B-cell lymphoma. A Extensive sclerosis with crush artefact in a case of primary bone diffuse large B-cell lymphoma mimicking sar­ coma. B PAX5 immunoreactivity highlights the spindle cell appearance of the neoplastic B cells.

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Bone tumours

paybal：https://www.paypal.me/andy19801210 rare cases of classic Hodgkin lymphoma primary in bone are described {2393}.

Immunohistochemistry The diagnostic work-up for primary lymphomas of bone includes a combi nation of light microscopy and a panel of immunohistochemical markers as used to evaluate other lym­ phoproliferative disorders. Most primary bone lymphomas are DLBCLs that express CD20, PAX5, and CD79a {617}. Optimally, an immunohistochemical panel to evaluate cases thought to be DLBCL includes CD20, PAX5, CD3, CD5, CD10, BCL6, BCL2, IRF4 (MUM1), MYC, and Ki-67, as well as in situ hybridization for EBV using EBV-encoded small RNA (EBER). Selected markers may be added in cases with unusual features. With this panel, primary bone DLBCL can be further subdivided into germinalcentre B-cell (GCB) type and non-GCB type using BCL6, CD10, and IRF4 (MUM1) immunohistochemistry (the Hans algo­ rithm) {73}: CD10+ or CD10-, BCL6+, IRF4 (MUM1)- supports GCB type, whereas CD10-, BCL6- or CD10-, BCL6+, IRF4 (MUM1)+ supports non-GCB type. Non-GCB type suggests an inferior prog nosis {2663}. ALCLs are diffusely positive for CD30 and are usually positive for at least one pan -T-cell marker such as CD3, CD2, CD4, or CD5. In cases with an ALKtranslocation, expression of ALK protein is observed (ALK-positive ALCL).

was found in approximately 20% of cases, BCL6 transloca­ tion in 14%, and MYC translocation in 10%. High-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements (double-hit lymphomas) {3011} primary in bone are rare {1861}. Recently, the genomic Iandscape of DLBCL has been evalu­ ated by extensive next-generation sequencing studies in large cohorts of B-cell lymphomas, identifying frequent driver muta­ tions in genes such as MYD88, CD79A/CD79B, CARD11, and TP53 that are associated with an adverse prog nosis and resista nee to therapy {2588}, although such studies focusi ng on primary lymphoma of bone are limited. In parallel with the recommendation for performing triple (BCL2IBCL6IMYC) FISH in DLBCL, it is likely that a targeted next-generation sequencing approach will become part of the routine DLBCL diagnostics in the near future, in order to better characterize the lymphomas and tailor therapeutic choices {3196}.

Essential and desirable diagnostic criteria Essential: lymphoma identified by histology and immunohistochemistry; only bone affected, with no previous or concurrent extraosseous disease except in regional lymph no des.

Staging Not clinically relevant

Cytology

Prognosis and prediction

Not clinically releva nt

Primary bone DLBCLs have a favourable prognosis. With current treatment protocols (chemotherapy followed by radiotherapy), overall survival is excellent {1360). Age is a significant factor associated with survival, with age > 60 years indicative of inferior survival {1361}. In general, GCB-type primary bone DLBCLs are associated with a better survival than the non-GCB type {1847}.

Diagnostic molecular pathology Clonal rearrangements of immunoglobulin heavy and light chain genes are detectable in primary bone DLBCL, whereas clonal rearrangement of the T-cell receptor genes are detectable in T-cell lymphomas. In primary bone DLBCL, BCL2translocation

Bone tumours

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paybal：https://www.paypal.me/andy19801210 Langerhans cell histiocytosis

Pileri SA Cheuk W Picarsic J

Definition Langerhans cell histiocytosis (LCH) is a clonal neoplastic pro­ liferation of myeloid dendritic cells expressing a Langerhans cell (LC) phenotype. LCH can be unifocal or multifocal within a single system (usually bone) or it can be multisystem {3078).

ICD-0 coding 9751/1 Langerhans cell histiocytosis NOS 9751/3 Langerhans cell histiocytosis, disseminated

ICD-11 coding 2B31.2 & XH1J18 Langerhans cell histiocytosis & Langerhans cell histiocytosis NOS

Related terminology Not recommended: Langerhans cell granulomatosis.

Solitary lesion Not recommended: histiocytosis X; eosinophilic granuloma.

Multiple lesions Not recommended: Hand-Schuller-Christian disease.

Cases with disseminated or visceral involvement Not recommended: Letterer-Siwe disease.

Subtype(s) None

Localization Single-system LCH predominantly invoIves the bone (skull, femur, vertebrae, pelvis, ribs, and mandible) and less comm only lymph node, skin, and lung. In multisystem LCH, the skin, bone, liver, spleen, and bone marrow are prefere ntially in volved.

Fig. 3.203 Langerhans cell histiocytosis involving diaphysis of the left tibia. A Plain X-ray shows a radiolucent lesion in the left tibia, with periosteal new bone forma­ tion. B In the same case, MRI shows an intramedullary lesion in the tibial diaphysis with erosion of the adjacent cortex.

Clinical features Signs and symptoms Patients with single-system LCH are usually older children or adults with a painful lytic lesion eroding the bone cortex. Solitary lesions at other sites present as masses. Patients with multifocal single-system LCH are usually you ng childre n with multiple or sequential destructive bone lesions, often associated with adjacent soft tissue masses. Diabetes insipidus follows cranial bone and parenchymal invoIvement. Patients with multisystem LCH are infants presenting with fever, cytopenias, skin and bone lesions, and hepatosplenomegaly {167,75}.

Epidemiology The annual incidenee in children is about 5 cases per 1 million population {1264}. The M:F ratio is 1.2:1 {75}. The annual incidence in adults is 1-2 cases per 1 million population. The disease is more cominon among individuals of European descent and Hispanics. LCH can also be associated with Erd­ heim-Chester Disease, either con comita ntly or precedi ng, with shared molecular alterations {901}.

Etiology Unknown

Pathogenesis

Fig.3.202 Langerhans cell histiocytosis. A CT with a C2 vertebral lytic lesion of Langerhans cell histiocytosis. B CT of the skull without contrast. Lytic lesion in the right frontal bone with associated soft tissue component. Margins should be left intact for proper healing in cases of bone Langerhans cell histiocytosis.

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Bone tumours

The cell of origin is closer to a myeloid dendritic cell than to an epidermal LC {74}. MAPK pathway activation plays a central role in LCH pathogenesis {75}. A misguided myeloid differentiation model has been proposed, in which activating MAPK mutations at a pluripotent haematopoietic, tissue-restricted, or local precursor level give rise to high-risk multisystem, multifocal low-risk, or unifocal LCH, respectively {75}. These mutations,

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Fig.3.204 Langerhans cell histiocytosis. A Low-power image of bone Langerhans cell histiocytosis with clusters of Langerhans cells and large numbers of eosinophils and osteoclast-like giant cells. B High-power image of Langerhans cell histiocytosis showing distinctive morphology of intermediate-sized cells with nuclear grooves, irregular nuclear contours, and pale eosinophilic cytoplasm.

especially BF?Z\F p.Val600Glu, may confer an advantage for tis­ sue site accumulati on via disrupted cell mi g rati on and apop­ tosis inhibition {1393}. Rare familial cases are reported {168}. About 30% of cases show clonal IGH, IGK, and/or TR gene rearrangements {561}.

Occasionally, eosinophilic microabscesses with central necrosis are found. LCH cells predominate in early lesions. In late lesions, they are decreased in number, with increased foamy macro­ phages and fibrosis. The ultrastructural hallmark is the cytoplas­ mic Birbeck granule, which is 200-400 nm long and 33 nm wide, with a tennis-racket shape and a zipper-like appearanee.

Macroscopic appearance Not clin ically re leva nt

Histopathology Diagnostic LCH cells are oval and measure about 10-15 pm. They are recognized by grooved, folded, inden ted, or lobed nuclei, as well as fine chromatin, inconspicuous nucleoli, and thin nuclear membranes. Nuclear atypia is minimal, but mitotic activity is variable and can be high without atypical forms. The cytoplasm is moderately abundant, slightly eosinophilic, and devoid of dendritic processes. The characteristic milieu includes variable numbers of eosinophils, histiocytes (both multinucleated LCH-type and osteoclast-type cells, especially in bone), neutrophils, and small lymphocytes. Plasma cells are usually sparse.

Immunohistochemistry LCH cells express CD1a, CD207 (langerin), S100, CD68, and HLA-DR {75}. CD45 expression is low. The BRAF p.Val600Glu mutation can be identified by a specific antibody {2246,214}. The Ki-67 proliferation index is highly variable (typically < 10% by double staining) {2511,1393}. Rare cases associated with fol­ licular lymphoma or B- or T-lymphoblastic leukaemia are con­ sidered a transdifferentiation phenomenon and behave more aggressively {3274,981,512}.

Differential diagnosis The differential diagnosis includes osteomyelitis and chondroblastoma.

Fig.3.205 Langerhans cell histiocytosis. A Langerhans cell histiocytosis with surface CD1a immunoreactivity on the majority of cells. B Langerhans cell histiocytosis with cytoplasmic granular positivity for CD207 (langerin) in the majority of Langerhans cells. C Langerhans cell histiocytosis with molecularly confirmed BR/lFp.Val600Glu mutation showing strong diffuse cytoplasmic granular VE1 positivity in Langerhans cells.

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paybal：https://www.paypal.me/andy19801210 Cytology Clusters of LCH cells are diagnostic, but caution is needed in lymph nodes because paracortical dendritic/Langerhans cells cannot be distinguished from sinus-based LCH cells.

Diagnostic molecular pathology MAPK pathway gene mutations are recorded in > 85% of cases. They affect BRAFor alter natively MAP2K1 or much more rarely ARAF. ERBB3, NRAS, and KRAS mutations can also occur in adults {75}.

Essential and desirable diagnostic criteria Essential: typical LC morphology. Desirable: CD1a, CD207, and S100 positivity; detection of MAPK pathway mutations.

Staging According to the Histiocyte Society's 2009 evaluation and treatment guidelines, single-system LCH is defined by the invoIvement of one organ/system (unifocal or multifocal), and

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Bone tumours

multisystem LCH is defined by the invoIvement of two or more organs/systems (± risk-organ involvement).

Prog nosis and prediction The clinical course is related to staging at presentation, with a > 99% survival rate for unifocal disease and < 20% mortality jn risk-organ multisystem LCH with proIonged therapy {1101,215-) 3078,75}. Progression from initially focal to multisystem LCH can occur, most comm only in infants with hypothalamic pituitary invoIvement. Patient age is a less important indicator than dis

ease extent {2151,3078}. Multisystem LCH can be complicated by macrophage activation syndrome {974}. BRAF p.Val600Glu mutation correlates with in creased relapse risk {282,1351} and pote ntially worse clinical parameters, including resista nee to first-line therapy and neurodegenerative CNS LCH {1351} In previously diagnosed LCH patients with BRAF p.Val600Glu mutation, additi onal lesi ons dem on strati ng BRAF p.Val600Glupositive, CD1a/CD207-negative histiocytes may still represent active disease {1810}.

paybal：https://www.paypal.me/andy19801210 Emile JF Haroche J Picarsic J Tirabosco R

Erdheim-Chester disease

Definition Erdheim-Chester disease (ECD) is a clonal systemic histiocytosiS with inflammation and fibrosis.

ICD-O coding 9749/3 Erdheim-Chester disease

ICD-11 coding 2B31 .Y & XH1VJ3 Other specified histiocytic or dendritic cell neoplasms & Erdheim-Chester disease

Related terminology None

Subtype(s)

Fig. 3.206 Erdheim-Chester disease. The hairy kidney sign. CT showing perirenal infiltration by Erdheim-Chester disease.

None

Localization ECD is a multisystem disease. Long bones are involved in > 90% of cases. Infiltration of the retroperitoneum (58%) or around aorta (46%) is also frequent {635}. Neurological or pituitary involvement occurs in 20-50% of cases. Infiltration of lungs, heart, skin (xanthelasma), or any other organ or soft tis­ sue may also occur, but the spleen, lymph nodes, and liver are gen erally spared.

Clinical features Signs and symptoms ECD may be asymptomatic; however, most patients have gen­ eral, inflammatory, or site-related symptoms, most of which are considered to be related to the inflammation and fibrosis asso­ ciated with the histiocytic infiltration of the tissues and organs. Bone pain (37-50%), exophthalmos (25%), xanthelasma (1926%), and diabetes insipidus (28%) are frequently reported. CNS disease presents with either tumour-like or neurodegenerativetype symptoms. Involvement of the basilar arteries can lead to stroke. Pulm on ary, re nal, en docri ne, or cardiac dysf unction may also be responsible for clinical manifestation, and 25-50% of Patients die from disease progress!on before treatment.

short-tau inversion recovery (STIR) MRI (B) showing heterogeneous marrow abnor­ mality throughout both femoral shafts in a 46-year-old man..

specific. It is also noteworthy that 10-20% of cases of ECD are associated with other forms of histiocytosis, such as Lan gerhans cell histiocytosis {1354,901}.

Imaging As many as 95% of patients with ECD have a symmetrical osteosclerosis of the leg bones, best visualized by PET with bilateral uptake of FDG. Bone lesions may be visualized on CT or MRI, but they are often missed on plain X-rays. Bilateral Peri nephritic in filtrati on, resp on sible for a hairy kidney aspect on CT, is noted in 66% of cases. Imaging may also disclose a coated aorta, corresponding to an infiltration of soft tissues surrounding abdominal or thoracic aorta. Detection of mass-like infiltration of the right atrium by MRI (33%) is highly suggestive 6 ECD. CT of the chest may show pleural and septal thickening, as well as serosal effusions. Infiltration of other organs is less

Epidemiology ECD is a rare but probably underdiagnosed disease. The median age at diagnosis is 55 years, with an M:F ratio of 3:1. Cases in children aged < 15 years are very rare and overlap with systemic juvenile xanthogranuloma.Etiology Unknown

Pathogenesis Most cases have an activating mutation of the MAPK path­ way. This mutation may also be present within bone mar­ row progenitors, and some patients may have an associated

Bone tumours

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Fig.3.208 Erdheim-Chester disease. Brain xanthogranuloma in a patient with typical bone lesions. A H&E staining. B Diffuse immunoreactivity for CD14. C Immunoreactiv't for factor Xllla.

myeloproliferative or myelodysplastic neoplasm {2433,50}. Recent data suggest that some cases of ECD result from tissue accumulation of histiocytes derived from mutated bone marrow progenitors {875}.

Macroscopic appearance Most of the samples obtained for diagnosis correspond to biopsies of peri re nal fat, bone, or skin. They are usually firm and sclerotic.

Histopathology Lesional tissue demonstrates infiltration of foamy, lipid-laden, an d/or small mono nuclear histiocytes associated with variable

proportions of Touton giant cells, small lymphocytes, plasma cells, and neutrophils, which is indistinguishable from xanthogranuloma. Fibrosis is usually present and sometimes predominant, leading to misinterpretation of the lesion as a reactive fibroinflammatory process. Admixed Langerhans cell histiocy­ tosis may be present in the same biopsy.

Immunohistochemistry The immunohistochemical profile is similar to that of xanthogranuloma, with ECD histiocytes positive for CD163, CD68, and CD14 and negative for CD1a and CD207. They may also be positive for factor Xllla and fascin, and less commonly for S100.

Fig. 3.209 Erdheim-Chester disease. A Characteristic bone infiltration by the histiocytic proliferation. B,C,D Retroperitoneal (perirenal) biopsy showing infiltration by foam\ histiocytes (B) or predominant fibrosis (C); immunohistochemistry shows expression of CD163 (D).

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Bone tumours

paybal：https://www.paypal.me/andy19801210 Expression of phosphorylated ERK is frequent in ECD histio­ cytes, and strong diffuse cytoplasmic VE1 monoclonal antibody overexpression may signal a B/?Z\Fp.Val600Glu mutation.

Patients without B/?Z\Fp.Val600Glu frequently have other mutations (also activating the MAPK cell signalling pathway) on ARAF, NRAS, KRAS, or MAP2K1 {817}. PIK3CA may also be mutated {903}.

Differential diagnosis

Cytology

Staging

Not clinically releva nt

Not clinically re leva nt

Essential: collections of bland foamy histiocytes in the appropri­ ate clin ical and radiological con text. Desirable: mutation analysis of the MAPK pathway.

Diagnostic molecular pathology

Prog nosis and prediction

A Bfl/4Fp.Val600Glu mutation is present in 50-60% of cases of ECD {1304}. This frequency may be underestimated, because the mutant allele frequency is < 5% in a quarter of cases {2069}.

CNS and cardiovascular invoIvement is associated with a worse prog nosis {635}. BRAF mutations do not have a prog nostic value, but targeted therapies might improve the prog nosis.

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Bone tumours

497

」

Essential and desirable diagnostic criteria

e 2deuo

ity

Disseminated xanthogranulomas with the relevant mutation of the MAPK pathway are now considered part of the same syn­ drome {901}. The differe ntial diag nosis mainly in eludes xanthogranuloma, as well as other inflammatory processes.

paybal：https://www.paypal.me/andy19801210 Rosenberg AE Demicco EG

Rosai-Dorfman disease

Defin iti on Rosai-Dorfman disease (RDD) is a histiocytic proliferation char­ acterized by large S100-positive histiocytes with emperipolesis.

ICD-0 coding None

ICD-11 coding EK92 Histiocytoses of uncertain malignant potential

Related terminology Not recommended: sinus histiocytosis with massive lymphaden opathy.

Subtype(s) None

Localization Primary in traosseous RDD most comm only affects the metaphysis of long bones and craniofacial skeleton {2204}. In 71% of cases, one bone is affected; the remainder involve multiple bones {2204}.

Fig. 3.210 Rosai-Dorfman disease. A Radiograph showing distal femur that ap­ pears unremarkable. B Tumour in medial femoral condyle that is bright on coronal fat-saturated T2-weighted image.

Clinical features Signs and symptoms Patients usually present with pain localized to the invoIved ana­ tomical site; pathological fracture is rare.

»

Fig.3.211 Rosai-Dorfman disease. A Lesion replaces the normal marrow and surrounds the bony trabeculae. B Numerous large histiocytes with abundant pale eosin°P''

cytoplasm are surrounded by chronic inflammatory cells. C Rosai-Dorfman histiocytes with emperipolesis. D Rosai-Dorfman histiocytes are strongly immunoreactive for o

498

Bone tumours

paybal：https://www.paypal.me/andy19801210 I imaging imaging studies reveal a well-defined lytic, sometimes expansile, septated mass. Cortical thickening and periosteal reaction L are present in a minority of cases {789}.

Epidemiology is a rare disease that usually prese nts in the lymph no des, but it may affect extra no dal sites in > 40% of cases; bone involvement occurs in 2-10% of patients {901}. Primary bone involvement is very rare, is associated with equal sex distribution, and may affect patients of any age (mean: 31 years) {2204}. rDD

Etiology F Unknown

pathogenesis

plai

a-

Constitutive activation of the RAS/MAPK pathway probably plays a role in a subset of cases, because this pathway is important in monocyte maturation {457}. Mutually exclusive mis­ sense mutations in NRAS, KRAS, MAP2K1, ARAF, and BRAF have been reported in 33-40% of tumours and are considered driver genetic aberrations {6,2622,973}. Germline mutations in SLC29A3 and FAS (TNFRSF6) are associated with patients who have the rare familial form of the disease {6}.

Fig.3.212 Rosai-Dorfman disease. Numerous neutrophils are present, which can lead to a misdiagnosis of osteomyelitis.

Differential diagnosis

Macroscopic appearance

The differential diag nosis in eludes osteomyelitis, Langerha ns cell histiocytosis, Erdheim-Chester disease, and lgG4-associated sclerosing lesion because RDD may also contain numerous lgG4-positive plasma cells {901}.

Tumours range in size from 1 to 7 cm; most are < 5 cm and are well defined and tan-grey, with a soft or gritty texture.

Cytology

Histopathology The tumour is poorly defi ned, replaces the marrow, in filtrates haversian systems, and is associated with local bone resorption {789}. The mass is characterized by sheets and clusters of large histiocytes with nuclei that range from round or oval to ren iform, with fine or vesicular chromati n and promine nt eosinophilic nucleoli. The cytoplasm is abundant and pale eosinophilic, and it demonstrates conspicuous emperipolesis (lymphocytophagocytosis) of lymphocytes, plasma cells, or neutrophils. The tumour cells are enmeshed in a fibrotic stroma that con tains a prominent mixed inflammatory infiltrate com­ posed of lymphocytes, plasma cells (often containing Russell bodies), neutrophils, foamy macrophages, and rare eosinophils. Microabscesses may be present. The neoplastic histiocytes are I variable in number and distribution, and they may be undersampled on biopsy.

FNA reveals large histiocytes in a mixed inflammatory back­ ground. Emperipolesis of inflammatory cells can usually be seen in the cytoplasm of the tumour cells {1959}.

Diagnostic molecular pathology Not clin ically releva nt

Essential and desirable diagnostic criteria Essential: large S100-positive, CD1a-negative histiocytes with cytoplasmic emperipolesis; plasma cell-rich inflammatory infiltrate.

Staging There is no applicable staging system. Imaging studies (e.g. FDG PET-CT) to identify additional sites of disease should be considered {6}.

Prog nosis and prediction I Immunohistochemistry The histiocytes express S100 and are negative for CD1a and CD207 {901}.

Prog nosis is good; one or more other organs become in volved in 58% of patients {2204}. Bone lesions are effectively treated for local control by curettage {789}.

liliC 00.

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j3enetic tumour syndromes of soft tissue and bone Edited by: Lazar AJ, Mertens F

€nch on dromatosis Li-Fraumeni syndrome McCune-Albright syndrome Multiple osteochondrorras Neurofibromatosis type 1 Rothmund-Thomson syndrome Werner syn drome

paybal：https://www.paypal.me/andy19801210 Genetic tumour syndromes of soft tissue and bone: Introduction

For more than a century, it has been recognized that hereditary factors can con tribute to the development of soft tissue and bone tumours. Often, these genetic variants have other phenotypic con sequences as well, resulti ng in clin ically recog nizable tumour-predisposing syndromes. With the rapidly increasing use of massively parallel sequencing of DNA in both diagnos­ tic pathology and clinical genetics, constitutional pathogenetic variants can now be routinely screened for and identified with great precision. This in turn makes it possible to identify at-risk individuals in affected families, who can then be offered genetic counselling. Information on underlying genetic variants can also have an important impact on the choice of therapy and surveil­ lance guidelines. Apart from traits showing Mendelian inherit­ ance, several disorders caused by postzygotic mutations have now been characterized at the molecular level; patients with these disorders may need distinet forms of therapy and personalized follow-up. The unbiased nature of massively parallel

Mertens F Lazar AJ

sequencing-based studies will undoubtedly continue to widen the spectrum of known predisposing genetic variants amona patients with soft tissue and bone tumours, also encompassinn monogenic and polygenic variants with only a moderate impact on tumour risk. This chapter provides detailed descriptions of a few selected disease syndromes, which are summarized in Table 4.01. These syndromes have been covered in detail because their clinical histopathological, and genetic characteristics are well charac­ terized or because their associated neoplasms have features that are different from those of their sporadic counterparts. Simi­ lar descriptions of other disorders associated with soft tissue or bone tumours, such as Beckwith-Wiedemann syndrome cherubism, and retinoblastoma, can be found in other volumes of this series. Table 4.02 presents a much more comprehensive listing of genes associated with disorders and syndromes that predispose individuals to soft tissue and bone tumours.

Table4.01 Summary of the seven syndromes presented in this chapter Locus

Gene

Gene/locus MIM number

Protein

2q34

IDH1

147700

IDH1

15q26

IDH2

147650

IDH2

AD

17p13

TP53

191170

p53

PZ

20q13

GNAS

139320

Gsa

Disease/phenotype

MIM number

Inheritance

Enchondromatosis (Ollier disease and Maffucci syndrome)

166000

PZ

Li-Fraumeni syndrome

151623

McCune-Albright syndrome

174800

Normal protein function

Isocitrate dehydrogenases; conversion of isocitrate to a-ketoglutarate; NADPH production and control of mitochondrial redox balance DNA damage response; "guardian of the

genome"

The alpha subunit of aG protein; signal transduction from seven transmembrane

receptors to the cAMP second messenger 133700

AD

8q24

EXT1

608177

EXT1

133701

AD

11p11

EXT2

608210

EXT2

Multiple osteochondromas

EXT1 and EXT2 form a hetero-oligomeric

Trichorhinophala ngeal syndrome type 2 (La nger-Giedion syndrome)

150230

Potocki-Shaffer syndrome

601224

8q24

A contiguous gene deletion syndrome encompassing EXT1

complex involved in heparan sulfate production, essential for bone and

cartilage formatio n 11p11

A contiguous gene deletion syndrome encompassing EXT2

Neurofibromatosis type 1

162200

AD

17q11

NF1

613113

Neurofibromin (NF1)

Rothmund-Thomson syndrome

268400

AR

8q24

RECQL4

603780

RECQL4

Regulation of RAS signalling

A DNA helicase critical for DNA repair; restricted tissue expression

A DNA helicase critical for DNA repair;

Werner syndrome

277700

AR

8p12

AD, autosomal dominant; AR, autosomal recessive; PZ, postzygotic.

502

Genetic tumour syndromes of soft tissue and bone

WRN

604611

WRN

i inix/aroolh/ expressed avnraecorl universally

paybal：https://www.paypal.me/andy19801210 Table4.02 Predisposing genetic disorders, ordered alphabetically by the gene(s) involved Gene(s)

Locus

Disorder

ACP5

19p13

Spondyloenchondrodysplasia

ACVH1

2q24

Fibrodysplasia ossificans progressiva

AKT1

14q32

Proteus syndrome

ANTXR1

2p13

Haemangioma, capillary infantile

ANTXR2

4q21

Hyaline fibromatosis syndrome Desmoid disease, hereditary

APC

5q22

Soft tissue and bone tumours

Inheritance

MIM number

AR

607944

Enchondromas

PZ/AD

135100

Progressive heterotopic ossification (myositis ossificans progressiva), proximal tibial osteochondromas

PZ

176920

Lipomas

AD

602089

Haemangiomas

AR

228600

Fibromatosis

AD

135290

Desmoid tumours

Familial adenomatous polyposis 1 (including Gardner syndrome)

AD

175100

Craniofacial osteomas, desmoid tumours, Gardner fibromas

BLM (RECQL3)

15q26

Bloom syn drome

AR

210900

Osteosarcomas

BRAF

7q34

Cardiofaciocutaneous syndrome

AD

115150

Giant cell lesions of small bones (central)

BUB1B

15q15

Mosaic variegated aneuploidy syndrome 1

AR

257300

Embryonal rhabdomyosarcomas

CHEK2

22q12

Li-Fraumeni syndrome 2

AD

609265

Osteosarcomas, rhabdomyosarcomas, other soft tissue sarcomas

Complex, including CDKN1C, KCNQ1OT1, ICR1, and H19

11p15

Beckwith-Wiedemann syndrome

PZ/AD

130650

Embryonal rhabdomyosarcomas, myxomas, fibromas, hamartomas

CRE3BP

16p13

Rubinstein-Taybi syn drome 1

AD

180849

Rhabdomyosarcomas, leiomyosarcomas, haemangiomas

DICER1

14q32

DICER 1 syndrome

AD

601200

Embryonal rhabdomyosarcomas

Multiple osteochondromas

AD

133700

EXT1

8q24

Trichorhinophalangeal syndrome type 2 (Langer-Giedion syndrome) Multiple osteochondromas

EXT2

150230 AD

133701

601224

Osteochondromas, secondary peripheral chondrosarcomas

11p11 Potocki-Shaffer syndrome

Osteochondromas, secondary peripheral chondrosarcomas

FH

1q43

Hereditary leiomyomatosis and renal cell cancer

AD

150800

Leiomyomas of the skin and uterus

FLT4

5q35

Haemangioma, capillary infantile

PZ

602089

Haemangiomas

GLMN

1p22

Glomuvenous malformations

AD

138000

Glomus tumours

Pseudohypoparathyroidism, type 1A

AD

103580

Cutaneous osteomas

McCune-Albright syndrome (including Mazabraud syndrome)

PZ

174800

Polyostotic fibrous dysplasia, osteosarcomas Mazabraud syndrome: intramuscular

Progressive osseous heteroplasia

AD

166350

Cutaneous osteomas

Pseudopseudohypoparathyroidism

AD

612463

Cutaneous osteomas

Costello syndrome

AD

218040

Embryonal rhabdomyosarcomas

PZ

166000

Enchondromas, chondrosarcomas Maffucci syndrome: haemangiomas, angio­

GNAS

20q13

HRAS

11p15

IDH1

2q34

Enchondromatosis (Ollier disease and Maffucci syndrome)

myxomas

IDH2

15q26

kdr

4q12

Haemangioma, capillary infantile

AD

602089

Haemangiomas

KIT

4q12

GIST, familial

AD

606764

GISTs

LEMD3

12q14

Buschke-Ollendorff syndrome (including isolated osteopoikilosis)

AD

166700

Enostoses

MAP2K1

15q22

Cardiofaciocutaneous syndrome

AD

615279

Giant cell lesions of small bones (central)

sarcomas

AD, autosomal dominant; AR, autosomal recessive; GIST, gastrointestinal stromal tumour; PZ, postzygotic; XD, X-linked dominant; XR, X-linked recessive.

Genetic tumour syndromes of soft tissue and bone

503

paybal：https://www.paypal.me/andy19801210 Table4.02 Predisposing genetic disorders, ordered alphabetically by the gene(s) involved (continued) Gene(s)

Locus

MEN1

11q13

MIDI

Xp22

MTAP

9p21

NBN

Disorder

Soft tissue and bone tumours

Inheritance

MIM number

Multiple endocrine neoplasia type 1

AD

131100

Lipomas

Opitz G/BBB syndrome, X-linked

XR

300000

Cranial osteomas

Diaphyseal medullary stenosis

AD

112250

Un differentiated pleomorphic sarcomas of bone

8q21

Nijmegen breakage syndrome

AR

251260

Rhabdomyosarcomas

NF1

17q11

Neurofibromatosis type 1

AD

162200

NF2

22q12

Neurofibromatosis type 2

AD

101000

GIST, familial

AD

606764

GIST-plus syndrome

AD

175510

Neurofibromas, malignant peripheral nerve sheath tumours, GISTs, giant cell lesions-of bone (central), rhabdomyosarcomas, glomus tumours

PDGFRA

4q12

Schwannomas

GISTs

PMS2

7p22

Mismatch repair cancer syndrome

AR

276300

Rhabdomyosarcomas

PORCN

Xp11

Focal dermal hypoplasia

XD

305600

Giant cell tumours of bone

POT1

7q31

Predisposition to angiosarcoma

AD

606478

Angiosarcomas

PRKAR1A

17q24

Carney complex, type 1

AD

160980

AD

109400

PZ/AD

158350

Lipomas, haemangiomas

Enchondromatosis (Ollier disease and Maffucci syndrome)

PZ

166000

Enchondromas, chondrosarcomas Maffucci syndrome: haemangiomas, angiosarcomas

LEOPARD syndrome 1

AD

151100

Metachondromatosis

AD

156250

Enchondromas, osteochondroma-like lesions

Noona n syn drome 1

AD

163950

Granular cell tumours, giant cell lesions of small bones (central)

Retinoblastoma

AD

180200

Osteosarcomas, lipomas, soft tissue sarcomas

Baller-Gerold syndrome

AR

218600

Osteosarcomas

RAPADILINO syndrome

AR

266280

Osteosarcomas

AR

268400

Osteosarcomas

9q22

Basal cell naevus syndrome

PTEN

10q23

Cowden syndrome 1

PTH1R

3p21

12q24

13q14

RB1

RECQL4

8q24

SDHA

5p15

Rothmund-Thomson syndrome

SDHB

1p36

SDHC

1q23

SDHD

11q23

SH3BP2

myxomas, melanocytic schwannomas Cardiac fibromas, rhabdomyosarcomas, fetal rhabdomyomas

PTCH1

PTPN11

Osteochondromyxomas, cardiac and other

AD?

Granular cell tumours, giant cell tumours of bone

GISTs

Paraganglioma and GIST (CarneyStratakis syndrome)

AD

606864

Paragangliomas, GISTs

4p16

Cherubism

AD

118400

Giant cell lesions of small bones

SMARCA4

19p13

Rhabdoid tumour predisposition syndrome 2

AD

613325

Malignant rhabdoid tumours

SMARCB1

22q11

Rhabdoid tumour predisposition syndrome 1

AD

609322

Malignant rhabdoid tumours

Embryonal rhabdomyosarcomas, granular cell tumours, giant cell lesions including giant cell lesions of small bones (central) and pigmented

SOS1

2p22

Noonan syn drome 4

AD

610733

SQSTM1

5q35

Paget disease of bone

AD

167250

Osteosarcomas

TBXT(T)

6q27

Chordoma, familial

AD

215400

Chordomas

villonodular synovitis

AD, autosomal dominant; AR, autosomal recessive; GIST, gastrointestinal stromal tumour; PZ, postzygotic; XD, X-linked dominant; XR, X-linked recessive.

504

Genetic tumour syndromes of soft tissue and bone

paybal：https://www.paypal.me/andy19801210 Table4.02 Predisposing genetic disorders, ordered alphabetically by the gene(s) involved (continued) Ger⑸

Locus

TEK

9p21

TNFRSF11A

18q21

Inheritance

MIM number

AD

600195

Paget disease of bone, early-onset

AD

602080

Polyostotic osteolytic dysplasia, hereditary expansile

AD

174810

Disorder

Venous malformations, multiple

cutaneous and mucosal

Soft tissue and bone tumours

Haema ngiomas

Osteosarcomas

17p13

Li-Fraumeni syndrome

AD

151623

Osteosarcomas, rhabdomyosarcomas, other soft tissue sarcomas

TSC1

9q34

Tuberous sclerosis 1

AD

191100

Fibromas, cardiac rhabdomyomas, angiomyolipomas, chordomas

TSC2

16p13

Tuberous sclerosis 2

AD

613254

Fibromas, cardiac rhabdomyomas, angiomyolipomas, chordomas

VHL

3p25

Von Hippel-Lindau syndrome

AD

193300

Haemangioblastomas

WRN

8p12

Werner syndrome

AR

277700

Bone and soft tissue sarcomas

ZNF687

1q21

Paget disease of bone 6

AD

616833

Giant cell tumours of bone

」

pe

TP53

ello

Q.

AD, autosomal dominant; AR, autosomal recessive; GIST, gastrointestinal stromal tumour; P乙 postzygotic; XD, X-linked dominant; XR, X-linked recessive.

Genetic tumour syndromes of soft tissue and bone

505

paybal：https://www.paypal.me/andy19801210 Bovee JVMG Alman BA

Enchondromatosis

Definition

Subtype(s)

Enchondromatosis is a heterogeneous skeletal disorder in which patients have multiple symptomatic cartilaginous neoplasms originating in the medulla of bone that cause bone expansion. Several subtypes are recognized, of which Ollier disease and Maffucci syndrome are the most common.

Ollier disease is the most common enchondromatosis subtype and is characterized by the occurrence of multiple cartilaginous masses originating in the medulla of bone, particularly affecting the short and long tubular bones of the limbs. When cutaneous soft tissue, or visceral haemangiomas are also present, the dis­ order is referred to as Maffucci syndrome. Other subtypes are extremely rare. Metachondromatosis is associated with osteochondroma-like lesions and enchondromas. The enchondroma­ tosis subtypes can be distinguished based on the distribution of the enchondromas, other accompanying symptoms, and the mode of inheritanee. See Table 4.03.

MIM numbering 166000 Ollier disease 614569 Maffucci syndrome

ICD-11 coding 2E83.Y Other specified benign osteogenic tumours

Localizati on

Related termi no logy Ollier disease Acceptable: dyschondroplasia; multiple cartilaginous enchon­ dromatosis; enchondromatosis Spranger type I, multiple enchon dramas.

Maffucci syndrome Acceptable: dyschondroplasia with haemangiomas; enchondromatosis with multiple caver nous haema ngiomas; Kast syndrome; haemangiomatosis chondrodystrophica; enchon­ dromatosis Spranger type II.

The enchondromas in Ollier disease and Maffucci syndrome primarily affect the short and long tubular bones of the extremi­ ties, but flat bones such as the pelvis and ribs may be involved. The craniofacial bones and vertebrae are usually spared, and one side of the body (or one extremity) is usually more severely affected. The lesions in metachondromatosis typically occur in han ds, feet, femora, tibiae, and the pelvis {1011}.

Clinical features Ollier disease is non-hereditary and usually manifests in early childhood. Enchondromas in the metaphyseal regions of long bones result in deformity and limb asymmetry, as well as

Table 4.03 Enchondromatosis subtypes (based on {2997}) Characteristics other than

multiple enchondromas

Previous Spranger classification

Heredity

Gene(s)

Reference(s)

MIM number

Ollier disease

Unilateral predominance

I

Sporadic: somatic mosaic

IDH1,IDH2(PTH1R)

{2430,96}

166000

Maffucci syndrome

Same as Ollier disease, with haemangioma

II

Sporadic: somatic mosaic

IDH1, IDH2

{2430,96}

614569

MC-HGA

Severe metaphyseal lesions, mild vertebral involvement, presence of D-2-HG in the urine, other

VI

Sporadic: somatic mosaic

IDH1

{3203}

614875

Metachondromatosis

Osteochondroma-like lesions (especially in the hands)

III

AD

PTPN11

{2900,389}

156250

AD

Unknow n

{2742,1482}

137360

IV

AR

ACP5

{425,1777,424}

607944

VII

AD?

COL2A1

{1253,2241}

一

Syndrome

Genochondromatosis

types 1 and 2

SPENCD

DSC

Symmetrical lesions, normal stature, type 1: thickened clavicles, type 2: normal clavicles

Metaphyseal dysplasia, platyspondyly, autoimmune disease, neurological dysfunction Metaphyseal enchondromas, anisospondyly and kyphoscoliosis, other

AD, autosomal dominant; AR, autosomal recessive; DSC, dysspondyloenchondromatosis; MC-HGA, metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria; SPENCD,

spondyloenchondrodysplasia.

506

Genetic tumour syndromes of soft tissue and bone

paybal：https://www.paypal.me/andy19801210 oCcasional pathological fractures. The extent of orthopaedic complications depends on the number and skeletal distribution of enchondromas. There is wide clinical variability with respect to size, number, locati on, age of on set, and requireme nt of sur­

complications due to mass effects {1011}. Most lesions regress in adulthood {1011}.

gery， Maffucci syndrome is also non-hereditary and presents at b『th or in early childhood with caver nous haema ngionnas of Me dermis, subcutis, or internal organs. In addition, spindle cell haemangioma, a vascular lesion with a high propensity for local recurrenee but no potential for metastasis, is overrepresented among patients with Maffucci syndrome {2477,960}. The skel­ etal features in Maffucci syndrome are indistinguishable from those in Ollier disease. Orthopaedic surgical intervention may be needed to treat the deformities. Excision of a symptomatic lesion, osteotomy or guided growth to correct malalignment, or bone lengthening is performed in appropriate patients. Affected individuals should be instructed to pay close attention to signs or symptoms heraldi ng maligna nt tran sformatio n {1801}. Patie nts with Ollier disease and Maffucci syndrome are at increased risk of devel­ oping chondrosarcomas, and patients with Ollier disease have an increased incidenee of gliomas and juvenile granulosa cell tumours {2429}. In Maffucci syn drome, an giosarcomas, astro­ cytomas, pituitary ade no mas, juve nile granu losa cell tumours, pancreatic ade no carci no mas, and single other tumours have been reported {2577,2429}. Metacho ndromatosis is a hereditary disorder whose lesions are mostly asymptomatic, although they may cause

The imaging features of Ollier disease and Maffucci syndrome are similar, except for the presence of haemangioma-associated phleboliths in Maffucci syndrome. Enchondromas present as multiple, oval-shaped, linear and/or pyramidal osteolytic lesions with well-defined margins in the metaphysis and/or diaphysis of bone. When cortical destruction and soft tissue extension are seen, this is suspicious for malignant transformation towards secondary central chondrosarcoma. The lesions in metachon­ dromatosis point towards the epiphysis, which is different from osteochondroma that points away from the joint, and there is a typical predilection for the hands and feet {1011}.

Imaging

Epidemiology Enchondromatosis is rare, but the exact incidence is unknown; the estimated prevale nee of Ollier disease is 1 case per 100 000 people {2861}. About 75% of patients with Ollier dis­ ease and Maffucci syndrome are diagnosed before the age of 20 years {3193}. Enchondromatosis has been described in many different ethnic groups, and there is no significant sex bias.

Etiology Ollier disease and Maffucci syndrome are not inherited. Most patients carry postzygotic mutations in the isocitrate

f'9-4.01 Ollier disease. Conventional radiographs of a child. A,B Progression in lower extremity deformity over time. C The deformity of the hand caused by multiple enchond「omas. D Multiple enchondromas (arrows) in the fifth ray of the hand of a young patient.

Genetic tumour syndromes of soft tissue and bone

507

paybal：https://www.paypal.me/andy19801210

A Fig.4.02 Ollier disease. A Tc-99m bone scintigraphy demonstrates unilateral occurrence with deformity of the right lower limb, showing multiple areas of focally increased uptake of the tracer in the femur and tibia. B Anteroposterior radiograph of the right knee and lower leg of the same patient shows structural changes in the marrow cavity and cortical bone of the femur and tibia, consisting of osteolysis and osteosclerosis. C In the proximal tibia, areas with mineralization (calcifications) can be appreciated (ar­ row). D Coronal fat-suppressed T1-weighted MRI of the femur after intravenous administration of contrast shows multiple partially lobulated areas with increased signal intensity due to enhancement of the chondromatous lesions. There is a large lesion in the distal diaphysis of the femur suggestive of chondrosarcoma (arrow). The enhancement demon­ strates rings and arcs (also known as septal or nodular enhancement) consistent with the chondromatous nature of the lesion.

dehydrogenase genes IDH1 and IDH2 in their enchondramas (87%), chondrosarcomas, and spindle cell haemangiomas (70%) {2430,96}. In total, 65 of 75 patients (87%) with Ollier dis­ ease and 17 of 21 patients (81%) with Maffucci syndrome were shown to carry mutations in their tumours {2430,96}. Mutations mostly affect the p.Arg132 position in exon 4 of IDH1 and include p.Arg132Cys (-65%), p.Arg132His (-15%), p.Arg132Gly (-5%), and other very rare variants affecting the p.Arg132 position. Mutations in /DA72(p.Arg172Ser) are rare {2430,96}. In Maffucci syndrome, only the p.Arg132Cys substitution is found. Multiple tumours within the same patient were shown to carry identical mutations. Also, mutations are found at a very low frequency in normal tissue in these patients {2430,96}. In addition, mutations in the PTH1FI gene, encoding a receptor for PTH and PTHrP, may account for rare patients with Ollier disease {1401}; how­ ever, such mutations have not been detected in other studies {2678,2430,96}. For some other conditions with multiple enchondromas, the genetic background has also been elucidated. PTPN11, a protein tyrosine phosphatase involved in RAS/MAPK signalling, was found to be mutated in patients with m etach on dromatosis

508

Genetic tumour syndromes of soft tissue and bone

{2900,389}. Mutations in ACP5 were found in patients with spondyloenchondrodysplasia {425,1777}. ACP5 encodes for TRAP, which is required for maintenance of osteopontin, a bone matrix protein.

Pathogenesis IDH1 and IDH2 are metabolic enzymes involved in the tricar­ boxylic acid cycle. IDH mutations were previously found in other tumours, mainly gliomas and acute myeloid leukaemia. Heterozygous IDH1 mutations lead to gain of function, and the mutant enzyme is responsible for increased production of the (onco)metabolite D-2-HG {96}. This causes, among other things, epigenetic changes including altered histone methylation and DNA hypermethylation {2430}. D-2-HG has been shown to promote chondrogenic differentiation and inhibit osteogenic differentiation of mesenchymal stem cells, the presumed pre­ cursor cells of enchondroma {2979,1528}. Thus, when IDH1 and IDH2 mutations occur in the mesoderm early after gastrulation. causing a somatic mosaic distribution of mutations within the mesenchymal tissues, this results in multifocal local production of D-2-HG in the developing skeleton, promoting chondrogenic

paybal：https://www.paypal.me/andy19801210 radiological features such as cortical destruction and soft tissue extension into account.

Cytology Not clinically re leva nt

Diagnostic molecular pathology The diagnosis of enchondromatosis is made on the basis of clinical and radiological data, so molecular analysis for IDH1 or IDH2 is not man datory for the diag no sis.

Essential and desirable diagnostic criteria

Fig.4.03 Maffucci syndrome. A Hand deformity due to multiple enchondromas; note the superficial haemangioma. B In another patient, multiple enchondromas with and without soft tissue extension in the second to fifth digits and the fifth metacarpal bone. In addition, phleboliths (arrows) can be seen in the soft tissue at the bases of the sec­ ond and fourth fingers, indicating haemangiomas.

d if fere ntiation ove r osteoge nic differe ntiati on, causi ng multiple enchondromas during skeletal maturation.

Macroscopic appearance Gross specimens are identical to those of sporadic enchondroma.

Histopathology Ench on dramas present as well-circumscribed n odules (see Enchondroma, p. 353). The cartilage is hypercellular and the nuclei are en larged and irregular. Within the con text of Ollier disease and Maffucci syn drome, in creased cellularity and some nuclear atypia are not sufficient to diagnose atypical cartilaginous tumour / chondrosarcoma, grade 1 (ACT/CS1); the distinotion should be made in a multidisciplinary team, taking

Essential: diagnosis is based on radiographic appearanee and clinical features; radiological presence of > 2 enchondromas; these enchondromas cause bone expansion and symptoms, and they may deform the bone.

Staging Not clinically re leva nt

Prognosis and prediction Patients with Ollier disease have a markedly increased risk of developi ng sec on dary chon drosarcomas. There are no large studies showing the incidenee of malignant transformation, but estimates have ranged from 5% to 50% {2789,2758,1879,3193}, and the risk is dependent on the location of the tumours. When patients have enchondromas restricted to hands and feet, the risk is less (-15%) than for patients in whom long bones are also affected (43-46%) {3193}. About 26% of the patients develop multiple chondrosarcomas {3193}. Continued or renewed growth in adults should raise suspicion for malignant progression. The risk of developing chondrosarcoma is possibly even higher among patients with Maffucci syndrome, with incidenee figures as high as 53% {3193}. In contrast, in metachondroma­ tosis the lesions often spontaneously regress and the risk of malignant progression is low {1011}.

Genetic tumour syndromes of soft tissue and bone

509

paybal：https://www.paypal.me/andy19801210 Li-Fraumeni syndrome

Malkin D Ballinger ML Bond GL Thomas DM

Definition Classic Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder in which the proband is diagnosed with a sarcoma at age < 45 years, has a first-degree relative with any cancer diagnosed at age < 45 years, and has another first- or seconddegree relative with any cancer at age < 45 years or a sarcoma at any age {1841,1842}. LFS is caused by germline mutations of the TP53 gene {1957}.

MIM numbering 151623 Li-Fraumeni syndrome

ICD-11 coding None

Anatomical site

Related termi no logy Acceptable: SBLA syndrome (sarcoma, breast cancer, leukae­ mia / lymphoma / lung carcinoma, ad renocortical carcinoma) {1920}.

Fig.4.04 Percentage distribution of 2095 tumours associated with TP53 germline

mutations, by anatomical site (adapted from the IARC TP53 Database).

Subtype(s) None ■ Mis sense 74%

Localization Tumours associated with this syndrome can arise at virtually any body site.

Clinical features LFS is characterized by early on set of a broad spectrum of cancers and a high lifetime cancer risk. Breast cancer - usu­ ally invasive carcinoma and commonly positive for ER, PR, and ERBB2 (HER2) - is the most comm on tumour in TP53 mutati on carriers (24-31.2%) {1996), followed by soft tissue sarcomas (11.6-17.8%), brain tumours (3.5-14%), osteosarcomas (12.613.4%), and adrenocortical tumours (6.5-9.9%) {2275,3075, 373}. Most LFS-associated brain tumours (69%) are astrocytic (astrocytoma or glioblastoma), followed by medulloblastoma / primitive neuroectodermal tumours (17%). Other tumours, including haematological malignancies and gastric, colorectal, bronchoalveolar, cervical, and ovarian carcinomas, occur less frequently, but (as with the common LFS tumours) do so at ages strikingly younger than in the general population {2275,373}. The patient age at diagnosis of tumours associated with TP53 germline mutations shows marked organ-specific differences. Adrenocortical carcinoma occurs primarily in children. Bone sarcomas occur mainly in adolescents, with a tendency shifted to the latter part of the first decade of life. Brain tumours and soft tissue sarcomas exhibit a biphasic age distribution, with a first peak in very early childhood (age < 5 years) and a second peak between the ages of 20 and 40 years; 10% of LFS patients develop gliomas, typically before the age of 45 years. As many as 5% of patients develop supratentorial primary 510

Genetic tumour syndromes of soft tissue and bone

■ Nonsense 7.4% ■ Frameshift 7.2% ■ Splice site 6.5%

■ Large deletions 1.4% ■ Intronic 1.1% ■ Silent 0.6%

■ Other 1.7%

Fig.4.05 Percentage distribution of 1219 TP53 germline mutations by mutation type,

neuroectodermal tumours, choroid plexus carcinomas, and medulloblastomas. Breast carcinomas are most prevalent in the third and fourth decades of life. Sex distribution shows an excess of brain tumours, haematopoietic cancers, and gastric can cer in men, and an excess of breast can cer, ad re no cortical carci noma, and non-melanoma skin cancer in women {3312(. Sarcomas represent 17.4% of all cancers in the IARC TP53 Database and 36.8% of all cancers in patients aged < 20 years. The most comm on types are osteosarcoma (40.4%), sarcoma NOS (17%), rhabdomyosarcoma (16.5%), leiomyosarcoma (9.1%), and liposarcoma (4.9%) {2354,371}. The incidence of osteosarcoma among female TP53 mutation carriers is slightly increased compared with a SEER Program dataset of sporadic cases, but for other sarcomas there are no substantive sex ratio differences. About 67% of sarcomas in carriers of ger_ mline TP53 mutation occur before the age of 19 years. Whereas

paybal：https://www.paypal.me/andy19801210 rhabdomyosarcoma and osteosarcoma are almost exclusively observed before the age of 19 years, liposarcoma and leiomyo­ sarcoma arise predominantly in adults. With respect to genotype-phe no type correlati ons, r habdomyosarcoma and osteo­ sarcoma show a higher than expected proportion of missense mutations in the TP53 DNA-binding domain, whereas liposarcomas and leiomyosarcomas are more frequently associated with frameshift, splice-site, and nonsense mutations {2354).

Epidemiology More than 1000 families have been reported worldwide with complete or partial (Li-Fraumeni-like syndrome [LFL]) pheno­ types, and many more have been identified but not reported. Deleterious mutations in the TP53 gene are the only known cause of LFS. The TP53 carrier rate is estimated to be approxi­ mately 1 case per 5000 individuals, although recent studies suggest it to be as high as 1 case per 500 individuals {748, 2575}. As ascertained on the basis of childhood soft tissue sar­ comas, the cumulative risks in kindreds by the ages of 20, 30, 40, and 50 years, respectively, are estimated to be 18%, 49%, 77%, and 93% for female carriers and 10%, 21%, 33%, and 68% for male carriers {3312}. On average, females exhibit an earlier age of on set than males (29 vs 40 years). The differences in risk remain after exclusion of breast, ovary, and prostate can­ cer. Gene carriers harbour an overall relative risk of additional malignancies of 5.3 (95% Cl: 2.8-7.8), with a cumulative prob­ ability of a second cancer occurrenee of 57% {1375}. However,

it is not clear whethe r the risk of a sec ond cance r is in creased in the radiation field of treated primary tumours. A unique population of TP53 mutation carriers is found in the south-eastern states of Brazil, where a 10-fold incidenee of ad re noc ortical carcinoma had bee n observed. Most of these individuals share a distinet germline mutation (p.Arg337His) within the oligomerization domain of TP53 {825}. The car­ rier rate of this mutation in this region is approximately 1 case per 300 individuals {1003}. An alysis of tumour patter ns in p.Arg337His carriers and their families reveals common fea­ tures of LFS/LFL, clearly establishing that this mutation predis­ poses individuals to a wide spectrum of multiple cancers {10}.

Etiology LFS is heritable, with autosomal dominant transmission. Delete­ rious germline TP53 mutations are found in approximately 80% of all individuals or families who meet the classic criteria for LFS, and in < 20% when a broader LFL definition is applied. p53 is a transcriptional activator that mediates cellular stress responses and initiates DNA repair, cell-cycle arrest, senescenee, and apoptosis {2068}. Almost 4000 distinct deleterious TP53 mutations have been reported. The vast majority of these are mis­ sense mutations, which have been systematically assessed for p53 loss of function, dominant-negative effect, and gain of func­ tion, all properties that can con tribute to tumorige nesis {1063, 2354,1457}.

Table4.04 Diagnostic criteria for Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome and criteria for TP53 genetic testing {2769,2912}

Criteria

Reference(s)

A proband with

• a sarcoma diagnosed before the age of 45 years, AND Classic LFS

{1842} • a first-degree relative with any cancer before the age of 45 years, AND • a first- or second-degree relative with any cancer before the age of 45 years or a sarcoma at any age

Birch definition: • a proband with any childhood cancer or sarcoma, brain tumour, or adrenocortical carcinoma diagnosed before the age of 45 years, AND

{328}

e.

• a first- or second-degree relative with a typical LFS cancer (sarcoma, breast cancer, brain tumour, adrenocortical carcinoma, or leukaemia) at any age, AND

Li-Fraumeni-like syndrome

• a first- or second-degree relative with any cancer before the age of 60 years

d in in ic al

Eeles definition:

{884} • Two first- or second-degree relatives with LFS-related malignancies at any age

A proband with • a tumour belonging to the LFS tumour spectrum (soft tissue sarcoma, osteosarcoma, premenopausal breast cancer, brain tumour, adrenocortical carcinoma, leukaemia, or bronchoalveolar lung cancer) before the age of 46 years, AND

53 s.

1a la of ：iy ic 3X ?ras

• at least one first- or second-degree relative with an LFS tumour (except breast cancer if the proband has breast cancer) before the age of 56 years or with multiple tumours

Chompret criteria

{585,3075,374}

OR

A proband with multiple tumours (except multiple breast tumours), two of which belong to the LFS tumour spectrum and the first of which occurred before the age of 46 years OR

A proband diagnosed with adrenocortical carcinoma or choroid plexus tumour, irrespective of family history

Genetic tumour syndromes of soft tissue and bone

511

paybal：https://www.paypal.me/andy19801210 Table4.05 Surveillance protocol for early tumour detection in TP53 mutation carriers {3201} Tumour type

Surveillance strategy

Age range

In children • Ultrasound of abdomen and pelvis every 3-4 months Adrenocortical carcinoma

• Bloodwork every 3-4 months:3 total testosterone, 17-OH-progesterone, DHEAS, androstenedione

Birth to 30 years

• 24-hour urine cortisol, if feasible

Brain tumour

• Annual MRI of the brain

Soft tissue and bone sarcoma

• Annual rapid whole-body MRI

Birth to 18 years

Leukaemia/lymphoma

• Bloodwork every 3-4 months: complete blood count profile, LDH, ESR

Birth to 18 years

Birth to 18 years

• Complete physical examination every 3-4 months, including anthropometric measurements plotted on a growth curve (with particular attention to rapid acceleration in weight or height), signs of virilization (pubic hair, axillary moisture, adult body odour, androgenic hair loss, clitoromegaly, penile growth), and full neurological assessment • Prompt evaluation with family physician for any medical concerns In adults

• Monthly breast self-examination

From 18 years onwards

• Semiannual clinical breast examination

From 20-25 years onwards or from 5-10 years younger than the earliest known breast cancer in the family (whichever comes first)

• Semiannual breast MRI +/- annual mammography6

20-75 years or from 5-10 years younger than the earliest known breast cancer in the family (whichever comes first)

Breast cancer

• Consider risk-reducing bilateral mastectomy Brain tumour

• Annual MRI of the brain

From 18 years on wards

• Annual rapid whole-body MRI Soft tissue and bone sarcoma

From 18 years onwards

• Ultrasound of abdomen and pelvis every 3-4 months

Colorectal cancer

• Biennial colono scopies

From 25 years on wards or from 10 years younger than the earliest known colon cancer in the family (whichever comes first)

Melanoma

• Annual dermatology examination

From 18 years on wards

Leukaemia/lymphoma

• Bloodwork every 3-4 months: complete blood count profile, LDH, ESR

From 18 years onwards

• Complete physical examination every 3-4 months • Prompt evaluation with family physician for any medical concerns

aSerial specimens should be obtained at the same time of day and processed in the same laboratory. bBreast ultrasonography with mammography as indicated by breast density, but not instead of breast MRI or mammography.

Pathogenesis Disruption of p53 function in LFS results primarily from missense mutations that lead to the synthesis of a stable full-length protein with a mutant DNA-binding core domain {2068,1144}. The most common TP53 germline mutations occur at codons 175, 248, 249, 273, and 281 {1457}. Although these locations are similar to the somatic mutation hotspots, splice-acceptor mutations are found more frequently in the germline. Germline TP53 deletions are rare. When the deletion breakpoint is within the open reading frame, an LFS can cer phe no type is observed; however, if the deletion breakpoints fall outside the open reading frame, the en suing phe no type is r estricted to a spectrum of conge nital anomalies including developmental delay, hypotonia, and hand/foot abnormalities with no associated cancer occurrenee {2849}. These observations suggest that qualitative defects in p53 structure are more conducive to aberrant DNA binding and dysfunctional transcriptional activation leading to malignant

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Genetic tumour syndromes of soft tissue and bone

transformation of cells. TP53 and MDM2 SNPs may affect the natural course {363,2613}. The observation of genetic anticipation (earlier age of can­ cer on set in successive gen erati ons) suggests a role of higher mutator phe no types with each generation. This observation may be explained by accelerated telomere attrition from generation to generation. In both adults and children, telomere length is shorter in TP53 mutation carriers affected by cancer than in non-affected carriers and wildtype controls {3020,3102}. Fur­ ther evide nee that profound genomic in stability is associated with accelerated phenotypes in LFS is found in the observation of increased frequency and complexity of DNA copy number variable regions in TP53 mutation carriers {2850}. Evidence that early TP53 mutation (a germline or early somatic event) induces catastrophic, irreversible DNA damage is found in the high fre­ quency of chromothripsis (shattered chromosomes) in TP53 mutation carriers who develop medulloblastoma {2584}. The inheritance of a TP53 mutation coupled with a somatic defect

paybal：https://www.paypal.me/andy19801210 jn another developmental pathway (in this case, sonic hedge­ hog sign ailing) leads to a sudde n catastrophic shattering and rearrangement of chromosomes, resulting in dramatic telomere dysfunction and rapid cellular proliferation. In summary, although germline TP53 mutations establish a baseline risk of tumour development in LFS, the specific phenotypes of individual patients are probably defined by a complex relation ship of modifying gen etic cofactors.

Diagnostic molecular pathology TP53 is the only gene, to date, that has been definitively associ­ ated with cancer risk in LFS and is considered diagnostic of the disease. Variants of uncertain significance have been reported in the context of single gene testing and multigene panel testing or whole-exome/genome sequencing. Their roles in the pathogen esis of LFS are con troversial.

Essential and desirable diagnostic criteria Macroscopic appearance

See Table 4.04 (p. 511).

The tumours in LFS patients have no macroscopic features that are distinct from those of their sporadic counterparts.

Staging

Histopathology

The staging system for cancers in LFS patients is the same as that for the tumours in their sporadic form.

The tumours in LFS patients have no histopathological features that are distinct from those of their sporadic counterparts. When p53 immunostaining is performed, the presence in tumour cells of missense gain-of-function mutant p53 expression, either in the con text of loss of heterozygosity or with retai ned expressi on of the wildtype TP53 allele, typically confers intense nuclear staining but does not ensure that a germline mutation will be demonstrated. Furthermore, an absence of immunopositiv­ ity does not necessarily rule out the presenee of a TP53 gene mutation, nor is it in formative of the germline TP53 status.

Cytology Not clinically releva nt

Prognosis and prediction To date, studies have not been able to definitively distinguish overall outcome differences between TP53 mutation carriers and patients with the same tumour occurring sporadically. There are isolated case reports suggesting poorer response to therapy or accelerated occurre nee of radiati on-in duced sec ond malignancies, but these findings have not been validated in large prospective cohorts. Similarly, there are currently no vali­ dated predictive markers of outcome, age of on set, or tumour type that are being applied in in dividual patie nts, although extensive research is being done in this field. Surveillanee strategies for early tumour detection in TP53 mutation carriers have been reported and are now widely used, with evidence of reduced mortality and treatment-related morbidity in patients who undergo surveillance (see Table 4.05) {3201,1696,215}.

Genetic tumour syndromes of soft tissue and bone

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paybal：https://www.paypal.me/andy19801210 McCune-Albright syndrome

Boyce AM Colli ns MT Siegal GP

Definition

ICD-11 coding

McCune-Albright syndrome (MAS) is a sporadic disorder char­ acterized by fibrous dysplasia of bone, cafe-au-lait skin lesions, and hyperfunctioning endocrinopathies.

FB80.0 Fibrous dysplasia of bone

Related terminology None

MIM numbering 174800 McCune-Albright syndrome

Subtype(s) None

R 0

Fig. 4.06 McCune-Albright syndrome. A A photograph of a child with cafe-au-lait macules demonstrating typical features, including jagged borders and location reflecting along the midline of the body. B A femoral radiograph shows diffuse involvement with fibrous dysplasia. Note the homogeneous ground-glass radiolucency and lack of defined cortice Bowing of the proximal femur has resulted in a coxa vara (shepherd's crook) deformity. C Testicular ultrasound shows extensive hyperechoic and hypoechoic lesions (blue ar rows). D CT shows fibrous dysplasia involving the left side of the mandible. Note the expansile lesions with a homogeneous ground-glass appearance (red arrow).

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Genetic tumour syndromes of soft tissue and bone

paybal：https://www.paypal.me/andy19801210

Fig.4.07 McCune-Albright syndrome. A Activating mutations (p.Arg201Cys or

闾

p.Arg201H in the gene encoding the a subunit of stimulatory G protein (Gs) abrogate the endogenous GTPase of the a subunit, leading to ligand-independent stimulation of adenylyl cyclase. The PKA or cAMP-dependent protein kinase pathway is shown on the right. The PKC pathway is shown on the left. The inability to hydrolyse GTP leads to persistent binding of Gsa to adenylyl cyclase and continuous synthesis of cAMP, which in turn overactivates the PKA pathway. PKA is composed of two regulatory subunits

(RS), which have binding sites for cAMP, and two catalytic subunits (CS) that, when dissociated, phosphorylate serine/threonine kinases (STK). The dissociated Py subu­ nits of Gs overactivate the PKC pathway. Phospholipase C (PLC) cleaves PIP2 into two intracellular messengers: diacylglycerol (DAG) and inositol trisphosphate (IP3). The latter triggers the release of sequestered calcium ions (Ca2+), which together with DAG activate PKC. B Normally, the hydrolysis of GTP associated with Gsa leads to disso­ ciation of Gsa-GDP from adenylyl cyclase and reassociation with the Py dimer to form the inactive heterotrimer. Ligand binding causes repetition of the cycle.

Localization Disease localization is probably determined by the developmental timing of the mutation, with earlier mutations resulting in more-widespread disease {1297}. Fibrous dysplasia may affect any area of the skeleton. Skin lesions are typically located along the midline of the body but may extend to involve the limbs. En docri no logical disease typically in volves the ovaries/testes, thyroid, pituitary, and/or ad re nal glan ds. Involveme nt in any of these areas may occu r in isolatio n or in combi nation with other disease features.

Clinical features The clinical features of MAS are variable, depending on the distribution of mutation-bearing cells and the specific role of adenylyl cyclase and its second messenger cAMP in affected tissues. In general, most manifestations start during infancy and childhood {1307,649}. Fibrous dysplasia can be mono static or polyostotic, and it presents with fractures, deformities, and pain {394}. Cranio facial fibrous dysplasia may uncommonly lead to neurological complications and functional deficits such as vision and hearing loss {695,392,2412}. Hyperfunctioning endocrinopathies include precocious puberty (more common in females), hyperthyroidism, growth hormone excess, hyperprolactinaemia, and hypercortisolism {649}. Renal phosphate wasting due to excess FGF23 production by fibrous dysplasia cells may result in rickets/osteomalacia and bone pain {2634}. Gastrointestinal features of MAS include panereatic intraductal Papillary mucinous neoplasms {2639}, gastric polyps {3307}, and hepatobiliary lesions {1124}. The association of fibrous

Fig. 4.08 Fibrous dysplasia. A A Masson-stained section taken from an iliac crest shows characteristic discontinuous trabeculae interspersed with fibrous tissue. B A high-power view of part of the area denoted by the box in panel A demonstrates typical features, including replacement of normal marrow structures with fibrous tissue (FT), representing proliferation of fibroblast-like bone marrow stromal cells, and woven bone (WB), which is poorly mineralized with prominent osteoid (0). Arrays of collagen bun­ dles (Sharpey fibres) are oriented perpendicularly to the osteoid. Note the high degree of vascularity with venous pooling (V).

dysplasia with intramuscular myxomas has previously been termed Mazabraud syndrome {1947}; however, myxomas are more accurately denoted as an additional feature of MAS.

Epidemiology MAS is rare, and the prevalence has been estimated to be 1 case per 100 000 to 1 million people {394}. All racial and ethnic groups are affected equally. The prevale nee is probably equal between males and females {394}.

Genetic tumour syndromes of soft tissue and bone

515

paybal：https://www.paypal.me/andy19801210 Etiology The molecular basis for MAS is a postzygotic somatic mutation in exon 8 of GNAS that replaces the residue arginine at position 201 with histidine or cysteine {3266,1913}. Pathogenic mutations occur at the p.Arg201 position in approximately 95% of patients, but infrequently other amino acid substitutions may occur {1462,2635}. GNAS encodes the alpha subunit of the stimulatory G protein 000, which couples heptahelical recep­ tors for hormone and neurotransmitters to activate adenylyl cyclase. These mutations activate Gsa, which leads to constitutive activation of adenylyl cyclase and production of cAMP {3266}.

Pathogenesis In skin and endocrine tissues, Gsa activation leads to overproduction of hormones that signal through this receptor (MSH, LH, FSH, TRH, GHRH, and ACTH) {394}. In bone, Gsa activation leads to impaired differentiation and proliferation of skel­ etal stem cells {2636}, resulting in formation of expansile bone lesions prone to fractures and deformity {394}.

Macroscopic appearance Skeletal imaging shows typical non-aggressive expansile lesions, which may be present in one or multiple bones. Radio­ graphically, lesions often have a homogeneous ground-glass appearanee with cortical thinning {1722}. Skin macules char­ acteristically show jagged borders and a distribution respecting the midline of the body {649}. Ovarian cysts are intermittently visible on ultrasound and may appear simple or complex {936}. Testicular abnormalities can be detected by ultrasound in approximately 80% of boys, including focal hyperechoic and hypoechoic lesions and microlithiasis {393}. Thyroid abnor­ malities are visible on ultrasound in approximately two thirds of patients, even in the absenee of frank hyperthyroidism, and include mixed cystic and solid lesions {521}. Pituitary invoIvement may show a variable appearance on MRI, including dif­ fuse pituitary en largeme nt, macroade no ma, microade no ma, or normal findings {2722,3207}.

Histopathology Fibrous dysplasia lesions are composed of proliferating fibro­ blast-like bone marrow stromal cells, which replace normal bone and marrow. Osteoid trabeculae are present throughout the lesions and are discontinuous and non-functional in their orientation {2636}. Trabeculae are frequently composed of poorly mineralized woven bone {2636}. Follicular cysts lined by granu­ losa cells are frequently identified in girls and women with ovarian involvement {2009,729}. In the testes, large foci of Leydig cell hyperplasia that cannot be definitively distinguished from Leydig cell tumours are comm only fou nd; however, malig nancy is very un comm on {393}. Thyroid findings commonly in elude follicula r ade no mas with papillary growth {2006}, and rare

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Genetic tumour syndromes of soft tissue and bone

Box4.01 Clinical diagnostic criteria for McCune-Albright syndrome McCune-Albright syndrome is diagnosed clinically in individuals with two or more of the following features: • Cafe-au-lait skin macules with characteristic features, including jagged borders and a distribution respecting the midline of the body • Polyostotic or monostotic fibrous dysplasia • Any of the following endocrinopathies: o Gonadotropin-independent precocious puberty o Testicular lesions with or without precocious puberty o Thyroid lesions with or without non-autoimmune hyperthyroidism o Growth hormone excess or mixed growth hormone and prolactin excess o Renal phosphate wasting with or without hypophosphataemia o Neonatal Cushing syndrome The presence of any feature of McCune-Albright syndrome should prompt evalu­ ation for additional manifestations. In individuals with isolated monostotic fibrous dysplasia, identification of a GNAS mutation is required to establish the diagnosis {394}. Detection of the GNAS mutation in genomic DNA from involved cells, either in the circulation or in lesional tissue, can aid in the diagnosis in selected patients. In addition, it can be difficult to detect the mutation if a sufficient number of involved cells are not available for analysis; therefore, most assays have only modest sensitivity {394}.

cases of thyroid carci noma have bee n reported {648}. Adrenal disease is characterized by unilateral or bilateral nodular hyper­ plasia with areas of atrophic cortex {488}.

Cytology Not clinically relevant

Diagnostic molecular pathology Not clin ically re leva nt

Essential and desirable diagnostic criteria See Box 4.01.

Staging Not clin ically releva nt

Prognosis and prediction Individuals with MAS have a variable prog nosis depending on disease location and severity. Endocrinopathies persist throughout childhood and adulthood, with the exception of FGF23-mediated hypophosphataemia, which may worsen during periods of rapid linear growth and ameliorate in adulthood {391}. En docri nopathies can gen erally be managed medically {394}, and optimizing endocrinopathies may improve skeletal outcomes in patients with fibrous dysplasia {1822,274,2412). GNAS mutations in MAS are weakly oncogenic, and affected tissues probably carry a small in creased risk of malignant transformation. Fibrous dysplasia rarely undergoes sarcoma­ tous transformation {2691,3045}; the risk may be increased by radiotherapy and uncontrolled growth hormone excess {2200(. Wome n with MAS are at in creased risk for breast can cer {1946|.

paybal：https://www.paypal.me/andy19801210 Bovee JVMG Hogendoorn PCW Sangiorgi L

Multiple osteochondromas

Definition

Clinical features

Multiple osteochondromas is an autosomal dominant condition in which patients develop multiple benign cartilage-capped neoplasms at the bone surface. It is caused by mutations in the EXT1 or EXT2gene.

Osteochondromas begin to develop and increase in size in the first two decades of life, ceasing to grow when the growth plates close at the end of puberty. They are pedunculated or sessile (broad base) and can vary widely in size. The majority are asymptomatic. The number of osteochondromas may vary significantly within and between families. In addition, a variety of orthopaedic deformities can be found, like deformities of the forearm (shortening of the ulna with resultant bowing of radius; 39-60%) (2767), inequality in limb length (10-50%), angulation of the knee (8-33%), deformity of the ankle (2-54%) {2767, 2826}, and disproportionate short stature (37-44%) {3285, 1823}. Other complications in elude bursa formatio n; arthri­ tis; and impi ngeme nt on adj ace nt tendons, n erves, vessels, or spinal cord {3285}. A reported 84% of patients with multi­ ple osteochondromas report frequent pain {733}, all of whom experienee a profound impact on quality of life {1195}. Patients with multiple osteochondromas may also show abnormal scar formation {1417} and malformed and/or displaced teeth with abnormal enamel {612,2934}. Symptomatic spinal involvement is rare {1502}. Approximately 70-75% of patients with the condi­ tion have a positive family history {1522}. The most importa nt complicati on of multiple osteoch on dra­ mas, estimated to occur in 0.5-5% of multiple osteochondro­ mas patie nts, is progressi on towards sec on dary peripheral atypical cartilaginous tumour (appendicular skeleton) / chon­ drosarcoma, grade 1 (axial skeleton, scapula, skull base, and pelvis) (ACT/CS1), or 一 rarely 一 to high-grade chondrosarcoma {3285,1823,2767}. About 75.2% occurs between the ages of 20 and 40 years and 56.2% at the pelvis and proximal femur {980}. Growth after puberty, increase in pain, or a thickness > 2 cm of the cartilaginous cap in adults should raise suspicion for sec on dary peripheral chon drosarcoma. Occasi on ally, mul­ tiple osteochondromas patients also develop central ACT/CS1 (-3.6%) {1196}. In Langer-Giedion syndrome, craniofacial dysmorphism and mental retardation are seen in addition to multiple osteochon­ dromas {1745}. Patients with Potocki-Shaffer syndrome present with enlarged parietal foramina, multiple osteochondromas, and sometimes cranio facial dysostosis and mental r etardati on {228}.

MIM numbering 133700 Exostoses, multiple, type I; EXT1 133701 Exostoses, multiple, type II; EXT2

ICD-11 codi ng LD24.20 Multiple osteochondromas

Related terminology Acceptable: hereditary multiple exostoses; multiple hereditary exostoses.

Subtype(s) Rarely, multiple osteochondromas is part of a contiguous gene deletion syndrome: Langer-Giedion syndrome (or trichorhinophalangeal syndrome type II) or Potocki-Shaffer syndrome (proximal 11p deletion syndrome, DEFECT11, 11p11.2 contigu­ ous gene deletion syndrome).

Localization Osteochondromas are located in bones that develop by enchondral ossification, especially the long bones of the extremities, predominantly around the knee, but flat bones like the ribs and pelvis may also be affected.

Imaging The diagnosis of multiple osteochondromas is confirmed by conventional radiographs. The size of the cartilaginous cap can be well established with T2-weighted MRI and CT to evaluate possible malignant transformation {1131,279}. A cartilage cap > 2 cm should be regarded with caution. The role of FDG PET needs to be further established {982}. Annual MRI screening of the affected bones, especially between 20 and 40 years of age, seems beneficial to discover potential malignant transformation at an early stage {980,1283}. Rg.4.09 Multiple osteochondromas. X-ray showing multiple osteochondromas.

Genetic tumour syndromes of soft tissue and bone

517

paybal：https://www.paypal.me/andy19801210 Epidemiology The prevale nee of multiple osteoch on dromas is about 1 case per 50 000 people within the general population {2767}, although this may be an un derestimation. The prevale nee may be slightly higher in males than females {3285,1823}.

Etiology Multiple osteochondromas is genetically heterogeneous and two genes, EXT1 at 8q24.11 {47} and EXT2 at 11p11.2 {2950,3321}, have been isolated. The EXT1 gene is composed of 11 exons and spa ns approximately 350 kb of genomic DNA {1908). The cDNA has a coding region of 2238 bp {47}. The EXT2 gene spa ns 108 kb and contains 16 exons, two of which (1a and 1b) are alter natively spliced {620}. It enc odes a 718 amino acid pro­ tein with substantial similarity to the EXT1 gene product, espe­ cially in the C-terminal region {2950,3321}. The EXT genes have orthologues in various species. With the currently used methods, germline inactivating EXT mutations or gross deletions are detected in > 90% of patients with multiple osteochondromas. EXT1 mutations are detected in about 65% of cases and EXT2 mutations in about 35% {1522}. Inactivating mutations (nonsense, frameshift, and splice-site mutations) represent the majority (75-80%) of mutations caus­ ing multiple osteochondromas {1522}. No hotspot mutations have been identified; mutations in EXT1 are spread over the different exons, whereas mutations in EXT2 more frequently affect the N-terminus. In the remaining cases of multiple osteochondromas, other alterations such as deep intronic or promoter mutations, inversions, translocations, or somatic mosaicism may be the underlying cause {1522,3015,3211,2534}. Osteochondromas develop upon biallelic inactivation of an EXT gene {381,2593}; thus, a second somatic hit is required to inactivate the other allele in a chondrocyte within the growth plate {1545} or in a mesenchymal progenitor cell from the peri­ chondrium {1436}. Both EXT genes are also invoIved in a contiguous gene deletion syndrome. In Langer-Giedion syndrome, the 8q24 dele­ tion includes the TRPS1 gene in addition to EXT1 {47,2171}. In Potocki-Shaffer syndrome, patients carry an 11p11.2-p12 deletion that includes ALX4 in addition to EXT2 {3320}.

Pathogenesis EXT1 and EXT2 mRNA is ubiquitously expressed {47,2950, 3321}. Loss of heterozygosity, aneuploidy, or other changes can occur in the cartilagi nous cap of osteoch on droma, in activating the second allele in at least a subset of the cells at the somatic level {2593,378,1437}. Somatic compound heterozygous muta­ tions in EXT1 or EXT2 have been reported, but other mecha­ nisms have been postulated {3411}. The gene products, EXT1 and EXT2, are endoplasmic reticulum-localized type II transmembrane glycoproteins that form a Golgi-localized heterooligomeric complex that catalyses heparan sulfate polymerization {1869,2034,2863}. Heparan sulfate signalling is involved in multiple signalling pathways, and EXT mutations therefore affect hedgehog {1692}, BMP {2408}, FGFR3 {2514), and WNT/ P-catenin pathway {2514} signalling. BMP signalling in particular

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Genetic tumour syndromes of soft tissue and bone

llhil ..

1 la lb 2 3 4 5 6 7 8 9 10 11 12 13 M Exon

Fig.4.10 Multiple osteochondromas. Genomic structure of the EXT1 and EXT2 genes. The grey boxes represent coding regions. The mutation spectrum for each gene is illustrated below the genomic structure to include the frequency of exon in­ volvement.

was shown to be crucial for osteochondroma development in mice, and inhibitors of BMP signalling (e.g. palovarotene) are currently in clin ical trials for the preve ntion of osteoch on drama formation in children with multiple osteochondromas {1473 1472,2871}.

Macroscopic appearance Gross specimens of the individual tumours are similar to spo­ radic osteoch on dromas.

Histopathology The tumours are histopathologically identical to their sporadic counterparts (see Osteochondroma, p. 356). Malignant transformati on leads to a sec on dary peripheral ACT/CS1 in the vast majority of cases. High-grade chondrosarcoma is rare (< 10%) {45}. Osteosarcoma, spindle cell sarcoma, and dedifferentiated chondrosarcoma are extremely rare {1741,385,2675}. On histol­ ogy alone, it is hard to distinguish osteochondroma from secondary peripheral ACT/CS1 in the setting of multiple osteochon­ dromas. Some clin ical and radiographic features, in eluding cartilaginous cap thickness, need to be evaluated to diagnose malignant transformation {749}. Multiple osteochondromas must be distinguished from metachondromatosis and from dysplasia epiphysealis hemimelica (Trevor disease), which are not related to EXT1 and EXT2 mutations. Clinical and radiological features and family history allow distinction.

Cytology Not clin ically re leva nt

Diagnostic molecular pathology The diagnosis of multiple osteochondromas is made on the basis of clinical and radiological data, so molecular analysis for germline mutations in EXT1 or EXT2 is not mandatory for the diag no sis. Moreover, to date a germline heterozygous EXT1 or EXT2 mutation is detected in 70-95% of the patients {1522}.

paybal：https://www.paypal.me/andy19801210 Essential and desirable diagnostic criteria Essential: radiologically at least two osteoch on dramas of the juxtaepiphyseal region of long bones; positive family history and/or a proven germline mutation in one of the EXT genes.

Staging Not clinically releva nt

prognosis and prediction Intrafamilial variability in clinical expression of the disease has been described, and at the moment no strong prognostic factor

predict! ng evolution of the disease (i.e. n umbe r of osteoch on dra­ mas in adult age, deformities) is known. Mutations in EXT1 seem associated with a more severe phenotype and shorter stature than EX72 mutations {2527,85,86,1508}, whereas patients with­ out a disease-causing EXT mutation usually have a mild pheno­ type. Additi onal (ge netic) factors con tribute to the final clinical presentation {1523}. Males seem to be characterized by a more severe clinical presentation than females. Because there is no evidenee for the presenee of any risk or protective factor related to malignant transformation, an adequate follow-up is required for all patients.

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Genetic tumour syndromes of soft tissue and bone

519

paybal：https://www.paypal.me/andy19801210 Legius E Brems H

Neurofibromatosis type 1

Definition Neurofibromatosis type 1 (NF1) is an autosomal dominant dis­ order characterized by cafe-au-lait spots, axillary and inguinal freckling, Lisch nodules of the iris, multiple neurofibromas, and an increased risk for various malignancies.

MIM numbering 162200 Neurofibromatosis type 1; NF1

ICD-11 coding LD2D.1 Neurofibromatoses

Related terminology

Fig.4.11 Neurofibromatosis type 1. A Multiple cafe-au-lait spots on the back. B Cu­ taneous neurofibromas.

Acceptable: von Recklinghausen disease.

Non-nervous system tumours Subtype(s) Jaffe-Campanacci syndrome; spinal neurofibromatosis; seg­ mental n eurofibromatosis

Localization NF1-related features usually develop in neural crest-derived cells such as Schwa nn cells, melanocytes, glial cells, ad re nal cells, and interstitial cells of Cajal.

Clinical features Typical manifestations include multiple cafe-au-lait spots, axillary/inguinal freckling, Lisch nodules, and optic pathway glio­ mas {1263}. Cafe-au-lait spots, the hallmark of NF1, may be present at birth and develop further during the first few years of life. Lisch nodules are asymptomatic iris hamartomas eas­ ily detected by slit-lamp exami nation. Bone abrto rmalities can cause serious complications in individuals with NF1. Severe scoliosis, sphenoid wing dysplasia, non-ossifying fibromas, and con genital tibial bowing are skeletal abno rmalities asso­ ciated with NF1 {2765}. Other clinical signs are short stature, macrocephaly, and deficits in attention and cognitive function. Less common complications in elude epilepsy and cardiovas­ cular problems.

Neoplastic disease spectrum Children (aged < 5 years) with NF1 have a higher risk of devel­ oping juvenile myelomonocytic leukaemia than children without NF1, although the annual incidenee is low (1 case per 20005000 people) {2855}. Individuals with NF1 are at increased risk of developing benign and malignant solid tumours of both nervous and non-nervous systems {404}. In children with cafeau-lait macules and maligna nt tumours, con stituti onal mismatch repair deficiency syndrome should be considered in the differential diagnosis {2973}.

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Genetic tumour syndromes of soft tissue and bone

An association between digital glomus tumours and NF1 has been described {2949}. Children with NF1 may develop non­ ossifying fibromas of the long bones, sometimes reported as Jaffe-Campanacci syndrome {2947}. Individuals with NF1 have a lifetime risk as high as 6% of developing gastrointestinal stro­ mal tumours {2304}, which mostly affect the small intestine and are multifocal {2122}. Systematic screening in a cohort of adults with NF1 detects phaeochromocytoma in > 5% {1237,1610}. Women with NF1 have an increased risk of developing breast cancer before the age of 50 years, and systematic screening is recommended starting from the age of 30 years {1421,3141}. Somatostatinomas (duodenal carci no ids) are rarely detected and are often metastatic when diagnosed {2609}.

Peripheral nervous system tumours Multiple cutaneous neurofibromas are benign peripheral nerve sheath tumours that typically develop starting at puberty and are present in > 90% of adults with NF1 {1263}. In contrast, stud­ ies suggest that plexiform neurofibromas are of congenital origin and occur in 30-50% of individuals with NF1 {1263}. Cutaneous neurofibromas are typically benign, whereas plexiform neurofi­ bromas have a risk of becoming malignant. Individuals with NF1 have a 9-15% lifetime risk of maligna nt peripheral n erve sheath tumour (MPNST) development {3141,938}. Individuals with a germli ne NF1 microdeleti on have an at least 2 times in creased risk of developing MPNSTs {762}.

CNS tumours Tumours of the optic pathway occur in 15% of children with NF1 {756}. Only one third of children with optic pathway gli°_ mas develop symptoms such as visual impairment. Most NF1associated brain tumours in children are classified as pilocytic astrocytoma WHO grade 1. Brain tumours in adults with NF1 are less comm on and have a higher malig nant pote ntial {728}.

paybal：https://www.paypal.me/andy19801210 Macroscopic appearance Not clinically relevant

Histopathology The tumours are histopathologically identical to their sporadic cou nterparts.

Cytology Not clin ically re leva nt

Diagnostic molecular pathology

NF1 is caused by inactivating mutations in the NF1 gene, mapping to chromosome band 17q11.2, that encodes neurofibro­ min (NF1) {3220,519,3202}. Neurofibromin (NF1) is expressed widely during embryonic development but most abundantly in the CNS. Neurofibromin (NF1) is expressed in Schwann cells, melanocytes, neurons and oligodendrocytes, leukocytes, adre­ nal medulla, and many other cell types. Half of the subjects with NF1 have a de novo mutation in the NF1 gene.

A pathogenic NF1 mutation can be detected in as many as 95% of individuals with NF1 {2102}. In 5% of cases, an NF1 microdeletion has been identified {1608}. Individuals with an NF1 microdeletion co-deleti ng the SUZ12 gene have an in creased risk of developing MPNST {762}. SUZ12 codes for a component of PRC2, which has been implicated in MPNST develop­ ment {761,1815,3396}. Women with NF1 microdeletions are underrepresented in the group of women with NF1 and breast cancer {1069}. A few other genotype-phe notype correlati ons have been reported. Individuals with NF1 with a specific 3 bp deletion (c.2970_2972del) or a missense mutation affecting p.Arg1809 do not show neurofibromas or other NF1-associated tumours and the disorder cannot be differentiated clinically from Legius syndrome {1662,2649,2513,3134}. Individuals with NF1 missense mutations affecting codons 844-848 have a higher incidenee of externally visible plexiform neurofibromas, sympto­ matic spinal neurofibromas, optic pathway glioma, and MPNST compared with the general NF1 population {1663}. In cases of mosaicism for the NF1 mutation, it is frequently not possible to detect the responsible postzygotic NF1 mutation in peripheral white blood cells, and the NF1 mutation can be identified only in purified cells from affected tissues (1935).

Pathogenesis

Essential and desirable diagnostic criteria

Neurofibromin (NF1) acts as a tumour suppress or {1824,2583}. Different interaction partners of neurofibromin (NF1) have been described, but the most important functional domain is the RAS-GAP-related domain. Neurofibromin (NF1) is a negative regulator of the RAS/MAPK pathway and stimulates the intrinsic GTPase activity of RAS, resulting in the conversion of RAS-GTP into inactive RAS-GDP {2583}. SPRED1 (the protein implicated in Legius syndrome) binds to neurofibromin (NF1) on both sides of the GAP-related domain and recruits neurofibromin (NF1) to the membrane where it can downregulate RAS-GTP {2961, 1371,873}. A second hit in NF1 has been reported in associated tumours such as MPNSTs, neurofibromas, neuroblastomas, astrocyto­ mas, gastrointestinal stromal tumours, optic pathway glioma, phaeochromocytomas, glomus tumours, juvenile myelomonocytic leukaemia, and breast cancer {404,3356}. A second hit has also been reported in non-tumoural manifestations such as cafe-au-lait spots {764} and pseudarthrosis tissue {2946,2734}. The heterozygous NF1 background in non-tumoural cells such as mast cells plays a role in oncogenesis in mouse models of NF1 {3347}.

Diagnostic criteria for NF1 were established during a consensus conference of the US National Institutes of Health (NIH) {2257}. Patients must exhibit two or more of the following features: > 6 cafe-au-lait spots (> 5 mm in diameter in children, > 15 mm in adults), > 2 cutaneous or subcutaneous neurofibromas or 1 plexiform neurofibroma, axillary/inguinal freckling, optic path­ way glioma, > 2 Lisch nodules in the iris, bone dysplasia, a firstdegree relative with NF1 (by the above criteria). In the revised criteria (not yet published at the time this text was prepared) a pathogenic NF1 mutation will be part of the criteria.

Fig.4.12 Neurofibromatosis type 1. The function of neurofibromin (NF1) in the RAS/ MAPK pathway. ERK, extracellular signal-regulated kinase; MEK, MAPK kinase.

Epidemiology NF1 is an autosomal dominant disorder with a birth incidenee of 1 case per 2000-3500 people {3140,1263}.

Etiology

Staging Not clinically relevant

Prognosis and prediction Individuals with NF1 have an in creased stan dardized mortality ratio of 3.22 (2.81-3.68) mainly resulting from malignancy and cardiovascular problems {3140}.

Genetic tumour syndromes of soft tissue and bone

521

paybal：https://www.paypal.me/andy19801210 Wang LL Hicks MJ

Rothmund-Thomson syndrome

Definition

Localization

Rothmund-Thomson syndrome (RTS) is an autosomal reces­ sive genodermatosis and cancer predisposition disorder, with a diagnostic hallmark of poikiloderma. Germline pathogenic variants in the RECQL4 gene are present in about two thirds of patie nts.

Not applicable

MIM numbering 268400 Rothmund-Thomson syndrome

ICD-11 coding LD2B Syndromes with premature ageing appearanee as a major feature

Related termi no logy Acceptable: poikiloderma congenitale; poikiloderma atrophicans and cataract.

Subtype(s) Rothmund-Thoms on syn drome type 1 (no RECQL4 mutations present); Rothmund-Thoms on syn drome type 2 (RECQL4 mutations present)

Clinical features The dermatological hallmark of RTS is an erythematous rash that starts on the cheeks in infancy and then spreads to the extremities and buttocks, typically with truncal and abdominal spari ng. The rash enters a chronic I if el ong phase with reticu­ lated hypopigmentation and hyperpigmentation, telangiectasia, and atrophy (collectively, poikiloderma) {1750,3237,3235, 1749}. Additional findings include small stature; sparse scalp hair, eyebrows, and eyelashes; dental and nail abnormalities; skeletal defects including fused or missing bones, osteoporosis {475}, radial ray defects, and brachymesophalangy; gastrointestinal disturbance (feeding problems, emesis, diarrhoea) in early childhood; cataracts; and an in creased risk of maligna ncy, most commonly osteosarcoma {3234} and squamous or basal cell carci noma of the skin {1509}. I n the abse nee of death from cancer, patients appear to have a normal lifespan, although fur­ ther natural history studies are needed {3237}. Patients with RTS type 1 more commonly show juvenile cataracts.

Fig. 4.13 Rothmund-Thomson syndrome. A Poikiloderma. Extensor surface of lower leg demonstrating the chronic phase with skin atrophy, marbleized mixed hypopigmen,a_ tion, and hyperpigmentation with telangiectasia. B Radial ray defect manifest as missing thumb.

522

Genetic tumour syndromes of soft tissue and bone

paybal：https://www.paypal.me/andy19801210 C-terminus of the gene (see figure in {1750}). The gene defect for RTS type 1 (i.e. patients lacking RECQL4 mutations) is currently not known.

Rothmund・Thomson Syndrome ] Cataracts

；

Poikiloderma Sparse Brows/Lashes

|

Sparse Scalp Hair

Pathoge nesis

Osteosarcoma ■■ Joint Dislocation ；Patellar Hypoplasia/Aplasia -----------

Craniosynostosis

Mental Retardation

Baller-Gerold Syndrome

Normal Intelligence

Radial Ray Defect ■ Diarrhea, Vomiting, Short Stature ； Feeding Problems in Infancy

;

[RAPADILINO SYNDROME"] 0 MB.

MB OBHi MM MM ■» MB MM MB MM

■» tj

Fig.4.14 Rothmund-Thomson syndrome, Baller-Gerold syndrome, and RAPADILI­ NO syndrome (associated with RECQL4 pathogenic variants) and their overlapping

clinical features.

Epidemiology RTS is a rare disorder with approximately 300 cases reported worldwide affecting all ethnic and racial groups {1750,3237, 3235,3234).

Etiology Germline pathogenic variants in the RECQL4 gene (8q24.3) are present in about two thirds of patients, designated as having RTS type 2 {3234}, which is associated with in creased risk of osteosarcoma and other bone abnormalities {2053}. Patients with RTS type 1 lack RECQL4 pathogenic variants; this form is more commonly associated with juvenile cataracts. Most of these are non sense or frameshift mutati ons and occur within the helicase domain, and less frequently within the N-terminus and

a-

RECQL4 is a member of the highly conserved RECQ DNA helicase family that shares sequenee homology in the helicase domain. RECQ helicases are able to unwind duplex DNA to provide single-stranded templates for basic cellular processes such as replication, repair, recombination, and transcription {687}. Germline mutations in three of the five human RECQ genes - BLM, WRN, and RECQL4 — give rise to Bloom syn­ drome, Werner syndrome, and RTS, respectively, and these disorders share overlapping features of growth deficiency, premature ageing, and significant predisposition to malignancy {3235}. RECQL4 is a multifunctional protein that has been impli­ cated in several processes, including DNA replication, DNA damage repair, and maintenance of telomeres and of mitochondrial DNA integrity {592,2165}. Genetically engineered mouse models of RTS dem on strate that Recql4 plays an importa nt role in normal haematopoiesis {2888} and bone development {1898, 2268}. Pathogenic variants in RECQL4 have also been identified in patients with RAPADILINO syndrome {2860} and BallerGerold syndrome {3178}, both of which have clinical features overlapping those of RTS.

Macroscopic appearance Patients with RTS type 2 are at increased risk of developing oste­ osarcoma (32%; mean age: 11 years) {1364}, as well as basal cell and squamous carci no mas (5%; mean age: 34 years), at an

Fig.4.15 Rothmund-Thomson syndrome. A Histopathological features of poikiloderma characteristically seen in Rothmund-Thomson syndrome, with prominent superficial dermal vessels, minimal basal cell vacuolization, and intraepidermal dyskeratotic cells. B Osteoblastic osteosarcoma, the most common malignancy seen in Rothmund-Thom­ son syndrome, displays pleomorphic osteoblasts and eosinophilic malignant osteoid.

Genetic tumour syndromes of soft tissue and bone

523

paybal：https://www.paypal.me/andy19801210 earlier age than in the general population {2951,2516}. Reported sites of RTS osteosarcoma are distal femur (50%), proximal tibia (25%), proximal humerus (25%), distal fibula (7%), distal ulna (7%), distal radius (7%), and patella (7%).

Histopathology Skin biopsies dem on strate characteristic histological features of poikiloderma, which can in elude hyperkeratosis, epidermal atrophy, intraepidermal dyskeratotic cells, basal cell vacuolization, melani n in conti nence, and promine nt superficial dermal vessels.

diagnosis of probable RTS is suggested by an atypical rash plus two of the other features, including sparse scalp hair, eye­ lashes, or eyebrows; short stature; gastrointestinal disturbance­ radial ray defects; radiological bone abnormalities (radial ray and ulnar defects, absent or hypoplastic patella, osteopenia, abnormal trabeculation; dental abnormalities; nail abnormali­ ties; hyperkeratosis; cataracts; and cancer (basal cell or squa­ mous cell carcinoma, osteosarcoma) {3235}.

Staging Not clinically relevant

Cytology

Prognosis and prediction

Not clinically r eleva nt

Patients with RTS type 2 (i.e. with RECQL4 pathogenic variants) are at in creased risk of developi ng osteosarcoma and of having bone disease, and therefore must be counselled and followed closely. Some patients who develop osteosarcoma may have increased chemotherapy toxicity, and this should be anticipated and monitored closely during treatment. Patients should have regular eye and skin examinations to check for cataracts and skin cancer, respectively. Siblings of affected individuals have a 25% risk of being affected, 50% risk of being an asymptomatic carrier, and 25% risk of being unaffected and not a carrier.

Diagnostic molecular pathology A definitive diagnosis of RTS type 2 can be made by molecular testing for biallelic pathogenic variants in the RECQL4 gene. Lack of pathogenic variants does not rule out a diagnosis of RTS. Additional information on genetic testing can be found in the review by Wang an d Pion {3237} and on the Gen etic Testi ng Registry website of the US National Institutes of Health (NIH; https://www.ncbi.nlm.nih.gov/gtr/conditions/C0032339/).

Essential and desirable diagnostic criteria Clinical diagnostic criteria: All patients with RTS have some form of poikilodermatous rash, which typically presents in infancy with erythema of the cheeks and face {1750,3237}. A

524

Genetic tumour syndromes of soft tissue and bone

paybal：https://www.paypal.me/andy19801210 Werner syndrome

Definition Werner syn drome (WS) is an autosomal recessive gen etic in sta­ bility and cancer predisposition syndrome caused by mutations in the WRN gene and whose global phe no type mimics prema­ ture ageing.

Monnat RJ Jr

alleles occur in population genomic data at higher frequency than suggested by these estimates (2.12% among 9019 indi­ viduals), which supports the idea that WS is underdiagnosed by virtue of an absenee of early, developmental features and a variable, slowly developi ng clin ical phe no type {1081}.

MIM numbering

Etiology

277700 Wemer syndrome

WS is caused by loss-of-function mutations in the 35-exon, 165 kb WRN gene (8p12), leading to loss of expression of the ubiquitously expressed WRN protein and its encoded helicase and exonuclease activities.

ICD-11 coding LD2B Syndromes with premature agei ng appears nee as a major feature

Pathoge nesis Related termi no logy Acceptable: progeria of the adult.

Subtype(s) None

Local izatio n

The 163 kDa WRN protein plays important roles in DNA metab­ olism. Loss of WRN perturbs DNA replication, recombination and repair, telomere maintenance, and gene expression. The resulti ng gen etic in stability, together with altered gene expression, probably drives cell loss, dysfunction, and senescenee in many cell lineages and tissues, leading to the cellular and clini­ cal phenotype of WS {3043,2391}.

Not applicable

Macroscopic appearance

Clinical features Patients with WS develop a prematurely aged appearance beginning in the second decade of life, and they are at increased risk of developing cancer and other clinically impor­ tant, age-associated non-neoplastic diseases. The elevated cancer risk in WS is selective and includes both epithelial and non-epithelial neoplasms. The most common causes of death are cancer and atherosclerotic cardiovascular disease. The most consistent clinical findings in WS, first seen after the age of 10 years, in elude bilateral cataracts, skin cha nges resem­ bling scleroderma, short stature with absenee of the pubertal growth spurt, and premature greying and loss of scalp hair. There may be affected siblings, as well as parental consanguin­ ity (third cousin or closer). Less consistent findings, especially in younger patients, include diabetes mellitus; hypogonadism; osteoporosis; soft tissue calcification; premature atherosclerotic cardiovascular disease; a high-pitched, squeaky, or hoarse voice; and flat feet. A scoring system developed from clinical findings and family history can identify a definite, probable, or possible diagnosis of WS {2390}. Additional information on WS can be found in the review by Oshima et al. {2390} and on the University of Was hi ngton's Werner Syn drome website (http:// www.werners yn drome.org/).

Epidemiology Patients with WS have been identified worldwide. Estimates of frequency or prevale nee from case counting and consanguinity data range from 1 case per 22 000 population to 1 case per 1 million populati on, with frequencies strongly in flue need by fou nder mutations and consanguinity {2763}. Known pathogenic WRN

Multisystem non-neoplastic pathology is comm on in WS patients coming to autopsy‘involving most notably the skin and cardio­ vascular system. These findings have been recently published, together with a comprehensive review of findings in WS patients coming to autopsy {3083}.

Histopathology Patients with WS are at increased risk of developing spe­ cific neoplasms. These increased-risk neoplasms represent approximately two thirds of reports of neoplasia in WS and are, in order of decreasing frequency, thyroid epithelial neoplasms, melanomas, meningiomas, haematological malignancies and preleukaemic disorders, soft tissue sarcomas, and primary bone neoplasms (see Box 4.02, p. 526). The most frequent soft tissue sarcomas documented in WS include undifferentiated pleomorphic sarcoma, fibrosarcoma, myxofibrosarcoma, and leiomyosarcoma. There are several reports of malignant periph­ eral nerve sheath tumours, pleomorphic rhabdomyosarcoma, synovial sarcoma, and undifferentiated spindle cell sarcoma. Osteosarcoma is the domi nant primary maligna nt bone tumour in WS, and there have been rare reports of chondrosarcoma or osteochondroma. Osteosarcomas may display osteoblastic or fibroblastic differentiation and be extraskeletal in location. These neoplasms all occur at significantly elevated risks of 8.9fold to 54-fold in patients with WS versus population controls {1775}. Several features of neoplasia in WS are of diagnostic as well as pathoge netic in terest. The early age at diag no sis, atypical sites and histologies, and especially multiple neoplasms all emphasize WS as a heritable cancer predisposition. The feature

Genetic tumour syndromes of soft tissue and bone

525

paybal：https://www.paypal.me/andy19801210 Box4.02 The histopathological spectrum of neoplasia in Werner syndrome (WS): a summary of reports of 255 neoplasms in 196 patients with WS (73% Japan-resident added reports from patients in a diversity of additional locations), updated through March 2019 {1775} Elevated-risk neoplasms (67%, n = 170)a

Less comm on neoplasms (33%, n = 85)b

Thyroid (16%, n = 40) Carcinomas (34) Follicular carcinoma (14)

Genitourinary (7%, n = 18) Transitional cell carcinoma (7) Ureteral (2) Bladder (5) Ovarian cystadenocarcinoma (2) Ovarian carcinoma NOS (2) Uterine (6) Carcinoma (2) Leiomyosarcoma (1) Leiomyoma (3) Prostate carcinoma (1)

Pap川ary carcinoma (8) Anaplastic carcinoma (3) Carcinoma NOS (9) Adenoma ⑹

Melanoma (13%, n = 33) Acral lentiginous melanoma (30) Cutaneous (18) Mucosal (12) Other/NOS (3) Meningioma (11%, n = 28)

Haematological/lymphoid (10%, n = 25) Leukaemias (12) Acute myeloid leukaemia: M1-M5, M7 (12) Preleukaemic disorders (11) Myelofibrosis/myelodysplasia (6) Refractory anaemia / excess blasts (5) T-cell leukaemia (1) Plasmacytoma (1)

Soft tissue sarcomas (9%, n = 24) Undifferentiated pleomorphic sarcoma (8) Leiomyosarcoma (4) Fibrosarcoma (5) Malignant peripheral nerve sheath tumour (2) Myxofibrosarcoma (1) Pleomorphic rhabdomyosarcoma (1) Synovial sarcoma (1) Un differentiated spindle cell sarcoma (1) Leiomyoma (1) Bone primary (8%, n = 20) Osteosarcoma (17) Osteoblastic/fibroblastic (17) Extraskeletal osteosarcoma (1) Chondrosarcoma (1) Osteochondroma (1)

'th

Non-melanoma skin (5%, n= 14) Squamous cell carcinoma (7) Basal cell carcinoma (5) Vulvar cancer (1) Spindle cell squamous cell carcinoma (1)

Gastrointestinal (4%, n = 11) Oesophageal carcinoma (1) Gastric carcinoma (6) Pancreatic carcinoma (4) H即atobiliary (4%, n= 10) Cholangiocarcinoma (6) Hepatoma (4) Oropharyngeal (3%, n = 8) Hard/soft palate squamous cell carcinoma (1) Tongue squamous cell carcinoma (1) Laryngeal/pharyngeal carcinoma NOS (3) Nasal carcinoma NOS (3)

Breast carcinoma (3%, n = 7) Lung (2%, n = 6) Squamous cell carcinoma (1) Adenocarcinoma NOS (2) Bron chioloalveolar carcinoma (1) Pulmonary leiomyosarcoma (1) Carcinoid (1) CNS (2%,n = 6) Glioblastoma (1) Low-grade glioma / glioma NOS (3) Spinal cord neoplasms (2) Haemangiolipoma (1) Cord neurinoma (1)

Adrenal gland (2%, n = 5)

Cortical carcinoma (2) Cortical adenoma (2)

Phaeochromocytoma (1)

'Patients with WS are at significantly elevated risk of developing the neoplasms listed in the left column ("elevated-risk neoplasms'5), with risks ranging from 8.9-fold to 54-fold higher than in population controls {1775}; these represent 67% of all neoplasms reported in patients with WS; multiple neoplasia is common: 22% of patients with WS have > 2 distinct neoplasms that in aggregate represent 40% of all neoplasms reported in WS. bPatients may be at elevated risk of a subset of the less common neoplasms listed in the right column, although the numbers are too small to firmly establish this in patients versus population controls.

of multiple neoplasms is especially notable: approximately 22% of patients with WS (43 of 199) had 1-4 additional concurrent or sequential neoplasms, often at different sites and times {1775}. The risk of melenoma is confined almost exclusively to subtypes that arise on the palms and soles (acral lentiginous melanoma) or in mucosa lining the nasal cavity, oesophagus, or vulva. Thy­ roid epithelial neoplasms are most often follicular, followed by the papillary or anaplastic subtypes. Thyroid neoplasms and melanomas are significantly underrepresented in patients with

526

Genetic tumour syndromes of soft tissue and bone

WS outside Japan for unknown reasons. Leukaemias cover the full spectrum of acute myelogenous leukaemias, and there have been reports of atypical leukaemias and preleukaemic marrow disorders such as myelodysplasia, myelofibrosis, and refractory anaemia with an excess of blasts. Rare lymphoid neoplasms (T-cell leukaemia, plasmacytoma) have also been reported. The elevated risk of developing these marrow-associated malignant or premalignant diseases may reflect the progressive accu^ mulation of bone marrow genetic damage in patients with

paybal：https://www.paypal.me/andy19801210 {2201}. Many other neoplasms, including common adult epi­ thelial malignancies, have been reported in patients with WS (see Box 4.02). However, none is clearly at elevated risk versus population control data {1775}. The histopathological spectrum of neoplasia in WS overlaps with (although it is distinet from) the elevated type-specific risk of specific neoplasms in the RECQ helicase deficiency syn­ dromes Bloom syndrome and Rothmund-Thomson syndrome (see Rothmund-Thomson syndrome, p. 522) {2175}.

Cytology

as atypical WS, which is caused by mutations in the unrelated LMNA gene {2391}. Additional information on WS-associated WRN mutations and on genetic testing can be found in the review by Oshima et al. {2390} and on the Gen etic Testi ng Reg­ istry website of the US National Institutes of Health (NIH; https:// www.ncbi.nlm.nih.gov/gtr/conditions/C0043119/).

Essential and desirable diagnostic criteria Essential: familial progeria with on set in childhood (autosomal r ecessive). Desirable: WFIN loss-of-function mutation.

Not clinically r eleva nt 」

Not clin ically re leva nt

2deuo

A definitive diagnosis of WS can be established by molecular testing for biallelic loss-of-function mutations in the WRN gene {2390}. WRN mutations and/or WRN protein loss can be espe­ cially helpfu I in establishing a diag nosis in you ng in dividuals in whom the WS clin ical phe notype may be inco mpletely penetra nt, as well as in disti nguishi ng WS from phe no copies such

p

Staging Diagnostic molecular pathology

Prognosis and prediction Patients with WS - and presumably their neoplasms 一 are hypersensitive to many classes of DNA-damaging anticancer thera­ pies. Conventional doses of these agents may lead to severe treatment-related toxicity or death {2808,1327}.

?r 3t i,

e e w •y IS ie nt j0

Genetic tumour syndromes of soft tissue and bone

527

paybal：https://www.paypal.me/andy19801210 Contributors

AGAIMY, Abbas

BAUMHOER, Daniel

Erlangen University Hospital

University Hospital Basel

Institute of Cancer and Genomic Sciences

KrankenhausstraBe 8-10

Schoenbeinstrasse 40

University of Birmingham

91054 Erlangen

4031 Basel

6 Mindelsohn Way

AG AR AM, Narasimha n P.

BIEGEL, Jaclyn A.

Memorial Sloan Kettering Cancer Center

Children's Hospital Los Angeles

BOV^E, Judith V.M.G. *

1275 York Avenue

Department of Pathology

Department of Pathology

New York NY 10065

4650 Sunset Boulevard, MS 173

Leiden University Medical Center

Los Angeles CA 90027

Albinusdreef 2

BOND, Gareth L.

Birmingham B15 2SY

AL-IBRAHEEMI, Alyaa

2333 ZA Leiden

Boston Children's Hospital

BILLINGS, Steven D.

300 Longwood Avenue

Cleveland Clinic

BOYCE, Alison M』

Boston MA 02115

9500 Euclid Avenue, L25

National In stitute of Dental and Craniofacial

Cleveland OH 44195

ALAGGIO, Rita

Research 30 Convent Drive, Room 228, MSC 4320

Ospedale Pediatrico Bambino Gesu

BLACK, Jennifer O.

Piazza Sant'Onofrio 4

Children's Hospital Colorado

00165 Rome RM

University of Colorado

BREDELLA, Miriam A.

13123 East 16th Avenue

Massachusetts General Hospital and

ALM AN, Benjamin A.

Aurora CO 80045

Duke University

Bethesda MD 20892

Harvard Medical School 55 Fruit Street

311 Trent Drive

BLAY, Jean-Yves *

Durham NC 27710

Centre Leon Berard and

AMARY, Fernanda

28 Promenade Bullukian

University Hospital Leuven /

Royal National Orthopaedic Hospital

69372 Lyon

Catholic University Leuven

Greater London HA7 4LP

BLOEM, Johan L.

3000 Leuven

ANTONESCU, Cristina R・

Albinusdreef 2

BRENN, Thomas

Memorial Sloan Kettering Cancer Center

2300 RC Leiden

Cumming School of Medicine

New York NY 10065

BODE-LESNIEWSKA, Beata

9-3535 Research Road North-West

Institute of Pathology and Molecular

Calgary AB T2L 2K8

ARGAN I, Ped ram

Pathology

Universite de Lyon

Brockley Hill

Boston MA 02114

BREMS, Hilde

Herestraat 49

Leiden University Medical Center

1275 York Avenue

University of Calgary

Johns Hopkins Hospital

University Hospital Zurich

BRIDGE, Julia A. *

Weinberg 2242, 401 North Broadway

Schmelzbergstrasse 12

Translational Genomics Research Institute

Baltimore MD 21231-2410

8091 Zurich

(T Gen) / Ashion 445 North Fifth Street

BAHRAMI, Armita

BOHLING, Tom O.

St. Jude Children's Research Hospital

University of Helsinki

Phoenix AZ 85004

262 Danny Thomas Place, MS 250

Box 3 (Fabianinkatu 33)

CALONJE, Jaime E.

Memphis TN 38105

00014 Helsinki

St John's Institute of Dermatology

BALDINI, Elizabeth H・

BOLAND, Jennifer M.

Westminster Bridge Road

Dana-Farber Cancer Institute and

Mayo Clinic

London SE1 7EH

Brigham and Women's Hospital

200 First Street South-West

75 Francis Street

Rochester MN 55905

CARNEIRO, Fatima

BONAR, S. Fiona M.

Rua Julio Amaral de Carvalho, 45

BALLINGER, Mandy L.

Douglass Hanly Moir Pathology

4200-135 Porto

Garvan Institute of Medical Research

14 Giffnock Avenue

384 Victoria Street

Macquarie Park NSW 2113

St Thomas' Hospital

Boston MA 02115

Darlinghurst NSW 2010

lpatimup/i3S

CARTER, Jodi M. Mayo Clinic

200 First Street South-West Rochester MN 55905

Indicates disclosure of interests (see p. 535).

528

Contributors

paybal：https://www.paypal.me/andy19801210 CATES, Justin M.M.

CREE, lan A.

DEMICCO, Elizabeth G. *

Vanderbilt University Medical Center

International Agency for Research on

University of Toronto

1161 21st Avenue South, MCN-3322

Cancer

Mount Sinai Hospital, 600 University Avenue

Nashville TN 37232

150 Cours Albert Thomas

Toronto ON M5G 1X5

69372 Lyon

CHAN, John K.C.

DESHPANDE, Vikram

Queen Elizabeth Hospital

CREYTENS, David

Massachusetts General Hospital

30 Gascoigne Road

Ghent University Hospital, Ghent University

55 Fruit Street, Warren 2

Department of Pathology

Bost on MA 02478

Kowloon, Hong Kong SAR

Corneel Heymanslaan 10

CHEN, Gang

9000 Ghent

Fujian Medical University Cancer Hospital and

DEYRUP, Andrea T. Duke Health

Fujian Cancer Hospital

CZERNIAK, Bogdan

Department of Pathology

420 Fuma Road

University of Texas

40 Duke Medicine Circle

Fuzhou 350014

MD Anderson Cancer Center

Room 206AM, Green Zone Durham NC 27710

CHEUK, Wah

1515 Holcombe Boulevard Houston TX 77030

DICKSON, Bren dan C. *

Queen Elizabeth Hospital Wylie Road

CUNHA, Isabela Werneck

Mount Sinai Hospital

Kowloon, Hong Kong SAR

Rede D'Or Sao Luiz

600 University Avenue

Rua das Perobas 344

Toronto ON M5G 1X5

CHEUNG, Annie Nga-Yin

Sao Paulo SP 04321-120

DOYLE, Leona A.

University of Hong Kong Queen Mary Hospital

DAL CIN, Paola

Brigham and Women's Hospital and

Pok Fu Lam Road

Brigham and Women's Hospital

Harvard Medical School

Hong Kong SAR

75 Francis Street, Shapiro 5-58

75 Francis Street

Boston MA 02115

Boston MA 02115

Memorial Sloan Kettering Cancer Center

DAVIS, Jessica L.

DRY, Sarah M.

1275 York Avenue

Oregon Health & Science University

University of California, Los Angeles (UCLA)

New York NY 10065

3181 South-West Sam Jackson Park Road

13-222 CHS, 10833 Le Conte Avenue

Portland OR 97239

Los Angeles CA 90095

CHI, Ping

CLETON-JANSEN, Anne-Marie A LAVA, Enrique *

EMILE, Jean-Francois *

Department of Pathology

de

Leiden University Medical Center

Hospital Universitario Virgen del Rocio-IBiS

APHP and Versailles University

Box 9600

University of Seville

9 Avenue Charles de Gaulle

2300 RC Leiden

Manuel Siu rot s/n

92104 Boulogne

41013 Seville

CLEVEN, Arjen H.G.

ENDO, Makoto

PINIEUX, Gonzague

Leiden University Medical Center

de

Albinusdreef 2

Tours University Hospital

1-1 3-

2333 ZA Leiden

Avenue de la Republique a

Fukuoka 812-8582

Kyushu University Maidashi, Higashi-ku

Chambray-les-Tours

COLXINS, Michael T. *

37044 Tours Cedex 9

National Institute of Dental and Cranio facial

FANBURG-SMITH, Julie C. Penn State Health

Research, NIH

de

30 Convent Drive, Building 30, Room 228

Institut Jules Bordet

500 University Avenue

Bethesda MD 20892-4320

1 Rue Heger-Bordet

Hershey PA 17033

SAINT AUBAIN SOMERHAUSEN, Nicolas

Milton S. Hershey Medical Center

1000 Brussels

COOL, Paul

FERGUSON, Peter M.

Robert Jones & Agnes Hunt Orthopaedic

DEBIEC-RYCHTER, Maria

Hospital

Catholic University of Leuven

Missenden Road, Camperdown

Gobowen

Herestraat 49

Sydney NSW 2050

Oswestry SY10 7AG

3000 Leuven

CRAGO, Aimee M.

DEI TOS, Angelo Paolo

Massachusetts General Hospital

Memorial Sloan Kettering Cancer Center

University of Padua School of Medicine

55 Fruit Street

1275 York Avenue, H1220 New York NY 10065

Piazza Ospedale 1

Boston MA 02114

31100 Treviso TV

Royal Prince Alfred Hospital

FERRY, Judith A.

FLANAGAN, Adrienne M. Royal National Orthopaedic Hospital

Brockley Hill Stanmore, Middlesex HA7 4LP

Indicates disclosure of interests (see p. 535).

Contributors

529

paybal：https://www.paypal.me/andy19801210 FLETCHER, Christopher D.M.

GRONCHI, Alessandro

HOWITT, Brooke E.

Brigham and Women's Hospital

Fondazione IRCCS Istituto Nazionale dei

Stanford University School of Medicine

75 Francis Street

Tumori

Department of Pathology, L235

Boston MA 02115

Via Venezian 1

300 Pasteur Drive

20133 Milan Ml

Stanford CA 94305

Radboudumc

HAMEED, Meera

HUANG, Hsuan-Ying *

Geert Groteplein 10

Memorial Sloan Ke廿e「ing Cancer Center 1275 York Avenue

Chang Gung University College of Medicine

FLUCKE, Uta

6500 HB Nijmegen

New York NY 10065

FOLPE, Andrew L. Mayo Clinic

Kaohsiung Chang Gung Memorial Hospital 123 Ta-Pei Road, Niao-Sung District

Kaohsiung City 83301

HAN, Anjia

200 First Street South-West

First Affiliated Hospital

HUANG, Shih-Chiang

Rochester MN 55905

Sun Yat-sen University

Chang Gung Memorial Hospital

58 Zhongshan II Road

No. 5, Fuxing Street, Guishan District

Guangzhou 510080

Taoyuan City 33305

Laarbeeklaan 101

HAROCHE, Julien

INWARDS, Carrie Y・

1090 Brussels

Hopital Pitie Salpetriere

Mayo Clinic

47-83 Boulevard de I'Hopital

200 First Street South-West

75013 Paris

Rochester MN 55905

200 First Street South-West

HEYMANN, Dominique *

IWASA, Yoko

Rochester MN 55905

Univeristy of Nantes

Kyoto City Hospital

FORSYTH, Ramses George Universitair Ziekenhuis Brussel

FRITCHIE, Karen J. Mayo Clinic

Inserm, Institut de Cancerologie de rOuest

1-2 Mibu Higashi-takadacho

FROHLING, Stefan *

Boulevard Jacques Monod

Kyoto 604-8845

National Center for Tumor Diseases and

44805 Saint-Herblain

JAMBHEKAR, NirmalaA.

German Cancer Research Center

Im Neuenheimer Feld 460

HICKS, M. John

69120 Heidelberg

Texas Children's Hospital

Vishnunagar, Naupada

Baylor College of Medicine

Thane West 400 602

4, Aamrai, Arvind

FUKUSHIMA, Mana

6621 Fannin Street, AB1195

Ehime University Hospital

Houston TX 77030

JO, Vickie Y・

HISAOKA, Masanori

Harvard Medical School

Shitsukawa, Toon-shi

Ehime 791-0295

Brigham and Women's Hospital and University of Occupational and Environmental

75 Francis Street

GAMBAROTTI, Marco

Health, Japan

Boston MA 02115

Department of Pathology

1-1 Iseigaoka, Yahatanishi-ku

IRCCS, Istituto Ortopedico Rizzoli

Kitakyushu 807-8555

Via di Barbiano 1/10

40136 Bologna BO

KALIL, Ricardo K. A.C.Camargo Cancer Center

HOGENDOORN, Pancras C.W.

Avenida Barao do Triunfo 1550

Leiden University Medical Center

Bage RS 96400-121

GIANNINI, Caterina

Box 9600

Mayo Clinic

2300 RC Leiden

KILPATRICK, Scott E.

University of Bologna)

HOLLMANN, Travis J.

9500 Euclid Avenue, L25

200 First Street South-West

Memorial Sloan Kettering Cancer Center

Cleveland OH 44195

Rochester MN 55905

1275 York Avenue

(and Alma Mater Studiorum -

Cleveland Clinic

New York NY 10065

KLEIN, Michael J.

Royal North Shore Hospital

HORNICK, Jas on L. *

535 East 70th Street

Pacific Highway

Brigham and Women's Hospital

New York NY 10021

St Leonards NSW 2065

Harvard Medical School

GILL, Anthony J.

Hospital for Special Surgery

75 Francis Street

KOHASHI, Kenichi

Boston MA 02115

Graduate School of Medical Sciences

9500 Euclid Avenue L25

HORVAI, Andrew E.

3-1-1 Maidashi, Higashi-ku

Cleveland OH 44195

Un iversity of California, San Fran cisco

Fukuoka 812-8582

GRAYSON, Wayne

1825 Fourth Street, M2354 San Francisco CA 94158

KONISHI, Eiichi

GOLDBLUM, John R. Cleveland Clinic

Kyushu University

University of the Witwatersrand

Kyoto Prefectural University of Medicine

7 York Road, Parktown

Kawaramachi Hirokoji, 465 Kajii-cho,

Johannesburg 2193

Kamigyo-ku

Kyoto 602-8566 Indicates disclosure of interests (see p. 535).

530

Contributors

paybal：https://www.paypal.me/andy19801210 LADANYI, Marc

LOKUHETTY, Dilani

MERTENS, Fredrik

Memorial Sloan Kettering Cancer Center

In ternational Agency for Research on

Department of Clinical Genetics

1275 York Avenue

Cancer

Lund University

New York NY 10065

150 Cours Albert Thomas

Akutgatan 8

69372 Lyon

22185 Lund

University of Queensland and

LORSBACH, Robert B.

MESSIOU, Christina

pathology Queensland

Cincinnati Children's Hospital Medical

Royal Marsden Hospital

Royal Brisbane and Women's Hospital

Center

Fulham Road

Herston QLD 4029

University of Cincinnati College of Medicine

London SW3 6JJ

LAROUSSERIE, Fr6d6rique

3333 Burnet Avenue, ML 1035 Cincinnati OH 45229

MIETTINEN, Markku

LUCAS, David R・

9000 Rockville Pike

University of Michigan

Building 10, Room 2S235C

NCRC Building 35, 2800 Plymouth Road

Bethesda MD 20892-0001

LAKH AN I, Sunil R. *

Hopital Cochin 27 Rue du Faubourg Saint-Jacques 75679 Paris

LASKIN, William Bradlyn

National Cancer Institute / NIH

Ann Arbor Ml 48109-2800

MOCH, Holger

Yale School of Medicine 310 Cedar Street

MAGRO, Gaetano

New Haven CT 06520-8023

University of Catania

University Hospital Zurich

Via Santa Sofia 87

Schmelzbergstrasse 12

95123 Catania CT

8091 Zurich

MONNAT, Raymond J. Jr

LAX, Sigurd F.

University of Zurich and

General Hospital Graz II Medical University of Graz

MAHAR, Annabelle M.

Goestingerstrasse 22

Royal Prince Alfred Hospital

University of Washington

8020 Graz

Missenden Road

Seattle WA 98195

Sydney NSW 2050

LAZAR, Alexander J・

MONTGOMERY, Elizabeth A.

University of Texas

MALKIN, David

Johns Hopkins Medical Institutions

MD Anderson Cancer Center

Hospital for Sick Children

Weinberg 2242, 401 North Broadway

1515 Holcombe Boulevard, Unit 85

University of Toronto

Baltimore MD 21231

Houston TX 77030

555 University Avenue Toronto ON M5G 1X8

LE LOARER, Francois

NASCIMENTO, Alessandra F. University of Florida

Universite de Bordeaux and

MARINO-ENRIQUEZ, Adrian

1600 South-West Archer Road

Instiiut Bergoni©

Brigham and Women's Hospital and

PO Box 100275

276 Cours de「Argonne

Harvard Medical School

Gainesville FL 32610

33000 Bordeaux

75 Francis Street

02115 Boston MA

NIELSEN, G. Petur

NTU Hospital, NTU College of Medicine

MATSUYAMA, Atsuji

55 Fruit Street

7 Chung-Shan South Road Taipei 10002

University of Occupational and Environmental

Boston MA 02114-2696

LEGIUS, Eric

Kitakyushu 807-8555

LEE, Jen-Chieh

Massachusetts General Hospital

Health

1-1 Iseigaoka, Yahatanishi-ku

University of Leuven

NIELSEN, Torsten O. University of British Columbia Anatomical Pathology JPN 1401

Herestraat 49

McCarthy, Edward F.

3000 Leuven

Johns Hopkins Hospital

855 West 12th Avenue

401 North Broadway

Vancouver BC V5Z 1M9

LESSNICK, Stephen L. *

Vancouver Hospital

Baltimore MD 21231

Nationwide Children's Hospital

NISHIO, Jun

Abigail Wexner Research Institute

McMENAMIN, Mairin E.

Fukuoka University

Center for Childhood Cancer and Blood

St. James's Hospital

7-45-1 Nanakuma, Jonan-ku

Diseases

James's Street

Fukuoka 814-0180

700 Children's Drive

Dublin D08NHY1

Columbus OH 43205

NORD, Karol in H.

MENTZEL, Thomas D.W.

Lund University

LIEGL-ATZWANGER, Bernadette

Dermatopathologie Bodensee

Division of Clinical Genetics, BMC C13

Diagnostic and Research Institute of

Siemensstrasse 6/1

22184 Lund

Pathology

88048 Friedrichshafen

Medical University Graz

NORTH, Paula E.

Neue Stiftingtalstrasse 6

Medical College of Wisconsin

8010 Graz

8700 Watertown Plank Road Milwaukee Wl 53226

Indicates disclosure of interests (see p. 535).

Contributors

531

paybal：https://www.paypal.me/andy19801210 NUCCI, Marisa R.

PFISTER, Stefan M. *

RODRIGUEZ, Fausto

Brigham and Women's Hospital

Hopp Children's Cancer Center Heidelberg

Johns Hopkins University

75 Francis Street

(KiTZ),

Sheikh Zayed Tower, Room M2101

Boston MA 02115

German Cancer Research Center (DKFZ), and

1800 Orleans Street

Heidelberg University Hospital

Baltimore MD 21231

OCHIAI, Atsushi

Im Neuenheimer Feld 280

National Cancer Center

69120 Heidelberg

ROGOZHIN, Dmitrii V.

PICARSIC, Jennifer

Pirogov, Russian National Research

6-5-1 Kashiwanoha Kashiwa 277-8577

Russian Children's Clinical Hospital of University of Pittsburgh School of Medicine

Medical University

ODA, Yoshinao

UPMC Children's Hospital of Pittsburgh

Leninskiy Prospekt, 117

Department of Anatomic Pathology

S-417 Biomedical Science Tower

Moscow 119571

Graduate School of Medical Sciences

200 Lothrop Street

Kyushu University

Pittsburgh PA 15261

3-1-1 Maidashi, Higashi-ku Fukuoka 812七582

ROSENBERG, Andrew E. Miller School of Medicine

PILERI, Stefano A.

University of Miami

European Institute of Oncology

1400 North-West 12th Avenue

O'DONNELL, PaulG.

Via Ripamonti, 435

Miami FL 33136

Royal National Orthopaedic Hospital

20141 Milan Ml

ROUS, Brian

Brockley Hill

PILLAY, Nischalan

Public Health England

University College London Cancer Institute

Victoria House, Capital Park

OLIVA, Esther

72 Huntley Street

Fulbourn, Cambridge CB21 XB

Massachusetts General Hospital

London WC1E6BT

Stanmore HA7 4LP

RUBIN, Brian P.

55 Fruit Street Boston MA 02114

POLLOCK, Raphael E.

Robert J. Tomsich Pathology &

Ohio State University

Laboratory Medicine Institute

OLIVEIRA, AndrG M.

460 West 10th Avenue

Cleveland Clinic, L25

Mayo Clinic

Columbus OH 43210

9500 Euclid Avenue

200 First Street South-West Rochester MN 55905

Cleveland OH 44195

PULS, Florian Sahlgrenska University Hospital

RUDZINSKI, Erin R. *

PANAGOPOULOS, loannis

Gula Straket 8

Seattle Children's Hospital

Section for Cancer Cytogenetics

41346 Gothenburg

4800 Sandpoint Way North-East

Institute for Cancer Genetics and Informatics

Seattle WA 98105

Norwegian Radium Hospital

REIS-FILHO, Jorge Sergio *

Oslo University Hospital

Memorial Sloan Ke廿ering Cancer Center

0424 Oslo

1275 York Avenue

Rizzoli Orthopedic Institute

New York NY 10065

Via Pupilli 1

PARHAM, David M.

SANGIORGI, Luca

40136 Bologna BO

Children's Hospital Los Angeles and

REITH, John D.

USC Keck School of Medicine

Cleveland Clinic

SBARAGLIA, Marta

4650 Sunset Boulevard, #43

9500 Euclid Avenue

Azienda ULSS2 Marca Trevigiana

Los Angeles CA 90027

Cleveland OH 44195

Piazza Ospedale 1

31100 Treviso TV

PATEL, Rajiv M.

REKHI, Bharat

Michigan Medicine, University of Michigan

Tata Memorial Centre, HBNI University

SCHAFERNAK, Kristian T.

2800 Plymouth Road, NCRC Building 35

Dr E「nest Borges Road, Parel Mumbai, Maharashtra 400012

Phoenix Children's Hospital

Ann Arbor Ml 48109-2800

1919 East Thomas Road

Phoenix AZ 85016

PEDEUTOUR, Florence *

REUSS, David Emanuel *

University of Nice-Cote d'Azur /

Heidelberg University and

SCIOT, Raf

Nice University Hospital

German Cancer Research Center

Department of Pathology

28 Avenue Valombrose

Im Neuenheimer Feld 224

University Hospital KULeuven

06107 Nice

69120 Heidelberg

Herestraat 49 3000 Leuven

PERRY, Arie

RIGHI, Alberto

University of California, San Francisco

IRCCS, Istituto Ortopedico Rizzoli

SCOLYER, Richard A.

505 Pqitiassus Avenue, M551

Via di Barbiano 1/10

San Francisco CA 94143-0102

40136 Bologna BO

Royal Prince Alfred Hospital, Melanoma Institute Australia, and

University of Sydney Missenden Road Camperdown

Sydney NSW 2050

Indicates disclosure of interests (see p. 535).

532

Contributors

paybal：https://www.paypal.me/andy19801210 l

SHI BATA, Tatsuhiro

SUURMEIJER, Albert J.H.

UD DIN, Nasir

Institute of Medical Scienee,

University Medical Center Groningen

Aga Khan University Hospital

University of Tokyo, and

Hanzeplein 1

Box 3500, Stadium Road

National Cancer Center Research Institute

9700 RB Groningen

Karachi 75300

SZUHAI, Karoly

UMETSU, Sarah E.

6-1 4-

Shirokanedai, Minato-ku

Tokyo 108-8639

I

Leiden University Medical Center

University of California, San Francisco

SIEGAL, Gene P.

Einthovenweg 20

505 Parnassus Avenue, Room M561, Box 0102

University of Alabama at Birmingham

2300 RC Leiden

San Francisco CA 94143

HSB 149K 619 19th Street South

TAN, Puay Hoon

van de

Birmingham AL 35249

Division of Pathology

Stanford University Medical Center

RIJN, Matt

Singapore General Hospital

1291 Welch Road

SINGER, Samuel

20 College Road, Academia, Level 7

Stanford CA 94305-5324

Memorial Sloan Kettering Cancer Center 1275 York Avenue

Singapore 169856

WANG, Jian

TAVORA, Fabio

270 Dong An Road

SINGH, Rajendra

Messejana Heart and Lung Hospital /

Shanghai 200032

Mount Sinai School of Medicine

Argos Laboratory

Diagnostics Tower

New York NY 10065

Fudan University Shanghai Cmncer Center

1 Gustave L. Levy Place

Avenida Santos Dumont 5753, #1607

WANG, Lisa L.

New York NY 10029

Fortaleza CE 60175-047

Baylor College of Medicine

SOARES, Fernando Augusto

THOMAS, David M. *

Houston TX 77030

1102 Bates Avenue, Suite 1200

Rede D'Or Hospitals

Garvan Institute of Medical Research

Rua das Perobas 266

370 Victoria Street

WANG, Wei-Lien

Sao Paulo SP 04321-120

Darlinghurst NSW 2010

University of Texas

SPECHT, Katja

THOMPSON, Lester D.R.

1515 Holcombe Boulevard, Unit 085,

Technical University of Munich

Woodland Hills Medical Center

Room B3.4611 Houston TX 77030

MD Anderson Cancer Center

Ismaninger Strasse 22

5601 De Soto Avenue

81675 Munich

Woodland Hills CA 91365

SRIGLEY, John R.

THWAY, Khin

Trillium Health Partners

Royal Marsden Hospital /

1176 Studley Avenue

Credit Valley Hospital Site

Institute of Cancer Research

Halifax NS B3H 3R7

2200 Eglinton Avenue West Mississauga ON L5M 2N1

203 Fulham Road

STAMENKOVIC, Ivan

TIRABOSCO, Roberto

Munster University Hospital

Lausanne University Hospital

Royal National Orthopaedic Hospital

Albert-Schweitzer-Campus 1

WANLESS, lan R.

London SW3 6JJ

Dalhousie University

WARDELMANN, Eva * Gerhard-Domagk-lnstitute of Pathology

I

25 Rue du Bugnon

Brockley Hill

Postal address: DomagkstraBe 17

1011 Lausanne

Stanmore, London HA7 4LP

49149 Munster

STEMMER-RACHAMIMOV, Anat Olga *

TIRODE, Franck

WASHINGTON, Mary K.

Massachusetts General Hospital

Centre LOon Berard

Vanderbilt University Medical Center

55 Fruit Street

28 Rue Laennec

C-3321 MCN

Boston MA 02114

69008 Lyon

Nashville TN 37232

STRATAKIS, Constantine A.

TSAO, Ming S.

WATANABE, Reiko

NICHD, National Institutes of Health

University Health Network

National Cancer Center Hospital East

200 Elizabeth Street, 11th Floor

6-5-1 Kashiwa no ha, Kashiwa-shi

I

31 Center Drive, Room 2A46

I

Bethesda MD 20892

Toronto ON M5G 2C4

Chiba 277-8577

SUMATHI, Vaiyapuri P.

TSUZUKI, Toyonori

WHITE, Valerie A.

I I

University Hospitals Birmingham and Royal Orthopaedic Hospital

Aichi Medical University Hospital

International Agency for Research on Cancer

1-1 Yazakokarimata

150 Cours Albert Thomas

I

Robert Aitken Institute of Clinical Research

Nagakute 480-1195

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Contributors

533

paybal：https://www.paypal.me/andy19801210 WUYTS, Wim

YAMAMOTO, Hidetaka

University of Antwerp and

Kyushu University

Fudan University Shanghai Cancer Center

Antwerp University Hospital

3-1-1 Maidashi, Higashi-ku

270 Dong An Road

Prins Boudewijnlaan 43

Fukuoka 812-8582

Shanghai 200032

YU, Lin

2650 Edegem

YAMASHITA, Kyoko

ZAMBRANO, Eduardo

YAMADA, Yuichi

Cancer Institute Hospital of

Stanford University Medical Center

Kyushu University

Japanese Foundation for Cancer Research

300 Pasteur Drive

3-1-1 Maidashi, Higashi-ku

3-8-31 Ariake, Koto-ku

Palo Alto CA 94305

Fukuoka 812-8582

Tokyo 135-8550

YAMAGUCHI, Takehiko

YOSHIDA, Akihiko

Saitama Medical Center

National Cancer Center Hospital

Dokkyo Medical University

1-1 5-

2-1-5 Minami-Koshigaya

Tokyo 104-0045

Koshigaya 343-8555

Indicates disclosure of interests (see p. 535).

534

Contributors

Tsukiji, Chuo-ku

paybal：https://www.paypal.me/andy19801210 Declaration of interests

Dr Blay reports receiving personal

Dr Frohling reports receiving personal

consultancy fees from, and that his unit

consultancy fees from Bayer, PharmaMar,

Cancer Research Center (DKFZ) benefits

at Centre Leon Berard ben efits from

Roche, Eli Lilly, and Amgen, as well as

from research fun ding from Pfizer, Lilly, Roche, Bayer, PharmaMar, and Charles River

Dr Pfister reports that his unit at the German

research funding from, Roche Novartis,

support for travel from PharmaMar, Roche,

GlaxoSmithKline, Lilly Bayer, MSD,

Eli Lilly, and Amgen, and that his unit at the

Laboratories, as well as holding a patent

PharmaMar, AstraZeneca, Bristol-Myers

National Center for Tumor Diseases and the

on a uDNA-methylation based method for

Squibb, AROG Pharmaceuticals, and

German Cancer Research Center benefits

classifying tumor species".

Deciphera Pharmaceuticals.

from research fundi ng from AstraZeneca and PharmaMar.

Dr Bov6e reports that her unit at Leiden

Dr Reis-Filho reports receiving personal consultancy fees from the Goldman Sachs

University Medical Center benefits from

Dr Heymann reports being a scientific board

Merchant Banking Division, as well as from

research funding from Servier.

member and cofounder of Atlantic Bone

VolitionRx, Paige.Al, Invicro, Genentech,

Scree n.

Dr Boyce reports benefiting from research fundi ng from Amge n.

Roche, and Ventana in his capacity as a scientific advisory board member.

Dr Hornick reports receiving personal consultancy fees from Eli Lilly Epizyme.

Dr Reuss reports that his institute, Heidelberg

consultancy fees from the Translational

Dr H.Y. Huang reports having received

Center, has licensed a patent to Cell Marque

Genomics Research Institute.

honoraria from Eli Lilly and Company.

Corporation.

Dr Collins reports that his unit at the National Institute of Dental and Craniofacial Research,

Dr Lakhani reports receiving personal consultancy fees from Sullivan Nicolaides

consultancy fees from Bayer.

NIH, benefited from research funding from

Pathology.

Dr Bridge reports receiving personal

University and the German Cancer Research

Dr Rudzinski reports receiving personal

Dr Stemmer-Rachamimov reports receiving

Amgen.

Dr Lessnick reports holding investment

personal consultancy fees from the

Dr de Alava reports receiving personal

interests in several private companies and

Neurofibromatosis Therapeutic Acceleration

consultancy fees from PharmaMar, Lilly,

in Salarius Pharmaceuticals in his capacity

Program (NTAP).

Pfizer, Roche, and Bristol-Myers Squibb, and

as a scientific advisory board member, and

that his unit at Hospital Universitario Virgen

that his unit at the University of Utah holds

Dr Thomas reports having received support

del Rocio-IBiS benefited from research

patents on “methods and compositions

for travel and accommodation from Illumina.

funding from PharmaMar.

for the diagnosis and treatment of Ewing's

Dr Demicco reports having received personal

sarcoma" and "diagnosis and treatment of

Dr Wardelmann reports receiving support

drug-resistant Ewing's sarcoma".

for travel from Milestone/Menarini, Bayer,

consultancy fees from Bayer and SARC.

Dr Dickson reports receiving non-monetary support from Illumina.

and Novartis, and honoraria from Nanobiotix,

Dr Pedeutour reports that her unit at the

as well as having received support for travel

Institute for Research on Cancer and Aging,

from PharmaMar and honoraria from Lilly

Nice, benefits from r esearch fun ding from the

Pharmaceuticals.

Alan B. Slifka Foundation and GEMLUC.

Dr Emile reports receiving personal consultancy fees from several pharmaceutical

companies to participate in scientific board meeti ngs.

Declaration of interests

535

paybal：https://www.paypal.me/andy19801210 IARC/WHO Committee for the International Classification of Diseases for Oncology (ICD-O) CREE, Ian A.

ROUS, Brian

ZNAOR, Ariana

Inte「national Agency for Research on Cancer

Public Health England

Inter national Agency for Research on Cancer

150 Cours Albert Thomas

Victoria House, Capital Park

150 Cours Albert Thomas

69372 Lyon

Fulbourn, Cambridge CB21 XB

69372 Lyon

FERLAY, Jacques

WATANABE, Reiko

International Agency for Research on Cancer

National Cancer Center Hospital East

150 Cours Albert Thomas

5-1 6-

69372 Lyon

Chiba 277-8577

JAKOB, Robert

WHITE, Valerie A.

Data Standards and Informatics

International Agency for Research on Cancer

Kashiwanoha, Kashiwa-shi

World Health Organization (WHO)

150 Cours Albert Thomas

20 Avenue Appia

69372 Lyon

1211 Geneva

536

ICD-0 Committee

paybal：https://www.paypal.me/andy19801210 Sources

Note: For all figures, tables, and boxes not listed below, the original source is this volume; the suggested source citation is WHO Classification of Tumours Editorial Board. Soft tissue and bone tumours. Lyon (France): Intemational Agency for Research on Cancer; 2020. (WHO classification of tumours series, 5th ed.; vol. 3). http://publications.iarc.fr/588.

TNM staging tables Brierley JD, Gospodarowicz MK, Wittekind C, editors. TNM classification of malignant tumours. 8th ed. Oxford (UK): Wiley Blackwell; 2017.

This edition first published 2017 © 2017 UICC Published 2017 by John Wiley & Sons, Ltd. Ali rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.

The right of the authors to be identified as the authors of this work has been asserted in accordance with law.

Figures 1.01 1.02 1.03A.B 1.04 1.05

1.06A.B 1.07A-D 1.08A.B 1.09A-D 1.10 1.11 1.12 1.13 1.14A.B 1.15A.B 1.16A-D 1.17A-D 1.18A-C 1.19 1.20 1.21

1.22

1.23A 1.23B 1.24A-C 1.25 1.26 1.27A.C.D 1.27B 1.28 1.29 1.30A-D 1.31A.B

Elizabeth Heidi Cheek, Mayo Clinic, Rochester MN Fritchie KJ Fritchie KJ Fritchie KJ Luca Busetto, Department of Medicine (DIMED), University of Padova, Padua Rosenberg AE Giannini C Giannini C Black JO Pedeutour F Pedeutour F Sciot R Sciot R Fukushima M Fukushima M Folpe AL Bridge JA Billings SD Billings SD Billings SD Reprinted, with permission, from: AIRP Database- case ID 23700 and 10344; copyright ACR Press Reprinted, with permission, from: AIRP Database- case ID 23700 and 10344; copyright ACR Press Fanburg-Smith JC Folpe AL Folpe AL Nord KH Nord KH Creytens D Marino-En「iquez A Creytens D Dei Tos AP Dei Tos AP Dei Tos AP

1.32 1.33 1.34 1.35 1.36A-C 1.37 1.38A-C 1.39 1.40 1.41 1.42

1.43A.B 1.44A.B 1.45A.B 1.46 1.47A.B 1.48A-D 1.49 1.50A.B 1.51A 1.51B 1.52A 1.52B 1.53A.B 1.53C 1.54A 1.54B 1.55A 1.55B 1.56A,B 1.57 1.58A-D 1.59A-D 1.60A.B 1.61A-C 1.62A-D

Pedeutour F Pedeutour F Pedeutour F Gronchi A Dei Tos AP Dei Tos AP Dei Tos AP Dei Tos AP Dei Tos AP Pedeutour F Cyril Fisher, Department of Musculoskeletal Pathology, Royal Orthopaedic Hospital NHS Foundation Trust, Robert Aitken Institute for Clinical Research, University of Birmingham, Birmingham Folpe AL Folpe AL Folpe AL Folpe AL Bridge JA Montgomery EA Pedeutour 匚 Creytens D Creytens D Folpe AL Oliveira AM Wang J Wang J Hornick JL Fletcher CDM Lazar AJ Wang WL Lazar AJ Rosenberg AE Rosenberg AE Rosenberg AE Liegl-Atzwanger B Hisaoka M Hisaoka M Al-lbraheemi A

1.63 1.64A.B 1.65A-D 1.66

1.67 1.68A.C.D 1.68B

Al-lbraheemi A Davis JL Davis JL Reprinted, with permission, from: Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. and Laskin WB, Miettinen M, Fetsch JF. Infantile digital fibroma/fibromatosis: a clinicopathologic and immunohistochemical study of 69 tumors from 57 patients with long-term follow-up. Am J Surg Pathol. 2009 Jan;33(1):1-13. PMID:18830128 Lazar AJ Laskin WB Reprinted, with permission, from: Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. and Laskin WB, Miettinen M, Fetsch JF. Infantile digital fibroma/fibromatosis: a

Sources

537

paybal：https://www.paypal.me/andy19801210

1.69A

1.69B 1.70A.B 1.70C.D 1.71A.B 1.72 1.73A 1.73B 1.73C.D 1.74A-C 1.75A-C 1.76A.B 1.77A-D 1.78A.B 1.79 1.80 1.81A.B 1.82A-C 1.83 1.84A-C 1.85A.B 1.86A-C 1.86D 1.87A.B 1.88A-D 1.89 1.90A.B

1.91A 1.91B 1.92A 1.92B-D 1.93

1.94A 1.94B 1.95A.B 1.96A.B 1.97A.B 1.98A.B 1.99A.B 1.100

538

clinicopathologic and immunohistochemical study of 69 tumors from 57 patients with long-term follow-up. Am J Surg Pathol. 2009 Jan;33(1):1-13. '

1.101A 1.101B

PMID:18830128 © Luc De Smet Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publicatio ns. iarc.fr/15. Lazar AJ Sciot R Hornick JL Lazar AJ Lazar AJ Howitt BE Fletcher CDM Magro G Howitt BE Fletcher CDM Sumathi VP PulsF Suurmeijer AJH Suurmeijer AJH Antonescu CR Fletcher CDM Fletcher CDM Fletcher CDM Fletcher CDM Fletcher CDM Wang J Mertens F Doyle LA Brenn T Brenn T © Cheryl M. Coffin Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (Franee): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. Fletcher CDM Thway K Fletcher CDM Nascimento AF Cyril Fisher, Department of Musculoskeletal Pathology, Royal Orthopaedic Hospital NHS Foundation Trust, Robert Aitken Institute for Clinical Research, University of Birmingham, Birmingham Messiou C Elizabeth Heidi Cheek, Mayo Clinic, Rochester MN Fritchie KJ Fritchie KJ Fritchie KJ Al-lbraheemi A Mentzel TDW Mentzel TDW

1.102 1.103A-D 1.104 1.105A

Sources

1.105B.C 1.106A.B 1.107A

1.107B 1.108

1.109A-E 1.110 1.111 1.112A-D 1.113 1.114 1.115 1.116A-D 1.117A.B 1.118 1.119 1.120A.B 1.121A.B 1.122A.B 1.123A-D 1.124A.B 1.125A 1.125B 1.126 1.127A 1.127B.C 1.128 1.129 1.130A-D 1.131 1.132A.B 1.133A-D 1.134A 1.134B 1.135A.B 1.136 1.137A-C 1.138 1.139A-D 1.140A.B 1.141 1.142

Mentzel TDW Iliana Tantcheva-Poor, Department of Dermatology, University of Cologne, Cologne Lazar AJ Mentzel TDW Lazar AJ Peter H. Hoeger, Departments of Paediatrics & Paediatric Dermatology, Catholic Children's Hospital Wilhelmstift, Hamburg Mentzel TDW Lazar AJ Adapted, with permission from Elsevier, from: Messiou C, Moskovic E, Vanel D, et al. Primary retroperitoneal soft tissue sarcoma: imaging appearances, pi廿alls and diagnostic algorithm. Eur J Surg Oncol. 2017 Jul;43(7):1191-8. PMID:28057392. Copyright 2017. Messiou C Elizabeth Heidi Cheek, Mayo Clinic, Rochester MN Demicco EG Demicco EG Demicco EG Demicco EG Demicco EG Antonescu CR Yamamoto H Yamamoto H Yamamoto H Yamamoto H Yamamoto H Bridge JA Mentzel TDW Mentzel TDW Folpe AL Folpe AL Antonescu CR Montgomery EA Montgomery EA Antonescu CR Montgomery EA Antonescu CR Bahrami A Davis JL Davis JL Davis JL Folpe AL Shibata T Huang HY Huang HY Huang HY Huang HY Fletcher CDM Doyle LA Folpe AL Doyle LA © Lars-Gunnar Kindblom Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013.

1.143A-D 1.144 1.145 1.146A-D 1.147A-D 1.148 1.149 1.150A.B 1.151A.B 1.152 1.153A-D 1.154A 1.154B 1.155A.B 1.156 1.157 1.158A.B 1.159A.B 1.160A.B 1.161 1.162 1.163 1.164A-C 1.165 1.166A-C 1.167A 1.167B.C 1.168 1.169

1.170A.B 1.171 1.172A-D 1.173A.B 1.174 1.175A-D 1.176A.B 1.177A-D 1.178

(WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc fr/15 Doyle LA Hornick JL Doyle LA de Saint Aubain Somerhausen N de Saint Aubain Somerhausen N de Saint Aubain Somerhausen N de Saint Aubain Somerhausen N Jo VY Jo VY Brenn T Brenn T Oliveira AM Nascimento AF Oliveira AM Calonje JE Fletcher CDM Calonje JE Calonje JE Calonje JE Calonje JE Calonje JE Montgomery EA Montgomery EA Montgomery EA Huang SC Huang SC Wang J Hornick JL WHO Classification of Tumours Editorial Board. Digestive system tumours. Lyon (France): International Agency for Research on Cancer; 2019. (WHO classification of tumours series, 5th ed.; vol. 1). https://publicati on s.iarc.fr/579. Thway K Thway K North PE Folpe AL North PE Folpe AL Fanburg-Smith JC Fanburg-Smith JC Reprinted, with permission, from: Nayler SJ, Rubin BP, Calonje E, et al. Composite hema ngioendothelioma: a complex, low-grade vascular lesion mimicking an giosarcoma. Am J Surg Pathol. 2000 Mar;24(3):35261. PMID:10716148 and Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (Franee): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15.

and Fletcher CDM, Unni KK, Mertens F, editors. Pathology and genetics of tumours of soft tissue and bone. Lyon (France): International Agency

paybal：https://www.paypal.me/andy19801210

1.179A-D 1.180A 1.180B 1.181A 1.181B 1.182A-D 1.183A.B 1.184A.B 1.185A

1.185B 1.186A.B 1.187A-C 1.188A.B 1.189A-D 1.190A.B 1.191A.B 1.192A.B 1.193 1.194A.B 1.195 1.196 1.197A.B 1.198A-D 1.199 1.200A.B 1.201A-C 1.202A.B 1.203A.B 1.204A.B 1.205A.B 1.206 1.207 1.208 1.209 1.210 1.211A 1.211B

1.212A.B

1.213 1.214 1.215

1.216 1.217A.B 1.218A.B

for Research on Cancer; 2002. (WHO classification of tumours series, 3rd ed.; vol. 5). https://publications.iarc.fr/5. Folpe AL Folpe AL Thway K Folpe AL Thway K Folpe AL Thway K Thway K Reprinted, with permission, from: Agaram NP, Zhang L, Cotzia P, at al. Expanding the spectrum of genetic alterations in pseudomyogenic hemangioendothelioma with recurrent novel ACTB-FOSB gene fusions. Am J Surg Pathol. 2018 Dec;42(12): 1653-61. PMID:30256258. https://journals 」ww.com/ajsp/ Agaram NP Hornick JL Hornick JL Hornick JL Rubin BP Rubin BP Rubin BP Antonescu CR Thway K Billings SD Billings SD Billings SD Hornick JL Specht K Folpe AL Folpe AL Mentzel TDW Mentzel TDW Mentzel TDW Mentzel TDW Folpe AL Matsuyama A Matsuyama A Matsuyama A Matsuyama A Matsuyama A Billings SD Sharon W. Weiss, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta GA Sharon W. Weiss, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta GA Billings SD Billings SD Adapted, with permission, from: Arva NC, Schafernak KT. Rare presentations of Epstein-Barr virus-associated smooth muscle tumor in children. Pediatr Dev Pathol. 2016 Mar-Apr; 19(2): 132-8. PMID:26230054 Soares FA Schafernak KT Schafernak KT

1.219A.B 1.220 1.221 1.222A 1.222B 1.223A-D 1.224 1.225 1.226 1.227A.B 1.228

1.229A-C 1.230 1.231 1.232A 1.232B.C 1.233A,B,D 1.233C 1.234A.B 1.235 1.236 1.237 1.238A,B,D 1.238C 1.239 1.240 1.241 1.242 1.243 1.244

1.245 1.246A-D 1.247A.B 1.248 1.249A-D 1.250A.B 1.251 1.252A.B 1.253 1.254A.B 1.255A.B 1.256A.B 1.257A-D 1.258A-C 1.259A-C 1.260

1.261 1.262A.B 1.263A.B 1.264 1.265

Fletcher CDM Fletcher CDM Mertens F Messiou C Nielsen GP Folpe AL Dry SM Folpe AL Dry SM Parham DM © S.B. Kapadia Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (Franee): Inter national Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. Parham DM Rudzinski ER Rudzinski ER Rudzinski ER Folpe AL Rudzinski ER Folpe AL Rudzinski ER Rudzinski ER Rudzinski ER Bode-Lesniewska B Kohashi K Bode-Lesniewska B Kohashi K Bode-Lesniewska B Bode-Lesniewska B Bridge JA Kohashi K © F.G. Barr Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). Mt ps://publicatio ns.ia「c.fi715. Montgomery EA Montgomery EA Montgomery EA Agaram NP Agaram NP Agaram NP Agaram NP Huang SC Huang SC WHO Classification of Tumours Editorial Board. Digestive system tumours. Lyon (Franee): International Agency for Research on Cancer; 2019. (WHO classification of tumours series, 5th ed.; vol. 1). https://publications.iarc.fr/579. Rosenberg AE Rosenberg AE Rosenberg AE Messiou C Hameed M

1.266A-D 1.267 1.268A.B 1.269A.B 1.270A-D 1.271A.B 1.272A-C 1.272D 1.273A.B 1.274A-C 1.275' 1.276A-D 1.277A.B 1.278 1.279 1.280A.B 1.281A 1.281B 1.282A-E 1.283 1.284A.B.D 1.284C 1.285A.B 1.286A.B 1.287A.B 1.288A.B 1.289 1.290A-D 1.291A-D 1.292 1.293 1.294 1.295A.B

1.296 1.297A-D 1.298A-C 1.299A-C 1.300 1.301A-D 1.302 1.303 1.304 1.305A.B 1.306 1.307A.B 1.308A.B 1.309 1.310 1.311 1.312A.B 1.313 1.314 1.315A-D 1.316 1.317A.B 1.318A-C 1.319A.B 1.320A-C 1.321

1.322A.B 1.323 1.324 1.325 1.326 1.327A 1.327B

Yamashita K Perry A Perry A Perry A Perry A Perry A Jo VY Perry A Jo VY Perry A Perry A Perry A Perry A Rodriguez F Perry A Perry A Rodriguez F Perry A Perry A Rodriguez F Fletcher CDM Folpe AL Hornick JL Hornick JL Hornick JL Rubin BP Rubin BP Fetsch J Ferguson PM Perry A Perry A Perry A Francineide Sadala de Souza, Surgical Pathology and Electron Microscopy Laboratory, SARAH Network of Rehabilitation Hospitals, Brasilia Federal District Perry A Perry A Stemmer-Rachamimov AO Hornick JL Nielsen GP Nielsen GP Nielsen GP Nielsen GP Nielsen GP Nielsen GP Antonescu CR Folpe AL Folpe AL Folpe AL Folpe AL Hameed M Nielsen GP Liegl-Atzwange「B Nielsen GP Liegl-Atzwange「B Nielsen GP Liegl-Atzwanger B Lazar AJ Nucci MR Bridge JA Luis Requena, Department of Dermatology, Fundacion Jimenez Diaz, Madrid Mentzel TDW Mentzel TDW Mentzel TDW Mentzel TDW Mentzel TDW Antonescu CR Chen G

Sources

539

paybal：https://www.paypal.me/andy19801210 1.328 1.329A.B 1.330 1.331 1.332A 1.332B 1.333A-D 1.334A.B 1.335A.B 1.336A.B 1.337A.B 1.338 1.339 1.340 1.341A.B 1.342A.B 1.343 1.344 1.345 1.346 1.347A-D 1.348 1.349A.C 1.349B.D 1.350A.C 1.350B 1.351 1.352A-D 1.353A-C 1.354A-D 1.355 1.356A.B 1.357A.B 1.358 1.359 1.360A-C 1.361A-C 1.362A-C 1.363A.B 1.364A.D 1.364B.C 1.365A.B 1.366

1.367 1.368A.B 1.369 1.370 1.371 1.372 1.373 1.374A.B 1.375A-D 1.376 1.377 1.378 1.379A.B 1.380A.B 1.381A-F 1.382A-C 1.383 1.384A.B 1.385 1.386A-C

540

Rekhi B Rekhi B Rekhi B Rekhi B Endo M Miettinen M Miettinen M Miettinen M Miettinen M JoVY JoVY Jo VY Jo VY Jo VY JoVY Folpe AL Folpe AL Folpe AL Folpe AL Folpe AL Boland JM Horvai AE Folpe AL Lee JC Lee JC Folpe AL Lee JC Suurmeijer AJH Suurmeijer AJH Suurmeijer AJH Suurmeijer AJH Suurmeijer AJH Suurmeijer AJH Ladanyi M Oda Y Oda Y Oda Y Oda Y Jambhekar NA Lazar AJ Jambhekar NA Lazar AJ © Nelson G. Ordonez Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. Fletcher CDM Fritchie KJ Fritchie KJ Fritchie KJ Fritchie KJ Bridge JA Lucas DR Lucas DR Horvai AE Horvai AE Horvai AE Horvai AE Antonescu CR Antonescu CR Antonescu CR Antonescu CR Oda Y Oda Y Oda Y Oda Y

Sources

1.387 1.388 1.389 1.390 1.391A 1.391B-E 1.392A.B 1.393A.B 1.394

1.395 1.396A.B

1.397A

1.397B-D 1.398 1.399A-C 1.400 1.401A-D 1.402

2.01 2.02 2.03 2.04A.B 2.05

2.06 2.07

2.08A-D

Biegel JA Hornick JL Hornick JL Hornick JL Fletcher CDM Hornick JL Hornick JL Argani P © Chin-Chen Pan Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (Franee): Inter national Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. Bode-Lesniewska B Adapted, with permission from Springer Nature, from: Bode-Lesniewska B, Zhao J, Speel EJ, et al. Gains of 12q13-14 and overexpression of mdm2 are frequent firidings in intimal sarcomas of the pulmonary artery. Virchows Arch. 2001 Jan;438(1):57-65. PMID:11213836. Copyright 2001. Adapted, with permission from Springer Nature, from: Bode-Lesniewska B, Zhao J, Speel EJ, et al. Gains of 12q13-14 and overexpression of mdm2 are frequent findings in intimal sarcomas of the pulmona「y artery. Virchows Arch. 2001 Jan;438(1):57-65. PMID:11213836. Copyright 2001. Debiec-Rychter M Debiec-Rychter M Bode-Lesniewska B Gronchi A Dei Tos AP Pillay N

O'Donnell PG de Alava E de Alava E de Alava E © Poul Sorensen Fletcher CDM, Bridge JA, Hogendoom PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (Franee): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. Lessnick SL Julie Gastier-Foster, Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus OH Szuhai K

2.09A-C 2.10A.B 2.11A.B 2.12A-C 2.13A.B.D 2.13C 2.14A.B 2.15 2.16A-D 2.17A-C 2.18

Szuhai K Le Loarer F Szuhai K Bridge JA Y oshida A Antonescu CR Yoshida A Antonescu CR Puls F Antonescu CR Antonescu CR

3.01

Bray F, Colombet M, Mery L, et al., editors. Cancer incidence in five continents. Volume XI. Lyon (Franee)： International Agency for Research on Cancer; 2017. (IARC Scientific Publication No. 166). http://ci5.iarc.fr/CI5-XI. Yoshida A Yoshida A Yoshida A Mertens F Bloem JL Yoshida A Yoshida A Sciot R Yoshida A Lucas DR Tirabosco R Lucas DR Tirabosco R Nielsen GP Lucas DR Lucas DR Bovee JVMG Lucas DR Bovee JVMG Rosenbe「g AE Heymann D Bovee JVMG Heymann D Reprinted, with permission from PNAS, from: Bovee JV. EXTra hit for mouse osteochondroma. Proc Natl Acad Sci USA. 2010 Feb 2;107(5):1813-4. PMID:20133829. Copyright 2010 National Academy of Sciences. Amary F Amary F Amary F Bloem JL © M.L. Ostrowski Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15.

3.02 3.03 3.04A.B 3.05 3.06A.B 3.06C 3.07A 3.07B 3.08A-D 3.09A.B 3.10 3.11A 3.11B.C 3.12A 3.12B 3.13 3.14 3.15A.C 3.15B 3.16 3.17A.B 3.18A.B 3.19A.B 3.20

3.21A.B 3.22 3.23A-D 3.24A.B 3.25

3.26A-C 3.26D

Bovee JVMG © M.L. Ostrowski Fletcher CDM, Bridge JA, Hogendoorn PCW, et al.,

paybal：https://www.paypal.me/andy19801210

3.27 3.28

3.29A.B

3.30A.B

3.31 A-C

3.32 3.33A-C 3.34 3.35 3.36A-C 3.37A.B 3.38A.B 3.39A-D 3.40A.B 3.41 3.42A.B 3.43A-C 3.44A

editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. Bridge JA © 丄 Aidan Carney Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. © J. Aidan Cmmey Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). Mt ps://publications.iarc.fr/15. © J. Aidan Carney Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. © J. Aidan Carney Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. O'Donnell PG Flanagan AM Tirabosco R Bovee JVMG Bovee JVMG Bovee JVMG Bovee JVMG Bloem JL Bloem JL Bovee JVMG Bovee JVMG Bovee JVMG © F. Bertoni Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013.

3.44B 3.45A.B 3.46A-C 3.47A-C 3.48A.B 3.49A-C 3.50A 3.50B 3.51A-D

3.52 3.53 3.54A-D 3.55A-C 3.56A-C 3.57A.B

3.58 3.59 3.60A

3.60B 3.61 3.62A.B 3.63A,B 3.64 3.65A.B 3.66A.B 3.67A.B 3.68 3.69 3.70 3.71 3.72 3.73A.B 3.74 3.75 3.76 3.77 3.78A-D 3.79A-C

(WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15 . Bovee JVMG Bovee JVMG Cleven AHG eleven AHG OdaY Baumhoer D Baumhoer D OdaY © Yasuaki Nakashima Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (Franee): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. de Pinieux G Yoshida A Fanburg-Smith JC Inwards CY Inwards CY © Johannes Bras Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (Franee): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. Baumhoer D Nielsen GP © Johannes Bras Academisch Medisch Centrum, Amsterdam Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (Franee): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. Baumhoer D Nielsen GP Amary F Amary F Klein MJ Amary F Horvai AE Amary F Nielsen GP Horvai AE Gambarotti M Yoshida A Sumathi VP Yoshida A Yoshida A Yoshida A Yoshida A Yoshida A O'Donnell PG O'Donnell PG

3.79D

3.80A-C 3.81A 3.81B 3.82 3.83A

3.83B 3.84 3.85 3.86 3.87A.B 3.88A.B 3.89 3.90A-C 3.91A.B 3.92 3.93A.B 3.94A.B

3.95A 3.95B

3.96A-C 3.96D 3.97A.B 3.98A.B 3.99A.B 3.100A.B 3.101 3.102 3.103 3.104 3.105 3.106 3.107 3.108 3.109 3.110 3.111 3.112A.B 3.113 3.114 3.115A.B

© Takeo Mats uno Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. Baumhoer D Baumhoer D Rosenberg AE Baumhoer D © Takeo Matsuno Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. Baumhoer D Rosenbe「g AE Rosenberg AE Rosenberg AE O'Donnell PG Wang J O'Donnell PG Wang J Wang J Wang J Nord KH Adapted, with permission from Oxford University Press, from: Klein MJ, Siegal GP. Osteosarcoma: anatomic and histologic variants. Am J Clin Pathol. 2006 Apr;125(4):555-81. PMID:16627266 Klein MJ Adapted, with per mission from Oxford University Press, from: Klein MJ, Siegal GP. Osteosarcoma: anatomic and histologic variants. Am J Clin Pathol. 2006 Apr; 125⑷:555-81. PMID:16627266 Klein MJ Bonar SFM Klein MJ Klein MJ O'Donnell PG O'Donnell PG Nielsen GP Bovee JVMG Nielsen GP Suurmeijer AJH Suurmeijer AJH Suurmeijer AJH Righi A Dei Tos AP Hameed M Righi A Yoshida A Rosenberg AE Rosenberg AE Rosenberg AE Rosenberg AE

Sources

541

paybal：https://www.paypal.me/andy19801210 3.116A-C 3.117A-C 3.118A.B 3.119A.B 3.120

3.121A.B 3.122A.B 3.123 3.124 3.125 3.126 3.127 3.128 3.129A.B 3.130 3.131A-C 3.132A.B 3.133A-C 3.134 3.135A.B 3.136A.B 3.137 3.138 3.139A-D 3.140A.B 3.141A.C.D 3.141B 3.142A.B 3.143A.B 3.144A.B 3.145A.B 3.146A,B 3.147 3.148A 3.148B 3.149A-C 3.150 3.151A.B 3.151C 3.152A-D 3.153 3.154A.B 3.155 3.156 3.157 3.158A.B 3.159 3.160

3.161 A-D 3.162

3.163

3.164A-D 3.165A-C 3.166A.B 3.167

542

Rosenberg AE Rosenberg AE Rosenberg AE Rosenberg AE Reprinted, with permission, from: Nielsen GP, Rosenberg A, editors. Diagnostic pathology: bone. 2nd ed. Philadelphia (PA): Elsevier; 2017. Copyright Elsevier 2017. Rosenberg AE Rosenberg AE Rosenberg AE Nielsen GP Nielsen GP Nielsen GP Nielsen GP Bovee JVMG Agaram NP Agaram NP Agaram NP Agaram NP O'Donnell PG O'Donnell PG O'Donnell PG Larousserie F Larousserie F Larousserie F Yoshida A Yoshida A Yoshida A Larousserie F Yoshida A Yoshida A Nielsen GP Baumhoer D Baumhoer D Baumhoer D O'Donnell PG Nielsen GP Yamaguchi T Yamaguchi T O'Donnell PG Tirabosco R Tirabosco R Tirabosco R Tirabosco R Tirabosco R O'Donnell PG Nielsen GP Tirabosco R Tirabosco R Adapted, with permission from Springer Nature Customer Service Centre GmbH: Springer Nature, from: Shih AR, Cote GM, Chebib I, et al. Clinicopathologic characteristics of poorly differentiated chordoma. Mod Pathol. 2018Aug;31(8):1237-45. PMID:29483606. Copyright 2018. Nielsen GP Doris E. Wenger, Department of Radiology, Mayo Clinic, Rochester MN Doris E. Wenger, Department of Radiology, Mayo Clinic, Rochester MN Fritchie KJ Nielsen GP Nielsen GP Nielsen GP

Sources

3.168A-C 3.169A.B 3.170A,B,D 3.170C

3.171A.B 3.172A.B 3.173A-C 3.174A

3.174B 3.175A-D 3.176A.B 3.177A-C 3.177D 3.178 3.179 3.180 3.181A 3.181B 3.182A.B 3.183A.B 3.184A.B 3.185A.B 3.186 3.187 3.188A.B 3.189A.B 3.190A-C 3.191A.B 3.191C 3.192 3.193 3.194 3.195A.B 3.196A.B 3.197 3.198A-C 3.199A.B 3.200A-C 3.201A,B 3.202A.B 3.203A.B 3.204A.B 3.205A-C 3.206 3.207A.B

3.208A-C 3.209A 3.209B-D 3.210A.B 3.211A,C,D 3.211B 3.212

Nielsen GP Nielsen GP Nielsen GP Reprinted, with permission, from: Nielsen GP, Rosenberg A, editors. Diagnostic pathology: bone. 2nd ed. Philadelphia (PA): Elsevier; 2017. Copyright Elsevier 2017. Nielsen GP Bovee JVMG Reith JD © Kalil RK Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (Franee): In ternational Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. Reith JD Reith JD Inwards CY Gambarotti M Inwards CY Bloem JL Siegal GP Siegal GP Hameed M Bovee JVMG Sumathi VP Rosenberg AE Rosenberg AE Rosenberg AE Rosenberg AE Rosenberg AE McCarthy EF McCarthy EF Czerniak B Czerniak B Inwards CY Kalil RK Kalil RK Kalil RK Kalil RK O'Donnell PG O'Donnell PG Ferry JA eleven AHG Cleven AHG Cleven AHG Picarsic J Cheuk W Picarsic J Picarsic J Haroche J Asif Saifuddin, Consultant Musculoskeletal Radiologist, Imaging Department, Royal National Orthopaedic Hospital, Brockley Hill, Stanmore Picarsic J Tirabosco R Emile JF Rosenberg AE Rosenberg AE Demicco EG Demicco EG

4.01 A-D 4.02A-D

Alman BA Reprinted, with permission, from: Fletcher CDM, Bridge JA, Hogendoorn PCW, et al.,' editors. WHO classification of tumours of soft tissue and bone. Lyon (Franee)： International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publicati on s.iarc.fr/15. and Pansuriya TC, Kroon HM,

4.03A.B

4.04

4.05

4.06A-D 4.07

Bovee JV. Enchondromatosis： insights on the different subtypes. Int J Clin Exp Pathol. 2010 Jun 26;3(6):55769. PMID:20661403 Reprinted, with permission, from: Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (Franee): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publicati on s.iarc.fr/15. and Pansuriya TC, Kroon HM, Bovee JV. Enchondromatosis: in sights on the different subtypes. Int J Clin Exp Pathol. 2010 Jun 26;3(6):557-69. PMID:20661403 Adapted from: IARC TP53 Database [Internet]. Lyon (Franee): International Agency for Research on Cancer; 2018. Version R19, August 2018. Available from: http://p53.iarc.fr/. Adapted from: IARC TP53 Database [Internet]. Lyon (Franee): Internationml Agency for Research on Cancer; 2018. Version R19, August 2018. Available from: http://p53.iarc.fr/.

Boyce AM © M.M. Cohen Jr Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (Franee): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. and Reprinted, with permission from Elsevier, from: Cohen MM Jr, Howell RE. Etiology of fibrous dysplasia and McCune-Albright syndrome. Int J Oral Maxillofac Surg. 1999 Oct;28(5):366-71.

PMID:10535539. Copyright 1999.

paybal：https://www.paypal.me/andy19801210 4.08A.B 4.09 4.10 4.11A.B 4.12 4.13A.B 4.14

4.15A.B

Boyce AM Wuyts W Wuyts W Legius E Brems H Wang LL Reprinted, with permission, from: Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. and Adapted, with permission from Elsevier, from: Larizza L, Magnani I, Roversi G. Rothmund-Thomson syndrome and RECQL4 defect: splitting and lumping. Cancer Lett. 2006 Jan 28;232( 1):107-20. PMID:16271439 Hicks MJ

syndrome: current status of clinical applications and future directions. Mol Diagn Ther. 2013 Feb;17(1):31-47. PMID:23355100. ©2013. and Adapted from Schneider K, Zelley K, Nichols KE, et al. LiFraumeni syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1999 Jan 19 [updated 2019 Nov 21]. PMID:20301488. © University of Washingto n 1993-2017. Gen eReviews® is a registered trademark of the University of Washington, Seattle. The content is used with permission. All rights reserved. Villani A, Shore A, Wasserman JD, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 2016 Sep;17 3:1295-305. PMID:27501770. Copyright 2016, with permission from Elsevier.

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3.05 3.06 4.01 4.02 4.03

4.04

Adapted from: WHO Classification of Tumours Editorial Board. Breast tumours. Lyon (France): In ternational Agency for Research on Cancer; 2019. (WHO classification of tumours series, 5th ed.; vol. 2). https://publications.iarc.fr/581. Demicco EG WHO Classification of Tumours Editorial Board. Digestive system tumours. Lyon (Franee): International Agency for Research on Cancer; 2019. (WHO classification of tumours series, 5th ed.; vol. 1). https://publications.iarc.fr/579. Miettinen MM, Antonescu CR, Fletcher CDM, et al. Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis 1a consensus overview. Hum Pathol. 2017 Sep;67:1-10. PMID:28551330 © Robert J. Grimer Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publicatio ns.ia「c.fi715. Modified, with permission, from Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res. 1980 Nov-Dec;(153): 106-20. PMID:7449206 Hornick JL Ferry JA Lazar AJ Mertens F Adapted, with permission, from Superti-Furga A, Spranger J, Nishimura G. Enchondromatosis revisited: new classification with molecular basis. Am J Med Genet C Semin Med Genet. 2012 Aug 15; 1600(3):154-64. PMID:22791316 Adapted, with permission from Springer Nature, from Sorrell AD, Espenschied CR, Culver JO, et al. Tumor protein p53 (TP53) testing and Li-Fraumeni

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Boxes Adapted from: Fritz A, Percy C, Jack A, et al., editors. In ternational classification of diseases for on oology (ICD-O). 3rd ed. 1 st rev. Geneva: World Health Organization; 2013. Adapted from: Fritz A, Percy C, Jack A, et al., editors. International classification of diseases for oncology (ICD-O). 3rd ed. 1 st rev. Geneva: World Health Organization; 2013. Monnat RJ Jr

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1.237: Bode-Lesniewska B 1.241: Bode-Lesniewska B 1.242: Bridge JA 1.267: Perry A 1.271B: Perry A 1.270D: Perry A 3.72: Sumathi VP 3.90B: Wang J 3.93A: Nord KH

Images on the chapter title pages Chapter Chapter Chapter Chapter

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1.20: Billings SD 2.17A: Antonescu CR 3.73A: Yoshida A 4.15B: Hicks MJ

Sources

543

paybal：https://www.paypal.me/andy19801210 References

1. Abbasi NR, Brownell I, Fangman W. Familial multiple an giolipomatosis. Dermatol Online J. 2007 Jan 27; 13(1 ):3. PMID:17511936 2. Abbott JJ, Oliveira AM, Nascimento AG. The prognostic significance of fibrosarcomatous transformation in dermatofibrosarcoma protuberans. Am J Surg Pathol. 2006 Apr;30(4):436-43. PMID:16625088 3. Abboudi H, Tschobotko B, Carr C, et al. Bilateral renal anastomosing hemangiomas: a tale of two kidneys. J Endourol Case Rep. 2017 Dec 1;3(1):176-8. PMID:29279869 4. Abdelwahab IF, Klein MJ, Hermann G, et al. An giosarcomas associated with bone infarcts. Skeletal Radiol. 1998 Oct;27(10):546-51. PMID:9840390 5. Abe S, Yamamoto A, Tamayama M, et al. Synovial hemangioma of the hip joint with pathological femoral neck fracture and extra-articular extension. J Orthop Sci. 2013 Jan;18(1):181-5. PMID:21773788 6. Abla O, Jacobsen E, Picarsic J, et al. Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfma Destombes disease. Blood. 2018 Jun 28;131(26):2877-90. PMID:29720485 7. Ablin DS, Jain K, Howell L, et al. Ultrasound and MR imaging of fibromatosis colli (sternomastoid tumor of infancy). Pediatr Radiol. 1998Apr;28(4):230-3. PMID:9545475 & Abraham SC, Krasinskas AM, Hofstetter WL, et al. "Seedling" mesenchymal tumors (gastrointestinal stromal tumors and leiomyomas) are common incidental tumors of the esophagogastric junction. Am J Surg Pathol. 2007 Nov;31(11):1629-35. PMID:18059218 9. Abramovici LC, Hytiroglou P, Klein RM, et al. Well-differentiated extraskeletal osteosarcoma: report of 2 cases, 1 with dedifferentiation. Hum Pathol. 2005 Apr;36(4):439-43. PMID:15892008 10. Achatz Ml, Zambetti GP. The inherited p53 mutation in the Brazilian population. Cold Spring Harb Perspect Med. 2016 Dec 1;6(12):a026195. PMID:27663983 11. Achten R, Debiec-Rychter M, De Wever I, et al. An unusual case of clear cell sarcoma arising in the jejunum highlights the diagnostic value of molecular genetic techniques in establishing a correct diagnosis. Histopathology. 2005 Apr;46(4):472-4. PMID:15810965 ' 12. Ackerman LV. Extra-osseous localized non-neoplastic bone and cartilage formation (so-called myositis ossificans): clinical and pathological confusion with malignant neoplasms. J Bone Joint Surg Am. 1958 Apr;40-A(2):279-9& PMID:13539055 13. Adams DM, Brandao LR, Peterman CM, et al. Vascular anomaly cases for the pediatric hematologist oncologists-An interdisciplinary review. Pediatr Blood Cancer. 2018 Jan;65(1):e26716. PMID:28727248 14. Adams DM, Trenor CC 3rd, Hammill AM, et al. Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies. Pediatrics. 2016 Feb;137(2):e20153257. PMID:26783326 15. Adams EL, Yoder EM, Kasdan ML. Giant cell tumor of the tendon sheath: experience with 65 cases. Eplasty. 2012;12:e50. PMID:23185646 16. Adams SC, Potter BK, Mahmood Z, et al.

544

Refere nces

Consequences and prevention of inadvertent internal fixation of primary osseous sarcomas. Clin Orthop Relat Res. 2009 Feb;467(2):51925. PMID:18937020 17. Addie RD, de Jong Y, Alberti G, et al. Exploratio n of the chondrosarcoma metabolome; the mTOR pathway as an important pro-survival pathway. J Bone Oncol. 2019 Jan 29;15:100222. PMID:30766792 18. Adelani MA, Schultenover SJ, Holt GE, et al. Primary leiomyosarcoma of extragnathic bone: clinicopathologic features and reevaluation of prognosis. Arch Pathol Lab Med. 2009 Sep;133(9):1448-56. PMID:19722754 19. Adeniran A, Al-Ahmadie H, Mahoney MC, et al. Granular cell tumor of the breast: a series of 17 cases and review of the literature. Breast J. 2004 Nov-Dec;10(6):528-31. PMID:15569210 20. Adler CP. Hemangioma of the bone. In: Bone diseases. Berlin (Germany): Sp「inger; 2000. pp. 370-5. 21. Agaimy A. An isometric cell lipoma: in sight from a case series and review of the literature on adipocytic neoplasms in survivors of 「etinoblastoma suggest a role for RB1 loss and possible relationship to fat-predominant ("fatonly") spindle cell lipoma. Ann Diagn Pathol. 2017Aug;29:52-6. PMID:28807343 22. Agaimy A. Microscopic intraneural perineurial cell proliferations in patients with neurofibromatosis type 1. Ann Diagn Pathol. 2014 Apr; 18⑵:95-8. PMID:24461704 23. Agaimy A. SWI/SNF complex-deficient soft tissue neoplasms: a pattern-based approach to diagnosis and differential diagnosis. Surg Pathol Clin. 2019 Mar;12(1):149-63. PMID:30709441 24. Agaimy A, Bieg M, Michal M, et al. Recurrent somatic PDGFRB mutations in sporadic infantile/solitary adult myofibromas but not in angioleiomyomas and myopericytomas. Am J Surg Pathol. 2017 Feb;41 (2):195-203. PMID:27776010 25. Agaimy A, Michal M, Chiosea S, et al. Phosphaturic mesenchymal tumors: clinicopathologic, immunohistochemical and molecular analysis of 22 cases expanding their morphologic and immunophenotypic spectrum. Am J Surg Pathol. 2017 Oct;41(10):1371-80. PMID:28614212 26. Agaimy A, Michal M, GiedlJ, etal. Superficial acral fibromyxoma: clinicopathological, immunohistochemical,日nd molecular study of 11 cases highlighting frequent Rb1 loss/ deletions. Hum Pathol. 2017 Feb;60:192-8. PMID:27825811 27. Agaimy A, Michal M, Thompson LD, et al. Angioleiomyoma of the sinonasal tract: analysis of 16 cases and review of the literature. Head Neck Pathol. 2015 Dec;9(4):463-73. PMID:26047608 28. AgaimyA, Wiinsch PH, HofstaedterF,etal. Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations. Am J Surg Pathol. 2007 Jan;31 (1):113-20. PMID:17197927 29. Agaimy A, Wiinsch PH, Schroeder J, et al. Low-grade abdominopelvic sarcoma with myofibroblastic features (low-grade myofibroblastic sarcoma): clinicopathological, immunohistochemical, molecular genetic and

ultrastructural study of two cases with literature review. J Clin Pathol. 2008 Mar;61 (3):301-6. PMID:17513510 30. Agaram NP, Chen CL, Zhang L, et al. Recurrent MYOD1 mutations in pediatric and adult sclerosing and spindle cell rhabdomyosarcomas: evidence for a comm on pathogenesis. Genes Chromosomes Cancer. 2014 Sep;53(9):779-87. PMID:24824843 31. Agaram NP, Chen HW, Zhang L, et al. EWSR1-PBX3: a novel gene fusion in myoepithelial tumors. Genes Chromosomes Cancer. 2015 Feb;54 ⑵:63—71. PMID:25231231 32. Agaram NP, LaQuaglia MP, Alaggio R, et al. MYOD1-mutant spindle cell and sclerosing rhabdomyosarcoma: an aggressive subtype irrespective of age. A reappraisal for molecular classification and risk stratification. Mod Pathol. 2019Jan;32(1):27-36. PMID:30181563 33. Agaram NP, LeLoarer FV, Zhang L, et al. USP6 gene rearrangements occur preferentially in giani cell reparative granulomas of the hands and feet but not in gnathic location. Hum Pathol. 2014 Jun;45(6):1147-52. PMID:24742829 34. Agaram NP, Prakash S, Antonescu CR. Deep-seated plexiform schwannoma: a pathologic study of 16 cases and comparative analysis with the superficial variety. Am J Surg Pathol. 2005 Aug;29(8):1042-8. PMID:16006798 35. Agaram NP, Sung YS, Zhang L, et al. Dichotomy of genetic abnormalities in PEComas with therapeutic implications. Am J Surg Pathol. 2015 Jun;39(6):813-25. PMID:25651471 36. Agaram NP, Zhang L, Cotzia P, et al. Expanding the spectrum of genetic alterations in pseudomyogenic hemangioendothelioma with recurrent novel ACTB-FOSB gene fusions. Am J Surg Pathol. 2018 Dec;42(12):1653-61. PMID:30256258 37. Agaram NP, Zhang L, LeLoarer F, et al. Targeted exome sequencing profiles genetic alterations in leiomyosarcoma. Genes Chromosomes Cancer. 2016 Feb;55(2):12430. PMID:26541895 38. Agaram NP, Zhang L, Sung YS, et al. Expanding the spectrum of intraosseous rh abdomyosarcoma: correlation between 2 distinct gene fusions and phenotype. Am J Surg Pathol. 2019 May;43(5):695-702. PMID:30720533 39. Agaram NP, Zhang L, Sung YS, et al. Extraskeletal myxoid chondrosarcoma with non-EWSR1-NR4A3 variant fusions correlate with rhabdoid phenotype and high-grade morphology. Hum Pathol. 2014 May;45(5):1084-91. PMID:24746215 40. Agaram NP, Zhang L, Sung YS, et al. Recurrent NTRK1 gene fusions define a novel subset of locally aggressive lipofibromatosislike neural tumors. Am J Surg Pathol. 2016 Oct;40(10):1407-16. PMID:27259011 41. Agarwal SK, Munjal M, Rai D, et al. Malignant transformation of vagal nerve schwannoma in to angiosarcoma: a rare event. J Surg Tech Case Rep. 2015 JanJun;7(1):17-9. PMID:27512546 42. Agnihotri S, Jalali S, Wilson MR, et al. The genomic landscape of schwannoma. Nat Genet.

2016 Nov;48(11):1339-48. PMID:27723760 43. Agrawal P, Srinivasan R, Rajwanshi A, et al. Fine needle aspiration cytology of paediatric soft tissue tumours highlighting challenqes in diagnosis of benign lesions and unusual malignant tumours. Cytopathology 2019 May;30(3):301-8. PMID:30848523 44. Aguilar-Frasco J, Ruben-Castillo c Rodriguez-Quintero JH, et al. Aggressive angiomyxoma: giant recurrence successfully treated with wide excision and adjuvant therapy with GnRH analogue. BMJ Case Rep 2018 Nov 28;11(1):e226973. PMID:30567120 45. Ahmed AR, Tan TS, Unni KK, et al. Secondary chondrosarcoma jn osteochondroma: report of 107 patients. Clin Orthop Relat Res. 2003 Jun;(411):193-206 PMID:12782876 46. Ahn D, Lee GJ, Sohn JH, et al. Fineneedle aspiration cytology versus core-needle biopsy for the diagnosis of extracranial head and neck schwannoma. Head Neck. 2018 Dec;40(12):2695-700. PMID:30457183 47. Ahn J, Ludecke HJ, Lindow S, et al. Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nat Genet. 1995 Oct; 11 (2):137-43. PMID:7550340 48. Aigner T, Dertinger S, Belke J, et al. Chondrocytic cell differentiation in clear cell chondrosarcoma. Hum Pathol. 1996 Dec;27(12):1301-5. PMID:8958302 49. Ainsworth KE, Chavhan GB, G叩ta AA, et al. Congenital infantile fibrosarcoma: review of imaging features. Pediatr Radiol. 2014 S即;44(9):1124-9. PMID:24706181 50. Aitken SJ, Presneau N, Tirabosco R, et al. An NRAS mutation in a case of ErdheimChester disease. Histopathology. 2015 Jan;66(2):316-9. PMID:24754681 51. Aitken-Saavedra J, da Silva KD, Gomes AP, et al. Clinicopathologic and immunohistochemical characterization of 14 cases of angioleiomyomas in oral cavity. Med Oral Patol Oral Cir Bucal. 2018 Sep 1;23(5):e564-8. PMID:30148476 52. Akaike K, Kurisaki-Arakawa A, Hara K, et al. Distinct clinicopathological features of NAB2-STAT6 fusion gene variants in solitary fibrous tumor with emphasis on the acquisition of highly malignant potential. Hum Pathol. 2015 Mar;46(3):347-56. PMID:25582503 53. Akbarnia BA, Wirth CR, Colman N. Fibrosarcoma arising from chronic osteomyelitis. Case report and review of the literature. J Bone Joint Surg Am. 1976 Jan;58(1):123-5. PMID:1249098 54. Akhlaghpoor S, Aziz Ahari A, Ahmadi SA, et al. Histological evaluation of drill fragments obtained during osteoid osteoma radiofrequency ablation. Skeletal Radiol. 2010 May;39(5):451-5. PMID:20204353 55. Al Dhaybi R, Powell J, McCuaig C, et al. Differentiation of vascular tumors f「onj vascular malformations by expression o Wilms tumor 1 gene: evaluation of 126 cases. J Am Acad Dermatol. 2010 Dec;63(6):1052PMID:21093662 -J 56. Al-Abbadi MA, Almasri NM, Al-Quran S, et al. Cytokeratin and epithelial membrane antigen expression in angiosarcomas, a immunohistochemical study of 33 cases. Arc

paybal：https://www.paypal.me/andy19801210 Pathol Lab Med. 2007 Feb;131 (2):288-92. PMID:17284115 57. Alaggio R, Cecchetto G, Bisogno G, et al. Inflammatory myofibroblastic tumors in childhood: a report from the Italian Cooperative Group studies. Cancer. 2010 Jan 1;116(1):21626. PMID:19852031 58. Alaggio R, Coffin CM, Weiss SW, et al. Liposarcomas in young patients: a study of 82 cases occurring in patients younger than 22 years of age. Am J Surg Pathol. 2009 M即;33(5):645-58. PMID:19194281 59. Alaggio R, Collini P, Randall RL, et al. Un differentiated high-grade pleomorphic sarcomas in children: a clinicopathologic study of 10 cases and review of literature. Pediatr Dev Pathol. 2010 May-Jun; 13(3):209-17. PMID:20055602 60. Alaggio R, Ninfo V, Rosolen A, et al. Primitive myxoid mesenchymal tumor of infancy: a clinicopathologic report of 6 cases. Am J Surg Pathol. 2006 Mar;30(3):388-94. PMID:16538060 61. Alaggio R, Zhang L, Sung YS, et al. A molecular study of pediatric spindle and sclerosing rhabdomyosarcoma: identification of novel and recurrent VGLL2-related fusions in infantile cases. Am J Surg Pathol. 2016 Feb;4O(2):224-35. PMID:26501226 62. Alassiri AH, Ali RH, Shen Y, et al. ETV6NTRK3 is expressed in a subset of ALKnegative inflammatory myofibroblastic tumors. Am J Surg Pathol. 2016 Aug;40(8):1051-61. PMID:27259007 63. Alberghini M, Kliskey K, Krenacs T, et al. Morphological and immunophenotypic features of primary and metastatic giant cell tumour of bone. Virchows Arch. 2010 Jan;456(1 ):97-103. PMID:20012988 64. Albergo JI, Gaston CL, Laitinen M, et al. Ewing's sarcoma: only patients with 100% of necrosis after chemotherapy should be classified as having a good response. Bone Joint J. 2016 Aug;98-B(8):1138-44. PMID:27482030 65. Albertini AF, Brousse N, Bodemer C, et al. Retiform hemangioendothelioma developed on the site of an earlier cystic lymphangioma in a six-year-old girl. Am J Dermatopathol. 2011 0ct;33(7):e84-7. PMID:21915027 66. Al-Daraji Wl, Miettinen M. Superficial acral fibromyxoma: a clinicopathological analysis of 32 tumors including 4 in the heel. J Cutan Pathol. 2008 Nov;35(11 ):1020-6. PMID:18537858 67. Al Hmada Y, Schaefer IM, Fletcher CDM. Hibernoma mimicking atypical lipomatous tumor: 64 cases of a morphologically distinct subset. Am J Surg Pathol. 2018 Jul;42(7):9517. PMID:29629919 68. Ali NM, Niada S, Brini AT, et al. Genomic and tran scriptomic characterisation of undifferentiated pleomorphic sarcoma of bone. J Pathol. 2019 Feb;247(2):166-76. PMID:30281149 69. Al-lbraheemi A, Ahrens WA, Fritchie K, et al. Malignant tenosynovial giant cell tumor: the true "synovial sarcoma?" A clinicopathologic, immunohistochemical, and molecular cytogenetic study of 10 cases, s叩porting origin from synoviocytes. Mod Pathol. 2019 Feb;32(2):242-51. PMID:30206409 70. Al-lbraheemi A, Folpe AL, PerezAtayde AR, et al. Aberrant receptor tyrosine kinase signaling in lipofibromatosis: a clinicopathological and molecular genetic study of 20 cases. Mod Pathol. 2019 Mar;32⑶:42334. PMID:30310176 71. Al-lbraheemi A, Inwards CY, Zreik RT, etal. Histologic spectrum of giant cell tumor (GCT) of bone in patients 18 years of age and below: a study of 63 patients. Am J Surg Pathol. 2016

Dec;40(12):1702-12. PMID:27526293 72. 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 Pathol. 2017 Apr;30(4):474-85. PMID:28059097 73. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000 Feb 3;403(6769):503-11. PMID:10676951 74. Allen CE, Li L, Peters TL, et al. Cell­ specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells. J Immunol. 2010 Apr 15;184(8):4557-67. PMID:20220088 75. Allen CE, Merad M, McClain KL. Langerhans-cell histiocytosis. N Engl J Med. 2018 Aug 30;379(9):856-68. PMID:30157397 76. Allen PW. Nodular fasciitis. Pathology. 1972 Jan;4(1):9-26. PMID:4501523 77. Allen PW. Recurring digital fibrous tumours of childhood. Pathology. 1972 Jul;4⑶05-23. PMID:4344937 78. Allen PW, Enzinger FM. Hemangioma of skeletal muscle. An analysis of 89 cases. Cancer. 1972 Jan;29(1):8-22. PMID:5061701 79. Allen PW, Enzinger FM. Juvenile aponeurotic fibroma. Cancer. 1970 Oct；26(4):857-67. PMID:5506609 80. Allevi F, Rabbiosi D, Colletti G, et al. Extensive rhabdomyoma of the head and neck 「egion: a case report and a literature review. Minerva Stomatol. 2013 Oct;62(10):387-95. PMID:24217686 81. Allison DB, VandenBussche CJ, Rooper LM, et al. Nodular fasciitis of the parotid gland: a challenging diagnosis on FNA. Cancer Cytopathol. 2018 Oct;126(10):872-80. PMID:30311731 82. Almond LM, Tirotta F, Tattersail H, et al. Diagnostic accuracy of percutaneous biopsy in retroperitoneal sarcoma. Br J Surg. 2019 Mar;106(4):395-403. PMID:30675910 83. Alqahtani A, Nguyen LT, Flageole H, et al. 25 years' experience with lymphangiomas in children. J Pediatr Surg. 1999 Jul;34(7):11648. PMID:10442614 84. Al-Qattan MM. Fibroma of tendon sheath of the hand: a series of 20 patients with 23 tumours. J Hand Surg Eur Vol. 2014 Mar;39(3):300-5. PMID:23212985 85. Alvarez C, Tredwell S, De Vera M, et al. The genotype-phenotype correlation of hereditary multiple exostoses. Clin Genet. 2006 Aug;70⑵:122-30. PMID:16879194 86. Alvarez CM, De Vera MA, Heslip TR, et al. Evaluati on of the anatomic burden of patie nts with hereditary multiple exostoses. Clin Orthop Relat Res. 2007 Sep;462(462):73-9. PMID:17589361 87. Alvarez OA, Kjellin I, Z叩pan CW. Thoracic lymphangiomatosis in a child. J Pediatr Hematol Oncol. 2004 Feb;26 ⑵36-41. PMID:14767208 88. Alvegard TA, Sigurdsson H, Mouridsen H, et al. Adjuvant chemotherapy with doxorubicin in high-grade soft tissue sarcoma: a randomized trial of the Scandinavian Sarcoma Group. J Clin Oncol. 1989 Oct;7(10):1504-13. PMID:2674336 89. Amadio PC, Reiman HM, Dobyns JH. Lipofibromatous hamartoma of nerve. J Hand Surg Am. 1988 Jan;13(1):67-75. PMID:3351231 90. Amanatullah DF, Clark TR, Lopez MJ, et al. Giant cell tumor of bone. Orthopedics. 2014 Feb;37(2) :112-20. PMID:24679193 91. Amary F, Berisha F, Ye H, et al. H3F3A (histone 3.3) G34W immunohistochemistry: a reliable marker defining benign and malignant

giant cell tumor of bone. Am J Surg Pathol. 2017 Aug;41 (8):1059-68. PMID:28505000 91A. Amary F, Markert E, Berisha F, et al. FOS expression in osteoid osteoma and osteoblastoma: a valuable ancillary diagnostic tool. Am J Surg Pathol. 2019 Dec;43(12):16617. PMID:31490237 92. Amary F, Perez-Casanova L, Ye H, et al. Synovial chondromatosis and soft tissue chondroma: extraosseous cartilaginous tumor defined by FN1 gene rearrangement. Mod Pathol. 2019 Dec;32(12): 1762-71. PMID:31273315 93. Amary MF, Bacsi K, Maggiani F, et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 2011 Jul;224(3):334-43. PMID:21598255 94. Amary MF, Berisha F, Bernardi FdelC, et al. Detection of SS18-SSX fusion transcripts in formalin-fixed paraffin-embedded neoplasms: analysis of conventional RT-PCR, qRT-PCR and dual color FISH as diagnostic tools for synovial sarcoma. Mod Pathol. 2007 Apr;20(4):482-96. PMID:17334349 95. Amary MF, Berisha F, Mozela R, et al. The H3F3 K36M mutant antibody is a sensitive and specific marker for the diagnosis of chondroblastoma. Histopathology. 2016 Jul;69(1):121-7. PMID:26844533 96. Amary MF, Damato S, Halai D, et al. Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nat Genet. 2011 Nov 6;43(12):1262-5. PMID:22057236 97. Amary MF, O'Donnell P, Berisha F, et al. Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma: characterization of five cases. Skeletal Radiol. 2013 Jul;42(7):947-57. PMID:23381465 9& Amary MF, Pauwels P, Meulemans E, et al. Detection of beta-catenin mutations in paraffinembedded sporadic desmoid-type fibromatosis by mutation-specific restrictio n enzyme digestion (MSRED): an ancillary diagnostictool. Am J Surg Pathol. 2007 Sep;31(9):1299-309. PMID:17721184 99. Amary MF, Ye H, Forbes G, et al. Isocitrate dehydrogenase 1 mutations (IDH1) and p16/ CDKN2A copy number change in conventional chondrosarcomas. Virchows Arch. 2015 Feb;466(2):217-22. PMID:25432631 100. Amelio JM, Rockberg J, Hernandez RK, et al. Population-based study of giant cell tumor of bone in Sweden (1983-2011). Cancer Epidemiol. 2016 Jun;42:82-9. PMID:27060625 101. Amin MB, Edge S, Greene F, etal., editors. AJCC cancer staging manual. 8th ed. New York (NY): Springer; 2017. 102. Amin MB, Patel RM, Oliveira P, et al. Alveolar soft-part sarcoma of the urinary bladder with urethral recurrence: a unique case with emphasis on differential diagnoses and diagnostic utility of an immunohistochemical panel including TFE3. Am J Surg Pathol. 2006 Oct;30(10):1322-5. PMID:17001165 103. Amir G, Mogle P, Sucher E. Case report 729. Myositis ossificans and aneurysmal bone cyst. Skeletal Radiol. 1992;21 (4):257-9. PMID:1626294 104. Amstalden EM, Carvalho RB, Pacheco EM, et al. Chondromatous hamartoma of the chest wall: description of 3 new cases and literature review. Int J Surg Pathol. 2006 Apr;14(2):119-26. PMID:16703172 105. Amyere M, Aerts V, Brouillard P, et al. Somatic uniparental isodisomy explains multifocality of glomuvenous malformations. Am J Hum Genet. 2013 Feb 7;92(2): 188-96. PMID:23375657 106. Anderson J, Gordon A, Pritchard-Jones

K, et al. Genes, chromosomes, and rhabdomyosarcoma. Genes Chromosomes Cancer. 1999 Dec;26(4):275-85. PMID:10534762 107. Anderson ND, de Borja R, Young MD, et al. Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors. Science. 2018 Aug 31 ;361 (6405):eaam8419. PMID:30166462 108. Anderson T, Zhang L, Hameed M, et al. Thoracic epithelioid malignant vascular tumors: a clinicopathologic study of 52 cases with emphasis on pathologic grading and molecular studies of WWTR1-CAMTA1 fusions.Am J Surg Pathol. 2015Jan;39(1):132-9. PMID:25353289 109. Anderson WJ, Hornick JL. Immunohistochemical correlates of recurrent genetic alterations in sarcomas. Genes Chromosomes Cancer. 2019 Feb;58⑵⑴ 123. PMID:30382607 110. Anderson WJ, Jo VY. Pleomorphic liposarcoma: updates and current differential diagnosis. Semin Diagn Pathol. 2019 Mar;36(2):122-8. PMID:30852046 111. Andreou D, Bielack SS, Carrie D, et al. The influence of tumor- and treatmentrelated factors on the development of local recurrence in osteosarcoma after adequate surgery. An analysis of 1355 patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. Ann Oncol. 2011 May;22(5):1228-35. PMID:21030381 112. Andresen KJ, Sundaram M, Unni KK, et al. Imaging features of low-grade central osteosarcoma of the long bones and pelvis. Skeletal Radiol. 2004 Jul;33(7):373-9. PMID:15175837 113. Angelini A, Guerra G, Mavrogenis AF, et al. Clinical outcome of central conventional chondrosarcoma. J Surg Oncol. 2012 Dec;106(8):929-37. PMID:22649023 114. Angelini A, Hassani M, Mavrogenis AF, et al. Chondroblastoma in adult age. Eur J Orthop Surg Traumatol. 2017 Aug;27(6):843-9. PMID:28634924 115. Angelini A, Mavrogenis AF, Gambarotti M, et al. Surgical treatment and results of 62 patients with epithelioid hemangioendothelioma of bone. J Surg Oncol. 2014 Jun;109(8):791-7. PMID:24643837 116. Angelini A, Mavrogenis AF, Trovarelli G, et al. Telangiectatic osteosarcoma: a review of 87 cases. J Cancer Res Clin Oncol. 2016 Oct;142(10):2197-207. PMID:27469493 117. Angervall L, Dahl I, Kindblom LG, et al. Spindle cell lipoma. Acta Pathol Microbiol Scand A. 1976 Nov;84(6):477-87. PMID:998247 118. Angervall L, Kindblom LG, Haglid K. Dermal nerve sheath myxoma. A light and electron microscopic, histochemical and immunohistochemical study. Cancer. 1984 Apr 15;53(8):1752-9. PMID:6365307 119. Anninga JK, Gelderblom H, Fiocco M, et al. Chemotherapeutic adjuvant treatment for osteosarcoma: Where do we stand? Eur J Cancer. 2011 Nov;47(16):2431-45. PMID:21703851 120. Anract P, De Pinieux G, Cottias P, et al. Malignant giant-cell tumours of bone. Clinico­ pathological types and prognosis: a review of 29 cases. Int Orthop. 1998;22(1 ):19-26. PMID:9549577 121. Antman K, Chang Y Kaposi's sarcoma. N Engl J Med. 2000 Apr 6;342(14):1027-38. PMID:10749966 122. Antman K, Ryan L, Borden E, et al. Pooled results from three randomized adjuvant studies of doxorubicin versus observation in soft tissue sarcoma: 10 year results and review of the literature. In: Salm on SE, editor. Adjuva nt therapy of cancer VI. Philadelphia (PA): WB Saunders; 1990. pp. 529-44.

Refere nces

545

paybal：https://www.paypal.me/andy19801210 123. Antonelli M, Raso A, Mascelli S, et al. SMARCB1/INI1 involvement in pediatric chordoma: a mutational and immunohistochemical analysis. Am J Surg Pathol. 2017 Jan;41(1):56-61. PMID:27635948 124. Antonescu C. Malignant vascular tumors­ an update. Mod Pathol. 2014 Jan;27 S叩pl 1:S30-8. PMID:24384851 125. Antonescu C. Round cell sarcomas beyond Ewing: emerging entities. Histopathology. 2014 Jan;64(1):26-37. PMID:24215322 126. Antonescu CR, Argani P, Erlandson RA, et al. Skeletal and extraskeletal myxoid chondrosarcoma: a comparative clinicopathologic, ultrastructural, and molecular study. Cancer. 1998 Oct 15;83(8):1504-21. PMID:9781944 127. Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005 Jun 1;11(11):4182-90. PMID: 15930355 128. Antonescu CR, Chen HW, Zhang L, et al. ZFP36-FOSB fusion defines a subset of epithelioid hemangioma with atypical features. Genes Chromosomes Cancer. 2014 Nov;53(11):951-9. PMID:25043949 129. Antonescu CR, Dal Cin P, Nafa K, et al. EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma. Genes Chromosomes Cancer. 2007 Dec;46(12):105160. PMID: 17724745 130. Antonescu CR, Elahi A, Healey JH, et al. Monoclonality of multifocal myxoid liposarcoma: confirmation by analysis of TLS-CHOP or EWSCHOP rearrangements. Clin Cancer Res. 2000 Jul；6(7):2788-93. PMID:10914725 131. Antonescu CR, Erlandson RA, Huvos AG. Primary leiomyosarcoma of bone: a clinicopathologic, immunohistochemical, and ultrastructural study of 33 patients and a literature review. Am J Surg Pathol. 1997 Nov;21(11):1281-94. PMID:9351566 132. Antonescu CR, Kawai A, Leung DH, et al. Strong association of SYT-SSX fusion type and morphologic epithelial differentiation in synovial sarcoma. Diagn Mol Pathol. 2000 Mar;9(1 ):1-8. PMID:10718206 133. Antonescu CR, Le Loarer F, Mosquera JM, et al. Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma. Genes Chromosomes Cancer. 2013 Aug;52⑹:775-84. PMID:23737213 134. Antonescu CR, Owosho AA, Zhang L, et al. Sarcomas with CIC-rearrangemenis are a distinct pathologic entity with aggressive outcome: a clinicopathologic and molecular study of 115 cases. Am J Surg Pathol. 2017 Jul;41(7):941-9. PMID:28346326 135. Antonescu CR, Romeo S, Zhang L, et al. Dedifferentiation in gastrointestinal stromal tumor to an anaplastic KIT-negative phenotype: a diagnostic pitfa上 morphologic and molecular characterization of 8 cases occurring either de novo or after imatinib therapy. Am J Surg Pathol. 2013 Mar;37(3):385-92. PMID:23348204 136. Antonescu OR, Rosenblum MK, Pereira P, et al. Sclerosing epithelioid fibrosarcoma: a study of 16 cases and confirmation of a clinicopathologically distinct tumor. Am J Surg Pathol. 2001 Jun;25(6):699-709. PMID: 11395547 137. Antonescu CR, Sung YS, Chen CL, et al. Novel ZC3H7B-BCOR, MEAF6-PHF1, and EPC1-PHF1 fusions in ossifying fibromyxoid tumors-molecular characterization shows genetic overlap with endometrial stromal sarcoma. Genes Chromosomes Cancer. 2014 Feb;53⑵:183—93. PMID:24285434 138. Antonescu CR, Sung YS, Zhang L, et al. Recurrent SRF-RELA fusions define a novel subset of cellular myofibroma/myopericytoma:

546

References

a potential diagnostic pitfall with sarcomas with myogenic differentiation. Am J Surg Pathol. 2017 May;41 (5):677-84. PMID:28248815 139. Antonescu CR, SuurmeijerAJ, Zhang L, et al. Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare novel RET rearrangement. Am J Surg Pathol. 2015 Jul;39(7):957-67. PMID:25723109 140. Antonescu CR, Tschernyavsky SJ, Decuseara R, et al. Prognostic impact of P53 status, TLS-CHOP fusion transcript structure, and histological grade in myxoid liposarcoma: a molecular and clinicopathologic study of 82 cases. Clin Cancer Res. 2001 Dec;7(12):397787.PMID:11751490 141. Antonescu CR, Tschernyavsky SJ, Woodruff JM, et al. Molecular diagnosis of clear cell sarcoma: detection of EWS-ATF1 and MITF-M transcripts and histopathological and ultrastructural analysis of 12 cases. J Mol Diagn. 2002 Feb;4(1):44-52. PMID:11826187 142. Antonescu CR, Yoshida A, Guo T, et al. KDR activating mutations in human angiosarcomas are sensitive to specific kinase inhibitors. Cancer Res. 2009 Sep 15;69(18):7175-9. PMID:19723655 143. Antonescu CR, Zhang L, Chang NE, et al. EWSR1-POU5F1 fusion in soft tissue myoepithelial tumors. A molecular analysis of sixty-six cases, including soft tissue, bone, and visceral lesions, showing comm on involvement of the EWSR1 gene. Genes Chromosomes Cancer. 2010 Dec;49(12):1114-24. PMID:20815032 144. Antonescu CR, Zhang L, Nielsen GP, et al. Consistent t(1;10) with rearrangements of TGFBR3 and MGEA5 in both myxoinflammatory fibroblastic sarcoma and hemosiderotic fibrolipomatous tumor. Genes Chromosomes Cancer. 2011 Oct;50(10):75764. PMID:21717526 145. Antonescu CR, Zhang L, Shao SY, et al. Frequent PLAG1 gene「ear「angements in skin and soft tissue myoepithelioma with ductal differentiation. Genes Chromosomes Cancer. 2013 Jul;52(7):675-82. PMID:23630011 146. Aoki J, Tanikawa H, Ishii K, et al. MR findings indicative of hemosiderin in giant­ cell tumor of bone: frequency, cause, and diagnostic significance. AJR Am J Roentgenol. 1996 Jan;166(1):145-8. PMID:8571864 147. Aoki T, Ozeki Y, Watanabe M, et al. Development of primary leiomyosarcoma of the sternum postirradiation: report of a case. Surg Today. 1998;28(12):1326-8. PMID:9872562 148. Aponte-Tinao LA, Piuzzi NS, Roitman P, et al. A high-grade sarcoma arising in a patient with recurrent benign giant cell tumor of the proximal tibia while receiving treatment with denosumab. Clin Orthop Relat Res. 2015 Sep;473(9):3050-5. PMID:25758379 149. Arata MA, Peterson HA, Dahlin DC. Pathological fractures through non-ossifying fibromas. Review of the Mayo Clinicexperienee. J Bone Joint Surg Am. 1981 Jul;63(6):980-8. PMID:7240338 150. Arbajian E, Koster J, Vult von Steyern F, et al. Inflammatory leiomyosarcoma is a distinct tumor characterized by near-haploidization, few somatic mutations, and a primitive myogenic gene expression signature. Mod Pathol. 2018 Jan;31 (1):93-100. PMID:28884746 151. Arbajian E, Magnusson L, Mertens F, etal. A novel GTF2I/NCOA2 fusion gene emphasizes the role of NCOA2 in soft tissue angiofibroma development. Genes Chromosomes Cancer. 2013 Mar;52(3):330-1. PMID:23225380 152. Arbajian E, Puls F, Antonescu CR, et al. In-depth genetic analysis of sclerosing epithelioid fibrosarcoma reveals recurrent genomic alterations and potential treatment

targets. Clin Cancer Res. 2017 Dec 1;23(23):7426-34. PMID:28939748 153. Arbajian E, Puls F, Magnusson L, et al. Recurrent EWSR1-CREB3L1 gene fusions in sclerosing epithelioid fibrosarcoma. Am J Surg Pathol. 2014 Jun;38(6):801-8. PMID:24441665 154. Argani P, Antonescu CR, lllei PB, et al. Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol. 2001 Jul;159(1):17992. PMID:11438465 155. Argani P, Aulmann S,川ei PB, et al. A distinctive subset of PEComas harbors TFE3 gene fusions. Am J Surg Pathol. 2010 Oct;34(10):1395-406. PMID:20871214 156. Argani P, Aulmann S, Karanjawala Z, et al. Melanotic Xp11 translocation renal cancers: a distinctive neoplasm with overlapping features of PEComa, carcinoma, and melanoma. Am J Surg Pathol. 2009 Apr;33(4):609-19. PMID:19065101 157. Argani P, Facchetti F, Inghirami G, et al. Lymphocyte-rich well-differentiated liposarcoma: report of nine cases. Am J Surg Pathol. 1997Aug;21(8):884-95. PMID:9255251 158. Argani P, Fritsch MK, Shuster AE, et al. Reduced sensitivity of paraffin-based RT-PCR assays for ETV6-NTRK3 fusion transcripts in morphologically defined infantile fibrosarcoma. Am J Surg Pathol. 2001 Nov;25(11):1461-4. PMID:11684968 159. Argani P, Kao YC, Zha叩 L, et al. Primary renal sarcomas with BCOR-CCNB3 gene fusion: a report of 2 cases showing histologic overlap with clear cell sarcoma of kidney, suggesting further link between BCOR-related sarcomas of the kidney and soft tissues. Am J Surg Pathol. 2017 Dec;41(12):1702-12. PMID:28817404 160. Argani P, Lal P, Hutchinson B, et al. Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay. Am J Surg Pathol. 2003 Jun;27(6):750-61. PMID:12766578 161. Argani P, Lewin JR, Edmonds P, et al. Primary renal sclerosing epithelioid fibrosarcoma: report of 2 cases with EWSR1CREB3L1 gene fusion. Am J Surg Pathol. 2015 Mar;39(3):365-73. PMID:25353281 162. Argani P, Zhong M, Reuter VE, et al. TFE3-fusion variant analysis defines specific clinicopathologic associations among Xp11 translocation cancers. Am J Surg Pathol. 2016 Jun;40(6):723-37. PMID:26975036 163. Argenyi ZB. Immunohistochemical characterization of palisaded, encapsulated neuroma. J Cutan Pathol. 1990 Dec;17(6):32935. PMID:1705947 164. Argenyi ZB, Cooper PH, Santa Cruz D. Plexiform and other unusual variants of palisaded encapsulated neuroma. J Cutan Pathol. 1993 Feb;20(1):34-9. PMID:8468415 165. Argenyi ZB, Van Rybroek JJ, Kemp JD, et al. Congenital angiomatoid malignant fibrous histiocytoma. A light-microscopic, immunopathologic, and electron-microscopic study. Am J Dermatopathol. 1988 Feb;10(1):5967. PMID:2845834 166. Arias-Stella JA 3rd, Benayed R, Oliva E, et al. Novel PLAG1 gene rearrangement distinguishes a subset of uterine myxoid leiomyosarcoma from other uterine myxoid mesenchymal tumors. Am J Surg Pathol. 2019 Mar;43(3):382-8. PMID:30489320 167. Arico M, Girschikofsky M, Genereau T, et al. Langerhans cell histiocytosis in adults. Report from the International Registry of the Histiocyte Society. Eur J Cancer. 2003 Nov;39(16):2341-8. PMID:14556926

468. Arico M, Haupt R, Russotto VS al. Langerhans cell histiocytosis jn J generations: a new family and review乌 the literature. Med Pediatr Oncol ?nni Feb;36⑵:314-6. PMID:11452942 ' 169. Arlotta P, Tai AK, Manfioletti G et al Transgenic mice expressing a truncated form of the high mobility group |・c pg嚣 develop adiposity and an abnormally hinh prevalence of lipomas. J Biol Chem. 2000 mL 12:275(19):14394-400. PMID:10747931 V

仃0. Arndt CA, Hammond S, Rodebera D, et al. Significance of persistent mature rhabdomyoblasts in bladder/prostate rhabdomyosarcoma: results from IRS iv j Pediatr Hematol Oncol. 2006 Sep28⑼，56J7 PMID:17006261 171. Arnold MA, Anderson JR, Gastier-Foster JM, et al. Histology, fusion status, and outcome in alveolar rhabdomyosarcoma with low-risk clinical features: a report from the Children s Oncology Group. Pediatr Blood Cancer 2016 Ap「;63⑷:634-9. PMID:26756883 172. Arnold WH. Hereditary bone dysplasia with sarcomatous degeneration. Study of a family. Ann Intern Med. 1973 Jun;78(6) 902-6 PMID:4713573 仃3. Arriola AG, Taylor LA, Asemota E, et al. Atypical retiform hemangioendothelioma arising in a patient with Milroy disease: a case report and review of the literature. J Cutan Pathol 2017 Jan;44(1 ):98-103. PMID:27730656 174. Arsenovic N, Ramaiya A, Moreira R. Symplastic glomangioma: information review and addition of a new case. I nt J Surg Pathol. 2011 Aug;19(4):499-501. PMID:19448066 175. Asahina M, Saito T, Arakawa A, et al. A case of primary spindle cell variant of embryonal rhabdomyosarcoma of the prostate. Int J Clin Exp Pathol. 2014 Jul 15;7(8):5181-5. PMID:25197394 仃6. Asano N, Yoshida A, Ogura K, et al. Prognostic value of relevant clinicopathologic variables in epithelioid sarcoma: a multiinstitutional retrospective study of 44 patients. Ann Surg Oncol. 2015 Aug;22(8):2624-32. PMID:25663591 177. Ashar HR, Fejzo MS, Tkachenko A, et al. Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains. Cell. 1995 Jul 14;82(1):57-65. PMID:7606786 仃8. Asmandar S, Ranganathan S, Ramirez R, et al. Myxoid lipoblastoma and mimickers on fine-needle biopsy in a child. Pediatr Dev Pathol. 2019 Mar-Apr;22 ⑵:157/0. PMID:30322346 179. Asp J, Sangiorgi L, Inerot SE, et al. Changes of the p16 gene but not the p53 gene in human chondrosarcoma tissues. Int J Cance匚 2000 Mar 15;85(6):782-6. PMID:10709095 180. Assoun J, Richardi G, Railhac JJ, et al. Osteoid osteoma: MR imaging versus CT. Radiology. 1994 Apr;191(1)：217-23. PMID:8134575 181. Atalar H, Gunay C, Yildiz Y, et al. Primary leiomyosarcoma of bone: a report on three patients. Clin Imaging. 2008 JulAug;32糾:321-5. PMID:18603190 182. Atanaskova Mesinkovska N, Buehler D, McClain CM, et al. Ossifying fibromyxoid tumor: a clinicopathologic analysis of 26 subcutaneous tumors with emphasis on differential diagnosis and prognostic factors. J Cutan Pathol. 20 8ep;42(9):622-31. PMID:25950586 183. Attwooll C, Tariq M, Harris M, et al. Identification of a novel fusion gene invo 需 hTAFII68 and CHN from a t(9;17)(q22；q鬥 translocation in an extraskeletal niyxw chondrosarcoma. Oncogene. 299 9;18(52):7599-601. PMID:10602520

paybal：https://www.paypal.me/andy19801210 184. Ausmus GG, Piliang MP, Bergfeld WF, et al. Soft-tissue perineurioma in a 20-year-old patient with neurofibromatosis type 1 (NF1): report of a case and review of the literature. J Cutan Pathol. 2007 8ep;34(9):726-30. PMID:17696922 185. Austin RM, Mack GR, Townsend CM, et al. Infiltrating (intramuscular) lipomas and angiolipomas. A clinicopathologic study of six cases. Arch Surg. 1980 Mar;115(3):281-4. PMID:7356383 186. Aw SJ, Chang KTE. Clear cell sarcoma of the kidney. Arch Pathol Lab Med. 2019 Aug；143(8):1022-6. PMID:30628851 187. Ayala AG, Ro JY, Bolio-Solis A, et al. Mesenchymal hamartoma of the chest wall in infants and children: a clinicopathological study of five patients. Skeletal Radiol. 1993 Nov;22(8):569-76. PMID:8291008 188. Ayala AG, Ro JY, Raymond AK, et al. Small cell osteosarcoma. A clinicopathologic study of 27 cases. Cancer. 1989 Nov 15;64(10):216273. PMID:2804905 189. Aydin H, Magi-Galluzzi C, Lane BR, et al. Renal angiomyolipoma: clinicopathologic study of 194 cases with emphasis on the epithelioid histology and tuberous sclerosis association. Am J Surg Pathol. 2009 Feb;33⑵:289-97. PM ID:18852677 190. Azura M, Vanel D, Alberghini M, et al. Parosteal osteosarcoma dedifferentiating into telangiectatic osteosarcoma: importance of lytic changes and fluid cavities at imaging. Skeletal Radiol. 2009 Jul;38(7):685-90. PMID:19271217 191. Azzopardi JG, Iocco J, Salm R. Pleomorphic lipoma: a tumour simulating liposarcoma. Histopathology. 1983 Jul;7(4):511-23. PMID:6884998 192. Bacchini P, Inwards C, Biscaglia R, et al. Chondroblastoma-like osteosarcoma. Orthopedics. 1999 Mar;22 ⑶:337-9. PMID:10192265 193. Bacci G, Fabbri N, Balladelli A, et al. Treatment and prognosis for synchronous multifocal osteosarcoma in 42 patients. J Bone Joint Surg Br. 2006 Aug;88(8):1071-5. PMID:16877608 194. Bacci G, Ferrari S, Bertoni E et al. Prognostic factors in nonmetastatic Ewing's sarcoma of bone treated with adjuvant chemotherapy: analysis of 359 patients at the Istituto Ortopedico Rizzoli. J Clin Oncol. 2000 Jan;18(1):4-11. PMID:10623687 195. Bacci G, Ferrari S, Ruggieri P, et al. Telangiectatic osteosarcoma of the extremity: neoadjuvant chemotherapy in 24 cases. Acta Orthop Scand. 2001 Apr;723:167-72. PMID:11372948 196. Bacci G, Longhi A, Ferrari S, et al. Prognostic significance of serum alkaline phosphatase in osteosarcoma of the extremity treated with neoadjuvant chemotherapy: recent experience at Rizzoli Institute. Oncol Rep. 2002 Jan-Feb;9(1):171-5. PMID:11748477 197. Bacci G, Longhi A, Versari M, et al. Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution. Cancer. 2006 Mar ,06⑸:1154-61. PMID:16421923 198. Bacci G, Picci P, Mercuri M, et al. Neoadjuvant chemotherapy for high grade malignant fibrous histiocytoma of bone. Clin Orthop Relat Res. 1998 Jan;(346): 178-89. PMID:9577426 199. Bague S, Folpe AL. Dermatofibrosarcoma protuberans presenting as a subcutaneous mass: a clinicopathological study of 15 cases with exclusive or near-exclusive subcutaneous involvement. Am J Dermatopathol. 2008 Aug;30(4):327-32. PMID:18645303

200. Bahadir B, Behzatoglu K, Hacihasanoglu E, et al. Atypical spindle cell/pleomorphic lipomatous tumor: a clinicopathologic, immunohistochemical, and molecular study of 20 cases. Pathol Int. 2018 Oct;68(10):550-6. PMID:30198097 201. Bahk WJ, Mirra JM. Pseudoanaplastic tumors of bone. Skeletal Radiol. 2004 Nov;33(11):641-8. PMID:15365783 202. Bahrami A, Dalton JD, Krane JF, et al. A subset of cutaneous and soft tissue mixed tumors are genetically linked to their salivary gland counterpart. Genes Chromosomes Cancer. 2012 Feb;51 (2):140-8. PMID:22038920 203. Bahrami A, Folpe AL. Adult-type fibrosarcoma: a reevaluation of 163 putative cases diagnosed at a single institution over a 48-year period. Am J Surg Pathol. 2010 Oct;34(10):1504-13. PMID:20829680 204. Bahrami A, Gown AM, Baird GS, et al. Aberrant expression of epithelial and neuroendocrine markers in alveolar rhabdomyosarcoma: a potentially serious diagnostic pitfail. Mod Pathol. 2008 Jul;21 ⑺:795-806. PMID:18487991 205. Bahrami A, Lee S, Schaefer IM, et al. TERT promoter mutations end prognosis in solitary fibrous tumor. Mod Pathol. 2016 Dec;29(1.2):1511-22.PMID:27562490 206. Bahrami A, Weiss SW, Montgomery E, et al. RT-PCR analysis for FGF23 using paraffin sections in the diagnosis of phosphaturic mesenchymal tumors with and without known tumor induced osteomalacia. Am J Surg Pathol. 2009 Sep;33(9):1348-54. PMID:19609206 207. Baker AC, Rezeanu L, O'Laughlin S, et al. Juxtacortical chondromyxoid fibroma of bone: a unique variant: a case study of 20 patients. Am J Surg Pathol. 2007 Nov;31(11):1662-& PMID:18059222 20& Balachandran K, Allen PW, MacCormac LB. Nuchal fibroma. A clinicopathological study of nine cases. Am J Surg Pathol. 1995 Mar; 19(3):313-7. PMID:7872429 209. Balakumar R, Farr MRB, Fernando M, et al. Adult-type rhabdomyoma of the larynx in Birt-Hogg-Dube syndrome: evidence for a real association. Head Neck Pathol. 2019 Sep;13(3):507-11. PMID:29744825 210. Baldauf MC, Orth MF, Dallmayer M, et al. Robust diagnosis of Ewing sarcoma by immu no histochemical detecti on of super­ enhancer-driven EW8R1-ETS targets. Oncotarget. 2017 Aug 4;9(2):1587-601. PMID:29416716 211. Baldini EH, Goldberg J, Jenner C, et al. Long-term outcomes after function­ sparing surgery without radiotherapy for soft tissue sarcoma of the extremities and trunk. J Clin Oncol. 1999 Oct;17(10):3252-9. PMID:10506627 212. Baldini EH, Lapidus MR, Wang Q, et al. Predictors for major wound complications followi ng preoperative radiotherapy and surgery for soft-tissue sarcoma of the extremities and trunk: importance of tumor proximity to skin surface. Ann Surg Oncol. 2013 May;20(5):1494-9. PMID:23242820 213. Bale TA, Oviedo A, Kozakewich H, et al. Intracranial myxoid mesenchymal tumors with EWSR1-CREB family gene fusions: myxoid variant of angiomatoid fibrous histiocytoma or novel entity? Brain Pathol. 2018 Mar;28⑵:勺8391.PMID:28281318 214. Ballester LY, Cantu MD, Lim KPH, et al. The use of BRAF V600E mutation-specific immunohistochemistry in pediatric Langerhans cell histiocytosis. Hematol Oncol. 2018 Feb;36(1 ):307-15. PMID:28219109 215. Ballinger ML, Best A, Mai PL, et al. Baseline surveillance in Li-Fraumeni syndrome

using whole-body magnetic resonance imaging: a meta-analysis. JAMA Oncol. 2017 Dec 1;3(12):1634-9. PMID:28772291 216. Ballinger ML, Goode DL, Ray-Coquard I, et al. Monogenic and polygenic determinants of sarcoma risk: an international genetic study. Lancet Oncol. 2016 Sep;17(9):1261-71. PMID:27498913 217. Bane BL, Evans HL, Ro JY, et al. Extraskeletal osteosarcoma. A clinicopathologic review of 26 cases. Cancer. 1990 Jun 15;65(12):2762-70. PMID:2160317 218. Banito A, Li X, Laporte AN, et al. The SS18SSX oncoprotein hijacks KDM2B-PRC1.1 to drive synovial sarcoma. Cancer Cell. 2018 Mar 12;33⑶:527-541.e8. PMID:29502955 219. Barker N. The canonical Wnt/betacateni n sign ailing pathway. Methods Mol Biol. 2008;468:5-15. PMID:19099242 220. Barnoud R, Sabourin JC, Pasquier D, et al. Immunohistochemical expression of WT1 by desmoplastic small round cell tumor: a comparative study with other small round cell tumors. Am J Surg Pathol. 2000 Jun;24⑹:8306. PMID:10843285 221. Barr FG, Duan F, Smith LM, etal. Genomic and clinical analyses of 2p24 and 12q13-q14 amplification in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group. Genes Chromosomes Cancer. 2009 Aug;48(8):661-72. PMID:19422036 222. Barr FG, Galili N, Holick J, et al. Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma. Nat Genet. 1993 Feb;3(2):113-7. PMID:8098985 223. Barr FG, Qualman 8J, Macris MH, et al. Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions. Cancer Res. 2002 Aug 15;62(16):4704-10. PMID:12183429 224. Barretina J, Taylor BS, Banerji S, et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat Genet. 2010 Aug;42(8):715-21. PMID:20601955 225. Barrott JJ, Ilium BE, Jin H, et al. Paracrine osteoprotegerin and p-catenin stabilization support synovial sarcomagenesis in periosteal cells. J Clin Invest. 2018 Jan 2;128(1 ):207-18. PMID:29202462 226. Barry HC. Paget's disease of bone. Edinburgh (UK): E&S Livingstone Ltd; 1969. 227. BarthelmeB S, Geddert H, Boitze C, et al. Solitary fibrous tumors/hemangiopericytomas with different variants of the NAB2-STAT6 gene fusion are characterized by specific histomorphology and distinct clinicopathological features. Am J Pathol. 2014 Apr; 184(4):120918. PMID:24513261 228. Bartsch O, Wuyts W, Van Hui W, et al. Delineation of a contiguous gene syndrome with multiple exostoses, enlarged parietal foramina, craniofacial dysostosis, and mental retardation, caused by deletions in the short arm of chromosome 11.Am J Hum Genet. 1996 Apr;58(4):734-42. PMID:8644736 229. Bartuma H, Domanski H代 Von Steyern FV, et al. Cytogenetic and molecular cytogenetic findings in lipoblastoma. Cancer Genet Cytogenet. 2008 May;183(1):60-3. PMID:18474299 230. Bartuma H, Hallor KH, Panagopoulos I, et al. Assessment of the clinical and molecular impact of different cytogenetic subgroups in a series of 272 lipomas with abnormal karyotype. Genes Chromosomes Cancer. 2007 Jun;46(6):594-606. PMID:17370328 231. Bartuma H, Nord KH, Macchia G, et al. Gene expression and single nucleotide polymorphism array analyses of spindle cell lipomas and conventional lipomas with 13q14

deletion. Genes Chromosomes Cancer. 2011 Aug;50(8):619-32. PMID:21563233 232. Bartuma H, Panagopoulos I, Collin A, et al. Expression levels of HMGA2 in adipocytic tumors correlate with morphologic and cytogenetic subgroups. Mol Cancer. 2009 Jun 9;8:36. PMID:19508721 233. Barzenje DA, Kolstad A, Ghanima W, et al. Long-term outcome of patients with solitary plasmacytoma treated with radiotherapy: a population-based, single-center study with median follow-up of 13.7 years. Hematol Oncol. 2018 Feb;36(1 ):217-23. PMID:28393375 234. Ba§arir K, §ahin E, Kalem M, et al. Parosteal lipoma as a rare cause of peripheral neuropathy and local irritation: a report of 12 cases. Acta Orthop Traumatol Turc. 2017 Dec;51 (6):474-7. PMID:29128312 235. Batalla A, Suh-Oh HJ, Pardavila R, et al. True cutaneous chondroma: a case report. J Cutan Pathol. 2015 Sep;42(9):657-9. PMID:25998426 236. Bauer TW, Dorfman HD, Latham JT Jr. Periosteal chondroma. A clinicopathologic study of 23 cases. Am J Surg Pathol. 1982 Oct;6(7):631-7. PMID:7180962 237. Baumhoer D, Amary F, Flanagan AM. An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing. Genes Chromosomes Cancer. 2019 Feb;58⑵:88-99. PMID:30582658 238. Baumhoer D, Brunner P, EppenbergerCastoriS, etal. Osteosarcomas of the jaws differ from their peripheral counterparts and require a distinct treatment approach. Experiences from the DOESAK Registry. Oral Oncol. 2014 Feb;50(2):147-53. PMID:24246156 239. Baumhoer D, Kovac M, Sperveslage J, et al. Activating mutations in the MAPkinase pathway define non-ossifying fibroma of bone. J Pathol. 2019 May;248(1):116-22. PMID:30549028 240. Baumhoer D, Smida J, Nathrath M, et al. The nature of the characteristic cementum-like matrix deposits in the walls of simple bone cysts. Histopathology. 2011 8ep;59(3):390-6. PMID:22034879 ' 241. Baxter KJ, Govsyeyev N, Namm JP, et al. Is multimodality therapy necessary for the management of pure myxoid liposarcomas? A multi-institutional series of pure myxoid liposarcomas of the extremities and torso. J Surg Oncol. 2015 Feb;111 (2):146-51. PMID:25213588 242. Bean GR, Joseph NM, Folpe AL, et al. Recurrent GNA14 mutations in anastomosing haemangiomas. Histopathology. 2018 Aug;73(2):354-7. PMID:29574926 243. Bean GR, Joseph NM, Gill RM, et al. Recurrent GNAQ mutations in anastomosing hemangiomas. Mod Pathol. 2017 May;30(5):722-7. PMID:28084343 244. Beck AH, Lee CH, Witten DM, et al. Discovery of molecular subtypes in leiomyosarcoma through in teg rative molecular profiling. Oncogene. 2010 Feb 11;29⑹:84554. PMID:19901961 245. Beckett JH, Jacobs AH. Recurring digital fibrous tumors of childhood: a review. Pediatrics. 1977 Mar;59(3):401-6. PMID:840560 246. Bedi DG, John SD, Swischuk LE. Fibromatosis colli of infancy: variability of sonographic appearance. J Clin Ultrasound. 1998 Sep;26(7):345-8. PMID:9719983 247. Beer TW, Drury P, Heenan PJ. Atypical fibroxanthoma: a histological and immunohistochemical review of 171 cases. Am J Dermatopathol. 2010 Aug;32(6):533-40. PMID:20526171 248. BeertE, Brems H, Daniels B, etal.Atypical neurofibromas in neurofibromatosis type 1 are

Refere nces

547

paybal：https://www.paypal.me/andy19801210 premalignant tumors. Genes Chromosomes Cancer. 2011 Dec;50(12):1021-32. PMID:21987445 249. Beghini A, Tibiletti MG, Roversi G, et al. Germline mutation in the juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa. Cancer. 2001 Aug 1;92(3):657-62. PMID:11505412 250. Begin LR, Clement PB, Kirk ME, et al. Aggressive angiomyxoma of pelvic soft parts: a clinicopathologic study of nine cases. Hum Pathol. 1985Jun;16(6):621-8. PMID:3997139 251. Begueret H, Galateau-Salle F, Guillou L, et al. Primary intrathoracic synovial sarcoma: a clinicopathologic study of 40 t(X;18)-positive cases from the French Sarcoma Group and the Mesopath Group. Am J Surg Pathol. 2005 Mar;29(3):339-46. PMID:15725802 252. Begum S, Emami N, Cheung A, et al. Cell­ type-specific regulation of distinet sets of gene targets by Pax3 and Pax3/FKHR. Oncogene. 2005 Mar 10;24(11):1860-72. PMID:15688035 253. Beham A, Badve S, Suster S, etal. Solitary myofibroma in adults: clinicopathological analysis of a series. Histopathology. 1993 Apr;22(4):335-41. PMID:8514276 254. Beham A, Fletcher CD. Intramuscular angioma: a clinicopathological analysis of 74 cases. Histopathology. 1991 Jan;18(1):53-9. PMID:2013460 255. Behjati S, Gundem G, Wedge DC, et al. Mutational sign atures of ion izing radiati on in second malignancies. Nat Commun. 2016 Sep 12;7:12605. PMID:27615322 256. Behjati S, Tarpey PS, Haase K, et al. Recurre nt mutati on of IGF signailing genes and distinet patterns of genomic rearrangement in osteosarcoma. Nat Commun. 2017 Jun 23;8:15936. PMID:28643781 257. Behjati S, Tarpey PS, Presneau N, et al. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat Genet. 2013 Dec;45(12):1479-82. PMID:24162739 258. Behjati S, Tarpey PS, Sheldon H, et al. Recurrent PTPRB and PLCG1 mutations in angiosarcoma. Nat Genet. 2014Apr;46(4):3769. PMID:24633157 259. Behzadi AH, Raza SI, Carrino JA, et al. Applications of PET/CT and PET/MR imaging in primary bone malignancies. PET Clin. 2018 Oct; 13(4):623-34. PMID:30219192 260. Bekers EM, Eijkelenboom A, Grunberg K, et al. Myositis ossificans - another condition with USP6 rearrangement, providing evidenee of a relationship with nodular fasciitis and aneurysmal bone cyst. Ann Diagn Pathol. 2018 Jun;34:56-9. PMID:29661729 261. Bekers EM, Groenen PJTA, Verdijk MAJ.et al. Soft tissue an giofibroma: clinicopathologic, immunohistochemical and molecular analysis of 14 cases. Genes Chromosomes Cancer. 2017 Oct;56(10):750-7. PMID:28639284 262. Belinsky MG, Rink L, Cai KQ, et al. Somatic loss of function mutations in neurofibromin 1 and MYC associated factor X genes identified by exome-wide sequencing in a wild-type GIST case. BMC Cancer. 2015 Nov 10;15:887. PMID:26555092 263. Bella GP, Manivel JC, Thompson RC Jr, et al. Intramuscular hemangioma: recurrenee risk related to surgical margins. Clin Orthop Relat Res. 2007 Jun;459(459):186-91. PMID:17438470 264. Bellini C, Rutigliani M, Boccardo FM, et al. Nuchal translucency and lymphatic system maldevelopment. J Perinat Med. 2009;37⑹:673-6. PMID:19591554 265. Bellon N, Fraitag S, Miquel C, et al. Cutaneous location of atypical teratoid/ rhabdoid tumour. Acta Derm Venereol. 2014

548

References

Jul;94(4):454-6. PMID:24284868 266. Ben-lzhak O, Elmalach I, Kerner H, et al. Pericardial myolipoma: a tumour presenting as a mediastinal mass and containing oestrogen receptors. Histopathology. 1996 Aug;29(2):184-6. PMID:8872156 267. Benli IT, Akalin S, Boysan E, et al. Epidemiological, clinical and radiological aspects of osteopoikilosis. J Bone Joint Surg Br. 1992 Jul;74(4):504-6. PMID:1624505 268. Benna C, Simioni A, Pasquali S, et al. Genetic susceptibility to bone and soft tissue sarcomas: a field synopsis and meta-analysis. Oncotarget. 2018 Apr 6;9(26):18607-26. PMID:29719630 269. Bennett JA, Braga AC, Pinto A, et al. Uteri ne PEComas: a morphologic, immunohistochemical, and molecular analysis of 32 tumors. Am J Surg Pathol. 2018 Oct;42(10): 1370-83. PMID:30001237 270. Bennicelli JL, Edwards RH, Barr FG. Mechanism for transcriptional gain of function resulting from chromosomal translocation in alveolar rhabdomyosarcoma. Proc Natl Acad Sci USA. 1996 May 28;93(11):5455-9. PMID:8643596 271. Berberi A, Noujeim Z. Epidemiology and relationships between CD4+ counts and oral lesions among 50 patients infected with human immunodeficiency virus. J Int Oral Health. 2015 Jan;7(1):18-21.PMID:25709361 272. Berg JC, Scheithauer BW, Spinner RJ, et al. Plexiform schwannoma: a clinicopathologic overview with emphasis on the head and neck region. Hum Pathol. 2008 May;39(5):633-40. PMID:18439936 273. Bergh P, Meis-Kindblom JM, Gherlinzoni F, et al. Synovial sarcoma: identification of low and high risk groups. Cancer. 1999 Jun 15;85(12):2596-607. PMID:10375108 274. Berglund JA, Tella SH, Tuthill KF, et al. Scoliosis in fibrous dysplasia/McCune-Albright syndrome: factors associated with curve progression and effects of bisphosphonates. J Bone Miner Res. 2018 Sep;33(9):1641-8. PMID:29669167 275. Berlin O, Stener B, Kindblom LG, et al. Leiomyosarcomas of venous origin in the extremities. A correlated clinical, roentgenologic, and morphologic study with diagnostic and surgical implications. Cancer. 1984 Nov 15;54(10):2147-59. PMID:6488138 276. Bernado L, Admella C, Lucaya J, et al. Infantile fibrosarcoma of femur. Pediatr Pathol. 1987;7(2):201-7. PMID:3658843 277. Bernal K, Nelson M, Neff JR, et al. Translocation (2;11)(q31;q12) is recurrent in collagenous fibroma (desmoplastic fibroblastoma). Cancer Genet Cytogenet 2004 Mar;149(2):161-3. PMID: 15036892 278. Bernard MA, Hall CE, Hogue DA, et al Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes. Cell Motil Cytoskeleton. 2001 Feb;48⑵:149-62. PMID:竹 169766 279. Bernard SA, Murphey MD, Flemming DJ, et al. Improved differentiatio n of benign osteochondromas from secondary chondrosarcomas with standardized measurement of cartilage cap at CT and MR imaging. Radiology. 2010 Jun;255(3):857-65. PMID:20392983 280. Bernstein KE, Lattes R. Nodular (pseudosarcomatous) fasciitis, a nonrecurrent lesion: clinicopathologic study of 134 cases. Cancer. 1982 Apr 15;49(8): 1668-78. PMID:6279273 281. Bernthal NM, Putnam A, Jones KB, et al. The effect of surgical margins on outcomes for low grade MPNSTs and atypical neurofibroma. J Surg Oncol. 2014 Dec;110⑺:813-6. PMID:25111615

282. Berres ML, Lim KP, Peters T, et al. BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med. 2014 Apr 7;211 (4):669-83. PMID:24638167 283. Berry AB, Jaffee I, Greenberg M, et al. Nodular fasciitis: definitive diagnosis by fine needle aspiration. Acta Cytol. 2016;60(1):1924. PMID:26981858 284. Berry M, Mankin H, Gebhardt M, et al. Osteoblastoma: a 30-year study of 99 cases. J Surg Oncol. 2008 Sep 1;98(3):179-83. PMID:18561158 285. Bertario L, Russo A, Sala P, etal. Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis. Int J Cancer. 2001 Mar 20;95(2):102-7. PMID:11241320 286. Bertoni F, Bacchini P, Capanna R, et al. Solid variant of aneurysmal bone cyst. Cancer. 1993 Feb 1;71 (3):729-34. PMID:8431852 287. Bertoni F, Bacchini P, Donati D, et al. Osteoblastoma-like osteosarcoma. The Rizzoli Institute experience. Mod Pathol. 1993 Nov;6⑹707-16. PMID:8302813 28& Bertoni F, Bacchini P, Staals EL. Giant cell-rich osteosarcoma. Orthopedics. 2003 Feb;26(2):179-81. PMID:12597223 289. Bertoni F, Bacchini P, Staals EL. Malignancy in giant cell tumor of bone. Cance匚 2003 May 15;97(10):2520-9. PMID:12733152 290. Bertoni F, Bacchini P, Staals EL, et al. Dedifferentiated parosteal osteosarcoma: the experience of the Rizzoli Institute. Cancer. 2005 Jun 1;103(11):2373-82. PMID:15852358 291. Bertoni F, Boriani S, Laus M, et al. Periosteal chondrosarcoma and periosteal osteosarcoma. Two distinct entities. J Bone Joint Surg Br. 1982;64 ⑶:370-6. PMID:7096408 292. Bertoni F, C即anna R, Calderoni P, et al. Primary central (medullary) fibrosarcoma of bone. Semin Diagn Pathol. 1984 Aug;1 ⑶:18598. PMID:6599928 293. Bertoni F, Present D, Bacchini P, et al. The Istituto Rizzoli experience with small cell osteosarcoma. Cancer. 1989 Dec 15;64(12):2591-9. PMID:2684389 294. Bertoni F, Present D, Sudanese A, et al. Giant-cell tumor of bone with pulmonary metastases. S仪 case reports and a review of the literature. Clin Orthop Relat Res. 1988 Dec;(237):275-85. PMID:3056645 295. Bertoni F, Unni KK, Beabout JW, et al. Chondroblastoma of the skull and facial bones. Am J Clin Pathol. 1987 Jul;88(1):1-9. PMID:3604981 296. Bertoni F, Unni KK, Beabout JW, et al. Chondrosarcomas of the synovium. Cancer. 1991 Jan 1;67(1):155-62. PMID:1985712 297. Bertoni F, Unni KK, Beabout JW, et al. Malignant giant cell tumor of the tendon sheaths and joints (malignant pigmented villonodular synovitis). Am J Surg Pathol. 1997 Feb;21 (2):153-63. PMID:9042281 298. Bertoni F, Unni KK, Beabout JW, et al. Parosteal osteoma of bones other than of the skull and face. Cancer. 1995 May 15;75(10):2466-73. PMID:7736390 299. Bertucci F, Bouvier-Labit C, Finetti P, et al. Gene expression profiling of solitary fibrous tumors. PLoS One. 2013 May 29;8(5):e64497. PMID:23734203 300. Bhagavan BS, Dorfman HD, Murthy MS, et al. Intravascular b「onchiolo-alveolar tumor (IVBAT): a low-grade sclerosing epithelioid angiosarcoma of lung. Am J Surg Pathol. 1982 Jan;6(1):41-52. PMID:6282146 301. Bhagavathi S, Fu K. Primary lymphoma of bone: a review. Semin Diagn Pathol. 2014 Jan;31 (1):48-52. PMID:24680182 302. Bhagavathi S, Micale MA, Les K, et al.

Primary bone diffuse large B-cell lymphoma， clinicopathologic study of 21 cases and review of literature. Am J Surg Pathol 200Q Oct;33(10):1463-9. PMID:19675454 ' 303. Bhamra JS, Al-Khateeb H, Dhinsa BS et al. Chondromyxoid fibroma management' a single institution experience of 22 cases World J Surg Oncol. 2014 Sep 12,12,283 PMID:25217119 304. Bhat A, Layfield LJ, Tewari SO, et al Solitary fibrous tumor of the ischioanal fossa-a multidisciplinary approach to management with radiologic-pathologic correlation. Radiol Case Rep. 2018 Mar 2; 13(2):468-74 PMID:29682137 305. Bhattacharya B, Dilworth HP, lacobuzioDonahue C, et al. Nuclear beta-catenin expression distinguishes deep fibromatosis from other benign and malignant fibroblastic and myofibroblastic lesions. Am J Surg Pathol 2005 May;29(5):653-9. PMID:15832090 ' 306. Bhawan J, Bacchetta C, Joris I, et al. A myofibroblastic tumor. Infantile digital fibroma (recurrent digital fibrous tumor of childhood). Am J Pathol. 1979 Jan;94(1):19-36. PMID:216266 307. Bhutoria B, Konar A, Chakrabarti S, et al. Retiform hemangioendothelioma with lymph node metastasis: a rare entity. Indian J Dermatol Venereol Leprol. 2009 JanFeb;75(1):60-2. PMID:19172034 308. Bianchi G, Sambri A, Righi A, et al. Histology and grading are important prognostic factors in synovial sarcoma. Eur J Surg Oncol 2017 S即;43(9):1733-9. PMID:28579008 309. Bianchini L, Birtwisle L, Saada E, et al. Identification of PPAP2B as a novel recurrent translocation partner gene of HMGA2 in lipomas. Genes Chromosomes Cancer. 2013 Jun;52(6):580-90. PMID:23508853 310. Bianco P, Riminucci M, Majolagbe A, et al. Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in nonMcCune-Albright fibrous dysplasia of bone. J Bone Miner Res. 2000 Jan;15(1):120-8. PMID:10646121 311. Bianco P, Wientroub S. Fibrous dysplasia. In: Glorieux FH, Pettifor JM, Juppner H, editors. Pediatric bone. Biology and diseases. 2nd ed. London (UK): Elsevier; 2011. pp. 589-614. 312. Biegel JA, Conard K, Brooks JJ. Translocation (11;22)(p13;q12): primary change in intra-abdominal desmoplastic small round cell tumor. Genes Chromosomes Cancer. 1993Jun;7(2):119-21.PMID:7687454 313. Biegel JA, Zhou JY, Rorke LB, etal.Germ­ line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 1999 Jan 1;59(1):74-9. PMID:9892189 314. Bielack SS, Kempf-Bielack B, Delling G, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002 Feb 1;20(3):776-90. PMID:11821461 315. Bielack SS, Schroeders 代 Fuchs N, et al. Malignant fibrous histiocytoma of bone: a retrospective EMSOS study of 125 cases. Acta Orthop Scand. 1999 Aug;70(4):353-60. PMID:10569265 316. Bigby SM, Symmans PJ, Miller MV, et al. Aggressive angiomyxoma [corrected] of the female genital tract and pelvis-clinicopathologic features with immunohistochemical analysis. Int J Gynecol Pathol. 2011 Sep;30(5):505-13. PMID:21804399 317. Biggar RJ. AIDS-related cancers in the era of highly active antiretroviral therapy. Oncology (Williston Park). 2001 Apr;15(4):439-40. discussion 448-9. PMID:11346932 318. Billeret Lebranchu V. [Granular *. tumoi Epidemiology of 263 cases]. r

r p c 3 A $ di 二 S 3： al fe Ar Pf

paybal：https://www.paypal.me/andy19801210 Anat Cytol Pathol. 1999;47(1):26-30. French. PMID:10089680 319. Billing V, Mertens F, Domanski HA, et al. Deep-seated ordinary and atypical lipomas: histopathology, cytogenetics, clinical features, and outcome in 215 tumours of the extremity and trunk wall. J Bone Joint Surg Br. 2008 Jul;90(7):929-33. PMID: 18591605 320. Billings SD, Folpe AL. Diagnostically challenging spindle cell lipomas: a report of 34 "low-fat" and "fat-free" variants. Am J Dermatopathol. 2007 Oct;29⑸:437-42. PMID:1789O91O 321. Billings SD, Folpe AL, Weiss SW. Do leiomyomas of deep soft tissue exist? An analysis of highly differentiated smooth muscle tumors of deep soft tissue supporting two distinct subtypes. Am J Surg Pathol. 2001 Sep；25(9): 1134-42. PMID:11688572 322. Billings SD, Folpe AL, Weiss SW. Epithelioid sarcoma-like hemangioendothelioma. Am J Surg Pathol. 2003 Jan;27(1):48-57. PMID:12502927 323. Billings SD, Giblen G, Fanburg-Smith JC. Superficial low-grade fibromyxoid sarcoma (Evans tumor): a clinicopathologic analysis of 19 cases with a unique observation in the pediatric population. Am J Surg Pathol. 2005 Feb;29⑵:204-10. PMID:15644777 324. Billings SD, McKenney JK, Folpe AL, et al. Cutaneous angiosarcoma following breast-conserving surgery and radiation: an analysis of 27 cases. Am J Surg Pathol. 2004 Jun;28⑹:781-8. PMID:15166670 325. Bindiganavile S, Han I, Yun JY, etal. Long­ term outcome of chondrosarcoma: a single institutional experience. Cancer Res Treat. 2015 Oct;47(4):897-903. PMID:25687868 326. Binh MB, Guillou L, Hostein I, et al. Dedifferentiated liposarcomas with diverge nt myosarcomatous differentiation developed in the internal trunk: a study of 27 cases and comparison to conventional dedifferentiated liposarcomas and leiomyosarcomas. Am J Surg Pathol. 2007 Oct;31 (10):1557-66. PMID:17895758 327. Binh MB, Sastre-Garau X, Guillou L, et al. MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes: a comparative analysis of 559 soft tissue neoplasms with genetic data. Am J Surg Pathol. 2005 Oct;29(10):1340-7. PMID:16160477 328. Birch JM, Hartley AL, Tricker KJ, et al. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 1994 Mar 1;54(5): 1298-304. PMID:8118819 329. Birdsall SH, Shipley JM, Summersgill BM, et al. Cytogenetic findings in a case of nodular fasciitis of the breast. Cancer Genet Cytogenet. 1995 Jun;81 (2):166-8. PMID:7621414 330. Bisceglia M, D'Angelo VA, Guglielmi G, et al. Dedifferentiated chordoma of the thoracic spine with rhabdomyosarcomatous differentiation. Report of a case and review of the literature. Ann Diagn Pathol. 2007 Aug;11(4):262-73. PMID:17630110 331 Bisceglia M, Magro G. Low-grade myofibroblastic sarcoma of the salivary gland. Am J Surg Pathol. 1999 Nov;23(11):1435-6. PMID:10555016 332. Bishop JA, Alaggio R, Zhang L, et al. Adamantinoma-like Ewing family tumors of the head and neck: a pitfall in the differential diagnosis of basaloid and myoepithelial carcinomas. Am J Surg Pathol. 2015 Sep;39(9):1267-74. PMID:26034869 333. Bixby SD, Hettmer S, Taylor GA, et al. Synovial sarcoma in children: imaging features and comm on benign mimics. AJR Am J Roentgenol. 2010 Oct;195(4):1026-32. PMID:20858835

334. Bjornsson J, McLeod RA, Unni KK, et al. Primary chondrosarcoma of long bones and limb girdles. Cancer. 1998 Nov 15;83(10):210519. PMID:9827715 335. Bjornsson J, Unni KK, Dahlin DC, et al. Clear cell chondrosarcoma of bone. Observations in 47 cases. Am J Surg Pathol. 1984 Mar;8(3):223-30. PMID:6703199 336. Blackburn PR, Davila JI, Jackson RA, et al. RNA sequencing identifies a novel USP9X-USP6 promoter swap gene fusion in a primary aneurysmal bone cyst. Genes Chromosomes Cancer. 2019 Aug;58(8):58994. PMID:30767316 337. Blakeley JO, Plotkin SR. Therapeutic advances for the tumors associated with neurofibromatosis type 1, type 2, and schwannomatosis. Neuro Oncol. 2016 May; 18(5):624-38. PMID:26851632 338. Blauvelt A. The role of human herpesvirus 8 in the pathogenesis of Kaposi's sarcoma. Adv Dermatol. 1999;14:167-206, discussion 207. PMID:10643499 339. Blay JY, El Sayadi H, Thiesse P, et al. Complete response to imatinib in relapsing pigmented villonodular synovitis/tenosynovial giant cell tumor (PVNS/TGCT). Ann Oncol. 2008 Apr;19(4):821-2. PMID:18296418 340. BlayJY, Soibinet P, Penel N.etal. Improved survival using specialized multidisciplinary board in sarcoma patients. Ann Oncol. 2017 Nov 1;28(11):2852-9. PMID:29117335 341. Bleeker JS, Quevedo JF, Folpe AL. "Malig nant" perivascular epithelioid cell neoplasm: risk stratification and treatment strategies. Sarcoma. 2012;2012:541626. PMID:22619565 342. Bleiweiss IJ, Klein MJ. Chondromyxoid fibroma: report of six cases with immunohistochemical studies. Mod Pathol. 1990 Nov;3(6):664-6. PMID:2263591 343. Bloem JL, Mulder JD. Chondroblastoma: a clinical and radiological study of 104 cases. Skeletal Radiol. 1985;14(1):1-9. PMID:4023729 344. Bloem JL, van der Heul RO, Schuttevaer HM, et al. Fibrous dysplasia vs adamantinoma of the tibia: differentiation based on discriminant analysis of clinical and plain film findings. AJR Am J Roentgenol. 1991 May;156(5):1017-23. PMID:2017924 345. Blumberg AK, Kay S, Adelaar RS. Nerve sheath myxoma of digital nerve. Cancel； 1989 Mar 15;63(6) :1215-8. PMID:2645040 346. Bo N, Wang D, Wu B, et al. Analysis of [3-catenin expression and exon 3 mutations in pediatric sporadic aggressive fibromatosis. Pediatr Dev Pathol. 2012 May-Jun;15(3):173-8. PMID:21323417 347. Bode-Lesniewska B, Frigerio S, Exner U, et al. Relevance of translocation type in myxoid liposarcoma and identification of a novel EWSR1-DDIT3 fusion. Genes Chromosomes Cancer. 2007 Nov;46(11):96171. PMID:17647282 348. Bode-Lesniewska B, Fritz C, Exner GU, et al. EWSR1-NFATC2 and FUS-NFATC2 gene fusion-associated mesenchymal tumors: clinicopathologic correlation and literature review. Sarcoma. 2019 Mar 26;2019:9386390. PMID:31049020 349. Bode-Lesniewska B, Zhao J, Speel EJ, et al. Gains of 12q13-14 and overexpression of mdm2 are frequent findings in intimal sarcomas of the pulmonary artery. Virchows Arch. 2001 Jan;438(1):57-65. PMID:11213836 350. Boeuf S, Bovee JV, Lehner B, et al. Correlation of hypoxic signalling to histological grade and outcome in cartilage tumours. Histopathology. 2010 Apr;56(5):641-51. PMID:20459575 351. Boikos SA, Pappo AS, Killian JK, et al.

Molecular subtypes of KIT/PDGFRA wild-type gastrointestinal stromal tumors: a report from the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol. 2016 Jul 1;2(7):922-8. PMID:27011036 352. Boland JM, Colby TV, Folpe AL. Liposarcomas of the mediastinum and thorax: a clinicopathologic and molecular cytogenetic study of 24 cases, emphasizing unusual and diverse histologic features. Am J Surg Pathol. 2012 Sep;36(9):1395-403. PMID:22895273 353. Boland JM, Folpe AL. Hemosiderotic fibrolipomatous tumor, pleomorphic hyalinizing angiectatic tumor, and myxoinflammatory fibroblastic sarcoma: related or not? Adv Anat Pathol. 2017 Sep;24(5):268-77. PMID:28375867 354. Boland JM, Folpe AL, Hornick JL, et al. Clusterin is expressed in normal synoviocytes and in tenosynovial giant cell tumors of localized and diffuse types: diagnostic and histogenetic implications. Am J Surg Pathol. 2009Aug;33(8):1225-9. PMID:19542874 355. Boland JM, Fritchie KJ, Erickson-Johnson MR, et al. Endobronchial lipomatous tumors: clinicopathologic analysis of 12 cases with molecular cytogenetic evidence sup porting classification as "lipoma". Am J Surg Pathol. 2013 Nov;37(11):1715-21. PMID:24121172 356. Boland JM, Weiss SW, Oliveira AM, et al. Liposarcomas with mixed well-differentiated and pleomorphic features: a clinicopathologic study of 12 cases. Am J Surg Pathol. 2010 Jun;34⑹:837-43. PMID:20431480 357. Bolen JW, Thorning D. Benign lipoblastoma and myxoid liposarcoma: a comparative lightand electron-microscopic study. Am J Surg Pathol. 1980Apr;4(2):163-74. PMID:7377463 358. Bollen L, Jacobs WCH, Van der Linden YM, et al. A systematic review of prognostic factors predicting survival in patients with spinal bone metastases. Eur Spine J. 2018 Apr;27⑷:799-805. PMID:29064040 359. Bollen L, Wibmer C, Van der Linden YM, et al. Predictive value of six prognostic scoring systems for spinal bone metastases: an analysis based on 1379 patients. Spine (Phila Pa 1976). 2016 Feb;41 ⑶:55—62. PMID:26866742 360. Bollen L, Wibmer C, Wang M, et al. Molecular phenotype is associated with survival in breast cancer patients with spinal bone metastases. Clin Exp Metastasis. 2015 Jan;32(1):1-5. PMID:25359620 361. Bompas E, Campion L, Italiano 代 et al. Outcome of 449 adult patients with rhabdomyosarcoma: an observational ambispective nationwide study. Cancer Med. 2018 Aug;7(8):4023-35. PMID:29956493 362. Bonar SF, Watson G, Gragnaniello C, et al. Intraosseous hibernoma: characterization of five cases and literature review. Skeletal Radiol. 2014 Jul;43(7):939-46. PMID:24705581 363. Bond GL, Hu W, Bond EE, et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell. 2004 Nov 24;119(5):591-602. PMID:15550242 364. Bonetti F, Martignoni G, Colato C, et al. Abdominopelvic sarcoma of perivascular epithelioid cells. Report of four cases in young women, one with tuberous sclerosis. Mod Pathol. 2001 Jun;14(6):563-8. PMID:11406657 365. Bontoux C, Baroudjian B, Le Maignan C, et al. CRTC1-TRIM11 fusion in a case of metastatic clear cell sarcoma: are CRTC1TRIM11 fusion-bearing tumors melanocytomas or clear cell sarcomas? Am J Surg Pathol. 2019 Jun;43(6):861-3. PMID:30676334 366. Bonvalot S, Miceli R, Berselli M, et al. Aggressive surgery in retroperitoneal soft tissue

sarcoma carried out at high-volume centers is safe and is associated with improved local control. Ann Surg Oncol. 2010 Jun;17(6):150714. PMID:20393803 367. Boon LM, Brouillard P, Irrthum A, et al. A gene for inherited cutaneous venous ano malies ("glomangiomas") localizes to chromosome 1p21-22. Am J Hum Genet. 1999 Jul;65(1):125-33. PMID:10364524 368. Borgers A, Peters S, Sciot R, et al. Giant cell tumor of distal phala nx in an adolesce nt with Goltz-Gorlin syndrome. Genet Couns. 2014;25(4):445-51. PMID:25804026 369. Boshoff C, Schulz TF, Kennedy MM, et al. Kaposi's sarcoma-associated herpesvirus infects endothelial and spindle cells. Nat Med. 1995 Dec;1(12):1274-8. PMID:7489408 370. Boshoff C, Whitby D, Hatziioannou T, et al. Kaposi's-sarcoma-associated herpesvirus in HIV-negative Kaposi's sarcoma. Lancet. 1995 Apr 22;345(8956):1043^1. PMID:7723505 371. Bouaoun L, Sonkin D, Ardin M, et al. TP53 variations in human cancers: new lessons from the IARC TP53 Database and genomics data. Hum Mutat. 2016 Sep;37(9):865-76. PMID:27328919 372. Boue DR, Parham DM, Webber B, et al. Clin icopathologicstudyofectomesenchymomas from Intergroup Rhabdomyosarcoma Study Groups III and IV. Pediatr Dev Pathol. 2000 May-Jun;3(3):290-300. PMID:10742419 373. Bougeard G, Renaux-Petel M, Flaman JM, et al. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol. 2015 Jul 20;33(21):2345-52. PMID:26014290 374. Bougeard G, Sesboue R, Baert-Desurmont S, et al. Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. J Med Genet. 2008 Aug;45(8):535-8. PMID:18511570 375. Boughzala-Bennadji R, Stoeckle E, Le Pechoux C, et al. Localized myxofibrosarcomas: roles of surgical margins and adjuvant radiation therapy. I nt J Radiat Oncol Biol Phys. 2018 Oct 1;102(2):399-406. PMID:30191871 376. Bourdeaut F, Freneaux P, Thuille B, et al. Extra-renal non-cerebral rhabdoid tumours. Pediatr Blood Cancer. 2008 Sep;51 (3):363-8. PMID:18506766 377. Bourgeois JM, Knezevich SR, Mathers JA, et al. Molecular detection of the ETV6NTRK3 gene fusion differentiates congenital fibrosarcoma from other childhood spindle cell tumors. Am J Surg Pathol. 2000 Jul;24⑺:93746. PMID:10895816 378. Bovee JV, Cleton-Jansen AM, KuipersDijkshoom NJ, et al. Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma. Genes Chromosomes Cancer. 1999 Nov;26⑶:23746. PMID:10502322 379. Bovee JV, Cleton-Jansen AM, Rosenberg C, et al. Molecular genetic characterization of both components of a dedifferentiated chondrosarcoma, with implications for its histogenesis. J Pathol. 1999 Dec;189(4):45462. PMID:10629543 380. Bovee JV, Cleton-Jansen AM, Taminiau AH, et al. Emerging pathways in the development of chondrosarcoma of bone and implications for targeted treatment. Lancet Oncol. 2005 Aug;6(8):599-607. PMID:16054571 381. Bovee JV, Cleton-Jansen AM, Wuyts W, et al. EXT-mutatio n analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Am J Hum Genet. 1999 Sep;65(3):689-98. PMID:10441575 382. Bovee JV, Hameetman L, Kroon HM, et al. EXT-related pathways are not invoIved in the pathogenesis of dysplasia epiphysealis

Refere nces

549

paybal：https://www.paypal.me/andy19801210 hemimelica and metachondromatosis. J Pathol. 2006 Jul;209(3):411-9. PMID:16622899 383. Bovee JV, Hogendoorn PC. Non-ossifying fibroma: a RAS-MAPK driven benign bone neoplasm. J Pathol. 2019 Jun;248⑵27-30. PMID:30809793 384. Bovee JV, Hogendoorn PC, Wunder JS, et al. Cartilage tumours and bone development: molecular pathology and possible therapeutic targets. Nat Rev Cancer. 2010 Jul;10(7):481-8. PMID:20535132 385. Bovee JV, Sakkers RJ, Geirnaerdt MJ, et al. Intermediate grade osteosarcoma and chondrosarcoma arising in an osteochondroma. A case report of a patient with hereditary multiple exostoses. J Clin Pathol. 2002 Ma「;55⑶:226-9. PMID:11896078 386. Bovee JV, van den Broek LJ, CletonJansen AM, et al. Up-regulation of PTHrP and Bcl-2 expression characterizes the progression of osteoch on droma towards peripheral chondrosarcoma and is a late event in central chondrosarcoma. Lab Invest. 2000 Dec;80(12):1925-34. PMID:11140704 387. Bovee JV, van der Heul RO, Taminiau AH, et al. Chondrosarcoma of the phalanx: a locally aggressive lesion with minimal metastatic potential: a report of 35 cases and a review of the literature. Cancer. 1999 Nov 1;86(9):172432. PMID:10547545 388. Bowe AE, Finnegan R, Jan de Beur SM, et al. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem Biophys Res Commun. 2001 Jun 22;284(4):977-81. PMID:11409890 389. Bowen ME, Boyden ED, Holm IA, et al. Loss-of-funotion mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome. PLoS Genet. 2011 Apr;7(4):e1002050. PMID:21533187 390. Bowne WB, Antonescu CR, Leung DH, et al. Dermatofibrosarcoma protuberans: a clinicopathologic analysis of patients treated and followed at a single institution. Cancer. 2000 Jun 15;88(12):2711-20. PMID:10870053 391. Boyce AM, Bhattacharyya N, Collins MT. Fibrous dysplasia and fibroblast growth factor-23 regulation. Curr Osteoporos Rep. 2013 Jun;11(2):65-71. PMID:23532406 392. Boyce AM, Brewer C, DeKlotz TR, et al. Association of hearing loss and otologic outcomes with fibrous dysplasia. JAMA Otolaryngol Head Neck Surg. 2018 Feb 1;144(2):102-7. PMID:29192304 393. Boyce AM, Chong WH, Shawker TH, etal. Characterization and management of testicular pathology in McCune-Albright syndrome. J Clin Endocrinol Metab. 2012 Sep;97(9):E1782-90. PMID:22745241 394. Boyce AM, Florenzano P, de Castro LF, et al. Fibrous dysplasia/McCune-Albright syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 2015 Feb 26 [updated 2019 Jun 27]. PMID:25719192 395. Braatz B, Evans R, Kelman A, et al. Perinatal evolution of mesenchymal hamartoma of the chest wall. J Pediatr Surg. 2010 Dec;45(12):e37-40. PMID:21129530 396. Brady MS, Gaynor JJ, Brennan MF. Radiation-associated sarcoma of bone and soft tissue. Arch Surg. 1992 Dec;127(12):1379-85. PMID:1365680 397. Brainard JA, Goldblum JR. Stromal tumors of the jejunum and ileum: a clinicopathologic study of 39 cases. Am J Surg Pathol. 1997 Apr;21 (4):407-16. PMID:9130987 398. Bramwell V, Rouesse J, Steward W, et al. Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma-reduced local recurrence but no improvement in survival: a study of the European Organization for Research

550

References

and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol. 1994 Jun;12(6):1137-49. PMID:8201375 399. Bramwell VH, Steward WP, Nooij M, et al. Neoadjuvant chemotherapy with doxorubicin and cisplatin in malignant fibrous histiocytoma of bone: a European Osteosarcoma Intergroup study. J Clin Oncol. 1999 Oct; 17(10):3260-9. PMID:10506628 400. Brandser EA, Goree JC, El-Khoury GY. Elastofibroma dorsi: prevale nee in an elderly patient population as revealed by CT. AJR Am J Roentgenol. 1998 Oct; 171 ⑷:977-80. PMID:9762978 401. Branstetter DG, Nelson SD, Manivel JC, et al. Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clin Cancer Res. 2012 Aug 15;18(16):4415-24. PMID:22711702 401A. Bray F, Colombet M, Mery L, et al., editors. Cancer incidence in five continents. Volume XI. Lyon (Fra nee): Internation al Age ncy for Research on Cancer; 2017. (IARC Scientific Publication No. 166). http://ci5.iarc.fr/CI5-XI. 402. Bredella MA, Caputo GR, Steinbach LS. Value of FDG positron emissi on tomography in conjunction with MR imaging for evaluating therapy response in patients with musculoskeletal sarcomas. AJR Am J Roentgenol. 2002 Nov;179⑸:1145-50. PMID:12388489 403. Bredella MA, Torriani M, Hornicek F, et al. Value of PET in the assessment of patients with neurofibromatosis type 1. AJR Am J Roentgenol. 2007 Oct; 189(4):928-35. PMID:17885067 404. Brems H, Beert E, de Ravel T, et al. Mechanisms in the pathogenesis of malignant tumours in neurofibromatosis type 1. Lancet Oncol. 2009 May;10(5):508-15. PMID:19410195 405. Brems H, Park C, Maertens O, et al. Glomus tumors in neu「ofib「omatosis type 1: genetic, functional, and clinical evidence of a novel association. Cancer Res. 2009 Sep 15:69(18):7393-401. PMID:19738042 406. Brenca M, Rossi S, Polano M, et al. Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST. J Pathol. 2016 Mar;238(4):543-9. PMID:26606880 407. Brennan B, De Salvo GL, Orbach D, et al. Outcome of extracranial malignant rhabdoid tumours in children registered in the European Paediatric Soft Tissue Sarcoma Study Group Non-Rhabdomyosarcoma Soft Tissue Sarcoma 2005 Study-EpSSG NRSTS 2005. Eur J Cancer. 2016 Jun;60:69-82. PMID:27082136 40& Brennan B, Stiller C, Bourdeaut F. Extracranial rhabdoid tumours: what we have learned so far and future directions. Lancet Oncol. 2013 Jul;14(8):e329-36. PMID:23816299 409. BrennerS, Bercovich Z, FeilerY,etal. Dual regulatory role of polyamines in adipogenesis. J Biol Chem. 2015 Nov 6;290(45):27384-92. PMID:26396188 410. Bridge JA, Bhatia PS, Anderson JR, et al. Biologic and clinical significanee of cytogenetic and molecular cytogenetic abnormalities in benign and malignant cartilaginous lesions. Cancer Genet Cytogenet. 1993 Sep;69(2):7990. PMID:8402563 411. Bridge JA, Dembinski A, DeBoer J, et al. Clonal chromosomal abnormalities in osteofibrous dysplasia. Implications for histopathogenesis and its relationship with adamantinoma. Cancer. 1994 Mar 15;73(6):1746-52. PMID:8156503 412. Bridge JA, Fidler ME, Neff JR, et al. Adamantinoma-like Ewing's sarcoma: genomic confirmation, phenotypic drift. Am J Surg Pathol.

1999 Feb;23(2):159-65. PMID:9989842 413. Bridge JA, Kanamori M, Ma Z, et al. Fusion of the ALK gene to the clathrin heavy chain gene, CLTC, in inflammatory myofibroblastic tumor. Am J Pathol. 2001 Aug;159(2):411-5. PMID:11485898 414. Bridge JA, Liu J, Qualman SJ, et al. Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes. Genes Chromosomes Cancer. 2002 Mar;33(3):310-21. PMID:11807989 415. Bridge JA, Nelson M, McComb E, et al. Cytogenetic findings in 73 osteosarcoma specimens and a review of the literature. Cancer Genet Cytogenet. 1997 May;95(1):7487. PMID:9140456 416. Bridge JA, Nelson M, Orndal C, et al. Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1)and 11p11-12 (EXT2) in patients with sporadic and hereditary osteochondromas. Cancer. 1998 May 1;82(9):1657-63. PMID:9576285 417. Bridge JA, Sreekantaiah C, Neff JR, et al. Cytogenetic findings in clear cell sarcoma of tendons and aponeuroses. Malignant melanoma of soft parts. Cancer Genet Cytogenet. 1991 Mar;52(1):101-6. PMID:2009504 418. Bridge JA, Sumegi J, Druta M, et al. Clinical, pathological, and genomic features of EWSR1-PATZ1 fusion sarcoma. Mod Pathol. 2019 Nov;32(11):1593-604. PMID:31189996 419. Bridge JA, Swarts SJ, Buresh C, et al. Trisomies 8 and 20 characterize a subgroup of benign fibrous lesions arising in both soft tissue and bone. Am J Pathol. 1999 Mar;154(3):72933. PMID:10079250 420. Brien EW, Mirra JM, Kerr R. Benign and malignant cartilage tumors of bone and joint: their anatomic and theoretical basis with an emphasis on radiology, pathology and clinical biology. I. The intramedullary cartilage tumors. Skeletal Radiol. 1997 Jun;26(6):325-53. PMID:9229417 421. Brien EW, Mirra JM, Luck JV Jr. Benign and malignant cartilage tumors of bone and joint: their anatomic and theoretical basis with an emphasis on radiology, pathology and clinical biology. II. Juxtacortical cartilage tumors. Skeletal Radiol. 1999 Jan;28(1):1-20. PMID:10068070 422. Brien GL, Remillard D, Shi J, etal. Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma. Elife. 2018 Nov 15;7:e41305. PMID:30431433 423. Brierley JD, Gospodarowicz MK, Wittekind C, editors. TNM classification of malignant tumours. 8th ed. Oxford (UK): Wiley Blackwell; 2017. 424. Briggs TA, Rice Gl, Adib N, et al. Spondyloenchondrodysplasia due to mutations in ACP5: a comprehensive survey. J Clin Immunol. 2016 Ap「;36⑶:220-34. PMID:26951490 425. Briggs TA, Rice Gl, Daly S, et al. Tartrateresistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nat Genet. 2011 Feb;43(2):127-31. PMID:21217755 426. Bright CJ, Hawkins MM, Winter DL, et al. Risk of soft-tissue sarcoma among 69 460 fiveyear survivors of childhood cancer in Europe. J Natl Cancer Inst. 2018 Jun 1;110(6):649-60. PMID:29165710 427. Brimo F, Robinson B, Guo C, et al. Renal epithelioid angiomyolipoma with atypia: a series of 40 cases with emphasis on clinicopathologic prognostic indicators of malignancy. Am J Surg Pathol. 2010 May;34 ⑸:715-22. PMID:20410812

428. Brinkman AS, Maxfield B, Gill K Pt A novel t(3;8)(p13;q21,1) translocation 驚 case of lipoblastoma. Pediatr Surq |nt ?鳥 Jul;28(7):737-40. PMID:22488564 ' Z 429- Beck JE, Perez-Atayde AR, Kozakewbh HP, et al. Cytogenetic aberrations in perineurioma: variation 皿小 」 丁 wwype. Amn J Surg Pathol. 2005 Sep；29(9)『64_9 PMID:16096405 430. Broehm CJ, Garbrecht EL, Wood J et al. Two cases of sarcoma arising in giant cell tumor of bone treated with denosumab Casp Rep Med. 2015;2015:767198. PMID:26798348 431. Broehm CJ, M'Lady G, Bocklage T, et al. Bizarre parosteal osteochondromatous proliferation: a new cytogenetic subgro叩 characterized by inversion of chromosome 7. Cancer Genet. 2013 Nov;206(11)-402-5 PMID:24412018 432. Brohl AS, Solomon DA, Chang W, et al. The genomic landscape of the Ewing sarcoma family of tumors reveals recurrent STAG2 mutation. PLoS Genet. 2014 Jul 10;10⑺:e1004475. PMID:25010205 433. Brouillard P, Boon LM, Mulliken JB, et al. Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations ("glomangiomas”). Am J Hum Genet. 2002 Apr;70⑷:866-74. PMID:11845407 434. Brown AD, Lopez-Terrada D, Denny C, et al. Promoters containing ATF-binding sites are de-regulated in cells that express the EWS/ATF1 oncogene. Oncogene. 1995 May 4;10(9):1749-56. PMID:7753552 435. Brown JG, Folpe AL, Rao P, et al. Primary vascular tumors and tumor-like lesions of the kidney: a clinicopathologic analysis of 25 cases. Am J Surg Pathol. 2010 Jul;34(7):942-9 PMID:20534992 436. Brown MT, Gikas PD, Bhamra JS. et al. How safe is curettage of low-grade cartilaginous neoplasms diagnosed by imaging with or without pre-operative needle biopsy? Bone Joint J. 2014 Aug;96-B(8):1098-105. PMID:25086127 437. Browne TJ, Fletcher CD. Haemosiderotic fibrolipomatous tumour (so-called haemosiderotic fibrohistiocytic lipomatous tumour): analysis of 13 new cases in support of a distinct entity. Histopathology. 2006 Mar;48(4):453-61. PMID:16487368 438. Brownstein CA, Adler F, Nelson-Williams C, et al. A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc Natl Acad Sci USA. 2008 Mar 4; 105(9):3455-60. PMID:18308935 439. Brundler MA, Kurek KC, Patel K, et al. Submucosal colonic lipoblastoma presenting with colo-colonic intussusception in an infant. Pediatr Dev Pathol. 2018 Jul-Aug;21 (4):401-5. PMID:28420321 440. Bryan RS, Dahlin DC, Sullivan CR. Lipoma of the tendon sheath. J Bone Joint Surg Am. 1956 Dec;38-A(6):1275-80. PMID:13376651 441. Buccoliero AM, Caporalini C, Scagnet M, et al. A diagnostic pitfail: atypical teratoid rhabdoid tumor versus dedifferentiated/poorly differentiated chordoma: analysis of a monoinstitutional series. Appl Immunohistochem Mol Morphol. 2019 Feb;27(2): 147-54. PMID:28777153 442. Buckingham M, Relaix F. PAX3 and PAX7 as upstream regulators of myogenesis. Semin Cell Dev Biol. 2015 Aug;44:115-25. PMID:26424495 443. Buddingh EP, Kuijjer ML, Duim RA, et ah Tumor-infiltrating macrophages are associated with metastasis suppression in high-gra ® osteosarcoma: a rationale for treatment J macrophage activating agents. Clin Cancer es. 2011 Apr15;17(8):2110-9. PMID:21372215

paybal：https://www.paypal.me/andy19801210 444. Bui KL, llaslan H, Bauer TW, et al. Cortical scalloping and cortical penetration by small eccentric chondroid lesions in the long tubular bones: not a sign of malignancy? Skeletal Radiol. 2009 Aug;38(8):791-6.PMID:19277645 445 Bulychova IV, Unni KK, Bertoni F, et al. Fibrocartilagenous mesenchymoma of bone. Am J Surg Pathol. 1993 Aug; 17(8):830-6. PMID:8338193 446. Burger B, Hershkovitz D, Indelman M, et al. Buschke-Ollendorff syndrome in a three-generatio n family: influenee of a novel LEMD3 mutation to tropoelastin expression. Eur J Dermatol. 2010 Nov-Dec;20(6):693-7. PMID:20732851 447 Biirgi J, Kunz B, Abrami L, et al. CMG2/ ANTXR2 regulates extracellular collagen VI which accumulates in hyaline fibromatosis syndrome. Nat Commun. 2017 Jun 12;8:15861. PMID:28604699 448. Burke A, Tavora F. The 2015 WHO classification of tumors of the heart and pericardium. J Thorac Oncol. 2016 Apr;11(4):441-52. PMID:26725181 449. Burke AP, Sobin LH, Shekitka KM, et al. Intra-abdominal fibromatosis. A pathologic analysis of 130 tumors with comparison of clinical subgroups. Am J Surg Pathol. 1990 Apr： 14⑷:335-41. PMID:2321698 45 Burke AP, Virmani R. Sarcomas of the great vessels. A clinicopathologic study. Cancer. 1993 Mar 1;71(5): 1761-73. PMID:8448740 451. Burke FD, Proud G, Lawson I J, et al. An assessment of the effects of exposure to vibration, smoking, alcohol and diabetes on the prevalence of D叩uytren's disease in 97,537 miners. J Hand Surg Eur Vol. 2007 Aug;32⑷:400-6. PMID:17950195 452. Bus MPA, Campanacci DA, Albergo JI, et al. Conventional primary central chondrosarcoma of the pelvis: prognostic factors and outcome of surgical treatment in 162 patients. J Bone Joint Surg Am. 2018 Feb 21 100(4):316-25. PMID:29462035 453. Byrne J, Blanc WA, Warburton D, et al. The significance of cystic hygroma in fetuses. Hum Pathol. 1984 Jan;15(1):61-7. PMID:6693110 454. Caballes AB, Abelardo AD, Farolan MJ, et al. Pediatric anastomosing hemangioma: case report and review of renal vascular tumors in children. Pediatr Dev Pathol. 2019 MayJun;22(3):269-75. PMID:30369288 455. Cacciatore M, Dei Tos AP. Challenging epithelioid mesenchymal neoplasms: mimics and traps. Pathology. 2014 Feb;46(2):126-34. PMID:24384587 456. Cahlon O, Brennan MF, Jia X, et al. A pc- (operative no mog ram for local recurre nee risk in extremity soft tissue sarcomas after limb­ sparing surgery without adjuvant radiation. Ann Surg. 2012 Feb;255(2):343-7. PMID:22143203 45 . Cai Y, Shi Z, Bai Y. Review of RosaiDorfman disease: new insights into the pathogenesis of this rare disorder. Acta Haematol.2017;138(1):14-23.PMID:28614806 45& Cai YC, McMenamin ME, Rose G, et al. Primary liposarcoma of the orbit: a clinicopathologic study of seven cases. Ann Diagn Pathol. 2001 Oct;5(5):255-66. PMID:11598853 459. Callegaro D, Miceli R, Bonvalot S, et al. Development and external validation of two nomograms to predict overall survival and occurrence of distant metastases in adults after surgical resection of localised soft-tissue sarcomas of the extremities: a retrospective analysis. Lancet Oncol. 2016 May;17(5):67180. PMID:27068860 460. Calonje E, Fletcher CD. Cutaneous intraneural glomus tumor. Am J Dermatopathol. 1995 Aug; 17(4):395-8. PMID:8600806 461. Calonje E, Fletcher CD. Myoid

differentiatio n in dermatofibrosarcoma protuberans and its fibrosarcomatous variant: clinicopathologic analysis of 5 cases. J Cutan Pathol. 1996 Feb;23(1):30-6. PMID:8720984 462. Calonje E, Fletcher CD, Wilson-Jones E, et al. Retiform hemangioendothelioma. A distinctive form of low-grade angiosarcoma delineated in a series of 15 cases. Am J Surg Pathol. 1994 Feb;18(2):115-25. PMID:8291650 463. Calonje E, Wadden C, Wilson-Jones E, et al. Spindle-cell non-pleomorphic atypical fibroxanthoma: analysis of a series and delineation of a distinctive variant. Histopathology. 1993 Mar;22(3):247-54. PMID:7684354 464. Caltabiano R, Magro G, Polizzi A, et al. A mosaic pattern of INI1/SMARCB1 protein expression distinguishes schwannomatosis and NF2-associated peripheral schwannomas from solitary peripheral schwannomas and NF2-associated vestibular schwannomas. Childs Nerv Syst. 2017 Jun;33⑹:933-40. PMID:28365909 465. Calvert GT, Randall RL, Jones KB, et al. At-risk populations for osteosarcoma: the syndromes and beyond. Sarcoma. 2012;2012:152382. PMID:22550413 466. Camacho-Vanegas O, Camacho SC, Till J, et al. Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts. Am J Hum Genet. 2012 Apr 6;90(4):614-27. PMID:22464254 467. Cameron D, Ong TH, Borzi P. Conservative management of mesenchymal hamartomas of the chest wall. J Pediatr Surg. 2001 S即;36(9):1346-9. PMID: 11528603 468. Campanacci M, Baldini N, Boriani S, et al. Giant-cell tumor of bone. J Bone Joint Surg Am. 1987 Jan;69(1):106-14. PMID:3805057 469. Campanacci M, Boriani S, Giunti A. Hemangioendothelioma of bone: a study of 29 cases. Cancer. 1980 Aug 15;46(4):804-14. PMID:7397643 470. Campanacci M.Laus M, Boriani S. Multiple non-ossifying fibromata with extraskeletal anomalies: a new syndrome? J Bone Joint Surg Br. 1983 Nov;65(5):627-32. PMID:6643569 471. Campbell RS, Grainger AJ, Mangham DC, et al. Intraosseous lipoma: report of 35 new cases and a review of the literature. Skeletal Radiol. 2003 Apr;32(4):209-22. PMID:12652336 472. Cancer Genome Atlas Research Network. Comprehensive and integrated genomic characterization of adult soft tissue sarcomas. Cell. 2017 Nov 2;171 ⑷:950-965.e28. PMID:29100075 473. Canter RJ, Qin LX, Maki RG, et al. A synovial sarcoma-specific preoperative nomogram supports a survival benefit to ifosfamide-based chemotherapy and improves risk stratification for patients. Clin Cancer Res. 2008 Dec 15;14(24):8191-7. PMID:19088035 474. Cantwell CP, Obyrne J, Eustace S. Current trends in treatment of osteoid osteoma with an emphasis on radiofrequency ablation. Eur Radiol. 2004 Apr; 14⑷:667-仃. PMID:14663625 475. Cao F, Lu L, Abrams SA, etal. Generalized metabolic bone disease and fracture risk in Rothmund-Thomson syndrome. Hum Mol Genet 2017 Aug 15;26(16):3046-55. PMID:28486640 476. Cao L, Yu Y, Bilke S, et al. Genome-wide identification of PAX3-FKHR binding sites in rhabdomyosarcoma reveals candidate target genes important for development and cancel： Cancer Res. 2010 Aug 15;70(16):6497-508. PMID:20663909 477. Cappelle S, Pans S, Sciot R. Imaging

features ofchondromyxoid fibroma: report of 15 cases and literature review. Br J Radiol. 2016 Aug;89(1064):20160088. PMID:27226218 478. Cappellesso R, d'Amore ES, Dall'lgna P, et al. Immunohistochemical expression of p16 in lipoblastomas. Hum Pathol. 2016 Jan;47(1):64-9. PMID:26514741 479. Caraway NP, Fanning CV, Wojcik EM, et al. Cytology of malignant melanoma of soft parts: fine-needle aspirates and exfoliative specimens. Diagn Cytopathol: 1993 Dec;9(6):632-8. PMID:8143535 480. Carlson JW, Fletcher CD. Immunohistochemistry for beta-catenin in the differential diagnosis of spindle cell lesions: analysis of a series and review of the literature. Histopathology. 2007 Oct;51 (4):509-14. PMID:17711447 481. Carlson ML, Osetinsky LM, Alon EE, et al. Tenosynovial giant cell tumors of the temporomandibular joint and lateral skull base: review of 11 cases. Laryngoscope. 2017 Oct;127(10):2340-6. PMID:27888510 482. Carneiro A, Francis P, Bendahi PO, et al. Indistinguishable genomic profiles and shared prognostic markers in undifferentiated pleomorphic sarcoma and leiomyosarcoma: different sides of a single coin? Lab Invest. 2009 Jun;89(6):668-75. PMID:19290004 483. Carney JA. Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): natural history, adrenocortical component, and possible familial occurrence. Mayo Clin Proc. 1999 Jun;74(6):543-52. PMID:10377927 484. Carney JA. Psammomatous melanotic schwannoma. A distinctive, heritable tumor with special associations, including cardiac myxoma and the Cushing syndrome. Am J Surg Pathol. 1990 Mar;14(3):206-22. PMID:2305928 485. Carney JA, Boccon-Gibod L, Jarka DE, et al. Osteochondromyxoma of bone: a congenital tumor associated with lentigines and other unusual disorders. Am J Surg Pathol. 2001 Feb;25⑵:164-76. PMID:11176065 486. Carney JA, Gordon H, Carpenter PC, et al. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore). 1985 Jul;64(4):270-83. PMID:4010501 487. Carney JA, Hruska LS, Beauchamp GD, et al. Dominant inheritance of the complex of myxomas, spotty pigmentation, and endocrine overactivity. Mayo Clin Proc. 1986 Mar;61 (3):165-72. PMID:3945116 488. Carney JA, Young WF, Stratakis CA. Primary bimorphic adrenocortical disease: cause of hypercortisolism in McCuneAlbright syndrome. Am J Surg Pathol. 2011 Sep;35(9):1311-26. PMID:21836496 489. Carrio M, Gel B, Terribas E, et al. Analysis of intratumor heterogeneity in neurofibromatosis type 1 plexiform neurofibromas and neurofibromas with atypical features: correlating his⑹ogical and genomic findings. Hum Mutat. 2018 Aug;39(8):1112-25. PMID:29774626 490. Carroll MB, Higgs JB. Synovial haemangioma presenting as a recurrent monoarticular haemarthrosis. Arch Dis Child. 2007 Jul;92(7):623-4. PMID:17588975 491. Carroll P, Henshaw RM, Garwood C, et al. Plantar fibromatosis: pathophysiology, surgical and nonsurgical therapies: an evidence-based review. Foot Ankle Spec. 2018 Apr; 11 (2):16876. PMID:29310463 492. Carter JM, Caron BL, Dogan A, et al. A novel chromogenic in situ hybridization assay for FGF23 mRNA in phosphaturic mesenchymal tumors. Am J Surg Pathol. 2015 Jan;39(1 )75-83. PMID:25025444 493. Carter JM, Howe BM, Hawse JR, et al.

CTNNB1 mutations and estrogen receptor expression in neuromuscular choristoma and its associated fibromatosis. Am J Surg Pathol. 2016 Oct;40(10):1368-74. PMID:27259010 494. Carter JM, O'Hara C, Dundas G, et al. Epithelioid malignant peripheral nerve sheath tumor arising in a schwannoma, in a patient with Mneuroblastoma-like” schwannomatosis and a novel germline SMARCB1 mutation. Am J Surg Pathol. 2012 Jan;36(1):154-60. PMID:22082606 495. Carter JM, Sukov WR, Montgomery E, et al. TGFBR3 and MGEA5 rearrangements in pleomorphic hyalinizing angiectatic tumors and the spectrum of related neoplasms. Am J Surg Pathol. 2014 Sep;38(9):1182-992. PMID:24705316 496. Carter JM, Wang X, Dong J, et al. USP6 genetic rearrangements in cellular fibroma of tendon sheath. Mod Pathol. 2016 Aug;29(8):865-9. PMID:27125357 497. Carter JM, Weiss SW, Linos K, et al. Superficial CD34-positive fibroblastic tumor: report of 18 cases of a distinctive low-grade mesenchymal neoplasm of intermediate (borderline) malignancy. Mod Pathol. 2014 Feb;27(2):294-302. PMID:23887307 498. Carter JM, Wenger DE, Rose PS, et al. Atypical notochordal cell tumors: a series of notochordal-derived tumors that defy current classification schemes. Am J Surg Pathol. 2017 Jan;41(1):39-48. PMID:27819871 499. Carter JM, Wu Y, Blessing MM, et al. Recurrent genomic alterations in soft tissue perineuriomas. Am J Surg Pathol. 2018 Dec;42(12):1708-14. PMID:30303818 500. CarugoA, Minelli R, Sapio L, etal. p53 is a master regulator of proteostasis in SMARCB1 ・ deficient malignant rhabdoid tumors. Cancer Cell. 2019 Feb 竹;35 ⑵:204-220.e9. PMID:30753823 501. Carvalho SD, Pissaloux D, Crombe A, et al. Pleomorphic sarcomas: the state of the art. Surg Pathol Clin. 2019 Mar;12(1):63-105. PMID:30709449 502. Casadei GP, Komori T, Scheithauer BW, et al. Intracranial parenchymal schwannoma. A clinicopathological and neuroimaging study of nine cases. J Neurosurg. 1993 Aug;79(2):21722. PMID:8331403 503. Casali PG, Abecassis N, Aro HT, et al. Gastrointestinal stromal tumours: ESMOEURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018 Oct 1;29(Suppl 4):iv68-78. PMID:29846513 504. Casali PG, Bielack S, Abecassis N, et al.. Bone sarcomas: ESMO-PaedCan-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018 Oct 1;29(Suppl 4):iv79-95. PMID:30285218 505. Casali PG, BlayJY, ESMO/CONTICANET/ EUROBONET Consensus Panel of experts. Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010 May;21 Suppl 5:v198-203. PMID:20555081 506. Casanova M, Ferrari A, Collini P, et al. Epithelioid sarcoma in children and adolescents: a report from the Italian Soft Tissue Sarcoma Committee. Cancer. 2006 Feb 1;106(3):708-17. PMID:16353216 507. Casas-Alba D, Martinez-Monseny A, Pino-Ramirez RM, et al. Hyaline fibromatosis syndrome: clinical update and phenotype­ genotype correlations. Hum Mutat. 2018 Dec;39(12):1752-63. PMID:30176098 50& Caspari R, Olschwang S, Friedl W, et al. Familial adenomatous polyposis: desmoid tumours and lack of ophthalmic lesions (CHRPE) associated with APC mutations beyond codon 1444. Hum Mol Genet. 1995

Refere nces

551

paybal：https://www.paypal.me/andy19801210 Mar;4(3):337-40. PMID:7795585 509. Cassidy MR, Lefkowitz RA, Long N, et al. Association of MRI T2 signal intensity with desmoid tumor progression during active observation: a retrospective cohort study. Ann Surg.2018Nov9. PMID:30418203 510. Cassier PA, Gelderblom H, Stacchiotti S, et al. Efficacy of imatinib mesylate for the treatment of locally advanced and/or metastatic tenosynovial giant cell tumor/pigmented villonodular synovitis. Cancer. 2012 Mar 15;118(6):1649-55. PMID:21823110 511. Cassier PA, Italiano A, Gomez-Roca CA, et al. CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose­ escalation and dose-expansion phase 1 study. Lancet Oncol. 2015 Aug;16(8):949-56. PMID:26179200 512. Castro EC, Blazquez C, Boyd J, et al. Clinicopathologic features of histiocytic lesions following ALL, with a review of the literature. Pediatr Dev Pathol. 2010 MayJun；13(3):225-37. PMID:19642834 513. Cates JM. Comparison of the AJCC, MSTS, and modified Spanier systems for clinical and pathologic staging of osteosarcoma. Am J Surg Pathol. 2017 Mar;41 (3):405-13. PMID:28195881 514. Cates JM, Rosenberg AE, O'Connell JX, et al. Chondroblastoma-like chondroma of soft tissue: an underrecognized variant and its differential diagnosis. Am J Surg Pathol. 2001 May;25(5):661-6. PMID:11342780 515. Cates JM, Stricker TP, Sturgeon D, et al. Desmoid-type fibromatosis-associated Gardner fibromas: prevalence and impact on local recurrence. Cancer Lett. 2014 Oct 28;353(2):176-81. PMID:25064609 516. Cates JMM. Modeling continuous prognostic factors in survival analysis: implications for tumor staging and assessing chemotherapy effect in osteosarcoma. Am J Surg Pathol. 2018 Apr;42(4):485-91. PMID:29200101 517. Cates JMM. Simple staging system for osteosarcoma performs equivalently to the AJCC and MSTS systems. J Orthop Res. 2018 Oct;36(10):2802-8. PMID:29718558 518. Cavazzana AO, Schmidt D, Ninfo V, et al. Spindle cell rhabdomyosarcoma. A prognostically favorable variant of rhabdomyosarcoma. Am J Surg Pathol. 1992 Mar;16(3):229-35. PMID:1599014 519. Cawthon RM, Weiss R, Xu GF, et al. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell. 1990 Jul 13;62(1 ):193201. PMID:2114220 520. Celebi JT, Tsou HC, Chen FF, et al. Phenotypic findings of Cowden syndrome and Bannayan-Zonana syndrome in a family associated with a single germline mutation in PTEN. J Med Genet. 1999 May;36(5):360-4. PMID:10353779 521. Cell FS, Coppotelli G, Chidakel A, et al. The role of type 1 and type 2 5'-deiodi nase in the pathophysiology of the 3,5,3'・triiodothyronine toxicosis of McCune-Albright syndrome. J Clin Endocrinol Metab. 2008 Jun;93⑹:2383-9. PMID:18349068 522. Cellier L, Perron E, Pissaloux D, et al. Cutaneous melanocytoma with CRTC1TRIM11 fusion: report of 5 cases resembling clear cell sarcoma. Am J Surg Pathol. 2018 Mar;42(3):382-91. PMID:29240581 523. Cerilli LA, Fechner RE. Angiosarcoma arising in a bone infarct. Ann Diagn Pathol. 1999 Dec;3⑹:370-3. PMID:10594289 524. Cesari M, Alberghini M, Vanel D, et al. Periosteal osteosarcoma: a single-institution experience. Cancer. 2011 Apr 15;117(8):17315. PMID:21472720

552

References

525. Cesari M, Bertoni F, Bacchini P, et al. Mesenchymal chondrosarcoma. An analysis of patients treated at a single institution. Tumori. 2007 Sep-Oct;93(5):423-7. PMID:18038872 526. Cessna MH, Zhou H, Sanger WG, et al. Expression of ALK1 and p80 in inflammatory myofibroblastic tumor and Rs mesenchymal mimics: a study of 135 cases. Mod Pathol. 2002 Sep;15(9):931-8. PMID:12218210 527. Cha YJ, Hong CK, Kim DS, et al. Poorly differentiated chordoma with loss ofSMARCBI/ INI1 expression in pediatric patients: a report of two cases and review of the literature. Neuropathology. 2018 Feb;38(1):47-53. PMID:28812319 528. Chaabane S, Bouaziz MC, Drissi C, et al. Periosteal chondrosarcoma. AJR Am J Roentgenol. 2009 Jan;192(1):W1-6. PMID:19098166 529. Chagarlamudi K, Devita R, Barr RG. Gastric lipoma: a review of the literature. Ultrasound Q. 2018 S 即;34 ⑶:119-21. PMID:29369244 530. Chakrapani A, Warrick A, Nelson D, et al. BRAF and KRAS mutations in sporadic glomus tumors. Am J Dermatopathol. 2012 Jul;34(5):533-5. PMID:22317887 531. Chamberlain BK, McClain CM, Gonzalez RS, et al. Alveolar soft part sarcoma and granular cell tumor: an immuno histochemical comparison study. Hum Pathol. 2014 May;45(5):1039-44. PMID:24746209 532. Chan CM, Lindsay AD, Spiguel ARV, et al. Periosteal osteosarcoma: a single-institutional study of factors related to oncologic outcomes. Sarcoma. 2018 Sep 27;2018:8631237. PMID:30363676 533. Chan JA, McMenamin ME, Fletcher CD. Synovial sarcoma in older patients: clinicopathological analysis of 32 cases with emphasis on unusual histological features. Histopathology. 2003 Jul;43(1 ):72-83. PMID:12823715 534. Chan JK, Cheuk W, Shimizu M. Anaplastic lymphoma kinase expression in inflammatory pseudotumors. Am J Surg Pathol. 2001 Jun;25(6):761-8. PMID:11395553 535. Chan JY, Gooi Z, Wong EW, et al. Low-grade myofibroblastic sarcoma: a population-based study. Laryngoscope. 2017 Jan;127(1):116-21. PMID:27377169 536. Chang A, Schuetze SM, Conrad EU 3rd, et al. So-called "inflammatory leiomyosarcoma": a series of 3 cases providing additional insights into a rare entity. Int J Surg Pathol. 2005 Apr; 13(2): 185-95. PMID:15864383 537. Chang CY, Gill CM, Joseph Simeone F, et al. Comparison of the diagnostic accuracy of 99 m-Tc-MDP bone scintigraphy and 18 F-FDG PET/CT for the detection of skeletal metastases. Acta Radiol. 2016 Jan;57(1):5865. PMID:25533313 538. Chang KTE, Goytain A, Tucker T, et al. Development and evaluation of a pan­ sarcoma fusion gene detection assay using the NanoString nCounter platform. J Mol Diagn. 2018Jan;20(1):63-77. PMID:29104083 539. Chang SE, Choi JH, Sung KJ, et al. A case of cutaneous low-grade myofibroblastic sarcoma. J Dermatol. 2001 Jul;28(7):383-7. PMID:11510507 540. Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus­ like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994 Dec 16;266(5192):1865-9. PMID:7997879 541. Chappell AG, Chase EP, Chang B, et al. Atypical fibroxanthoma in a 13-year-old Guatemalan girl with xeroderma pigmentosum. Pediatr Dermatol. 2016 May;33⑶:e228-9. PMID:27046537 542. Chapurlat RD, Meunier PJ. Fibrous

dysplasia of bone. Baillieres Best Pract Res Clin Rheumatol. 2000 Jun;14(2):385-98. PMID:10925751 543. Charville GW, Wang WL, Ingram DR, et al. EWSR1 fusion proteins mediate PAX7 expression in Ewing sarcoma. Mod Pathol. 2017 Sep;30(9):1312-20. PMID:28643791 544. Chase DR, Enzinger FM. Epithelioid sarcoma. Diagnosis, prognostic indicators, and treatment. Am J Surg Pathol. 1985 Apr;9(4):241-63. PMID:4014539 . 545. Chaudhry IH, Kazakov DV, Michal M, et al. Fibro-osseous pseudotumor of the digit: a clinicopathological study of 17 cases. J Cutan Pathol. 2010Mar;37(3):323-9. PMID:19678826 546. Chavez JA, Ud Din N, Memon A, et al. Anaplastic chordoma with loss of INI1 and brachyury expression in a 2-year-old girl. Clin Neuropathol. 2014 Nov-Dec;33(6):418-20. PMID:25074874 547. Chbani L, Guillou L, Terrier P, et al. Epithelioid sarcoma: a clin icopathologic and immunohistochemical analysis of 106 cases from the French sarcoma group. Am J Clin Pathol. 2009 Feb;131 (2):222-7. PMID:19141382 548. Cheah A, Billings S, Goldblum J, et al. Spindle cell/pleomorphic lipomas of the face: an under-recognized diagnosis. Histopathology. 2015 Feb;66(3):430-7. PMID:25219904 549. Chebib I, Hornicek FJ, Nielsen GP, et al. Cytomorphologic features that distinguish schwannoma from other low-grade spindle cell lesions. Cancer Cytopathol. 2015 Mar;123(3):仃 1-9. PMID:25641870 550. Chen BJ, Marino-Enriquez A, Fletcher CD, et al. Loss of retinoblastoma protein expression in spindle cell/pleomorphic lipomas and cytogenetically related tumors: an immunohistochemical study with diagnostic implications. Am J Surg Pathol. 2012 Aug;36(8):1119-28. PMID:22790852 551. Chen CC, Liau CT, Chang CH, et al. Giant cell tumors of the bone with pulmonary metastasis. Orthopedics. 2016 JanFeb;39(1):e68-73. PMID:26730686 552. Chen CW, Chang WC, Lee HS, et al. MRI features of lipoblastoma: differentiating from other palpable lipomatous tumor in pediatric patients. Clin Imaging. 2010 NovDec;34(6):453-7. PMID:21092875 553. Chen E, Fletcher CD. Cellular angiofibroma with atypia or sarcomatous transformation: clinicopathologic analysis of 13 cases. Am J Surg Pathol. 2010 May;34(5):70714. PMID:20305534 554. Chen E, O'Connell F, Fletcher CD. Dedifferentiated leiomyosarcoma: clinicopathological analysis of 18 cases. Histopathology. 2011 Dec;59(6):1135-43. PMID:22175893 555. Chen G, Folpe AL, Colby TV, et al. Angiomatoid fibrous histiocytoma: unusual sites and unusual morphology. Mod Pathol. 2011 Dec;24(12):1560-70. PMID:21822206 556. Chen G, Xu Q, Zhang B, et al. Parosteal osteosarcoma of the fibula in a middle-aged patient: a case report. Medicine (Baltimore). 2019 Jan;98⑵:"3857. PMID:30633158 557. Chen H, Zhang 8, Wen JC, et al. Several types of soft tissue sarcomas originate from the malignant transformation of adipose tissuederived stem cells. Mol Med Rep. 2010 MayJun;3(3):441-8. PMID:21472259 558. Chen S, Fritchie K, Wei S, et al. Diagnostic utility of IDH1/2 mutations to distinguish dedifferentiated chondrosarcoma from undifferentiated pleomorphic sarcoma of bone. Hum Pathol. 2017 Jul;65:239-46. PMID:28552826 559. Chen S, Zheng Y, Chen L, et al. A broad ligament solitary fibrous tumor with

Doege-Potter syndrome. Medicine (Baltimore 2018 Sep;97(39):e12564. PMID:30278559 560. Chen ST, Lee JC. An inflammatorv myofibroblastic tumor in liver with ALK a h RANBP2 gene rearrangement: combination of distinct morphologic, immunohistochemical and genetic features. Hum Pathol 20dr Dec;39(12):1854-8. PMID:18701132 ' 561. Chen W, Wang J, Wang E, et al Detection of clonal lymphoid 'receptor gene rearrangements in Langerhans cell histiocytosis. Am J Surg Pathol 2010 Jul;34(7): 1049-57. PMID:20551822 ' 562. Chen X, Bahrami A, Pappo A, et al Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep. 2014Apr 107(1)-i0412. PMID:24703847 563. Chen Y, Wang F, Han A. Fat-forming solitary fibrous tumor of the kidney: a case report and literature review. Int J Clin Exp Pathol 2015 Jul 1 ;8(7):8632-5. PMID:26339447 564. Chen YY, Yen HH, Soon MS. Solitary gastric melanotic schwannoma: sonographic findings. J Clin Ultrasound. 2007 Jan;35⑴ 524. PMID:17111368 565. Chen Z, Liu C, Patel AJ, et al. Cells of origin in the embryonic nerve roots for NF1-associated plexiform neurofibroma. Cancer Cell. 2014 Nov 10;26(5):695-706 PMID:25446898 566. Cheng JC, Au AW. Infantile torticollis: a review of 624 cases. J Pediatr Orthop. 1994 Nov-Dec; 14(6):802-8. PMID:7814599 567. Cheng JC, Tang SP, Chen TM. Sternocleidomastoid pseudotumor and congenital muscular torticollis in infants: a prospective study of 510 cases. J Pediatr. 1999 Jun;134(6):712-6. PMID:10356139 56& Cheng JC, Wong MW, Tang SP, et al. Clinical determinants of the outcome of manual stretching in the treatment of congenital muscular torticollis in infants. A prospective study of eight hundred and twenty-one cases. J Bone Joint Surg Am. 2001 May;83(5):679-87. PMID:11379737 569. Chervenak FA, Isaacson G, Blakemore KJ, et al. Fetal cystic hygroma. Cause and natural history. N Engl J Med. 1983 Oct6;309(14):8225. PMID:6888468 570. Chesi M, Bergsagel PL. Molecular pathogenesis of multiple myeloma: basic and clinical updates. Int J Hematol. 2013 Mar;97(3):313-23. PMID:23456262 571. Chetty R, Vajpeyi R, Penwick JL. Psammomatous melanotic schwannoma presenting as colonic polyps. Virchows Arch. 2007 Sep;451 ⑶:717—20. PMID:17622556 572. Cheung H, Lau RL, Hsu SY. Case report: primary high grade surface osteosarcoma. Clin Radiol. 1995 Mar;50(3): 194-7. PMID:7889716 573. Cheung YH, Gayden T, Campeau PM, et al. A recurrent PDGFRB mutation causes familial infantile myofibromatosis. Am J Hum Genet. 2013 Jun 6;92(6):996-1000. PMID:23731537 574. Chew FS, Hudson TM. Radionuclide bone scanning of osteosarcoma: falsely extended uptake patterns. AJR Am J Roentgenol. 1982 Jul;139(1):49-54. PMID:6283871 575. Chibon F, Lagarde P, Salas S, et al. Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexity. Nat Med. 2010 Jul;16(7):781-7. PMID:20581836 576. Chibon F, Mairal A, Freneaux P, et al. The RB1 gene is the target of chromosome 13 deletions in malignant fibrous histiocytoma. Cancer Res. 2000 Nov 15;60(22):6339-45. PMID:11103795 577. Chmielecki J, Crago AM, Rosenberg M,

paybal：https://www.paypal.me/andy19801210 et al. Whole-exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nat Genet. 2013 Feb;45(2):131-2. PMID:23313954 578. Cho JH, Joo YH, Kim MS, et al. Venous hemangioma of parapharyngeal space with calcification. Clin Exp Otorhinolaryngol. 2011 Dec；4(4):207-9. PMID:22232718 579. Cho KR, Woodruff JD, Epstein JI. Leiomyoma of the uterus with multiple extrauterine smooth muscle tumors: a case report suggesting multifocal origin. Hum Pathol. 1989 Jan;20(1):80-3. PMID:2912878 580. Cho SJ, Horvai A. Chondro-osseous lesions of soft tissue. Surg Pathol Clin. 2015 Sep；8(3):419-44. PMID:26297064 581. Cho YJ, Kim JY Alveolar soft part sarcoma: clinical presentation, treatment and outcome in a series of 19 patients. Clin Orthop Surg. 2014 Mar;6(1):80-6. PMID:24605193 582. Choi BB, Jee WH, Sunwoo HJ, et al. MR differentiation of low-grade chondrosarcoma fiom enchondroma. Clin Imaging. 2013 MayJun;37 ⑶:542-7.PMID:23041161 583. Choi LE, Healey JH, Kuk D, etal. Analysis of outcomes in extraskeletal osteosarcoma: a review of fifty-three cases. J Bone Joint Surg Am. 2014 Jan 1;96(1):e2. PMID:24382730 ' 584. Choi ML, Wey PD, Borah GL. Pediatric peripheral neuropathy in proteus syndrome. Ann Plast Surg. 1998 May;40(5):528-32. PMID:9600441 585. ChompretA, Abel A, Stoppa-Lyonnet D, et al. Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet. 2001 Jan;38(1):43-7. PMID:11332399 586. Chong Y, Eom M, Min HJ, et al. Symplastic glomus tumor: a case report. Am J Dermatopathol. 2009 Feb;31(1):71-3. PMID: 19155729 587. Choong PF, Pritchard DJ, Rock MG, et al. Low grade central osteogenic sarcoma. A long­ term followup of 20 patients. Clin Orthop Relat Res. 1996 Jan;(322):198-206. PMID:8542697 588. Chou AJ, Geller DS, Gorlick R. Therapy for osteosarcoma: Where do we go from here? Paediatr Drugs. 2008; 10(5):315-27. PMID:18754698 589. Chougule A, Taylor MS, Nardi V, et al. Spindle and round cell sarcoma with EWSR1-PATZ1 gene fusion: a sarcoma with polyphenotypic differentiation. Am J Surg Pathol. 2019Feb;43(2):220-8. PMID:30379650 590. Chow LT, Allen PW, Kumta SM, et al. Angiomatoid malignant fibrous histiocytoma: report of an unusual case with highly aggressive clinical course. J Foot Ankle Surg. 1998 MayJun;37(3):235-8. PMID:9638550 591. Christopherson WM, Foote FW Jr, Stewart FW. Alveolar soft-part sarcomas; structurally characteristic tumors of uncertain histogenesis. Cancer. 1952 Jan;5(1):100-11. PMID:14886902 592. Chu WK, Hickson ID. RecQ helicases: multifunctional genome caretakers. Nat Rev Cancer. 2009 Sep;9(9):644-54. PMID:19657341 593. Chudasama P, Konrad A, Jochmann R, et al. Structural proteins of Kaposi's sarcoma・ associated herpesvirus antagonize p53mediated apoptosis. Oncogene. 2015 Jan 29;34(5):639-49. PMID:24469037 5,4. Chudasama P, Mughal SS, Sanders MA, et al. Integrative genomic and transcriptomic analysis of leiomyosarcoma. Nat Commun. 2018 Jan 10;9(1):144. PMID:29321523 595. Chun HE, Lim EL, Heravi-Moussavi A, et al. Genome-wide profiles of extra-eranial malignant rhabdoid tumors reveal heterogeneity and dysregulated developmental pathways. Cancer Cell. 2016 Mar 14;29(3):394-406. PMID:26977886 596. Chun KA, Cho IH, Won KJ, et al.

Osteoblastoma as a cause of osteomalacia assessed by bone scan. Ann Nucl Med. 2003 Jul;17(5):411-4. PMID:12971642 597. Chun YS, Wang L, Nascimento AG, et al. Pediatric inflammatory myofibroblastic tumor: anaplastic lymphoma kinase (ALK) expression and prognosis. Pediatr Blood Cancer. 2005 Nov;45(6):796-801. PMID:15602716 598. Chung BM, Hong SH, Yoo HJ, et al. Magnetic resonance imaging follow-叩 of chondroid tumors: regression vs. progression. Skeletal Radiol. 2018 Jun;47(6) :755-61. PMID:29197957 599. Chung EB. Pitfalls in diagnosing benign soft tissue tumors in infancy and childhood. Pathol Annu. 1985;20(Pt 2):323-86. PMID:3892466 600. Chung EB, Enzinger FM. Benign lipoblastomatosis. An analysis of 35 cases. Cancer. 1973 Aug;32(2):482-92. PMID:4353020 601. Chung EB, Enzinger FM. Chondroma of soft parts. Cancer. 1978 Apr;41(4):1414-24. PMID:76505 602. Chung EB, Enzi叩er FM. Extraskeletal osteosarcoma. Cancer. 1987 Sep 1;60(5):1132-42. PMID:3475157 603. Chimg EB, Enzinger FM. Infantile fibrosarcoma. Cancer. 1976 Aug;38(2):729-39. PMID:974993 604. Chung EB, Enzinger FM. Infantile myofibromatosis. Cancer. 1981 Oct 15;48(8): 1807-18. PMID:7284977 605. Chung EB, Enzinger FM. Malignant melanoma of soft parts. A reassessment of clear cell sarcoma. Am J Surg Pathol. 1983 Jul;7⑸:405-13. PMID:6614306 606. Chung EB, Enzinger FM. Proliferative fasciitis. Cancer. 1975 Oct;36(4): 1450-8. PMID:1058047 607. Church AJ, Calicchio ML, Nardi V, et al. Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy. Mod Pathol. 2018 Mar;31 (3):463-73. PMID:29099503 608. Ciatti R, Mariani PP. Fibroma of tendon sheath located within the ankle joint capsule. J Orthop Traumatol. 2009 Sep;10(3):147-50. PMID:19644650 609. Cibull TL, Gleason BC, O'Malley DP, et al. Malign ant cuta neous glomus tumor prese nting as a rapidly growing leg mass in a pregnant woman. J Cutan Pathol. 2008Aug;35(8):765-9. PMID:18422692 610. Clark SK, Smith TG, Katz DE, et al. Identification and progress!on of a desmoid precursor lesion in patients with familial adenomatous polyposis. Br J Surg. 1998 Jul;85(7):970-3. PMID:9692575 611. Clay MR, Martinez AP, Weiss SW, et al. MDM2 and CDK4 immunohistochemistry: should it be used in problematic differentiated lipomatous tumors?: a new perspective. Am J Surg Pathol. 2016 Dec;40(12):1647-52. PMID:27508976 612. Clement A, Wiweger M, von der Hardt S, et al. Regulation of zebrafish skeletogenesis by ext2/dackel and papstl/pinscher. PLoS Genet. 2008 Jul 25;4(7):e1000136. PMID:18654627 613. Cleton-Jansen AM, Timmerman MC, van de Vijver MJ, et al. A distinct phenotype characterizes tumors from a putative genetic trait involving chondrosarcoma and breast cancer occurring in the same patient. Lab Invest. 2004 Feb;84(2):191-202. PMID:14661035 614. eleven AH, Briaire-de Bruijn I, Szuhai K, et al. DOG1 expression in giant-cellcontaining bone tumours. Histopathology. 2016 May;68(6):942-5. PMID:26402312 615. eleven AH, Hocker S, Briaire-de Bruijn I, et al. Mutation analysis of H3F3A and H3F3B

as a diagnostic tool for giant cell tumor of bone and chondroblastoma. Am J Surg Pathol. 2015 Nov;39⑴):1576-83. PMID:26457357 616. eleven AH, Zwartkruis E, Hogendoorn PC, et al. Periosteal chondrosarcoma: a histopathological and molecular analysis of a rare chondrosarcoma subtype. Histopathology. 2015 Oct;67(4):483-90. PMID:25648524 617. eleven AHG, Hogendoorn PCW. Hematopoietic tumors primarily presenting in bone. Surg Pathol Clin. 2017 Sep;10⑶:675PMID:28797508 91. 618. eleven AHG, Suijker J, Agrogiannis G, et al. IDH1 or -2 mutations do not predict outcome and do not cause loss of 5-hydroxymethylcytosine or altered histone modifications in central chondrosarcomas. Clin Sarcoma Res. 2017 May 4;7:8.PMID:28484589 619. Clifton-Bligh RJ, Hofman MS, Duncan E, et al. Improving diagnosis of tumor-induced osteomalacia with gallium-68 DOTATATE PET/CT. J Clin Endocrinol Metab. 2013 Feb;98(2):687-94. PMID:23295468 620. Clines GA, Ashley JA, Shah S, et al. The structure of the human multiple exostoses 2 gene and characterization of homologs in mouse and Caenorhabditis elegans. Genome Res. 1997Apr;7(4):359-67. PMID:9110175 621. Cocco E, Scaltriti M, DrilonA. NTRK fusion­ positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018 Dec;15(12):731-47. PMID:30333516 622. Cocks M, Helmke E, Meyers CA, et al. Bizarre parosteal osteochondromatous proliferation: 16 cases with a focus on histologic variability. J Orthop. 2018 Jan 31;15(1):138-42. PMID:29657458 623. Coffin CM, Alaggio R. Adipose and myxoid tumors of childhood and adolescence. Pediatr Dev Pathol. 2012;15(1 Suppl):239-54. PMID:22420730 624. Coffin CM, Alaggio R. Fibroblastic and myofibroblastic tumors in children and adolescents. Pediatr Dev Pathol. 2012;15(1 Suppl):127-80. PMID:22420727 625. Coffin CM, Dehner LP. Fibroblasticmyofibroblastic tumors in children and adolescents: a clinicopathologic study of 108 examples in 103 patients. Pediatr Pathol. 1991 Jul-Aug;11(4):569-88. PMID:1946077 626. Coffin CM, Hornick JL, Fletcher CD. Infla mmatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol. 2007 Apr;31 (4):509-20. PMID:17414097 627. Coffin CM, Hornick JL, Zhou H, et al. Gardner fibroma: a clinicopathologic and immunohistochemical analysis of 45 patients with 57 fibromas. Am J Surg Pathol. 2007 Mar;31 (3):410-6. PMID:17325483 628. Coffin CM, Jaszcz W, O'Shea PA, et al. So-called congenital-infantile fibrosarcoma: Does it exist and what is it? Pediatr Pathol. 1994 Jan-Feb;14(1):133-50. PMID:8159611 629. Coffin CM, Lowichik A, Putnam A Lipoblastoma (LPB): a clinicopathologic and immunohistochemical analysis of 59 cases. Am J Surg Pathol. 2009 Nov;33(11):1705-12. PMID:19738456 630. Coffin CM, Patel A, Perkins S, et al. ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in in佃mmatory myofibroblastic tumor. Mod Pathol. 2001 Jun;14(6):569-76. PMID:11406658 631. Coffin CM, Watterson J, Priest JR, et al. Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). A clinicopathologic and immunohistochemical study of 84 cases. Am J Surg Pathol. 1995 Aug;19(8):859-72. PMID:7611533

632. Cohen JI, Dropulic L, Hsu AP, et al. Association of GATA2 deficiency with severe primary Epstein-Barr virus (EBV) infection and EBV-associated cancers. Clin Infect Dis. 2016 Jul1;63(1):41-7. PMID:27169477 633. Cohen JN, Sabnis AJ, Krings G, et al. EWSR1-NFATC2 gene fusion in a soft tissue tumor with epithelioid round cell morphology and abundant stroma: a case report and review of the literature. Hum Pathol. 2018 Nov;81:28190. PMID:29626598 634. Cohen MC, Drut R, Garcia C, et al. Mesenchymal hamartoma of the chest wall: a cooperative study with review of the literature. Pediatr Pathol. 1992 Jul-Aug;12(4):525-34. PMID:1409151 635. Cohen-Aubart F, Emile JF, Carrat F, et al. Phenotypes and survival in Erdheim-Chester disease: results from a 165-patient cohort. Am J Hematol. 2018 May;93⑸:E们4-7. PMID:29396850 636. Cohen-Gogo S, Cellier C, Coindre JM, et al. Ewing-like sarcomas with BCOR-CCNB3 fusion transcript: a clinical, radiological and pathological retrospective study from the Societe Fran^aise des Cancers de UEnfant. Pediatr Blood Cancer. 2014 Dec;61(12):21918. PMID:25176412 637. Coindre JM. Grading of soft tissue sarcomas: review and update. Arch Pathol Lab Med. 2006 Oct;130(10):1448-53. PMID:17090186 63& Coindre JM, de Mascarel A, Trojani M, et al. Immunohistochemical study of rhabdomyosarcoma. Unexpected staining with S100 protein and cytokeratin. J Pathol. 1988 Jun;155(2):127-32. PMID:2455782 639. Coindre JM, 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. J Pathol. 2004 Jul;203(3):822-30. PMID:15221942 640. Coindre JM, Hostein I, Terrier P, et al. Diagnosis of clear cell sarcoma by real-time reverse transcriptase-polymerase chain reaction analysis of paraffin embedded tissues: clinicopathologic and molecular analysis of 44 patients from the French sarcoma group. Cancer. 2006 S即 1;107(5):1055-64. PMID:16878328 641. Coindre JM, Mariani O, Chibon F, et al. Most malignant fibrous histiocytomas developed in the retroperitoneum are dedifferentiated liposarcomas: a review of 25 cases initially diagnosed as malignant fibrous histiocytoma. Mod Pathol. 2003 Mar; 16(3):25662. PMID:12640106 642. Coindre JM, Terrier P, Guillou L, et al. Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer. 2001 May 15;91(10):1914-26. PMID:11346874 643. Coli A, Novello M, Tamburrini G, et al. Intracranial neuromuscular choristoma: report of a case with literature review. Neuropathology. 2017Aug;37(4):341-5. PMID:28168739 644. Collini P, Negri T, Barisella M, et al. High-grade sarcomatous overgrowth in solitary fibrous tumors: a clinicopathologic study of 10 cases. Am J Surg Pathol. 2012 Aug;36(8):1202-15. PMID:22613995 645. Collins DH. Paget's disease of bone; incidence and subclinical forms. Lancet. 1956 Jul 14;271(6933):51-7. PMID:13347083 646. Collins MH, Chatten J. Lipoblastoma/ lipoblastomatosis: a clinicopathologic study of 25 tumors. Am J Surg Pathol. 1997 Oct;21(10):1131-7. PMID:9331284 647. Collins MS, Koyama T, Swee RG, et al.

Refere nces

553

paybal：https://www.paypal.me/andy19801210 Clear cell chondrosarcoma: radiographic, computed tomographic, and magnetic resonance findings in 34 patients with pathologic correlation. Skeletal Radiol. 2003 Dec;32(12):687-94. PMID:14530882 64& Collins MT, Sarlis NJ, Merino MJ, et al. Thyroid carcinoma in the McCune-Albright syndrome: contributory role of activating Gs alpha mutations. J Clin Endocrinol Metab. 2003 Sep;88(9):4413-7. PMID:12970318 649. Collins MT, Singer FR, Eugster E. McCuneAlbright syndrome and the extraskeletal manifestations of fibrous dysplasia. Orphanet J Rare Dis. 2012 May 24;7 Suppl 1:S4. PMID:22640971 650. Colombo C, Bolshakov S, Hajibashi S, et al. "Difficult to diagnose' desmoid tumours: a potential role for CTNNB1 mutational analysis. Histopathology. 2011 Aug;59(2):336-40. PMID:21884214 651. Colombo C, Foo WC, Whiting D, et al. FAP-related desmoid tumors: a series of 44 patients evaluated in a cancer referral center. Histol Histopathol. 2012 May;27(5):641-9. PMID:22419028 652. Colombo C, Miceli R, Lazar AJ, et al. CTNNB1 45F mutation is a molecular prognosticator of increased postoperative primary desmoid tumor recurrence: an independent, multicenter validation study. Cancer. 2013 Oct 15; 119(20):3696-702. PMID:23913621 653. Combemale P, Valeyrie-Allanore L, Giammarile F, et al. Utility of 18F-FDG PET with a semi-quantitative index in the detection of sarcomatous transformation in patients with neurofibromatosis type 1. PLoS One. 2014 Feb 6;9(2):e85954.PMID:24516522 654. Conner JR, Hornick JL. SATB2 is a novel marker of osteoblastic differentiation in bone and soft tissue tumours. Histopathology. 2013 Jul;63(1) :36-49. PMID23701429 655. Cook GJ, Fogelman I. The role of nuclear medicine in monitoring treatment in skeletal malignancy. Semin Nucl Med. 2001 Jul;3M3) :206-11.PMID:11430527 656. Cook JR, Dehner LP, Collins MH, et al. An aplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: a comparative immunohistochemical study. Am J Surg Pathol. 2001 Nov;25(11):1364-71. PMID:11684952 657. Cooper JG, Edwards SL, Holmes JD. Kaposiform haemangioendothelioma: case report and review of the literature. Br J Plast Surg. 2002 Mar;55(2):163-5. PMID:11987956 65& Copie-Bergma n C, Niedobitek G, Mangham DC, et al. Epstein-Barr virus in B-cell lymphomas associated with chronic suppurative inflammation. J Pathol. 1997 Nov;183(3):287-92. PMID:9422983 659. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011 Nov 17:11(12):865-78. PMID:22089421 660. Corless CL, Schroeder A, Griffith D, et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 2005 Aug 10:23(23):5357-64. PMID:15928335 661. Cossarizza A, Mussini C, Vigano A. Mitochondria in the pathogenesis of lipodystrophy induced by anti-HIV antiretroviral drugs: actors or bystanders? Bioessays. 2001 Nov;23( 11):1070-80. PMID:11746223 662. Cossu S, Satta R, Cottoni F, et al. Lymphangioma-like variant of Kaposi's sarcoma: clinicopathologic study of seven cases with review of the literature. Am J Dermatopathol. 1997 Feb; 19(1): 16-22. PMID:9056649 663. Costa FD, Folpe AL. Intratesticular

554

References

kaposiform haemangioendothelioma in adults: a report of two cases. J Clin Pathol. 2013 Jul;66(7):623-6. PMID:23493478 664. Costa J, Wesley RA, Glatstein E, et al. The grading of soft tissue sarcomas. Results of a clinicohistopathologic correlation in a series of 163 cases. Cancer. 1984 Feb 1;53(3):530-41. PMID:6692258 665. Costa MJ, Weiss SW. Angiomatoid malignant fibrous histiocytoma. A follow-up study of 108 cases with evaluation of possible histologic predictors of outcome. Am J Surg Pathol. 1990 Dec;14(12):1126-32. PMID:2174650 666. Costelloe CM, Chuang HH, Madewell JE. FDG PET/CT of primary bone tumors. AJR Am J Roentgenol. 2014 Jun;202(6):W521-31. PMID:24848845 667. Costelloe CM, Madewell JE. Radiography in the initial diagnosis of primary bone tumors. AJR Am J Roentgenol. 2013 Jan;200(1 ):3-7. PMID:23255735 66& Courcoutsakis N, Prassopoulos P, Stratakis C. Carney complex: one more entity with skin and bone manifestations. Radiographics. 2015 Jan-Feb;35(1):296-7. PMID:25590407 669. Courcoutsakis NA, Tatsi C, Patronas NJ, et al. The complex of myxomas, spotty skin pigmentation and endocrine overactivity (Carney complex): imaging findings with clinical and pathological correlation. Insights Imaging. 2013 Feb;4(1):119-33. PMID:23315333 670. Crago AM, Chmielecki J, Rosenberg M, et al. Near universal detection of alterations in CTNNB1 and Wnt pathway regulators in desmoid-type fibromatosis by whole-exome sequencing and genomic analysis. Genes Chromosomes Cancer. 2015 Oct;54(10):606PMID:26171757 15. 671. Crago AM, Denton B, Salas S, et al. A prognostic nomogram for prediction of recurrence in desmoid fibromatosis. Ann Surg. 2013Aug;258(2):347-53. PMID:23532110 ° 672. Crago AM, Socci ND, DeCarolis P, et al. Copy number losses define subgroups of dedifferentiated liposarcoma with poor prognosis and genomic instability. Clin Cancer Res. 2012 Mar 1;18(5):1334-40. PMID:22241790 673. Crapanzano JP, Cardillo M, Lin O, et al. Cytology of desmoplastic small round cell tumor. Cancer. 2002 Feb 25;96(1):21-31. PMID:11836699 674. Crasta K, Ganem NJ, Dagher R, et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature. 2012 Jan 18;482(7383):53-8. PMID:22258507 675. Craver RD, Henrich S, Kao YS. Fibrous lipoblastoma with 8q11.2 abnormality. Cancer Genet Cytogenet. 2006 Dec;171(2):112-4. PMID:17116489 676. Creytens D. A contemporary review of myxoid adipocytic tumors. Semin Diagn Pathol. 2019 Mar;36(2):129-41. PMID:30853315 677. Creytens D, Ferdinande L, van Gorp J, et al. Atypical spindle cell lipomatous tumor with benign heterologous (metaplastic) cartilaginous differentiation. Int J Surg Pathol. 2019 Aug;27 ⑸:521-3. PMID:30370805 678. Creytens D, Mentzel T, Ferdinande L, et al. "Atypical" pleomorphic lipomatous tumor: a clinicopathologic, immunohistochemical and molecular study of 21 cases, emphasizing its relationship to atypical spindle cell lipomatous tumor and suggesting a morphologic spectrum (atypical spindle cell/pleomorphic lipomatous tumor). Am J Surg Pathol. 2017 Nov;41 (11):1443-55. PMID:28877053 679. Creytens D, Mentzel T, Ferdinande L, et al. Tat-rich" (spindle cell-poor) variants of atypical spindle cell lipomatous tumors show

similar morphologic, immunohistochemical and molecular features as "dysplastic lipomas": Are they related lesions? Comment on Michal et al (2018). Am J Surg Pathol. 2019 Feb;43⑵:2889. PMID:30211727 680. Creytens D, Mentzel T, Ferdinande L, et al. Atypical mitoses are present in otherwise classical pleomorphic lipomas-reply. Hum Pathol. 2018 Nov;81:300-2. PMID:30084357 681. Creytens D, Mentzel T, Ferdinande L, etal. Atypical multivacuolated lipoblasts and atypical mitoses are not compatible with the diagnosis of spindle cell/pleomorphic lipoma. Hum Pathol. 2018Apr;74:188-9. PMID:29317234 682. Creytens D, van Gorp J, Ferdinande L, et al. Array-based comparative genomic hybridization analysis of a pleomorphic myxoid liposarcoma. J Clin Pathol. 2014 Sep;67(9):834-5. PMID:24970901 683. Creytens D, van Gorp J, Savoia S, et al. Atypical spindle cell lipoma: a clinicopathologic, immunohistochemical, and molecular study emphasizing its relationship to classical spindle cell lipoma. Virchows Arch. 2014 Jul;465(1):97108. PMID:24659226 684. Creytens D, Van Gorp J, Speel EJ, et al. Characterization of the 12q amplicons in lipomatous soft tissue tumors by multiplex ligation-dependent probe amplification-based copy number analysis. Anticancer Res. 2015 Apr;35(4):1835^12. PMID:25862836 685. Crim J, Schmidt R, Layfield L, et al. Can imaging criteria distinguish enchondroma from grade 1 chondrosarcoma? Eur J Radiol. 2015 Nov;84(11):2222-30. PMID:26220916 686. Crompton BD, Stewart C, Taylor-Weiner A, et al. The genomic landscape of pediatric Ewing sarcoma. Cancer Discov. 2014 Nov;4(11):1326-41. PMID:25186949 687. Croteau DL, Popuri V, Opresko PL, et al. Human RecQ helicases in DNA repair, recombination, and replication. Annu Rev Biochem. 2014;83:519-52. PMID:24606147 688. Crowson AN, Carlson-Sweet K, Macinnis C, et al. Clear cell atypical fibroxanthomas clinicopathologic study. J Cutan Pathol. 2002 Jul;29(6):374-81. PMID:12135470 689. Cruz-Mojarrieta J, Navarro S, GomezCabrera E, et al. Malignant granular cell tumor of soft tissues: a study of two new cases. Int J Surg Pathol. 2001 Jul;9(3):255-9. PMID:11584326 690. Cui JF, Chen HS, Hao DP, et al. Magnetic resonance features and characteristic vascular pattern of alveolar soft-part sarcoma. On col Res Treat. 2017;40(10):580-5. PMID:28950275 691. Cullen D, Diaz Recuero JL, Cullen R, et al. Superficial acral fibromyxoma: report of 13 cases with new immunohistochemical findings. Am J Dermatopathol. 2017 Jan;39(1):14-22. PMID:28045748 692. Cummings OW, Ulbright TM, Young RH, et al. Desmoplastic small round cell tumors of the paratesticular region. A report of six cases. Am J Surg Pathol. 1997 Feb;21 (2):219-25. PMID:9042290 693. Cupp JS, Miller MA, Montgomery KD, et al. Translocation and expression of CSF1 in pigmented villonodular synovitis, tenosynovial giant cell tumor, rheumatoid arthritis and other reactive synovitides. Am J Surg Pathol. 2007 Jun;31 ⑹:970-6. PMID:17527089 694. Curran-Melendez SM, Dasher DA, Groben P, et al. Case report: meningothelial hamartoma of the scalp in a 9-year-old child. Pediatr Dermatol. 2011 Nov-Dec;28(6):677-80. PMID:21906138 695. Cutler CM, Lee JS, Butman JA, et al. Long-term outcome of optic nerve encasement and optic nerve decompression in patients with fibrous dysplasia: risk factors for blindness and safety of observation. Neurosurgery.

2006 Nov;59⑸:仙彳-7, discussion 1017 0 PMID:17143235 696. CuvielloA, Goyal A, ZickA, et al. Sporadic malignant glomus tumor of the brachial plexus with response to targeted therapy directed against oncogenic BRAF. JCO Precis Oncol 2018;2018. PMID:30556047 697. Czerniak B. Osteosarcoma. In: Dorfman and Czerniak's bone tumors. 2nd ed Philadelphia (PA): Elsevier; 2015. pp. 200-355 69& Czerniak B. Vascular lesions.斤 Dorfman and Czerniak's bone tumors. 2nd ed Philadelphia (PA): Elsevier; 2015. pp. 903-89. 699. Dabska M. Malignant endovascular papillary angioendothelioma of the skin in childhood. Clinicopathologic study of 6 cases. Cancer. 1969 Sep;24 ⑶:5O3-1O PMID:5343389 700. Dabska M. Parachordoma: a new clinicopathologic entity. Cancer. 1977 Oct;40(4):1586-92. PMID:907973 701. Dabska M, Koszarowski T. Clinical and pathologic study of aponeurotic (epithelioid) sarcoma. Pathol Annu. 1982;17(Pt 1):129-53 PMID:6750534 702. DaCambra MP, Gupta SK, Ferri-deBarros F. Subungual exostosis of the toes: a systematic review. Clin Orthop Relat Res. 2014 Apr;472(4):1251-9. PMID:24146360 703. D'Adamo DR. Appraising the current role of chemotherapy for the treatment of sarcoma. Semin Oncol. 2011 Oct;38 Suppl 3:S19-29 PMID:22055968 704. Dadone B, Refae S, Lemarie-Delaunay C, et al. Molecular cytogenetics of pediatric adipocytic tumors. Cancer Genet. 2015 Oct;208(10):469-81. PMID:26319758 705. Dadone-Montaudie B, Alberti L, Due A, et al. Alternative PDGFD rearrangements in dermatofibrosarcomas protuberans without PDGFB fusions. Mod Pathol. 2018 Nov;31(11):1683-93. PMID:29955147 706. Daffner RH, Kirks DR, Gehweiler JA Jr, et al. Computed tomography of fibrous dysplasia. AJR Am J Roentgenol. 1982 Nov;139(5):943-8. PMID:6981980 707. Dagrada GP, Spagnuolo RD, Mauro V, et al. Solitary fibrous tumors: loss of chimeric protein expression and genomic instability mark dedifferentiation. Mod Pathol. 2015 Aug;28(8):1074-83. PMID:26022454 708. Dahl NA, Sheil A, Knapke S, et al. Gardner fibroma: clinical and histopathologic implications of germline APC mutation association. J Pediatr Hematol Oncol. 2016 Jul;38⑸:e154-7. PMID:26840078 709. Dahlen A, Debiec-Rychter M, Pedeutour F, et al. Clustering of deletions on chromosome 13 in benign and low-malignant lipomatous tumors. Int J Cancer. 2003 Feb 20;103(5):61623. PMID:12494468 710. Dahlen A, Mertens F, Rydholm A, et al. Fusion, disruption, and expression of HMGA2 in bone and soft tissue chondromas. Mod Pathol. 2003 Nov;16(11):1132-40. PMID:14614053 711. Dahlin DC. Case report 189. Infantile fibrosarcoma (congenital fibrosarcoma-like fibromatosis). Skeletal Radiol. 1982;8(1)：77七 PMID:7079792 712. Dahlin DC, Beabout JW. Dedifferentiation of low-grade chondrosarcomas. Cancer. 1971 Aug;28(2):461-6. PMID:5566365 713. Dahlin DC, Bertoni F, Beabout JW. et al. Fibrocartilaginous mesenchymoma with low-grade malignancy. Skeletal Radiol. 1984;12(4):263-9. PMID:6505732 714. Dahlin DC, Ivins JC. Benign chondroblastoma. A study of 125 cases. Cancer. 1972Aug;30(2):401-13. PMID:5051664 715. Dahlin LB, Scherman P, Besjakov J.el al. Intraneural glomus tumor of "uncertain malignant potential" and with BRAF muta io

paybal：https://www.paypal.me/andy19801210

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in the median nerve - an unusual case. Clin Neuropathol. 2017 Jul/Aug;36(4):164-70. PMID:28438258 716. Dal Cin P, Kozakewich HP, Goumnerova L, et al. Variant translocations involving 16q22 and 17p13 in solid variant and extraosseous forms of aneurysmal bone cyst. Genes Chromosomes Cancer. 2000 Jun;28⑵:233-4. PMID:10825009 717. Dal Cin P, Pauwels P, Poldermans LJ, et al. Clonal chromosome abnormalities in a so-called Dupuytren's subungual exostosis. Genes Chromosomes Cancer. 1999 Feb;24(2):1624 PMID:9885985 718. Dal Cin P, Pauwels P, Sciot R, et al. Multiple chromosome rearrangements in a fibrosarcoma. Cancer Genet Cytogenet. 1996 Apr;87⑵H76-8. PMID:8625267 719. Dal Cin P, Sciot R, Brys P, etal. Recurrent chromosome aberrations in fibrous dysplasia of the bone: a report of the CHAMP study group. CHromosomes And MorPhology. Cancer Genet Cytogenet. 2000 Oct 1;122(1):30-2. PMID:11104029 720. Dal Cin P, Sciot R, De Smet L, et al. Tanslocation 2;11 in a fibroma of tendon sheath. Histopathology. 1998 May;32(5):433-5. PMID:9639118 721. Dal Cin P, Sciot R, Fletcher CD, et al. Inflammatory leiomyosarcoma may be characterized by specific near-haploid chromosome changes. J Pathol. 1998 May;185(1):112-5. PMID:9713368 722. Dal Cjn P, Sciot R, Polito P, et al. Lesions of 13q may occur independently of deletion of 16q in spindle cell/pleomorphic lipomas. Histopathology. 1997 Sep;31 (3):222-5. PMID:9354891 723. Dalal KM, Kattan MW, Antonescu CR, et al. Subtype specific prognostic nomogram for patients with primary liposarcoma of the retroperitoneum, extremity, or trunk. Ann Surg. 2006 Sep;244(3):381-91. PMID:16926564 724. Daldrup-Link HE, Franzius C, Link TM, et al. Whole-body MR imaging for detection of bone metastases in children and young adults: comparison with skeletal scintigraphy and FDG PET. AJR Am J Roentgenol. 2001 Jul; 177(1 ):229-36. PMID:11418435 725. Dale S, Breidahl WH, Baker D, et al. Severe toxic osteoblastoma of the humerus associated with diffuse periostitis of multiple bones. Skeletal Radiol. 2001 Aug;30(8):464-8. PMID:11479753 726. Damato S, Alorjani M, Bonar F, et al. IDH1 mutations are not found in cartilaginous tumours other than central and periosteal chondrosarcomas and enchondromas. Histopathology. 2012 Jan;60(2):363-5. PMID:22074484 727 Dancer JY, Henry SP, Bondaruk J, et al. Expression of master regulatory genes controlling skeletal development in benign cartilage and bone forming tumors. Hum Pathol. 2010 Dec;41 (12):1788-93. PMID:21078438 72& D'Angelo F, Ceccarelli M, Tala, et al. The molecular landscape of glioma in patients with neurofibromatosis 1. Nat Med. 2019 Jan;25(1 ):176-87. PMID:30531922 729. Danon M, Robboy SJ, Kim S, et al. Cushing syndrome, sexual precocity, and polyostotic fibrous dysplasia (Albright syndrome) in infancy. J Pediatr. 1975 Dec;87(6 Pt 1):917-21. PMID:171361 730. Dantey K, Schoedel K, Yergiyev 0, et al. Ossifying fibromyxoid tumor: a study of 6 cases of atypical and malignant variants. Hum Pathol. 2017 Feb;60:174-9. PMID:27816723 731 Dantonello TM, Leuschner I, Vokuhl C, et al. Malignant ectomesenchymoma in children and adolescents: report from the Cooperative Weichteilsarkom Studiengruppe (CWS).

Pediatr Blood Cancer. 2013 Feb;60(2):224-9. PMID:22535600 732. Dar P, Karmin I, Einstein MH. Arteriovenous malformations of the uterus: long-term follow-up. Gynecol Obstet Invest. 2008;66(3):157-61. PMID:18544994 733. Darilek S, Wicklund C, Novy D, et al. Hereditary multiple exostosis and pain. J Pediatr Orthop. 2005 May-Jun;25(3):369-76. PMID:15832158 734. Daroca PJ Jr, Pulitzer DR, LoCicero J 3rd. Ossifying fasciitis. Arch Pathol Lab Med. 1982 Dec; 106(13):682-5. PMID:6814399 735. Dashti NK, Wehrs RN, Thomas BC, et al. Spindle cell rhabdomyosarcoma of bone with FUS-TFCP2 fusion: confirmation of a very recently described rhabdomyosarcoma subtype. Histopathology. 2018 Sep;73⑶:51420. PMID:29758589 736. Datta V, Rawal YB, Mincer HH, et al. Myopericytoma of the oral cavity. Head Neck. 2007 Jun;29(6):605-8. PMID: 17252599 737. Davicioni E, Anderson MJ, Finckenstein FG, et al. Molecular classification of rhabdomyosarcoma-genotypic and phenotypic determinants of diagnosis: a report from the Children's Oncology Group. Am J Pathol. 2009 Feb;174(2):550-64. PMID:19147825 738. Davicioni E, Finckenstein FG, Shahbazian V, et al. Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas. Cancer Res. 2006 Jul 15;66(14):6936-46. PMID:16849537 739. Davids JR, Wenger DR, Mubarak SJ. Congenital muscular torticollis: sequela of intrauterine or perinatal compartment syndrome. J Pediatr Orthop. 1993 MarApr;13(2):141-7.PMID:8459000 740. Davis AM, O'Sullivan B, Turcotte R, et al. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncoi. 2005Apr;75(1):48-53.PMID:15948265 741. Davis IJ, Kim JJ, Ozsolak E et al. Oncogenic MITF dysregulation in clear cell sarcoma: defining the MiT family of human cancers. Cancer Cell. 2006 Jun;9⑹:473-84. PMID:16766266 742. Davis JL, Horvai AE. Special AT-rich sequence-binding protein 2 (SATB2) expression is sensitive but may not be specific for osteosarcoma as compared with other high­ grade primary bone sarcomas. Histopathology. 2016 Jul;69(1):84-90. PMID:26644288 743. Davis JL, Lockwood CM, Stohr B, et al. Expanding the spectrum of pediatric NTRK-rearranged mesenchymal tumors. Am J Surg Pathol. 2019 Apr;43(4):435-45. PMID:30585824 744. Davis LE, Nusser KD, Przybyl J, et al. Discovery and characterization of recurrent, targetable ALK fusions in leiomyosarcoma. Mol Cancer Res. 2019 Mar;17⑶:676-85. PMID:30518629 745. Davis Rl, Hamilton A, Biggart JD. Primary synovial chondromatosis: a clinicopathologic review and assessment of malig nant potential. Hum Pathol. 1998 Jul;29(7):683-8. PMID:9670824 746. Davis RJ, D'Cruz CM, Lovell MA, et al. Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma. Cancer Res. 1994 Jun 1 ;54(11 ):2869-72. PMID:8187070 747. de Alava E, Ladanyi M, Rosai J, et al. Detection of chimeric transcripts in desmoplastic small round cell tumor and related developmental tumors by reverse transcriptase polymerase chain reaction. A specific diagnostic assay. Am J Pathol. 1995 Dec;147(6):1584-91. PMID:7495283

748. de Andrade KC, Mirabello L, Stewart DR, et al. Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history. Hum Mutat. 2017 Dec;38(12):1723-30. PMID:28861920 749. de Andrea CE, Kroon HM, Wolterbeek R, et al. Interobserver reliability in the histopathological diagnosis of cartilaginous tumors in patients with multiple osteochondromas. Mod Pathol. 2012 S即;25(9): 1275-83. PMID:22555180 750. de Andrea CE, Prins FA, WiwegerMI, etal. Growth plate regulation and osteochondroma formation: insights from tracing proteoglycans in zebrafish models and human cartilage. J Pathol. 2011 Jun;224(2):160-8. PMID:21506131 751. de Andrea CE, Reijnders CM, Kroon HM, et al. Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT. Oncogene. 2012 Mar 1;31(9):1095-104. PMID:21804604 752. de Andrea CE, Wiweger M, Prins F, et al. Primary cilia organization reflects polarity in the growth plate and implies loss of polarity and mosaicism in osteochondroma. Lab Invest. 2010Jul;90(7):1091-101.PMID:20421870 753. de Andrea CE, Wiweger Ml, Bovee JV, et al. Peripheral chondrosarcoma progression is associated with increased type X collagen and vascularisation. Virchows Arch. 2012 Jan;460(1 ):95-102. PMID:22116208 754. de Andrea CE, Zhu JF, Jin H, et al. Cell cycle deregulation and mosaic loss of Ext1 drive peripheral chondrosarcomagenesis in the mouse and reveal mn intrinsic cilia deficiency. J Pathol. 2015 Jun;236(2):210-8. PMID:25644707 755. De Beur SM, Finnegan RB, Vassiliadis J, et al. Tumors associated with oncogenic osteomalacia express genes important in bone and mineral metabolism. J Bone Miner Res. 2002 Jun;17⑹:0O2「O. PMID:12054166 756. de Blank PMK, Fisher MJ, Liu GT, et al. Optic pathway gliomas in neurofibromatosis type 1: an update: surveillance, treatment indications, and biomarkers of vision. J Neuroophthalmol. 2017 Sep;37 S叩pl 1:82332. PMID:28806346 757. de Camargo OP, dos Santos Machado TM, Croci AT, et al. Primary bone lymphoma in 24 patients treated between 1955 and 1999. Clin Orthop Relat Res. 2002 Apr;(397):271-80. PMID:11953618 75& De Coninck T, Jans L, Sys G, et al. Dynamic contrast-enhanced MR imaging for differentiation between enchondroma and chondrosarcoma. Eur Radiol. 2013 Nov;23(11):3140-52. PMID:23771600 759. de Jong Y, Monderer D, Brandinelli E, et al. Bcl-xl as the most promising Bcl-2 family member in targeted treatment of chondrosarcoma. Oncogenesis. 2018 S即 21;7(9):74. PMID:30242253 760. De Los Santos-Aguilar RG, Chavez-Villa M, Contreras AG, et al. Successful multimodal treatment of an IGF2-producing solitary fibrous tumor with acromegaloid changes and hypoglycemia. J Endocr Soc. 2019 Jan 8;3(3):537-43. PMID:30788455 761. De Raedt T, Beert E, Pasmant E, et al. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521 ):24751.PMID:25119042 762. De Raedt T, Brems H, Wolkenstein P, et al. Elevated risk for MPNST in NF1 microdeletion patients. Am J Hum Genet. 2003 May;72(5):1288-92. PMID:12660952 763. de Saint Aubain Somerhausen N, Coindre JM, Debiec-Rychter M, et al. Lipoblastoma in

adolescents and young adults: report of six cases with FISH analysis. Histopathology. 2008 Feb;52(3):294-8. PMID:18269579 764. De Schepper S, Maertens O, Callens T, et al. Somatic mutation analysis in NF1 cafe au lait spots reveals two NF1 hits in the melanocytes. J Invest Dermatol. 2008 Apr; 128(4):1050-3. PMID:17914445 765. de Silva MV, McMahon AD, Paterson L, et al. Identification of poorly differentiated synovial sarcoma: a comparison of clinicopathological and cytogenetic features with those of typical synovial sarcoma. Histopathology. 2003 S即;43(3):220-30. PMID:12940774 766. de Vreeze RS, de Jong D, Tielen IH, et al. Primary retroperitoneal myxoid/round cell liposarcoma is a nonexisting disease: an immunohistochemical and molecular biological analysis. Mod Pathol. 2009 Feb;22(2):223-31. PMID:18820664 767. De Wever I, Dal Cin P, Fletcher CD, et al. Cytogenetic, clinical, and morphologic correlations in 78 cases of fibromatosis: a report from the CHAMP Study Gro叩. CHromosomes And Morphology. Mod Pathol. 2000 Oct;13(10):1080-5. PMID:11048801 768. de Andrea CE, San-Julian M, Bovee JVMG. Integrating morphology and genetics in the diagnosis of cartilage tumors. Surg Pathol Clin. 2017 Sep;10(3):537-52. PMID:28797501 769. Debelenko LV, Arthur DC, Pack SD, et al. Identification of CARS-ALK fusion in primary and metastatic lesions of an inflammatory myofibroblastic tumor. Lab Invest. 2003 Sep;83(9):1255-65. PMID:13679433 770. Debiec-Rychter M, Sciot R, Le Cesne A, et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer. 2006 May;42(8):1093-103. PMID:16624552 771. Deen M, Ebrahim S, SchloffD, etal. A novel PLAG1-RAD51L1 gene fusion resulting from a t(8;14)(q12;q24) in a case of lipoblastoma. Cancer Genet. 2013 Jun;206⑹:233-7. PMID:23890983 772. Deenik W, Mooi WJ, Rutgers EJ, et al. Clear cell sarcoma (malignant melanoma) of soft parts: a clinicopathologic study of 30 cases. Cancer. 1999 Sep 15;86(6):969-75. PMID:10491522 773. de Feraudy S, Fletcher CD. Intradermal nodular fasciitis: a rare lesion analyzed in a series of 24 cases. Am J Surg Pathol. 2010 Sep;34(9):1377-81. PMID:20716998 774. Dei Tos AP, Doglioni C, Piccinin S, et al. Molecular abnormalities of the p53 pathway in dedifferentiated liposarcoma. J Pathol. 1997 Jan;181(1):8-13. PMID:9071997 775. Dei Tos AP, Maestro R, Doglioni C, et al. Tumor suppressor genes and related molecules in leiomyosarcoma. Am J Pathol. 1996 Apr;148(4):1037-45. PMID:8644845 776. Dei Tos AP, Maestro R, Doglioni C, et al. Ultraviolet-induced p53 mutations in atypical fibroxanthoma. Am J Pathol. 1994 Jul;145(1):11-7. PMID:8030743 777. Dei Tos AP, Seregard S, Calonje E, et al. Giant cell angiofibroma. A distinctive orbital tumor in adults. Am J Surg Pathol. 1995 Nov;19(11):1286-93. PMID:7573691 778. Dei Tos AP. Liposarcomas: diagnostic pitfalls and new insights. Histopathology. 2014 Jan;64(1):38-52. PMID:24118009 779. Dei Tos AP, Mentzel T, Fletcher CD. Primary liposarcoma of the skin: a rare neoplasm with unusual high grade features. Am J Dermatopathol. 1998 Aug;20(4):332-8. PMID:9700369 780. Del Castillo M, Chibon F, Arnould L, et al. Secretory breast carcinoma: a histopathologic and genomic spectrum characterized by a joint specific ETV6-NTRK3 gene fusion. Am

Refere nces

555

paybal：https://www.paypal.me/andy19801210 J Surg Pathol. 2015 Nov;39⑴):1458-67. PMID:26291510 781. Delaney D, Diss TC, Presneau N, et al. GNAS1 mutations occur more commonly than previously thought in intramuscular myxoma. Mod Pathol. 2009 May;22(5):718-24. PMID:19287459 782. Della Rocca C, HuvosAG. Osteoblastoma: varied histological presentations with a benign clinical course. An analysis of 55 cases. Am J Surg Pathol. 1996 Jul;20(7):841-50. PMID:8669532 783. DeMay RM, Kay S. Granular cell tumor of the breast. Pathol Annu. 1984;19(Pt 2):121-48. PMID:6095165 784. Demertzis JL, Kyriakos M, Loomans R, et al. Synovial hemangioma of the hip joint in a pediatric patient. Skeletal Radiol. 2014 Jan;43(1 ):107-13. PMID:24061493 785. Demicco EG. Molecular 叩dates in adipocytic neoplasms. Semin Diagn Pathol. 2019 Mar;36(2):85-94. PMID:30857767 786. Demicco EG, Deshpande V, Nielsen GP, et al. Well-differentiated osteosarcoma of the jaw bones: a clinicopathologic study of 15 cases. Am J Surg Pathol. 2010 Nov;34(11):1647-55. PMID:20975343 787. Demicco EG, Harms PW, Patel RM, et al. Extensive survey of STAT6 expression in a large series of mesenchymal tumors. Am J Clin Pathol. 2015 May;143(5):672-82. PMID:25873501 78& Demicco EG, Park MS, Araujo DM, et al. Solitary fibrous tumor: a clinicopathological study of 110 cases and proposed risk assessment model. Mod Pathol. 2012 Sep;25(9):1298-306. PMID:22575866 789. Demicco EG, Rosenberg AE, Bj6「nsson J, et al. Primary Rosai-Dorfman disease of bone: a clinicopathologic study of 15 cases. Am J Surg Pathol. 2010 Sep;34(9): 1324-33. PMID:20679880 790. Demicco EG, Wagner MJ, Maki RG, et al. Risk assessment in solitary fibrous tumors: validation and refinement of a risk stratification model. Mod Pathol. 2017 Oct;30(10):1433-42. PMID:28731041 791. Demicco EG, Wani K, Ingram D, et al. TERT promoter mutations in solitary fibrous tumour. Histopathology. 2018 Nov;73(5):84351.PMID:29985536 792. Denadai R, Raposo-Amaral CE, Bertoia D, et al. Identification of 2 novel ANTXR2 mutations in patients with hyaline fibromatosis syndrome and proposal of a modified grading system. Am J Med Genet A. 2012 Apr; 158A(4):732-42. PMID:22383261 793. Derkinderen DJ, Koten JW, Wolterbeek R, et al. Non-ocular cancer in hereditary retinoblastoma survivors and relatives. Ophthalmic Paediatr Genet. 1987 Mar;8(1):235. PMID:3587888 794. Derre J, Lagace R, Nicolas A, et al. Leiomyosarcomas and most malignant fibrous histiocytomas share very similar comparative genomic hybridization imbalances: an analysis of a series of 27 leiomyosarcomas. Lab Invest. 2001 Feb;81 (2):211-5. PM I D:11232643 795. de Saint Aubain Somerhausen N, Fletcher CD. Leiomyosarcoma of soft tissue in children: clinicopathologic analysis of 20 cases. Am J Surg Pathol. 1999 Jul;23(7):755-63. PMID:10403297 796. de Saint Aubain Somerhausen N, Rubin BP, Fletcher CD. Myxoid solitary fibrous tumor: a study of seven cases with emphasis on differential diagnosis. Mod Pathol. 1999 May;12(5):463-71. PMID:10349983 797. deSantos LA, Edeiken B. Purely lytic osteosarcoma. Skeletal Radiol. 1982;9(1):1-7. PMID:6961529 798. Deshmukh C, Bakshi A, Parikh P, et al.

556

References

Primary non-Hodgkin's lymphoma of the bone: a single institution experience. Med Oncol. 2004;21 (3):263-7. PMID:15456954 799. Deshpande V, Nielsen GP, Rosenthal DI, et al. Intraosseous benign notochord cell tumors (BNCT): further evidence supporting a relationship to chordoma. Am J Surg Pathol. 2007 Oct;31(10):1573-7. PMID:17895760 800. Deshpande V, Rosenberg AE, O'Connell JX, etal. Epithelioid angiosarcoma of the bone: a series of 10 cases. Am J Surg Pathol. 2003 Jun;27⑹:709「6. PMID:12766574 801. de Silva MV, Reid R. Chondroblastoma: varied histologic appearance, potential diagnostic pitfalls, and clinicopathologic features associated with local recurrence. Ann Diagn Pathol. 2003 Aug;7(4):205-13. PMID:12913842 802. de Silva MV, Reid R. Myositis ossificans and fibroosseous pseudotumor of digits: a clinicopathological review of 64 cases with emphasis on diagnostic pitfalls. I nt J Surg Pathol. 2003 Jul;11(3):187-95. PMID:12894350 803. De Smet L, Sciot R, Legius E. Multifocal glomus tumours of the fin gers in two patients with neurofibromatosis type 1. J Med Genet. 2002 Aug;39(8):e45.PMID:12161612 804. Desurmont T, Lefevre JH, Shields C, et al. Desmoid tumour in familial adenomatous polyposis patients: responses to treatments. Fam Cancer. 2015 Mar;14(1):31-9. PMID:25315103 805. de Trey LA, Schmid S, Huber GF. Multifocal adult rhabdomyoma of the head and neck manifestation in 7 locations and review of the literature. Case Rep Otolaryngol. 2013;2013:758416. PMID:23841004 806. Deuquet J, Lausch E, Superti-Furga A, et al. The dark sides of capillary morphogenesis gene 2. EMBO J. 2012 Jan 4;31(1):3-13. PMID:22215446 807. Devaney K, Vinh TN, Sweet DE. Synovial hemangioma: a report of 20 cases with differential diagnostic considerations. Hum Pathol. 1993 Jul;24(7):737-45. PMID:8319952 808. Dewaele B, Floris G, Finalet-Ferreiro J, et al. Coactivated platelet-derived growth factor receptor alpha and epidermal growth factor receptor are potential therapeutic targets in intimal sarcoma. Cancer Res. 2010 Sep 15;70(18):7304-14. PMID:20685895 809. Dewaele B, Libbrecht L, Levy G, et al. A novel EWS-CREB3L3 gene fusion in a mesenteric sclerosing epithelioid fibrosarcoma. Genes Chromosomes Cancer. 2017 Sep;56(9):695-9. PMID:28569045 810. Deyrup AT, Chibon F, Guillou L, et al. Fibrosarcoma-like lipomatous neoplasm: a reappraisal of so-called spindle cell liposarcoma defining a unique lipomatous tumor unrelated to other liposarcomas. Am J Surg Pathol. 2013 Sep;37(9):1373-8. PMID:23887155 811. Deyrup AT, Lee VK, Hill CE, et al. EpsteinBarr virus-associated smooth muscle tumors are distinctive mesenchymal tumors reflect!ng multiple infection events: a clinicopathologic and molecular analysis of 29 tumors from 19 patients. Am J Surg Pathol. 2006 Jan;30(1 ):7582. PMID:16330945 812. Deyrup AT, Miettinen M, North PE, et al. Angiosarcomas arising in the viscera and soft tissue of children and young adults: a clinicopathologic study of 15 cases. Am J Surg Pathol. 2009 Feb;33(2) :264-9. PMID:1 旳87547 813. Deyrup AT, Tighiouart M, Montag AG, et al. Epithelioid hemangioendothelioma of soft tissue: a proposal for risk stratification based on 49 cases. Am J Surg Pathol. 2008 Jun;32(6):924-7. PMID:18551749 814. Deyrup AT, Weiss SW. Grading of soft tissue sarcomas: the challenge of providing precise information in an imprecise world.

Histopathology. 2006 Jan;48(1):42-50. PMID:16359536 815. Dhondt E, Oudenhoven L, Khan S, et al. Nora's lesion, a distinct radiological entity? Skeletal Radiol. 2006 Jul;35(7):497-502. PMID:16602017 816. Di Vito A, Scali E, Ferraro G, et al. Elastofibroma dorsi: a histochemical and immunohistochemical study. Eur J Histochem. 2015 Feb 19;59(1 ):2459. PMID:25820560 817. Diamond EL, Durham BH, Haroche J, et al. Diverse and targetable kinase alterations drive histiocytic neoplasms. Cancer Discov. 2016 Feb;6(2):154-65. PMID:26566875 81& Dias P, Chen B, Dilday B, et al. Strong immunostaining for myogenin in rhabdomyosarcoma is significantly associated with tumors of the alveolar subclass. Am J Pathol. 2000 Feb;156⑵:399708. PMID:10666368 819. Diaz-Cascajo C, Weyers W, Borghi S. Pigmented atypical fibroxanthoma: a tumor that may be easily mistaken for malignant melanoma. Am J Dermatopathol. 2003 Feb;25(1):1-5. PMID:12544091 820. Diaz-Perez JA, Nielsen GP, Antonescu C, et al. EW8R1/FUS-NFATc2 rearranged round cell sarcoma: clinicopathological series of 4 cases and literature review. Hum Pathol. 2019 Aug;90:45-53.PMID:31078563 821. Dickey ID, Rose PS, Fuchs B, et al. Dedifferentiated chondrosarcoma: the role of chemotherapy with updated outcomes. J Bone Joint Surg Am. 2004 Nov;86(11):2412-8. PMID:15523011 822. Dickson BC, Gortzak Y, Bell RS, et al. p63 expression in adamanti no ma. Virchows Arch. 2011 Jul;459(1):109-13. PMID:21674157 823. Dickson BC, Hornick JL, Fletcher CD肌 et al. Dermatofibrosarcoma protuberans with a novel COL6A3-PDGFD fusion gene and apparent predilection for breast. Genes Chromosomes Cancer. 2018 S即;57(9):43745. PMID:30014607 824. Dictor M. Human herpesvirus 8 and Kaposi's sarcoma. Semin Cutan Med Surg. 1997 Sep;16(3):181-7. PMID:9300629 825. DiGiammarino EL, Lee AS, Cadwell C, et al. A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Biol. 2002 Jan;9(1):12-6. PMID:11753428 826. Dimitrakopoulou-Strauss A, Strauss LG, Schwarzbach M, et al. Dynamic PET 18F-FDG studies in patients with primary and recurrent soft-tissue sarcomas: impact on diagnosis and correlation with grading. J Nucl Med. 2001 May;42(5):713-20. PMID:11337565 827. Dimitrijevic MV, Sopta J, Ivisevic TB, et al. Chondroma of the tongue. J Craniofac Surg. 2019 Jun;30(4):e315-7. PMID:30845089 82& Dishop MK, O'Connor WN, Abraham S, et al. Primary cardiac lipoblastoma. Pediatr Dev Pathol. 2001 May-Jun;4(3):276-80. PMID:11370265 829. Dittmer DP, Damania B. Kaposi sarcomaassociated herpesvirus: immunobiology, oncogenesis, and therapy. J Clin Invest. 2016 Sep 1;126(9):3165-75. PMID:27584730 830. Divisato G, Formicola D, Esposito T, et al. ZNF687 mutations in severe Paget disease of bone associated with giant cell tumor. Am J Hum Genet. 2016 Feb 4;98⑵:275-86. PMID:26849110 831. Dixon AY, McGregor DH, Lee SH. Angiolipomas: an ultrastcuctural and clinicopathological study. Hum Pathol. 1981 Aug;12(8):739-47. PMID:7026412 832. Domanski HA, Carlen B, Jonsson K, et al. Distinct cytologic features of spindle cell lipoma. A cytologic-histologic study with clinical, radiologic, electron microscopic, and

cytogenetic correlations. Cancer 2001 25;93(6):381-9. PMID:11748578 833. Domanski HA, Carlen B, Sloth M et al. Elastofibroma dorsi has distinct cytomorphologic features, making diagnostic surgical biopsy unnecessary: cytomorpholoqic study with clinical, radiologic, and election microscopic correlations. Diagn Cytopathol 2003 Dec;29(6):327-33. PMID:14648789 834. Domont J, Salas S, Lacroix L, et al High frequency of beta-catenin heterozygous mutations in extra-abdominal fibromatosisa potential molecular tool for disease management. Br J Cancer. 2010 Mar 16;102(6):1032-6. PMID:20197769 835. Domovitov SV, Healey JH. Primary malignant giant-cell tumor of bone has high survival rate. Ann Surg Oncol. 2010 Mar;17 ⑶:694-701. PM ID: 19902306 836. Domson GF, Shahlaee A, Reith JD, et al. Infarct-associated bone sarcomas. Clin Orthop Relat Res. 2009 Jul;46W7)-1820-5 PMID:19229663 837. Donmez FYJuzun U, Ba§aran C, etal. MRI findings in parosteal osteosarcoma: correlation with histopathology. Diagn Interv Radiol. 2008 Sep;14(3):142-52. PMID:18814136 83& Donner LR, Silva T, Dobin SM. Clonal rearrangement of 15p11.2, 16p11.2, and 16p13.3 in a case of nodular fasciitis: additional evidence favoring nodular fasciitis as a benign neoplasm and not a reactive tumefaction. Cancer Genet Cytogenet. 2002 Dec; 139(2):138-40. PMID:12550774 839. Dorfman HD. New knowledge of fibro­ osseous lesions of bone. IntJSurg Pathol. 2010 Jun;18(3 Suppl):62S-5S. PMID:20484264 840. Dorfman HD. Proceedings: Malignant transformation ofbenign bone lesions. Proc Natl Cancer Conf. 1972;7:901-13. PMID:4764948 841. Dorfman HD, Weiss SW. Borderline osteoblastic tumors: problems in the differential diagnosis of aggressive osteoblastoma and low-grade osteosarcoma. Semin Diagn Pathol. 1984Aug;1(3):215-34. PMID:6600112 842. dos Santos NR, de Bruijn DR, van Kessel AG. Molecular mechanisms underlying human synovial sarcoma development. Genes Chromosomes Cancer. 2001 Jan;30(1):1-14. PMID:11107170 843. Douis H, Jeys L, Grimer R, et al. Is there a role for diffusion-weighted MRI (DWI) in the diagnosis of central cartilage tumors? Skeletal Radiol. 2015 Jul;44(7):963-9. PMID:25744812 844. Douis H, Singh L, Saifuddin A. MRI differentiation of low-grade from high-grade appendicular chondrosarcoma. Eur Radiol. 2014 Jan;24(1 ):232-40. PMID:24337911 845. Dounies R, Chwals WJ, Lally KP, et al. Hamartomas of the chest wall in infants. Ann Thorac Surg. 1994 Apr;57(4):868-75. PMID:8166533 " 846. Douya H, Yokoyama R, Beppu Y, et al. Malignant fibrous histiocytoma associated with diaphyseal medullary stenosis. Clin Orthop Relat Res. 2002 Jul;(400):211-6. PMID:12072764 848. Downes KA, Goldblum JR, Montgomery EA, et al. Pleomorphic liposarcoma: a clinicopathologic analysis of 19 cases. Mod Pathol. 2001 Mar;14(3):179-84. PMID:11266523 849. Doyle LA, Fletcher CD, Hornick JL. Nuclear expression of CAMTA1 distinguishes epithelioi hemangioendothelioma from histologic mimi黑 Am J Surg Pathol. 2016 Jan;40(1)：94-102. PMID:26414223 . 850. Doyle LA, Hornick JL. EW鸡 rearrangements in sclerosing epithelioi fibrosarcoma. Am J Surg Pathol. 2 Oct;37(10):1630-1. PMID:24025527 851. Doyle LA, Hornick JL, Fletcher bu.

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PEComa of the gastrointestinal tract: clinicopathologic study of 35 cases with evaluation of prognostic parameters. Am J Surg Pathol. 2013 Dec;37(12):1769-82. PMID:24061520 852. Doyle LA, Moller E, Dal Cin P, etal. MUC4 is a highly sensitive and specific marker for lowgrade fibromyxoid sarcoma. Am J Surg Pathol. 2011 May;35⑸:733-41. PMID:21415703 853. Doyle LA, Nelson D, Heinrich MC, et al. Loss of succinate dehydrogenase subunit B (SDHB) expression is limited to a distinctive subset of gastric wild-type gastrointestinal stromal tumours: a comprehensive genotypephenotype correlation study. Histopathology. 2012 Nov;61(5):801-9. PMID:22804613 854. Doyle LA, Vivero M, Fletcher CD, et al. Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics. Mod Pathol. 2014 Mar;27(3):390-5. PMID:24030747 855. 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 J Surg Pathol. 2012 Oct;36(10):1444-51. PMID:22982887 856. Draper GJ, Sanders BM, Kingston JE. Second primary neoplasms in patients with retinoblastoma. Br J Cancer. 1986 May;53(5):661-71. PMID:3718823 857. Dray MS, McCarthy SW, Palmer AA, et al. Myopericytoma: a unifying term for a spectrum of tumours that show overlapping features with myofibroma. A review of 14 cases. J Clin Pathol. 2006Jan;59(1):67-73. PMID:16394283 858. Dreux N, Marty M, Chibon F, et al. Value and limitation of immunohistochemical expression of HMGA2 in mesenchymal tumors: about a series of 1052 cases. Mod Pathol. 2010 Dec;23(12):1657-66. PMID:20834238 859. Drilon AD, Popat S, Bhuchar G, et al. Extraskeletal myxoid chondrosarcoma: a retrospective review from 2 referral centers emphasizing long-term outcomes with surgery and chemotherapy. Cancer. 2008 Dec 15:113(12):3364-71. PMID:18951519 860. Dry SM, Jorgensen JL, Fletcher CD. Leiomyosarcomas of the oral cavity: an unusual topographic subset easily mistaken for nonmesenchymal tumours. Histopathology. 2000 Mar;36(3):210-20. PMID:10692022 、 861. Duan F, Smith LM, Gustafson DM, et al. Genomic and clinical analysis of fusion gene amplification in「habdomyosarcoma: a report from the Children's Oncology Group. Genes Chromosomes Cancer. 2012 iul;5讯7):662-74. PMID:22447499 862. DuBois 8G, Laetsch TW, Federman N, et al. The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas. Cancer. 2018 Nov 1；124(21):4241-7. PMID:30204247 863. Ducatman BS, Scheithauer BW, Piepgras DG, et al. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer. 1986 May 15;57(10):2006-21. PMID:3082508 864. Duchman KR, Lynch CF, Buckwaiter JA, et al. Estimated cause-specific survival continues to improve over time in patients with chondrosarcoma. Clin Orthop Relat Res. 2014 Aug;472(8):2516-25.PMID:24706044 865. Ducimetiere F, Lurkin A, Ranchere-Vince D et al. Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One. 2011;6(8):e20294. PMID:21826194 866. Duhamel LA, Ye H, Halai D, et al. Frequency of mouse double minute 2 (MDM2) and mouse double minute 4 (MDM4)

amplification in parosteal and conventional osteosarcoma subtypes. Histopathology. 2012 Jan;60⑵:357-9. PMID:22074548 867. Dujardin F, Binh MB, Bouvier C, et al. MDM2 and CDK4 immunohistochemistry is a valuable tool in the differential diagnosis of lowgrade osteosarcomas and other primary fibroosseous lesions of the bone. Mod Pathol. 2011 May;24(5):624-37. PMID:21336260 868. Duke D, Dvorak A, Harris TJ, et al. Multiple retiform hemangioendotheliomas. A low-grade angiosarcoma. Am J Dermatopathol. 1996 Dec;18(6):606-10. PMID:8989934 869. Dumont C, Monforte M, Flandrin A, et al. Prenatal management of congenital infantile fibrosarcoma: unexpected outcome. Ultrasound Obstet Gynecol. 2011 Jun;37 ⑹:733-5. PMID:21618315 870. Dumont SN, Lazar AJ, Bridge JA, et al. PAX3/7-FOXO1 fusion status in older rhabdomyosarcoma patient population by fluorescent in situ hybridization. J Cancer Res Clin Oncol. 2012 Feb;138(2):213-20. PMID:22089931 871. Dundr P, Nemejcova K, Laco J, et al. Anastomosing hemangioma of the ovary: a clinicopathological study of six cases with stromal luteinization. Pathol Oncol Res. 2017 Oct;23(4):717-22. PMID:28050796 872. Dunham C, Hussong J, Seiff M, et al. Primary intracerebral angiomatoid fibrous histiocytoma: report of a case with a t(12;22) ©3^2) causing type 1 fusion of the EW8 and ATF-1 genes. Am J Surg Pathol. 2008 Mar;32(3):478-84. PMID:18300800 873. Dunzendorfer-Matt T, Mercado EL, Maly K, et al. The neurofibromin recruitment factor Spredl binds to the GAP related domain without affecting Ras inactivation. Proc Natl Acad Sci USA. 2016 Jul 5;113(27):7497-502. PMID:27313208 874. Dupree WB, Langloss JM, Weiss SW. Pigmented dermatofibrosarcoma protuberans (Bednar tumor). A pathologic, ultrastructural, and immunohistochemical study. Am J Surg Pathol. 1985 Sep;9(9):630-9. PMID:3901787 875. Durham BH, Roos-Weil D, Baillou C, et al. Functional evidence for derivation of systemic histiocytic neoplasms from hematopoietic stem/progenitor cells. Blood. 2017 Jul 13;130(2):176-80. PMID:28566492 876. Dymock RB, Allen PW, Stirling JW, et al. Giant cell fibroblastoma. A distinctive, recurrent tumor of childhood. Am J Surg Pathol. 1987 Apr;11 (4):263-71. PMID:3565673 877. Eaton KW, Tooke LS, Wainwright LM, et al. Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatr Blood Cancer. 2011 Jan;56(1):7-15. PMID:21108436 878. Ebeid WA, Hasan BZ, Badr IT, et al. Functional and oncological outcome after treatment of chondroblastoma with intralesional curettage. J Pediatr Orthop. 2018 Nov 8. PMID:30418383 879. Eckardt JJ, Grogan TJ. Giant cell tumor of bone. Clin Orthop Relat Res. 1986 Mar;(204):45-58. PMID:3514036 880. Eckardt JJ, Pritchard DJ, Soule EH. Clear cell sarcoma. A clinicopathologic study of 27 cases. Cancer. 1983 Oct 15;52(8): 1482-8. PMID:6616410 881. Ecker BL, Peters MG, McMillan MT, et al. Implications of lymph node evaluation in the management of resectable soft tissue sarcoma. Ann Surg Oncol. 2017 Feb;24(2):425-33. PMID:27785659 882. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future ofTNM.Ann Surg Oncol. 2010 Jun;17(6):14714. PMID:20180029

883. Eefting D, Schrage YM, Geirnaerdt MJ, et al. Assessment of interobserver variability and histologic parameters to improve reliability in classification and grading of central cartilaginous tumors. Am J Surg Pathol. 2009 Jan;33(1):50-7. PMID:18852676 884. Eeles RA. Germline mutations in the TP53 gene. Cancer Surv. 1995;25:101-24. PMID:8718514 885. Egbert RC, Folsom R, Bell J, et al. Denosumab therapy for giant cell tumor of bone pulmonary metastasis. Case Rep Orthop. 2017;2017:2302597. PMID:28573059 886. Eilber FC, Brennan MF, Eilber FR, et al. Chemotherapy is associated with improved survival in adult patients with primary extremity synovial sarcoma. Ann Surg. 2007 Jul;246(1):105-13. PMID:17592298 887. Eilber FC, Brennan MF, Eilber FR, et al. Validatio n of the postoperative no mogram for 12-year sarcoma-specific mortality. Cancer. 2004 Nov 15;101(10):2270-5. PMID:15484214 888. Eilber FC, Eilber FR, Eckardt J, et al. The impact of chemotherapy on the survival of patients with high-grade primary extremity liposarcoma. Ann Surg. 2004 Oct;240(4):68695, discussion 695-7. PMID:15383796 889. Einarsdottir H, Skoog L, Soderlund V, et al. Accuracy of cytology for diagnosis of lipomatous tumors: comparison with magnetic resonance and computed tomography findings in 175 cases. Acta Radiol. 2004 Dec;45(8):8406. PMID:15690614 890. El Aouni N, Laurent I, Terrier P, et al. Granular cell tumor of the breast. Diagn Cytopathol. 2007 Nov;35(11):725-7. PMID:17924412 891. El Beaino M, Roszik J, Livingston JA, et al. Mesenchymal chondrosarcoma: a review with emphasis on its fusion-d「iven biology. Curr Oncol Rep. 2018 Mar 26;20(5):37. PMID:29582189 892. Elco CP, Marino-Enriquez A, Abraham JA, et al. Hybrid myxoinflammatory fibroblastic sarcoma/hemosiderotic fibrolipomatous tumor: report of a case providing further evidence for a pathogenetic link. Am J Surg Pathol. 2010 Nov;34(11):1723-7. PMID:20871391 893. El-Galaly TC, Jakobsen LH, Hutchings M, et al. Routine imaging for diffuse large B-cell lymphoma in first complete remission does not improve post-treatment survival: a DanishSwedish population-based study. J Clin Oncol. 2015 Dec 1;33(34):3993-8. PMID:26438115 894. Elgar F, Goldblum JR. Well-differentiated liposarcoma of the retroperitoneum: a clinicopathologic analysis of 20 cases, with particular attention to the extent of lowgrade dedifferentiation. Mod Pathol. 1997 Feb;10(2):113-20.PMID:9127316 895. el-Jabbour JN, Bennett MH, Burke MM, et al. Proliferative myositis. An immunohistochemical and ultrastructural study. Am J Surg Pathol. 1991 Jul;15(7):654-9. PMID:2058761 896. El-Kamah GY, Fong K, El-Ruby M, et al. Spectrum of mutations in the ANTXR2 (CMG2) gene in infantile systemic hyalinosis and juvenile hyaline fibromatosis. Br J Dermatol. 2010 Jul;163(1):213-5. PMID:20331448 897. El-Maouche D, Sadowski SM, P即adakis G乙 et al. 68Ga-DOTATATE for tumor localization in tumor-induced osteomalacia. J Clin Endocrinol Metab. 2016 Oct;101 (10):357581.PMID:27533306 898. El-Monem MH, Gaafar AH, Magdy EA. Lipomas of the head and neck: presentation variability and diagnostic work-up. J Laryngol Otol. 2006 Jan;120(1):47-55. PMID:16359147 899. El-Rifai W, Sarlomo-Rikala M, Knuutila S, et al. DNA copy number changes in development and progression in leiomyosarcomas of soft

tissues. Am J Pathol. 1998 Sep;153(3):985-90. PMID:9736047 900. Emberger M, Laimer M, Steiner H, et al. Retiform hemangioendothelioma: presentation of a case expressing D2-40. J Cutan Pathol. 2009 Sep;36(9):987-90. PMID:19674202 901. Emile JF, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016 Jun 2;127(22):2672-81. PMID:26966089 902. Emile JF, Brahimi S, Coindre JM, et al. Frequencies of KIT and PDGFRA mutations in the MolecGIST prospective population­ based study differ from those of advanced GISTs. Med Oncol. 2012 Sep;29(3):1765-72. PMID:21953054 903. Emile JF, Diamond EL, Helias-Rodzewicz Z, et al. Recurrent RAS and PIK3CA mutations in Erdheim-Chester disease. Blood. 2014 Nov 6;124(19):3016-9. PMID:25150293 904. Emmerich D, Zemojtel T, Hecht J, et al. Somatic neurofibromatosis type 1 (NF1) inactivation events in cutaneous neurofibromas of a single NF1 patient. Eur J Hum Genet. 2015 Jun;23(6):870-3. PMID:25293717 905. Endo M, Kohashi K, Yamamoto H, et al. Ossifying fibromyxoid tumor presenting EP400-PHF1 fusion gene. Hum Pathol. 2013 Nov;44(11):2603-8. PMID:23806526 906. Eng C. PTEN hamartoma tumor syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 2001 Nov 29 [updated 2016 Jun 2]. PMID:20301661 907. Engert F, Kovac M, Baumhoer D, et al. Osteosarcoma cells with genetic signatures of BRCAness are susceptible to the PARP inhibitor talazoparib alone or in combination with chemotherapeutics. Oncotarget. 2017 Jul 25;8(30):48794-806. PMID:27447864 908. Enjolras O, Wassef M, Mazoyer E, et al. Infants with Kasabach-Merritt syndrome do not have "true" hemangiomas. J Pediatr. 1997 Apr;130(4):631-40. PMID:9108863 909. Enneking WF. A system of staging musculoskeletal neoplasms. Clin Orthop Relat Res. 1986 Mar;(204):9-24. PMID:3456859 910. Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res. 1980 Nov-Dec;(153):106-20. PMID:7449206 911. Ensoli B, Sgadari C, Barillari G, et al. Biology of Kaposi's sarcoma. Eur J Cancer. 2001 Jul;37(10):1251-69. PMID:11423257 912. Enzinger FM. Angiomatoid malignant fibrous histiocytoma: a distinct fibrohistiocytic tumor of children and young adults simulating a vascular neoplasm. Cance r. 1979 Dec;44(6):2147-57. PMID:228836 913. Enzinger FM. Clear-cell sarcoma of tendons and aponeuroses. An analysis of 21 cases. Cancer. 1965 Sep;18:1163-74. PMID:14332545 914. Enzinger FM. Intramuscular myxoma; a review and follow-up study of 34 cases. Am J Clin Pathol. 1965 Feb;43:104-13. PMID:14253111 915. Enzinger FM, Dulcey F. Proliferative myositis. Report of thirty-three cases. Cancer. 1967 Dec;20(12):2213-23. PMID:6073898 916. Enzinger FM, Harvey DA. Spindle cell lipoma. Cancer. 1975 Nov;36(5):1852-9. PMID:1192370 917. Enzinger FM, Shiraki M. Extraskeletal myxoid chondrosarcoma. An analysis of 34 cases. Hum Pathol. 1972 Sep;3⑶:421-35. PMID:4261659 918. Enzinger FM, Weiss SW, Liang CY. Ossifying fibromyxoid tumor of soft parts. A clinicopathological analysis of 59 cases. Am J Surg Pathol. 1989 Oct;13(10):817-27. PMID:2476942

Refere nces

557

paybal：https://www.paypal.me/andy19801210 919. Enzinger FM. Winslow DJ. Liposarcoma. A study of 103 cases. Virchows Arch Pathol Anat Physiol Klin Med. 1962;335:367-88. PMID:13890373 920. Enzinger FM, Zhang RY. Plexiform fibrohistiocytic tumor presenting in children and young adults. An analysis of 65 cases. Am J Surg Pathol. 1988 Nov;12(11):818-26. PMID:2847569 921. Eppsteiner RW, DeYoung BR, Milhem MM, et al. Leiomyosarcoma of the head and neck: a population・based analysis. Arch Otolaryngol Head Neck Surg. 2011 Sep;137(9):921-4. PMID:21930982 922. Epstein DS, Pashaei S, Hunt E Jr, et al. Pustulo-ovoid bodies of Milian in granular cell tumors. J Cutan Pathol. 2007 May;34(5):405-9. PMID:17448196 923. 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 Sep;473(3):351-60. PMID:29623468 924. 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 Oct;91(10):142733. PMID:21826056 925. Erickson-Johnson MR, Seys AR, Roth CW, et al. Carboxypeptidase M: a biomarker for the discrimination of well-differentiated liposarcoma from lipoma. Mod Pathol. 2009 Dec;22(12):1541-7. PMID:19820690 926. Eriksson M, Hardell L, Adami HO. Exposure to dioxi ns as a risk factor for soft tissue sarcoma: a population-based case­ control study. J Natl Cancer Inst. 1990 Mar 21;82(6):486-90. PMID:2313720 927. Erkek S, Johann PD, Finetti MA, et al. Comprehensive analysis of chromatin states in atypical teratoid/rhabdoid tumor identifies diverging roles for SWI/SNF and polycomb in gene regulation. Cancer Cell. 2019 Jan 14;35(1):95-110.e8. PMID:30595504 928. Erlich SA, Tymianski M, Kiehl TR. Cellular schwa nnoma of the abduce ns n erve: case report and review of the literature. Clin Neurol Neurosurg. 2009 Jun;111 (5):467-71. PMID:19200646 929. Errani C, Sung YS, Zhang L, et al. Monoclonality of multifocal epithelioid hemangioendothelioma of the liver by analysis of WWTR1-CAMTA1 breakpoints. Cancer Genet. 2012 Jan-Feb;205(1-2):12-7. PMID:22429593 930. Errani C, Tsukamoto S, Ciani G, et al. Risk factors for local recurrence from atypical cartilaginous tumour and enchondroma of the long bones. Eur J Orthop Surg Traumatol. 2017 Aug;27⑹:805-11. PMID:28501961 931. Errani C, Zhang L, Panicek DM, et al. Epithelioid hemangioma of bone and soft tissue: a reappraisal of a controversial entity. Clin Orthop Relat Res. 2012 May;470(5):1498506. PMID:21948309 932. Errani C, Zhang L, Sung YS, et al. A novel VWVTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosomes Cancer. 2011 Aug;50(8):644-53. PMID:21584898 933. Erstine EM, Ko JS, Rubin BP, et al. Broadening the anatomic landscape of sclerosing perineurioma: a series of 5 cases in nonacral sites. Am J Dermatopathol. 2017 Sep;39(9):679-81. PMID:27845943 934. Espinosa I, Lee CH, Kim MK, et al. A novel monoclonal antibody against DOG1 is a sensitive and specific marker forgastrointestinal stromal tumors. Am J Surg Pathol. 2008

558

References

Feb;32(2):210-8. PMID:18223323 935. Estourgie SH, Nielsen GP, Ott MJ. Metastatic patterns of extremity myxoid liposarcoma and their outcome. J Surg On col. 2002 Jun;80⑵:89-93. PMID:12173385 936. Estrada A, Boyce AM, Brillante BA, et al. Long-term outcomes of letrozole treatment for precocious puberty in girls with McCuneAlbright syndrome. Eur J Endocrinol. 2016 Nov; 175(5):477-83. PMID:27562402 937. Evans DG. Neurofibromatosis type 2 (NF2): a clinical and molecular review. Orphanet J Rare Dis. 2009 Jun 19;4:16. PMID:19545378 938. Evans DG, Huson SM, Birch JM. Malignant peripheral nerve sheath tumours in inherited disease. Clin Sarcoma Res. 2012 Oct 4;2(1):17. PMID:23036231 939. Evans HL. Alveolar soft-part sarcoma. A study of 13 typical examples and one with a histologically atypical comporient. Cancer. 1985 Feb 15;55(4):912-7. PMID:3967185 940. Evans HL. Atypical lipomatous tumor, its variants, and its combined forms: a study of 61 cases, with a minimum follow-up of 10 years. Am J Surg Pathol. 2007 Jan;31(1):1-14. PMID:17197914 941. Evans HL. Desmoplastic fibroblastoma. A report of seven cases. Am J Surg Pathol. 1995 Sep;19(9):1077-81. PMID:7661281 942. Evans HL. Liposarcoma: a study of 55 cases with a reassessment of its classification. Am J Surg Pathol. 1979 Dec;3(6):507-23. PMID:534388 943. Evans HL. Low-grade fibromyxoid sarcoma. A report of 12 cases. Am J Surg Pathol. 1993 Jun;17 ⑹:595-600. PMID:8333558 944. Evans HL. Low-grade fibromyxoid sarcoma. A report of two metastasizing neoplasms having a deceptively benign appearance. Am J Clin Pathol. 1987 Nov;88(5):615-9. PMID:3673943 945. Evans HL. Low-grade fibromyxoid sarcoma: a clinicopathologic study of 33 cases with long-term follow-up. Am J Surg Pathol. 2011 Oct;35(10):1450-62. PMID:21921785 946. Evans HL. Synovial sarcoma. A study of 23 biphasic and 17 probable monophasic examples. Pathol Annu. 1980;15(Pt 2):309-31. PMID:6256705 947. Evans HL, Ayala AG, Romsdahl MM. Prognostic factors in chondrosarcoma of bone: a clinicopathologic analysis with emphasis on histologic grading. Cancer. 1977 Aug;40(2):818-31.PMID:890662 94& Evans HL, Khurana KK, Kemp BL, et al. Heterologous elements in the dedifferentiated component of dedifferentiated liposarcoma. Am J Surg Pathol. 1994 Nov;18(11):1150-7. PMID:7943536 949. Evans HL, RaymondAK.AyalaAG. Vascular tumors of bone: a study of 17 cases other than ordinary hemangioma, with an evaluation of the relationship of hemangioendothelioma of bone to epithelioid hemangioma, epithelioid hemangioendothelioma, and high­ grade an giosarcoma. Hum Pathol. 2003 Jul;34(7):680-9. PMID:12874764 950. Evans S, Boffano M, Chaudhry S, et al. Synovial chondrosarcoma arising in synovial chondromatosis. Sarcoma. 2014;2014:647939. PMID:24737946 951. Eyden BP, Manson C, Banerjee SS, et al. Sclerosing epithelioid fibrosarcoma: a study of five cases emphasizing diagnostic criteria. Histopathology. 1998 Oct;33(4):354-60. PMID:9822926 952. Eypper EH, Lee JC, Tarasen AJ, et al. An algorithmic approach to the management of infantile digital fibromatosis: review of literature and a case report. Eplasty. 2018 May 7;18:e19. PMID:29780440

953. Eyssartier E, Villemagne T, Maurin L, et al. Intrascrotal lipoblastoma: a report of two cases and a review of the literature. J Pediatr Urol. 2013 Dec;9(6 Pt B):e151-4. PMID:23664430 954. Faivre L, Nivelon-Chevallier A, Kottler ML, et al. Mazabraud syndrome in two patients: clinical overlap with McCune-Albright syndrome. Am J Med Genet. 2001 Mar 1;99(2):132-6. PMID:11241472 955. Falco NA, Upton J. Infantile digital fibromas. J Hand Surg Am. 1995 Nov;20(6):1014-20. PMID:8583050 956. Falk S, Schmidts HL, Muller H, et al. Autopsy findings in AIDS-a histopathological analysis of fifty cases. Klin Wochenschr. 1987 Jul 15;65(14):654-63. PMID:3626432 957. Falleti J, De Cecio R, Mentone A, et al. Extraskeletal chondroma of the masseter muscle: a case report with review of the literature. Int J Oral Maxillofac Surg. 2009 Aug;38(8):895-9. PMID:19349148 958. Fallon SC, Brandt ML, Rodriguez JR, et al. Cytogenetic analysis in the diagnosis and management of lipoblastomas: results from a single institution. J Surg Res. 2013 Sep;184(1):341-6. PMID:23751806 959. Fan XL, Han ZJ, Gong XY, et al. Morphological classification for predict!on of malignant transformation in multiple exostoses. Eur Rev Med Pharmacol Sci. 2014;18(6):8405. PMID:24706308 960. Fanburg JC, Meis-KindblomJM, Rosenberg AE. Multiple enchondromas associated with spindle-cell hema ngioendotheliomas. An overlooked variant of Maffucci's syndrome. Am J Surg Pathol. 1995 Sep;19(9):1029-38. PMID:7661276 961. Fanburg JC, Rosenberg AE, Weaver DL, et al. Osteocalcin and osteonectin immuno「eactivity in the diagnosis of osteosarcoma. Am J Clin Pathol. 1997 Oct; 108⑷:464—73. PMID:9322601 962. Fanburg-Smith JC, Auerbach A, Marwaha JS, et al. Immunoprofile of mesenchymal chondrosarcoma: aberrant desmin and EMA expression, retention of INI1, and negative estrogen receptor in 22 female-predominant central nervous system and musculoskeletal cases. Ann Diagn Pathol. 2010 Feb;14(1):8-14. PMID:20123451 963. Fanburg-Smith JC, Auerbach A, Marwaha JS, et al. Reappraisal of mesenchymal chondrosarcoma: novel morphologic observations of the hyaline cartilage and endochondral ossification and beta-catenin, Sox9, and osteocalcin immunostaining of 22 cases. Hum Pathol. 2010 May;41 (5):653-62. PMID:20138330 964. Fanburg-Smith JC, Devaney KO, Miettinen M, et al. Multiple spindle cell lipomas: a report of 7 familial and 11 nonfamilial cases. Am J Surg Pathol. 1998Jan;22(1):40-8. PMID:9422314 965. Fanburg-Smith JC, Hengge M, Hengge UR, et al. Extrarenal rhabdoid tumors of soft tissue: a clinicopathologic and immunohistochemical study of 18 cases. Ann Diagn Pathol. 1998 Dec;2(6):351-62. PMID:9930572 966. Fanburg-Smith JC, Meis-Kindblom JM, Fante R, et al. Malignant granular cell tumor of soft tissue: diagnostic criteria and clinicopathologic correlation. Am J Surg Pathol. 1998 Jul;22(7):779-94. PMID:9669341 967. Fanburg-Smith JC, Michal M, Partanen TA, et al. Papillary intralymphatic angioendothelioma (PILA): a report of twelve cases of a distinctive vascular tumor with phenotypic features of lymphatic vessels. Am J Surg Pathol. 1999 Sep;23(9):1004-10. PMID:10478659 968. Fanburg-Smith JC, Miettinen M. Angiomatoid "malignant" fibrous histiocytoma: a clinicopathologic study of 158 cases and

further exploration of the myoid phenotvDA Hum Pathol. 1999 Nov;30⑴)133芒 PMID:10571514 969. Fanburg-Smith JC, Miettinen m Liposarcoma with meningothelial-like whorlsa study of 17 cases of a distinctive histological pattern associated with dedifferentiated liposarcoma. Histopathology ㈡昶 Nov;33(5):414-24. PMID:9839165 970. Fanburg-Smith JC, Miettinen M, Folpe AL, et al. Lingual alveolar soft part sarcoma14 cases: novel clinical and morphologicai observations. Histopathology 2004 Nov;45(5):526-37. PMID:15500657 971. Fang D, Gan H, Lee JH, et al. The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas. Science. 2016 Jun 10:352(6291):1344-8. PMID:27229140 972. Farshid G, Pradhan M, Goldblum J, et al. Leiomyosarcoma of somatic soft tissuesa tumor of vascular origin with multivariate analysis of outcome in 42 cases. Am J Surq Pathol. 2002 Jan;26(1):14-24. PMID:11756765 973. Fatobene G, Haroche J, HeliasRodzwicz Z, et al. BRAF V600E mutation detected in a case of Rosai-Dorfman disease. Haematologica. 2018 Aug;103(8):e377-9 PMID:29748446 974. Favara BE, Jaffe R, Egeler RM. Macrophage activation and hemophagocytic syndrome in Langerhans cell histiocytosis: report of 30 cases. Pediatr Dev Pathol. 2002 Mar-Apr;5(2): 130-40. PMID:11910507 975. Fayette J, Martin E, Piperno-Neumann S, et al. Angiosarcomas, a heterogeneous group of sarcomas with specific behavior depending on primary site: a retrospective study of 161 cases. Ann Oncol. 2007 Dec;18(12):2030-6. PMID:17974557 976. Feany MB, Anthony DC, Fletcher CD. Nerve sheath tumours with hybrid features of neurofibroma and schwannoma: a conceptual challenge. Histopathology. 1998 May;32(5):405-10. PMID:9639114 977. Fedele M, Crescenzi E, Cerchia L. The POZ/BTB and AT-hook containing zinc finger 1 (PATZ1) transcription regulator: physiological functions and disease involvement. Int J Mol Sci. 2017 Nov 24;18(12):E2524. PMID:29186807 978. Fedorova O, Petukhov A, Daks A, et al. Orphan receptor NR4A3 is a novel target of p53 that contributes to apoptosis. Oncogene. 2019 Mar;38(12):2108-22. PMID:30455429 979. Feely MG, Boehm AK, Bridge RS, et al. Cytogenetic and molecular cytogenetic evidence of recurrent 8q24.1 loss in osteochondroma. Cancer Genet Cytogenet. 2002 Sep;137(2):102-7. PMID:12393280 980. Fei L, Ngoh C, Porter DE. Chondrosarcoma transformation in hereditary multiple exostoses: a systematic review and clinical and cost­ effectiveness of a proposed screening model. J Bone Oncol. 2018 Oct 4;13:114-22. PMID:30591865 981. Feldman AL, Berthold F, Arceci RJ, et al. Clonal relationship between precursor T-lymphoblastic leukaemia/lymphoma and Langerhans-cell histiocytosis. Lancet Oncol. 2005 Jun;6(6):435-7. PMID:15925822 982. Feldman F, Vanheertum R, Saxena C. 18Fluoro-deoxyglucose positron emission tomography evaluation of benign versus malignant osteochondromas: preliminary observations. J Comput Assist Tomogr. 2006 Sep-Oct;30(5):858-64. PMID:16954943 983. Fergusson IL. Haemangiomata of skeletal muscle. Br J Surg. 1972 Aug;59(8):634-7. PMID:5069204 984. Ferlay J, Ervik M, Lam F, et al. Global Cancer Observatory: Cancer Today [Internet]. Lyon (France): International Agency fo「

paybal：https://www.paypal.me/andy19801210 Research on Cancer; 2018. Available from: https://gco.iarc.fr/today. 985. Fernanda Amary M, Ye H, Berisha F, et al. Fibroblastic growth factor receptor 1 amplification in osteosarcoma is associated with poor response to neo-adjuvant chemotherapy. Cancer Med. 2014 Aug;3(4):980-7. PMID:24861215 986. Fernandez A, Conrad M, Gill RM, et al. Solitary fibrous tumor in the abdomen 日nd pelvis: a case series with radiological findings and treatment recommendations. Clin Imaging. 2018 Mar-Apr;48:48-54. PMID:29028514 987. Fernandez AP, Sun Y, Tubbs RR, et al. FISH for MYC amplification and anti-MYC immunohistochemistry: useful diagnostic tools in the assessment of secondary angiosarcoma and atypical vascular proliferations. J Cutan Pathol. 2012 Feb;39 ⑵:234-42. PMID:22121953 988. Ferrara N. Vascular endothelial growth factor: molecular and biological aspects. Curr Top Microbiol Immunol. 1999;237:1-30. PMID:9893343 989. Ferrari S, Smeland S, Mercuri M, et al. 'eoadjuvant chemotherapy with high-dose ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups. J Clin Oncol. 2005 Dec 1 ;23(34):8845-52. PMID:16246977 90. Ferreira J, Esteves G, Fonseca R, et al. Fine-needle aspiration of lipoblastoma: cytological, molecular, and clinical features. Cancer Cytopathol. 2017 Dec;125(12):934-9. MID:28902468 991. Ferreiro JA, Nascimento AG. Hyaline­ cell rich chondroid syringoma. A tumor mimicking malignancy. Am J Surg Pathol. 1995 Aug; 19(8):912-7. PMID:7541966 992. Ferrer-Santacreu EM, Ortiz-Cruz EJ, Gonzalez-Lopez JM, etal. Enchondroma versus tow-grade chondrosarcoma in appendicular skeleton: clinical and radiological criteria. J Oncol. 2012;2012:437958. PMID:22593766 993. Fetsch JF, Laskin WB, Hallman JR, et al. Neurothekeoma: an analysis of 178 tumors with detailed immunohistochemical data and long-term patient follow-up information. Am J Surg Pathol. 2007 Jul;31 (7):1103-14. PMID:17592278 994. Fetsch JF, Laskin WB, Lefkowitz M, et al. Aggressive angiomyxoma: a clinicopathologic study of 29 female patients. Cancer. 1996 Jul 1;78(1):79-90. PMID:8646730 995. Fetsch JF, Laskin WB, Miettinen M. .erve sheath myxoma: a clinicopathologic and immunohistochemical analysis of 57 morphologically distinctive, S-100 proteinand GFAP-positive, myxoid peripheral nerve sheath tumors with a predilection for the extremities and a high local recurrence rate. Am J Surg Pathol. 2005 Dec;29(12):1615-24. PMID:16327434 996. Fetsch JF, Laskin WB, Miettinen M. Palmar-plantar fibromatosis in children and preadolescents: a clinicopathologic study of 56 cases with newly recognized demographics and extended follow-up information. Am J Surg Pathol. 2005 Aug;29(8):1095-105. PMID:16006806 997. Fetsch JF, Laskin WB, Miettinen M. Superficial acral fibromyxoma: a clinicopathologic and immunohistochemical analysis of 37 cases of a distinctive soft tissue tumor with a predilection for the fingers and toes. Hum Pathol. 2001 Jul;32(7):704-14. PMID:11486169 99& Fetsch JF, Miettinen M. Calcifying aponeurotic fibroma: a clinicopathologic study of 22 cases arising in uncommon sites.

Hum Pathol. 1998 Dec;29(12): 1504-10. PMID:9865839 999. Fetsch JF, Miettinen M. Sclerosing perineurioma: a clinicopathologic study of 19 cases of a distinctive soft tissue lesion with a predilection for the fingers and palms of young adults. Am J Surg Pathol. 1997 Dec;21 (12):1433-42. PMID:9414186 1000. Fetsch JF, Miettinen M, Laskin WB, et al. A clinicopathologic study of 45 pediatric soft tissue tumors with an admixture of adipose tissue and fibroblastic elements, and a proposal for classification as lipofibromatosis. Am J Surg Pathol. 2000 Nov;24(11):1491-500. PMID:11075850 1001. Fetsch JF, Sesterhenn IA, Miettinen M, et al. Epithelioid hemangioma of the penis: a clinicopathologic and immunohistochemical analysis of 19 cases, with special reference to exuberant examples often confused with epithelioid hemangioendothelioma and epithelioid angiosarcoma. Am J Surg Pathol. 2004Apr;28⑷:523-33. PMID:15087672 1002. Fetsch JF, Vinh TN, Remotti F, et al. Tenosynovial (extraarticular) chondromatosis: an analysis of 37 cases of an underrecognized clinicopathologic entity with a strong predilection for the hands and feet and a high local recurrence rate. Am J Surg Pathol. 2003 Sep;27(9):1260-8. PMID:12960811 1003. Figueiredo BC, Sandrini R, Zambetti GP, et al. Penetrance of ad re nocortical tumours associated with the germline TP53 R337H mutation. J Med Genet. 2006 Jan;43(1):91-6. PMID:16033918 1004. Filie AC, Lage JM, Azumi N. Immunoreactivity of S100 protein, alpha-1antitrypsin, and CD68 in adult and congenital granular cell tumors. Mod Pathol. 1996 Sep;9(9):888-92. PMID:8878020 1005. Finkelstein JL, Gala P, Rochford R, et al. HIV/AID8 and lipodystrophy: implications for clinical management in resource-limited settings. J IntAIDS Soc. 2015 Jan 15;18:19033. PMID:25598476 1006. Finos L, Righi A, Frisoni T, et al. Primary extraskeletal myxoid chondrosarcoma of bone: report of three cases and review of the literature. Pathol Res Pract. 2017 May;213(5):461-6. PMID:28249774 1007. Fiore M, Ford S, Callegaro D, et al. Adequate local control in high-risk soft tissue sarcoma of the extremity treated with surgery alone at a reference centre: Should radiotherapy still be a standard? Ann Surg Oncol. 2018 Jun;25⑹:1536-43. PMID:29470819 1008. Fiore M, Grosso F, Lo Vullo S, et al. Myxoid/round cell and pleomorphic liposarcomas: prognostic factors and survival in a series of patients treated at a single institution. Cancer. 2007 Jun 15;109(12):252231.PMID:17510918 1009. Fiore M, Rimare仪 F, Mariani L, et al. Desmoid-type fibromatosis: a front-line conservative approach to select patients for surgical treatment. Ann Surg Oncol. 2009 Sep;16(9):2587-93. PMID:19568815 1010. Fisher C, Folpe AL, Hashimoto H, et al. Intra-abdominal synovial sarcoma: a clinicopathological study. Histopathology. 2004 S即;45(3):245-53. PMID:15330802 1011. Fisher TJ, Williams N, Morris L, et al. Metachondromatosis: more than just multiple osteochondromas. J Child Orthop. 2013 Dec;7(6):455-64. PMID:24432109 1012. Fittall MW, Mifsud W, Pillay N, et al. Recurrent rearrangements of FOS and FOSB define osteoblastoma. Nat Commun. 2018 Jun 1;9(1):2150. PMID:29858576 1013. Flanagan BP, Helwig EB. Cutaneous lymphangioma. Arch Dermatol. 1977 Jan;113(1):24-30. PMID:831620

1014. Fletcher CD. Angiomatoid "malignant fibrous histiocytoma": an immunohistochemical study indicative of myoid differentiation. Hum Pathol. 1991 Jun;22(6):563-8. PMID:1650754 1015. Fletcher CD. Benign fibrous histiocytoma of subcutaneous and deep soft tissue: a clinicopathologic analysis of 21 cases. Am J Surg Pathol. 1990 S即;14(9):801-9. PMID:2167613 1016. Fletcher CD. Pleomorphic malignant fibrous histiocytoma: fact or fiction? A critical reappraisal based on 159 tumors diagnosed as pleomorphic sarcoma. Am J Surg Pathol. 1992 Mar;16(3):213-28. PM1D:1317996 1017. Fletcher CD. Solitary circumscribed neuroma of the skin (so-called palisaded, encapsulated neuroma). A clinicopathologic and immunohistochemical study. Am J Surg Pathol. 1989Jul;13(7):574-80. PMID:2660609 1018. Fletcher CD. Undifferentiated sarcomas: what to do? And does it matter? A surgical pathology perspective. Ultrastruct Pathol. 2008 Mar-Apr;32(2):3仁6. PMID:18446665 1019. Fletcher CD, Akerman M, Dal Cin P, et al. Correlation between clinicopathological features and karyotype in lipomatous tumors. A report of 178 cases from the Chromosomes and Morphology (CHAMP) Collaborative Study G「o叩.Am J Pathol. 1996 Feb;148⑵:623-30. PMID:8579124 1020. Fletcher CD, Beham A, Bekir S, et al. Epithelioid angiosarcoma of deep soft tissue: a distinctive tumor readily mistaken for an epithelial neoplasm. Am J Surg Pathol. 1991 Oct;15(10):915-24. PMID:1718176 1021. Fletcher CD, Dal Cin P, de Wever I, et al. Correlation between clinicopathological features and karyotype in spindle cell sarcomas. A report of 130 cases from the CHAMP study group. Am J Pathol. 1999 Jun;154(6):1841-7. PMID:10362810 1022. Fletcher CD, Davies SE. Benign plexiform (multinodular) schwannoma: a rare tumour unassociated with neurofibromatosis. Histopathology. 1986 Sep;10(9):971-80. PMID:3096870 1023. Fletcher CD, Gustafson P, Rydholm A, et al. Clinicopathologic re-evaluation of 100 malignant fibrous histiocytomas: prognostic relevance of subclassification. J Clin Oncol. 2001 Jun 15;19(12):3045-50. PMID:11408500 1024. Fletcher CD, Martin-Bates E. Intramuscular and intermuscular lipoma: neglected diagnoses. Histopathology. 1988 Mar; 12(3):275-87. PMID:3366443 、 1025. Fletcher CD, Martin-Bates E. Spindle cell lipoma: a clinicopathological study with some original observations. Histopathology. 1987 Aug;竹⑹:803-17. PMID:3623439 、 1026. Fletcher CD, Tsang WY, Fisher C, et al. Angiomyofibroblastoma of the vulva. A benign neoplasm distinct from aggressive angiomyxoma. Am J Surg Pathol. 1992 Apr; 16(4):373-82. PMID:1314521 1027. Fletcher CDM, Bridge JA, Hogendoorn PCW, et al., editors. WHO classification of tumours of soft tissue and bone. Lyon (France): International Agency for Research on Cancer; 2013. (WHO classification of tumours series, 4th ed.; vol. 5). https://publications.iarc.fr/15. 1028. Fletcher JA, Naeem R, Xiao S, et al. Chromosome aberrations in desmoid tumors. Trisomy 8 may be a predictor of recurrence. Cancer Genet Cytogenet. 1995 Feb;79(2):13943. PMID:7889507 1029. Fletcher JS, Wu J, Jessen WJ, et al. Cxcr3-expressing leukocytes are necessary for neurofibroma formation in mice. JCI Insight. 2019 Feb 7;4(3):98601. PMID:30728335 1030. Flieder DB, Moran CA, Suster S. Primary alveolar soft-part sarcoma of the mediastinum: a clinicopathological and immunohistochemical

study of two cases. Histopathology. 1997 Nov;31 (5):469-73. PMID:9416489 1031. Flores RJ, Harrison DJ, Federman NC, et al. Alveolar soft part sarcoma in children and young adults: a report of 69 cases. Pediatr Blood Cancer. 2018 May;65(5):e26953. PMID:29350467 1032. Floris G, Deraedt K, Samson I, et al. Epithelioid hemangioma of bone: a potentially metastasizing tumor? Int J Surg Pathol. 2006 Jan;14(1):9-15, discussio n 16-20. PMID:16501828 1033. Flucke U, Hulsebos TJ, van Krieken JH, et al. Myxoid epithelioid sarcoma: a diagnostic challenge. A report on six cases. Histopathology. 2010 Nov;57(5):753-9. PMID:21083605 1034. Flucke U, Mentzel T, Verdijk MA, et al. EWSR1-ATF1 chimeric transcript in a myoepithelial tumor of soft tissue: a case report. Hum Pathol. 2012 May;43⑸:764-8. PMID:22154050 1035. Flucke U, Palmedo G, Blankenhorn N, et al. EWSR1 gene rearrangement occurs in a subset of cutaneous myoepithelial tumors: a study of 18 cases. Mod Pathol. 2011 Nov;24(11):1444-50. PMID:21725291 1036. Flucke U, Shepard SJ, Bekers EM, et al. Fibro-osseous pseudotumor of digits ・ expanding the spectrum of clonal transient neoplasms harboring USP6 rearrangement. Ann Diagn Pathol. 2018 Aug;35:53-5. PMID:29787930 1037. Flucke U, Tops BB, de Saint Aubain Somerhausen N, et al. Presence of C11orf95MKL2 fusion is a consistent finding in chondroid lipomas: a study of eight cases. Histopathology. 2013 May;62(6):925-30. PMID:23672313 彳038. Flucke U, Tops BB, van Diest PJ, et al. Desmoid-type fibromatosis of the head and neck region in the paediatric population: a clinicopathological and genetic study of seven cases. Histopathology. 2014 May;64(6):76976. PMID:24206198 1039. Flucke U, van Noesel MM, Wijnen M, et al. TFG-MET fusion in an infantile spindle cell sarcoma with neural features. Genes Chromosomes Cancer. 2017 Sep;56(9):663-7. PMID:28510278 1040. Flucke U, van Krieken JH, Mentzel T. Cellular angiofibroma: analysis of 25 cases emphasizing its relationship to spindle cell lipoma and mammary-type myofibroblastoma. Mod Pathol. 2011 Jan;24(1):82-9. PMID:20852591 1041. Flucke U, Vogels RJ, de Saint Aubain Somerhausen N, et al. Epithelioid hema ngioendothelioma: clin icopathologic, immunhistochemical, and molecular genetic analysis of 39 cases. Diagn Pathol. 2014 Jul 1;9:131.PMID:24986479 1042. Folk GS, Williams SB, Foss RB, et al. Oral and maxillofacial sclerosing epithelioid fibrosarcoma: report of five cases. Head Neck Pathol. 2007 Sep;1(1):13-20. PMID:20614275 1043. Folkert MR, Singer S, Brennan MF, et al. Comparison of local recurrence with conventional and intensity-modulated radiation therapy for primary soft-tissue sarcomas of the extremity. J Clin Oncol. 2014 Oct 10;32(29):3236-41. PMID:25185087 1044. Folpe AL, Agoff SN, Willis J, et al. Parachordoma is immunohistochemically and cytogenetically distinct from axial chordoma and extraskeletal myxoid chondrosarcoma. Am J Surg Pathol. 1999 Sep;23(9):1059-67. PMID:10478665 1045. Folpe AL, Billings SD, McKenney JK, et al. Expression ofclaudin-1, a recently described tight junction-associated protein, distinguishes soft tissue perineurioma from potential mimics. Am J Surg Pathol. 2002 Dec;26(12):1620-6. PMID:12459629

Refere nces

559

paybal：https://www.paypal.me/andy19801210 1046. Folpe AL, Chand EM, Goldblum JR, et al. Expression of Fli-仁 a nuclear transcription factor, distinguishes vascular neoplasms from potential mimics. Am J Surg Pathol. 2001 Aug;25(8):1061-6. PMID:11474291 1047. Folpe AL, Devaney K, Weiss SW. Lipomatous hema ngiope「icytoma: a rare variant of hemangiopericytoma that may be confused with liposarcoma. Am J Surg Pathol. 1999 Oct;23(10):1201-7. PMID:10524520 1048. Folpe AL, Deyrup AT. Alveolar soft-part sarcoma: a review and update. J Clin Pathol. 2006 Nov;59(11):1127-32. PMID:17071801 1049. Folpe AL, Fanburg-Smith JC, Billings SD, et al. Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature. Am J Surg Pathol. 2004 Jan;28(1):1-30. PMID:14707860 1050. Folpe AL, Fanburg-Smith JC, Miettinen M, et al. Atypical and malignant glomus tumors: analysis of 52 cases, with a proposal for the reclassification of glomus tumors. Am J Surg Pathol. 2001 Jan;25(1):1-12. PMID:11145243 1051. Folpe AL, Goldblum JR, Rubin BP, et al. Morphologic and immunophenotypic diversity in Ewing family tumors: a study of 66 genetically confirmed cases. Am J Surg Pathol. 2005 Aug;29(8): 1025-33. PMID:16006796 1052. Folpe AL, Goodman ZD, Ishak KG, et al. Clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres: a novel member of the perivascular epithelioid clear cell family of tumors with a predilection for children and young adults. Am J Surg Pathol. 2000 Sep;24(9):1239-46. PMID:10976698 1053. Folpe AL, Graham RP, Martinez A, et al. Mesenchymal chondrosarcomas showing immunohistochemical evidence of rhabdomyoblastic differentiation: a potential diagnostic pitfall. Hum Pathol. 2018 Jul;77:2834. PMID:29559236 1054. Folpe AL, Kwiatkowski DJ. Perivascular epithelioid cell neoplasms: pathology and pathogenesis. Hum Pathol. 2010 Jan;41(1):115. PMID:19604538 1055. Folpe AL, Lane KL, Pauli G, et al. 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 high-grade areas. Am J Surg Pathol. 2000 Oct;24(10):1353-60. PMID:11023096 1056. Folpe AL, McKenney JK, Bridge JA, et al. Sclerosing rhabdomyosarcoma in adults: report of four cases of a hyalinizing, matrix­ rich variant of rhabdomyosarcoma that may be confused with osteosarcoma, chondrosarcoma, or angiosarcoma. Am J Surg Pathol. 2002 Sep;26⑼:竹75—83. PMID:12218574 1057. Folpe AL, Mentzel T, Lehr HA, et al. Perivascular epithelioid cell n eoplasms of soft tissue and gynecologic origin: a clinicopathologic study of 26 cases and review of the literature. Am J Surg Pathol. 2005 Dec;29(12):1558-75.PMID:16327428 1058. Folpe AL, Morris RJ, Weiss SW. Soft tissue giant cell tumorof low malignant potential: a proposal for the reclassification of malignant giant cell tumor of soft parts. Mod Pathol. 1999 Sep;12(9):894-902. PMID: 10496598 1059. Folpe AL, Weiss SW. Ossifying fibromyxoid tumor of soft parts: a clinicopathologic study of 70 cases with emphasis on atypical and malignant variants. Am J Surg Pathol. 2003 Apr;27(4):421-31. PMID: 12657926 1060. Folpe AL, Weiss SW. Pleomorphic hyalinizing angiectatic tumor: analysis of 41 cases supporting evolution from a distinctive precursor lesion. Am J Surg Pathol. 2004 Nov;28(11):1417-25.PMID:15489645

560

References

1061. Font RL, Jurco S 3rd, Zimmerman LE. Alveolar soft-part sarcoma of the orbit: a clinicopathologic analysis of seventeen cases and a review of the literature. Hum Pathol. 1982 Jun;13(6):569-79. PMID:7076238 1062. Foo WC, Cruise MW, Wick MR, et al. Immunohistochemical staining for TLE1 distinguishes synovial sarcoma from histologic mimics.Am J Clin Pathol. 2011 Jun;135(6):83944. PMID:21571956 1063. Fortuno C, James PA, Young EL, et al. Improved, ACM&compliant, in silico prediction of pathogenicity for missense substitutions encoded by TP53 variants. Hum Mutat. 2018 Aug;39(8):1061-9. PMID:29775997 1064. Fox MD, Billings SD, Gleason BC, et al. Cutaneous meningioma: a potential diagnostic pitfall in p63 positive cutaneous neoplasms. J Cutan Pathol. 2013 Oct;40(10):891-5. PMID:23924346 1065. Fox MD, Billings SD, Gleason BC, et al. Expression of MiTF may be help仙 in differentiating cellular neurothekeoma from plexiform fibrohistiocytic tumor (histiocytoid predominant) in a partial biopsy specimen. Am J Dermatopathol. 2012 Apr;34(2): 157-60. PMID:22441367 1066. Fox VL, Yasuda J, Al-lbraheemi A, et al. Metastatic rhabdomyosarcoma mimicking autoimmune pancreatitis diagnosed by EUSguided fine-needle biopsy. Gastrointest Endosc. 2018 Sep;88(3):562-3. PMID:29627494 1067. Franchi A, Bacchini P, Della Rocca C, et al. Central low-grade osteosarcoma with pagetoid bone formation: a potential diagnostic pitfail. Mod Pathol. 2004 Mar;17(3):288-91. PMID:14976532 1068. Frassica FJ, Unni KK, Beabout JW, et al. Dedifferentiated chondrosarcoma. A report of the clinicopathological features and treatment of seventy-eight cases. J Bone Joint Surg Am. 1986 Oct;68(8):1197-205. PMID:3021775 1069. Frayling IM, Mautner VF, van Minkelen R, et al. Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation. J Med Genet. 2019 Apr;56(4):209PMID:30530636 19. 1070. French CA, Mentzel T, Kutzner H, et al. Intradermal spindle cell/pleomorphic lipoma: a distinct subset. Am J Dermatopathol. 2000 Dec;22(6):496-502. PMID:11190440 1071. Frezza AM, Cesari M, Baumhoer D, et al. Mesenchymal chondrosarcoma: prognostic factors and outcome in 113 patients. A European Musculoskeletal Oncology Society study. Eur J Cancer. 2015 Feb;51 (3):374-81. PMID:25529371 1072. Frierson HF, Cooper PH. Myxoid variant of dermatofibrosarcoma protuberans. Am J Surg Pathol. 1983 Jul;7(5):445-50. PMID:6614310 1073. Frierson HF Jr, Fechner RE, Stallings RG, et al. Malignant fibrous histiocytoma in bone infarct. Association with sickle cell trait and alcohol abuse. Cancer. 1987 Feb 1;59(3):496-500. PMID:3791158 1074. Friis RB, Safwat A, Baad-Hansen T, et al. Solitary fibrous tumour: a single institution retrospective study and further validation of a prognostic risk assessment system. Clin Oncol (R Coll Radiol). 2018 Dec;30(12):798-804. PMID:30206022 1075. Fritchie K, Jensch K, Moskalev EA, et al. The impact of histopathology and NAB2STAT6 fusion subtype in classification and grading of meningeal solitary fibrous tumor/ hemangiopericytoma. Acta Neuropathol. 2019 Feb;137(2):307-19. PMID:30584643 1076. Fritchie KJ, Renner JB, Rao KW, et al. Osteolipoma: radiological, pathological, and cytogenetic analysis of three cases.

Skeletal Radiol. 2012 Feb;41 (2):237-44. PMID:21822651 1077. Fritz A, Percy C, Jack A, et al., editors. International classification of diseases for oncology (ICD-O). 3rd ed. 1st rev. Geneva (Switzerland): World Health Organization; 2013. 1078. Fritz B, Schubert F, Wrobel G, et al. Microarray-based copy number and expression profiling in dedifferentiated and pleomorphic liposarcoma. Cancer Res. 2002 Jun 1;62(11):2993-8. PMID:12036902 1079. Fromm J, Klein A, Baur-Melnyk A, et al. Survival and prognostic factors in conventional central chondrosarcoma. BMC Cancer. 2018 Aug 24;18(1):849. PMID:30143018 1080. Frustaci S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol. 2001 Mar 1;19(5): 1238-47. PMID:11230464 1081. Fu W, Ligabue A, Rogers KJ.etal. Human RECQ helicase pathogenic variants, population variation and "missing" diseases. Hum Mutat. 2017 Feb;38(2):193-203. PMID:27859906 1082. Fu Y, Kang H, Zhao H, et al. Sunitinib for patients with locally advanced or distantly metastatic dermatofibrosarcoma protuberans but resistant to imatinib. Int J Clin Exp Med. 2015 May 15;8(5):8288-94. PMID:26221412 1083. Fuca G, Hindi N, Ray-Coquard I, et al. Treatment outcomes and sensitivity to hormone therapy of aggressive angiomyxoma: a multicenter, international, retrospective study. Oncologist. 2019 Jul;24(7):e536-41. PMID:30518617 1084. Fuchs J, Dantonello TM, Blumenstock G, et al. Treatment and outcome of patients suffering from perineal/perianal rhabdomyosarcoma: results from the CWS trials-retrospective clinical study. Ann Surg. 2014 Jun;259(6):1166-72. PMID:24045440 1085. Fujimura Y, Ohno T, Siddique H, et al. The EWS-ATF-1 gene involved in malignant melanoma of soft parts with t(12;22) chromosome translocation, encodes a constitutive transcriptional activator. Oncogene. 1996 Jan 4;12(1):159-67. PMID:8552387 1086. Fukuda T, Igarashi T, Hiraki H, et al. Abnormal pigmentation of schwannoma attributed to excess production of neuromelanin-like pigment. Pathol Int. 2000 Mar;50(3):230-7. PMID:10792787 1087. Fukuda T, Ishikawa H, Ohnishi Y, et al. Extraskeletal myxoid chondrosarcoma arising from the retroperitoneum. Am J Clin Pathol. 1986Apr;85⑷:514-9. PMID:3953507 1088. Fukuda W, Moroha曲 S, Fukuda I. Intimal sarcoma of the pulmonary artery­ diagnostic challenge. Acta Cardiol. 2011 Aug;66(4):539-41. PMID:21894817 1089. Fukuda Y, Miyake H, Masuda Y, et al. Histogenesis of unique elastinophilic fibers of elastofibroma: ultrastructural and immunohistochemical studies. Hum Pathol. 1987 May;18(5):424-9. PMID:3552953 1090. Fukunaga M, Endo Y, Masui F, et al. Retiform haemangioendothelioma. Virchows Arch. 1996 Jul;428(4-5):301-4. PMID:8764941 1091. Fukunaga M, Naganuma H, Nikaido T, et al. Extrapleural solitary fibrous tumor: a report of seven cases. Mod Pathol. 1997 May; 10(5):443-50. PMID:9160308 1092. Fukunaga M, Suzuki K, Saegusa N, et al. Composite hemangioendothelioma: report of 5 cases including one with associated Maffucci syndrome. Am J Surg Pathol. 2007 Oct;31(10):1567-72. PMID:17895759 1093. Fukushima M, Schaefer IM, Fletcher CD. Myolipoma of soft tissue: clinicopathologic analysis of 34 cases. Am J Surg Pathol. 2017 Feb;41 (2):153-60. PMID:27635945

1094. Furey JG, Ferrer-Torrer-Torells m Reagan JW. Fibrosarcoma arising at th' site of bone infarcts. A report of 2 cases j Bone Joint Surg Am. 1960 Jul;42-A802 in PMID:13849880 1095. Furlong MA, Fanburg-Smith JC, Childers EL. Lipoma of the oral and maxillofacial region­ site and subclassification of 125 cases Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004 Oct;98(4):441-50. PMID:15472660 1096. Furlong MA, Fanburg-Smith jc Miettinen M. The morphologic spectrum of hibernoma: a clinicopathologic study of pg cases. Am J Surg Pathol. 2001 Jun-25(6)-809 14. PMID:11395560 4097. Furlong MA, Mentzel T, Fanburg-Smith JC. Pleomorphic rhabdomyosarcoma in adultsa clinicopathologic study of 38 cases with emphasis on morphologic variants and recent skeletal muscle-specific markers. Mod Pathol 2001 Jun;14(6):595-603. PMID:11406662 109& Fusumae T, Kamiya K, Maekawa T, et al. Clear cell sarcoma with intraepidermal nests requiring the differential diagnosis of malignant melanoma. J Dermatol. 2018 Jan;45(1)-1l5-6 PMID:28256744 1099. Futani H, Okayama A, Maruo S, et al. The role of imaging modalities in the diagnosis of primary dedifferentiated parosteal osteosarcoma. J Orthop Sci. 2001;6(3):290-4 PMID:11484126 1100. Gaal J, Stratakis CA, Carney JA, et al. SDHB immunohistochemistry: a use仙 tool in the diagnosis of Camey-Stratakis and Carney triad gastrointestinal stromal tumors. Mod Pathol. 2011 Jan;24(1):147-51 PMID:20890271 1101. Gadner H, Minkov M, Grois N, et al. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood. 2013 Jun 20;121(25):5006-14. PMID:23589673 1102. Gadwal SR, Fanburg-Smith JC, Gannon FH, et al. Primary chondrosarcoma of the head and neck in pediatric patients: a clinicopathologic study of 14 cases with a review of the literature. Cancer. 2000 May 1;88(9):2181-8. PMID:10813732 1103. Gaertner EM, Steinberg DM, Huber M, et al. Pulmonary and mediastinal glomus tumorsreport of five cases including a pulmonary glomangiosarcoma: a clinicopathologic study with literature review. Am J Surg Pathol. 2000 Aug;24(8):1105-14. PMID:10935651 1104. Gaffney EF, Dervan PA, Fletcher CD. Pleomorphic rhabdomyosarcoma in adulthood. Analysis of 11 cases with definition of diagnostic criteria.Am J Surg Pathol. 1993 Jun;17(6):6019. PMID:8333559 1105. Galgano MA, Goulart CR, Iwenofu H, et al. Osteoblastomas of the spine: a comprehensive review. Neurosurg Focus. 2016 Aug;41(2):E4. PMID:27476846 1106. Galili N, Davis RJ, Fredericks WJ, et al. Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar 市abdomyosarcoma. Nat Genet. 1993 Nov;5⑶:230-5. PMID:8275086 1107. Gallager RL, Helwig EB. Neurothekeoma-a benign cutaneous tumor of neural origin. Am J Clin Pathol. 1980 Dec"⑹:759-64. PMID:7446487 1108. Galli SJ, Weintraub HP, Proppe KH. Malignant fibrous histiocytoma and pleomorphic sarcoma in association with medullary bone infarcts. Cancer. 1978 Feb;41 (2):607-19. PMID:204409 1109. Gambarotti M, Benini S, Gamberi G.etal. CIC-DUX4 fusion-positive round-cell sarcomas of soft tissue and bone: a single-institution morphological and molecular analysis of seven cases. Histopathology. 2016 Oct;69(4):624-34. PMID:27079694

paybal：https://www.paypal.me/andy19801210 1110. Gambarotti M, Dei Tos AP, Vanel D, et al. Osteoblastoma-like osteosarcoma: high-grade or low-grade osteosarcoma? Histopathology. 2019 Feb;74⑶:494-503. PMID:30152881 ' 1111. Gambarotti M, Righi A, Frisoni T, et al. Dedifferentiated chondrosarcoma with "adamantinoma-like" features: a case report and review of literature. Pathol Res Pract. 2017 Jun;213(6):698-701. PMID:28551382 1112. Gambarotti M, Righi A, Sbaraglia M, et al. Intraosseous papillary intralymphatic angioendothelioma (PILA): one new case and review of the literature. Clin Sarcoma Res. 2018 Jan 30;8:1.PMID:29423171 1113. Gambarotti M, Righi A, Vanel D, et al. Fibrocartilaginous mesenchymoma of bone: a single-institution experience with molecular investigations and a review of the literature. Histopathology. 2017 Jul;71 (1):134-42. PMID:28239886 1114. Ganem D, Ziegelbauer J. MicroRNAs of Kaposi's sarcoma-associated herpes virus. Semin Cancer Biol. 2008 Dec;18(6):437-40. PMID:19013245 1115. Gao SJ, Kingsley L, Hoover DR, et al. Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of *s Kaposi sarcoma. N Engl J Med. 1996 Jul 25:335(4):233-41. PMID:8657239 1116. Garcia CA, Spencer RP. Bone and ln-111 octreotide imaging in oncogenic osteomalacia: a case report. Clin Nucl Med. 2002 Aug;27(8):582-3. PMID:12170004 1117. Garcia R代 Inwards CY, Unni KK. Benign bone tumors-recent developments. Semin Diagn Pathol. 2011 Feb;28(1):73-85. PMID:21675379 1118. Garner HW, Kransdorf MJ, Peterson JJ. Posttherapy imaging of musculoskeletal neoplasms. Radiol Clin North Am. 2011 Nov;49(6):1307-23, vii. PMID:22024300 1119. Garsed DW, Marshall OJ, Corbin VD, et al. The architecture and evolution of cencer neochromosomes. Cancer Cell. 2014 Nov 10:26(5):653-67. PMID:25517748 1120. Gasparini P, Facchinetti F, Boeri M, et al. Prognostic determinants in epithelioid sarcoma. Eur J Cance 匚 2011 Jan;47 ⑵:287-95. PMID:20932739 1121. Gasparotto D, Rossi S, Polano M, et al. Quadruple-negative GIST is a sentinel for unrecognized neurofibromatosis type 1 syndrome. Clin Cancer Res. 2017 Jan 1;23(1):273-82. PMID:27390349 1122. Gatta G, Capocaccia R, Botta L, et al. Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol. 2017 Aug;18(8):1022-39. PMID:28687376 1123. Gatta G, van der Zwan JM, Casali PG, et al. Rare cancers are not so rare: the rare cancer burden in Europe. Eur J Cancer. 2011 Nov;47(17):2493-511. PMID:22033323 1124. Gaujoux S, Salenave S, Ronot M, et al. Hepatobiliary and pancreatic neoplasms in patients with McCune-Albright syndrome. J Clin Endocrinol Metab. 2014 Jan;99(1):E97-101. PMID:24170100 1125. Gearhart MD, Corcoran CM, Wamstad JA, et al. Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets. Mol Cell Biol. 2006 Sep;26(18):6880-9. PMID:16943429 1126. Gebhard S, Coindre JM, Michels JJ, et al. Pleomorphic liposarcoma: clinicopathologic, immunohistochemical, and follow-up analysis of 63 cases: a study from the French Federation of Cancer Centers Sarcoma Group. Am J Surg Pathol. 2002 M即;26(5):601-16. PMID:11979090 1127. Gebre-Medhin S, Nord KH, Moller E, et

al. Recurrent rearrangement of the PHF1 gene in ossifying fibromyxoid tumors. Am J Pathol. 2012 Sep;181(3):1069-77. PMID:22796436 馅28. Geirnaerdt MJ, Bloem JL, Eulderink F, et al. Cartilaginous tumors: correlation of gadolinium-enhanced MR imaging and histopathologic findings. Radiology. 1993 Mar;186(3):813-7. PMID:8430192 1129. Geirnaerdt MJ, Bloem JL, van der Woude HJ, et al. Chondroblastic osteosarcoma: characterisation by gadolinium-enhanced MR imaging correlated with histopathology. Skeletal Radiol. 1998 Mar;27(3):145-53. PMID:9554005 1130. Geirnaerdt MJ, Hermans J, Bloem JL, et al. Usefulness of radiography in differentiati叩 enchondroma from central grade 1 chondrosarcoma. AJR Am J Roentgenol. 1997 Oct; 169(4):1097-104. PMID:9308471 1131. Geirnaerdt MJ, Hogendoorn PC, Bloem JL, et al. Cartilaginous tumors: fast contrastenhanced MR imaging. Radiology. 2000 Feb;214(2):539 6. * PMID:10671608 1132. Gelderblom H, Hogendoorn PC, Dijkstra SD, et al. The clinical approach towards chondrosarcoma. Oncologist. 2008 Mar;13(3):320-9. PMID: 18378543 1133. George S, Serrano C, Hensley ML, et al. Soft tissue and uterine leiomyosarcoma. J Clin Oncol. 2018 Jan 10;36(2):144-50. PMID:29220301 1134. Gerald WL, Haber DA. The EWS-WT1 gene fusion in desmoplastic small round cell tumor. Semin Cancer Biol. 2005 Jun;15(3):197205. PMID:15826834 1135. Gerald WL, Ladanyi M, de Alava E, et al. Clinical, pathologic, and molecular spectrum of tumors associated with t(11;22)(p13;q12): desmoplastic small round-cell tumor and its variants. J Clin Oncol. 1998 Sep; 16(9):302836. PMID:9738572 1136. Gerald WL, Miller HK, Battifora H, et al. Int「a-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 Jun;15(6):499-513. PMID:1709557 1137. Gerald WL, Rosai J, Ladanyi M. Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round cell tumor. Proc Natl Acad Sci USA. 1995 Feb 14;92(4): 1028-32. PMID:7862627 1138. Gherlinzoni F, Rock M, Picci P. Chondromyxoid fibroma. The experienee at the Istituto Ortopedico Rizzoli. J Bone Joint Surg Am. 1983 Feb;65(2):198-204. PMID:6337162 1139. Ghodke K, 8het T, Epari S, et al. A retrospective study of correlation of morphologic patterns, MIB1 proliferation index, and survival analysis in 134 cases of plasmacytoma. Ann Diagn Pathol. 2015 Jun;19(3):117-23. PMID:25842207 1140. Gholami S, Cassidy MR, Kirane A, et al. Size and location are the most important risk factors for malignant behavior in resected solitary fibrous tumors. Ann Surg Oncol. 2017 Dec;24(13):3865-71. PMID:29039030 1141. Ghosh S, Sinha R, Bandyopadhyay R, et al. Oncogenous osteomalacia. J Cancer Res Ther. 2009 Jul-Sep;5(3):210-2. PMID:19841566 1142. Ghostine B, Sebaaly A, Ghanem I. Multifocal metachronous giant cell tumor: case report and review of the literature. Case Rep Med. 2014;2014:678035. PMID:24511316 1143. Giacchero D, Maire G, Nuin PA, et al. No correlation between the molecular subtype of COL1A1-PDGFB fusion gene and the clinico-histopathological features of dermatofibrosarcoma protuberans. J Invest Dermatol. 2010 Mar; 130(3):904-7. PMID:19890351

1144. Giacomelli AO, Yang X, Lintner RE, et al. Mutational processes shape the landscape of TP53 mutations in human cancer. Nat Genet. 2018 Oct;50(10):1381-7. PMID:30224644 1145. Giacomini CP, Sun S, Varma S, et al. Breakpoint analysis of transcriptional and genomic profiles uncovers novel gene fusions spanning multiple human cancer types. PLoS Genet. 2013 Apr;9(4):e1003464. PMID:23637631 1146. Giannico G, Holt GE, Homlar KC, et al. Osteoblastoma characterized by a three-way translocation: report of a case and review of the literature. Cancer Genet Cytogenet. 2009 Dec;195(2):168-71. PMID:19963118 1147. Giannini C, Scheithauer BW, Jenkins RB, et al. Soft-tissue perineurioma. Evidenee for an abnormality of chromosome 22, criteria for diagnosis, and review of the literature. Am J Surg Pathol. 1997 Feb;21 (2): 164-73. PMID:9042282 1148. Giarola M, Stagi L, Presciuttini S, et al. Screening for mutations of the APC gene in 66 Italian familial adenomatous polyposis patients: evidence for phenotypic differences in cases with and without identified mutation. Hum Mutat. 1999;13(2):116-23. PMID:10094547 1149. Gibas Z, Miettinen M. Recurrent parapharyngeal rhabdomyoma. Evidence of neoplastic nature of the tumor from cytogenetic study. Am J Surg Pathol. 1992 Jul;16(7):721-8. PMID:1530111 1150. Gibault L, Perot G, Chibon F, et al. New insights in sarcoma oncogenesis: a comprehensive analysis of a large series of 160 soft tissue sarcomas with complex genomics. J Pathol. 2011 Jan;223(1):64-71. PMID:21125665 1151. Gibbons D, Leitch M, Coscia J, et al. Fine needle aspiration cytology and histologic findings of granular cell tumor of the breast: review of 19 cases with clinical/radiologic correlation. Breast J. 2000 Jan;6(1):27-30. PMID:11348331 1152. Gill AJ, Chou A, Vilain R, et al. Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types. Am J Surg Pathol. 2010 May;34(5):636-44. PMID:20305538 1153. Gill R, O'Donnell RJ, Horvai A. Utility of immunohistochemistry for endothelial markers in distinguishing epithelioid hema ngioendothelioma from carcinoma metastatic to bone. Arch Pathol Lab Med. 2009 Jun;133(6):967-72. PMID:19492891 1154. Gill RM, Buelow B, Mather C, et al. Hepatic small vessel neoplasm, a rare infiltrative vascular neoplasm of uncertain malignant potential. Hum Pathol. 2016 Aug;54:143-51. PMID:27090685 1155. Gillespie WJ, Frampton CM, Henderson RJ, et al. The incidence of cancer following total hip replacement. J Bone Joint Surg Br. 1988 Aug;70(4):539-42. PMID:3403594 1156. Girolami I, Mancini I, Simoni A, et al. Denosumab treated giant cell tumour of bone: a morphological, immunohistochemical and molecular analysis of a series. J Clin Pathol. 2016 Mar;69(3):240-7. PMID:26338802 1157. Gisselsson D, Domanski HA, Hoglund M, et al. Unique cytological features and chromosome aberrations in chondroid lipoma: a case report based on fine-needle aspiration cytology, histopathology, electron microscopy, chromosome banding, and molecular cytogenetics. Am J Surg Pathol. 1999 Oct;23(10):1300-4. PMID:10524534 1158. Gisselsson D, Hibbard MK, Dal Cin P, et al. PLAG1 alterations in lipoblastoma: involvement in varied mesenchymal cell types and evidence for alternative oncogenic mechanisms. Am J Pathol. 2001 Sep; 159⑶:955-62. PMID:11549588

1159. Gisselsson D, Hoglund M, Mertens F, et al. Hibernomas are characterized by homozygous deletions in the multiple endocrine neoplasia type I region. Metaphase fluorescence in situ hybridization reveals complex rearrangements not detected by conventional cytogenetics. Am J Pathol. 1999 Jul;155(1):61-6.PMID:10393837 1160. Gisselsson D, Palsson E, Hoglund M, et al. Differentially amplified chromosome 12 sequences in low- and high-grade osteosarcoma. Genes Chromosomes Cancer. 2002 Feb;33(2):133-40. PMID:11793439 1161. Giuffrida AY, Burgueno JE, Koniaris LG, et al. Chondrosarcoma in the United States (1973 to 2003): an analysis of 2890 cases from the SEER database. J Bone Joint Surg Am. 2009 May;91(5):1063-72. PMID:19411454 1162. Giunti A, Laus M. Malignant tumours in chronic osteomyelitis. (A report of thirty nine cases, twenty s仪 with long term follow up). Ital J Orthop Traumatol. 1978 Aug;4(2):171-82. PMID:757960 1163. Gladdy RA, Qin LX, Moraco N, et al. Do radiation-associated soft tissue sarcomas have the same prognosis as sporadic soft tissue sarcomas? J Clin Oncol. 2010 Apr 20;28(12):2064-9. PMID:20308666 1164. Gladdy RA, Qin LX, Moraco N, et al. Predictors of survival and recurrence in primary leiomyosarcoma. Ann Surg Oncol. 2013 Jun;20⑹851-7. PMID:23354568 1165. Gleason BC, Fletcher CD. Deep "benign" fibrous histiocytoma: clinicopathologic analysis of 69 cases of a rare tumor indicating occasional metastatic potential. Am J Surg Pathol. 2008 Mar;32(3):354-62. PMID:18300816 1166. Gleason BC, Fletcher CD. Myoepithelial carcinoma of soft tissue in children: an aggressive neoplasm analyzed in a series of 29 cases. Am J Surg Pathol. 2007 Dec;31(12):1813-24. PMID:18043035 1167. Gleason BC, Hornick JL. Inflammatory myofibroblastic tumours: Where are we now? J Clin Pathol. 2008 Apr;61 (4):428-37. PMID:17938159 1168. Gleason BC, Liegl-Atzwanger B, Kozakewich HP, et al. Osteofibrous dysplasia and adamantinoma in children and adolescents: a clinicopathologic reappraisal. Am J Surg Pathol. 2008 Mar;32(3):363-76. PMID:18300815 1169. Gleason BC, Nascimento AF. HMB45 and Melan-A are useful in the differential diagnosis between granular cell tumor and malignant melanoma. Am J Dermatopathol. 2007 Feb;29(1):22-7. PMID:17284958 1170. Godette GA, O'Sullivan M, Menelaus MB. Plantar fibromatosis of the heel in children: a report of 14 cases. J Pediatr Orthop. 1997 JanFeb;17(1):16-7. PMID:8989694 1171. Goedert J J. The epidemiology of acquired immunodeficiency syndrome malignancies. Semin Oncol. 2000 Aug;27(4):390-401. PMID:10950365 1172. Goedhart LM, Ploegmakers JJ, Kroon HM, et al. The presentation, treatment and outcome of periosteal chondrosarcoma in the Netherlands. Bone Joint J. 2014 Jun;96-B(6):823-8. PMID:24891585 1173. Goetz SP, Robinson RA, Landas SK. Extraskeletal myxoid chondrosarcoma of the pleura. Report of a case clinically simulating mesothelioma. Am J Clin Pathol. 1992 Apr;97(4):498-502. PMID:1553915 1174. Goh GH, Teh M, Vanecek T, et al. Primary pulmonary clear cell sarcoma-the first two reported cases. Virchows Arch. 2016 Jul;469(1):111-7. PMID:27112339 1175. Gold JS, Gonen M, Gutierrez A, et al. Development and validation of a prognostic no mogram for recurre nce・f「ee survival after

Refere nces

561

paybal：https://www.paypal.me/andy19801210 complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. Lancet Oncol. 2009 Nov;10(11):104552. PMID:19793678 1176. Goldberg J, Azizad S, Bandovic J, et al. Primary mediastinal giant cell tumor. Rare Tumors. 2009 Dec 28;1 ⑵:e45. PMID:21139924 1177. Goldblum JR, Appelman HD. Stromal tumors of the duodenum. A histologic and immunohistochemical study of 20 cases. Am J Surg Pathol. 1995 Jan;19(1):71-80. PMID:7528472 1178. Goldblum JR, Reith JD, Weiss SW. Sarcomas arising in dermatofibrosarcoma protubera ns: a reappraisal of biologic behavior in eighteen cases treated by wide local excision with extended clinical follow up. Am J Surg Pathol. 2000 Aug;24(8):1125-30. PMID:10935653 1179. Goldblum JR, Rice TW. Epithelioid angiosarcoma of the pulmonary artery. Hum Pathol. 1995 Nov;26(11):1275-7. PMID:7590704 1180. Golden T, Siordia JA. Osteochondromyxoma: review of a rare Camey complex criterion. J Bone Oncol. 2016 Jul 12;5(4):194-7. PMID:28008382 1181. Goldenberg RR, Campbell CJ, Bonfiglio M. Giant-cell tumor of bone. An analysis of two hundred and eighteen cases. J Bone Joint Surg Am. 1970 Jun;52(4):619-64. PMID:5479455 1182. Gologorsky Y, Gologorsky D, Yarygina AS, et al. Familial multiple lipomatosis: report of a new family. Cutis. 2007 Mar;79(3):227-32. PMID:17674589 1183. Gomes CC, Gayden T, Bajic A, et al. TRPV4 and KRAS and FGFR1 gain-offunotion mutations drive giant cell lesions of the jaw. Nat Commun. 2018 Nov 1;9(1):4572. PMID:30385747 1184. Gomez CS, Calonje E, Ferrar DW, et al. Lymphangiomatosis of the limbs. Clinicopathologic analysis of a series with a good prognosis. Am J Surg Pathol. 1995 Feb; 19⑵:125-33. PMID:7832272 1185. Gong L, Liu W, Sun X, et al. Histological and clinical characteristics of malignant giant cell tumor of bone. Virchows Arch. 2012 Mar;460⑶:327-34. PMID:22350004 1186. Gonzaga Ml, Grant L, Curtin C, et al. The epidemiology and survivorship of clear cell sarcoma: a National Cancer Database (NCDB) review. J Cancer Res Clin Oncol. 2018 Sep;144(9):1711-6. PMID:29961184 1187. Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. 2009 Mar 10;27(8):1250-6. PMID:19204208 1188. Gonzalez-Perez L, Alvarez-Arguelles H, Ramos Gutierrez VJ, et al. Bladder fetal rhabdomyoma intermediate type. Urol Int. 2018;101 ⑵【240-4. PMID:29224022 1189. Goodlad JR, Mentzel T, Fletcher CD. Low grade fibromyxoid sarcoma: clinicopathological analysis of eleven new cases in support of a distinct entity. Histopathology. 1995 Mar;2603):229—37. PMID:7797200 1190. Goodwin ML」in H, Straessler K, et al. Modeling alveolar soft part sarcomagenesis in the mouse: a role for lactate in the tumor microenvironment. Cancer Cell. 2014 Dec 8；26(6):851-62. PMID:25453902 1191. Gordon A, McManus A, Anderson J, et al. Chromosomal imbalances in pleomorphic rhabdomyosarcomas and identification of the alveolar rhabdomyosarcoma-associated PAX3FOXO1A fusion gene in one case. Cancer Genet Cytogenet. 2003 Jan 1;140(1):73-7. PMID:12550764 1192. Gordon AT, Brinkschmidt C, Anderson J,

562

References

et al. A novel and consistent amplicon at 13q31 associated with alveolar rhabdomyosarcoma. Genes Chromosomes Can cer. 2000 Jun;28⑵:220-6. PMID:10825007 1193. Gorunova L, Vult von Steyern F, Storlazzi CT, et al. Cytogenetic analysis of 101 giant cell tumors of bone: nonrandom patterns of telomeric associations and other structural aberrations. Genes Chromosomes Cancer. 2009 Jul;48(7):583-602. PMID:19396867 1194. Goto T, Ishida T, Motoi N, et al. Primary leiomyosarcoma of the femur. J Orthop Sci. 2002;7(2):267-73. PMID:11956991 1195. Goud AL, de Lange J, Scholtes VA, et al. Pain, physical and social functioning, and quality of life in individuals with multiple hereditary exostoses in the Netherlands: a national cohort study. J Bone Joint Surg Am. 2012 Jun 6;94(11):1013-20. PMID:22637207 1196. Goud AL, Wuyts W, Bessems J, et al. Intraosseous atypical chondroid tumor or chondrosarcoma grade 1 in patients with multiple osteochondromas. J Bone Joint Surg Am. 2015 Jan 7;97(1):24-31. PMID:25568391 1197. Gounder MM, Lefkowitz RA, Keohan ML, et al. Activity of sorafenib against desmoid tumor/deep fibromatosis. Clin Cancer Res. 2011 Jun 15;17(12):4082-90. PMID:21447727 1198. Gounder MM, Mahoney MR, Van Tine BA, et al. Sorafenib for advanced and refractory desmoid tumors. N Engl J Med. 2018 Dec 20;379(25):2417-28. PMID:30575484 1199. Gounder MM, Maki RG. Molecular basis for primary and secondary tyrosine kinase inhibitor resistance in gastrointestinal stromal tumor. Cancer Chemother Pharmacol. 2011 Jan;67 Suppl1:S25-43. PMID:21116624 1200. Gounder MM, Thomas DM, Tap WD. Locally aggressive connective tissue tumors. J Clin Oncol. 2018 Jan 10;36⑵:202-9. PMID:29220303 1201. Gounder MM, Zhu G, Roshal L, et al. Immunologic correlates of the abscopal effect in a SMARCB1/INI1-negative poorly differentiated chordoma after EZH2 inhibition and radiotherapy. Clin Cancer Res. 2019 Apr 1;25(7):2064-71. PMID:30642912 1202. Graadt van Roggen JF, McMenamin ME, Belchis DA, et al. Reticular perineurioma: a distinctive variant of soft tissue perineurioma. Am J Surg Pathol. 2001 Apr;25(4):485-93. PMID:11257623 1203. Graadt van Roggen JF, Mooi WJ, Hogendoorn PC. Clear cell sarcoma of tendons and aponeuroses (malignant melanoma of soft parts) and cutaneous melanoma: exploring the histogenetic relationship between these two clinicopathological entities. J Pathol. 1998 Sep;186(1):3-7.PMID:9875133 1204. Graham R, Krishnamurthy S, Oliveira A, et al. Frequent expression of fibroblast growth factor-23 (FGF23) mRNAin aneurysmal bone cysts and chondromyxoid fibromas. J Clin Pathol. 2012 Oct;65(10):907-9. PMID:22933546 1205. 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 Nov;35(11):1615-25. PMID:21997683 1206. Graham 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 Nov;37(11 ):1751-5. PMID:23887158 1207. Granter SR, Badizadegan K, Fletcher CD. Myofibromatosis in adults, glomangiopericytoma, and myopericytoma: a spectrum of tumors showing perivascular myoid differentiation. Am J Surg Pathol. 1998 May;22(5):513-25. PMID:9591720

1208. Granter SR, Nucci MR, Fletcher CD. Aggressive angiomyxoma: 「e即 praisal of its relationship to angiomyofibroblastoma in a series of 16 cases. Histopathology. 1997 Jan;30⑴:3-10. PMID:9023551 1209. Granter SR, Weilbaecher KN, Quigley C, etal.Clearcell sarcoma shows immunoreactivity for microphthalmia transcription factor: further evidence for melanocytic differentiation. Mod Pathol. 2001 Jan;14(1):6-9. PMID:11211309 1210. Grass B, Wachtel M, Behnke S, et al. Immunohistochemical detection of EGFR, fibrillin-2, P-cadherin and AP2beta as biomarkers for rhabdomyosarcoma diag nosties. Histopathology. 2009 Jun;54(7):873-9. PMID:19469909 1211. Gray MJ, Kannu P, Sharma S, et al. Mutations preventing regulated exon skipping in MET cause osteofibrous dysplasia. Am J Hum Genet. 2015 Dec 3;97⑹:837-47. PMID:26637977 1212. Greditzer HG 3rd, McLeod RA, Unni KK, et al. Bone sarcomas in Paget disease. Radiology. 1983 Feb;146 ⑵:327-33. PMID:6571760 1213. Green NM, Pagkalos J, Jeys LM, et al. Humeral simple bone cysts: observational versus interventi onal management. J Pediatr Orthop. 2019 Jul;39 ⑹:e472-7. PMID:30702640 1214. Green WM, Yonescu R, Morsberger L, et al. Utilization of a TFE3 break-apart FISH assay in a renal tumor consultation service. Am J Surg Pathol. 2013 Aug;37(8):1150-63. PMID:23715164 1215. Greene AK, Karnes J, Padua HM, et al. Diffuse lipofibromatosis of the lower extremity masquerading as a vascular anomaly. Ann Plast Surg. 2009 Jun;62⑹:703—6. PMID:19461290 1216. Greene AK, Liu AS, Mulliken JB, et al. Vascular anomalies in 5,621 patients: guidelines for referral. J Pediatr Surg. 2011 Sep;46(9):1784-9. PMID:21929990 1217. Greiss ME, Williams DH. Macrodystrophia lipomatosis in the foot. A case report and review of the literature. Arch Orthop Trauma Surg. 1991;110(4):220-1.PMID:1892721 1218. Griewank KG, Schilling B, Murali R, et al. TERT promoter mutations are frequent in atypical fibroxanthomas and pleomorphic dermal sarcomas. Mod Pathol. 2014 Apr;27⑷:502-8. PMID:24030750 1219. Griewank KG, Wiesner T, Murali R, et al. Atypical fibroxanthoma and pleomorphic dermal sarcoma harbor frequent NOTCH1/2 and FAT1 mutations and similar DNA copy number alteration profiles. Mod Pathol. 2018 Mar;31 (3):418-2& PMID:29099504 1220. 6「iffin CA, Hawkins AL, Dvorak C, et al. Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Cancer Res. 1999 Jun 15;59(12):2776-80. PMID:10383129 1221. Grimer R, Athanasou N, Gerrand C, et al. UK guidelines for the management of bone sarcomas. Sarcoma. 2010;2010:317462. PMID:21253474 1222. Grimer RJ, Bielack S, Flege S, et al. Periosteal osteosarcoma-a European review of outcome. Eur J Cancer. 2005 Dec;41 (18):280611. PMID:16290134 1223. Grimer RJ, Briggs TW. Earlier diagnosis of bone and soft-tissue tumours. J Bone Joint Surg Br. 2010 Nov;92(11):1489-92. PMID:21037340 1224. Grimer RJ, GoshegerG, TaminiauA, etal. Dedifferentiated chondrosarcoma: prognostic factors and outcome from a European group. Eur J Cance匚 2007 Sep;43(14):2060-5. PMID:17720491 1225. Gronchi A, Casali PG, Mariani L, et al. Status of surgical margins and prognosis in adult soft tissue sarcomas of the extremities: a

series of patients treated at a single institute J Clin Oncol. 2005 Jan 1;23⑴加器 PMID:15625364 1226. Gronchi A, Collini P, Miceli R, et a| Myogenic differentiation and histoloqic grading are major prognostic determinants in retroperitoneal liposarcoma. Am J Surq pathni 2015 Mar;39(3):383-93. PMID:25581729 1227. Gronchi A, Ferrari S, Quagliuolo V et al Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patie罷 with high-risk soft-tissue sarcomas (ISGSTS 1001): an international, open-label' randomised, controlled, phase 3, multicentre trial. Lancet Oncol. 2017 Jun;18(6) *812 22 PMID:28499583 1228. Gronchi A, Frustaci S, Mercuri M, et al Short, full-dose adjuvant chemotherapy in highrisk adult soft tissue sarcomas: a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. J Clin Oncol 2012 Mar 10;30(8):850-6. PMID:22312103 ' 1229. Gronchi 代 Lo Vullo S, Colombo C, et al. Extremity soft tissue sarcoma in a series of patients treated at a single institution: local control directly impacts survival. Ann Surg. 2010 Mar;251 (3):506-11, PMID:20130465 1230. Gronchi A, Lo Vullo S, Fiore M, et al. Aggressive surgical policies in a retrospectively reviewed single-institution case series of retroperitoneal soft tissue sarcoma patients. J Clin Oncol. 2009 Jan 1;27(1):24-30 PMID:19047283 1231. Gronchi A, Miceli R, Allard MA, et al. Personalizing the approach to retroperitoneal soft tissue sarcoma: histology-specific patterns of failure and postrelapse outcome after primary extended resection. Ann Surg Oncol. 2015 May;22(5):1447-54. PMID:25300609 1232. Gronchi A, Miceli R, Shurell E, et al. Outcome prediction in primary resected retroperitoneal soft tissue sarcoma: histology­ specific overall survival and disease-free survival nomograms built on major sarcoma center data sets. J Clin Oncol. 2013 May 1;31(13):1649-55. PMID:23530096 1233. Gronchi A, Strauss DC, Miceli R, et al. Variability in patterns of recurre nee after resection of primary retroperitoneal sarcoma (RPS): a report on 1007 patients from the Multi-institutional Collaborative RPS Working Group. Ann Surg. 2016 May;263(5): 1002-9. PMID:26727100 1234. Gronchi A, Verderio P, De Paoli A, et al. Quality of surgery and neoadjuvant combined therapy in the ISG-GEIS trial on soft tissue sarcomas of limbs and trunk wall. Ann Oncol. 2013 Mar;24(3):817-23. PMID:23110811 1235. Groom KR, Murphey MD, Howard LM, et al. Mesenchymal hamartoma of the chest wall: radiologic manifestations with emphasis on cross-sectional imaging and histopathologic comparison. Radiology. 2002 Jan;222(1 ):20511.PMID:11756727 1236. Grosso F, Jones RL, Demetri GD, et al. Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. Lancet Oncol. 2007 Jul;8(7):595-602. PMID:17586092 1237. Gruber LM, Erickson D, BabovicVuksanovic D, et al. Pheochromocytoma and paraganglioma in patients with neurofibromatosis type 1. Clin Endocrinol (Oxf). 2017 Jan;86(1):141-9. PMID:27460956 1238. Grunewald TGP, Cidre-Aranaz F, Surdez D, et al. Ewing sarcoma. Nat Rev Dis Primers. 2018 Jul 5;4(1):5. PMID:29977059 1239. Gryder BE, Yohe ME, Chou HC, et al. PAX3-FOXO1 establishes myogenic super enhancers and confers BET bromodomain vulnerability. Cancer Discov. 201 Aug;7(8):884-99. PMID:28446439

paybal：https://www.paypal.me/andy19801210 1240. Guccion JG, Font RL, EnzingerFM, et al. Extraskeletal mesenchymal chondrosarcoma. Arch Pathol. 1973 May;95(5):336-40. PMID:4694076 1241. Gui H, Lhospital E, Staddon AP, et al. Combined sclerosing and spindle cell rhabdomyosarcoma in previous craniotomy site: a case report and a review of the literature. !nt J Surg Pathol. 2019 May;27(3):328-35. PMID:30270691 1242. Guilhamo n P, Eskandarpour M, Halai D, et al. Meta-analysis of IDH-mutant cancers identifies EBF1 as an interaction partner for TET2. Nat Commun. 2013;4:2166. PMID:23863747 ：243. Guillou L, Aurias A. Soft tissue sarcomas with complex genomic profiles. Virchows Arch. 2010 Feb;456(2):201-仃.PMID:202仃954 1244. Guillou L, Benhattar J, Bonichon F, et al. Histologic grade, but not SYT-SSX fusion type, is an important prognostic factor in patients with synovial sarcoma: a multicenter, retrospective analysis. J Clin Oncol. 2004 Oct 15;22(20):4040-50. PMID:15364967 1245. Guillou L, Benhattar J, Gengler C, et al. Translocation-positive low-grade fibromyxoid sarcoma: clinicopathologic and molecular analysis of a series expanding the morphologic spectrum and suggesting potential relationship to sclerosing epithelioid fibrosarcoma: a study from the French Sarcoma Group. Am J Surg Pathol. 2007 Sep;31(9):1387-402. PMID:17721195 (246. Guillou L, Coindre JM, Bonichon F, et al. Comparative study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol. 1997 Jan;15(1):350-62. PMID:8996162 1247. Guillou L, Gebhard S, Coindre JM. Lipomatous hema ngiope「icytoma: a fat­ containing variant of solitary fibrous tumor? Clinicopathologic, immunohistochemical, and ultrastructural analysis of a series in favor of a unifying concept. Hum Pathol. 2000 Sep;31(9):1108-15. PMID:11014579 1248. Guillou L, Gebhard S, Coindre JM. Orbital and extraorbital giant cell angiofibroma: a giant cell-rich variant of solitary fibrous tumor? Clinicopathologic and immunohistochemical analysis of a series in favor of a unifying concept. Am J Surg Pathol. 2000 Jul;240):9719. PMID:10895819 1249. Guillou L, Wadden C, Coindre JM, et al. Troximal-type" epithelioid sarcoma, a distinctive aggressive neoplasm showing ■ habdoid features. Clinicopathologic, immunohistochemical, and ultrastructural study of a series. Am J Surg Pathol. 1997 Feb;21 (2): 130-46. PMID:9042279 250. Gulia A, Puri A, Pruthi M, et al. Oncological and functional outcome of periosteal osteosarcoma. Indian J Orthop. 2014 May;48(3):279-84. PMID:24932034 1251. Gurniis A, Yildirim SV, Kizilkilig O, et al. Case report: seizures in a child caused by a large venous angioma. J Child Neurol. 2007 Jun;22(6):787-9. PMID:17641273 1252. Gundle KR, Kafchinski L, Gupta S, et al. Analysis of margin classification systems for assessing the risk of local recurrence after soft tissue sarcoma resection. J Clin Oncol. 2018 Mar 1;36(7):704-9. PMID:29346043 1253. Gune§ N, Ye§il G, Beng K, et al. Longitudinal follow-up of two patients with dysspondyloenchondromatosis due to novel heterozygous mutations in COL2A1. Mol Syndromol. 2018 May;9(3): 134-40. PMID:29928178 1254. Guo R, Wang X, Chou MM, et al. PPP6R3-USP6 amplification: novel

oncogenic mechanism in malignant nodular fasciitis. Genes Chromosomes Cancer. 2016 Aug;55⑹:640-9. PMID:27113271 1255. Guo T, Zhang L, Chang NE, et al. Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions. Genes Chromosomes Cancer. 2011 Jan;50(1):25-33. PMID:20949568 1256. Guo X, Forgo E, van de Rijn M. Molecular subtyping of leiomyosarcoma with 3' end RNA sequencing. Genom Data. 2015 Sep 1;5:3667. PMID:26240788 1257. Guo X, Jo VY, Mills AM, et al. Clinically relevant molecular subtypes in leiomyosarcoma. Clin Cancer Res. 2015 Aug 1;21(15):3501-11. PMID:25896974 1258. Gupta G, Garg R, Wadhwa C, et al. A rare primary dumbbell lipoblastoma. Asian J Neurosurg. 2018 Jan-Mar;13(1):83-5. PMID:29492129 1259. GurbuzAK, Giardiello FM, Petersen GM, et al. Desmoid tumours in familial adenomatous polyposis. Gut. 1994 Mar;35 ⑶:377-81. PMID:8150351 1260. Gurney JG, Davis S, Severson RK, et al. Trends in cancer incidence among children in the U.S. Cancer. 1996 Aug 1;78(3):532-41. PMID:8697401 1261. Guseva NV, Jaber O, Tanas MR, et al. Anchored multiplex PCR for targeted nextgeneration sequencing reveals recurrent and novel USP6 fusions and upregulation of USP6 expression in aneurysmal bone cyst. Genes Chromosomes Cancer. 2017Apr;56(4):266-77. PMID:27910166 1262. Gustafson P. Soft tissue sarcoma. Epidemiology and prognosis in 508 patients. Acta Orthop Scand S叩pl. 1994 Jun;259:1-31. PMID:8042499 1263. Gutmann DH, Ferner RE, Listernick RH, et al. Neurofibromatosis type 1. Nat Rev Dis Primers. 2017 Feb 23;3:17004. PMID:28230061 1264. Guyot-Goubin A, Donadieu J, Barkaoui M, et al. Descriptive epidemiology of childhood Langerhans cell histiocytosis in France, 20002004. Pediatr Blood Cancer. 2008 Jul;51(1):715. PMID:18260117 1265. Hachisuga T, Hashimoto H, Enjoji M. Angioleiomyoma. A clinicopathologic reappraisal of 562 cases. Cancer. 1984 Jul 1;54(1):126-30. PMID:6722737 1266. Hachitanda Y, Toyoshima 8, Akazawa K, et al. N-myc gene amplification in rhabdomyosarcoma detected by fluorescence in situ hybridization: its correlation with histologic features. Mod Pathol. 1998 Dec;11(12):1222-7. PMID:9872655 1267. Hachitanda Y, Tsuneyoshi M, Daimaru Y, et al. Extraskeletal myxoid chondrosarcoma in young children. Cancer. 1988 Jun 15;61(12):2521-6. PMID:2835146 1268. Hacker U, Nybakken K, Perrimon N. Heparan sulphate proteoglycans: the sweet side of development. Nat Rev Mol Cell Biol. 2005 Jul；6(7):530-41. PMID:16072037 1269. Hadj-Hamou N8, Ugolin N, Ory C, et al. A transcriptome signature distinguished sporadic from postradiotherapy radiationinduced sarcomas. Carcinogenesis. 2011 Jun;32⑹:929-34. PMID:21470956 1270. Hahn HP, Fletcher CD. Primary mediastinal liposarcoma: clinicopathologic analysis of 24 cases. Am J Surg Pathol. 2007 Dec;31(12):1868-74. PMID:18043041 1271. Hahn PF, Rosenthal DI, Ehrlich MG. Case report 286: gas within a solitary bone cyst of the proximal end of the left humerus. Skeletal Radiol. 1984;12(3):214-7. PMID:6494941 1272. Haibach H, Farrell C, Dittrich FJ. Neoplasms arising in Pagefs disease of bone:

a study of 82 cases. Am J Clin Pathol. 1985 May;83(5):594-600. PMID:3857854 1273. Haimes JD, Stewart CJR, Kudlow BA, et al. Uterine inflammatory myofibroblastic tumors frequently harbor ALK fusions with IGFBP5 and THBS1. Am J Surg Pathol. 2017 Jun;41 (6):773-80. PMID:28490045 1274. Hajdu M, Singer S, Maki RG, et al. IGF2 over-expression in solitary fibrous tumours is independent of anatomical location and is related to loss of imprinting. J Pathol. 2010 Jul;221 (3):300-7. PMID:20527023 1275. Haller F, Knopf J, Ackermann A, et al. Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a prominent myopericytic/ haemangiopericytic pattern. J Pathol. 2016 Apr;238(5):700-10. PMID:26863915 1276. Hallin M, Schneider N, Thway K. Welldifferentiated liposarcoma with hibernomalike morphology. Int J Surg Pathol. 2016 Oct;24(7):620-2. PMID:27272683 1277. Hallor KH, Heidenblad M, Brosjo O, et al. Tiling resolution array comparative genomic hybridization analysis of a fibrosarcoma of bone. Cancer Genet Cytogenet. 2007 Jan 1;172(1):80-3. PMID:17175386 1278. Hallor KH, Mertens F, Jin Y, et al. Fusion of the EWSR1 and ATF1 genes without expression of the MITF-M transcript in angiomatoid fibrous histiocytoma. Genes Chromosomes Cancer. 2005 Sep;44(1):97102. PMID:15884099 1279. Hallor KH, Sciot R, Staaf J, et al. Two genetic pathways, t(1;10) and amplification of 3p11-12, in myxoinflammatory fibroblastic sarcoma, haemosiderotic fibrolipomatous tumour, and morphologically similar lesions. J Pathol. 2009 Apr;217(5)716-27. PMID:19199331 1280. Hallor KH, Staaf J, Bovee JV, et al. Genomic profiling of chondrosarcoma: chromosomal patterns in central and peripheral tumors. Clin Cancer Res. 2009 Apr 15;15(8):2685-94. PMID:19336518 1281. Hamblen DL, Carter RL. Sarcoma and joint replacement. J Bone Joint Surg Br. 1984 Nov;66⑸:625-7. PMID:6094586 、 1282. Hameed M, Mandelker D. Tumor syndromes predisposing to osteosarcoma. Adv Anat Pathol. 2018 Jul;25(4):217-22. PMID:29668499 1283. Hameetman L, Bovee JV, Taminiau AH, et al. Multiple osteochondromas: clinicopathological and genetic spectrum and suggestions for clinical management. Hered Cancer Clin Pract. 2004 Nov 15;2(4):161-73. PMID:20233460 1284. Hameetman L, Rozeman LB, Lombaerts M, et al. Peripheral chondrosarcoma progression is accompanied by decreased Indian Hedgehog signalling. J Pathol. 2006 Aug;209(4):501-11. PMID:16755518 1285. Hameetman L, Szuhai K, Yavas A, et al. The role of EXT1 in nonhereditary osteochondroma: identification of homozygous deletions. J Natl Cancer Inst. 2007 Mar 7;99⑸:396-406. PMID:17341731 1286. Han HJ, Lim GY, You CY. A large infiltrating fibrous hamartoma of infancy in the abdominal wall with rare associated tuberous sclerosis. Pediatr Radiol. 2009 Jul;39(7):743-6. PMID:19319513 1287. Han J, Murthy R, Wood B, et al. ER stress signalling through elF2a and CHOP, but not IRE1a, attenuates adipogenesis in mice. Diabetologia. 2013 Apr;56(4):911-24. PMID:23314846 1288. Han JW, Kim H, Youn JK, et al. Analysis of clinical features of lipoblastoma in children. Pediatr Hematol Oncol. 2017 May;34(4):21220. PMID:29035641

1289. Han 乙 Liu Y, Hao X, et al. Large intraosseous lipoma of the skull: a case report and review of the literature. World Neurosurg. 2018 Dec;120:525-9. PMID:30268544 1290. Hancock BJ, St-Vil D, Luks Fl, et al. Complications of lymphangiomas in children. J Pediatr Surg. 1992 Feb;27⑵:220-4, discussion 224-6. PMID:1564622 1291. Handa U, Bal A, Mohan H, et al. Fine needle aspiration cytology in the diagnosis of bone lesions. Cytopathology. 2005 Apr; 16(2):59-64. PMID:15787646 ' 1292. Hang JF, Chen PC. Parosteal osteosarcoma. Arch Pathol Lab Med. 2014 May;138(5):694-9. PMID:24786129 1293. Haniball J, Sumathi VP, Kindblom LG, et al. Prognostic factors and metastatic patterns in primary myxoid/round-cell liposarcoma. Sarcoma. 2011;2011:538085. PMID:22190864 1294. Hanna SA, Tirabosco R, Amin A, et al. Dedifferentiated chordoma: a report of four cases arising 'de novo'. J Bone Joint Surg Br. 2008 May;90(5):652-6. PMID:18450635 1295. Hanrahan CJ, Shah LM. MRI of spinal bone marrow: part 2, T1-weighted imaging-based differential diagnosis. AJR Am J Roentgenol. 2011 Dec;197(6):1309-21. PMID:22109284 1296. Hansen MF, Seton M, Merchant A. Osteosarcoma in Paget's disease of bone. J Bone Miner Res. 2006 Dec;21 S叩pl 2:58-63. PMID:17229010 1297. Happle R. The McCune-Albright syndrome: a lethal gene surviving by mosaicism. Clin Genet. 1986 Apr;29(4):321-4. PMID:3720010 1298. Happle R, Konig A. Type 2 segmental manifestation of multiple glomus tumors: a review and reclassification of 5 case reports. Dermatology. 1999;198(3):270-2. PMID:10393451 1299. Harati K, Lange K, Goertz O, et al. A single-institutional review of 68 patients with dermatofibrosarcoma protuberans: wide re-excision after inadequate previous surgery results in a high rate of local control. World J Surg Oncol. 2017 Jan 5;15(1):5. PMID:28056985 1300. Hardcastle P, Nade S, Arnold W. Hereditary bone dysplasia with malignant change. Report of three families. J Bone Joint Surg Am. 1986 Sep;68(7):1079-89. PMID:3745248 1301. Hardell L, Eriksson M. The association between soft tissue sarcomas and exposure to phenoxyacetic acids. A new case-referent study. Cancer. 1988 Aug 1;62⑶:652-6. PMID:3390800 1302. Harder A, Wesemann M, Hagel C, et al. Hybrid neurofibroma/schwannoma is overrepresented among schwannomatosis and neurofibromatosis patients. Am J Surg Pathol. 2012 May;36(5):702-9. PMID:22446939 1303. Harms D. Alveolar rhabdomyosarcoma: a prognostically unfavorable 市abdomyosarcoma type and its necessary distinction from embryonal rhabdomyosarcoma. Curr Tbp Pathol. 1995;89:273-96. PMID:7882714 1304. Haroche J, Charlotte F, Arnaud L, et al. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non­ Langerhans cell histiocytoses. Blood. 2012 Sep 27;120(13):2700-3. PMID:22879539 1305. Harris M, Coyne J, Tariq M, et al. Extraskeletal myxoid chondrosarcoma with neuroendocrine differentiation: a pathologic, cytogenetic, and molecular study of a case with a novel translocation t(9;17)(q22;q11.2). Am J Surg Pathol. 2000 Jul;24(7):1020-6. PMID:10895826 1306. Harris WH, Dudley HR Jr, Barry RJ. The natural history of fibrous dysplasia.

Ref ere nces

563

paybal：https://www.paypal.me/andy19801210 An orthopaedic, pathological, and roentgenographic study. J Bone Joint Surg Am. 1962 Mar;44-A:207-33. PMID:14036060 1307. Hart ES, Kelly MH, Brillante B, et al. Onset, progression, and plateau of skeletal lesions in fibrous dysplasia and the relationship to functional outcome. J Bone Miner Res. 2007 Sep;22(9):1468-74. PMID:17501668 1308. Hart J, Gardner JM, Edgar M, et al. Epithelioid schwan nomas: an analysis of 58 cases including atypical variants. Am J Surg Pathol. 2016 May;40(5):704-13. PMID:26752543 1309. Harvell JD. Multiple spindle cell lipomas and dermatofibrosarcoma protuberans within a single patient: evidence for a common neoplastic process of interstitial dendritic cells? J Am Acad Dermatol. 2003 Jan;48(1):82-5. PMID:12522375 1310. Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer. 2013 Apr;13(4):246-57. PMID:23467301 1311. Hasegawa T, Hirose T, Kudo E, et al. Immunophenotypic heterogeneity in osteosarcomas. Hum Pathol. 1991 Jun;22(6):583-90. PMID:1864588 1312. Hasegawa T, Matsuno Y, Shimoda T, et al. Extrathoracic solitary fibrous tumors: their histological variability and potentially aggressive behavior. Hum Pathol. 1999 Dec;30(12):1464-73. PMID:10667425 1313. Hasegawa T, Matsuno Y, Shimoda T, et al. Proximal-type epithelioid sarcoma: a clinicopathologic study of 20 cases. Mod Pathol. 2001 Jul;14(7):655-63. PMID:11454997 1314. Hasegawa T, Seki K, Ono K, et al. Angiomatoid (malignant) fibrous histiocytoma: a peculiar low-grade tumor showing immunophenotypic heterogeneity and ultrastructural variations. Pathol I nt. 2000 Sep;50(9):731-8.PMID:11012987 1315. Hasegawa T, Yamamoto S, Yokoyama R, et al. Prognostic significance of grading and staging systems using MIB-1 score in adult patients with soft tissue sarcoma of the extremities and trunk. Cancer. 2002 Aug 15;95(4):843-51. PMID:12209729 1316. Hashimoto H, Daimaru Y, Tsuneyoshi M, et al. Leiomyosarcoma of the external soft tissues. A clinicopathologic, immunohistochemical, and electron microscopic study. Cancer. 1986 May 15;57(10):2077-88. PMID:3513942 13 仃.Hashimoto H, Tsuneyoshi M, Daimaru Y, et al. Intramuscular myxoma. A clinicopathologic, immunohistochemical, and electron microscopic study. Cancer. 1986 Aug 1;58⑶:740-7. PMID:3524794 1318. Hasselblatt M, Thomas C, Hovestadt V, et al. Poorly differentiated chordoma with SMARCB1/INI1 loss: a distinct molecular entity with dismal prognosis. Acta Neuropathol. 2016 Jul;132(1):149-51. PMID:27067307 1319. Hattinger CM, Tarkkanen M, Benini S, et al. Genetic analysis of fibrosarcoma of bone, a rare tumour entity closely related to osteosarcoma and malignant fibrous histiocytoma of bone. Eur J Cell Biol. 2004 Sep;83(9):483-91. PMID:15540465 1320. Hauben E, van den Broek LC, Van Marek E, et al. Adamantinoma-like Ewing's sarcoma and Ewing's-like adamantinoma. The t(11; 22), t(21; 22) status. J Pathol. 2001 Sep;195(2):218-21. PMID:11592101 1321. Hauben El, Jundt G, Cleton-Jansen AM, et al. Desmoplastic fibroma of bone: an immunohistochemical study including beta-catenin expressio n and mutational analysis for beta-catenin. Hum Pathol. 2005 Sep;36(9):1025-30. PMID:16153468 1322. Hauben El, Weeden S, Pringle J, et al. Does the histological subtype of high-grade

564

Refere nces

central osteosarcoma influence the response to treatment with chemotherapy and does it affect overall survival? A study on 570 patients of two consecutive trials of the European Osteosarcoma Intergroup. Eur J Can cer. 2002 Jun;38(9):1218-25. PMID:12044509 1323. Havik AL, Bruland O, Myrseth E, et al. Genetic landscape of sporadic vestibular schwannoma. J Neurosurg. 2018 Mar; 128(3):911-22. PMID:28409725 1324. Hawkins DS, Chi YY, Anderson JR, et al. Addition of vincristine and irinotecan to vincristine, dactinomycin, and cyclophosphamide does not improve outcome for intermediate-risk rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2018 Sep 20;36(27):2770-7. PMID:30091945 1325. Hawkins DS, Gupta AA, Rudzinski ER. What is new in the biology and treatment of pediatric rhabdomyosarcoma? Curr Opin Pediatr. 2014 Feb;26(1):50-6. PMID:24326270 1326. Hawley IC, Krausz T, Evans DJ, et al. Spindle cell lipoma-a pseudoangiomatous variant. Histopathology. 1994 Jun;24(6):565-9. PMID:8063285 1327. Hayashi K, Tasaka T, Kondo T, et al. Successful cord blood transplantation in a Werner syndrome patient with high-risk myelodysplastic syndrome. Intern Med. 2019 Jan1;58(1):109-13. PMID:30146558 1328. Haynes AB, Pollock RE. Lumping, splitting, and making sense: implications of soft tissue sarcoma staging for prognosis, therapy, and research. Ann Surg Oncol. 2013 Oct;20(11):3355-6. PMID:23780383 1329. Hays DM, Newton W Jr, Soule EH, et al. Mortality among children with rhabdomyosarcomas of the alveolar histologic subtype. J Pediatr Surg. 1983 Aug;18(4):412-7. PMID:6620082 1330. Hazelbag HM, Fleuren GJ, Cornelisse CJ, et al. DNA aberrations in the epithelial cell component of adamantinoma of long bones. Am J Pathol. 1995 Dec; 147(6):1770-9. PMID:7495301 1331. Hazelbag HM, Fleuren GJ, vd Broek LJ, et al. Adamantinoma of the long bones: keratin subclass immunoreactivity pattern with reference to its histogenesis. Am J Surg Pathol. 1993 Dec;17(12):1225-33. PMID:7694513 1332. Hazelbag HM, Laforga JB, Roels HJ, et al. Dedifferentiated adamantinoma with revertant mesenchymal phenotype. Am J Surg Pathol. 2003 Dec;27(12):1530-7. PMID:14657712 1333. Hazelbag HM, Taminiau AH, Fleuren GJ, et al. Adamantinoma of the long bones. A clinicopathological study of thirty-two patients with emphasis on his⑹ ogical subtype, precursor lesion, and biological behavior. J Bone Joint Surg Am. 1994 Oct;76(10):1482-99. PMID:7929496 1334. Hazelbag HM, Wessels JW, Mollevangers P, et al. Cytogenetic analysis of adamantinoma of long bones: further indications for a common histogenesis with osteofibrous dysplasia. Cancer Genet Cytogenet. 1997 Aug;97(1):511.PMID:9242211 1335. He X, Pang Z, Zhang X, etal. Consistent amplification of FRS2 and MDM2 in low-grade osteosarcoma: a genetic study of 22 cases with clinicopathologic analysis. Am J Surg Pathol. 2018 Sep;42(9):1143-55. PMID:30001240 1336. Healey JH, Ghelman B. Osteoid osteoma and osteoblastoma. Current concepts and recent advances. Clin Orthop Relat Res. 1986 Mar;(204):76-85. PMID:3956019 1337. Hebert-Blouin MN, Scheithauer BW, Amrami KK, et al. Fibromatosis: a potential sequela of neuromuscular choristoma. J Neurosurg. 2012 Feb;116 ⑵:399-408. PMID:21819193

1338. Hechtman JF, Benayed R, Hyman DM, et al. Pan-Trk immunohistochemistry is an efficient and reliable screen for the detection of NTRK fusions. Am J Surg Pathol. 2017 Nov;41(11):1547-51. PMID:28719467 1339. Hedayati V, Thway K, Thomas JM, et al. MEN1 syndrome and hibernoma: an uncommonly recognised association? Case Rep Med. 2014;2014:804580. PMID:25309600 1340. Heenan PJ, Quirk CJ, Papadimitriou JM. Epithelioid sarcoma. A diagnostic problem. Am J Dermatopathol. 1986 Apr;8(2):95-104. PMID:3717528 1341. Heidenblad M, Hallor KH, Staaf J, et al. Genomic profiling of bone and soft tissue tumors with supernumerary「ing chromosomes using tiling resolution bacterial artificial chromosome microarrays. On cogene. 2006 Nov 9;25(53):7106-16. PMID:16732325 1342. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003 Jan 31;299(5607):708-10. PMID:12522257 1343. Heitzer E, Sunitsch S, Gilg MM, et al. Expanded molecular profiling of myxofibrosarcoma reveals potentially actionable targets. Mod Pathol. 2017 Dec;30(12):1698-709. PMID:28776571 1344. Helias-Rodzewicz Z, Perot G, Chibon F, etal. YAP1 and VGLL3, encoding two cofactors of TEAD transcription factors, are amplified and overexpressed in a subset of soft tissue sarcomas. Genes Chromosomes Cancer. 2010 Dec;49(12):1161-71. PMID:20842732 1345. Hellemans J, Preobrazhenska O, Willaert A, et al. Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nat Genet. 2004 Nov;36(11):1213-8. PMID:15489854 1346. Hemsrichart V, Charoenkwan P. Fatal bilateral con genital mese nchymal hamartoma of the chest wall. J Med Assoc Thai. 2007 Nov;90(11):2519-23. PMID:18181344 1347. Henderson ER, Paia E, Angelini A, et al. Dedifferentiated peripheral chondrosarcoma: a review of radiologic characteristics. Sarcoma. 2013;2013:505321. PMID:23589702 1348. Henderson H, Peng YJ, Salter DM. Anticalponin 1 antibodies highlight intracytoplasmic inclusions of infantile digital fibromatosis. Histopathology. 2014 Apr;64(5):752-5. PMID:24117680 1349. Henricks WH, Chu YC, Goldblum JR, et al. Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation. Am J Surg Pathol. 1997 Mar;21 (3):271-81. PMID:9060596 1350. Herbst KL. Rare adipose disorders (RADs) masquerading as obesity. Acta Pharmacol Sin. 2012 Feb;33(2):155-72. PMID:22301856 1351. Heritier S, Emile JF, Barkaoui MA, et al. BRAF mutation correlates with high-risk Langerhans cell histiocytosis and increased resistance to first-line therapy. J Clin Oncol. 2016 Sep 1;34(25):3023-30. PMID:27382093 1352. Hernandez JL, Rodriguez-Parets JO, Valero JM, et al. High-resolution genome­ wide analysis of chromosomal alterations in elastofibroma. Virchows Arch. 2010 Jun;456(6):681-7. PMID:20422214 1353. Herrera-Goepfert R. Postradiati on synovial sarcoma of the comm on bile duct: a previously unreported anatomic site. Int J Surg Pathol. 2018 Aug;26(5):469-74. PMID:29336183 1354. Hervier B, Haroche J, Arnaud L, et al. Association of both Langerhans cell histiocytosis and Erdheim-Chester disease linked to the BRAFV600E mutation. Blood. 2014 Aug 14;124(7):1119-26. PMID:24894769

1355. Heslin MJ, Lewis JJ, Woodruff JM et al Core needle biopsy for diagnosis of extremity soft tissue sarcoma. Ann Surg Oncol 1997 j.[ Aug;4(5):425-31. PMID:9259971 1356. Hettmer S, Archer NM, Somers GR et al. Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers. Cancer 2014 Anr 1;120(7):1068-75. PMID:24382691 P 1357. Hettmer S, Teot LA, van Hummelen P, et al. Mutations in Hedgehog pathway genes in fetal rhabdomyomas. J Pathol 2013 Sep;231 (1):44-52. PMID:23780909 ' 1358. Hewitt KM, Ellis G, Wiggins R, et al Parosteal osteosarcoma: case report and review of the literature. Head Neck 2008 Jan;30(1 ):122-6. PMID:17615569 1359. Heymann S, Delaloge S, Rahal A, et al. Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li-Fraumeni syndrome. Radiat Oncol 2010 Nov 8;5:104. PMID:21059199 1360. Heyning FH, Hogendoom PC, Kramer MH, et al. Primary lymphoma of bone: extranodal lymphoma with favourable survival independent of germinal centre, post-germinal centre or indeterminate phenotype. J ciin Pathol. 2009 Sep;62(9):820-4. PMIDH9734480 1361. Heyning FH, Hogendoom PC, Kramer MH, et al. Primary non-Hodgkin's lymphoma of bone: a clinicopathological investigation of 60 cases. Leukemia. 1999 Dec;13(12):2094-8 PMID:10602434 1362. Hibbard MK, Kozakewich HP, Dal Cin P, et al. PLAG1 fusion oncogenes in lipoblastoma. Cancer Res. 2000 S即 1;60(17):4869-72 PMID:10987300 1363. Hibbitts E, Chi YY, Hawkins DS, et al. Refinement of risk stratification for childhood rhabdomyosarcoma using FOXO1 fusion status in addition to established clinical outcome predictors: a report from the Children's Oncology Group. Cancer Med. 2019 Oct;8(14):6437-48. PMID:31456361 1364. Hicks MJ, Roth JR, Kozinetz CA, et al. Clinicopathologic features of osteosarcoma in patients with Rothmund-Thomson syndrome. J Clin Oncol. 2007 Feb 1;25(4):370-5. PMID:17264332 1365. Higham CS, Dombi E, Rogiers A, et al. The characteristics of 76 atypical neurofibromas as precursors to neurofibromatosis 1 associated malignant peripheral nerve sheath tumors. Neuro Oncol. 2018 May 18;20⑹:81825. PMID:29409029 1366. Hilal L, Barada K, Mukherji D, et al. Gastrointestinal (Gl) leiomyosarcoma (LMS) case series and review on diagnosis, management, and prognosis. Med Oncol. 2016 Feb;33⑵:20. PMID:26786155 1367. Hill DA, Pfeifer JD, Marley EF, etal. WT1 staining reliably differentiates desmoplastic small round cell tumor from Ewing sarcoma/ primitive neuroectodermal tumor. An immunohistochemical and molecular diagnostic study. Am J Clin Pathol. 2000 Sep;114(3):34553. PMID:10989634 1368. Hill S, Rademaker M. A collection of rare anomalies: multiple digital glomuvenous malformations, epidermal naevus, temporal alopecia, heterochromia and abdominal lipoblastoma. Clin Exp Dermatol. 2009 Dec;34(8):e862-4. PMID:20055849 1369. Hirai K, Takeuchi S, Bessho R. et al. Venous hemangioma of the anterior mediastinum. J Nippon Med Sch. 2010 Apr;77(2):115-8. PMID:20453425 1370. Hiraki-Hotokebuchi Y, Yamada ， Kohashi K, et al. Alteration of PDGFRp-AktmTOR pathway signaling in fibrosarcomatous transformatio n of dermatofibrosarcoma protuberans. Hum Pathol. 2017 Sep;67:60 • PMID:28711648

paybal：https://www.paypal.me/andy19801210 1371. Hi rata Y, Brems H, Suzuki M, et al. Interaction betwee n a domai n of the negative regulator of the Ras-ERK pathway, SPRED1 protein, and the GTPase-activating proteinrelated domain of neurofibromin is implicated in Legius syndrome and neurofibromatosis type 1. J Biol Chem. 2016 Feb 12;291 ⑺:3124-34. PMID:26635368 1372. Hirose T, Hasegawa T, Seki K, et al. Atypical glomus tumor in the mediastinum: a case report with immunohistochemical and ultrastructural studies. Ultrastruct Pathol. 1996 S即-Oct;20(5):45仁6. PMID:8883329 1373. Hirose T, Scheithauer BW, Sano T. Perineurial malignant peripheral nerve sheath tumor (MPNST): a clinicopathologic, immunohistochemical, and ultrastructural study of seven cases. Am J Surg Pathol. 1998 Nov;22(11 ):1368-78. PMID:9808129 1374. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998 Jan 23;279(5350):577-80. PMID:9438854 1375. Hisada M, Garber JE, Fung CY, et al. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst. 1998 Apr 15;90(8):606-11. PMID:9554443 1376. Hisaoka M, Hashimoto H. Extraskeletal myxoid chondrosarcoma: updated clinicopathological and molecular genetic characteristics. Pathol lnt.2005Aug;55(8):45363. PMID: 15998372 1377. Hisaoka M, Ishida T, Imamura T, et al. TFG is a novel fusion partner of NOR1 in extraskeletal myxoid chondrosarcoma. Genes Chromosomes Cancer. 2004 Aug;40(4):325-8. PMID:15188455 1378. Hisaoka M, Ishida T, Kuo TT, et al. Clear cell sarcoma of soft tissue: a clinicopathologic, immunohistochemical, and molecular analysis of 33 cases. Am J Surg Pathol. 2008 Mar;32(3):452-60. PMID:18300804 1379. Hisaoka M, Okamoto S, Yokoyama K, et al. Coexpression of NOR1 and SIX3 proteins in extraskeletal myxoid chondrosarcomas without detectable NR4A3 fusion genes. Cancer Genet Cytogenet. 2004 Jul 15;152(2):101-7. PMID:15262426 1380. Hisaoka M, Sheng WQ, Tanaka A, et al. HMGIC alterations in smooth muscle tumors of soft tissues and other sites. Cancer Genet Cytogenet. 2002 Oct 1;138(1):50-5. PMID:12419585 1381. Hocar O, Le Cesne A, Berissi S, et al. Clear cell sarcoma (malignant melanoma) of soft parts: a clinicopathologic study of 52 cases. Dermatol Res Pract. 2012;2012:984096. PMID:22693489 1382. Hoch B, Hermann G, Klein MJ, et al. Ossifying chondroid lipoma. Skeletal Radiol. 2008 May;37(5):475-80. PMID:18259746 383. Hoch BL, Garcia RA, Smalberger GJ. Chondroid tenosynovial giant cell tumor: a clinicopathological and immunohistochemical analysis of 5 new cases. Int J Surg Pathol. 2011 Apr;19(2):180-7. PMID:21087985 1384. Hoch BL, Nielsen GP, Liebsch NJ, et al. Base of skull chordomas in children and adolescents: a clinicopathologic study of 73 cases.Am J Surg Pathol. 2006 Jul;30(7):811-8. PMID:16819322 1385. Hoeber I, Spillane AJ, Fisher C, et al. Accuracy of biopsy techniques for limb and limb girdle soft tissue tumors. Ann Surg Oncol. 2001 Jan-Feb;8(1):80-7. PMID:11206230 386. Hoesly PM, Lowe GC, Lohse CM, et al. Prognostic impact of fibrosarcomatous transformatio n in dermatofibrosarcoma protuberans: a cohort study. J Am Acad Dermatol. 2015 Mar;72 ⑶ 4 9-25. PMID:25582537 1387. Hoffman A, Ghadimi MP, Demicco

EG, et al. Localized and metastatic myxoid/ 「ound cell liposarcoma: clinical and molecular observations. Cancer. 2013 May 15;119(10):1868-77. PMID:23401071 1388. Hofvander J, Arbajian E, Stenkula KG, et al. Frequent low-level mutations of protein kinase D2 in angiolipoma. J Pathol. 2017 Apr;241 (5):578-82. PMID:28139834 1389. Hofvander J, Jo VY, Ghanei I, et al. Comprehensive genetic analysis of a paediatric pleomorphic myxoid liposarcoma reveals near-haploidization and loss of the RB1 gene. Histopathology. 2016 Jul;69(1):141-7. PMID:26647907 1390. Hofvander J, Tayebwa J, Nilsson J, et al. Recurrent PRDM10 gene fusions in undifferentiated pleomorphic sarcoma. Clin Cancer Res. 2015 Feb 15;21 (4):864-9. PMID:25516889 1391. Hofvander J, Viklund B, Isaksson A, et al. Different patterns of clonal evolution among different sarcoma subtypes followed for up to 25 years. Nat Commun. 2018 Sep 10;9(1):3662. PMID:30201954 1393. Hogstad B, Berres ML, Chakraborty R, et al. RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions. J Exp Med. 2018 Jan 2;215(1):319-36. PMID:29263218 1394. Hohenberger P, Ronellenfitsch U, Oladeji O, et al. Pattern of recurrence in patients with ruptured primary gastrointestinal stromal tumour. Br J Surg. 2010 Dec;97(12):1854-9. PMID:20730857 1395. Holden CA, Spittle MF, Jones EW. An giosarcoma of the face and scalp, prognosis and treatment. Cancer. 1987 Mar 1 ;59(5):104657. PMID:3815265 1396. Hollmann TJ, Bovee JV, Fletcher CD. Digital fibromyxoma (superficial acral fibromyxoma): a detailed characterization of 124 cases. Am J Surg Pathol. 2012 Jun;36⑹:789-9& PMID:22367301 1396A. Hollmann TJ, Hornick JL. INI1deficient tumors: diagnostic features and molecular genetics. Am J Surg Pathol. 2011 Oct;35(10):e47-63. PMID:21934399 1397. Hollowood K, Holley MP, Fletcher CD. Plexiform fibrohistiocytic tumour: clinicopathological, immunohistochemical and ultrastructural analysis in favour of a myofibroblastic lesion. Histopathology. 1991 Dec;19(6):503-13. PMID:1723956 ' 1398. Holsten T, BensS, Oyen F, et al. Germline variants in SMARCB1 and other members of the BAF chromatin-remodeling complex across human disease entities: a meta-analysis. Eur J Hum Genet. 2018 Aug;26(8):1083-93. PMID:29706634 1399. Holzapfel BM, Geitner U, Diebold J, et al. Synovial hemangioma of the knee joint with cystic invasion of the femur: a case report and review of the literature. Arch Orthop Trauma Surg. 2009 Feb;129(2):143-8. PMID:18758797 1399A. Hoot AC, Russo P, Judkins AR, et al. Immunohistochemical analysis of hSNF5/ INI1 distinguishes renal and extra-renal malignant rhabdoid tumors from other pediatric soft tissue tumors. Am J Surg Pathol. 2004 Nov;28(11):1485-91.PMID:15489652 1400. Hopkins SM, Freitas EL. Bilateral osteochondroma of the ribs in an infant: an unusual cause of cyanosis. J Thorac Cardiovasc Surg. 1965 Feb;49:247-9. PMID:14256326 1401. Hopyan S, Gokgoz N, Poon R, et al. A mutant PTH/PTHrP type I receptor in enchondromatosis. Nat Genet. 2002 Mar;30⑶:306「0. PMID:11850620 1402. Horiuchi K, Yabe H, Mukai M, et al. Multiple smooth muscle tumors arising in deep soft tissue of lower limbs with uterine

leiomyomas. Am J Surg Pathol. 1998 Jul;22⑺:897-901. PMID:9669352 1403. Hornick JL. Subclassification of pleomorphic sarcomas: How and why should we care? Ann Diagn Pathol. 2018 Dec;37:11824. PMID:30340082 1404. Hornick JL, Bosenberg MW, Mentzel T, et al. Pleomorphic liposarcoma: clinicopathologic analysis of 57 cases. Am J Surg Pathol. 2004 Oct;28(10):1257-67. PMID:15371941 1405. Hornick JL, Bundock EA, Fletcher CD. Hybrid schwannoma/perineurioma: clinicopathologic analysis of 42 distinctive benign nerve sheath tumors. Am J Surg Pathol. 2009 Oct;33(10):1554-61. PMID:19623031 1406. Hornick JL, Dal Cin P, Fletcher CD. Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am J Surg Pathol. 2009 Apr;33(4):542-50. PMID:19033866 1407. Hornick JL, Fletcher CD. Cellular neurothekeoma: detailed characterization in a series of 133 cases. Am J Surg Pathol. 2007 Ma「;31 (3):32970. PMID:17325474 1408. Hornick JL, Fletcher CD. Cutaneous myoepithelioma: a clinicopathologic and immunohistochemical study of 14 cases. Hum Pathol. 2004 Jan;35(1):14-24. PMID:14745720 1409. Hornick JL, Fletcher CD. Intraabdominal cystic lymphangiomas obscured by marked s 叩erimposed reactive changes: clinicopathological analysis of a series. Hum Pathol. 2005 Apr;36 ⑷:426-32. PM1D:15892005 1410. Hornick JL, Fletcher CD. Intraarticular nodular fasciitis-a rare lesion: clinicopathologic analysis of a series. Am J Surg Pathol. 2006 Feb;30⑵:237-41. PMID:16434899 1411. Hornick JL, Fletcher CD. Myoepithelial tumors of soft tissue: a clinicopathologic and immunohistochemical study of 101 cases with evaluation of prognostic parameters. Am J Surg Pathol. 2003 Sep;27(9):1183-96. PMID:12960802 1412. Hornick JL, Fletcher CD. Pseudomyogenic hema ngioe ndothelioma: a distinctive, often multicentric tumor with indolent behavior. Am J Surg Pathol. 2011 Feb;35(2):190-201. PMID:21263239 1413. Hornick JL, Fletcher CD. Sclerosing PEComa: clinicopathologic analysis of a distinctive variant with a predilection for the retroperitoneum. Am J Surg Pathol. 2008 Apr;32⑷:493—501. PMID:18223480 1414. Hornick JL, Fletcher CD. Soft tissue perineurioma: clinicopathologic an alysis of 81 cases including those with atypical histologic features. Am J Surg Pathol. 2005 Jul;29(7):845-58. PMID:15958848 1415. Hornick JL, Sholl LM, Dal Cin P, et al. Expression of ROS1 predicts ROS1 gene rearrangement in inflammatory myofibroblastic tumors. Mod Pathol. 2015 May;28(5):732-9. PMID:25612511 1416. Horvai A, Dashti NK, Rubin BP, et al. Genetic and molecular reappraisal of spindle cell adamantinoma of bone reveals a small subset of misclassified intraosseous synovial sarcoma. Mod Pathol. 2019 Feb;32(2):231-41. PMID:30206413 1417. Hosalkar H, Greenberg J, Gaugler RL, et al. Abnormal scarring with keloid formation after osteochondroma excision in children with multiple hereditary exostoses. J Pediatr Orthop. 2007 Apr-May;27⑶:333-7. PMID:17414021 1418. Hostein I, Andraud-Fregeville M, Guillou L, et al. Rhabdomyosarcoma: value of myogenin expression analysis and molecular testing in diagnosing the alveolar subtype: an analysis of 109 paraffin-embedded specimens. Cancer. 2004 Dec 15;101(⑵:2817—24. PMID:15536621

1419. Hottenrott G, Mentzel T, Peters A, et al. Intravascular ("intimal") epithelioid angiosarcoma: clinicopathological and immunohistochemical analysis of three cases. Virchows Arch. 1999 Nov;435⑸:473-8. PMID:10592050 1420. Houdek MT, Sherman CE, Inwards CY, et al. Adamantinoma of bone: long-term follow-up of 46 consecutive patients. J Surg Oncol. 2018 Dec;118(7):1150-4. PMID:30332521 1421. Howell SJ, Hockenhull K, Salih Z, et al. Increased risk of breast cancer in neurofibromatosis type 1: current insights. Breast Cancer (Dove Med Press). 2017 Aug 21;9:531-6. PMID:28860858 1422. Howitt BE, Fletcher CD. Mammary­ type myofibroblastoma: clinicopathologic characterization in a series of 143 cases. Am J Surg Pathol. 2016 Mar;40(3):361-7. PMID:26523539 1423. Howlader N, Noone AM, Krapcho M, et al., editors. Surveillanee, Epidemiology, and End Results (SEER) Program [Internet]. Bethesda (MD): National Cancer Institute; 2011. SEER Cancer Statistics Review, 19752008; based on November 2010 SEER data submission, posted to the SEER website in 2011. Available from: https://seer.cancer.gov/ archive/csr/1975_2008/. 1424. Howley S, Stack D, Morris T, et al. Ectomesenchymoma with t(1;12)(p32;p13) evolving from embryonal rhabdomyosarcoma shows no rearrangement of ETV6. Hum Pathol. 2012 Feb;43(2):299-302. PMID:21803398 1425. Huang D, Sumegi J, Dal Cin P, et al. C11orf95-MKL2 is the resulting fusion oncogene of t(11;16)(q13;p13) in chondroid lipoma. Genes Chromosomes Cancer. 2010 Sep;49(9):810-8. PMID:20607705 1426. Huang HY, Antonescu CR. Epithelioid variant of pleomorphic liposarcoma: a comparative immunohistochemical and ultrastructural analysis of six cases with emphasis on overlapping features with epithelial malignancies. Ultrastruct Pathol. 2002 Sep-Oct;26(5):299-308. PMID:12396240 1427. Huang HY, Brennan MF, Singer S, et al. Distant metastasis in retroperitoneal dedifferentiated liposarcoma is rare and rapidly fatal: a clinicopathological study with emphasis on the low-grade myxofibrosarcoma-like pattern as an early sign of dedifferentiation. Mod Pathol. 2005 Jul;18(7):976-84. PMID:15832195 1428. Huang HY, Lal P, Qin J, et al. Low-grade myxofibrosarcoma: a clinicopathologic analysis of 49 cases treated at a single institution with simultaneous assessment of the efficacy of 3-tier and 4-tier grading systems. Hum Pathol. 2004 May;35(5):612-21. PMID:15138937 1429. Huang HY, Park N, Erlandson R代 et al. Immunohistochemical and ultrastructural comparative study of external lamina structure in 31 cases of cellular, classical, and melanotic schwannomas. Appl Immunohistochem Mol Morphol. 2004 Mar;12(1):50-8. PMID:15163020 1430. Huang SC, Alaggio R, Sung YS, et al. Frequent HRAS mutations in malignant ectomesenchymoma: overlapping genetic abnormalities with embryonal rhabdomyosarcoma. Am J Surg Pathol. 2016 Jul;40(7):876-85. PMID:26872011 1431. Huang SC, Chen HW, Zhang L, et al. Novel FUS-KLF17 and EWSR1-KLF17 fusions in myoepithelial tumors. Genes Chromosomes Cancer. 2015 May;54⑸:26775. PMID:25706482 1432. 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 Oct;39(10):1313-21. PMID:26135557

Refere nces

565

paybal：https://www.paypal.me/andy19801210 1433. Huang SC, Zhang L, Sung YS, et al. Recurrent CIC gene abnormalities in angiosarcomas: a molecular study of 120 cases with concurrent investigation of PLCG1, KDR, MYC, and FLT4 gene alterations. Am J Surg Pathol. 2016 May;40(5):645-55. PMID:26735859 1434. Huang SC, Zhang L, Sung YS, et al. Secondary EWSR1 gene abnormalities in SMARCBI-deficient tumors with 22q1112 regional deletions: potential pitfalls in interpreting EWSR1 FISH results. Genes Chromosomes Cancer. 2016 Oct;55(10):76776. PMID:27218413 1435. Hudson TM, Schiebler M, Springfield DS, et al. Radiology of giant cell tumors of bone: computed tomography, arthro-tomography, and scintigraphy. Skeletal Radiol. 1984;11(2):8595. PMID:6322349 1436. Huegel J, Mundy C, Sgariglia F, et al. Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones: a mechanism likely deranged in hereditary multiple exostoses. Dev Biol. 2013 May 1;377(1):100-12. PMID:23458899 1437. Huegel J, Sgariglia F, EnomotoIwamoto M, et al. Heparan sulfate in skeletal development growth, and pathology: the case of hereditary multiple exostoses. Dev Dyn. 2013 Sep;242(9):1021-32. PMID:23821404 1438. Huh WW, Yuen C, Munsell M, et al. Liposarcoma in children and young adults: a multi-institutional experience. Pediatr Blood Cancer. 2011 Dec 15;57(7):1142-6. PMID:21394894 1439. Hung YP, Fletcher CD, Hornick JL. Evaluation of ETV4 and WT1 expression in CIOrearranged sarcomas and histologic mimics. Mod Pathol. 2016 Nov;29(11):132434. PMID:27443513 1440. Hung YP, Fletcher CD, Hornick JL. FOSB is a useful diagnostic marker for pseudomyogenic hemangioe ndothelioma. Am J Surg Pathol. 2017 May;41 (5):596-606. PMID:28009608 1441. Hung YP, Fletcher CDM. Myopericytomatosis: clinicopathologic analysis of 11 cases with molecular identification of recurrent PDGFRB alterations in myopericytomatosis and myopericytoma. Am J Surg Pathol. 2017 Aug;41 (8):1034-44. PMID:28505006 1442. Hung YP, Fletcher CDM, Hornick JL. Evaluation of pan-TRK immunohistochemistry in infantile fibrosarcoma, lipofibromatosislike neural tumour and histological mimics. Histopathology. 2018 O比73(4):634-44. PMID:29863809 1443. Hunt SJ, Santa Cruz DJ, Barr RJ. Cellular angiolipoma. Am J Surg Pathol. 1990 Jan;14(1):75-81.PMID:2294783 1443A. Huss S, Kunstlinger H, Wardelmann E, et al.Asubset of gastrointestinal stromal tumors previously regarded as wild-type tumors carries somatic activating mutations in KIT exon 8 (p.D419del). Mod Pathol. 2013 Jul;26(7):100412. PMID:23599150 1444. Hussein K, Rath B, Ludewig B, et al. Clinico-pathological characteristics of different types of immunodeficiency-associated smooth muscle tumours. Eur J Cancer. 2014 Sep;50(14):2417-24. PMID:25027306 1445. Hussong JW, Brown M, Perkins SL, et al. Comparison of DNA ploidy, histologic, and immunohistochemical findings with clinical outcome in inflammatory myofibroblastic tumors. Mod Pathol. 1999 Mar;12(3):279-86. PMID:10102613 1446. Hutter RV, Stewart FW, Foote FW Jr. Fasciitis. A report of 70 cases with follow-up proving the benignity of the lesion. Cancer.

566

References

1962 Sep-Oct; 15:992-1003. PMID:14450278 1447. Huvos AG, Butler A, Bretsky SS. Osteogenic sarcoma associated with Paget's disease of bone. A clinicopathologic study of 65 patients. Cancer. 1983 Oct 15;52(8):1489-95. PMID:6577936 1448. Huvos AG, Heilweil M, Bretsky SS. The pathology of malignant fibrous histiocytoma of bone.Astudyof 130 patients. Am J Surg Pathol. 1985 Dec;9(12):853-71. PMID:3000204 1449. Huvos AG, Higinbotham NL. Primary fibrosarcoma of bone. A clinicopathologic study of 130 patients. Cancer. 1975 Mar;35(3):83747. PMID:1053940 1450. Huvos AG, Rosen G, Dabska M, et al. Mesenchymal chondrosarcoma. A clinicopathologic analysis of 35 patients with emphasis on treatment. Cancer. 1983 Apr 1;51(7):1230-7. PMID:6825046 1451. Huvos AG, Woodard HQ, Cahan WG, et al. Postradiation osteogenic sarcoma of bone and soft tissues. A clinicopathologic study of 66 patients. Cancer. 1985 Mar 15;55(6):1244-55. PMID:3855683 1452. Huvos AG, Woodard HQ, Heilweil M. Postradiati on maligna nt fibrous histiocytoma of bone. A clinicopathologic study of 20 patients. Am J Surg Pathol. 1986 Jan;10(1):9-18. PMID:3006524 1453. Huvos AG. Malignant surface lesions of bone. Curr Diagn Pathol. 2001 Dec;7(4):24750. doi:10.1054/cdip.2001.0081. 1454. Huwait H, Meneghetti A, Nielsen TO. Kaposi sarcoma of the ad re nal gland resembling epithelioid angiosarcoma: a case report. Sarcoma. 2011;2011:898257. PMID:21845069 1455. Huynh KD, Fischle W, Verdin E, et al. BCoR, a novel corepressor involved in BCL-6 repression. Genes Dev. 2000 Jul 15;14(14):1810-23. PMID:10898795 1456. Hwang JS, Beebe KS, Rojas J, et al. Malignant granular cell tumor of the thigh. Orthopedics. 2011 Aug 8;34(8):e428-31. PMID:21815590 1457. IARC TP53 Database [Internet]. Lyon (France): International Agency for Research on Cancer; 2019. Version R20, July 2019. Available from: http://p53.iarc.fr/. 1458. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Surgical implants and other foreign bodies. IARC Monogr Eval Carcinog Risks Hum. 1999;74:ixi, 1-409. PMID: 10804970 1459. Ida CM, Wang X, Erickson-Johnson MR, et al. Primary retroperitoneal lipoma: a soft tissue pathology heresy?: report of a case with classic histologic, cytogenetics, and molecular genetic features. Am J Surg Pathol. 2008 Jun;32(6):951-4.PMID:18551755 1460. Idbaih A, Coindre JM, Derre J, et al. Myxoid malignant fibrous histiocytoma and pleomorphic liposarcoma share very similar genomic imbalances. Lab Invest. 2005 Feb;85(2): 176-81. PMID:15702084 1461. Ide F, Mishima K, Yamada H, et al. Perivascular myoid tumors of the oral region: a clinicopathologic re-evaluation of 35 cases. J Oral Pathol Med. 2008 Jan;37(1):43-9. PMID:18154577 1462. Idowu BD, Al-Adnani M, O'Donnell P, et al. A sensitive mutation-specific screening technique for GNAS1 mutations in cases of fibrous dysplasia: the first report of a codon 227 mutation in bone. Histopathology. 2007 May;50(6):691-704. PMID:17493233 1463. lezzoni JC, Fechner RE, Wong LS, et al. Aggressive angiomyxoma in males. A report of four cases. Am J Clin Pathol. 1995 Oct;104(4):391-6. PMID:7572787 1464. Ikediobi Nl, Iyengar V, Hwang L, et al. Infantile myofibromatosis: support for

autosomal dominant inheritance. J Am Acad Dermatol. 2003 Aug;49(2 Suppl Case Reports):S148-50. PMID:12894106 1465. Ilica AT, Mossa-Basha M, Zan E, et al. Cranial intraosseous meningioma: spectrum of neuroimaging findings with respect to histopathological grades in 65 patients. Clin Imaging. 2014 Sep-Oct;38(5):599-604. PMID:24997535 1466. Illueca C, Machado I, Cruz J, et al. Pleomorphic hyalinizing angiectatic tumor: a report of 3 new cases, 1 with sarcomatous myxofibrosarcoma component and another with unreported soft tissue palpebral location. Appl Immunohistochem Mol Morphol. 2012 Jan;20(1 ):96-101. PM!D:22024990 1467. Imataki O, Uemura M, Uchida S, et al. Complete mimicry: a case of alveolar rhabdomyosarcoma masquerading as acute leukemia. Diagn Pathol. 2017 Nov 2;12(1):77. PMID:29096655 1468. Inamura K, Kobayashi M, Nagano H, et al. A novel fusion of HNRNPA1-ALK in inflammatory myofibroblastic tumor of urinary bladder. Hum Pathol. 2017 Nov;69:96-100. PMID:28504207 1469. Inatomi Y, Ito T, Nagae K, et al. Hybrid perineurioma-neurofibroma in a patient with neurofibromatosis type 1, clinically mimicking malignant peripheral nerve sheath tumor. Eur J Dermatol. 2014 May-Jun;24(3):412-3. PMID:24751814 1470. Inoue YZ, Frassica FJ, Sim FH, et al. Clinicopathologic features and treatment of postirradiation sarcoma of bone and soft tissue. J Surg Oncol. 2000 Sep;75(1):42-50. PMID:11025461 1471. International Association of Cancer Registries (IACR) [Internet]. Lyon (France): International Agency for Research on Cancer; 2019. ICD-O-3.2; updated 2019 Apr 23. Available from: http://www. iacr.com.fr/index.php?option=com_ content&view=article&id=149:icd-o-32&catid=80<emid 二545. 1472. Inubushi T, Lemire I, Irie F, et al. Palovarotene inhibits osteochondroma formation in a mouse model of multiple hereditary exostoses. J Bone Miner Res. 2018 Apr;33(4):658-66. PMID:29120519 1473. Inubushi T, Nozawa S, Matsumoto K, et al. Aberrant perichondrial BMP signaling mediates multiple osteochondromagenesis in mice. JCI Insight. 2017 Aug 3;2(15):90049. PMID:28768899 1474. Inyang A, Mertens F, Puls F, etal. Primary pseudomyogenic hemangioendothelioma of bone. Am J Surg Pathol. 2016 May;40(5):58798. PMID:26872012 1475. lolascon A, Faienza MF, Coppola B, et al. Analysis of cyclin-dependent kinase inhibitor genes (CDKN2A, CDKN2B, and CDKN2C) in childhood rhabdomyosarcoma. Genes Chromosomes Cancer. 1996 Apr; 15(4):217-22. PMID:8703847 1476. lorizzo LJ 3rd, Brown MD. Atypical fibroxanthoma: a review of the literature. Dermatol Surg. 2011 Feb;37 ⑵:146-57. PMID:21269345 1477. Ippolito E, Bray EW, CorsiA,etal. Natural history and treatment of fibrous dysplasia of bone: a multicenter clinicopathologic study promoted by the European Pediatric Orthopaedic Society. J Pediatr Orthop B. 2003 May; 12(3): 155-77. PMID:12703030 1478. Iqbal CW, St Peter S, Ishitani MB. Pediatric dermatofibrosarcoma protuberans: multi-institutional outcomes. J Surg Res. 2011 Sep;170(1):69-72. PMID:21429521 1479. Ireland DC, Soule EH, Ivins JC. Myxoma of somatic soft tissues. A report of 58 patients, 3 with multiple tumors and fibrous dysplasia of

bone. Mayo Clin Proc. 1973 Jun;48(6)-4O1 m PMID:4709710 1480. Ishak KG, Sesterhenn IA, Goodman ZD et al. Epithelioid hemangioendothelioma of the liver: a clinicopathologic and follow-up study Of 32 cases. Hum Pathol. 1984 Sep;15(9) *839 5? PMID:6088383 1481. Ishida T, Yamamoto M, Goto T, et al Clear cell chondrosarcoma of the pelvis in a skeletally immature patient. Skeletal Radiol 1999 May;28(5):290-3. PMID:10424338 1482. Isidor B, Guillard S, Hamel A, et al Genochondromatosis type II： report' of a new patient and further delineation of the phenotype. Am J Med Genet A. 2007 Auq 15;143A(16):1919-21. PMID:17632779 1483. Itakura E, Yamamoto H, Oda Y, et al Detection and characterization of vascular endothelial growth factors and their receptors in a series of angiosarcomas. J Surg Oncol 2008 Jan 1;97(1):74-81. PMID:18041747 1484. Itala A, Leerapun T, Inwards C et al. An institutional review of clear celi chondrosarcoma. Clin Orthop Relat Res. 2005 Nov;440(440):209-12. PMID:16239809 1485. Italiano A, Bianchini L, Gjemes E, et al. Clinical and biological significance of CDK4 amplification in well-differentiated and dedifferentiated liposarcomas. Clin Cancer Res. 2009 Sep 15;15(18):5696-703 PMID:19737942 1486. Italiano A, Bianchini L, Keslair F, et al. HMGA2 is the partner of MDM2 in welldifferentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon. Int J Cancer. 2008 May 15;122(10):2233-41. PMID:18214854 1487. Italiano A, Chambonniere ML, Attias R, et al. Monosomy 7 and absence of 12q amplification in two cases of spindle cell liposarcomas. Cancer Genet Cytogenet. 2008 Jul 15;184(2):99-104. PMID:18617058 1488. Italiano A, Chen CL, Thomas R, et al. Alterations of the p53 and PIK3CA/AKT/mTOR pathways in angiosarcomas: a pattern distinct from other sarcomas with complex genomics. Cancer. 2012 Dec 1;118(23):5878-87. PMID:22648906 1489. Italiano A, Di Mauro I, Rapp J, et al. Clinical effect of molecular methods in sarcoma diagnosis (GENSARC): a prospective, multicentre, observational study. Lancet Oncol. 2016Apr;17(4):532-8. PMID:26970672 1490. Italiano A, Lagarde P, Brulard C, et al. Genetic profiling identifies two classes of softtissue leiomyosarcomas with distinct clinical characteristics. Clin Cancer Res. 2013 Mar 1;19(5):1190-6. PMID:23329812 1491. Italiano A, Maire G, Sirvent N, et al. Variability of origin for the neocentromeric sequences in analphoid supernumerary marker chromosomes of well-differentiated liposarcomas. Cancer Lett. 2009 Jan 18;273(2):323-30. PMID:18823700 1492. Italiano A, Sung YS, Zhang L, et al. High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1negative undifferentiated small blue round cell sarcomas. Genes Chromosomes Cancer. 2012 Mar;51 (3):207-18. PMID:22072439 1493. Ito M, Barys L, O'Reilly T, et al. Comprehensive mapping of p53 pathway alterations reveals an apparent role for both SNP309 and MDM2 amplification in sarcomagenesis. Clin Cancer Res. 2011 Feb 1;仃⑶:416-26. PMID:21159888 1493A. Ito T, Yamamura M, Hirai T, et al. Gastrointestinal stromal tumors with exon 8 c-kit gene mutation might occur at extragastric sites and have metastasis-prone nature. Int J Clin Exp Pathol. 2014 Oct 15;7(11):8024-31. PMID:25550846

paybal：https://www.paypal.me/andy19801210 1494. Ito Y, Maeda D, Yoshida M, et al. Cardiac intimal sarcoma with PDGFRp mutation and co-amplification of PDGFRa and MDM2: an autopsy case an a lyzed by wholeexome sequencing. Virchows Arch. 2017 Sep；471 ⑶:423-& PMID:28474091 1495. Ivins JC, Dockerty MB, Ghormley RK. Fibrosarcoma of the soft tissues of the extremities; a review of 78 cases. Surgery. 1950 Sep;28(3):495-508. PMID:14776656 1496. Iwasa Y, Fletcher CD. Cellular angiofibroma: clin icopathologic and immunohistochemical analysis of 51 cases. Am J Surg Pathol. 2004 Nov;28(11):1426-35. PMID:15489646 1497. Iwasaki H, Kikuchi M, Mori R, et al. Infantile digital fibromatosis. Ultrastructural, histochemical, and tissue culture observations. Cancer. 1980 Nov 15;46(10):2238-47. PMID:6253042 1498. Iyer VK, Agarwala S, Verma K. Fineneedle aspiration cytology of clear-cell sarcoma of the kidney: study of eight cases. Diagn Cytopathol. 2005 Aug;33(2):83-9. PMID:16007650 1499. Izquierdo FM, Ramos LR, SanchezHerraez S, et al. Dedifferentiated classic adamantinoma of the tibia: a report of a case with eventual complete revertant mesenchymal phenotype. Am J Surg Pathol. 2010 Sep;34(9):1388-92. PMID:20717000 1500. Izumi T, Oda Y, Hasegawa T, et al. Prognostic significance of dysadherin expression in epithelioid sarcoma and its diagnostic utility in distinguishing epithelioid sarcoma from malignant rhabdoid tumor. Mod Pathol. 2006 Jun;19 ⑹:820-31. PMID:16557275 1501. JaafarR, Tang IP, Jong DE, et al. Cervical lipoblastoma: an uncommon presentation. Ear Nose Throat J. 2015 Jul;94(7):E8-10. PMID:26214680 1502. Jackson TJ, Shah AS, Arkader A. Is routine spine MRI necessary in skeletally immature patients with MHE? Identifying patients at risk for spinal osteochondromas. J Pediatr Orthop. 2019 Feb;39⑵:e147-52. PMID:29016429 1503. Jacoby LB, MacCollin M, Barone R, et al. Frequency and distribution of NF2 mutations in schwan no mas. Genes Chromosomes Cancer. 1996 Sep;17(1):45-55. PMID:8889506 1504. Jacquot C, Szymanska J, Nemana LJ, et al. Soft-tissue aneurysmal bone cyst with iranslocation t(17;17)(p13;q21) corresponding to COL1A1 and USP6 loci. Skeletal Radiol. 2015 Nov;44(11):1695-9. PMID:26142538 1505. Jaffe HL. Osteoid-osteoma. Proc R Soc Med. 1953 Dec;46(12):1007-12. PMID:13120827 1506. Jaffe HL, Lichtenstein L. Nonosteogenic fibroma of bone. Am J Pathol. 1942 Mar;18(2):205-21. PMID: 19970624 1507. Jaffe N, Spears R, Eftekhari F, et al. Pathologic fracture in osteosarcoma. Impact of chemotherapy on primary tumor and survival. Cancer. 1987 Feb 15;59(4):701-9. PMID:3492261 1508. Jager M, Westhoff B, Portier S, et al. Clinical outcome and genotype in patients with hereditary multiple exostoses. J Orthop Res. 2007 Dec;25(12):1541-51. PMID:17676624 1509. Jaju PD, Ransohoff KJ, Tang JY, et al. Familial skin cancer syndromes: increased risk of nonmelanotic skin cancers and extracutaneous tumors. J Am Acad Dermatol. 2016 Mar;74 ⑶:437-51, quiz 452-4. PMID:26892653 1510. Jakowski JD, Wakely PE Jr. Primary intrathoracic low-grade fibromyxoid sarcoma. Hum Pathol. 2008 Apr;39(4):623-8. PMID:18275982

1511. Jalali M, Netscher DT, Connelly JH. Glomangiomatosis. Ann Diagn Pathol. 2002 Oct;6(5):326-8. PMID: 12376927 1512. Jamshidi F, Bashashati A, Shumansky K, et al. The genomic landscape of epithelioid sarcoma cell lines and tumours. J Pathol. 2016 Jan;238(1):63-73. PMID:26365879 1513. Janeway KA, Kim SY, Lodish M, et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci USA. 2011 Jan 4;108(1):314-8. PMID:21173220 1514. Jarvi OH, Lansimies PH. Subclinical elastofibromas in the scapular region in an autopsy series. Acta Pathol Microbiol Scand A. 1975 Jan;83(1):87-108. PMID:1124654 1515. Jarvinen HJ, Peltomaki P. The complex genotype-phenotype relationship in familial adenomatous polyposis. Eur J Gastroenterol Hepatol. 2004 Jan;16(1):5-8. PMID:15095846 1516. Jawad MU, Extein J, Min ES, et al. Prognostic factors for survival in patients with epithelioid sarcoma: 441 cases from the SEER database. Clin Orthop Relat Res. 2009 Nov;467(11):2939-48. PMID:19224301 1517. Jawad MU, Scully SP. In brief: classifications in brief: Mirels' classification: metastatic disease in long bones and impending pathologic fracture. Clin Orthop Relat Res. 2010 Oct;468(10):2825-7. PMID:20352387 1518. Jee WH, Choi KH, Choe BY, et al. Fibrous dysplasia: MR imaging characteristics with radiopathologic correlation. AJR Am J Roentgenol. 1996 Dec;167(6):1523-7. PMID:8956590 1519. Jee WH, Park YK, McCauley TR, et al. Chondroblastoma: MR characteristics with pathologic correlation. J Comput Assist Tomogr. 1999 Sep-Oct;23(5):721-6. PMID:10524855 1520. Jelinek JS, Murphey MD, Kransdorf MJ, et al. Parosteal osteosarcoma: value of MR imaging and CT in the prediction of histologic grade. Radiology. 1996 Dec;201 (3):837-42. PMID:8939240 1521. Jennes I, de Jong D, Mees K, et al. Breakpoint characterization of large deletions in EXT1 or EXT2 in 10 multiple osteochondromas families. BMC Med Genet. 2011 Jun 26;12:85. PMID:21703028 1522. Jennes I, Pedrini E, Zuntini M, et al. Multiple osteochondromas: mutation update and description of the Multiple Osteochondromas Mutation Database (MOdb). Hum Mutat. 2009 Dec;30(12):1620-7. PMID:19810120 1523. Jennes I, Zuntini M, Mees K, et al. Identification and functional characterization of the human EXT1 promoter region. Gene. 2012 Jan 15;492(1):148-59. PMID:22037484 1524. Jennings TA, Peterson L, Axiotis CA, et al. An giosarcoma associated with foreign body material. A report of three cases. Cancer. 1988 Dec 1;62(11):2436-44. PMID:3052791 1525. Jeon DG, Song WS, Kong CB, et al. MFH of bone and osteosarcoma show similar survival and chemosensitivity. Clin Orthop Relat Res. 2011 Feb;469⑵:584-90. PMID:20559764 1526. Jha P, Moosavi C, Fanburg-Smith JC. Giant cell fibroblastoma: an update and addition of 86 new cases from the Armed Forces Institute of Pathology, in honor of Dr. Franz M. Enzinger. Ann Diagn Pathol. 2007 Apr;11(2):81-8. PMID:17349565 1527. Jhala DN, Eltoum I, Carroll AJ, et al. Osteosarcoma in a patient with McCuneAlbright syndrome and Mazabraud's syndrome: a case report emphasizing the cytological and cytogenetic findings. Hum Pathol. 2003 Dec;34(12):1354-7. PMID:14691924 1528. Jin Y, Elalaf H, Watanabe M, et al. Mutant IDH1 dysregulates the differentiation of mesenchymal stem cells in association with gene-specific histone modifications to

cartilage- and bone-related genes. PLoS One. 2015 Jul 10;10(7):e0131998. PMID:26161668 1529. Jin Y, Moller E, Nord KH, et al. Fusion of the AHRR and NCOA2 genes through a recurrent translocation t(5;8)(p15;q13) in soft tissue angiofibroma results in upregulation of aryl hydrocarbon receptor target genes. Genes Chromosomes Cancer. 2012 May;51 (5):51020. PMID:22337624 1530. Jing W, Lan T, Chen H, etal. Amplification of FRS2 in atypical lipomatous tumour/welldifferentiated liposarcoma and de-differentiated liposarcoma: a clinicopathological and genetic study of 146 cases. Histopathology. 2018 Jun;72(7):1145-55. PMID:29368794 1531. Jo VY, Antonescu CR, Zhang L, et al. Cutaneous syncytial myoepithelioma: clinicopathologic characterizatio n in a series of 38 cases. Am J Surg Pathol. 2013 May;37(5):710-8. PMID:23588365 1532. Jo VY, Fletcher CD. p63 immunohistochemical staining is limited in soft tissue tumors. Am J Clin Pathol. 2011 Nov; 136(5):762-6. PMID:22031315 1533. Jo VY, Fletcher CDM. SMARCB1/ INI1 loss in epithelioid schwannoma: a clinicopathologic and immunohistochemical study of 65 cases. Am J Surg Pathol. 2017 Aug;41(8):1013-22. PMID:28368924 1534. Joensuu H, Hohenberger P, Corless CL. Gastrointestinal stromal tumour. Lancet. 2013 S即 14;382(9896):973-83. PMID:23623056 1535. Joensuu H, Rutkowski P, NishidaT, etal. KIT and PDGFRA mutations and the risk of Gl stromal tumor recurrenee. J Clin Oncol. 2015 Feb 20;33(6):634-42. PMID:25605837 1536. Joensuu H, Vehtari A, Riihimaki J, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol. 2012 Mar;13(3):265-74. PMID:22153892 1537. Joensuu H, Wardelmann E, Sihto H, et al. Effect of KIT and PDGFRA mutations on survival in patients with gastrointestinal stromal tumors treated with adjuvant imatinib: an exploratory analysis of a randomized clinical trial. JAMA Oncol. 2017 May 1;3(5):602-9. PMID.28334365 1538. Johann PD, Erkek S, Zapatka M, et al. Atypical teratoid/市abdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell. 2016 Mar 14;29(3):379-93. PMID:26923874 1539. 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 Aug;40(8):1084-9. PMID:26945338 1540. Johnson A, Severson E, Gay L, et al. Comprehensive genomic profiling of 282 pediatric low- and high-grade gliomas reveals genomic drivers, tumor mutational burden, and hypermutation signatures. Oncologist. 2017 Dec;22(12):1478-90. PMID:28912153 1541. Johnson LC. A general theory of bone tumors. Bull N Y Acad Med. 1953 Feb;29(2):164-71. PMID:13009398 1542. Jokinen CH, Ragsdale BD, Argenyi ZB. Expanding the clinicopathologic spectrum of palisaded encapsulated neuroma. J Cutan Pathol. 2010 Jan;37(1):43-8. PMID:19614730 1542A. Jones AC, Prihoda TJ, Kacher JE, etal. Osteoblastoma of the maxilla and mandible: a report of 24 cases, review of the literature, and discussion of its relationship to osteoid osteoma of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006 Nov; 102(5):639-50. PMID:17052641 1543. Jones FE, Soule EH, Coventry MB. Fibrous xanthoma of synovium (giant-cell tumor of tendon sheath, pigmented nodular synovitis).

A study of one hundred and eighteen cases. J Bone Joint Surg Am. 1969 Jan;51 (1):76-86 PMID:4303016 1544. Jones KB, Barrott JJ, Xie M, et al. The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis. Oncogene. 2016 Sep 22;35(38):5021-32. PMID:26947017 1545. Jones KB, Piombo V, Searby C, et al. A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes. Proc Natl Acad Sci USA. 2010 Feb 2;107(5) :20549. PMID:20080592 1546. Jones RL, Fisher C, Al-Muderis O, et al. Differential sensitivity of liposarcoma subtypes to chemotherapy. Eur J Cancer. 2005 Dec;41(18):2853-60. PMID:16289617 1547. Jong R, Kandel R, Fornasier V, et al. Alveolar soft part sarcoma: review of nine cases including two cases with unusual histology. Histopathology. 1998 Jan;32(1):638. PMID:9522219 1548. Jonigk D, Laenger F, Maegel L, et al. Molecular and clinicopathological analysis of Epstein-Barr virus-associated posttransplant smooth muscle tumors. Am J Transplant. 2012 Jul;12(7):1908-17. PMID:22420456 1549. Jordanov Ml. The "rising bubble" sign: a new aid in the diagnosis of unicameral bone cysts. Skeletal Radiol. 2009 Jun;38⑹:597600. PMID:19288095 1550. Joseph CG, Hwang H, Jiao Y, et al. Exomic analysis of myxoid liposarcomas, synovial sarcomas, and osteosarcomas. Genes Chromosomes Cancer. 2014 Jan;53⑴:15-24. PMID:24190505 1551. Joseph NM, Brunt EM, Marginean C, etal. Frequent GNAQ and GNA14 mutations in hepatic small vessel neoplasm. Am J Surg Pathol. 2018 Sep;42(9):1201-7. PMID:29975248 1552. Jour G, Liu Y, Ricciotti R, et al. Glandular differentiation in dedifferentiated chondrosarcoma: molecular evidence of a rare phenomenon. Hum Pathol. 2015 S即;46(9): 1398-404. PMID:26198745 1553. Jour G, Oultache A, Sadowska J, et al. GNAS mutations in fibrous dysplasia: a comparative study of standard sequencing and locked nucleic acid PCR sequencing on decalcified and nondecalcified formalinfixed paraffi n・embedded tissues. Appl Immunohistochem Mol Morphol. 2016 Oct;24(9):660-7. PMID:26574629 1554. Jour G, Wang L, Middha S, et al. The molecular landscape of extraskeletal osteosarcoma: a clinicopathological and molecular biomarker study. J Pathol Clin Res. 2015 Oct 29;2(1):9-20. PMID:27499911 1555. Jundt G, Remberger K, Roessner A, et al. Adamantinoma of long bones. A histopathological and immunohistochemical study of 23 cases. Pathol Res Pract. 1995 Mar;191 (2):112-20. PMID:7567680 1556. Jung SM, Chang PY, Luo CC, et al. Lipoblastoma/lipoblastomatosis: a clinicopathologic study of 16 cases in Taiwan. Pediatr Surg Int. 2005 Oct;21 (10):809-12. PMID:16180007 1557. Jurcic V, Zidar A, Montiel MD, et al. Myxoinflammatory fibroblastic sarcoma: a tumor not restricted to acral sites. Ann Diagn Pathol. 2002 Oct;6(5):272-80. PMID:12376919 1558. Kacerovska D, Michal M, Kuroda N, et al. Hybrid peripheral nerve sheath tumors, including a malignant variant in type 1 neurofibromatosis. Am J Dermatopathol. 2013 Aug;35⑹:64仁9. PMID:23676318 1559. Kadoch C, Crabtree GR. Reversible disruption of mSWI/SNF (BAF) complexes by the SS1&SSX oncogenic fusion in synovial sarcoma. Cell. 2013 Mar 28;153(1):71-85. PMID:23540691

References

567

paybal：https://www.paypal.me/andy19801210 1560. Kager L, Zoubek A, Potschger U, et al. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol. 2003 May 15;21(10):2011-8. PMID:12743156 1561. Kai K, Kusano K, Sakai M, et al. Active neovascularization and possible vascular­ centric development of gastric and periscapular elastofibromas. Virchows Arch. 2009 Feb;454(2):181-8. PMID:19132384 1562. Kaim AH, Hugli R, Bonel HM, et al. Chondroblastoma and clear cell chondrosarcoma: radiological and MRI characteristics with histopathological correlation. Skeletal Radiol. 2002 Feb;31 (2):8895. PMID:11828329 1563. Kalil RK, Inwards CY, Unni KK, et al. Dedifferentiated clear cell chondrosarcoma. Am J Surg Pathol. 2000 Aug;24(8):1079-86. PMID:10935648 1564. Kamarashev J, French LE, Dummer R, et al. Symplastic glomus tumor - a rare but distinct Benign histological variant with analogy to other 'ancient' benign skin neoplasms. J Cutan Pathol. 2009 0ct;36(10):1099-102. PMID:19602065 1565. Kanamori M, Antonescu CR, Scott M, et al. Extra copies of chromosomes 7, 8,12, 19, and 21 are recurrent in adamantinoma J Mol Diagn. 2001 Feb;3(1):16-21. PMID:11227067 1566. Kandil DH, Kida M, Laub DR, et al. Sarcomatous transformation in a cellular angiofibroma: a case report. J Clin Pathol. 2009 Oct;62(10):945-7. PMID:19783726 1567. Kang HJ, Park JH, Chen W, et al. EWS-WT1 oncoprotein activates neuronal reprogramming factor ASCL1 and promotes neural differentiation. Cancer Res. 2014 Aug 15:74(16):4526-35. PMID:24934812 1568. Kang HS, Kim T, Oh S, et al. Intraosseous lipoma: 18 years of experience at a single institution. Clin Orthop Surg. 2018 Jun;10(2):234-9. PMID:29854348 1569. Kang Y, Pekmezci M, Folpe AL, et al. Diagnostic utility of SOX10 to distinguish malignant peripheral nerve sheath tumor from synovial sarcoma, including intraneural synovial sarcoma. Mod Pathol. 2014 Jan;27(1):55-61. PMID:23929265 1570. Kanojia D, Nagata Y, Garg M, et al. Genomic landscape of liposarcoma. Oncotarget. 2015 Dec 15;6(40):42429-44. PMID:26643872 1571. Kansara M, Teng MW, Smyth MJ, et al. Translational biology of osteosarcoma. Nat Rev Cancer. 2014 Nov;14(11):722-35. PMID:25319867 1572. Kanu A, Oermann CM, Malicki D, et al. Pulmonary lipoblastoma in an 18-monthold child: a unique tumor in children. Pediatr Pulmonol. 2002 Aug;34⑵:150-4. PMID:12112785 1573. Kao YC, Fletcher CDM, Alaggio R, et al. Recurrent BRAF gene fusions in a subset of pediatric spindle cell sarcomas: expanding the genetic spectrum of tumors with overlapping features with infantile fibrosarcoma. Am J Surg Pathol. 2018Jan;42(1):28-3& PMID:28877062 1574. Kao YC, Flucke U, EijkelenboomA, et al. Novel EWSR1-SMAD3 gene fusions in a group of acral fibroblastic spindle cell neoplasms. Am J Surg Pathol. 2018 Apr;42(4):522-8. PMID:29309308 1575. Kao YC, Lan J, TaiHC, et al. Angiomatoid fibrous histiocytoma: clinicopathological and molecular characterisation with emphasis on variant histomorphology. J Clin Pathol. 2014 Mar;67(3):210-5. PMID:24043718 1576. Kao YC, Owosho AA, Sung YS, et al. BCOR-CCNB3 fusion positive sarcomas: a clinicopathologic and molecular analysis of

568

Refere nces

36 cases with comparison to morphologic spectrum and clinical behavior of other round cell sarcomas. Am J Surg Pathol. 2018 May;42(5):604-15. PMID:29300189 1577. Kao YC, Ranucci V, Zhang L, et al. Recurrent BRAF gene rearrangemen恰 in myxoinflammatory fibroblastic sarcomas, but not hemosiderotic fibrolipomatous tumors. Am J Surg Pathol. 2017 Nov;41(11):1456-65. PMID:28692601 157& Kao YC, Sung YS, Chen CL, et al. ETV transcriptional 叩regulation is more reliable than RNA sequencing algorithms and FISH in diagnosing round cell sarcomas with CIC gene rearrangements. Genes Chromosomes Cancer. 2017 Jun;56(6):501-10. PMID:28233365 1579. 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 Dec;40(12):1670-8. PMID:27428733 1580. Kao YC, Sung YS, Zhang L, et al. EWSR1 fusions with CREB family transcription factors define a novel myxoid mesenchymal tumor with predilection for intracranial location. Am J Surg Pathol. 2017 Apr;41 (4):482-90. PMID:28009602 1581. Kao YC, Sung YS, Zhang L, et al. Expanding the molecular signature of ossifying fibromyxoid tumors with two novel gene fusions: CREBBP-BCORL1 and KDM2AWWTR1. Genes Chromosomes Cancer. 2017 Jan;56(1):42-50. PMID:27537276 1582. Kao YC, Sung YS, Zhang L, et al. Recurrent BCOR internal tandem duplication and YWHAE-NUTM2B fusions in soft tissue undifferentiated round cell sarcoma of infancy: overlapping genetic features with clear cell sarcoma of kidney. Am J Surg Pathol. 2016 Aug;40(8): 1009-20. PMID:26945340 1583. Kapadia SB, Meis JM, Frisman DM, et al. Fetal rhabdomyoma of the head and neck: a clinicopathologic and immunophenotypic study of 24 cases. Hum Pathol. 1993 Jul;24(7):75465. PMID:8319954 1584. Karamchandani JR, Nielsen TO, van de Rijn M, etal. Sox 10 and S100 in the diagnosis of soft-tissue neoplasms. Appl Immunohistochem Mol Morphol. 2012 0ct;20(5):445-50. PMID:22495377 1585. Karamzadeh Dashti N, Bahrami A, Lee SJ, et al. BRAF V600E mutations occur in a subset of glomus tumors, and are associated with malignant histologic characteristics. Am J Surg Pathol. 2017 Nov;41 (11):1532-41. PMID:28834810 1586. Karanian M, Perot G, Coindre JM, et al. Fluorescence in situ hybridization analysis is a helpful test for the diagnosis of dermatofibrosarcoma protuberans. Mod Pathol. 2015 Feb;28(2):230-7. PMID:25081750 1587. Karlsson P, Holmberg E, Samuelsson A, et al. Soft tissue sarcoma after treatment for breast cancer-a Swedish population-based study. Eur J Cancer. 1998 Dec;34(13):2068-75. PMID:10070313 1588. Karnak l, Senocak ME, Ciftci AO, et al. Inflammatory myofibroblastic tumor in children: diagnosis and treatment. J Pediatr Surg. 2001 Jun;36(6):908-12. PMID:11381424 1589. Kashima TG, Dongre A, Flanagan AM, et al. Podoplanin expression in adamantinoma of long bones and osteofibrous dysplasia. Virchows Arch. 2011 Jul;459(1):41-6. PMID:21499851 1590. Kasper B, Baumgarten C, Garcia J, et al. An update on the management of sporadic desmoid-type fibromatosis: a Europea n Consensus Initiative between Sarcoma PAtients EuroNet (SPAEN) and European Organization for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone

Sarcoma Group (STBSG). Ann Oncol. 2017 Oct 1；28(10):2399-408. PMID:28961825 1591. Kato I, Furuya M, Matsuo K, et al. Giant cell tumours of bone treated with denosumab: histological, immunohistochemical and H3F3A mutatio n analyses. Histopathology. 2018 May;72(6):914-22. PMID:29206281 1592. Kato I, Yoshida A, Ikegami M, et al. FOSL1 immunohistochemistry clarifies the distinction between desmoplastic fibroblastoma and fibroma of tendon sheath. Histopathology. 2016 Dec;69(6):1012-20. PMID:27442992 1593. Kaur S, Vauhkonen H, Bohling T, et al. Gene copy number changes in dermatofibrosarcoma protuberans - a fineresolution study using array comparative genomic hybridization. Cytogenet Genome Res. 2006;115(3-4):283-8. PMID:17124411 1594. Kavalar R, Fokter SK, Lamovec J. Total hip arthroplasty-related osteoge nic osteosarcoma: case report and review of the literature. Eur J Med Res. 2016 Mar 1;21:8. PMID:26931145 1595. Kawaguchi K, Oda Y, Saito T, et al. Mechanisms of inactivation of the p16INK4a gene in leiomyosarcoma of soft tissue: decreased p16 expression correlates with promoter methylation and poor prognosis. J Pathol. 2003 Nov;201 ⑶:487-95. PMID:14595762 1596. Kawamoto EH, Weidner N, Agostini RM Jr, et al. Malignant ectomesenchymoma of soft tissue. Report of two cases and review of the literature. Cancer. 1987 May 15;59(10):1791802. PMID:2950992 1597. Kawamura-Saito M, Yamazaki Y, Kaneko K, et al. Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Hum Mol Genet. 2006 Jul 1;15(13):2125-37. PMID:16717057 159& Kawanowa K, SakumaY, Sakurai S, etal. High incidence of microscopic gastrointestinal stromal tumors in the stomach. Hum Pathol. 2006 Dec;37(12): 1527-35. PMID:16996566 1599. Kawashima A, Magid D, Fishman EK, et al. Parosteal ossifying lipoma: CT and MR findings. J Comput Assist Tomogr. 1993 JanFeb;17(1 ):147-50. PMID:8419426 1600. Kayani B, Sharma A, Sewell MD, et al. A review of the surgical management of extrathoracic solitary fibrous tumors. Am J Clin Oncol. 2018 Jul;41 (7):687-94. PMID:27893469 1601. Kazakov DV, Pavlovsky M, Mukensnabl P, et al. Pleomorphic hyalinizing angiectatic tumor with a sarcomatous component recurring as high-grade myxofibrosarcoma. Pathol Int. 2007 May;57(5):281-4. PMID:17493176 1602. Kazmierczak B, Dal Cin P, Wanschura S, et al. Cloning and molecular characterization of part of a new gene fused to HMGIC in mesenchymal tumors. Am J Pathol. 1998 Feb; 152(2):431-5. PMID:9466569 1603. Keasbey LE. Juvenile aponeurotic fibroma (calcifying fibroma); a distinctive tumor arising in the palms and soles of young children. Cancer. 1953 Mar;6(2):338-46. PMID:13032926 1604. Keel SB, Jaffe KA, Petur Nielsen G, et al. Orthopaedic implant-related sarcoma: a study of twelve cases. Mod Pathol. 2001 Oct; 14(10):969-77. PMID:11598166 1605. Keel SB, Rosenberg AE. Hemorrhagic epithelioid and spindle cell hemangioma: a newly recognized, unique vascular tumor of bone. Cancer. 1999 May 1;85(9):1966-72. PMID:10223237 1606. Keeney GL, Unni KK, Beabout JW, et al. Adamantinoma of long bones. A clinicopathologic study of 85 cases. Cancer. 1989 Aug 1;64(3):730-7. PMID:2743266 1607. Kehrer-Sawatzki H, Farschtschi S,

Mautner VF, et al. The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis. Hum Genet 2017 Feb;136(2):129^8. PMID:27921248 ' 1608. Kehrer-Sawatzki H, Mautner VF Cooper DN. Emerging genotype-phenotype relationships in patients with large NF1 deletions. Hum Genet. 2017 Apr; 136⑷ 349 76. PMID:28213670 1609. Kelley MJ, Shi J, Ballew B, et al Characterization of T gene sequence variants and germline d叩lications in familial and sporadic chordoma. Hum Genet 2014 Oct;133(10):1289-97. PMID:24990759 1610. Kepenekian L, Mognetti T, Lifante JC, et al. Interest of systematic screening of pheochromocytoma in patients with neurofibromatosis type 1. Eur J Endocrinol 2016 Oct; 175(4):335-44. PMID:27450695 1611. Keraliya AR, Tirumani SH, Shinagare AB, et al. Solitary fibrous tumors: 2016 imaging update. Radiol Clin North Am. 2016 May;54(3):565-79. PMID:27153789 1612. Kern JB, HiiA, Kruse MJ, etal. A leukemic presentation of alveolar rhabdomyosarcoma in a 52-year-old woman without an identifiable primary tumor. Int J Surg Pathol. 2015 Feb;23(1):75-7. PMID:25305220 1613. Kern WH. Proliferative myositis; a pseudosarcomatous reaction to injury: a report of seven cases. Arch Pathol. 1960 Feb;69:20916. PMID:14408614 1614. Kerrey B, Reed J. A neonate with respiratory distress and a chest wall deformity. Pediatr Emerg Care. 2007 Aug;23(8):565-9. PMID:17726418 1615. Kervarrec T, Collin C, Larousserie F, et al. H3F3 mutation status of giant cell tumors of the bone, chondroblastomas and their mimics: a combined high resolution melting and pyrosequencing approach. Mod Pathol. 2017 Mar;30(3):393-406. PMID:28059095 1616. Kesserwan C, Sokolic R, Cowen EW, et al. Multicentric dermatofibrosarcoma protuberans in patients with adenosine deaminase-deficient severe combined immune deficiency. J Allergy Clin Immunol. 2012 Mar;129⑶:762-769.e1. PMID:22153773 1617. Kevorkian J, Cento DP. Leiomyosarcoma of large arteries and veins. Surgery. 1973 Mar;73(3):390^100. PMID:4687797 1618. Khan S, Jetley S, Jairajpuri 乙 et al. Fibromatosis colli - a rare cytological diagnosis in infantile neck swellings. J Clin Diagn Res. 2014 Nov;8(11):FD08-09. PMID:25584233 1619. Khan SK, Yadav PS, Elliott G, et al. Induced Gnas R201H expression from the endogenous Gnas locus causes fibrous dysplasia by up-regulating Wnt/p-catenin signaling. Proc Natl Acad Sci USA. 2018 Jan 16;115(3):E418-27. PMID:29158412 1620. Khoo M, Pressney I, Hargunani R, et al. Melanotic schwannoma: an 11-year case series. Skeletal Radiol. 2016 Jan;45(1):29-34. PMID:26386847 1621. Kikuchi Y, Yamaguchi T, Kishi H, et al. Pulmonary tumor with notochordal differentiation: report of 2 cases suggestive of benign notochordal cell tumor of extraosseous origin. Am J Surg Pathol. 2011 Aug;35(8):115864. PMID:21716081 1622. Kilciksiz S, Karakoyun-Celik O, Agaoglu FY, et al. A review for solitary plasmacytoma of bone and extramedullary plasmacytoma. ScientificWorldJournal. 2012;2012:895765. PMID:22654647 1623. Killian JK, Miettinen M, Walker RL, et al. Recurrent epimutation of SDHC in gastrointestinal stromal tumors. Sci Transl Med2014 Dec24;6(268):268ra177.PMID:25540324 1624. Kilpatrick SE, Doyon J, Choong PF, et

paybal：https://www.paypal.me/andy19801210 al. The clinicopathologic spectrum of myxoid and round cell liposarcoma. A study of 95 cases. Cancer. 1996 Apr 15;77(8):1450-8. PMID:8608528 1625. Kilpatrick SE, Hitchcock MG, Kraus MD, et al. Mixed tumors and myoepitheliomas of soft tissue: a clinicopathologic study of 19 cases with a unifying concept. Am J 8urg Pathol. 1997 Jan;21 (1):13-22. PMID:8990137 1626. Kilpatrick SE, Inwards CY, Fletcher CD, et al. Myxoid chondrosarcoma (chordoid sarcoma) of bone: a report of two cases and review of the literature. Cancer. 1997 May 15;79(10):1903-10. PMID:9149016 1627. Kilpatrick SE, Mentzel T, Fletcher CD. Leiomyoma of deep soft tissue. Clinicopathologic analysis of a series. Am J Surg Pathol. 1994 Jun;18(6):576-82. PMID:8179073 1628. Kim C, Kim MY, Kang JW, et al. Pulmonary artery intimal sarcoma versus pulmonary artery thromboembolism: CT and clinical findings. Korean J Radiol. 2018 JulAug; 19(4):792-802. PMID:29962886 1629. Kim DW, Shin JH, Lee HJ, et al. Spindle cell rhabdomyosacoma of uterus: a case study. Korean J Pathol. 2013 Aug;47(4):388-91. PMID:24009636 1630. Kim J, Kumar R, Raymond AK, etal. Nonepiphyseal chondroblastoma arising in the iliac bone, and complicated by an aneurysmal bone cyst: a case report and review of the literature. Skeletal Radiol. 2010 Jun;39(6):583-7. PMID: 19936740 1631. Kim J, McNiff JM. Keloidal atypical fibroxanthoma: a case series. J Cutan Pathol. 2009 May;36(5):535-9. PMID:19476521 1632. Kim JY, Jung WH, Yoon CS, et al. Mesenchymal hamartomas of the chest wall in infancy: radiologic and pathologic correlation. Yonsei Med J. 2000 Oct;41 (5):615-22. PMID:11079622 1633. Kim S, Lee HJ, Jun HJ, et al. The hTAF II 68-TEC fusion protein functions as a strong transcriptional activator. I nt J Cancer. 2008 Jun 1;122(11):2446-53. PMID:18330902 1634. Kim SH, Lee JH, Kim DC, et al. Subcutaneous venous hema ngioma of the breast. J Ultrasound Med. 2007 Aug;26(8):1097-100. PMID:17646373 1635. Kindblom LG, Angervall L, Stener B, et al. Intermuscular and intramuscular lipomas and hiberno mas. A clin ical, roentgenologic, histologic, and prognostic study of 46 cases. Cancer. 1974 Mar;33(3):754-62. PMID:4815578 1636. Kindblom LG, Meis-Kindblom JM. Chondroid lipoma: an ultrastructural and immunohistochemical analysis with further observations regarding its differentiation. Hum Pathol. 1995 Jul;26(7):706-15. PMID:7628841 1637. Kindblom LG, Remotti HE, Aldenborg F, et al. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol. 1998 May; 152(5): 125969. PMID:9588894 1638. King DG, Saifuddin A, Preston HV, et al. Magnetic resonance imaging of juxta-articular myxoma. Skeletal Radiol. 1995 Feb;24(2):1457. PMID:7747183 1639. King EA, Hanauer DA, Choi SW, et al. Osteochondromas after radiation for pediatric malignancies: a role for expanded counseling for skeletal side effects. J Pediatr Orthop. 2014 Apr-May;34⑶:331-5. PMID:23965908 1640. Kinkor Z, Vanecek T, Svajdler M Jr, et al. [Where does Ewing sarcoma end and begin two cases of unusual bone tumors with t(20;22) (EWSR1-NFATc2) alteration]. Cesk Patol. 2014 Apr;5O⑵:87-5. Czech. PMID:24758504 1641. Kinoshita K, Isozaki K, Hirota S, et al.

c-kit gene mutation at exon 17 or 13 is very rare in sporadic gastrointestinal stromal tumors. J Gastroenterol Hepatol. 2003 Feb;18(2):14751. PMID:12542597 1642. Kirkpatrick CJ, Alves A, Kohler H, et al. Biomaterial-induced sarcoma: a novel model to study preneoplastic change. Am J Pathol. 2000 Apr;156(4):1455-67. PMID:10751369 1643. Kirschner LS, Carney JA, Pack SD, et al. Mutations of the gene encoding the protein kinase A type l-alpha regulatory subunit in patients with the Carney complex. Nat Genet. 2000 Sep;26(1):89-92. PMID:10973256 1644. Kirwan EO, Hutton PA, Pozo JL, et al. Osteoid osteoma and benign osteoblastoma of the spine. Clinical presentation and treatment. J Bone Joint Surg Br. 1984 Jan;66(1):21-6. PMID:6693472 1645. Kishi S, Monma H, Hori H, et al. First case report of a huge giant cell tumor of soft tissue originating from the retroperitoneum. Am J Case Rep. 2018 Jun 5;19:642-50. PMID:29867073 1646. Kitsoulis P, Vlychou M, PapoudouBai A, et al. Primary lymphomas of bone. Anticancer Res. 2006 Jan-Feb;26(1A):325-37. PMID:16475714 1647. Kiuru M, Hameed M, Busam KJ. Compound clear cell sarcoma misdiagnosed as a Spitz nevus. J Cutan Pathol. 2013 Nov;40(11):950-4. PMID:23980901 1648. Kiuru-Kuhlefelt S, Sarlomo-Rikala M, Larramendy ML, et al. FGF4 and INT2 oncogenes are amplified and expressed in Kaposi's sarcoma. Mod Pathol. 2000 Apr; 13(4):433-7. PMID:10786811 1649. Klapsinou E, Despoina P, Dimitra D. Cytologic findings and potential pitfalls in proliferative myositis and myositis ossificans diagnosed by fine needle aspiration cytology: report of four cases and review of the literature. Diagn Cytopathol. 2012 Mar;40(3):239-44. PMID:20890998 1650. Kleer CG, Unni KK, McLeod RA. Epithelioid hemangioendothelioma of bone. Am J Surg Pathol. 1996 Nov;20(11):1301-11. PMID:8898834 1651. Klein MJ. From a pathologist. Skeletal Radiol. 2016 Nov;45(11 ):1553-4. PMID:27585444 1652. Klein MJ, Siegal GP. Osteosarcoma: anatomic 日nd histologic variants. Am J Clin Pathol. 2006 Apr;125(4):555-81. PMID:16627266 1653. Kleinerman RA, Tucker MA, Ta rone RE, et al. Risk of new cancers after radiotherapy in Iong-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol. 2005 Apr 1;23(10):2272-9. PMID:15800318 1654. Klijanienko J, Caillaud JM, Orbach D, et al. Cyto-histological correlations in primary, recuirent and metastatic rhabdomyosarcoma: the Institut Curie's experience. Diagn Cytopathol. 2007Aug;35(8):482-7. PMID:17636492 1655. Knezevich SR, Garnett MJ, Pysher TJ, et al. ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic n ephroma and congenital fibrosarcoma. Cancer Res. 1998 Nov 15;58(22):5046-8. PMID:9823307 1656. Knobel D, Zouhair A, Tsang RW, et al. Prognostic factors in solitary plasmacytoma of the bone: a multicenter Rare Cancer Network study. BMC Cancer. 2006 May 5;6:118. PMID: 16677383 1657. Knutsen T, Gobu V, Knaus R, et al. The interactive online SKY/M-FISH & CGH Database and the Entrez Cancer Chromosomes Search Database: linkage of chromosomal aberrations with the genome sequence. Genes Chromosomes Cancer. 2005 Sep;44(1):52-64. PMID:15934046

1658. Ko JS, Billings SD, Lanigan CP, et al. Fully automated dual-color dual-hapten silver in situ hybridization staining for MYC amplification: a diagnostic tool for discriminating secondary angiosarcoma. J Cutan Pathol. 2014 Mar;41 (3):286-92. PMID:24329959 1659. Ko JS, Daniels B, Emanuel PO, et al. Spindle cell lipomas in women: a report of 53 cases. Am J Surg Pathol. 2017 Sep;41 (9):1267-74. PMID:28719462 1660. Kobayashi H, Kaneko G, Uchida A. Retroperitoneal venous hemangioma. I nt J Urol. 2010 Jun;17(6):585-6. PMID:20438591 1661. Kobos R, Nagai M, Tsuda M, et al. Combining integrated genomics and functional genomics to dissect the biology of a cancerassociated, aberrant transcription factor, the ASPSCR1-TFE3 fusion oncoprotein. J Pathol. 2013Apr;229(5):743-54. PMID:23288701 1662. Koczkowska M, Callens T, Gomes A, et al. Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation. Genet Med. 2019 Apr;21 ⑷:867-76. PMID:30190611 1663. Koczkowska M, Chen Y, Callens T, et al. Genotype-phenotype correlation in NF1: evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844-848. Am J Hum Genet. 2018 Jan 4;102(1):69-87. PMID:29290338 1664. Kodet R, Newton WA Jr, Sachs N, et al. Rhabdoid tumors of soft tissues: a clinicopathologic study of 26 cases enrolled on the Intergroup Rhabdomyosarcoma Study. Hum Pathol. 1991 Jul;22⑺:674-84. PMID:1712749 1665. Koelsche C, Hartmann W, Schrimpf D, et al. Array-based DNA-methylation profiling in sarcomas with small blue round cell histology provides valuable diagnostic information. Mod Pathol. 2018 Aug;31 (8): 1246-56. PMID:29572501 1666. Koelsche C, Kriegsmann M, Kommoss FKF, et al. DNA methylation profiling distinguishes Ewing-like sarcoma with EWSR1NFATc2 fusion f「om Ewing sarcoma. J Cancer Res Clin Oncol. 2019 May;145(5):1273-81. PMID:30895378 1667. Koelsche C, Renner M, Hartmann W, et al. TERT promoter hotspot mutations are recurrent in myxoid liposarcomas but rare in other soft tissue sarcoma entities. J Exp Clin Cancer Res. 2014 Apr 11;33:33. PMID:24726063 166& Koelsche C, Schweizer L, Renner M, et al. Nuclear relocation of STAT6 reliably predicts NAB2-STAT6 fusion for the diagnosis of solitary fibrous tumour. Histopathology. 2014 Nov;65(5):613-22. PMID:24702701 ' 1669. Koelsche C, Stichel D, Griewank KG, et al. Genome-wide methylation profiling and copy number analysis in atypical fibroxanthomas and pleomorphic dermal sarcomas indicate a similar molecular phenotype. Clin Sarcoma Res. 2019 Feb 14;9:2. PMID:30809375 1670. 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 Mar;40(3):349-55. PMID:18973917 1671. Kohashi K, Nakatsura T, Kinoshita Y, et al. Glypican 3 expression in tumors with loss of SMARCB1/INI1 protein expression. Hum Pathol. 2013 Apr;44(4):526-33. PMID:23084579 1672. Kohashi K, Oda Y. Oncogenic roles of SMARCB1/INI1 and its deficient tumors. Cancer Sci. 2017Apr;108(4):547-52. PMID:28109176 1673. Kohashi K, Tanaka Y, Kishimoto H, et al. Reclassification of rhabdoid tumor and pediatric undifferentiated/unclassified sarcoma

with complete loss of SMARCB1/INI1 protein expression: three subtypes of rhabdoid tumor according to their histological features. Mod Pathol. 2016 Oct;29(10):1232-42. PMID:27338635 1674. Kohashi K, Yamada Y, Hotokebuchi Y, et al. ERG and SALL4 expressions in SMARCB1 /IN11 -deficient tumors: a useful tool for distinguishing epithelioid sarcoma from malignant rhabdoid tumor. Hum Pathol. 2015 Feb;46(2):225-30. PMID:25479928 1675. Kohashi K, Yamamoto H, Kumagai R, et al. Differential microRNA expression profiles between malignant rhabdoid tumor and epithelioid sarcoma: miR193a-5p is suggested to downregulate SMARCB1 mRNA expression. Mod Pathol. 2014 Jun;27(6):832-9. PMID:24287458 1676. Kohashi K, Yamamoto H, Yamada Y, et al. SWI/SNF chromatin-remodeling complex status in SMARCB1 /IN11 -preserved epithelioid sarcoma. Am J Surg Pathol. 2018 Mar;42(3):312-8. PMID:29309303 1677. Kohsaka S, Shukla N, Ameur N, et al. A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations. Nat Genet. 2014 Jun;46(6):595-600. PMID:24793135 1678. Koivunen P, Lopponen H, Fors AP, et al. The growth rate of osteomas of the para nasal sinuses. Clin Otolaryngol Allied Sci. 1997 Apr;22⑵:11M. PMID:9160920 1679. Koizumi H, Mikami M, Doi M, et al. Clonality analysis of nodular fasciitis by HUMARA-methylation-specific PCR. Histopathology. 2005 Sep;47(3):320-1. PMID:16115235 1680. Kondo S, Yoshizaki T, Minato H, et al. Myofibrosarcoma of the nasal cavity and paranasal sinus. Histopathology. 2001 Aug;39(2):216-7. PMID:11493344 ' 1681. Konishi E, Nakashima Y, Iwasa Y, et al. Immunohistochemical analysis for Sox9 reveals the cartilaginous character of chondroblastoma and chondromyxoid fibroma of the bone. Hum Pathol. 2010 Feb;41 ⑵:208「3. PMID:19801163 1682. Konishi E, Nakashima Y, Mano M, et al. Chondroblastoma of extra-eraniofacial bones: clinicopathological analyses of 103 cases. Pathol Int. 2017 Oct;67(10):495-502. PMID:28971570 1683. Konwaler BE, Keasbey L, Kaplan L. Subcutaneous pseudosarcomatous fibromatosis (fasciitis). Am J Clin Pathol. 1955 Mar;25⑶:241-52. PMID:14361319 1684. Koplas MC, Lefkowitz RA, Bauer TW, et al. Imaging findin gs, prevale nee and outcome of de novo and secondary malignant fibrous histiocytoma of bone. Skeletal Radiol. 2010 Aug;39(8):791-8. PM ID: 19936744 1685. Korkmaz MF, Elli M, Ozkan MB, et al. Osteopoikilosis: report of a familial case and review of the literature. Rheumatol Int. 2015 May;35(5):921-4. PMID:25352085 1686. Kostine M, Cieven AH, de Miranda NF, et al. Analysis of PD-L1, T-cell infiltrate and HLA expression in chondrosarcoma indicates potential for response to immunotherapy specifically in the dedifferentiated subtype. Mod Pathol. 2016 Sep;29(9):1028-37. PMID:27312065 1687. Kotiligam D, Lazar AJ, Pollock RE, et al. Desmoid tumor: a disease opportune for molecular insights. Histol Histopathol. 2008 Jan;23(1 ):117-26. PMID:17952864 168& Koubaa Mahjoub W, Jouini R, Khanchel F, et al. Neuroblastoma-like schwannoma with giant rosette: a potential diagnostic pitfail for hyalinizing spindle cell tumor. J Cutan Pathol. 2019 Mar;4603):234-7. PMID:30582192

Refere nces

569

paybal：https://www.paypal.me/andy19801210 1689. Koutlas IG, Scheithauer BW. Palisaded encapsulated ("solitary circumscribed") neuroma of the oral cavity: a review of 55 cases. Head Neck Pathol. 2010 Mar;4(1):1526. PMID:20237984 1690. Kovac M, Blattmann C, Ribi S, et al. Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. Nat Commun. 2015 Dec 3;6:8940. PMID:26632267 1691. Kovarik CL, Barrett T, Auerbach A, et al. Acral myxoinflammatory fibroblastic sarcoma: case series and immunohistochemical analysis. J Cutan Pathol. 2008 Feb;35 ⑵:192-6. PMID:18190444 1692. Koziel L, Kunath M, Kelly OG, et al. Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev Cell. 2004 Jun;6(6):801-13. PMID:15177029 1693. Kramer K, Hicks DG, Palis J, et al. Epithelioid osteosarcoma of bone. Immunocytochemical evidence suggesting diverge nt epithelial and mesenchymal differentiation in a primary osseous neoplasm. Cancer. 1993 May 15;71(10):2977-82. PMID:7683966 1694. Krane JF, Bertoni F, Fletcher CD. Myxoid synovial sarcoma: an undera 叩「eciated morphologic subset. Mod Pathol. 1999 May; 12(5):456-62. PMID:10349982 1695. Kransdorf MJ, Sweet DE. Aneurysmal bone cyst: concept, controversy, clinical presentation, and imaging. AJR Am J Roentgenol. 1995 Mar;164(3):573-80. PMID:7863874 1696. Kratz CP, Achatz Ml, Brugieres L, et al. Cancer screeni叩 recommendations for individuals with Li-Fraumeni syndrome. Clin Cancer Res. 2017 Jun 1;23(11):e38-45. PMID:28572266 1697. Kraus MD, Guillou L, Fletcher CD. Welldifferentiated inflammatory liposarcoma: an uncommon and easily overlooked variant of a common sarcoma. Am J Surg Pathol. 1997 May;21 (5):518-27. PMID:9158675 1698. Kreshak J, Larousserie F, Picci P, et al. Difficulty distinguishing benign notochordal cell tumor from chordoma further suggests a link between them. Cancer Imaging. 2014 Apr 22;14:4. PMID:25609192 1699. Kresse SH, Ohnstad HO, Bjerkehagen B, et al. DNA copy number changes in human malignant fibrous histiocytomas by array comparative genomic hybridisation. PLoS One. 2010 Nov 9;5(11):e15378. PMID:21085701 1700. Krieg AH, Hefti F, Speth BM, et al. Synovial sarcomas usually metastasize after >5 years: a multicenter retrospective analysis with minimum follow-up of 10 years for survivors. Ann Oncol. 2011 Feb;22(2):458-67. PMID:20716627 1701. Kristensen IB, Sunde LM, Jensen OM. Chondrosarcoma. Increasing grade of malignancy in local recurrence. Acta Pathol Microbiol Immunol Scand A. 1986 Mar;94(2):73-7. PMID:3716804 1702. Kryvenko ON, Gupta NS, Meier FA, et al. Anastomosing hemangioma of the genitourinary system: eight cases in the kidney and ovary with immunohistochemical and ultrastructural analysis. Am J Clin Pathol. 2011 Sep;136⑶:450-7. PMID:21846922 1703. Kubo T, Shimose S, Fujimori J, et al. Prognostic value of SS1&SSX fusion type in synovial sarcoma; systematic review and meta­ analysis. Springerplus. 2015 Jul 25;4:375. PMID:26217552 1704. Kubota T, Moritani S, Terasaki H. Orbital venous hemangioma. Graefes Arch Clin Exp Ophthalmol. 2012 Jan;250(1):157-8. PMID:21234590

570

References

仃05. Kulkarni KR, Jambhekar NA. Epithelioid hemangioendothelioma of bone-a clinicopathologic and immunohistochemical study of 7 cases. Indian J Pathol Microbiol. 2003 Oct;46(4):600-4. PMID:15025353 仃06. Kumar B, Pradhan A. Diagnosis of stemomastoid tumor of infancy by fine-needle aspiration cytology. Diagn Cytopathol. 2011 Jan;39(1):13-7. PMID:20091898 1707. Kumar E, Patel NR, Demicco EG, et al. Cutaneous nodular fasciitis with genetic analysis: a case series. J Cutan Pathol. 2016 Dec;43(12):1143-9. PMID:27686647 1708. Kumar R. New insights into phosphate homeostasis: fibroblast growth factor 23 and frizzled-related protein-4 are phosphaturic factors derived from tumors associated with osteomalacia. Curr Opin Nephrol Hypertens. 2002 Sep;11 (5):547-53. PMID:12187320 仃09. Kumar R. Phosphatonin-a new phosphaturetic hormone? (lessons from tumou卜induced osteomalacia and X・linked hypophosphataemia). Nephrol Dial Transplant. 1997 Jan;12(1):11-3. PMID:9027763 1710. Kumar R, Deaver MT, Czerniak BA, et al. Intraosseous hibernoma. Skeletal Radiol. 2011 May;40(5):641-5. PMID:21207023 仃1*. Kumar R, Duran C, Amini B, et al. Periosteal mesenchymal chondrosarcoma of the tibia with multifocal bone metastases: a case report. Skeletal Radiol. 2017 Jul;46(7):995-1000. PMID:28352960 仃*12. Kumar R, Lefkowitz RA, Neto AD. Myxoinflammatory fibroblastic sarcoma: clinical, imaging, management and outcome in 29 patients. J Comput Assist Tomogr. 2017 Jan;41(1):104-15. PMID:27560024 ' 1713. Kumaratilake JS, Krishnan R, LomaxSmith J, et al. Elastofibroma: disturbed elastic fibrillogenesis by periosteal-derived cells? An immunoelectron microscopic and in situ hybridization study. Hum Pathol. 1991 Oct;22(10):1017-29. PM ID: 1842374 1714. Kundangar R, Pandey V, Acharya KK, et al. An intraarticular fibroma of the tendon sheath in the knee joint. Knee Surg Sports Traumatol Arthrosc. 2011 Nov;19(11):1830-3. PMID:21340629 1715. Kunze E, Enderle A, Radig K, et al. Aggressive osteoblastoma with focal malignant transformation and development of pulmonary metastases. A case report with a review of literature. Gen Diagn Pathol. 1996 May; 141(56):377-92. PMID:8780939 1716. Kurisaki-Arakawa A, Akaike K, Hara K, et al. A case of dedifferentiated solitary fibrous tumor in the pelvis with TP53 mutation. Virchows Arch. 2014 Nov;465(5):615-21. PMID:25015562 1717. KurtAM, Unni KK, McLeod RA, etal. Lowgrade intraosseous osteosarcoma. Cancer. 199C Mar 15;65(6):1418-28. PMID:2306687 1718. Kurt AM, Unni KK, Sim FH, et al. Chondroblastoma of bone. Hum Pathol. 1989 0ct;20(10):965-76. PMID:2793161 1719. Kurtkaya-Yapicier O, Scheithauer BW, Woodruff JM, et al. Schwannoma with rhabdomyoblastic differentiation: a unique variant of malignant triton tumor. Am J Surg Pathol. 2003 Jun;27(6):848-53. PMID:12766593 1720. Kurtycz DF, Logrono R, Hoerl HD, et al. Diagnosis of fibromatosis colli by fineneedle aspiration. Diagn Cytopathol. 2000 Nov;23(5):338M2. PMID:11074630 1721. Kurzawa P, Kattapurain S, Hornicek FJ, et al. Primary myoepithelioma of bone: a report of 8 cases. Am J Surg Pathol. 2013 Jul;37(7):960-8. PMID:23681076 1722. Kushchayeva YS, Kushchayev SV, Glushko TY, et al. Fibrous dysplasia for radiologists: beyond ground glass bone matrix.

Insights Imaging. 2018 Dec;9(6):1035-56. PMID:30484079 1723. Kutzner H, Mentzel T, Palmedo G, et al. Plaque-like CD34-positive dermal fibroma ("medallion-like dermal dendrocyte hamartoma"): clinicopathologic, immunohistochemical, and molecular analysis of 5 cases emphasizing i恰 distinction from superficial, plaque-like dermatofibrosarcoma protuberans. Am J Surg Pathol. 2010 Feb;34(2):190-201. PMID:20061935 1724. Kwittken J, Branche M. Fasciitis ossificans. Am J Clin Pathol. 1969 Feb;51 (2):251-5. PMID:4974865 1725. Labelle Y, Bussieres J, Courjal F, et al. The EWS/TEC fusion protein encoded by the t(9;22) chromosomal translocation in human chondrosarcomas is a highly potent transcriptional activator. Oncogene. 1999 May 27;18(21):3303-8. PMID:10359536 1726. Labelle Y, Zucman J, Stenman G, et al. Oncogenic conversion of a novel orphan nuclea「receptor by chromosome translocation. Hum Mol Genet. 1995 Dec;4(12):2219-26. PMID:8634690 1727. Lack EE, Worsham GF, Callihan MD, et al. Granular cell tumor: a clinicopathologic study of 110 patients. J Surg Oncol. 1980;13(4):301PMID:6246310 16. 1728. Ladanyi M, Antonescu CR, Drobnjak M, etal. The precrystalline cytoplasmic granules of alveolar soft part sarcoma contain monocarboxylate transporter 1 and CD147. Am J Pathol. 2002 Apr;160(4):1215-21. PMID:11943706 1729. Ladanyi M, Antonescu CR, Leung DH, et al. Impact of SYT-SSX fusion type on the clinical behavior of synovial sarcoma: a multiinstitutional retrospective study of 243 patients. Cancer Res. 2002 Jan 1;62(1):135-40. PMID:11782370 仃30. Ladanyi M, Gerald W. Fusion of the EWS and WT1 genes in the desmoplastic small round cell turn or. Can cer Res. 1994 Jun 1;54(11):2837-40. PMID:8187063 仃31. Ladanyi M, Lui MY, Antonescu CR, et al. The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene. 2001 Jan 4;20(1):48-57. PMID:11244503 1732. Lae M, Ahn EH, Mercado GE, et al. Global gene expression profiling of PAX-FKHR fusion-positive alveolar and PAX-FKHR fusion­ negative embryonal rhabdomyosarcomas. J Pathol. 2007 Jun;212(2):143-51. PMID:17471488 1733. Laetsch TW, DuBois SG, Mascarenhas L, et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 2018 May;19(5):70514. PMID:29606586 仃34. Lagarde P, Perot G, Kauffmann A, et al. Mitotic checkpoints and chromosome instability are strong predictors of clinical outcome in gastrointestinal stromal tumors. Clin Cancer Res. 2012 Feb 1;18(3):826-38. PMID:22167411 1735. Lahat G, Dhuka AR, Hallevi H, et al. An giosarcoma: clinical and molecular insights. Ann Surg. 2010 Jun;251 (6):1098-106. PMID:20485141 1736. Lai FM, Allen PW, Yuen PM, et al. Locally metastasizi ng vascular tumor. Spindle cell, epithelioid, or unclassified hemangioendothelioma? Am J Clin Pathol. 1991 Nov;96(5):660-3. PMID:1951188 1737. Lakkaraju A, Sinha R, Garikipati R, et al. Ultrasound for initial evaluation and triage of clinically suspicious soft-tissue masses. Clin Radiol. 2009 Jun;64(6):615-21. PMID:19414084

1738. Lal DR, Su WT, Wolden SL, etal. Results of multimodal treatment for desmoplastic small round cell tumors. J Pediatr Surq 2005 Jan;40(1):251-5. PMID:15868593 1739. Lam SW, Cleton-Jansen AM, eleven AHG, et al. Molecular analysis of gene fusions in bone and soft tissue tumors by anchored multiplex PCR-based targeted next-generation sequencing. J Mol Diagn. 2018 Sep;20⑸£5363. PMID:30139549 1739A. Lam SW, elevenAHG, Kroon HM, etal Utility of FOS as diagnostic marker for osteoid osteoma and osteoblastoma. Virchows Arch 2019 Nov 25. PMID:31768625 1740. Lambert I, Debiec-Rychter M, Guelinckx P, et al. Acral myxoinflammatory fibroblastic sarcoma with unique clonal chromosomal changes. Virchows Arch. 2001 May;438(5):509-12. PMID:11407481 1741. Lamovec J, Spiler M, Jevtic V. Osteosarcoma arising in a solitary osteochondroma of the fibula. Arch Pathol Lab Med. 1999 Sep;123(9):832-4. PMID:10458834 1742. Lan F, Shi Y. Histone H3.3 and cancer: a potential reader connection. Proc Natl Acad Sci USA. 2015 Jun 2;112(22):6814-9 PMID:25453099 仃43. Lane KL, Shannon RJ, Weiss SW. Hyalinizing spindle cell tumor with giant rosettes: a distinctive tumor closely resembling low-grade fibromyxoid sarcoma. Am J Surg Pathol. 1997 Dec;21(12):1481-8 PMID:9414192 1744. Lang FF, Macdonald OK, Fuller GN, et al. Primary extradural meningiomas: a report on nine cases and review of the literature from the era of computerized tomography scanning. J Neurosurg. 2000 Dec;93(6):940-50. PMID:11117866 1745. Langer LO Jr, Krassikoff N, Laxova R, et al. The tricho-rhino-phalangeal syndrome with exostoses (or Langer-Giedion syndrome): four additional patients without mental retardation and review of the literature. Am J Med Genet. 1984 Sep;19(1):81-112. PMID:6496574 1746. Langezaal SM, Graadt van Roggen JF, Cleton-Jansen AM, et al. Malignant melanoma is genetically distinct from clear cell sarcoma of tendons and aponeurosis (malignant melanoma of soft parts). Br J Cancer. 2001 Feb;84(4):535-8. PMID:11207050 1747. Lao IW, Yu L, Wang J. S叩erficial CD34-positive fibroblastic tumour: a clinicopathological and immunohistochemical study of an additional series. Histopathology. 2017 Feb;70(3):394-401. PMID:27636918 仃48. Lappa E, Drakos E. Anastomosing hemangioma: short review of a benign mimicker of angiosarcoma. Arch Pathol Lab Med. 2019 Apr 8. PMID:30958692 仃49. Larizza L, Magnani I, Roversi G. Rothmund-Thomson syndrome and RECQL4 defect: splitting and lumping. Cancer Lett. 2006 Jan 28;232(1):107-20. PMID:16271439 1750. Larizza L, Roversi G, Volpi L. RothmundThomso n syndrome. Orphanet J Rare Dis. 2010 Jan 29;5:2. PMID:20113479 1751. Larramendy ML, Gentile M, Soloneski S, et al. Does comparative genomic hybridization reveal distinct differences in DNA copy number sequence patterns between leiomyosarcoma and malignant fibrous histiocytoma? Cancer Genet Cytogenet. 2008 Nov;187(1)：M・ PMID:18992634 1752. Larrea-Oyarbide N, ValmasedaCastellon E, Berini-Aytes L, et al. Osteomas o the craniofacial region. Review of 106 cases. J Oral Pathol Med. 2008 Jan;37(1)：38-42. PMID:18154576 . 仃53. Larsson SE, Lorentzon R, Boquisi L. Fibrosarcoma of bone. A demograp ic, clinical and histopathological study of all case

paybal：https://www.paypal.me/andy19801210 recorded in the Swedish cancer registry from 1958 to 1968. J Bone Joint Surg Br. 1976 Nov;58-B(4):412-7. PMID:1071089 仃54. Laskin WB, Fanburg-Smith JC, Burke AP, et al. Leiomyosarcoma of the inferior vena cava: clinicopathologic study of 40 cases. Am J Surg Pathol. 2010 Jun;34(6):873-81. PMID:20463568 仃55. Laskin WB, Fetsch JF, Miettinen M. Myxoinflammatory fibroblastic sarcoma: a clinicopathologic analysis of 104 cases, with emphasis on predictors of outcome. Am J Surg Pathol. 2014 Jan;38(1):1-12. PMID:24121178 仃56. Laskin WB, Fetsch JF, Miettinen M. The "neu「othekeoma": immunohistochemical analysis distinguishes the true nerve sheath myxoma from its mimics. Hum Pathol. 2000 Oct;31(10):1230-41. PMID:11070116 仃57. Laskin WB, Fetsch JF, Mostofi FK. Angiomyofibroblastomalike tumor of the male genital tract: analysis of 11 cases with comparison to female angiomyofibroblastoma and spindle cell lipoma.Am J Surg Pathol. 1998 Jan;22(1):6-16. PMID:9422311 仃58. Laskin WB, Fetsch JF, Tavassoli FA. Angiomyofibroblastoma of the female genital tract: analysis of 17 cases including a lipomatous variant. Hum Pathol. 1997 Sep;28(9):1046-55. PMID:9308729 仃59. Laskin WB, Miettinen M. Epithelioid sarcoma: new insights based on an extended immunohistochemical an alysis. Arch Pathol Lab Med. 2003 Sep;127(9):1161-8. PMID:12946229 仃60. Laskin WB, Miettinen M, Fetsch JF. Infantile digital fibroma/fibromatosis: a clinicopathologic and immunohistochemical study of 69 tumors from 57 patients with long-term follow-up. Am J Surg Pathol. 2009 Jan;33(1):1-13. PMID:18830128 1761. Laskin WB, Silverman TA, Enzinger FM. Postradiati on soft tissue sarcomas. An an alysis of 53 cases. Cancer. 1988 Dec 1;62(11):233040. PMID:3179948 仃62. Laskin WB, Weiss SW, Bratthauer GL. Epithelioid variant of malignant peripheral nerve sheath tumor (malignant epithelioid schwannoma). Am J Surg Pathol. 1991 Dec;15( 12):113675. PMID:1746681 1763. Lasota J, Corless CL, Heinrich MC, et al. Clinicopathologic profile of gastrointestinal stromal tumors (GISTs) with primary KIT exon 13 or exon 17 mutations: a multicenter study on 54 cases. Mod Pathol. 2008 Apr;21 (4):476-84. PMID:18246046 1764. Lasota J, Fetsch JF, Wozniak A, et al. The neurofibromatosis type 2 gene is mutated in perineurial cell tumors: a molecular genetic study of eight cases. Am J Pathol. 2001 Apr; 158(4):1223-9. PMID:11290539 1765. Lasota J, Miettinen M. Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology. 2008 Sep;53(3):245-66. PMID:18312355 1766. Lassaletta L, Torres-Martin M, PenaGranero C, et al. NF2 genetic alterations in sporadic vestibular schwannomas: clinical implications. Otol Neurotol. 2013 Sep;34(7):1355-61. PMID:23921927 1767. Latz S, Ellinger J, Goltz D, et al. Spindle cell rhabdomyosarcoma of the prostate. Int J Urol. 2013 S即;20(9):935-7. PMID:23320845 1768. Lau CC, Harris CP, Lu XY, et al. Frequent amplification and「ea「rangement of chromosomal bands 6p12-p21 and 17p11.2 in osteosarcoma. Genes Chromosomes Cancer. 2004 Jan;39(1):11-21. PMID:14603437 1769. Lau K, Massad M, Pollak C, et al. Clinical patterns and outcome in epithelioid hemangioendothelioma with or without pulmonary involvement: insights from

an internet registry in the study of a rare cancer. Chest. 2011 Nov;140(5):1312-8. PMID:21546438 仃70. Lau PP, Lui PC, Lau GT, et al. EWSR1-CREB3L1 gene fusion: a novel alternative molecular aberration of low-grade fibromyxoid sarcoma. Am J Surg Pathol. 2013 May;37(5):734-8. PMID:23588368 1771. Lau PP, Wong OK, Lui PC, et al. Myopericytoma in patients with AIDS: a new class of Epstein-Barr virus-associated tumor. Am J Surg Pathol. 2009 Nov;33(11):1666-72. PMID:19675451 1772. Lau SK, Klein R, Jiang 乙 et al. Myopericytoma of the kidney. Hum Pathol. 2010 Oct;41(10):1500-4. PMID:20655090 1773. Lauer DH, Enzinger FM. Cranial fasciitis of childhood. Cancer. 1980 Jan 15;45(2):401-6. PMID:7351023 1774. Lauer SR, Edgar MA, Gardner JM, et al. Soft tissue chordomas: a clinicopathologic analysis of 11 cases. Am J Surg Pathol. 2013 May;37(5):719-26. PMID:23588366 1775. Lauper JM, Krause A, Vaughan TL, et al. Spectrum and risk of neoplasia in Werner syndrome: a systematic review. PLoS One. 2013;8(4):e59709. PMID:23573208 1776. Laurini JA, Zhang L, Goldblum JR, et al. Low-grade fibromyxoid sarcoma of the small intestine: report of 4 cases with molecular cytogenetic confirmation. Am J Surg Pathol. 2011 Jul;35(7):1069-73. PMID:21677541 1777. Lausch E, Janecke A, Bros M, et al. Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity. Nat Genet. 2011 Feb;43(2):132-7. PMID:21217752 1778. Lawrence B, Perez-Atayde A, Hibbard MK, et al. TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. Am J Pathol. 2000 Aug; 157(2):377-84. PMID:10934142 1779. Layfield LJ, Emerson L, Crim JR, et al. Squamous differentiation and cytokeratin expression in an osteosarcoma: a case report and review of the literature. Clin Med Pathol. 2008;1:55-9. PMID:21876652 1780. Lazar AJ, Hajibashi S, Lev D. Desmoid tumor: from surgical extirpation to molecular dissection. Curr Opin On col. 2009 Jul;21(4):352-9. PMID:19436199 1781. Lazar AJ, Tuvin D, Hajibashi S, et al. Specific mutations in the beta-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors. Am J Pathol. 2008 Nov; 173(5):1518-27. PMID:18832571 1782. Le Guellec S, Chibon F, Ouali M, et al. Are peripheral purely undifferentiated pleomorphic sarcomas with MDM2 amplification dedifferentiated liposarcomas? Am J Surg Pathol. 2014 Mar;38(3):293-304. PMID:24525499 1783. Le Guellec S, Decouvelaere AV, Filleron T, et al. Malignant peripheral nerve sheath tumor is a challenging diagnosis: a systematic pathology review, immunohistochemistry, and molecular analysis in 160 patients from the French Sarcoma Group database. Am J Surg Pathol. 2016 Jul;40(7):896-908. PMID:27158754 1784. Le Guellec S, Lesluyes T, Sarot E, et al. Validation of the Complexity INdex in SARComas prognostic signature on formalin-fixed, paraffin-embedded, soft-tissue sarcomas. Ann Oncol. 2018 Aug 1;29(8):182835. PMID:29860427 1785. Le Guellec S, Soubeyran I, Rochaix P, et al. CTNNB1 mutation analysis is a useful tool for the diagnosis of desmoid tumors: a study of 260 desmoid tumors and 191 potential morphologic mimics. Mod Pathol. 2012 Dec;25(12):1551-8. PMID:22766794

1786. Le Guellec S, Velasco V, Perot G, et al. ETV4 is a useful marker for the diagnosis of CIC-rearranged undifferentiated round-cell sarcomas: a study of 127 cases including mimicking lesions. Mod Pathol. 2016 Dec;29(12):1523-31. PMID:27562494 1787. Le Huu AR, Jokinen CH, Rubin BP, et al. Expression of Proxl, lymphatic endothelial nuclear transcription factor, in Kaposiform hemangioendothelioma and tufted angioma. Am J Surg Pathol. 2010 Nov;34(11):1563-73. PMID:20975337 1788. Le Loarer F, Pissaloux D, Watson S, et al. Clinicopathologic features of CIC-NUTM1 sarcomas, a new molecular variant of the family of CIC-fused sarcomas. Am J Surg Pathol. 2019 Feb;43(2):268-76. PMID:30407212 1789. Le Loarer F, Watson S, Pierron G, et al. SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas. Nat Genet. 2015 Oct;47(10):12005. PMID:26343384 1790. Le Loarer F, Zhang L, Fletcher CD, et al. Consistent SMARCB1 homozygous deletions in epithelioid sarcoma and in a subset of myoepithelial carcinomas can be reliably detected by FISH in archival material. Genes Chromosomes Cancer. 2014 Jun;53⑹:47586. PMID:24585572 1791. Le LQ, Shipman T, Burns DK, et al. Cell of origin and microenvironment contribution for NF1-associated dermal neurofibromas. Cell Stem Cell. 2009 May 8;4(5):453-63. PMID:19427294 1792. Leake JF, Buscema J, Cho KR, et al. Dermatofibrosarcoma protuberans of the vulva. Gynecol Oncol. 1991 Jun;41 (3):245-9. PMID:1869103 1793. Leao JC, Caterino-De-Araujo A, Porter SR, et al. Human herpesvirus 8 (HHV-8) and the etiopathogenesis of Kaposi's sarcoma. Rev Hosp Clin Fac Med Sao Paulo. 2002 JulAug;57(4):175-86. PMID:12244338 1794. LeBoit PE, Burg G, Weedon D, et al., editors. Pathology and genetics of skin tumours. Lyon (France): International Agency for Research on Cancer; 2005. (WHO classification of tumours series, 3rd ed.; vol. 6). https://publications.iarc.fr/6. 1795. Lee AF, Hayes MM, Lebrun D, et al. FLI-1 distinguishes Ewing sarcoma from small cell osteosarcoma and mesenchymal chondrosarcoma. Appl Immunohistochem Mol Morphol. 2011 May; 19 ⑶:233-8. PMID:21084965 仃96. Lee AJ, Brenner L, Mourad B, et al. Gastrointestinal Kaposi's sarcoma: case report and review of the literature. World J Gastrointest Pharmacol Ther. 2015 Aug 6;6(3):89-95. PMID:26261737 1797. Lee ATJ, Thway K, Huang PH, et al. Clinical and molecular spectrum ofliposarcoma. J Clin Oncol. 2018 Jan 10;36(2):151-9. PMID:29220294 1798. Lee AY, Agaram NP, Qin LX, et al. Optimal percent myxoid component to predict outcome in high-grade myxofibrosarcoma and undifferentiated pleomorphic sarcoma. Ann Surg Oncol. 2016 Mar;23(3):818-25. PMID:26759307 1799. Lee CH, Ou WB, Marino-Enriquez A, et al. 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma. Proc Natl Acad Sci USA. 2012 Jan 17; 109(3):929-34. PMID:22223660 1800. Lee DH, Jung SH, Yoon TM, et al. Characteristics of para nasal sinus osteoma and treatment outcomes. Acta Otolaryngol. 2015 Jun;135⑹:602-7. PMID:25719573 1801. Lee FY, Mankin HJ, Fondren G, et al. Chondrosarcoma of bone: an assessment

of outcome. J Bone Joint Surg Am. 1999 Mar;81 (3):326-38. PMID:10199270 1802. Lee FY, Yu J, Chang SS, et al. Diagnostic value and limitations of fluorine-18 fluorodeoxyglucose positron emissi on tomography for cartilaginous tumors of bone. J Bone Joint Surg Am. 2004 Dec;86(12):267785. PMID:15590853 1803. Lee JC, Jeng YM, Su SY, et al. Identification of a novel FN1-FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour. J Pathol. 2015 Mar;235(4):539-45. PMID:25319834 1804. Lee JC, Li CF, Huang HY, et al. ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1ALK fusions in epithelioid inflammatory myofibroblastic sarcoma. J Pathol. 2017 Feb;241 (3):316-23. PMID:27874193 1805. Lee JC, Liang CW, Fletcher CD. Giant cell tumor of soft tissue is genetically distinct from its bone counterpart. Mod Pathol. 2017 May;30(5):728-33. PMID:28084336 1806. Lee JC, Su SY, Changou CA, et al. Characterization of FN1-FGFR1 and novel FN1-FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors. Mod Pathol. 2016 Nov;29(11):1335-46. PMID:27443518 1807. Lee JP, Blake Sullivan C, Bayon R, et al. Adult type rhabdomyoma presenting as a parathyroid adenoma. Head Neck. 2019 Feb;41(2):E30-3. PMID:30537102 1808. Lee JS, Fetsch JF, Wasdhal DA, et al. A review of 40 patients with extraskeletal osteosarcoma. Can cer. 1995 Dec 1;76(11):2253-9. PMID:8635029 1809. Lee LH, Bos GD, Marsh WL Jr, et al. Fine-needle aspiration cytology of sclerosing perineurioma. Ann Diagn Pathol. 2004 Apr;8⑵:80-6. PMID:15060885 1810. Lee LH, Gasilina A, Roychoudhury J, et al. Real-time genomic profiling of histiocytoses identifies early-kinase domai n BRAF alterations while improvi ng treatment outcomes. JCI Insight. 2017 Feb 9;2(3):e89473. PMID:28194436 1811. Lee MJ, Sallomi DF, Munk PL, et al. Pictorial review: giant cell tumours of bone. Clin Radiol. 1998 Jul;53(7):481-9. PMID:9714386 1812. Lee PJ, Yoo NS, Hagemann IS, et al. Spectrum of mutations in leiomyosarcomas identified by clinical targeted next-generation sequencing. Exp Mol Pathol. 2017 Feb;102(1):156-61. PMID:28093192 1813. Lee SE, Lee EH, Park H, et al. The diagnostic utility of the GNAS mutation in patients with fibrous dysplasia: meta-analysis of 168 sporadic cases. Hum Pathol. 2012 Aug;43(8):1234^12. PMID:22245114 1814. Lee SM, Zhang W, Fernandez MR Atypical fibroxanthoma arising in a young patient with Li-Fraumeni syndrome. J Cutan Pathol. 2014 Mar;41 (3):303-7. PMID:24299451 1815. Lee W, Teckie S, Wiesner T, et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat Genet. 2014 Nov;46(11):1227-32. PMID:25240281 1816. Lee WK, Ko HC, Kim BS, etal. Soft tissue chondroma on the lip: clinical, histopathological and ultrasonographic findings. Australas J Dermatol. 2018 Aug;59(3):e227-8. PMID:29115679 1817. Lee YF, John M, Edwards S, et al. Molecular classification of synovial sarcomas, leiomyosarcomas and maligna nt fibrous histiocytomas by gene expression profiling. Br J Cancer. 2003 Feb 24;88⑷:510-5. PMID:12592363 1818. Lee YF, Roe T, Mangham DC, et al. Gene expression profiling identifies distinct

References

571

paybal：https://www.paypal.me/andy19801210 molecular subgroups of leiomyosarcoma with clinical relevance. Br J Cancer. 2016 Oct 11;115(8):1000-7. PMID:27607470 1819. Lee YS, Dutta A. The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev. 2007 May 1;21(9):1025-30. PMID:17437991 1820. Lee-Jones L, Aligianis I, Davies PA, et al. Sacrococcygeal chordomas in patients with tuberous sclerosis complex show somatic loss of TSC1 or TSC2. Genes Chromosomes Cancer. 2004 S 即;41(1):80-5. PMID:15236319 1821. Leen SL, Clarke PM, Chapman J, et al. Composite hemangioendothelioma of the submandibular region. Head Neck Pathol. 2015 Dec;9(4):519-24. PMID:25666464 1822. Leet Al, Chebli C, Kushner H, et al. Fracture incidence in polyostotic fibrous dysplasia and the McCune-Albright syndrome. J Bone Miner Res. 2004 Apr; 19(4):571-7. PMID: 15005844 1823. Legeai-Mallet L, Munnich A, Maroteaux P, et al. Incomplete penetrance and expressivity skewing in hereditary multiple exostoses. Clin Genet. 1997 Jul;52(1):12-6. PMID:9272707 1824. Legius E, Marchuk DA, Collins FS, et al. Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nat Genet. 1993 Feb;3(2):122-6. PMID:8499945 1825. Leithner A, Windhager R, Lang S, et al. Aneurysmal bone cyst. A population based epidemiologic study and literature review. Clin Orthop Relat Res. 1999 Jun;(363):176-9. PMID:10379320 1826. Lemos MM, Karlen J, Tani E. Fine-needle aspiration cytology of angiomatoid malignant fibrous histiocytoma. Diagn Cytopathol. 2005 Aug;33⑵F6-21. PMID:16007669 1827. Lemos MM, Kindblom LG, MeisKindblom JM, et al. Fine-needle aspiration characteristics of hibernoma Cancer. 2001 Jun 25;93(3):206-10. PMID:11391608 1828. Lesluyes T, Delespaul L, Coindre JM, et al. The CINSARC signature as a prognostic marker for clinical outcome in multiple neoplasms. Sci Rep. 2017 Jul 14;7(1 ):5480. PMID:28710396 1829. Leu HJ, Makek M. Intramural venous leiomyosarcomas. Cancer. 1986 Apr 1;57(7):1395-400. PMID:3081244 1830. Leuschner I, Newton WA Jr, Schmidt D, et al. Spindle cell variants of embryonal rhabdomyosarcoma in the paratesticular region. A report of the Intergroup Rhabdomyosarcoma Study. Am J Surg Pathol. 1993 Mar;17⑶:22 *130. PMID:8434703 1831. Lev D, Kotilingam D, Wei C, et al. Optimizing treatment of desmoid tumors. J Clin Oncol. 2007 May 1;25(13):1785-91. PMID: 17470870 1832. Levine AM, Tulpule A. Clinical aspects and management of AIDS-related Kaposi's sarcoma. Eur J Cancer. 2001 Jul;37(10):128895. PMID:11423260 1833. Levy A, Le Pechoux C, Terrier P, et al. Epithelioid sarcoma: need for a multimodal approach to maximize the chances of curative conservative treatment. Ann Surg Oncol. 2014 Jan;21 (1):269-76. PMID:24046109 1834. Lewis MM, Kenan S, Yabut SM, et al. Periosteal chondroma. A report of ten cases and review of the literature. Clin Orthop Relat Res. 1990 Jul;(256):185-92. PMID:2194723 1835. Lex JR, Evans S, Stevenson JD, et al. Dedifferentiated chondrosarcoma of the pelvis: clinical outcomes and current treatment. Clin Sarcoma Res. 2018 Dec 14;8:23. PMID:30559960 1836. Li B, Li Y, Tian XY, et al. Unusual multifocal intraosseous papillary intralymphatic angioendothelioma (Dabska tumor) of

572

References

facial bones: a case report and review of literature. Diagn Pathol. 2013 Sep 24;8:160. PMID:24063649 1837. Li CF, Fang FM, Lan J, et al. AMACR amplification in myxofibrosarcomas: a mechanism of overexpression that promotes cell proliferation with therapeutic relevance. Clin Cancer Res. 2014 Dec 1;20(23):6141-52. PMID:25384383 1838. Li CF, Wang JM, Kang HY, et al. Characterization of gene amplification-driven SKP2 overexpression in myxofibrosarcoma: potential implications in tumor progress!on and therapeutics. Clin Cancer Res. 2012 Mar 15;18(6):1598-610. PMID:22322669 1839. Li CF, Wang JW, Huang WW, et al. Malignant diffuse-type tenosynovial giant cell tumors: a series of 7 cases comparing with 24 benign lesions with review of the literature. Am J Surg Pathol. 2008 Apr;32(4):587-99. PMID:18301053 1840. Li FP, Fletcher JA, Heinrich MC, et al. Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. J Clin Oncol. 2005 Apr 20:23(12):2735-43. PMID:15837988 1841. Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med. 1969 Oct;71(4):747-52. PMID:5360287 1842. Li FP, Fraumeni JF Jr, Mulvihill JJ, etal.A cancer family syndrome in twenty・fou「kindreds. Cancer Res. 1988 Sep 15;48(18):5358-62. PMID:3409256 1843. Li G, Ogose A, Kawashima H, et al. Cytogenetic and real-time quantitative reverse­ transcriptase polymerase chain reacti on analyses in pleomorphic rhabdomyosarcoma. Cancer Genet Cytogenet. 2009 Jul;192(1):1-9. PMID:19480930 、 1844. Li W, Molnar SL, Mott M, et al. Superficial CD34-positive fibroblastic tumor: cytologic features, tissue correlation, ancillary studies, and differential diagnosis of a recently described soft tissue neoplasm. Diagn Cytopathol. 2016 Nov;44(11):926-30. PMID:27432164 1845. Li W, Wang Q, Feng Q, et al. Oncogenic KSHV-encoded interferon regulatory factor upregulates HMGB2and CMPK1 expression to promote cell invasion by disrupting a complex lncRNA-OIP5-AS1/miR-218-5p network. PLoS Pathog. 2019 Jan 30;15(1):e1007578. PMID:30699189 1846. Li WS, Liao IC, Wen MC, et al. BCORCCNB3-positive soft tissue sarcoma with round-cell and spindle-cell histology: a series of four cases highlighting the pitfall of mimicking poorly differentiated synovial sarcoma. Histopathology. 2016 Nov;69(5):792-801. PMID:27228320 1847. Li X, Xu-Monette ZY, Yi S, et al. Primary bone lymphoma exhibits a favorable prog nosis and distinct gene expression signatures resembling diffuse large b-cell lymphoma derived from centrocytes in the germinal center. Am J Surg Pathol. 2017 Oct;41(10):1309-21. PMID:28817403 1848. Liang CA, Jambusaria-Pahlajani A, Karia PS, et al. A systematic review of outcome data for dermatofibrosarcoma protuberans with and without fibrosarcomatous change. J Am Acad Dermatol. 2014Oct;71(4):781-6. PMID:24755121 1849. Liao CP, Booker RC, Brosseau JP, et al. Contributions of inflammation and tumor microenvironment to neurofibroma tumorigenesis. J Clin Invest. 2018 Jul 2;128(7):2848-61. PMID:29596064 1850. Liao CP, Pradhan S, Chen 乙 et al. The role of nerve microenvironment for neurofibroma development. Oncotarget. 2016 Sep 20;7(38):61500-8. PMID:27517146 1851. Lidang Jensen M, Schumacher B, Myhre

Jensen O, et al. Extraskeletal osteosarcomas: a clinicopathologic study of 25 cases. Am J Surg Pathol. 1998 May;22⑸:588-94. PMID:9591729 1852. Lieberman PH, Brennan MF, Kimmel M, et al. Alveolar soft-part sarcoma. A clinico­ pathologic study of half a century. Cancer. 1989 Jan 1;63(1):1-13. PMID:2642727 1853. Liede A, Hernandez RK, Tang ET, et al. Epidemiology of benign giant cell tumor of bone in the Chinese population. J Bone Oncol. 2018 Jul 26;12:96-100. PMID:30148063 1854. Liegl B, Bennett MW, Fletcher CD. Microcystic/reticular schwannoma: a distinct variant with predilection for visceral locations. Am J Surg Pathol. 2008 Jul;32(7):1080-7. PMID:18520439 1855. Liegl B, Fletcher CD. Ischemic fasciitis: analysis of 44 cases indicating an inconsistent association with immobility or debilitation. Am J Surg Pathol. 2008 Oct;32(10):1546-52. PMID:18724246 1856. Liegl B, Hornick JL, Antonescu CR, et al. Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after tyrosine kinase inhibitor therapy: a novel form of tumor progression. Am J Surg Pathol. 2009 Feb;33(2):218-26. PMID:18830121 1857. Liegl B, Hornick JL, Fletcher CD. Primary cutaneous PEComa: distinctive clear cell lesions of skin. Am J Surg Pathol. 2008 Ap「;32⑷:608-14. PMID:18277881 1858. Ligon AH, Moore SD, Parisi MA, et al. Constitutional rearrangement of the architectural factor HMGA2: a novel human phenotype including overgrowth and lipomas. Am J Hum Genet. 2005 Feb;76⑵:340-8. PMID:15593017 1859. Lillo Osuna MA, Garcia-Lopez J, El Ayachi I, et al. Activation of estrogen receptor alpha by decitabine inhibits osteosarcoma growth and metastasis. Cancer Res. 2019 Mar 15；79(6):1054-68. PMID:30593524 1860. Um YH, Bacchiocchi A, Qiu J, et al. GNA14 somatic mutation causes congenital and sporadic vascular tumors by MAPK activation. Am J Hum Genet. 2016 Aug 4;99⑵:443-50. PMID:27476652 1861. Lima FP, Bousquet M, Gomez-Brouchet A, et al. Primary diffuse large B-cell lymphoma of bone displays preferential rearrangements of the c-MYC or BCL2 gene. Am J Clin Pathol. 2008 May;129(5):723-6. PMID:18426731 1862. Limon J, Szadowska A, lliszko M, et al. Recurrent chromosome changes in two adult fibrosarcomas. Genes Chromosomes Cancer. 1998 Feb;21(2):119-23. PMID:9491323 1863. Lin F, Hu Y, Zhao L, et al. The epidemiological and clinical features of primary giant cell tumor around the knee: a report from the multicenter retrospective study in china. J Bone Oncol. 2016 Feb 11;5(1):38-42. PMID:26998425 1864. Lin HK, Wang JD, Fu LS. Recurrent hemarthrosis in a boy with synovial hemangioma: a case report. J Pediatr Orthop B. 2011 Mar;20(2):81-3. PMID:21088622 1865. Lin J, Bigge J, Ulbright TM, et al. Anastomosing hemangioma of the liver and gastrointestinal tract: an unusual variant histologically mimicking angiosarcoma. Am J Surg Pathol. 2013Nov;37(11):1761-5. PMID:23887160 1866. Lin J, Yao L, Mirra JM, et al. Osteochondromalike parosteal osteosarcoma: a report of six cases of a new entity. AJR Am J Roentgenol. 1998 Jun;170(6):1571-7. PMID:9609176 1867. Lin JJ, Lin F. Two entities in angiolipoma. A study of 459 cases of lipoma with review of literature on infiltrating angiolipoma. Cancer. 1974 Sep；34(3):720-7. PMID:4855281 1868. Lin Y, Seger N, Tsagkozis P, et al.

Telomerase promoter mutations and copy number alterations in solitary fibrous tumours J Clin Pathol. 2018 Sep;71(9)&2-9 PMID:29703757 1869. Lind T, Tufaro F, McCormick C, et al The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. J Biol Chem 1998 Oct 9;273(41 ):26265-8, PMID:9756849 1870. Linn SC, West RB, Pollack JR, et al. Gene expression patterns and gene copy number changes in dermatofibrosarcoma protuberans Am J Pathol. 2003 Dec; 163(6):2383-95 PMID:14633610 1871. Linos K, Carter JM, Gardner JM, et al Myofibromas with atypical features: expanding the morphologic spectrum of a benign entity Am J Surg Pathol. 2014 Dec;38(12):1649-54 PMID:24921644 1872. Lips DJ, Barker N, Clevers H, et al. The role of APC and beta-catenin in the aetiology of aggressive fibromatosis (desmoid tumors). Eur J Surg Oncol. 2009 Jan;35⑴:3-10 PMID:18722078 1873. Lisle DA, Ault DJ, Earwaker JW. Mesenchymal hamartoma of the chest wall in infants: report of three cases and literature review. Australas Radiol. 2003 Mar;47(1):7882. PMID:12581063 1874. Littrell LA, Wenger DE, Wold LE, et al. Radiographic, CT, and MR imaging features of dedifferentiated chondrosarcomas: a retrospective review of 174 de novo cases. Radiographics. 2004 Sep-Oct;24⑸ J397~409 PMID:15371616 1875. Liu C, Xi Y, Li M, et al. Dedifferentiated chondrosarcoma: radiological features, prognostic factors and survival statistics in 23 patients. PLoS One. 2017 Mar 16;12(3):e0173665. PMID:28301537 1876. Liu GY, Song H, Xu XL. Multiple palisaded encapsulated neuromas in siblings: a case report and review of the published work. J Dermatol. 2016 May;43⑸:560-3. PMID:26460241 1877. Liu H, Sukov WR, Ro JY. The t(1;10) (p22;q24) TGFBR3/MGEA5 translocation in pleomorphic hyalinizing angiectatic tumor, myxoinflammatory fibroblastic sarcoma, and hemosiderotic fibrolipomatous tumor. Arch Pathol Lab Med. 2019 Feb;143⑵:212-21. PMID:29979612 1878. Liu J, Guzman MA, Pezanowski D, et al. FOXO1-FGFR1 fusion and amplification in a solid variant of alveolar rhabdomyosarcoma. Mod Pathol. 2011 Oct;24(10):1327-35. PMID:21666686 1879. Liu J, Hudkins PG, Swee RG, et al. Bone sarcomas associated with Ollier's disease. Cancer. 1987 Apr 1;59(7):1376-85. PMID:3815310 1880. Liu PT, Kujak JL, Roberts CC, et al. The vascular groove sign: a new CT finding associated with osteoid osteomas. AJR Am J Roentgenol. 2011 Jan;196(1):168-73. PMID:21178063 1881. Liu Q, Wang G, Lyu Y, et al. The miR590/Acvr2a/Terf1 axis regulates telomere elongation and pluripotency of mouse iPSCs. Stem Cell Reports. 2018 Jul 10;11(1)：88-101. PMID:29910124 1882. Liu W, Jiang L, Jin Y, et al. Alveolar rhabdomyosarcoma of the sphenoid sinus mimicking optic neuritis presenting with intermittent visual loss in an adult. Onco Targets Ther. 2016 Oct 14;9:6333-6. PMID:27932889 1883. Llamas-Velasco M, Kempf W, Cota C, et al. Multiple eruptive epithelioid hemangiomas, a subset of cutaneous cellular epithelioid hemangioma with expression of FOS-B. Am J Surg Pathol. 2019 Jan;43(1)：26-34. PMID:29266025

paybal：https://www.paypal.me/andy19801210 1884. Llombart B, Monteagudo C, Sanmartin 0, et al. Dermatofibrosarcoma protuberans: a clinicopathological, immunohistochemical, genetic (C0L1A1-PDGFB), and therapeutic study of low-grade versus high-grade (fibrosarcomatous) tumors. J Am Acad Dermatol. 2011 Sep;65 ⑶:564-75. PMID:21570152 1885. Llombart B, Sanmartin 0, LopezGuerrero JA, et al. Dermatofibrosarcoma protuberans: clinical, pathological, and genetic (COL1A1-PDGFB ) study with therapeutic implications. Histopathology. 2009 Jun;54(7):860-72. PMID:19635106 ' 1886. Llombart B, Serra-Guillen C, Rubio L, et al. Subcutaneous dermatofibrosarcoma protuberans, a rare subtype with predilection for the head: a retrospective series of 18 cases. J Am Acad Dermatol. 2017 Sep;77(3):503-511. e1. PMID:28420485 1887. Llombart-Bosch A, Machado I, Navarro S, et al. Histological heterogeneity of Ewing's sarcoma/PNET: an immunohistochemical analysis of 415 genetically confirmed cases with clinical support. Virchows Arch. 2009 Nov;455(5):397-411. PMID:19841938 1888. Lodwick GS, Wilson AJ, Farrell C, et al. Determining growth rates of focal lesions of bone from radiographs. Radiology. 1980 Mar;134(3):577-83. PMID:6928321 1889. Logan PM, Janzen DL, O'Connell JX, et al. Chondroid lipoma: MRI appearances with clinical and histologic correlation. Skeletal Radiol. 1996Aug;25(6):592-5. PMID:8865499 1890. Lohman n DR, Gillessen-Kaesbach G. Multiple subcutaneous granular-cell tumours in a patient with Noonan syndrome. Clin Dysmorphol. 2000 Oct;9(4):301-2. PMID:11045593 1891. Longhi A, Bielack SS, Grimer R, et al. Extraskeletal osteosarcoma: a European Musculoskeletal Oncology Society study on 266 patients. Eur J Cancer. 2017 Mar;74:9-16. PMID:28167373 1892. Longo JF, Weber SM, Turner-Ivey BP, et al. Recent advances in the diagnosis and pathogenesis of neurofibromatosis type 1 (NFI)-associated peripheral nervous system neoplasms. Adv Anat Pathol. 2018 Sep;25⑸:353-6& PMID:29762158 1893. Lopez C, Thomas DV, Davies AM. Neoplastic transformation and tumour-like lesions in Pagefs disease of bone: a pictorial review. Eur Radiol. 2003 Dec;13 Suppl 4:L15163. PMID:15018182 1894. Lopez-Ben R, Pitt MJ, Jaffe KA, et al. Osteosarcoma in a patient with McCuneAlbright syndrome and Mazabraud's syndrome. Skeletal Radiol. 1999 Sep;28(9):522-6. PMID:10525796 1895. Lovly CM, Gupta A, Lipson D, et al. Inflammatory myofibroblastic tumors harbor multiple potentially actionable kinase fusions. Cancer Discov. 2014 Aug;4(8):889-95. PMID:24875859 1896. Lowry KC, Estroff JA, Rahbar R. The presentation and management of fibromatosis colli. Ear Nose Throat J. 2010 Sep;89(9):E4-8. PMID:20859860 1897. Lu C, Ramirez D, Hwang S, etal. Histone H3K36M mutation and trimethylation patterns in chondroblastoma. Histopathology. 2019 Jan;74(2):291-9. PMID:30098026 1898. Lu L, Harutyunyan K, Jin W, et al. RECQL4 regulates p53 function in vivo during skeletogenesis. J Bone Miner Res. 2015 Jun;30(6):1077-89. PMID:25556649 1899. Lu L, Jin W, Liu H, et al. RECQ DNA helicases and osteosarcoma. Adv Exp Med Biol. 2014;804:129-45. PMID:24924172 1900. Lubin J, Rywlin AM. Lymphoma-like lymph node changes in Kaposi's sarcoma.

Two additional cases. Arch Pathol. 1971 Nov;92(5):338-41. PMID:4938888 1902. Lucas DR, Fletcher CD, Adsay NV, et al. High-grade extraskeletal myxoid chondrosarcoma: a high-grade epithelioid malignancy. Histopathology. 1999 Sep;35(3):201-8. PMID:10469211 1903. Lucas DR, Miller PR, Mott MP, et al. Arthroplasty-associated malignant fibrous histiocytoma: two case reports. Histopathology. 2001 Dec;39⑹:620-8. PMID:11903581 1904. Lucas DR, Nascimento AG, Sanjay BK, et al. Well-differentiated liposarcoma. The Mayo Clinic experience with 58 cases. Am J Clin Pathol. 1994 Nov;102(5):677-83. PMID:7942636 1905. Lucas DR, Nascimento AG, Sim FH. Clear cell sarcoma of soft tissues. Mayo Clinic experience with 35 cases. Am J Surg Pathol. 1992 Dec;16(12):1197-204. PMID:1463095 1906. Lucas DR, Shukla A, Thomas DG, et al. Dedifferentiated liposarcoma with inflammatory myofibroblastic tumor-like features. Am J Surg Pathol. 2010 Jun;34⑹:844-51. PMID:20431481 1907. Lucas DR, Unni KK, McLeod RA, et al. Osteoblastoma: clinicopathologic study of 306 cases. Hum Pathol. 1994 Feb;25(2):117-34. PMID:8119712 1908. Ludecke HJ, Ahn J, Lin X, et al. Genomic organization and promoter structure of the human EXT1 gene. Genomics. 1997 Mar 1;40⑵:351-4. PMID:9119404 1909. Ludwig K, Alaggio R, Zin A, et al. BCOR-CCNB3 undifferentiated sarcomaDoes immunohistochemistry help in the identification? Pediatr Dev Pathol. 2017 JulAug;20(4):321-9. PMID:28420319 1910. Lugowska I, Teterycz P, Mikula M, et al. IDH1/2 mutations predict shorter survival in chondrosarcoma. J Cancer. 2018 Feb 28;9(6):998-1005. PMID:29581779 1911. Luis PP, Quinonez E, Nogales FF, et al. Lipomatous variant of angiomyofibroblastoma involving the vulva: report of 3 cases of an extremely rare neoplasm with discussion of the differential diagnosis. Int J Gynecol Pathol. 2015 Mar;34(2):204-7. PMID:25675192 1912. Luks VL, Kamitaki N, Vivero MP, et al. Lymphatic and other vascular malformative/ overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr. 2015 Apr;166 (4):1048-54.3,5. PMID:25681199 1913. Lumbroso S, Paris F, Sultan C. Activating Gsalpha mutations: analysis of 113 patients with signs of McCune-Albright syndrome-a European Collaborative Study. J Clin Endocrinol Metab. 2004 May;89(5):2107-13. PMID:15126527 1914. Lundgren L, Kindblom LG, Willems J, et al. Proliferative myositis and fasciitis. A light and electro n microscopic, cytologic, DNA-cytometric and immunohistochemical study. APMIS. 1992 May; 100(5):437-48. PMID:1586481 1915. Luzar B, Antony F, Ramdial PK, et al. Intravascular Kaposi *s sarcoma - a hitherto unrecognized phenomenon. J Cutan Pathol. 2007 Nov;34(11):861-4. PMID:17944727 1916. Luzar B, Calonje E. Morphological and immunohistochemical characteristics of atypical fibroxanthoma with a special emphasis on potential diagnostic pitfalls: a review. J Cutan Pathol. 2010 Mar;37(3):301-9. PMID:19807823 1917. Luzar B, Martin B, Fisher C, et al. Cutaneous malignant glomus tumours: applicability of currently established malignancy criteria for tumours occurring in the skin. Pathology. 2018 Dec;50(7):711-7. PMID:30314644 1918. Lv Y, Liu Y, Li X, et al. Plasmacytoma with crystal-storing histiocytosis exhibiting

FGFR3 and IgH translocation. Pathology. 2015 Jan;47(1):82-5. PMID:25474517 1919. Lyle PL, Amato CM, Fitzpatrick JE, et al. Gastrointestinal melanoma or clear cell sarcoma? Molecular evaluation of 7 cases previously diagnosed as malign ant melanoma Am J Surg Pathol. 2008 Jun;32⑹:858-66. PMID:18408594 1920. Lynch HT, Guirgis HA. Childhood cancer and the SBLA syndrome. Med Hypotheses. 1979 Jan;5(1 ):15-22. PMID:459966 1921. Lynskey SJ, Pianta MJ. MRI and thallium features of pigmented villonodular synovitis and giant cell tumours of tendon sheaths: a retrospective single centre study of imaging and literature review. Br J Radiol. 2015;88(1056):20150528. PMID:26440548 1922. Lyons LL, North PE, Mac-Moune Lai F, et al. Kaposiform hemangioendothelioma: a study of 33 cases emphasizing its pathologic, immunophenotypic, and biologic uniqueness from juvenile hemangioma. Am J Surg Pathol. 2004 May;28(5):559-68. PMID:15105642 1923. Dutta M, Kundu S, Roy S, et al. Lipoblastomatosis of the retropharyngeal space: pathogenesis, presentation, and management, with a focus on head-neck lipoblastoma(toses). B-ENT. 2016;12(1):33-9. PMID:27097392 1924. Macarenco R8, Erickson-Johnson M, Wang X, et al. Retroperitoneal lipomatous tumors without cytologic atypia: Are they lipomas? A clinicopathologic and molecular study of 19 cases. Am J Surg Pathol. 2009 Oct;33(10):1470-6. PMID:19654500 1925. MacCarthy A, Bayne AM, Brownbill PA, et al. Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004. Br J Cancer. 2013 Jun 25;108(12):2455-63. PMID:23674091 1926. Macchia G, Trombetta D, Moller E, et al. FOSL1 as a candidate target gene for 11q12 rearrangements in desmoplastic fibroblastoma. Lab Invest. 2012 May;92 ⑸:735-43. PMID:22411068 1927. MacCollin M, Chiocca EA, Evans DG, et al. Diagnostic criteria for schwannomatosis. Neurology. 2005 Jun 14;64(11):1838-45. PMID:15955931 1928. Machado I, Lopez-Soto MV, Rubio L, et al. Soft tissue myoepithelial carcinoma with rhabdoid-like features and EWSR1 rearrangement: fine needle aspiration cytology with histologic correlation. Diagn Cytopathol. 2015 May;43(5):421-6. PMID:25693574 1929. Machado I, Navarro S, Picci P, et al. The utility of SATB2 immunohistochemical expressio n in distinguishing between osteosarcomas 日nd their malignant bone tumor mimickers, such as Ewing sarcomas and chondrosarcomas. Pathol Res Pract. 2016 Sep;212(9):811-6. PMID:27465835 1930. Machado I, Noguera R, Mateos EA, et al. The many faces of atypical Ewing's sarcoma. A true entity mimicking sarcomas, carcinomas and lymphomas. Virchows Arch. 2011 Mar;458(3):281-90. PMID:21181413 1931. Machado I, Yoshida A, Morales MGN, et al. Review with novel markers facilitates precise categorization of 41 cases of diagnostically challenging, "undifferentiated small round cell tumors". A clinicopathologic, immunophenotypic and molecular analysis. Ann Diagn Pathol. 2018Jun;34:1-12. PMID:29661713 1932. Machen SK, Easley KA, Goldblum JR. Synovial sarcoma of the extremities: a clinicopathologic study of 34 cases, including semi-quantitative an alysis of spindled, epithelial, and poorly differentiated areas. Am J Surg Pathol. 1999 Mar;23(3):268-75. PMID:10078916 1933. MacNeill AJ, Miceli R, Strauss DC, et al. Post-relapse outcomes after primary

extended resection of retroperitoneal sarcoma: a report from the Trans-Atlantic RPS Working Group. Cancer. 2017 Jun 1;123(11):1971-8. PMID:28152173 1934. Madigan CE, Armenian SH, Malogolowkin MH, et al. Extracranial malignant rhabdoid tumors in childhood: the Childrens Hospital Los Angeles experience. Cancer. 2007 Nov 1;110(9):2061-6. PMID:17828773 1935. Maertens O, De Schepper S, Vandesompele J, et al. Molecular dissection of isolated disease features in mosaic neurofibromatosis type 1. Am J Hum Genet. 2007Aug;81 ⑵:243-51. PMID:17668375 1936. Magg T, Schober T, Walz C, et al. Epstein・Barr virus+ smooth muscle tumors as manifestation of primary immunodeficiency disorders. Front Immunol. 2018 Feb 27;9:368. PMID:29535735 1937. Maggiani F, Debiec-Rychter M, Vanbockrijck M, et al. Cellular angiofibroma: another mesenchymal tumour with 13q14 involvement, suggesting a link with spindle cell lipoma and (extra)-mammary myofibroblastoma. Histopathology. 2007 Sep;51 ⑶:410-2. PMID:17727484 1938. Magnusson L, Hansen N, Saba KH, et al. Loss of the tumour suppressor gene AIP mediates the browning of human brown fat tumours. J Pathol. 2017 Oct;243(2):160-4. PMID:28722204 1939. Magro G, Emmanuele C, Lopes M, et al. Solitary fibrous tumour of the kidney with sarcomatous overgrowth. Case report and review of the literature. APMIS. 2008 Nov;116(11):1020-5. PMID:19133003 1940. Magro G, Righi A, Caltabiano R, et al. Vulvovaginal an giomyofibroblastomas: morphologic, immunohistochemical, and fluorescence in situ hybridization analysis for deletion of 13q14 region. Hum Pathol. 2014 Aug;45(8):1647-55. PMID:24880711 1941. Magro G, Righi A, Casorzo L, et al. Mammary and vaginal myofibroblastomas are genetically related lesions: fluorescence in situ hybridization analysis shows deletion of 13q14 region. Hum Pathol. 2012 Nov;43(11):1887-93. PMID:22575260 1942. Mahajan A, Manchandia TC, Gould G, et al. De novo arteriovenous malformations: case report and review of the literature. Neurosurg Rev. 2010Jan;33(1):115-9. PMID:19787381 1943. Maheshwari AV, Jelinek JS, Seibel NL, et al. Bilateral synchronous tibial periosteal osteosarcoma with familial incidence. Skeletal Radiol. 2012 Aug;41 (8):1005-9. PMID:22349598 1944. Mahoney SE, Yao Z, Keyes CC, et al. Genome-wide DNA methylatio n studies suggest distinct DNA methylation patterns in pediatric embryonal and alveolar rhabdomyosarcomas. Epige netics. 2012 Apr;7(4):400-8. PMID:22419069 1945. Maire G, Forus A, Foa C, et al. 11q13 alterations in two cases of hibernoma: large heterozygous deletions and rearrangement breakpoints near GARP in 11q13.5. Genes Chromosomes Cancer. 2003 Aug;37⑷:38995. PMID:12800150 1946. Majoor BC, Boyce AM, Bovee JV, et al. Increased risk of breast cancer at a young age in women with fibrous dysplasia. J Bone Miner Res. 2018 Jan;33(1):84-90. PMID:28856726 1947. Majoor BCJ, van de Sande MAJ, Appelman-Dijkstra NM, et al. Prevalence and clinical features of Mazabraud syndrome: a multicenter European study. J Bone Joint Surg Am. 2019 Jan 16;101 (2):160-8. PMID:30653046 1948. Makhlouf HR, Ishak KG, Goodman ZD. Epithelioid hemangioendothelioma of the liver: a clinicopathologic study of 137 cases. Cancer.

Refere nces

573

paybal：https://www.paypal.me/andy19801210 1999 Feb1;85(3):562-82. PMID:10091730 1949. Makhlouf HR, Ishak KG, Shekar R, et al. Melanoma markers in angiomyolipoma of the liver and kidney: a comparative study. Arch Pathol Lab Med. 2002 Jan;126(1):49-55. PMID:11800647 1950. Maki RG, Wathen JK, Patel SR, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]. J Clin Oncol. 2007 Jul 1;25(19):2755-63. PMID:17602081 1951. Makise N, Sekimizu M, Konishi E, et al. H3K27me3 deficiency defines a subset of dedifferentiated chondrosarcomas with characteristic clinicopathological features. Mod Pathol. 2019 Mar;32 ⑶:435-45. PMID:30291346 1952. Makley JT, Dunn MJ. Prostaglandin synthesis by osteoid osteoma. Lancet. 1982 Jul 3;2(8288):42. PMID:6123769 1953. Malempati S, Hawkins DS. Rhabdomyosarcoma: review of the Children's Oncology Group (COG) Soft-Tissue Sarcoma Committee experience and rationale for current COG studies. Pediatr Blood Cancer. 2012 Jul 15;59(1):5-10. PMID:22378628 1954. Malhas AM, Grimer RJ, Abudu A, et al. The final diagnosis in patients with a suspected primary malignancy of bone. J Bone Joint Surg Br. 2011 Jul;93(7):980-3. PMID:21705575 1955. Malhas AM, Sumathi VP, James SL, et al. Low-grade central osteosarcoma: a difficult condition to diagnose. Sarcoma. 2012:2012:764796. PMID:22851905 1956. Malinowska I, Kwiatkowski DJ, Weiss S, et al. Perivascular epithelioid cell tumors (PEComas) harboring TFE3 gene rearrangements lack the TSC2 alterations characteristic of conventional PEComas: further evidence for a biological distinction. Am J Surg Pathol. 2012 May;36(5):783-4. PMID:22456611 1957. Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990 Nov 30;250(4985):1233-8. PMID:1978757 1958. Mallet JF, Rigault P, Padovani JP, et al. [Non-ossifying fibroma in children: a surgical condition?]. Chir Pediatr. 19800(3):179-89. French. PMID:7408072 1959. Mallick S, Ghosh R, Iyer VK, et al. Cytomorphological and morphometric analysis of 22 cases of Rosai-Dorfman disease: a large series from a tertiary care centre. Acta Cytol. 2013;57(6):625-32. PMID:24192148 1960. Man TK, Lu XY, Jaeweon K, et al. Genome-wide array comparative genomic hybridization analysis reveals distinct amplifications in osteosarcoma. BMC Cancer. 2004 Aug 7;4:45. PMID:15298715 1961. Mancini I, Righi A, Gambarotti M, et al. Phenotypic and molecular differences between giant-cell tumour of soft tissue and its bone counterpart. Histopathology. 2017 Sep;71 (3):453-60. PMID:28477388 1962. Mandahl N, Fletcher CD, Dal Cin P, et al. Comparative cytogenetic study of spindle cell and pleomorphic leiomyosarcomas of soft tissues: a report from the CHAMP Study Group. Cancer Genet Cytogenet. 2000 Jan 1;们6(1):66-73. PMID:10616536 1963. Mandahl N, Gustafson P, Mertens F, et al. Cytogenetic aberrations and their prognostic impact in chondrosarcoma. Genes Chromosomes Cancer. 2002 Feb;33(2):188200. PMID: 11793445 1964. Mandahl N, Heim S, Willen H, et al. Characteristic karyotypic anomalies identify

574

Refere nces

subtypes of malignant fibrous histiocytoma. Genes Chromosomes Cancer. 1989 Sep;1(1):9-14. PMID:2562116 1965. Mandahl N, Hoglund M, Mertens F, et al. Cytogenetic aberrations in 188 benign and borderline adipose tissue tumors. Genes Chromosomes Cancer. 1994 Mar;9(3):207-15. PMID:7515663 1966. Mandahl N, Mertens F, Willen H, et al. Non random pattern of telomeric associations in atypical lipomatous tumors with ring and giant marker chromosomes. Cancer Genet Cytogenet. 1998 May;103(1):25-34. PMID:9595041 1967. Manfrini M, Fiscina S, Righi A, et al. Multiple or metastatic clear cell chond「osa「coma: a case report. Clin Sarcoma Res. 2014 Sep 16;4:12. PMID:25289140 1968. Mangat KS, Jeys LM, Carter SR. Latest developments in limb-salvage surgery in osteosarcoma. Expert Rev Anticancer Ther. 2011 Feb; 11 (2):205-15. PMID:21342040 1969. Mangham DC,Athanasou NA. Guidelines for histopathological specimen examination and diagnostic reporting of primary bone tumours. Clin Sarcoma Res. 2011 Jul 25;1(1):6. PMID:22613930 1970. Mangham DC, Davie MW, Grimer RJ. Sarcoma arising in Paget's disease of bone: declining incidence and increasing age at presentation. Bone. 2009 Mar;44(3):431-6. PMID:19064007 1971. Mangham DC, Williams A, Lalam RK, et al. Angiomatoid fibrous histiocytoma of bone: a calcifying sclerosing variant mimicking osteosarcoma. Am J Surg Pathol. 2010 Feb;34⑵:279-85. PMID:20090505 1972. Manley PN, Abu-Abed S, Kirsch R, et al. Familial PDGFRA-mutation syndrome: somatic and gastrointestinal phenotype. Hum Pathol. 2018Jun;76:52-7. PMID:29486293 1973. Manner J, Radlwimmer B, Hohenberger P, et al. MYC high level gene amplification is a distinctive feature of angiosarcomas after irradiation or chronic lymphedema. Am J Pathol. 2010 Jan;176(1):34-9. PMID:20008140 1974. Marchand L, Decaussin-Petrucci M, Giraud S, et al. Hibernoma and multiple endocrine neoplasia type 1 syndrome: a non・ fortuitous association? A case report and literature review. Ann Endocrinol (Paris). 2017 Jul;78(3):194-7. PMID:28478946 1975. Marees T, Moll AC, Imhof SM, et al. Risk of second malignancies in survivors of retinoblastoma: more than 40 years of follow-up. J Natl Cancer Inst. 2008 Dec 17;100(24):1771-9. PMID:19066271 1976. Marek T, Mahan MA, Carter JM, et al. Lipomatosis of nerve and overgrowth: Is there a preference for motor (mixed) vs. sensory nerve involvement? Acta Neurochir (Wien). 2019 Apr;161 (4):679-84. PMID:30798481 1977. Marek T, Spinner RJ, Syal A, et al. Strengthening the association of lipomatosis of nerve and nerve-territory overgrowth: a systematic review. J Neurosurg. 2019 Mar 29:1-9. PMID:30925468 1978. Mariani O, Brennetot C, Coindre JM, et al. JUN oncogene amplification and overexpression block adipocytic differentiation in highly aggressive sarcomas. Cancer Cell. 2007Apr;11(4):361-74.PMID:17418412 1979. Marina N, Gebhardt M, Teot L, et al. Biology and therapeutic advances for pediatric osteosarcoma. Oncologist. 2004;9(4):422-41. PMID:15266096 1980. Marino-Enriquez A, Fletcher CD. Angiofibroma of soft tissue: clinicopathologic characterization of a distinctive benign fibrovascular neoplasm in a series of 37 cases. Am J Surg Pathol. 2012 Apr;36(4):500-8. PMID:22301504

1981. Marino-Enriquez A, Fletcher CD, Dal Cin P, et al. Dedifferentiated liposarcoma with "homologous” lipoblastic (pleomorphic liposarcoma-like) differentiation: clinicopathologic and molecular analysis of a series suggesting revised diagnostic criteria. Am J Surg Pathol. 2010 Aug;34(8):1122-31. PMID:20588177 1982. Marino-Enriquez A, Lauria A, Przybyl J, etal. BCOR internal tandem duplication in high­ grade uterine sarcomas. Am J Surg Pathol. 2018 Mar;42(3):33541. PMID:29200103' 1983. Marino-Enriquez A, Nascimento AF, Ligon AH, et al. Atypical spindle cell lipomatous tumor: clinicopathologic characterization of 232 cases demon strati ng a morphologic spectrum. Am J Surg Pathol. 2017 Feb;41 (2):234-44. PMID:27879515 1984. 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 Pathol. 2011 Jan;35⑴:135-44. PMID:21164297 1985. Marks E, Ewart M. Infantile digital fibroma: a rare fibromatosis. Arch Pathol Lab Med. 2016 Oct;140(10):1153-6. PMID:27684985 1986. Marshall-Taylor C, Fanburg-Smith JC. Hemosiderotic fibrohistiocytic lipomatous lesion: ten cases of a previously undescribed fatty lesion of the foot/ankle. Mod Pathol. 2000 Nov;13(11):1192-9. PMID:11106076 1987. Martignetti JA, Desnick RJ, Aliprandis E, et al. Diaphyseal medullary stenosis with malignant fibrous histiocytoma: a hereditary bone dysplasia/cancer syndrome maps to 9p21 22. Am J Hum Genet. 1999 Mar;64(3):801-7. PMID:10053015 1988. Martignetti JA, Tian L, Li D, et al. Mutations in PDGFRB cause autosomaldominant infantile myofibromatosis. Am J Hum Genet 2013 Jun 6;92⑹:1001-7. PMID:23731542 1989. Martignoni G, Gobbo S, Camparo P, et al. Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions. Mod Pathol. 2011 Oct;24(10):1313-9. PMID:21602817 1990. Martin C, McCarthy EF. Giant cell tumor of the sacrum and spine: series of 23 cases and a review of the literature. Iowa Orthop J. 2010;30:69-75. PMID:21045974 1991. Martin SE, Dwyer A, Kissane JM, et al. Small-cell osteosarcoma. Cancer. 1982 Sep 1;50(5):990-6. PMID:6953993 1992. Martin-Carbonero L, Barrios A, Saballs P, et al. Pegylated liposomal doxorubicin plus highly active antiretroviral therapy versus highly active antiretroviral therapy alone in HIV patients with Kaposi's sarcoma. AIDS. 2004 Aug 20;18(12):1737-40. PMID:15280789 1993. Martinez JA, Quecedo E, Fortea JM, et al. Pleomorphic angioleiomyoma. Am J Dermatopathol. 1996 Aug ;18(4) :409-12. PMID:8879307 1994. Martinez V, Sissons HA. Aneurysmal bone cyst. A review of 123 cases including primary lesions and those secondary to other bone pathology. Cancer. 1988 Jun 1;61 (11 ):2291-304. PMID:2835141 1995. Martins C, Fonseca I, Roque L, et al. PLAG1 gene alterations in salivary gland pleomorphic adenoma and carcinoma ex-pleomorphic adenoma: a combined study using chromosome banding, in situ hybridization and immunocytochemistry. Mod Pathol. 2005 Aug;18(8):1048-55. PMID:15920557 1996. Masciari S, Dillon DA, Rath M, et al. Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast Cancer Res Treat.

2012Jun;13303):1125-30. PMID:22392042 1997. Masciocchi C, Zugaro L, Arrigoni F, et al. Radiofrequency ablation versus magnetic resonance guided focused ultrasound surgery for minimally invasive treatment of osteoid osteoma: a propensity score matchinq study. Eur Radiol. 2016 Aug;26(8)-2472-8l PMID:26612546 1998. Mason EF, Hornick JL. Conventional risk stratification fails to predict progression of succinate dehydrogenase-deficient gastrointestinal stromal tumors: a clinicopathologic study of 76 cases. Am J Surg Pathol. 2016 Dec;40(12):1616-21 PMID:27340750 1999. Massei F, Laccetta G, Barrani M, et al Osteoid osteoma mimicking monoarticular juvenile idiopathic arthritis in a girl. Pediatr Int 2016Aug;58(8):791-4. PMID:27325304 2000. Massengill AD, Seeger LL, Eckardt JJ. The role of plain radiography, computed tomography, and magnetic resonance imaging in sarcoma evaluation. Hematol Oncol Clin North Am. 1995 Jun;9(3):571-604 PMID:7649943 2001. Massi D, Beltrami G, Mela MM, et al. Prognostic factors in soft tissue leiomyosarcoma of the extremities: a retrospective analysis of 42 cases. Eur J Surg Oncol. 2004 Jun;30⑸:56572. PMID:15135488 2002. Masson-Lecomte A, Rocher L, Ferlicot S, et al. High-flow priapism due to a malignant glomus tumor (glomangiosarcoma) of the corpus cavernosum. J Sex Med. 2011 Dec;8(12):3518-22. PMID:19912496 2003. Mastboom MJL, Hoek DM, Bovee JVMG, et al. Does CSF1 overexpression or rearrangement influence biological behaviour in tenosynovial giant cell tumours of the knee? Histopathology. 2019 Jan;74 ⑵:332~~40. PMID:30152874 2004. Mastboom MJL, Palmerini E, Verspoor FGM, et al. Surgical outcomes of patients with diffuse-type tenosynovial giant-cell tumours: an international, retrospective, cohort study. Lancet Oncol. 2019 Jun;20 ⑹:877-曲 PMID:31029509 2005. Mastboom MJL, Verspoor FGM, Verschoor AJ, et al. Higher incidence rates than previously known in tenosynovial giant cell tumors. Acta Orthop. 2017 Dec;88⑹:688-94. PMID:28787222 2006. Mastorakos G, Mitsiades NS, Doufas AG, et al. Hyperthyroidism in McCune-Albright syndrome with a review of thyroid abnormalities s仪ty years after the first report. Thyroid. 1997 Jun;7(3):433-9. PMID:9226216 2007. Mastrangelo T, Modena P, Tornielli S, et al. A novel zinc finger gene is fused to EWS in small round cell tumor. Oncogene. 2000 Aug 3;19(33):3799-804. PMID:10949935 2008. Masuda Y, Kurisaki-Arakawa A, Hara K, et al. A case of dedifferentiated solitary fibrous tumor of the thoracic cavity. Int J Clin Exp Pathol. 2013 Dec 15;7(1 ):386-93. PMID:24427361 2009. Matarazzo P, Lala R, Andreo M, et al. McCune-Albright syndrome: persistence of autonomous ovarian hyperfunction during adolescence and early adult age. J Pediatr Endocrinol Metab. 2006 May; 19 Suppl 2:60717. PMID:16789624 2010. Mathew J, Sen S, Chandi SM, et al. Pulmonary lipoblastoma: a case report. Pediatr Surg Int 2001 Sep;17(7):54M. PMID:11666056 2011. Matsubara M, Tanikawa H, Mogami Y, et al. Carpal tunnel syndrome due to fibrolipomatous hamartoma of the median nerve in Klippel-Trenaunay syndrome. A case report. J Bone Joint Surg Am. 2009 May;91 (5): 1223-7PMID:19411473

paybal：https://www.paypal.me/andy19801210 2012. Matsumoto K, Irie F, Mackem S, et al. A mouse model of chondrocyte-specific somatic mutation reveals a role for Ext1 loss of heterozygosity in multiple hereditary exostoses. Proc Natl Acad Sci USA. 2010 Jun 15:107(24):10932-7. PMID:20534475 2013. Matsumoto K, Ishizawa M, Okabe H, et al. Hemangioma of bone arising in the ulna: imaging findings with emphasis on MR. Skeletal Radiol. 2000Apr;29⑷:231-4. PMID:10855473 2014. Matsu no T, Unni KK, McLeod RA, et al. Telangiectatic osteogenic sarcoma. Cancer. 1976 Dec;38(6):253877. PMID:1069603 2015. Matsuoka K, Ueda M, Miyamoto Y. Giant intramuscular haemangioma of the chest wall with osteolytic change. Eur J Cardiothorac Surg. 2012 May;41 (5):1202-3. PMID:22219438 2016. Matsuura S, Ishii T, Endo M, et al. Epithelial and cartilaginous differentiation in clear cell chondrosarcoma. Hum Pathol. 2013 Feb;44(2):237-43. PMID:22944296 2017. Matsuyama A, Hisaoka M, Hashimoto H. Angioleiomyoma: a clinicopathologic and immunohistochemical reappraisal with special reference to the correlation with myopericytoma. Hum Pathol. 2007 Apr;38(4):645-51. PMID:17270242 2018. Matsuyama A, Hisaoka M, Shimajiri S, et al. Molecular detection of FUS-CREB3L2 fusion transcripts in low-grade fibromyxoid sarcoma using formalin-fixed, paraffin-embedded tissue specimens. Am J Surg Pathol. 2006 Sep;30(9): 1077-84. PMID:16931951 2019. Matsuyama A, Shiba E, Umekita Y, et al. Clinicopathologic diversity of undifferentiated sarcoma with BCOR-CCNB3 fusion: analysis of 11 cases with a reappraisal of the utility of immunohistochemistry for BCOR and CCNB3. Am J Surg Pathol. 2017 Dec;41(12):1713-21. PMID:28877060 2020. Matyakhina L, Pack S, Kirschner LS, et al. Chromosome 2 (2p16) abnormalities in Carney complex tumours. J Med Genet. 2003 Apr;40(4):268-77. PMID:12676898 2021. Mayr-Kanhauser S, Behmel A, Aberer W. Multiple glomus tumors of the skin with maleto-male transmission over four generations. J Invest Dermatol. 2001 Mar;116(3):475-6. PMID:11231328 2022. McBride MJ, Pulice JL, Beird HC, et al. The SS18-SSX fusion oncoprotein hijacks BAF complex targeting and function to drive synovial sarcoma. Cancer Cell. 2018 Jun 11;33(6):1128-1141.e7. PMID:29861296 2023. McCann JM, Tyler D Jr, Foss RD. Sino-orbital osteoma with osteoblastoma­ like features. Head Neck Pathol. 2015 Dec;9(4):503-6. PMID:25663319 2024. McCarter MD, Lewis JJ, Antonescu CR, et al. Extraskeletal osteosarcoma: analysis of outcome of a rare neoplasm. Sarcoma. 2000;4(3):119-23. PMID:18521290 2025. McCarthy AJ, Chetty R. Tumours composed of fat are no longer a simple diagnosis: an overview of fatty tumours with a spindle cell component. J Clin Pathol. 2018 Jun;71 (6):483-92. PMID:29358476 2026. McCarthy DM, Dorr CA, Mackintosh CE. Unilateral localised gigantism of the extremities with lipomatosis, arthropathy and psoriasis. J Bone Joint Surg Br. 1969 May;51 (2):348-53. PMID:5770417 2027. McCarthy EF, Dorfman HD. Vascular and cartilaginous hamartoma of the ribs in infancy with secondary aneurysmal bone cyst formation. Am J Surg Pathol. 1980 Jun;4(3):247-53. PMID:7396066 202& McCarthy EF, Lietman S, Argani P, et al. Endovascular papillary angioendothelioma (Dabska tumor) of bone. Skeletal Radiol. 1999 Feb;28⑵:100-3. PMID:10197456 2029. McCarville MB, MuzzafarS, Kao SC.etal.

Imaging features of alveolar soft-part sarcoma: a report from Children's Oncology Group Study ARST0332. AJR Am J Roentgenol. 2014 Dec;203(6):1345-52. PMID:25415714 2030. McCluggage WG, Connolly L, McBride HA. HMGA2 is a sensitive but not specific immunohistochemical marker of vulvovaginal aggressive angiomyxoma. Am J Surg Pathol. 2010 Jul;34(7): 1037-42. PMID:20551826 2031. McCluggage WG, Ganesan R, Hirschowitz L, et al. Cellular angiofibroma and related fibromatous lesions of the vulva: report of a series of cases with a morphological spectrum wider than previously described. Histopathology. 2004 Oct;45(4):360-8. PMID:15469474 2032. McCluggage WG, Lioe TF, McClelland HR, et al. Rhabdomyosarcoma of the uterus: report of two cases, including one of the spindle cell variant. Int J Gynecol Cancer. 2002 JanFeb;12(1):128-32. PMID:11860548 2033. McCluggage WG, Longacre TA, Fisher C. Myogenin expression in vulvovaginal spindle cell lesions: analysis of a series of cases with an emphasis on diagnostic pitfalls. Histopathology. 2013 Oct;63(4):545-50. PMID:23944986 ' 2034. McCormick C, Duncan G, Goutsos KT, et al. The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. Proc Natl Acad Sci USA. 2000 Jan 18;97(2):668-73. PMID:10639137 2035. McCormick D, Mentzel T, Beham A, etal. Dedifferentiated liposarcoma. Clinicopathologic analysis of 32 cases suggesting a better prognostic subgroup among pleomorphic sarcomas. Am J Surg Pathol. 1994 Dec;18(12):1213-23. PMID:7977944 2036. McGregor DB, Partensky C, Wilboum J, et al. An IARC evaluation of polychlorinated dibenzo-p-dioxi ns and polychlorinated dibenzofurans as risk factors in human carcinogenesis. Environ Health Perspect. 1998 Apr; 106 Suppl 2:755-60. PMID:9599727 2037. McHugh JB, Mukherji SK, Lucas DR. Sino-orbital osteoma: a clinicopathologic study of 45 surgically treated cases with emphasis on tumors with osteoblastoma-like features. Arch Pathol Lab Med. 2009 Oct;133(10):1587-93. PMID:19792048 2038. McIntyre BA, Brouillard P, Aerts V, et al. Glomulin is predominantly expressed in vascular smooth muscle cells in the embryonic and adult mouse. Gene Expr Patterns. 2004 May;4(3):351-8. PMID:15053987 2039. McLeod RA, Beabout JW. The 「oentgenographic features of chon droblastoma. Am J Roentgenol Radium Ther Nucl Med. 1973 Jun;118(2):464-71. PMID:4712761 2040. McLeod RA, Dahlin DC. Hamartoma (mesenchymoma) of the chest wall in infancy. Radiology. 1979 Jun;131 (3):657-61. PMID:441372 * 2041. McMaster MJ, Soule EH, Ivins JC. Hema ngiopericytoma. A clinicopathologic study and Iong-term followup of 60 patients. Cancer. 1975 Dec;36⑹:2232-44. PMID:1203874 2042. McMaster ML, Goldstein AM, Bromley CM, et al. Chordoma: incidenee and survival patterns in the United States, 1973-1995. Cancer Causes Control. 2001 Jan;12(1):1-11. PMID:11227920 2043. McMaster ML, Goldstein AM, Parry DM. Clinical features distinguish childhood chordoma associated with tuberous sclerosis complex (TSC) from chordoma in the general paediatric population. J Med Genet. 2011 Jul；48(7):444-9. PMID:21266383 2044. McMenamin ME, Calonje E. Intravascular myopericytoma. J Cutan Pathol. 2002 Oct;29(9):557-61. PMID:12358814

2045. McMenamin ME, Fletcher CD. Expanding the spectrum of malignant change in schwannomas: epithelioid malignant change, epithelioid malignant peripheral nerve sheath tumor, and epithelioid angiosarcoma: a study of 17 cases. Am J Surg Pathol. 2001 Jan;25(1 ):13-25. PMID:11145248 2046. McMenamin ME, Fletcher CD. Malignant myopericytoma: expanding the spectrum of tumours with myopericytic differentiation. Histopathology. 2002 Nov;41 (5):450-60. PMID:12405913 2047. McMenamin ME, Fletcher CD. Mammary-type myofibroblastoma of soft tissue: a tumor closely related to spindle cell lipoma. Am J Surg Pathol. 2001 Aug;25⑹H022-9. PMID:11474286 2048. McMonagle B, Connor S, Gleeson M. Venous haemangioma of the mandibular division of the trigeminal nerve. J Laryngol Otol. 2011 Jun;125(6):649-50. PMID:21356142 2049. McTighe S, Chernev I. Intramuscular lipoma: a review of the literature. Orthop Rev (Pavia). 2014 Dec 16;6(4):5618. PMID:25568733 2050. Medeiros F, Corless CL, Duensing A, et al. KIT-negative gastrointestinal stromal tumors: proof of concept and therapeutic implications. Am J Surg Pathol. 2004 Jul;28(7):889-94. PMID:15223958 2051. Medeiros F, Erickson-Johnson MR, Keeney GL, et al. Frequency and characterization of HMGA2 and HMGA1 rearrangements in mesenchymal tumors of the lower genital tract. Genes Chromosomes Cancer. 2007 Nov;46(11):981-90. PMID:17654722 2052. Mehnert F, Beschorner R, Kuker W, et al. Retroclival ecchordosis physaliphora: MR imaging and review of the literature. AJNR Am J Neuroradiol. 2004 Nov-Dec;25(10):1851-5. PMID:15569763 2053. Mehollin-Ray AR, Kozinetz CA, Schlesinger AE, et al. Radiographic abno rmalities in Rothmund-Thomson syndrome and genotype-phenotype correlation with RECQL4 mutation status. AJR Am J Roentgenol. 2008 Aug;191 ⑵:W62-6. PMID:18647888 2054. Meijer D, de Jong D, Pansuriya TC, et al. Genetic characterization of mesenchymal, clear cell, and dedifferentiated chondrosarcoma. Genes Chromosomes Cancer. 2012 Oct;51 (10):899-909. PMID:22674453 2055. Meijer D, Gelderblom H, Karperien M, et al. Expression of aromatase and estrogen receptor alpha in chondrosarcoma, but no beneficial effect of inhibiting estrogen signaling both in vitro and in vivo. Clin Sarcoma Res. 2011 Jul 25;1(1):5. PMID:22613849 2056. Meis JM, Dorfman HD, Nathanson SD, et al. Primary malignant giant cell tumor of bone: "dedifferentiated" giant cell tumor. Mod Pathol. 1989 Sep;2(5):541-6. PMID:2554283 2057. Meis JM, EnzingerFM. Chondroid lipoma. A unique tumor simulating liposarcoma and myxoid chondrosarcoma. Am J Surg Pathol. 1993 Nov;17(11):1103-12. PMID:8214255 2058. Meis JM, Enzinger FM. Juxta-articular myxoma: a clinical and pathologic study of 65 cases. Hum Pathol. 1992 Jun;23⑹:639-46. PMID:1592386 2059. Meis JM, Enzinger FM. Myolipoma of soft tissue. Am J Surg Pathol. 1991 Feb;15(2):1215. PMID:1703396 2060. Meis JM, Enzinger FM. Proliferative fasciitis and myositis of childhood. Am J Surg Pathol. 1992 Apr;16(4):364-72. PMID:1566969 2061. Meis JM, Raymond AK, Evans HL, et al. ■'Dedifferentiated" chordoma. A clinicopathologic and immunohistochemical study of three cases. Am J Surg Pathol. 1987

Jul;11(7):516-25. PMID:2440324 2062. Meis-Kindblom JM, Bergh P, Gunterberg B, et al. Extraskeletal myxoid chondrosarcoma: a reappraisal of its morphologic spectrum and prognostic factors based on 117 cases. Am J Surg Pathol. 1999 Jun;23⑹:636-50. PMID:10366145 2063. Meis-Kindblom JM, Kindblom LG. Acral myxoinflammatory fibroblastic sarcoma: a lowgrade tumor of the hands and feet. Am J Surg Pathol. 1998Aug;22(8):911-24. PMID:9706971 2064. Meis-Kindblom JM, Kindblom LG. Angiosarcoma of soft tissue: a study of 80 cases. Am J Surg Pathol. 1998 Jun;22⑹:68397. PMID:9630175 2065. Meis-Kindblom JM, Kindblom LG, Enzinger FM. Sclerosing epithelioid fibrosarcoma. A variant of fibrosarcoma simulating carcinoma. Am J Surg Pathol. 1995 Sep;19(9):979-93. PMID:7661286 2066. Meister P, Buckmann FW, Konrad E. Extent and level of fascial involvement in 100 cases with nodular fasciitis. Virchows Arch A Pathol Anat Histol. 1978 Oct 26;380⑵:仃7-85. PMID:153036 2067. Mejia-Guerrero S, Quejada M, Gokgoz N, et al. Characterization of the 12q15 MDM2 and 12q13-14 CDK4 amplicons and clinical correlations in osteosarcoma. Genes Chromosomes Cancer. 2010 Jun;49(6):51825. PMID:20196171 2068. Mello SS, Attardi LD. Deciphering p53 signaling in tumor suppression. Curr Opin Cell Biol.2018Apr;51:65-72. PMID:29195118 2069. Melloul S, Helias-Rodzewicz Z, CohenAubart F, et al. Highly sensitive methods are required to detect mutations in histiocytoses. Haematologica. 2019 Mar; 104(3):e97-9. PMID:30262559 2070. Meloni-Ehrig AM, Riggott L, Christacos NC, et al. A case of lipoblastoma with seven copies of chromosome 8. Cancer Genet Cytogenet. 2009 Apr 1;190(1):49-51. PMID:19264235 2071. Mendenhall WM, Mendenhall CM, Mendenhall NP. Solitary plasmacytoma of bone and soft tissues. Am J Otolaryngol. 2003 NovDec;24(6):395-9. PMID:14608572 2072. Mendenhall WM, Zlotecki R代 Scarborough MT. Dermatofibrosarcoma protuberans. Cance r. 2004 Dec 1;101(11):2503-8. PMID:15503305 2073. Mendlick MR, Nelson M, Pickering D, et al. Translocation t(1;3)(p36.3;q25) is a nonrandom aberration in epithelioid hemangioendothelioma. Am J Surg Pathol. 2001 May;25(5):684-7. PMID:11342784 2074. Meneses MF, Unni KK, Swee RG. Bizarre parosteal osteochondromatous proliferation of bone (Nora's lesion). Am J Surg Pathol. 1993 Jul;17(7):691-7. PMID:8317609 2075. Menke JR, Raleigh DR, Gown AM, et al. Somatostatin receptor 2a is a more sensitive diagnostic marker of meningioma than epithelial membrane antigen. Acta Neuropathol. 2015 Sep;130(3):441-3. PMID:26195322 2076. Mentzel T, Beham A, Calonje E, et al. Epithelioid hemangioe ndothelioma of skin and soft tissues: clinicopathologic and immunohistochemical study of 30 cases. Am J Surg Pathol. 1997 Apr;21 (4):363-74. PMID:9130982 2077. Mentzel T, Beham A, Katenkamp D, et al. Fibrosarcomatous ("high-grade") dermatofibrosarcoma protubera ns: clinicopathologic and immunohistochemical study of a series of 41 cases with emphasis on prognostic significance. Am J Surg Pathol. 1998 May;22(5):576-87. PMID:9591728 2078. Mentzel T, Calonje E, Fletcher CD. Lipoblastoma and lipoblastomatosis: a clinicopathological study of 14 cases.

Ref ere nces

575

paybal：https://www.paypal.me/andy19801210 Histopathology. 1993 Dec;23(6):527-33. PMID:8314236 2079. Mentzel T, Calonje E, Nascimento AG, et al. Infantile hemangiopericytoma versus infantile myofibromatosis. Study of a series suggesting a continuous spectrum of infantile myofibroblastic lesions. Am J Surg Pathol. 1994 Sep;18(9):922-30. PMID:8067513 2080. Mentzel T, Calonje E, Wadden C, et al. Myxofibrosarcoma. Clinicopathologic analysis of 75 cases with emphasis on the low-grade variant. Am J Surg Pathol. 1996Apr;20(4):391405. PMID:8604805 2081. Mentzel T, Dei Tos AP, Sapi Z, et al. Myopericytoma of skin and soft tissues: clinicopathologic and immunohistochemical study of 54 cases. Am J Surg Pathol. 2006 Jan;30(1):104-13. PMID:16330949 2082. Mentzel T, Dei Tos AP, Fletcher CD. Perineurioma (storiform perineurial fibroma): clinico-pathological analysis of four cases. Histopathology. 1994 Sep;25(3):261-7. PMID:7821894 2083. Mentzel T, Dry S, Katenkamp D, et al. Low-grade myofibroblastic sarcoma: analysis of 18 cases in the spectrum of myofibroblastic tumors. Am J Surg Pathol. 1998 Oct;22(10):1228-3& PMID:9777985 2084. 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 Aug;35(2):114-20. PMID:10460655 2085. Mentzel T, Katenkamp D. Sclerosing, pseudovascular rhabdomyosarcoma in adults. Clinicopathological and immunohistochemical analysis of three cases. Virchows Arch. 2000 Apr;436(4):305-11. PMID:10834531 2086. Mentzel T, Kutzner H. Reticular and plexiform perineurioma: clinicopathological and immunohistochemical analysis of two cases and review of perineurial neoplasms of skin and soft tissues. Virchows Arch. 2005 Oct;447(4):677-82. PMID:16133356 2087. Mentzel T, Mazzoleni G, Dei Tos AP, et al. Kaposiform hemangioendothelioma in adults. Clinicopathologic and immunohistochemical analysis of three cases. Am J Clin Pathol. 1997 Oct;108(4):450-5. PMID:9322599 208& Mentzel T, Palmedo G, Kuhnen C. Welldifferentiated spindle cell liposarcoma ('atypical spindle cell lipomatous tumor') does not belong to the spectrum of atypical lipomatous tumor but has a close relationship to spindle cell lipoma: clinicopathologic, immunohistochemical, and molecular analysis of s仪 cases. Mod Pathol. 2010 May;23(5):729-36. PMID:20228779 2089. Mentzel T, Reisshauer S, Riitten A, et al. Cutaneous clear cell myomelanocytic tumour: a new member of the growing family of perivascular epithelioid cell tumours (PEComas). Clinicopathological and immunohistochemical analysis of seven cases. Histopathology. 2005 May;46(5):498-504. PMID:15842631 2090. Mentzel T, Requena L, Brenn T. Atypical fibroxanthoma revisited. Surg Pathol Clin. 2017 Jun;10(2):319-35. PMID:28477883 2091. Mentzel T, Schildhaus HU, Palmedo G, et al. Postradiation cutaneous angiosarcoma after treatment of breast carcinoma is characterized by MYC amplification in contrast to atypical vascular lesions after radiotherapy and control cases: clinicopathological, immunohistochemical and molecular analysis of 66 cases. Mod Pathol. 2012 Jan;25(1):7585. PMID:21909081 2092. Mentzel T, Stengel B, Katenkamp D. [Retiform hemangioendothelioma. Clinico ・ pathologic case report and discussion of the

576

Refere nces

group of low malignancy vascular tumors], Pathologe. 1997 S即;18(5):390-4. German. PMID:9432675 2093. Merchant W, Calonje E, Fletcher CD. Inflammatory leiomyosarcoma: a morphological subgroup within the heterogeneous family of so-called inflammatory malignant fibrous histiocytoma. Histopathology. 1995 Dec;27(6):525-32. PMID:8838332 2094. Mertens F, Fletcher CD, Antonescu CR, et al. Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3L1 fusion gene. Lab Invest. 2005 Mar;85(3):40815. PMID:15640831 2095. Mertens F, Fletcher CD, Dal Cin P, et al. Cytogenetic analysis of 46 pleomorphic soft tissue sarcomas and correlation with morphologic and clinical features: a report of the CHAMP Study Group. Chromosomes and MorPhology. Genes Chromosomes Cancer. 1998 May;22(1 ):16-25. PMID:9591630 2096. Mertens F, Larramendy M, Gustavsson 代 et al. Radiation-associated sarcomas are characterized by complex karyotypes with frequent rearrangements of chromosome arm 3p. Cancer Genet Cytogenet. 2000 Jan 15;116(2):89-96. PMID:10640139 2097. Mertens F, Moller E, Mandahl N, et al. The t(X;6) in subungual exostosis results in transcriptional deregulation of the gene for insulin receptor substrate 4. Int J Cancer. 2011 Jan 15;128⑵:487-9h PMID:20340132 2098. Mertens F, Rydholm 代 Brosjd O, et al. Hibernomas are characterized by rearrangements of chromosome bands 11q1321. Int J Cancer. 1994 Aug 15;58(4):503-5. PMID:8056446 2099. Mertens F, Rydholm A, Kreicbergs A, et al. Loss of chromosome band 8q24 in sporadic osteocartilaginous exostoses. Genes Chromosomes Cancer. 1994 Jan;9(1):8-12. PMID:7507706 2100. Mertens F, Willen H, Rydholm A, et al. Trisomy 20 is a primary chromosome aberration in desmoid tumors. Int J Cancer. 1995 Nov 15;63⑷:527-9. PMID:7591262 2101. Mervak TR, Unni KK, Pritchard DJ, et al. Telangiectatic osteosarcoma. Clin Orthop Relat Res. 1991 Sep;(270):135-9. PMID:1884532 2102. Messiaen LM, Callens T, Mortier G, et al. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat. 2000;15(6):541-55. PMID:10862084 2103. Messina C, Christie D, Zucca E, et al. Primary and secondary bone lymphomas. Cancer Treat Rev. 2015 Mar;41 (3):235-46. PMID:25698636 2104. Messiou C, Bonvalot S, Gronchi A, et al. Evaluation of response after pre-operative radiotherapy in soft tissue sarcomas; the European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) and Imaging Group recommendations for radiological examination and reporting with an emphasis on magnetic resonance imaging. Eur J Cancer. 2016 Mar;56:37-44. PMID:26802529 2105. Meyer WH, Spunt SL. Soft tissue sarcomas of childhood. Cancer Treat Rev. 2004 May;30(3):269-80. PMID: 15059650 2106. Micci F, Panagopoulos I, Bjerkehagen B, et al. Deregulation of HMGA2 in an aggressive angiomyxoma with t(11;12)(q23;q15). Virchows Arch. 2006Jun;448(6):838-42. PMID:16568309 2107. Michal M. Inflammatory myxoid tumor of the soft parts with bizarre giant cells. Pathol Res Pract. 1998; 194(8):529-33. PMID:9779486 2108. Michal M. Retroperitoneal myolipoma. A tumour mimicking retroperitoneal

angiomyolipoma and liposarcoma with myosarcomatous differentiation. Histopathology. 1994Jul;25(1):86-8. PMID:7959650 2109. Michal M, Berry RS, Rubin BP, et al. EWSR1-SMAD3-rearranged fibroblastic tumor: an emerging entity in an increasingly more complex group of fibroblastic/myofibroblastic neoplasms. Am J Surg Pathol. 2018 Oct;42(10):1325-33. PMID:29957732 2110. Michal M, Fanburg-Smith JC, Lasota J, et al. Minute synovial sarcomas of the hands and feet: a clinicopathologic study of 21 tumors less than 1 cm. Am J Surg Pathol. 2006 Jun;30⑹:721-6. PMID:16723849 2111. Michal M, Fetsch JF, Hes O, et al. Nuchal-type fibroma: a clinicopathologic study of 52 cases. Cancer. 1999 Jan 1;85(1):156-63. PMID:9921988 2112. Michal M, Kazakov DV, Belousova I, et al. A benign neoplasm with histopathological features of both schwannoma and retiform perineurioma (benign schwannomaperineurioma): a report of six cases of a distinctive soft tissue tumor with a predilection for the fingers. Virchows Arch. 2004 Oct;445(4):347-53. PMID:15322875 2113. Michal M, Kazakov DV, Hadravsky L, et al. Lipoblasts in spindle cell and pleomorphic lipomas: a close scrutiny. Hum Pathol. 2017 Jul;65:140-6. PMID:28546131 2114. Michal M, Miettinen M. Myoepitheliomas of the skin and soft tissues. Report of 12 cases. Virchows Arch. 1999 May;434(5):393-400. PMID:10389622 2115. Michel BC, D'Avino AR, Cassel SH, et al. A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation. Nat Cell Biol. 2018 Dec;20(12):1410-20. PMID:30397315 2116. Micheli A, Trapani S, Brizzi I, et al. Myositis ossificans circumscripta: a paediatric case and review of the literature. Eur J Pediatr. 2009 May; 168(5):523-9. PMID:19130083 2117. 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 Jul;12(7):7228. PMID:10430277 2118. Miettine n M, Fanburg-Smith JC, Virolainen M, et al. Epithelioid sarcoma: an immunohistochemical analysis of 112 classical and variant cases and a discussion of the differential diagnosis. Hum Pathol. 1999 Aug;30(8):93442. PMID:10452506 2119. Miettinen M, Felisiak-Golabek A, Wang Z, et al. GIST manifest!ng as a retroperitoneal tumor: clinicopathologic immunohistochemical, and molecular genetic study of 112 cases. Am J Surg Pathol. 2017 May;41 ⑸:577-85. PMID:28288036 2120. Miettinen M, Fetsch JF. Collagenous fibroma (desmoplastic fibroblastoma): a clinicopathologic analysis of 63 cases of a distinctive soft tissue lesion with stellate-shaped fibroblasts. Hum Pathol. 1998 Jul;290):67682. PMID:9670823 2121. Miettinen M, Fetsch JF. Distribution of keratins in normal endothelial cells and a spectrum of vascular tumors: implications in tumor diagnosis. Hum Pathol. 2000 Sep;31 (9): 1062-7. PMID:11014572 2122. Miettinen M, Fetsch JF, Sobin LH, et al. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol. 2006 Jan;30(1):90-6. PMID:16330947 2123. Miettinen M, Finnell V, Fetsch JF. Ossifying fibromyxoid tumor of soft parts-a clinicopathologic and immunohistochemical study of 104 cases with long-term follow-up and a critical review of the literature. Am J Surg Pathol. 2008 Jul;32(7):996-1005.

PMID:18469710 2124. Miettinen M, Furlong M, Sarlomo-Rika|a M, et al. Gastrointestinal stromal tumors intramural leiomyomas, and leiomyosarcomas in the rectum and anus: a clinicopathologic immunohistochemical, and molecular genetic study of 144 cases. Am J Surg Pathol 2001 Sep;25(9):1121-33. PMID:11688571 2125. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 2006 May;23(2):70-83. PMID:17193820 2126. Miettinen M, Lasota J, Sobin LH Gastrointestinal stromal tumors of the stomach in children and young adults: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases with long-term follow-up and review of the literature. Am J Surg Pathol 2005 Oct;29(10):1373-81. PMID:16160481 2127. Miettinen M, Lehto VP, Virtanen I Malignantfibrous histiocytoma within a recurrent chordoma. A light microscopic, electron microscopic, and immunohistochemical study. Am J Clin Pathol. 1984 Dec;82(6):738-43 PMID:6095644 2128. Miettinen M, Limon J, Niezabitowski A, et al. Patterns of keratin polypeptides in 110 biphasic, monophasic, and poorly differentiated synovial sarcomas. Virchows Arch. 2000 Sep;437(3):275-83. PMID:11037348 2129. Miettinen M, Lindenmayer AE, Chaubal A. Endothelial cell markers CD31, CD34, and BNH9 antibody to H- and Y-antigensevaluation of their specificity and sensitivity in the diagnosis of vascular tumors and comparison with von Willebrand factor. Mod Pathol. 1994Jan;7(1):82-90. PMID:7512718 2130. Miettinen M, Makhlouf H, Sobin LH, et al. Gastrointestinal stromal tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long­ term follow-up. Am J Surg Pathol. 2006 Ap「;30⑷:477-89. PMID:16625094 2131. Miettinen M, McCue PA, SarlomoRikala M, et al. Sox10-a marker for not only schwannian and melanocytic neoplasms but also myoepithelial cell tumors of soft tissue: a systematic analysis of 5134 tumors. Am J Surg Pathol. 2015 Jun;39(6):826-35. PMID:25724000 2132. Miettinen M, Paal E, Lasota J, et al. Gastrointestinal glomus tumors: a clinicopathologic, immunohistochemical, and molecular genetic study of 32 cases. Am J Surg Pathol. 2002 Mar;26(3):301-11. PMID:11859201 2133. Miettinen M, Sarlomo-Rikala M, Sobin LH, et al. Esophageal stromal tumors: a clinicopathologic, immunohistochemical, and molecular genetic study of 17 cases and comparison with esophageal leiomyomas and leiomyosarcomas. Am J Surg Pathol. 2000 Feb;24(2):211-22. PMID:10680889 2134. Miettinen M, Sarlomo-Rikala M, Sobin LH, et al. Gastrointestinal stromal tumors and leiomyosarcomas in the colon: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases. Am J Surg Pathol. 2000 Oct;24(10):1339-52. PMID:11023095 2135. Miettinen M, Sobin LH, Lasota JGastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol. 2005 Jan;29(1):52-68. PMID:15613856 2136. Miettinen M, Sobin LH, Lasota J. True smooth muscle tumors of the small intestine, a clinicopathologic, immunhistochemical,日n molecular genetic study of 25 cases. Am J S黑 Pathol. 2009 Mar;33(3):430-6. PMID:18971781

paybal：https://www.paypal.me/andy19801210 2137. Miettinen M, Wang Z, Sarlomo-Rikala M, et al. ERG expression in epithelioid sarcoma: a diagnostic pitfail. Am J 8urg Pathol. 2013 Oct;37(10):1580-5. PMID:23774169 2138. Miettinen M, Wa叩 ZF. Proxl transcription factor as a marker for vascular tumorsevaluation of 314 vascular endothelial and 1086 nonvascular tumors. Am J Surg Pathol. 2012 Mar;36(3):351-9. PMID:22067331 2139. Miettinen M, Wang ZF, Lasota J. DOG1 antibody in the differential diagnosis of gastrointestinal stromal tumors: a study of 1840 cases. Am J Surg Pathol. 2009 S即;33(9):1401-8. PMID:19606013 2140. Miettinen M, Wang ZF, Paetau A, et al. ERG transcription factor as an immunohistochemical marker for vascular endothelial tumors and prostatic carci noma. Am J Surg Pathol. 2011 Mar;35(3):432-41. PMID:21317715 2141. Miettinen M, Wang ZF, SarlomoRikala M, et al. Succinate dehydrogenase­ deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol. 2011 Nov;35(11 ):1712-21. PMID:21997692 2142. Miettinen MM, Antonescu CR, Fletcher CDM, et al. Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis 1-a consensus overview. Hum Pathol. 2017 Sep;67:1-10.PMID:28551330 2143. Mihic-Probst D, Zhao J, Saremaslani P, et al. CGH analysis shows genetic similarities and differences in atypical fibroxanthoma and undifferentiated high grade pleomorphic sarcoma. Anticancer Res. 2004 JanFeb;24(1 ):19-26. PMID:15015571 2144. Mikesell KV, KulaylatAN, Donaldson KJ, et al. A rare soft tissue tumor masquerading as a parathyroid adenoma in a patient with Birt-Hogg-Dube syndrome and multiple cervical endocrinopathies. Case Rep Pathol. 2014;2014:753694. PMID:25610687 2145. Miki Y, Abe S, Tokizaki T, et al. Imaging characteristics of calcified leiomyoma of deep soft tissue. J Orthop Sci. 2007 Nov;12(6):6015,PMID:18040645 2146. Milchgrub S, Ghandur-Mnaymneh L, Dorfman HD, et al. Synovial sarcoma with extensive osteoid and bone formation. Am J Surg Pathol. 1993 Apr;17(4):357-63. PMID:7684201 2147. Miller KK, Daly PA, Sentochnik D, et al. Pseudo-Cushing's syndrome in human immunodeficiency virus-infected patients. Clin Infect Dis. 1998 Jul;27(1):68-72. PMID:9675454 2148. Miller TT. Bone tumors and tumorlike conditions: analysis with conventional radiography. Radiology. 2008 Mar;246(3):66274. PMID:18223119 2149. Miller-Breslow A, Dorfma n HD. Dupuytren's (subungual) exostosis. Am J Surg Pathol. 1988 May; 12⑸:368-78. PMID:3284396 2150. Mills AM, Beck AH, Montgomery KD, et al. Expression of subtype-specific group 1 leiomyosarcoma markers in a wide variety of sarcomas by gene expression analysis and immunohistochemistry. Am J Surg Pathol. 2011 Apr;35⑷:583-9. PMID:21412072 2151. Minkov M, Grois N, Heitger A, et al. Response to initial treatment of multisystem Langerhans cell histiocytosis: an important prognostic indicator. Med Pediatr Oncol. 2002 Dec;39(6):581-5. PMID:12376981 2152. Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the

Surveillance, Epidemiology, and End Results Program. Cancer. 2009 Apr 1;115(7):1531-43. PMID:19197972 2153. Miranda C, Nucifora M, Molinari F, et al. KRAS and BRAF mutations predict primary resistance to imatinib in gastrointestinal stromal tumors. Clin Cancer Res. 2012 Mar 15:18(6):1769-76. PMID:22282465 2154. Mirra JM, Bullough PG, Marcove RC, et al. Malignant fibrous histiocytoma and osteosarcoma in association with bone infarcts; report of four cases, two in caisson workers. J Bone Joint Surg Am. 1974 Jul;56(5):932-40. PMID:4367886 2155. Mirra JM, Gold R, Downs J, et al. A new histologic approach to the differentiation of enchondroma and chondrosarcoma of the bones. A clinicopathologic analysis of 51 cases. Clin Orthop Relat Res. 1985 Dec;(201 ):214-37. PMID:4064409 2156. Mirra JM, Kessler S, Bhuta S, et al. The fibroma-like variant of epithelioid sarcoma. A fibrohistiocytic/myoid cell lesion often confused with benign and malignant spindle cell tumors. Cancer. 1992 Mar 15;69(6):1382-95. PMID:1371711 2157. Mirza B, Weedon D. Atypical fibroxanthoma: a clinicopathological study of 89 cases. Australas J Dermatol. 2005 Nov;46⑷:235-& PMID:16197421 2158. Mishra SS, Senapati SB, Dhir MK, et al. Intracranial giant cell tumor of soft tissue: mimicking a glioma. Neurol India. 2013 MarApr;61 ⑵:192-3・ PMID:23644334 2159. Missiaglia E, Williamson D, Chisholm J, et al. PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification. J Clin Oncol. 2012 May 10;30(14):1670-7. PMID:22454413 2160. Mitelman F, Johansson B, Mertens F. Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer [Internet]. Bethesda (MD): National Cancer Institute; 2019. Available from: https://cgap.nci. nih.gov/Chromosomes/Mitelman. 2161. Mito JK, Mitra D, Doyle LA. Radiationassociated sarcomas: an update on clinical, histologic, and molecular features. Surg Pathol Clin. 2019 Mar;12(1 ):139-48. PMID:30709440 2162. Mittal S, Goswami C, Kanoria N, et al. Post-irradiati on an giosarcoma of bone. J Cancer Res Ther. 2007 Apr-Jun;3(2):96-9. PMID:17998731 2163. Miyajima K, Oda Y, Oshiro Y, et al. Clinicopathological prognostic factors in soft tissue leiomyosarcoma: a multivariate analysis. Histopathology. 2002 Apr;40(4):353-9. PMID:11943020 2164. Miyano G, Hayashi T, Arakawa A, et al. Giant omental lipoblastoma and CD56 expression. Afr J Paediatr Surg. 2013 JanApr; 10(1):32-4. PMID:23519855 2165. Mo D, Zhao Y, Balajee AS. Human RecQL4 helicase plays multifaceted roles in the genomic stability of normal and cancer cells. Cancer Lett. 2018 Jan 28;413:1-10. PMID:29080750 2166. Mobley BC, McKenney JK, Bangs CD, et al. Loss of SMARCB1/INI1 expression in poorly differentiated chordomas. Acta Neuropathol. 2010 Dec;120(6):745-53. PMID:21057957 2167. Mohajeri A, Tayebwa J, Collin A, et al. Comprehensive genetic analysis identifies a pathognomonic NAB2/STAT6 fusion gene, nonrandom secondary genomic imbalances, and a characteristic gene expression profile in solitary fibrous tumor. Genes Chromosomes Cancer. 2013 Oct;52(10):873-86. PMID:23761323 2168. Mohamed AN, Zalupski MM, Ryan JR, et al. Cytogenetic aberrations and DNA ploidy

in soft tissue sarcoma. A Southwest Oncology Group study. Cancer Genet Cytogenet. 1997 Nov;99⑴:45-53. PMID:9352795 2169. Mohseny AB, Szuhai K, Romeo S, et al. Osteosarcoma originates from mesenchymal stem cells in consequence of aneuploidization and genomic loss of Cdkn2. J Pathol. 2009 Nov;219(3):294-305. PMID:19718709 2170. Moller E, Hornick JL, Magnusson L, et al. FUS-CREB3L2/L1 -positive sarcomas show a specific gene expression profile with up regulation of CD24 and FOXL1. Clin Cancer Res. 2011 May 1;17(9):2646-56. PMID:21536545 2171. Momeni P, Glockner G, Schmidt O, et al. Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhinophalangeal syndrome type I. Nat Genet. 2000 Jan;24(1):71-4. PMID:10615131 2172. Momosaka D, Togao O, Hiwatashi A, et al. Spindle cell/sclerosing rhabdomyosarcoma with intracranial invasion without destroying the bone of the skull base: a case report and literature review. Acta Radiol Open. 2017 Aug 18;6(8):2058460117727316. PMID:28839951 2173. Monaghan H, Salter DM, Al-Nafussi A. Giant cell tumour of tendon sheath (localised nodular tenosynovitis): clinicopathological features of 71 cases. J Clin Pathol. 2001 May;54(5):404-7. PMID:11328844 2174. Monda L, Wick MR. S-100 protein immunostaining in the differential diagnosis of chondroblastoma. Hum Pathol. 1985 Mar;16(3):287-93. PMID:2579018 2175. Monnat RJ Jr. Cancer pathogenesis in the human RecQ helicase deficiency syndromes. In: Goto M, Miller RW, editors. From premature gray hair to helicase ・ Werner syndrome: implications for aging and cancer. Tokyo (Japan): Japan Scientific Societies Press; 2001. (Gann Monograph on Cancer Research No. 49). pp. 83-94. 2176. Montgomery E, Epstein JI. Anastomosing hemangioma of the genitourinary tract: a lesion mimicking angiosarcoma. Am J Surg Pathol. 2009 Sep;33(9):1364-9. PMID:19606014 2177. Montgomery E, Goldblum JR, Fisher C. Myofibrosarcoma: a clinicopathologic study. Am J Surg Pathol. 2001 Feb;25(2):219-28. PMID:11176071 2178. Montgomery E, Lee JH, Abraham SC, et al. Superficial fibromatoses are genetically distinct from deep fibromatoses. Mod Pathol. 2001 Jul;14(7):695-701. PMID:11455002 2179. Montgomery EA, Devaney KO, Giordano TJ, et al. Inflammatory myxohyaline tumor of distal extremities with virocyte or ReedSternberg-like cells: a distinctive lesion with features simulating inflammatory conditions, Hodgkin's disease, and various sarcomas. Mod Pathol. 1998Apr;11(4):384-91. PMID:9578090 2180. Montgomery EA, Meis JM. Nodular fasciitis. Its morphologic spectrum and immunohistochemical profile. Am J Surg Pathol. 1991 Oct;15(10):942-8. PMID:1928550 2181. Montgomery EA, Meis JM, Mitchell MS, et al. Atypical decubital fibroplasia. A distinctive fibroblastic pseudotumor occurring in debilitated patients. Am J Surg Pathol. 1992 Jul;16(7):708-15. PMID:1530110 2182. Moon NF. Adamantinoma of the appendicular skeleton in children. Int Orthop. 1994; 18(6):379-88. PMID:7698872 2183. Moore Dalal K, Antonescu CR, Dematteo RP, et al. EBV-associated smooth muscle neoplasms: solid tumors arising in the presence of immunosuppression and autoimmune diseases. Sarcoma. 2008;2008:859407. PMID:19079588 2184. Moore PS, Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and those without

HIV infection. N Engl J Med. 1995 May 4;332(18):1181-5. PMID:7700310 2185. Moore TE, King AR, Kathol MH, et al. Sarcoma in Paget disease of bone: clinical, radiologic, and pathologic features in 22 cases. AJR Am J Roentgenol. 1991 Jun;156(6):1199203. PMID:2028867 2186. Moosavi C, Jha P, Fanburg-Smith JC. An update on plexiform fibrohistiocytic tumor and addition of 66 new cases from the Armed Forces Institute of Pathology, in honor of Franz M. Enzinger, MD. Ann Diagn Pathol. 2007 Oct;11(5):313-9. PMID:17870015 2187. Moosavi CA, Al-Nahar LA, Murphey MD, et al. Fibroosseous [corrected] pseudotumor of the digit: a clinicopathologic study of 43 new cases. Ann Diagn Pathol. 2008 Feb;12(1):21-8. PMID:18164411 2188. Moran CA, Suster S. Angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma) of the lung: a clinicopathologic and immunohistochemical study of two cases. Am J Clin Pathol. 2005 May; 123(5):762-5. PMID:15981816 2189. Moreau LC, Turcotte R, Ferguson P, et al. Myxoidcell liposarcoma (MRCLS) revisited: an analysis of 418 primarily managed cases. Ann Surg Oncol. 2012 Apr;19(4):1081-8. PMID:22052112 2190. Morency E, Laskin W, Lin X. Cytologic and histologic features of pleomorphic undifferentiated sarcoma arising in a hybrid hemosiderotic fibrolipomatous tumor and pleomorphic hyalinizing angiectatic tumor: report of an unusual case with a literature review. Acta Cytol. 2015;59 ⑹:493-7. PMID:26841226 2191. Morerio C, Nozza P, Tassano E, et al. Differential diagnosis of lipoma-like lipoblastoma. Pediatr Blood Cancer. 2009 Jan;52(1):132-4. PMID:18798558 2192. Morerio C, Rapella A, Rosanda C, et al. PLAG1-HAS2 fusion in lipoblastoma with masked 8q intrachromosomal rearrangement. Cancer Genet Cytogenet. 2005 Jan 15;156⑵:183-4. PMID:15642402 2193. Moretti VM, Brooks JS, Ogilvie CM. Case report: hemosiderotic fibrohistiocytic lipomatous lesion: a clinicopathologic characterization. Clin Orthop Relat Res. 2010 Oct;468(10):2808-13. PMID:20127213 2194. Morgan MB, Swann M, Somach S, et al. Cutaneous an giosarcoma: a case series with prognostic correlation. J Am Acad Dermatol. 2004 Jun;50⑹:867-74. PMID:15153886 2195. Mori T, Nakayama R, Endo M, et al. Forty-eight cases of leiomyosarcoma of bone in Japan: a multicenter study from the Japanese musculoskeletal on cology group. J Surg On col. 2016 Sep;114(4):495-500. PMID:27302734 2196. Morioka H, Takahashi S, Araki N, et al. Results of sub-analysis of a phase 2 study on trabectedin treatment for extraskeletal myxoid chondrosarcoma and mesenchymal chondrosarcoma. BMC Cancer. 2016 Jul 14;16:479. PMID:27418251 2197. Morosi C, Stacchiotti S, Marchiano A, et al. Correlation between radiological assessment and histopathological diagnosis in retroperitoneal tumors: analysis of 291 consecutive patients at a tertiary reference sarcoma center. Eur J Surg Oncol. 2014 Dec;40(12): 1662-70. PMID:25454827 2198. Morotti RA, Nicol KK, Parham DM, et al. An immunohistochemical algorithm to facilitate diagnosis and subtyping of rhabdomyosarcoma: the Childrerfs dncology Group experience. Am J Surg Pathol. 2006 Aug;30⑹:962-8. PMID:16861966 2199. Morris-Stiff G, Falk GA, El-Hayek K, et al. Jejunal cavernous lymphangioma. BMJ Case Rep. 2011 May 12;2011:bcr0320114022.

Refere nces

577

paybal：https://www.paypal.me/andy19801210 PMID:22696733 2200. Mortensen A, Bojsen-Moller M, Rasmussen P. Fibrous dysplasia of the skull with acromegaly and sarcomatous transformation. Two cases with a review of the literature. J Neurooncol. 1989 May;7⑴:25-9. PMID:2754454 2201. Moser MJ, Bigbee WL, Grant SG, et al. Genetic instability and hematologic disease risk in Werner syndrome patients and heterozygotes. Cancer Res. 2000 May 1;60(9):2492-6. PMID:10811130 2202. Moser RP Jr, Kransdorf MJ, Gilkey FW, et al. From the archives of the AFIP. Giant cell tumor of the upper extremity. Radiographics. 1990 Jan;10(1):83-102. PMID:2296699 2203. Moses AV, Jarvis MA, Raggo C, et al. A functional genomics approach to Kaposi's sarcoma. Ann N Y Acad Sci. 2002 Dec;975:180-91. PMID:12538164 2204. Mosheimer BA, Oppl B, Zandieh S, et al. Bone involvement in Rosai-Dorfman disease (RDD): a case report and systematic literature review. Curr Rheumatol Rep. 2017 May;19(5):29. PMID:28401384 2205. Mosquera JM, Fletcher CD. Expanding the spectrum of malignant progression in solitary fibrous tumors: a study of 8 cases with a discrete anaplastic component-ls this dedifferentiated SFT? Am J Surg Pathol. 2009 Sep;33(9):1314-21. PMID:19718788 2206. Mosquera JM, Sboner A, Zhang L, et al. Novel MIR143-NOTCH fusions in benign and malignant glomus tumors. Genes Chromosomes Cancer. 2013 Nov;52(11):107587. PMID:23999936 2207. Mosquera JM, Sboner A, Zhang L, et al. Recurrent NCOA2 gene rearrangements in congenital/infantile spindle cell rhabdomyosarcoma. Genes Chromosomes Cancer. 2013 Jun;52(6):538-50. PMID:23463663 2208. Mountricha A, Zotalis N, Giannakou N, et al. Osteochondromyxoma of maxilla: case report. Skull Base. 2009; 19(S 02):A101. doi:10.1055/s-2009-1224448. 2209. Mravic M, LaChaud G, Nguyen A, et al. Clinical and histopathological diagnosis of glomus tumor: an institutional experience of 138 cases. I nt J Surg Pathol. 2015 May;23(3):1818. PMID:25614464 2210. Mukai M, Torikata C, Iri H, et al. Immunohistochemical identificatio n of aggregated actin filaments in formalinfixed, paraffin-embedded sections. I. A study of infantile digital fibromatosis by a new pretreatment. Am J Surg Pathol. 1992 Feb;16⑵:110-5. PMID:1310240 2211. Mukai M, Torikata C, Iri H, et al. Infantile digital fibromatosis. An electron microscopic and immunohistochemical study. Acta Pathol Jpn. 1986 Nov;36(11):1605-15. PMID:3811906 2212. Mukaihara K, Tanabe Y, Kubota D, et al. Cabozantinib and dastinib exert anti-tumor activity in alveolar soft part sarcoma. PLoS One. 2017 Sep 25;12(9):e0185321. PM ID28945796 2213. Mukherjee D, Chaichana KL, Gokaslan ZL, et al. Survival of patients with malignant primary osseous spinal neoplasms: results from the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2003. J Neurosurg Spine. 2011 Feb;14(2):143-50. PMID:21184634 2214. Mundada P, Becker M, Lenoir V, et al. High resolution MRI of nail tumors and tumor­ like conditions. Eur J Radiol. 2019 Mar;112:93105. PMID:30777226 2215. Mungo DV, Zhang X, O'Keefe RJ, et al. COX-1 and COX-2 expression in osteoid osteomas. J Orthop Res. 2002 Jan;20(1):15962. PMID:11853083 2216. Muramatsu K, lhara K, Tani Y, et al.

578

References

Intramuscular hemangioma of the upper extremity in infants and children. J Pediatr Orthop. 2008 Apr-May;28 ⑶:387-90. PMID:18362809 22仃.Muramatsu K, Iwanaga R, Sakai T. Synovial hemangioma of the knee joint in pediatrics: our case series and review of literature. Eur J Orthop Surg Traumatol. 2019 Aug;29(6):1291-6. PMID:30980138 2218. Muroya K, Nishimura G, Douya H, et al. Diaphyseal medullary stenosis with malignant fibrous histiocytoma: further evidenee for loss of heterozygosity involving 9p21-22 in tumor tissue. Genes Chromosomes Cancer. 2002 Mar;33(3):326-8. PMID:11807991 2219. Murphey MD, Carroll JF, Flemming DJ, et al. From the archives of the AFIP: benign musculoskeletal lipomatous lesions. Radiographics. 2004 Sep-Oct;24(5):1433-66. PMID:15371618 2220. Murphey MD, Choi JJ, Kransdorf MJ, et al. Imaging of osteochondroma: variants and complications with radiologic-pathologic correlation. Radiographics. 2000 SepOct;20(5):1407-34. PMID:10992031 2221. Murphey MD, Jelinek JS, Temple HT, et al. Imaging of periosteal osteosarcoma: radiologic-pathologic comparison. Radiology. 2004 Oct;233(1):129-38. PMID:15333772 ' 2222. Murphey MD, Johnson DL, Bhatia PS, et al. Parosteal lipoma: MR imaging characteristics. AJR Am J Roentgenol. 1994 Jan;162(1):105-10. PMID:8273646 2223. Murphey MD, Nomikos GC, Flemming DJ, et al. From the archives of AFIP. Imaging of giant cell tumor and giant cell reparative granuloma of bone: radiologic-pathologic correlation. Radiographics. 2001 SepOct;21(5):1283-309. PMID:11553835 2224. Murphey MD, Rhee JH, Lewis RB, et al. Pigmented villonodular synovitis: radiologicpathologic correlation. Radiographics. 2008 Sep-Oct;28(5):1493-518. PMID:18794322 2225. Murphey MD, Vidal JA, Fanburg-Smith JC, et al. Imaging of synovial chondromatosis with radiologic-pathologic correlation. Radiographics. 2007 Sep-Oct;27(5):1465-88. PMID:17848703 2226. Murphey MD, Walker EA, Wilson AJ, et al. From the archives of the AFIP: imaging of primary chondrosarcoma: radiologic-pathologic correlation. Radiographics. 2003 SepOct;23(5):1245-78. PMID:12975513 2227. Murphey MD, wan Jaovisidha S, Temple HT, et al. Telangiectatic osteosarcoma: radiologic-pathologic comparison. Radiology. 2003 Nov;229(2):545-53. PMID:14512511 " 2228. Murphy BA, Kilpatrick SE, Panella MJ, et al. Extra-acral calcifying aponeurotic fibroma: a distinctive case with 23-year follow-up. J Cutan Pathol. 1996 Aug;23(4):369-72. PMID:8864926 2229. Musso N, Caronia FP, Castorina S, et al. Somatic loss of an EXT2 gene mutation during malignant progress!on in a patient with hereditary multiple osteochondromas. Cancer Genet. 2015 Mar;208⑶:62-7. PMID:25744876 2230. Musumeci O, Barca E, Lamperti C, et al. Lipomatosis incidence and characteristics in an Italian cohort of mitochondrial patients. Front Neurol. 2019 Feb 27;10:160. PMID:30873109 2231. Myers BW, Masi AT. Pigmented villonodular synovitis and tenosynovitis: a clinical epidemiologic study of 166 cases and literature review. Medicine (Baltimore). 1980 May;59(3):223-38. PMID:7412554 2232. Myhre-Jensen O. A consecutive 7-year series of 1331 benign soft tissue tumours. Clinicopathologic data. Comparison with sarcomas. Acta Orthop Scand. 1981 Jun;52(3):287-93. PMID:7282321 2233. Myhre-Jensen O, Kaae S, Madsen EH, et al. Histopathological grading in soft-tissue

tumours. Relation to survival in 261 surgically treated patients. Acta Pathol Microbiol Immunol Scand A. 1983 Mar;91 (2):145-50. PMID:6846018 2234. Mylona S, Patsoura S, Galani P, et al. Osteoid osteomas in common and in technically challenging locations treated with computed tomography-guided percutaneous radiofrequency ablation. Skeletal Radiol. 2010 May;39(5):443-9. PMID:20066410 2235. Nagai M, Tanaka S, Tsuda M, et al. Analysis of transforming activity of human synovial sarcoma-associated chimeric protein SYT-SSX1 bound to chromatin remodeling factor hBRM/hSNF2 alpha. Proc Natl Acad Sci USA. 2001 Mar 27;98(7):3843-8. PMID:11274403 2236. Nagamine N, Nohara Y, Ito E. Elastofibroma in Okinawa. A clinicopathologic study of 170 cases. Cancer. 1982 Nov 1;50(9):1794-805. PMID:7116305 2237. Nagano Y, Uchida K, Inoue M, et al. Mesenteric lipoblastoma presenting as a small intestinal volvulus in an infant: a case report and literature review. Asian J Surg. 2017 Jan;40(1):70-3. PMID:28034384 2238. Nagira K, Yamamoto T, Akisue T, et al. Scrape and fine-needle aspiration cytology of extraskeletal osteosarcoma. Diagn Cytopathol. 2002 Sep;27(3):177-80. PMID:12203867 2239. Naka T, Fukuda T, Shinohara N, et al. Osteosarcoma versus malignant fibrous histiocytoma of bone in patients older than 40 years. A clinicopathologic and immunohistochemical analysis with special reference to maligna nt fibrous histiocytoma­ like osteosarcoma. Cancer. 1995 Sep 15;76(6):972-84. PMID:8625223 2240. Nakajima H, Sim FH, Bond JR, et al. Small cell osteosarcoma of bone. Review of 72 cases. Cancer. 1997 Jun 1;79(11):2095-106. PMID:9179055 2241. Nakane T, Tando T, Aoyagi K, et al. Dysspondyloenchondromatosis: another COL2A1-related skeletal dysplasia? Mol Syndromol. 2011 Dec;2(1):21-6. PMID:22570642 2242. Nakanishi K, Yoshikawa H, Ueda T, et al. Postradiation sarcomas of the pelvis after treatment for uterine cervical cancer: review of the CT and MR findings of five cases. Skeletal Radiol. 2001 Mar;30 ⑶H32-7. PMID:11357450 2243. Nakayama R, Jagannatha n JP, Ramaiya N, et al. Clinical characteristics and treatment outcomes in six cases of malignant tenosynovial giant cell tumor: initial experience of molecularly targeted therapy. BMC Cancer. 2018 Dec 29;18(1):1296. PMID:30594158 2244. Nakayama RT, Pulice JL, Valencia AM, et al. 8MARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters. Nat Genet. 2017 Nov;49(11):1613-23. PMID:28945250 2245. Nakayama-lchiyama S, Yokote T, Hirata Y, et al. Multiple cytokine-producing plasmablastic solitary plasmacytoma of bone with polyneuropathy, organomegaly, endocrinology, monoclonal protein, and skin changes syndrome. J Clin Oncol. 2012 Mar 1;30⑺:e91-4. PMID:22231043 2246. Nann D, Schneckenburger P, Steinhilber J, et al. Pediatric Langerhans cell histiocytosis: the impact of mutational profile on clinical progress!on and late sequelae. Ann Hematol. 2019 Jul;98(7):1617-26. PMID:30923995 2247. Narchi H. Four half-siblings with infantile myofibromatosis: a case for autosomalrecessive inheritance. Clin Genet. 2001 Feb;59(2):134-5. PMID:11260217 2248. Narendra S, Valente A, Tull J, et al. DDIT3 gene break-apart as a molecular marker for diagnosis of myxoid liposarcomaassay validation and clinical experience.

Diagn Mol Pathol. 2011 Dec;20(4)218-24 PMID:22089349 2249. Narvaez JA, Martinez S, Dodd LG et al. Acral myxoinflammatory fibroblastic sarcomas: MRI findings in four cases. AJR Am J Roentgenol. 2007 May; 188(5)-1302-5 PMID:17449774 2250. Nascimento AF, Bertoni F, Fletcher CD. Epithelioid variant of myxofibrosarcoma­ expanding the clinicomorphologic spectrum of myxofibrosarcoma in a series of 17 cases Am J Surg Pathol. 2007 Jan;31(1)-99-i05 PMID:17197925 2251. Nascimento AF, Fletcher CD. Spindle cell rhabdomyosarcoma in adults. Am J Surg Pathol 2005 Aug;29(8):1106-13. PMID:16006807 2252. Nascimento AF, Fletcher CD. The controversial nosology of benign nerve sheath tumors: neurofilament protein staining demonstrates intratumoral axons in many sporadic schwannomas. Am J Surg Pathol 2007 Sep;31 (9):1363-70. PMID:17721192 2253. Nascimento AF, McMenamin ME, Fletcher CD. Liposarcomas/atypical lipomatous tumors of the oral cavity: a clinicopathologic study of 23 cases. Ann Diagn Pathol. 2002 Ap「;6⑵:83-93. PMID:12004355 2254. Nascimento AF, Raut CP, Fletcher CD. Primary angiosarcoma of the breast: clinicopathologic analysis of 49 cases, suggesting that grade is not prognostic. Am J Surg Pathol・ 2008 Dec;32(12):1896-904 PMID:18813119 2255. Nascimento AG, Kurtin PJ, Guillou L, et al. Dedifferentiated liposarcoma: a report of nine cases with a peculiar neurallike whorling pattern associated with metaplastic bone formation. Am J Surg Pathol. 1998 Aug;22(8):945-55. PMID:9706974 2256. National Institute for Health and Care Excellence (NICE). Suspected cancer: recognition and referral (NG12). London (UK): NICE; 2015 Jun [updated 2017 Jul]. Available from: https://www.nice.org.uk/guidance/ng12. 2257. National Institutes of Health Consensus Development Conference. Neurofibromatosis. Conference statement. Arch Neurol. 1988 May;45(5):575-8. PMID:3128965 2258. Naughton PA, Wandling M, Phade S, et al. Intimal angiosarcoma causing abdominal aortic rupture. J Vase Surg. 2011 Mar;53(3):818-21. PMID:21215575 2259. Naumann M, Schalke B, Klopstock T, et al. Neurological multisystem manifestation in multiple symmetric lipomatosis: a clinical and electrophysiological study. Muscle Nerve. 1995 Jul;18(7):693-8. PMID:7783758 2260. Nayler SJ, Rubin BP, Calonje E, et al. Composite hemangioendothelioma: a complex, low-grade vascular lesion mimicking angiosarcoma. Am J Surg Pathol. 2000 Mar;24(3):352-61. PMID:10716148 2261. Naylor MF, Nascimento AG, Sherrick AD. et al. Elastofibroma dorsi: radiologic findings in 12 patients. AJR Am J Roentgenol. 1996 Sep;167(3):683-7. PMID:8751681 2261A. Nedopil 代 Raab P, Rudert M. Desmoplastic fibroma: a case report with three years of clinical and radiographic observation and review of the literature. Open Orthop J2013;8:40-6. PMID:23459513 2262. Negri T, Brich S, Conca E, et al. Receptor tyrosine kinase pathway analysis sheds light on similarities between clear-cell sarcoma and metastatic melanoma. Genes Chromosomes Cancer. 2012 Feb;51 ⑵:伯〜 26. PMID:22045652 2263. Nelson AC, Pillay N, Henderson S, et aL An integrated functional genomics approacl identifies the regulatory network directed by brachyury (T) in chordoma. J Pathol. 201 Nov;228(3):274-85. PMID:22847733

paybal：https://www.paypal.me/andy19801210 2264. Neumann JA, Garrigues GE, Brigman BE, et al. Synovial chondromatosis. JBJS Rev. 2016 May 10;4(5):01874474-20160500000005. PMID:27490219 2265. NeuvilleA, Chibon F, Coindre JM. Grading of soft tissue sarcomas: from histological to molecular assessment Pathology. 2014 Feb;46(2):113-20. PMID:24378389 ' 2266. Neuville A, Collin F, Bruneval P, et al. Intimal sarcoma is the most frequent primary cardiac sarcoma: clin icopathologic and molecular retrospective analysis of 100 primary cardiac sarcomas. Am J Surg Pathol. 2014 Apr;38(4):461-9. PMID:24625414 2267. Newton WA Jr, Gehan E代 Webber BL, et al. Classification of rhabdomyosarcomas and related sarcomas. Pathologic aspects and proposal for a new classification-an Intergroup Rhabdomyosarcoma study. Cancel： 1995 Sep 15；76(6):1073-85. PMID:8625211 2268. Ng AJ, Walia MK, Smeets MF, et al. The DNA helicase RECQL4 is required for normal osteoblast expansion and osteosarcoma formation. PLoS Genet. 2015 Apr 10;11 ⑷:e1005160. PMID:25859855 2269. Ng C, Schwartzman L, Moadel R, et al. Osteopoikilosis: a benign condition with the appearance of metastatic bone disease. J Clin Oncol. 2015 Jun 20;33(18):e77-8. PMID:24663043 2270. Ng DWJ, Tan GHC, Soon JJY, et al. The approach to solitary fibrous tumors: Are clinicopathological features and nomograms accurate in the predict!on of prognosis? Int J Surg Pathol. 2018 Oct;26(7):600-8. PMID:29772933 2271. Ng TL, Gown AM, Barry TS,et al. Nuclear beta-catenin in mesenchymal tumors. Mod Pathol. 2005 Jan;18(1):68-74. PMID:15375433 2272. Ng VY, Louie P, Punt S, et al. Malignant transformation of synovial chondcomatosis: a systematic review. Open Orthop J. 2017 May 31;11:517-24. PMID:28694891 2273. Nguyen TH, Barr FG. Therapeutic approaches targeting PAX3-FOXO1 and its regulatory and transcriptional pathways in rhabdomyosarcoma. Molecules. 2018 Oct 28;23(11):E2798. PMID:30373318 2274. Niamba P, Leaute-Labreze C, Boralevi F, etal. Further documentation of spontaneous regression of infantile digital fibromatosis. Pediatr Dermatol. 2007 May-Jun;24(3):280-4. PMID: 17542881 2275. Nichols KE, Malkin D, Garber JE, et al. Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev. 2001 Feb;10(2):83-7. PMID:11219776 2276. Nichols RE, Dixon LB. Radiographic analysis of solitary bone lesions. Radiol Clin North Am. 2011 Nov;49(6):1095-114, v. PMID:22024290 2277. Nicholson SA, Hill DA, Foster KW, et al. Fine-needle as pi ratio n cytology of mesenchymal hamartoma of the chest wall. Diagn Cytopathol. 2000 Jan;22(1):33-8. PMID:10613971 2278. Nicol KK, Ward WG, Savage PD, et al. Fine-needle aspiration biopsy of skeletal versus extraskeletal osteosarcoma. Cancer. 1998 Jun 25;84(3):176-85. PMID:9678733 2279. Nicolaides A, Huang YQ, Li JJ, et al. Gene amplification and multiple mutations of the K-ras oncogene in Kaposi's sarcoma. Anticancer Res. 1994 May-Jun;14(3A):921-6. PMID:8074494 2280. Nicolas MM, Tamboli P, Gomez JA, et al. Pleomorphic and dedifferentiated leiomyosarcoma: clinicopathologic and immunohistochemical study of 41 cases. Hum Pathol. 2010 May;41 (5):663-71. PMID:20004935 *1. 228 Nielsen GP, Dickersin GR, Provenzal

JM, et al. Lipomatous hemangiopericytoma. A histologic, ultrastructural and immunohistochemical study of a unique variant of hemangiopericytoma. Am J Surg Pathol. 1995 Jul;19(7):748-56. PMID:7793472 2282. Nielsen GP, Fletcher CD, Smith MA, et al. Soft tissue aneurysmal bone cyst: a clinicopathologic study of five cases. Am J Surg Pathol. 2002 Jan;26(1):64-9. PMID:11756770 2283. Nielsen GP, Keel SB, Dickersin GR, et al. Chondromyxoid fibroma: a tumor showing myofibroblastic, myochondroblastic, and chondrocytic differentiation. Mod Pathol. 1999 May;12(5):514-7. PMID:10349990 2284. Nielsen GP, O'Connell JX, Dickersin GR, et al. Chondroid lipoma, a tumor of white fat cells. A brief report of two cases with ultrastructural analysis. Am J Surg Pathol. 1995 Nov;19(11):1272-6. PMID:7573689 2285. Nielsen GP, O'Connell JX, Dickersin GR, et al. Collagenous fibroma (desmoplastic fibroblastoma): a report of seven cases. Mod Pathol. 1996 Jul;9(7):781-5. PMID:8832562 2286. Nielsen GP, O'Connell JX, Rosenberg AE. Intramuscular myxoma: a clinicopathologic study of 51 cases with emphasis on hypercellular and hypervascular variants. Am J Surg Pathol. 1998 Oct;22(10):1222-7. PMID:9777984 2287. Nielsen GP, Oliva E, Young RH, et al. Alveolar soft-part sarcoma of the female genital tract: a report of nine cases and review of the literature. Int J Gynecol Pathol. 1995 Oct; 14(4):283-92. PMID:8598329 2288. Nielsen GP, Rosenberg AE, Young RH, et al. Angiomyofibroblastoma of the vulva and vagina. Mod Pathol. 1996 Mar;9(3):284-91. PMID:8685229 2289. Nielsen GP, Srivastava A, Kattapuram S, et al. Epithelioid hemangioma of bone revisited: a study of 50 cases. Am J Surg Pathol. 2009 Feb;33(2):270-7. PMID:18852673 2290. Nielsen TO, Poulin NM, Ladanyi M. Synovial sarcoma: recent discoveries as a roadmap to new avenues for therapy. Cancer Discov. 2015Feb;5(2):124-34. PMID:25614489 2291. Nielsen TO, West RB, Linn SC, et al. Molecular characterisation of soft tissue tumours: a gene expression study. Lancet. 2002 Apr13;359(9314):1301-7. PMID:11965276 2292. Nieuwenhuis MH, Casparie M, MathusVliegen LM, et al. A nation-wide study comparing sporadic and familial adenomatous polyposis-related desmoid-type fibromatoses. Int J Cancer. 2011 Jul 1;129(1 ):256-61. PMID:20830713 2293. Nieuwenhuis MH, De Vos Tot Nederveen Cappel W, Botma A, et al. Desmoid tumors in a Dutch cohort of patients with familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2008 Feb;6 (2):215-9. PMID: 18237870 2294. Nieuwenhuis MH, Vasen HF. Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature. Crit Rev Oncol Hematol. 2007 Feb;61 ⑵:153-61.PMID:17064931 2295. Niini T, Lahti L, Michelacci F, et al. Array comparative genomic hybridization reveals frequent alterations of G1/S checkpoint genes in undifferentiated pleomorphic sarcoma of bone. Genes Chromosomes Cancer. 2011 May;50(5):291-306. PMID:21254299 2296. Niini T, Lopez-Guerrero JA, Ninomiya S, et al. Frequent deletion of CDKN2A and recurrent coamplification of KIT, PDGFRA, and KDR in fibrosarcoma of bone-an array comparative genomic hybridization study. Genes Chromosomes Cancer. 2010 Feb;49(2):132-43. PMID: 19862822 2297. Nilbert M, Mandahl N, Heim S, et al. Cytogenetic abnormalities in an angioleiomyoma. Cancer Genet Cytogenet.

1989Jan;37(1):61-4. PMID:2917333 2298. Nilesh K, Mukherji S. Congenital muscular torticollis. Ann Maxillofac Surg. 2013 Jul;3(2):198-200. PMID:24205484 2299. Nilsson B, Bumming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era-a population-based study in western Sweden. Cancer. 2005 Feb 15;103(4):821-9. PMID:15648083 2300. Nilsson M, Domanski HA, Mertens F, et al. Molecular cytogenetic characterization of recurrent translocation breakpoints in bizarre parosteal osteochondromatous proliferation (Nora's lesion). Hum Pathol. 2004 Sep;35⑼:1063-9. PMID:15343507 2301. NishidaJ, Morita T, OgoseA, etal. Imaging characteristics of deep-seated lipomatous tumors: intramuscular lipoma, intermuscular lipoma, and lipoma-like liposarcoma. J Orthop Sci. 2007 Nov;12(6):533^11. PMID:18040635 2302. Nishida J, Sim FH, Wenger DE, et al. Malignant fibrous histiocytoma of bone. A clinicopathologic study of 81 patients. Cancer. 1997 Feb 1;79(3):482-93. PMID:9028358 2303. Nishida N, Yutani C, Ishibashi-Ueda H, et al. Histopathological characterization of aortic intimal sarcoma with multiple tumor emboli. Pathol Int. 2000 Nov;50(11):923-7. PMID:11107072 2304. Nishida T, Tsujimoto M, Takahashi T, et al. Gastrointestinal stromal tumors in Japanese patients with neurofibromatosis type I. J Gastroenterol. 2016 Jun;51 (6):571-8. PMID:26511941 2305. Nishiguchi T, Mochizuki K, Ohsawa M, et al. Differentiating benign notochordal cell tumors from chordomas: radiographic features on MRI, CT, and tomography. AJR Am J Roentgenol. 2011 Mar;196(3):644-50. PMID:21343509 2306. Nishio J, Akiho S, Iwasaki H, et al. Translocation t(2;11) is characteristic of collagenous fibroma (desmoplastic fibroblastoma). Cancer Genet. 2011 Oct;204(10):569-71. PMID:22137488 2307. Nishio J, Iwasaki H, Nagatomo M, et al. Fibroma of tendon sheath with 11q rearrangements. Anticancer Res. 2014 Sep;34(9):5159-62. PMID:25202108 2308. Nishio J, Iwasaki H, Ohjimi Y, et al. Chromosomal imbalances in angioleiomyomas by comparative genomic hybridization. Int J Mol Med. 2004 Jan;13(1):13-6. PMID:14654964 2309. Nishio J, Reith JD, Ogose A, et al. Cytogenetic findings in clear cell chondrosarcoma. Cancer Genet Cytogenet. 2005 Oct 1;162(1):74-7. PMID:16157204 2310. Nishio JN, Iwasaki H, Ohjimi Y, et al. Gain of Xq detected by comparative genomic hybridization in elastofibroma. Int J Mol Med. 2002 Sep;10⑶:277-80. PMID:12165800 2311. Nitta Y, Miyachi M, Tomida A, et al. Identification of a novel BOC-PLAG1 fusion gene in a case of lipoblastoma. Biochem Biophys Res Commun. 2019Apr23;512(1):4952. PMID:30857637 2312. Niu X, Zhang Q, Hao L, et al. Giant cell tumor of the extremity: retrospective analysis of 621 Chinese patients from one institution. J Bone Joint Surg Am. 2012 Mar 7;94(5):461-7. PMID:22398741 2313. NofalA, Sanad M, Assaf M, etal. Juvenile hyaline fibromatosis and infantile systemic hyalinosis: a unifying term and a proposed grading system. J Am Acad Dermatol. 2009 Oct;61 (4):695-700. PMID:19344977 2314. Nojima T, Unni KK, McLeod RA, et al. Periosteal chondroma and periosteal chondrosarcoma. Am J Surg Pathol. 1985 Sep;9(9):666-77. PMID:4051099

2315. Nonaka D, Chiriboga L, Rubin BP. Sox10: a pan-schwannian and melanocytic marker. Am J Surg Pathol. 2008 Sep;32(9):1291-8. PMID:18636017 2316. Nonomura A, Kurumaya H, Kono N, et al. Primary pulmonary artery sarcoma. Report of two autopsy cases studied by immunohistochemistry and electron microscopy, and review of 110 cases reported in the literature. Acta Pathol Jpn. 1988 Jul;38(7):883-96. PMID:3055809 2317. Nooij MA, Whelan J, Bramwell VH, et al. Doxorubicin and cisplatin chemotherapy in high-grade spindle cell sarcomas of the Bone, other than osteosarcoma or maligna nt fibrous histiocytoma: a European Osteosarcoma Intergroup study. Eur J Cancer. 2005 Jan;41 (2):225-30. PMID:15661546 2318. Nord KH, Lilljebjorn H, Vezzi F, et al. GRM1 is upregulated through gene fusion and promoter swapping in chondromyxoid fibroma. Nat Genet. 2014 May;46⑸:4：4-7. PMID:24658000 2319. Nord KH, Magnusson L, Isaksson M, et al. Concomitant deletions of tumor suppressor genes MEN1 and AIP are essential for the pathogenesis of the brown fat tumor hibernoma. Proc Natl Acad Sci USA. 2010 Dec 7;107(49):21122-7. PMID:21078971 2320. Nord KH, Nilsson J, Arbajian E, et al. Recurrent chromosome 22 deletions in osteoblastoma affect inhibitors of the Wnt/betacatenin signaling pathway. PLoS One. 2013 Nov 13;8(11):e80725. PMID:24236197 2321. Nord KH, Paulsson K, Veerla S, et al. Retained heterodisomy is associated with high gene expression in hyperhaploid inflammatory leiomyosarcoma. Neoplasia. 2012 Sep;14(9):807-12. PMID:23019412 2322. Norman A, Abdelwahab IF, Buyon J, et al. Osteoid osteoma of the hip stimulating an early onset of osteoarthritis. Radiology. 1986 Feb;158(2):417-20. PMID:3941866 2323. Norman A, Steiner GC. Bone erosion in synovial chondromatosis. Radiology. 1986 Dec;16"3):749-52. PMID:3786727 2324. North PE. Classification and pathology of congenital and perinatal vascular anomalies of the head and neck. Otolaryngol Clin North Am. 2018 Feb;51(1):1-39. PMID:29217054 2325. North PE. Pediatric vascular tumors and malformations. Surg Pathol Clin. 2010 Sep;3(3):455-94. PMID:26839221 2326. North PE, Waner M, Mizeracki A, et al. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol. 2001 May; 137(5):559-70. PMID:11346333 2327. North PE, Waner M, Mizeracki A, et al. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol. 2000 Jan;31(1):1122. PMID:10665907 2328. Nota SP, Braun Y, Schwab JH, et al. The identification of prognostic factors and survival statistics of conventional central chondrosarcoma. Sarcoma. 2015;2015:623746. PMID:26633939 2329. Noujaim J, Thway K, Jones RL, et al. Adult pleomorphic rhabdomyosarcoma: a multicentre retrospective study. Anticancer Res. 2015 Nov;35(11):6213-7. PMID:26504053 2330. Novelli M, Rossi S, Rodriguez-Justo M, et al. DOG1 and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal tumours. Histopathology. 2010 Aug;57(2):259-70. PMID:20716168 2331. Nucci MR, Granter SR, Fletcher CD. Cellular angiofibroma: a benign neoplasm distinct from angiomyofibroblastoma and spindle cell lipoma. Am J Surg Pathol. 1997 Jun;21 (6):636-44. PMID:9199640

Refere nces

579

paybal：https://www.paypal.me/andy19801210 2332. Nucci MR, Weremowicz S, Neskey DM, et al. Chromosomal translocation t(8;12) induces aberrant HMGIC expression in aggressive angiomyxoma of the vulva. Genes Chromosomes Cancer. 2001 Oct;32(2):仃2-6. PMID:11550285 2333. Nunez AL, Elgin JN, Fatima H. Fine-needle aspiration biopsy of alveolar rhabdomyosarcoma of Stensen's duct: a case report and review of the literature. Diagn Cytopathol. 2014 Dec;42(12):1069-74. PMID:24599626 2334. Nunez JH, Barrera-Ochoa S, Knorr J, et al. Soft-tissue chondroma within the exten sor tendon of the in dex fin ger in a child. Hand Surg Rehabil. 2018 Oct;37(5):326-7. PMID:30033358 2335. Nuovo MA, Norman A, Chumas J, et al. Myositis ossificans with atypical clinical, radiographic, or pathologic findings: a review of 23 cases. Skeletal Radiol. 1992;21 ⑵:87-101. PMID:1566115 2336. Nusse R, Clevers H. Wnt/p-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017 Jun 1;169⑹:985-99. PMID:28575679 2337. Nyquist KB, Panagopoulos I, Thorsen J, et al. Whole-transcriptome sequencing identifies novel IRF2BP2-CDX1 fusion gene brought about by translocation t(1;5)(q42;q32) in mesenchymal chondrosarcoma. PLoS One. 2012;7(11):e49705. PMID:23185413 2338. Oakley RH, Carty H, Cudmore RE. Multiple benign mesenchymomata of the chest wall. Pediatr Radiol. 1985;15(1):58-60. PMID:3969297 2339. Oberlin O, Rey A, Lyden E, et al. Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from United States and European cooperative groups. J Clin Oncol. 2008 May 10;26(14):2384-9. PMID:18467730 2340. 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 Oct;23(2):187-93. PMID:9739023 2341. Ockner DM, Sayadi H, Swanson PE, et al. Genital angiomyofibroblastoma. Comparison with aggressive angiomyxoma and other myxoid neoplasms of skin and soft tissue. Am J Clin Pathol. 1997 Jan;107(1):36-44. PMID:8980365 2342. O'Connell JX, Fanburg JC, Rosenberg AE. Giant cell tumor of tendon sheath and pigmented villonodular synovitis: immunophenotype suggests a synovial cell origin. Hum Pathol. 1995 Jul;26(7):771-5. PMID7628850 2343. O'Connell JX, Kattapuram SV, MankinHJ, et al. Epithelioid hemangioma of bone. A tumor often mistaken for low-grade 亦giosarcoma or malignant hemangioendothelioma. Am J Surg Pathol. 1993 Jun;17(6):610-7. PMID:8333560 2344. O'Connell JX, Nielsen GP, Rosenberg AE. Epithelioid vascular tumors of bone: a review and proposal of a classification scheme. Adv Anat Pathol. 2001 Mar;8(2):74-82. PMID:11236956 2345. O'Connell JX, Wehrli BM, Nielsen GP, et al. Giant cell tumors of soft tissue: a clinicopathologic study of 18 benign and malignant tumors. Am J Surg Pathol. 2000 Mar;24(3):386-95. PMID:10716152 2346. Oda Y, Izumi T, Harimaya K, et al. Pigmented villonodular synovitis with chondroid metaplasia, resembling chondroblastoma of the bone: a report of three cases. Mod Pathol. 2007 May;20(5):545-51. PMID:17334342 2347. Oda Y, Miyajima K, Kawaguchi

580

Refere nces

K, et al. Pleomorphic leiomyosarcoma: clinicopathologic and immunohistochemical study with special emphasis on its distinction from ordinary leiomyosarcoma 日 nd malign ant fibrous histiocytoma. Am J Surg Pathol. 2001 Aug;25(8): 1030-8. PMID:11474287 2348. Oda Y, Tsuneyoshi M. Extrarenal rhabdoid tumors of soft tissue: clinicopathological and molecular genetic review and distinction from other soft-tissue sarcomas with rhabdoid features. Pathol I nt. 2006 Jun;56(6):287-95. PMID:16704491 2349. Oda Y, Yamamoto H, Takahira T, et al. Frequent alteration of p16(INK4a)/p14(ARF) and p53 pathways in the round cell component of myxoid/round cell liposarcoma: p53 gene alterations and reduced p14(ARF) expression both correlate with poor prognosis. J Pathol. 2005 Dec;207(4):410-21. PMID:16177957 2350. Odell JM, Benjamin DR. Mesenchymal hamartoma of chest wall in infancy: natural history of two cases. Pediatr Pathol. 1986;5(2):135-46. PMID:3763502 2351. Odink AE, van Asperen CJ, Vandenbroucke JP, et al. An association between cartilaginous tumours and breast cancer in the national pathology registration in the Netherlands points towards a possible genetic trait. J Pathol. 2001 Feb;193(2):190-2. PMID:11180165 2352. O'Driscoll D, Athanasian E, Hameed M, et al. Radiological imaging features and clinicopathological correlation of hemosiderotic fibrolipomatous tumor: experience in a single tertiary cancer center. Skeletal Radiol. 2015 May;44(5):641-8. PMID:25527465 2353. Ognjanovic S, Linabery AM, Charbonneau B, et al. Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975-2005. Cancer. 2009 Sep 15;115(18):4218-26. PMID:19536876 2354. Ognjanovic S, Olivier M, Bergemann TL, et al. Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 Database. Cancer. 2012 Mar 1;118(5):1387-96. PMID:21837677 2355. Ogose A, Hotta T, Emura I, et al. Recurrent malignant variant of phosphaturic mesenchymal tumor with oncoge nic osteomalacia. Skeletal Radiol. 2001 Feb;30(2):99-103. PMID:11310207 2356. Ogose A, Yazawa Y, Ueda T, et al. Alveolar soft part sarcoma in Japan: multiinstitutional study of 57 patients from the Japanese Musculoskeletal Oncology Group. Oncology. 2003;65(1):7-13. PMID:12837977 2357. Ogura K, Hosoda F, Arai Y, et al. Integrated genetic and epigenetic analysis of myxofibrosarcoma. Nat Commun. 2018 Jul 17;9(1):2765. PMID:30018380 2358. Ogura K, Hosoda F, Nakamura H, et al. Highly recurrent H3F3A mutations with additional epigenetic regulator alterations in giant cell tumor of bone. Genes Chromosomes Cancer. 2017 Oct;56(10):711-8. PMID:28545165 2359. Oguro S, Okuda S, Sugiura H, et al. Giant cell tumors of the bone: changes in image features after denosumab administration. Magn Reson Med Sci. 2018 Oct 10; 17(4):325-30. PMID:29386457 2360. Oh JE, Ohta T, Satomi K, etal. Alterations in the NF2/LATS1/LATS2/YAP pathway in schwannomas. J Neuropathol Exp Neurol. 2015 Oct;74(10):952-9. PMID:26360373 2361. Ohsawa M, Naka N, Tomita Y, et al. Use of immunohistochemical procedures in diagnosing angiosarcoma. Evaluation of 98 cases. Cancer. 1995 Jun 15;75(12):2867-74. PMID:7773935 2362. Ojha SS, Naik LP, Fernandes GC, et al. Key cytological findings in FNA from

infantile digital fibromatosis. Acta Cytol. 2011;55(5):481-4. PMID:21986179 2363. Okada K, Frassica FJ, Sim FH, et al. Parosteal osteosarcoma. A clinicopathological study. J Bone Joint Surg Am. 1994 Mar;76(3):366-78. PMID:8126042 2364. Okada K, Hasegawa T, Yokoyama R, et al. Osteosarcoma with cytokeratin expression: a clinicopathological study of s仪 cases with an emphasis on differential diagnosis from metastatic cancer. J Clin Pathol. 2003 Oct;56(10):742-6. PMID:14514776 2365. Okada K, Unni KK, Swee RG, et al. High grade surface osteosarcoma: a clinicopathologic study of 46 cases. Cancer. 1999 Mar 1;85(5):1044-54. PMID:10091787 2366. Okada T, Lee AY, Qin LX, et al. lntegrin-a10 dependency identifies RAC and RICTOR as therapeutic targets in high-grade myxofibrosarcoma. Cancer Discov. 2016 Oct;6(10):1148-65. PMID:27577794 2367. Okamoto S, Hisaoka M, Ishida T, et al. Extraskeletal myxoid chondrosarcoma: a clinicopathologic, immunohistochemical, and molecular analysis of 18 cases. Hum Pathol. 2001 Oct;32(10):1116-24. PMID:11679947 2368. Okamoto S, Hisaoka M, Meis-Kindblom JM, et al. Juxta-articular myxoma and intramuscular myxoma are two distinct entities. Activating Gs alpha mutation at Arg 201 codon does not occur in juxta-articular myxoma. Virchows Arch. 2002 Jan;440(1):12-5. PMID:11942570 2369. Okubo T, Saito T, Mitomi H, et al. p53 mutations may be involved in malignant transformation of giant cell tumor of bone through interaction with GPX1. Virchows Arch. 2013Jul;463(1):67-77. PMID:23748877 2370. Oliveira AM, Chou MM. The TRE17/ USP6 oncogene: a riddle wrapped in a mystery inside an en igma. Front Biosci (Schol Ed). 2012 Jan1;4:321-34. PMID:22202063 2371. Oliveira AM, Chou MM. USP6-induced neoplasms: the biologic spectrum of aneurysmal bone cyst and nodular fasciitis. Hum Pathol. 2014 Jan;45(1):1-11. PMID:23769422 2372. Oliveira AM, Dei Tos AP, Fletcher CD, et al. Primary giant cell tumor of soft tissues: a study of 22 cases. Am J Surg Pathol. 2000 Feb;24⑵:248-56. PMID:10680893 2373. Oliveira AM, Hsi BL, Weremowicz S, et al. USP6 (Tre2) fusion oncogenes in aneurysmal bone cyst. Cancer Res. 2004 Mar 15;64(6):1920-3. PMID:15026324 2374. Oliveira AM, Perez-Atayde AR, Dal Cin P, et al. Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes. Oncogene. 2005 May 12;24(21):3419-26. PMID:15735689 2375. Oliveira AM, Perez-Atayde AR, Inwards CY, et al. USP6 and CDH11 oncogenes identify the neoplastic cell in primary aneurysmal bone cysts and are absent in so-called secondary aneurysmal bone cysts. Am J Pathol. 2004 Nov;165(5):1773-80. PMID:15509545 2376. Oliveira AM, Sebo TJ, McGrory JE, et al. Extraskeletal myxoid chondrosarcoma: a clinicopathologic, immunohistochemical, and ploidy analysis of 23 cases. Mod Pathol. 2000 Aug;13(8):900-8. PMID:10955458 2377. Oliveira VC, van der Heijden L, van der Geest IC, et al. Giant cell tumours of the small bones of the hands and feet: long-term results of 30 patients and a systematic literature review. Bone Joint J. 2013 Jun;95-B(6):838-45. PMID:23723282 2378. Olofson A, Marotti J, Tafe LJ, et al. Int「anodal meningothelial proliferation in a patient with Cowden syndrome: a case report. Hum Pathol. 2017Aug;66:183-7. PMID:28315423 2379. Olsen SH, Thomas DG, Lucas DR. Cluster analysis of immunohistochemical

profiles in synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewinq sarcoma. Mod Pathol. 2006 May;19(5)-65g_68 PMID:16528378 2380. Olsen TG, Helwig EB. Angiolymphoid hyperplasia with eosinophilia. a clinicopathologic study of 116 patients. J Am Acad Dermatol. 1985 May;12(5 Pt 1)781-96 PMID:4008683 2381. Olson DR, Schowinsky jy Immunohistochemical analysis of HMGA2 expression fails to provide evidence of a neoplastic basis for primary1 synovial lipomatosis. Histopathology. 2015 Sep;67⑶:420-2. PMID:25585965 2382. Olsson L, Paulsson K, Bovee JV et al. Clonal evolution through loss of chromosomes and subsequent polyploidization in chondrosarcoma. PLoS One 2011;6(9):e24977. PMID:21949816 2383. O'Neill AC, Craig JW, Silverman SG, et al. Anastomosing hemangiomas: locations' of occurrence, imaging features, and diagnosis with percutaneous biopsy. Abdom Radiol (NY) 2016 Jul;41 (7):1325-32. PMID:26960722 2384. Ong KW, Teo M, Lee V, et al. Expression of EBV latent antigens, mammalian target of rapamycin, and tumor s叩pression genes in EBV-positive smooth muscle tumors: clinical and therapeutic implications. Clin Cancer Res 2009 Sep 1;15(17):5350-8. PMID:19706821 2385. Onishi Y, Kitajima K, Senda M, et al. FDG-PET/CT imaging of elastofibroma dorsi. Skeletal Radiol. 2011 Jul;40(7):849-53 PMID:20978756 2386. Orbach D, Rey A, Cecchetto G, et al. Infantile fibrosarcoma: management based on the European experience. J Clin Oncol. 2010 Jan 10;28(2):318-23. PMID:19917847 2387. Ortins-Pina A, Llamas-Velasco M, Turpin S, et al. FOSB immunoreactivity in endothelia of epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia). J Cutan Pathol. 2018Jun;45(6):395-402. PMID:29527734 2388. Ortonne N, Wolkenstein P, Blakeley JO, et al. Cutaneous neurofibromas: current clinical and pathologic issues. Neurology. 2018 Jul 10;91(2 Suppl 1):S5-13. PMID:29987130 2389. Orvieto E, Furlanetto A, Laurino L, et al. Myxoid and round cell liposarcoma: a spectrum of myxoid adipocytic neoplasia. Semin Diagn Pathol. 2001 Nov; 18(4):267-73. PMID:11757867 2390. Oshima J, Martin GM, Hisama FM. Werner syndrome. In: Adam MP, Ardinger HH, Pagon RA, etal., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 2002 Dec 2 [updated 2016 Sep 29], PMID:20301687 2391. Oshima J, Sidorova JM, Monnat RJ Jr. Werner syndrome: clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev. 2017 Jan;33:105-14. PMID:26993153 2392. Oshiro Y, Shiratsuchi H, Tamiya S, et al. Extraskeletal myxoid chondrosarcoma with rhabdoid features, with special reference to its aggressive behavior. Int J Surg Pathol. 2000 Apr;8(2):145-52. PMID:11493979 2393. Ostrowski ML, Inwards CY, Strickler JG, et al. Osseous Hodgkin disease. Cancer. 1999 Mar 1;85(5):1166-7& PMID:10091803 2394. Ostrowski ML, Unni KK, Banks PM, et al. Malignant lymphoma of bone. Cancer. 1986 Dec 15;58(12):2646-55. PMID:3779614 2395. O'Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet. 2002 Jun 29;359(9325):2235-41. PMID:12103287 2396. Ote EL, Oriuchi N, Miyashita G, et al. Pulmonary artery intimal sarcoma: the role of 18F-fluorodeoxyglucose positron emission

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paybal：https://www.paypal.me/andy19801210 tomography in monitoring response to treatment. Jpn J Radiol. 2011 May;29(4):27982. PMID:21607843 2397. Otsuka H, Kohashi K, Yoshimoto M, et al. Immunohistochemical evaluation of H3K27 trimethylation in malignant peripheral nerve sheath tumors. Pathol Res Pract. 2018 Mar;214(3):417-25. PMID:29482987 2398. Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treat Res. 2009;152:313. PMID:20213383 2399. Ottaviani S, Ayral X, Dougados M, et al. Pigmented villonodular synovitis: a retrospective single-center study of 122 cases and review of the literature. Semin Arthritis Rheum. 2011 Jun;40(6):539-46. PMID:20884045 2400. Outani H, Imura Y, TanakaT, et al. Clinical outcomes of patients with epithelioid sarcomas: impact and management of nodal metastasis. Int J Clin Oncol. 2018 Feb;23(1 ):181-8. PMID:28799063 2401. Ouyang 乙 Wang S, Zeng M, et al. Therapeutic effect of palbociclib in chondrosarcoma: implication of cyclindependent kinase 4 as a potential target. Cell Commun Signal. 2019 Feb 26;17(1):17. PMID:30808351 2402. Owosho AA, Zhang L, Rosenblum MK, et al. High sensitivity of FISH analysis in detecting homozygous SMARCB1 deletions in poorly differentiated chordoma: a clinicopathologic and molecular study of nine cases. Genes Chromosomes Cancer. 2018 Feb;57(2):89-95. PMID:29119645 2403. Ozaki T, Liljenqvist U, Halm H, etal. Giant cell tumor of the spine. Clin Orthop Relat Res. 2002 Aug;(401 ):194-201. PMID:12151896 2404. Ozaki T, Schaefer KL, Wai D, et al. Genetic imbalances revealed by comparative genomic hybridization in osteosarcomas. Int J Cancer. 2002 Dec 1;102(4):355-65. PMID: 12402305 2405. Ozisik YY, Meloni AM, Peier A, et al. Cytogenetic findings in 19 malignant bone tumors. Cancer. 1994 Oct 15;74(8):2268-75. PMID:7922978 2406. Ozkoc G, Gonlusen G, Ozalay M, et al. Giant chondroblastoma of the scapula with pulmonary metastases. Skeletal Radiol. 2006 Jan;35(1):42-8. PMID:16007463 2407. Paal E, Miettinen M. Retroperitoneal leiomyomas: a clinicopathologic and immunohistochemical study of 56 cases with a comparison to retroperitoneal leiomyosarcomas. Am J Surg Pathol. 2001 Nov;25(11):1355-63. PMID:11684951 2408. Pacifici M. The pathogenic roles of heparan sulfate deficiency in hereditary multiple exostoses. Matrix Biol. 2018 Oct;71-72:28-39. PMID:29277722 2409. Pagonidis K, Raissaki M, Gourtsoyiannis N. Proliferative myositis: value of imaging. J Comput Assist Tomogr. 2005 JanFeb;29(1 ):108-11. PMID:15665694 2410. Palmerini E, Chawla NS, Ferrari S, et al. Denosumab in advanced/unresectable giant­ cell tumour of bone (GCTB): for how long? Eur J Cancer. 2017 May;76:118-24. PMID:28324746 2411. Pan CC, Chung MY, Ng KF, et al. Constant allelic alteration on chromosome 16p (TSC2 gene) in perivascular epithelioid cell tumour (PEComa): genetic evidence for the relationship of PEComa with angiomyolipoma. J Pathol. 2008 Feb;2143:387-93. PMID:18085521 2412. Pan KS, Heiss JD, Brown SM, et al. Chiari I malformation and basilar invagination in fibrous dysplasia: prevalence, mechanisms, and clinical implications. J Bone Miner Res. 2018 Nov;33(11):1990-8. PMID:29924878 2413. Panagopoulos I, Gorunova L, Agostini A, et al. Fusion of the HMGA2 and C9orf92 genes

in myolipoma with t(9;12)(p22;q14). Diagn Pathol. 2016 Feb 9;11:22. PMID:26857357 2414. Panagopoulos I, Gorunova L, Andersen K, et al. Consistent involvement of chromosome 13 in angiolipoma. Cancer Genomics Proteomics. 2018 Jan-Feb;15(1):61-5. PMID:29275363 2415. Panagopoulos I, Gorunova L, Bjerkehagen B, et al. Fusion of the genes EWSR1 and PBX3 in retroperitoneal leiomyoma with t(9;22)(q33;q12). PLoS One. 2015 Apr 14; 10(4):e0124288. PMID:25875009 2416. Panagopoulos I, Gorunova L, Bjerkehagen B, et al. Loss of chromosome 13 material in cellular angiofibromas indicates pathogenetic similarity with spindle cell lipomas. Diagn Pathol. 2017 Feb 13;12(1):17. PMID:28193293 24 仃.Panagopoulos I, Gorunova L, Bjerkehagen B, et al. Novel KAT6BKANSL1 fusion gene identified by RNA sequenci 叩 in retroperitoneal leiomyoma with t(10;17)(q22;q21). PLoS One. 2015 Jan 26;10(1):e0117010. PMID:25621995 2418. Panagopoulos I, Gorunova L, Bjerkehagen B, et al. The recurrent chromosomal translocation t(12;18) (q14~15;q12~21) causes the fusion gene HMGA2-SETBP1 and HMGA2 expression in lipoma and osteochondrolipoma. Int J Oncol. 2015 Sep;47(3):884-90. PMID:26202160 2419. Panagopoulos I, Gorunova L, Brunetti M, et al. Genetic heterogeneity in leiomyomas of deep soft tissue. Oncotarget. 2017 Jul 25;8(30):48769-81. PMID:28591699 2420. Panagopoulos I, Gorunova L, LundIversen M, et al. Recurrent fusion of the genes FN1 and ALK in gastrointestinal leiomyomas. Mod Pathol. 2016 Nov;29(11):1415-23. PMID:27469327 2421. Panagopoulos I, Gorunova L, Taksdal I, et al. Recurrent 12q13-15 chromosomal aberrations, high frequency of isocitrate dehydrogenase 1 mutations, and absence of high mobility group AT-hook 2 expression in periosteal chondromas. Oncol Lett. 2015 Jul;10(1):163-7.PMID:26170993 2422. Panagopoulos I, Mencinger M, Dietrich CU, etal. Fusion of the RBP56 and CHN genes in extraskeletal myxoid chondrosarcomas with translocation t(9;17)(q22;q11). Oncogene. 1999 Dec 9;18(52):7594-8. PMID:10602519 2423. Panag叩oulos I, Mertens F, DebiecRychter M, et al. Molecular genetic characterization of the EWS/ATF1 fusion gene in clear cell sarcoma of tendons and aponeuroses. Int J Cancer. 2002 Jun 1;99(4):560-7. PMID:11992546 2424. Panagopoulos I, Mertens F, Isaksson M, et al. Absence of mutations of the BRAF gene in malignant melanoma of soft parts (clear cell sarcoma of tendons and 即oneuroses). Cancer Genet Cytogenet. 2005 Jan 1;156(1):74-6. PMID:15588860 2425. Panagopoulos I, Mertens F, Isaksson M, et al. Molecular genetic characterization of the EWS/CHN and RBP56/CHN fusion genes in extraskeletal myxoid chondrosarcoma. Genes Chromosomes Cancer. 2002 Dec;35(4):34052. PMID:12378528 2426. Panagopoulos I, Storlazzi CT, Fletcher CD, et al. The chimeric FUS/CREB3I2 gene is specific for low-grade fibromyxoid sarcoma. Genes Chromosomes Cancer. 2004 Jul;40⑶:218-28. PMID:15139001 2427. Pang LJ, Chang B, Zou H, et al. Alveolar soft part sarcoma: a bimarker diagnostic strategy using TFE3 immunoassay and ASPLTFE3 fusion transcripts in paraffin-embedded tumor tissues. Diagn Mol Pathol. 2008 Dec;17(4):245-52. PMID:18382356 242& Panoutsakopoulos G, Pandis N,

Kyriazoglou I, et al. Recurrent t(16;17) (q22;p13) in aneurysmal bone cysts. Genes Chromosomes Cancer. 1999 Nov;26(3):265-6. PMID:10502326 2429. Pansuriya TC, Kroon HM, Bovee JV. Enchondromatosis: insights on the different subtypes. Int J Clin Exp Pathol. 2010 Jun 26;3(6):557-69. PMID:20661403 2430. Pansuriya TC, van Eijk R, d'Adamo P, et al. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet. 2011 Nov 6;43(12):1256-61. PMID:22057234 2431. Papagelopoulos PJ, Galanis E, Frassica FJ, et al. Primary fibrosarcoma of bone. Outcome after primary surgical treatment. Clin Orthop Relat Res. 2000 Apr;(373):88-103. PMID:10810466 2432. Papagelopoulos PJ, Galanis EC, Sim FH, etal. Clinicopathologicfeatures, diagnosis, and treatment of malignant fibrous histiocytoma of bone. Orthopedics. 2000 Jan;23(1):59-65, quiz 66-7. PMID:10642003 2433. Papo M, Diamond EL, Cohen-Aubart F, et al. High prevalence of myeloid neoplasms in adults with non-Langerhans cell histiocytosis. Blood. 2017 Aug 24;130(8):1007-13. PMID:28679734 2434. Papp G, Krausz T, Stricker TP, et al. SMARCB1 expression in epithelioid sarcoma is regulated by miR-206, miR-381, and miR-671-5p on both mRNA and protein levels. Genes Chromosomes Cancer. 2014 Feb;53(2):168-76. PMID:24327545 2435. "ppo 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 Feb;26⑵&-4. PMID:8531857 2436. Pareja F, Brandes AH, Basili T, et al. Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors. Nat Commun. 2018 Aug 30;9(1):3533. PMID:30166553 2437. Parfitt JR, McLean CA, Joseph MG, et al. Granular cell tumours of the gastrointestinal tract: expression of nestin and clinicopathological evaluation of 11 patients. Histopathology. 2006 Mar;48(4):424-30. PMID:16487364 2438. Parham DM, Barr FG. Classification of rhabdomyosarcoma and its molecular basis. Adv Anat Pathol. 2013 Nov;20(6):387-97. PMID:24113309 2439. Parisi M, Grenda E, Hatziagorou E, et al. Chest wall lipoblastoma in a 3 year-old boy. Respir Med Case Rep. 2019 Jan 19;26:200-2. PMID:30723667 2440. Park CH, Kim KI, Um YT, et al. Ruptured giant intrathoracic lipoblastoma in a 4-monthold infant: CT and MR findings. Pediatr Radiol. 2000 Jan;30⑴:38 0. * PMID:10663508 2441. Park EA, Hong SH, Choi JY, et al. Glomangiomatosis: magnetic resonance imaging findings in three cases. Skeletal Radiol. 2005 Feb;34⑵:108-". PMID:15372213 2442. Park JE. Long-term natural history of a neuromuscular choristoma of the sciatic nerve: a case reporta nd literature review. Clin Imaging. 2019 May-Jun;55:18-22. PMID:30708195 ' 2443. Park JO, Qin LX, Prete FP, et al. Predicting outcome by growth rate of locally recurrent retroperitoneal liposarcoma: the one centimeter per month rule. Ann Surg. 2009 Dec;250(6):977-82. PMID:19953716 2444. Park JY, Cohen C, Lopez D, et al. EGFR exon 20 insertion/duplication mutations characterize fibrous hamartoma of infancy. Am J Surg Pathol. 2016 Dec;40(12):1713-8. PMID:27631514 2445. Park SA, Kim HS. F-18 FDG PET/ CT evaluation of sacrococcygeal chordoma.

Clin Nucl Med. 2008 Dec;33(12):906-8. PMID:19033806 2446. Park SY, Jin SP, Yeom B, et al. Multiple fibromas of tendon sheath: unusual presentation. Ann Dermatol. 2011 Sep;23 Suppl 1:S45-7. PMID:22028571 2447. Park YK, Cho CH, Chi 8G, et al. Low incidence of genetic alterations of the p16CDKN2a in clear cell chondrosarcoma. Int J Oncol. 2001 Oct;19(4):749-53. PMID:11562750 2448. Park YK, Park HR, Chi SG, et al. Overexpression of p53 and absent genetic mutation in clear cell chondrosarcoma. Int J Oncol. 2001 Aug;19(2):353-7. PMID:11445851 2449. Park YK, Unni KK, Beabout JW, et al. Oncogenic osteomalacia: a clinicopathologic study of 17 bone lesions. J Korean Med Sci. 1994Aug;9(4):289-98. PMID:7848576 2450. Park YK, Unni KK, Kim YW, et al. Primary alveolar soft part sarcoma of bone. Histopathology. 1999 Nov;35 (5):411-7. PMID:10583555 2452. Parmar V, Peters RT, Cheesman E, et al. Congenital infantile fibrosarcoma of the colon: a case series and literature review. Pediatr Surg Int. 2014 Oct;30(10):1079-85. PMID:25150723 2453. Parsons 代 Sheehan DJ, Sangueza OR Retiform hemangioendotheliomas usually do not express D2-40 and VEGFR-3. Am J Dermatopathol. 2008 Feb;30(1):31-3. PMID:18212541 2454. Parta M, Cuellar-Rodriguez J, Freeman AF, et al. Resolution of multifocal Epstein-Barr virus-related smooth muscle tumor in a patient with GATA2 deficiency following hematopoietic stem cell transplantation. J Clin Immunol. 2017 Jan;37(1):61-6. PMID:27924436 2455. Pasini B, McWhinney SR, Bei T, et al. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet. 2008 Jan;16(1):7988. PMID:17667967 2456. Pasquali S, Gronchi A, Strauss D, et al. Resectable extra-pleural and extra-meningeal solitary fibrous tumours: a multi-centre prognostic study. Eur J Surg Oncol. 2016 Jul;42(7):1064-70. PMID:26924782 2457. Pasquali S, Pizzamiglio S, Touati N, et al. The impact of chemotherapy on survival of patients with extremity and trunk wall soft tissue sarcoma: revisiting the results of the EORTCSTBSG 62931 randomised trial. Eur J Cancer. 2019 Mar;109:51-60. PMID:30690293 2458. Patchefsky AS, EnzingerFM. Intravascular fasciitis: a report of 17 cases. Am J Surg Pathol. 1981 Jan;5(1):29-36. PMID:7246849 2459. Patel KH, Gikas PD, Pollock RC, et al. Pigmented villonodular synovitis of the knee: a retrospective analysis of 214 cases at a UK tertiary referral centre. Knee. 2017 Aug;24(4):808-15. PMID:28442184 2460. Patel KU, Szabo SS, Hernandez VS, et al. Dermatofibrosarcoma protubera ns COL1A1 ・ PDGFB fusion is identified in virtually all dermatofibrosarcoma protuberans cases when investigated by newly developed multiplex reverse transcription polymerase chain reaction and fluorescence in situ hybridization assays. Hum Pathol. 2008 Feb;39(2):184-93. PMID:17950782 2461. Patel NR, Chrisinger JSA, Demicco EG, et al. USP6 activation in nodular fasciitis by promoter-swapping gene fusions. Mod Pathol. 2017 Nov;30(11):1577-88. PMID:28752842 2462. Patel SR. Radiation-induced sarcoma. Curr Treat Options Oncol. 2000 Aug;1 (3):25861.PMID:12057168 2463. Patil DT, Laskin WB, Fetsch JF, et al. Inguinal smooth muscle tumors in women-a

Ref ere nces

581

paybal：https://www.paypal.me/andy19801210 dichotomous group consisting of Mullerian-type leiomyomas and soft tissue leiomyosarcomas: an analysis of 55 cases. Am J Surg Pathol. 2011 Mar;35(3):315-24. PMID:21297441 2464. Patil PA, McKenney JK, Trpkov K, et al. Renal leiomyoma: a contemporary multiinstitution study of an infrequent and frequently misclassified neoplasm. Am J Surg Pathol. 2015 Mar;39(3):349-56. PMID:25517956 2465. Patil S, Perry A, Maccollin M, et al. Immunohistochemical analysis s 叩 ports a role for INI1/SMARCB1 in hereditary forms of schwannomas, but not in solitary, sporadic schwannomas. Brain Pathol. 2008 Oct;18(4):517-9. PMID:18422762 2466. Patton A, Page R, Googe PB, et al. Myxoid atypical fibroxanthoma: a previously undescribed variant J Cutan Pathol. 2009 Nov;36(11):1177-84. PMID:19320792 2467. Pavel E, Nadella K, Towns WH 2nd, et al. Mutation of Prkarl a causes osteoblast neoplasia driven by dysregulation of protein kinase A. Mol Endocrinol. 2008 Feb;22⑵:43040. PMID:17932105 2468. Pawel BR, Hamoudi AB, Asmar L, et al. Un differentiated sarcomas of children: pathology and clinical behavior-a n Intergroup Rhabdomyosarcoma study. Med Pediatr Oncol. 1997 Sep;29(3):170-80. PMID:9212841 2469. Peachey RD, Lim CC, Whimster IW. Lymphangioma of skin. A review of 65 cases. Br J Dermatol. 1970 Nov;83(5):519-27. PMID:5484713 2470. Peacock JD, Dykema KJ, Toriello HV, et al. Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations. Am J Med Genet A. 2015 Jul;167⑺:1429—35. PMID:25808193 2471. Pederiva F, Zanazzo GA, Gregori M, et al. Suprascapular lipoblastoma extending in to the thorax. APSP J Case Rep. 2013 May 27;4(2):20. PMID:24040598 2472. Pedeutour F, Forus A, Coindre JM, et al. Structure of the supernumerary ring and giant rod chromosomes in adipose tissue tumors. Genes Chromosomes Cancer. 1999 Jan;24(1):30-41.PMID:9892106 2473. Pedeutour F, Simon MP, Minoletti F, et al. Ring 22 chromosomes in dermatofibrosarcoma protuberans are low-level amplifiers of chromosome 17 and 22 sequences. Cancer Res. 1995Jun 1 ;55(11 ):2400-3. PMID:7757993 2474. Peh WC. The role of imaging in the staging of bone tumors. Crit Rev Oncol Hematol. 1999 Jul;31 ⑵:147-67. PMID:10451800 2475. Pekmezci M, Cuevas-Ocampo AK, Perry A, et al. Significance of H3K27me3 loss in the diagnosis of malignant peripheral nerve sheath tumors. Mod Pathol. 2017 Dec;3O(12):1710-9. PMID:28776579 2476. Pekmezci M, Reuss DE, Hirbe AC, et al. Morphologic and immunohistochemical features of malignant peripheral nerve sheath tumors and cellular schwannomas. Mod Pathol. 2015 Feb;28⑵:187-200. PMID:25189642 2477. Pellegrini AE, Drake RD, Qualman SJ. Spindle cell hemangioendothelioma: a neoplasm associated with Maffucci's syndrome. J Cutan Pathol. 1995 Apr;22⑵:彳73-6. PMID:7560353 2478. Pellestor F. Chromoanagenesis: cataclysms behind complex chromosomal rearrangements. Mol Cytogenet. 2019 Feb 11;12:6. PMID:30805029 ' 2479. Pellin A, Monteagudo C, Lopez-Gines C, et al. New type of chimeric fusion product between the EWS and ATFI genes in clear cell sarcoma (malignant melanoma of soft parts). Genes Chromosomes Cancer. 1998 Dec;23(4):358-60. PMID:9824209 2480. Pelmus M, Guillou L, Hostein I, et al. Monophasic fibrous and poorly differentiated

582

References

synovial sarcoma: immunohistochemical reassessment of 60 t(X;18)(SYT-SSX)positive cases. Am J Surg Pathol. 2002 Nov;26(11):1434-40. PMID:12409719 2481. Pemov A, Hansen NF, Sindiri S, et al. Low mutation burden and frequent loss of CDKN2A/B and SMARCA2, but not PRC2, define pre-malignant neurofibromatosis type 1-associated atypical neurofibromas. Neuro Oncol. 2019 Feb 5. PMID:30722027 2482. Pemov A, Li H, Patidar R, et al. The primacy of NF1 loss as the driver of tumorigenesis in n eurofibromatosis type 1-associated plexiform n eurofibromas. Oncogene. 2017 Jun 1;36(22):3168-77. PMID:28068329 2483. Penel N, Bui BN, Bay JO, et al. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study. J Clin Oncol. 2008 Nov 10;26(32):5269-74. PMID:18809609 2484. Penel N, Coindre JM, Giraud A, et al. Presentation and outcome of frequent and rare sarcoma histologic subtypes: a study of 10,262 patients with localized visceral/ soft tissue sarcoma managed in reference centers. Cancer. 2018 Mar 15;124(6):1179-87. PMID:29211310 2485. Penel N, Taieb S, Ceugnart L, et al. Report of eight recent cases of locally advanced primary pulmonary artery sarcomas: failure of doxorubicin-based chemotherapy. J Thorac Oncol. 2008Aug;3(8):907-11. PMID:18670310 2486. Penman HG, Ring PA. Osteosarcoma in association with total hip replacement. J Bone Joint Surg Br. 1984 Nov;66(5):632-4. PMID:6594340 2487. Pennacchioli E, Fiore M, Collini P, et al. Alveolar soft part sarcoma: clinical presentation, treatment, and outcome in a series of 33 patients at a single institution. Ann Surg Oncol. 2010 Dec;17(12):3229-33. PMID:20593242 2488. Pepper T, Falla L, Brennan PA. Soft tissue giant cell tumour of low malignant potential arising in the masseter-a rare entity in the head and neck. Br J Oral Maxillofac Surg. 2010 Mar;48(2):149-51. PMID:19615796 2489. Perera U, Kennedy BA, Hegele RA. Multiple symmetric lipomatosis (Madelung disease) in a large Canadian family with the mitochondrial MTTK c.8344A>G variant. J Investig Med High Impact Case Rep. 2018 Sep 29;6:2324709618802867. PMID:30283804 2490. Perez-Mancera PA, Bermejo-Rodriguez C, Sanchez-Martin M, et al. FUS-DDIT3 prevents the development of adipocytic precursors in liposarcoma by repressing PPARgamma and C/EBPalpha and activating elF4E. PLoS One. 2008 Jul 2;3(7):e2569. PMID:18596980 2491. Perosio PM, Weiss SW. Ischemic fasciitis: a juxta-skeletal fibroblastic proliferation with a predilection for elderly patients. Mod Pathol. 1993 Jan;6(1):69-72. PMID:8426859 2492. Perot G, Chibon F, Montero A, et al. Constant p53 pathway inactivation in a large series of soft tissue sarcomas with complex genetics. Am J Pathol. 2010 Oct; 177(4):208090. PMID:20884963 2493. Perret R, Chalabreysse L, Watson S, et al. SMARCA4-deficient thoracic sarcomas: clinicopathologic study of 30 cases with an emphasis on their nosology and differential diagnoses. Am J Surg Pathol. 2019 Apr;43⑷:455-65. PMID:30451731 2494. Perry A, Roth KA, Banerjee R, et al. NF1 deletions in S-100 protein-positive and negative cells of sporadic and neurofibromatosis 1 (NFI)-associated plexiform neurofibromas and malignant peripheral nerve sheath tumors. Am J Pathol. 2001 Jul;159(1):57-61. PMID:11438454

2495. Perry JA, Kiezun A, Tonzi P, et al. Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc Natl Acad Sci USA. 2014 Dec 23;111(51):E5564-73. PMID:25512523 2496. Perry KD, Al-Lbraheemi 代 Rubin BP, et al. Composite hemangioendothelioma with n euroendocrine marker expression: an aggressive variant. Mod Pathol. 2017 Nov;30(11):1589-602. PMID:28731049 2497. Pervaiz N, Colterjohn N, Farrokhyar F, et al. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer. 2008 Aug 1;113 ⑶:573-81. PMID:18521899 2498. Peter S, Matevz S, Borut P. Spinal dumbbell lipoblastoma: a case-based update. Childs Nerv Syst. 2016 Nov;32(11):2069-73. PMID:27444294 2499. Peters TL, Kumar V, Polikepahad S, et al. BCOR-CCNB3 fusions are frequent in undifferentiated sarcomas of male children. Mod Pathol. 2015 Apr;28(4):575-86. PMID:25360585 2500. Peterse EFP, Niessen B, Addie RD, et al. Targeting glutaminolysis in chondrosarcoma in context of the IDH1/2 mutation. Br J Cancer. 2018 Apr; 118(8):1074-83. PMID:29576625 2501. Peterse EFP, van den Akker BEWM, Niessen B, et al. NAD synthesis pathway interference is a viable therapeutic strategy for chondrosarcoma. Mol Cancer Res. 2017 Dec;15(12):1714-21.PMID:28860121 2502. Peterson LJ. Granular-cell tumor. Review of the literature and report of a case. Oral Surg Oral Med Oral Pathol. 1974 May;37(5):728-35. PMID:4363978 2503. Petit MM, Mols R, Schoenmakers EF, et al. LPP, the preferred fusion partner gene of HMGIC in lipomas, is a novel member of the LIM protein gene family. Genomics. 1996 Aug 15;36(1):118-29. PMID:8812423 2504. Petra M, Gibbons CL, Athanasou NA. Leiomyosarcoma of bone arising in association with a bone infarct. Sarcoma. 2002;6(1):47-50. PMID:18521345 2505. Pettinato G, Manivel JC, De Rosa N, et al. Inflammatory myofibroblastic tumor (plasma cell granuloma). Clinicopathologic study of 20 cases with immunohistochemical and ultrastructural observations. Am J Clin Pathol. 1990 Nov;94(5):53876. PMID:2239820 2506. Pfeifer FM, Bridge JA, Neff JR, et al. Cytogenetic findings in aneurysmal bone cysts. Genes Chromosomes Cancer. 1991 Nov;3⑹:416-9. PMID:1777412 2507. Pham NS, Poirier B, Fuller SC, et al. Pediatric lipoblastoma in the head and neck: a systematic review of 48 reported cases. I nt J Pediatr Otorhinolaryngol. 2010 Jul;74(7):7238. PMID:20472310 、 2508. Philippe-Chomette P, Kabbara N, Andre N, et al. Desmoplastic small round cell tumors with EWS-WT1 fusion transcript 泊 children and young adults. Pediatr Blood Cancer. 2012 Jun;58(6):891-7. PMID:22162435 2509. Picci P, Manfrini M, Fabbri N, et al„ editors. Atlas of musculoskeletal tumors and tumorlike lesions. The Rizzoli Case Archive. Cham (Switzerland): Springer International Publishing; 2014. 2510. Pierron G, Tirade F, Lucchesi C, et al. A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Genet. 2012 Mar4;44⑷:461—6. PMID:22387997 2511. Piled SA, Grogan TM, Harris NL, et al. Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61

cases. Histopathology. 2002 JuI;41(1)-i_29 PMID:12121233 2512. Pillay N, Plagnol V, Tarpey PS, et al A comm on single-nucleotide variant in T is strongly associated with chordoma. Nat Genet 2012 Nov;44(11):1185-7. PMID:23064415 2513. Pinna V, Lanari V, Daniele P, et al p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas. Eur J Hum Genet 2015 Aug;23(8):1068-71. PMID:25370043 2514. Piombo V, Jochmann K, Hoffmann D et al. Signaling systems affecting the severity of multiple osteochondromas. Bone. 2018 Jun;111:71-81.PMID:29545125 2515. Pipes GC, Creemers EE, Olson EN. The myocardin family of transcriptional coactivators: versatile regulators of cell growth, migration： and myogenesis. Genes Dev. 2006 Jun 15;20(12):1545-56. PMID:16778073 2516. Piquero-Casals J, Okubo AY, Nico MM. Rothmund-Thomson syndrome in three siblings and development of cutaneous squamous cell carcinoma. Pediatr Dermatol. 2002 JulAug;19⑷:312-6. PMID:12220274 2517. Pisters PW, Harrison LB, Leung DH, etal. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol. 1996 Mar; 14(3):859-68 PMID:8622034 2518. Pisters PW, Leung DH, Woodruff J, et al. Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol. 1996 May;14(5):1679-89. PMID:8622088 2519. Pisters PW, Pollock RE, Lewis VO, et al. Long-term results of prospective trial of surgery alone with selective use of radiation for patients with T1 extremity and trunk soft tissue sarcomas. Ann Surg. 2007 Oct;246(4):675-81, discussion 681-2. PMID:17893504 2520. Pitchford CW, Schwartz HS, Atkinson JB, et al. Soft tissue perineurioma in a patient with neurofibromatosis type 2: a tumor not previously associated with the NF2 syndrome. Am J Surg Pathol. 2006 Dec;30(12):1624-9. PMID:17122521 2521. Plaszczyca A, Nilsson J, Magnusson L, et al. Fusions involving protein kinase C and membrane-associated proteins in benign fibrous histiocytoma. Int J Biochem Cell Biol. 2014Aug;53:475-81. PMID:24721208 2522. Plusje LG, Bastiaens M, Chang A, et al. Infantile-type digital fibromatosis tumour in an adult. Br J Dermatol. 2000 Nov; 143(5): 1107-8. PMID:11069537 2523. Policarpio-Nicolas ML, Abbott TE, Dalkin AC, et al. Phosphaturic mesenchymal tumor diagnosed by fine-needle aspiration and core biopsy: a case report and review of literature. Diagn Cytopathol. 2008 Feb;36(2):115-9. PMID:18181193 2524. Pollock M, Nicholson Gl, NukadaH.etal. Neuropathy in multiple symmetric lipomatosis. Madelung's disease. Brain. 1988 Oct;111(Pt 5):1157-71. PMID:3179687 2525. Pollock R, Lang A, Ge T, et al. Wild-type p53 and a p53 temperature-sensitive mutant suppress human soft tissue sarcoma by enhancing cell cycle control. Clin Cancer Res. 1998 Aug;4(8):1985-94. PMID:9717829 2526. Pope V, Dupuis L, Kannu P, et al. Buschke-Ollendorff syndrome: a novel case series and systematic review. Br J Dermatol. 2016 Apr; 174(4):723-9. PMID:26708699 2527. Porter DE, Lonie L, Fraser M, et al. Severity of disease and risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study. J Bone Joint Surg Br. 2004 Sep;86(7):1041-6. PMID:15446535 2528. Porter SB, Blount BW. Pseudotumor of infancy and congenital muscular torticollis.

paybal：https://www.paypal.me/andy19801210 Am Fam Physician. 1995 Nov 1;52(6):1731-6. PMID:7484683 2529. Portera CA Jr, Ho V, Patel SR, et al. Alveolar soft part sarcoma: clinical course and patterns of metastasis in 70 patients treated at a single institution. Cancer. 2001 Feb 1;91 (3):585-91. PMID:11169942 2530. Potter BK, Freedman BA, Lehman RA Jr, et al. Solitary epiphyseal enchondromas. J Bone Joint Surg Am. 2005 Jul;87⑺:1551-60. PMID:15995123 2531. Powers MP, Wang WL, Hernandez VS, et al. Detection of myxoid liposarcomaassociated FUS-DDIT3 rearrangement variants including a newly identified breakpoint using an optimized RT-PCR assay. Mod Pathol. 2010 Oct;23(10):1307-15. PMID:20581806 2532. Prada CE, Jousma E, Rizvi TA, et al. Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol. 2013 Jan;125(1):159-68. PMID:23099891 2533. Pradhan A, Grimer RJ, Abudu A, et al. Epithelioid sarcomas: How important is locoregional control? Eur J Surg Oncol. 2017 Sep;43(9):1746-52. PMID:28756018 2534. Pramparo T, Gregato G, De Gregori M, et al. Reciprocal translocation associated with multiple exostoses in seven members of a three gen eration family and discovered through an infertile male. Am J Med Genet A. 2003 Nov 15;123A(1):79-83. PMID:14556251 2535. Prat J, Woodruff JM, Marcove RC. Epithelioid sarcoma: an analysis of 22 cases indicating the prognostic significance of vascular invasion and regional lymph node metastasis. Cancer. 1978 Apr;41 (4): 1472-87. PMID:639005 2536. Prescott RJ, Husain EA, Abdellaoui A, et al. Superficial acral fibromyxoma: a clinicopathological study of new 41 cases from the U.K.: Should myxoma (NOS) and fibroma (NOS) continue as part of 21st-century reporting? Br J Dermatol. 2008 Dec; 159(6):1315-21. PMID:18764846 2537. Present D, Bacchini P, Pignatti G, et al. Clear cell chondrosarcoma of bone. A report of 8 cases. Skeletal Radiol. 1991 ;20(3):187-91. PMID:2057790 2538. Presneau N, Baumhoer D, Behjati S, et al. Diagnostic value of H3F3A mutations in giant cell tumour of bone compared to osteoclast­ rich mimics. J Pathol Clin Res. 2015 Mar 16:1(2):113-23. PMID:27499898 2539. Presneau N, ShalabyA, Ye H, etal. Role of the transcription factor T (brachyury) in the pathogenesis of sporadic chordoma: a genetic and functional-based study. J Pathol. 2011 Feb;223(3):327-35. PMID:21171078 2540. Preston DL, Ron E, Yonehara S, et al. Tumors of the nervous system and pituitary gland associated with atomic bomb radiation exposure. J Natl Cancer Inst 2002 Oct 16;94(20):1555-63. PMID: 12381708 2541. Pretell-Mazzini J, Murphy RF, Kushare I, et al. Unicameral bone cysts: general characteristics and management controversies. J Am Acad Orthop Surg. 2014 May;22(5):295303. PMID24788445 2542. Price CH. The incidence of osteogenic sarcoma in South-West England and i恰 relationship to Pagefs disease of bone. J Bone Joint Surg Br. 1962 May;44-B:366-76. PMID:14038496 2543. Price EB Jr, Silliphant WM, Shuman R. Nodular fasciitis: a clinicopathologic analysis of 65 cases. Am J Clin Pathol. 1961 Feb;35:12236. PMID:13737962 2544. Prieto-Granada C, Zhang L, Chen HW, et al. A genetic dichotomy between pure sclerosing epithelioid fibrosarcoma (SEF) and hybrid SEF/low-grade fibromyxoid sarcoma:

a pathologic and molecular study of 18 cases. Genes Chromosomes Cancer. 2015 Jan;54(1):28-38. PMID:25231134 2545. Prieto-Granada CN, Wiesner T, Messina JL, et al. Loss of H3K27me3 expression is a highly sensitive marker for sporadic and radiation-induced MPNST. Am J Surg Pathol. 2016Apr;40(4):479-89. PMID:26645727 2546. Pringle LM, Young R, Quick L, et al. Atypical mechanism of NF-kB activation by TRE17/ubiquitin-specific protease 6 (USP6) oncogene and its requirement in tumorigenesis. Oncogene. 2012 Jul 26;31 (30):3525-35. PMID:22081069 2547. Pritchard-Jones K, Fleming S. Cell types expressing the Wilms' tumour gene (WT1) in Wilms' tumours: implications for tumour histogenesis. Oncogene. 1991 Dec;6(12):2211-20. PMID:1722569 2548. Pulitzer DR, Martin PC, Reed RJ. Epithelioid glomus tumor. Hum Pathol. 1995 Sep;26(9):1022-7. PMID:7672784 2549. Pulitzer DR, Martin PC, Reed RJ. Fibroma of tendon sheath. A clinicopathologic study of 32 cases. Am J Surg Pathol. 1989 Jun;13(6):472-9. PMID:2729499 2550. Puls F, Hofvander J, Magnusson L, et al. FN1-EGF gene fusions are recurrent in calcifying aponeurotic fibroma. J Pathol. 2016 Mar;238(4):502-7. PMID:26691015 2551. Puls F, Magnusson L, NiblettA,etal. Non­ fibrosing sclerosing epithelioid fibrosarcoma: an unusual variant. Histopathology. 2016 Apr;68(5):760-3. PMID:26212576 、 2552. Puls F, Niblett A, Marland G, et al. BCOR-CCNB3 (Ewing-like) sarcoma: a clinicopathologic analysis of 10 cases, in comparison with conventional Ewing sarcoma. Am J Surg Pathol. 2014 Oct;38(10):1307-18. PMID:24805859 2553. Puls F, Pillay N, Fagman H, et al. PRDM10-rearranged soft tissue tumor: a clinicopathologic study of 9 cases. Am J Surg Pathol. 2019Apr;43(4):504-13. PMID:30570551 2554. Putra J, Al-lbraheemi A. Adipocytic tumors in children: a contemporary review. Semin Diagn Pathol. 2019 Mar;36(2):95-104. PMID:30850231 2555. Pyakurel P, Montag U, Castanos-Velez E, et al. CGH of microdissected Kaposi's sarcoma lesions reveals recurrent loss of chromosome Y in early and additional chromosomal changes in late tumour stages. AIDS. 2006 Sep 11;20(14):1805-12. PMID:16954721 2556. Qaddoumi I, Orisme W, Wen J, et al. Genetic alterations in un comm on low-grade neuroepithelial tumors: BRAE FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol. 2016 Jun;131(6):833V5. PMID:26810070 2557. Qian X, Hornick JL, Cibas ES, et al. Angicmatoid fibrous histiocytoma a series of five cytologic cases with literature review and emphasis on diagnostic pitfalls. Diagn Cytopathol. 2012 Aug;40 S叩pl 2:E86-93. PMID:22045622 2558. Qualman S, Lynch J, Bridge J, et al. Prevalence and clinical impact of anaplasia in childhood rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Cancer. 2008 Dec 1;113(11):3242-7. PMID:18985676 2559. Quante M, Patel NK, Hill S, et al. Epithelioid hemangioendothelioma presenting in the skin: a clinicopathologic study of eight cases. Am J Dermatopathol. 1998 Dec;20(6):541-6. PMID:9855348 2560. Quick L, Young R, Henrich IC, et al. Jak1-STAT3 signals are essential effectors of the USP6/TRE17 oncogene in tumorigenesis. Cancer Res. 2016 Sep 15;76(18):5337-47. PMID:27440725

2562. Quint LE, Gross BH, Glazer GM, et al. CT evaluation of chondroblastoma. J Comput Assist Tomogr. 1984 Oct;8(5):907-10. PMID:6470260 2563. Qureshi AA, Shott S, Mallin BA, et al. Current trends in the management of adamantinoma of long bones. An international study. J Bone Joint Surg Am. 2000 Aug；82(8):1122-31. PMID:10954102 2564. Raab SS, Silverman JF, McLeod DL, et al. Fine needle aspiration biopsy of fibromatoses. Acta Cytol. 1993 May-Jun;37(3):323-8. PMID:8498134 2565. Raddaoui E, Donner LR, Panagopoulos I. Fusion of the FUS and ATF1 genes in a large, deep-seated angiomatoid fibrous histiocytoma. Diagn Mol Pathol. 2002 Sep;11 ⑶:157-62. PMID:12218455 2566. Rady PL, Hodak E, Yen A, et al. Detection of human herpesvirus-8 DNA in Kaposi's sarcomas from iatrogenically immunosuppressed patients. J Am Acad Dermatol. 1998 Mar;38 ⑶:429-37. PMID:9520025 2567. Raggo C, Ruhl R, McAllister S, et al. Novel cellular genes essential for transformation of endothelial cells by Kaposi's sarcoma-associated herpesvirus. Cancer Res. 2005 Jun 15;65(12):5084-95. PMID:15958552 2568. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014 Nov;15(12):e538-48. PMID:25439696 2569. Rakheja D, Cunningham JC, Mitui M, et al. A subset of cranial fasciitis is associated with dysregulation of the Wnt/beta-catenin pathway. Mod Pathol. 2008 Nov;21(11):13306. PMID:18587328 2570. Ramachandra S, Hollowood K, Bisceglia M, et al. In佃mmatory pseudotumour of soft tissues: a clinicopathological and immunohistochemical analysis of 18 cases. Histopathology. 1995 Oct;27(4):313-23. PMID:8847061 2571. Ramani P, Cowell JK. The expression pattern of Wilms' tumour gene (WT1) product in normal tissues and paediatric「enal tumours. J Pathol. 1996 Jun;179(2):162-8. PMID:8758208 2572. Ramaswamy PV, Storm CA, Filiano JJ, et al. Multiple granular cell tumors in a child with Noonan syndrome. Pediatr Dermatol. 2010 Mar-Apr;27⑵:209-11. PMID:20537083 2573. Ramesh P, Annapureddy SR, Khan F, et al. Angioleiomyoma: a clinical, pathological and radiological review. I nt J Clin Pract. 2004 Jun;58(6):587-91. PMID:15311559 2574. Ramirez JA, Laskin WB, Guitart J. Lymphangioma-like Kaposi sarcoma. J Cutan Pathol. 2005 Apr;32(4):286-92. PMID:15769278 2575. Rana HQ, Gelman R, LaDuca H, et al. Differences in TP53 mutation carrier phenotypes emerge from panel-based testing. J Natl Cancer Inst. 2018 Aug 1;110(8):863-70. PMID:29529297 2576. Raney RB, Meza J, Anderson JR, et al. Treatment of children and adolescents with localized parameningeal sarcoma: experience of the Intergroup Rhabdomyosarcoma Study Group protocols IRS-II through -IV, 1978-1997. Med Pediatr Oncol. 2002 Jan;38(1):22-32. PMID:11835233 2577. Ranger A, Szymczak A. Do intracranial neoplasms differ in Ollier disease and Maffucci syndrome? An in-depth analysis of the literature. Neurosurgery. 2009 Dec;65(6):110613, discussion 1113-5. PMID:19934970 2578. Rankine AJ, Filion PR, Platten MA, et al. Perineurioma: a clinicopathological study of eight cases. Pathology. 2004 Aug;36(4):30915. PMID:15370128

2579. Rao L, KiniAC, Valiathan M, etal. Infantile cartilaginous hamartoma of the rib. A case report. Acta Cytol. 2001 Jan-Feb;45(1):69-73. PMID:11213507 2580. Rao Q, Shen Q, Xia QY, et al. PSF/ SFPQ is a very comm on gene fusion part ne「in TFE3 rearrangement-associated perivascular epithelioid cell tumors (PEComas) and melanotic Xp11 translocation renal cancers: clinicopathologic, immunohistochemical, and molecular characteristics suggesting classification as a distinct entity. Am J Surg Pathol. 2015 S即;39(9):1181-96. PMID:26274027 2581. Rao S, Rajkumar A, Elizabeth MJ, et al. Pathology of synovial lipomatosis and its clinical significance. J Lab Physicians. 2011 Jul;3(2):84-8. PMID:22219560 2582. Rao U, Cheng A, Didolkar MS. Extraosseous osteogenic sarcoma: clinicopathological study of eight cases and review of literature. Cancer. 1978 Apr;41 ⑷:1488-96. PMID:346199 2583. Ratner N, Miller SJ. A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer. 2015 May;15(5):290-301. PMID:25877329 2584. Rausch T, Jones DT, Zapatka M, et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell. 2012 Jan 20;148(1-2):59-71. PMID:22265402 2585. Raut CP, Callegaro D, Miceli R, et al. Predicting survival in patients undergoing resection for locally recurrent retroperitoneal sarcoma: a study and novel nomogram from TARPSWG. Clin Cancer Res. 2019 Apr 15;25(8):2664-71. PMID:30723141 2586. Ravegnini G, Marino-Enriquez A, Slater J, et al. MED12 mutations in leiomyosarcoma and extrauterine leiomyoma. Mod Pathol. 2013 May;26(5):743-9. PMID:23222489 2587. Rawlinson NJ, West WW, Nelson M, et al. Aggressive angiomyxoma with t(12;21) and HMGA2 rearrangement: report of a case and review of the literature. Cancer Genet Cytogenet. 2008 Mar;181 ⑵19-24. PMID:18295664 2588. Reddy A, Zhang J, Davis NS, et al. Genetic and functional drivers of diffuse large B cell lymphoma. Cell. 2017 Oct 5;171 ⑵:481494,e15. PMID:28985567 2589. Reed RJ, Fine RM, Meltzer HD. Palisaded, encapsulated neuromas of the skin. Arch Dermatol. 1972 Dec;106(6):865-70. PMID:4639250 2590. Reeves BR, Fletcher CD, Gusterson BA. Translocation t(12;22)(q13;q13) is a nonrandom rearrangement in clear cell sarcoma. Cancer Genet Cytogenet. 1992 Dec;64(2):101-3. PMID:1486556 2591. Reichek JL, Duan F, Smith LM, et al. Genomic and clinical analysis of amplification of the 13q31 chromosomal region in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group. Clin Cancer Res. 2011 Mar15;17(6):1463-73. PMID:21220470 2592. Reid R, de Silva MV, Paterson L, et al. Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes share a common t(7; 16)(q34;p11) translocation. Am J Surg Pathol. 2003 Sep;27(9): 1229-36. PMID:12960807 2593. Reijnders CM, Waaijer CJ, Hamilton A, et al. No h即loinsufficiency but loss of heterozygosity for EXT in multiple osteochondromas. Am J Pathol. 2010 Oct;177(4):1946-57. PMID:20813973 2594. Reilly KM, Kim A, Blakely J, et al. Neurofibromatosis type 1-associated MPNST state of the science: outlining a research

Refere nces

583

paybal：https://www.paypal.me/andy19801210 agenda for the future. J Natl Cancer Inst. 2017 Aug 1;109(8):djx124. PMID:29117388 2595. Reimann JD, Fletcher CD. Myxoid dermatofibrosarcoma protuberans: a rare variant analyzed in a series of 23 cases. Am J Surg Pathol. 2007 Sep;31 (9):1371-7. PMID:17721193 2596. Reisenauer JS, Mneimneh W, Jenkins S, et al. Comparison of risk stratification models to predict recurrence and survival in pleuropulmonary solitary fibrous tumor. J Thorac Oncol. 2018 Sep;13(9):1349-62. PMID:29935303 2597. Reiseter T, Nordshus T, Borthne A, et al. Lipoblastoma: MRI appearances of a rare paediatric soft tissue tumour. Pediatr Radiol. 1999 Jul;29(7):542-5. PMID:10398794 2598. Reitamo JJ, Hayry P, Nykyri E, et al. The desmoid tumor. I. Incidenee, sex-, age- and anatomical distribution in the Finnish population. Am J Clin Pathol. 1982 Jun;77(6):665-73. PMID:7091046 2599. Reith JD, Donahue Fl, Hornicek FJ. Dedifferentiated parosteal osteosarcoma with rhabdomyosarcomatous differentiation. Skeletal Radiol. 1999 Sep;28(9):527-31. PMID:10525797 2600. Rekhi B, Adamane S, Ghodke K, et al. Angiomatoid fibrous histiocytoma: clinicopathological spectrum of five cases, including EWSR1-CREB1 positive result in a single case. Indian J Pathol Microbiol. 2016 Apr-Jun;59⑵:148-52. PMID:27166030 2601. Rekhi B, Banerjee D, Gala K, et al. Superficial CD34-positive fibroblastic tumor in the forearm of a middle-aged patient: a newly described, rare soft-tissue tumor. Indian J Pathol Microbiol. 2018 Jul-Sep;61 (3):421-4. PMID:30004071 2602. Rekhi B, Deshmukh M, Jambhekar NA Low-grade fibromyxoid sarcoma: a clinicopathologic study of 18 cases, including histopathologic relationship with sclerosing epithelioid fibrosarcoma in a subset of cases. Ann Diagn Pathol. 2011 Oct;15⑸:3O3-11. PMID:21550274 2603. Rekhi B, Gorad BD, Chinoy RF. Clinicopathological features with outcomes of a series of conventional and proximal-type epithelioid sarcomas, diagnosed over a period of 10 years at a tertiary cancer hospital in India. Virchows Arch. 2008Aug;453⑵:141-53. PMID:18607629 2604. Rekhi B, Gupta C, Chinnaswamy G, et al. Clinicopathologic features of 300 rhabdomyosarcomas with emphasis upon differential expression of skeletal muscle specific markers in the various subtypes: a single institutional experience. Ann Diagn Pathol. 2018 Oct;36:50-60. PMID:30098515 2605. Rekhi B, Ingle A, Agarwal M, et al. Alveolar soft part sarcoma 'revisited': clinicopathological review of 47 cases from a tertiary cancer referral centre, including immunohistochemical expressio n of TFE3 i n 22 cases and 21 other tumours. Pathology. 2012 Jan;44(1):11-7. PMID:22173238 2606. Rekhi B, Kaur A, Puri A, et al. Primary leiomyosarcoma of bone-a clinicopathologic study of 8 uncommon cases with immunohistochemical analysis and clinical outcomes. Ann Diagn Pathol. 2011 Jun;15(3):147-56. PMID:21393038 2607. Rekhi B, Kosemehmetoglu K, Rane S, et al. Poorly differentiated chordomas showing loss of INI1/SMARCB1: a report of 2 rare cases with diagnostic implications. Int J Surg Pathol. 2018 Oct;26(7):637-43. PMID:29623728 2608. Rekhi B, Upadhyay P, Ramteke MP, et al. MYOD1 (L122R) mutations are associated with spindle cell and sclerosing rhabdomyosarcomas with aggressive clinical

584

References

outcomes. Mod Pathol. 2016 Dec;29(12):153240. PMID:27562493 2609. Relles D, Baek J, Witkiewicz A, et al. Periampullary and duodenal neoplasms in neurofibromatosis type 1: two cases and an updated 20-year review of the literature yielding 76 cases. J Gastrointest Surg. 2010 Jun;14(6):1052-61. PMID:20300877 2610. Remstein ED, Arndt CA, Nascimento AG. Plexiform fibrohistiocytic tumor: clinicopathologic analysis of 22 cases. Am J Surg Pathol. 1999 Jun;23⑹:662-70. PMID:10366148 2611. Ren G, Esposito M, Kang Y. Bone metastasis and the metastatic niche. J Mol Med (Berl). 2015 Nov;93(11):1203-12. PMID:26275789 2612. Renard C, Pissaloux D, Decouvelaere AV, et al. Non-rhabdoid pediatric SMARCB1deficient tumors: overlap between chordomas and malignant rhabdoid tumors? Cancer Genet. 2014 Sep;207(9):384-9. PMID:25053104 2613. Renaux-Petel M, Sesboue R, BaertDesurmont S, et al. The MDM2 285G-309G haplotype is associated with an earlier age of tumour onset in patients with Li-Fraumeni syndrome. Fam Cancer. 2014 Mar;13(1):12730. PMID:23884452 2614. Rendina D, De Filippo G, Ralston SH, et al. Clinical characteristics and evolution of giant cell tumor occurring in Paget's disease of bone. J Bone Miner Res. 2015 Feb;30⑵:257-63. PMID:25196811 2615. Requena L, Luis Diaz J, Manzarbeitia F, et al. Cutaneous composite hemangioendothelioma with satellitosis and lymph node metastases. J Cutan Pathol. 2008 Feb;35⑵:225-30. PMID: 18190450 2616. Reul H, Eichler M, Potthast K, et al. In vitro testing of heart valve wear outside of the manufacturers laboratory-requirements and controversies. J Heart Valve Dis. 1996 Jun;5 Suppl 1:S97-103, discussion 103-4. PMID:8803761 2617. Revell MP, Deshmukh N, Grimer RJ, et al. Periosteal osteosarcoma: a review of 17 cases with mean follow-up of 52 months. Sarcoma. 2002;6(4): 123-30. PMID:18521348 2618. Reye RD. Recurring digital fibrous tumors of childhood. Arch Pathol. 1965 Sep;80:22831. PMID:14322942 2619. Ribeiro S, Napoli I, White IJ, et al. Injury signals cooperate with Nf1 loss to relieve the tumor-suppressive environment of adult peripheral nerve. Cell Rep. 2013 Oct 17;5(1):126-36. PMID:24075988 2620. Ribi S, Baumhoer D, Lee K, et al. TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome. On cotarget. 2015 Apr 10;6(10):7727-40. PMID:25762628 2621. Richardson TE, Butt YM, Torrealba JR, et al. Meningothelial-like nodules of the lung show SSTR2a immunohistochemical staining. Arch Pathol Lab Med. 2018 Jul;142(7):781-2. PMID:29939782 2622. Richardson TE.Wachsmann M, Oliver D, et al. BRAF mutation leading to central nervous system Rosai-Dorfman disease. Ann Neurol. 2018 Jul;84(1):147-52. PMID:30014527 2623. Rieker RJ, Joos S, Bartsch C, et al. Distinct chromosomal imbalances in pleomorphic and in high-grade dedifferentiated liposarcomas. Int J Cancer. 2002 May 1;99(1):68-73. PMID:11948494 2624. Rieker RJ, Quentmeier A, Weiss C, et al. Cystic lymphangioma of the small-bowel mesentery: case report and a review of the literature. Pathol Oncol Res. 2000;6(2):146-8. PMID:10936792 2625. Riester SM, Torres-Mora J, Dudakovic A, et al. Hypoxia-related microRNA-210

is a diagnostic marker for discriminating osteoblastoma and osteosarcoma. J Orthop Res. 2017 May;35 ⑸:1137-46. PMID:27324965 2626. Righi A, Gambarotti M, Benini S, et al. MDM2 and CDK4 expression in periosteal osteosarcoma. Hum Pathol. 2015 Apr;46(4):549-53. PMID:25680902 2627. Righi A, Gambarotti M, Longo S, et al. Small cell osteosarcoma: clinicopathologic, immunohistochemical, and molecular analysis of 36 cases. Am J Surg Pathol. 2015 May;39(5):691-9. PMID:25723116 2628. Righi A, Gambarotti M, Manfrini M, et al. Sclerosing epithelioid fibrosarcoma of the thigh: report of two cases with synchronous bone metastases. Virchows Arch. 2015 Sep;467⑶:339-44. PMID:26209924 2629. Righi A, Gambarotti M, Sbaraglia M, et al. Metastasizing tenosynovial giant cell tumour, diffuse type/pigmented villonodular synovitis. Clin Sarcoma Res. 2015 Jun 6;5:15. PMID:26052431 2630. Righi A, Mancini I, Gambarotti M, et al. Histone 3.3 mutations in giant cell tumor and giant cell-rich sarcomas of bone. Hum Pathol. 2017 Oct;68:128-35. PMID:28899740 2631. Righi A, Paioli A, Dei Tos AP, et al. High-grade focal areas in low-grade central osteosarcoma: high-grade or still low-grade osteosarcoma? Clin Sarcoma Res. 2015 Oct 29;5:23. PMID:26524981 2632. Righi A, Sbaraglia M, Gambarotti M, et al. Extra-axial chordoma: a clinicopathologic analysis of s仪 cases. Virchows Arch. 2018 Jun;472(6):1015-20. PMID:29560513 2633. Rimareix F, Bardot J, Andrac L, et al. Infantile digital fibroma-report on eleven cases. Eur J Pediatr Surg. 1997 Dec;7(6):345-8. PMID:9493986 2634. Riminucci Mf Collins MT, Fedarko NS, et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest. 2003 Sep;112(5):683-92. PMID:12952917 2635. Riminucci M, Fisher LW, Majolagbe A, et al. A novel GNAS1 mutation, R201G, in McCune-Albright syndrome. J Bone Miner Res. 1999 Nov;14(11):1987-9. PMID:10571700 2636. Riminucci M, Liu B, Corsi A, et al. The histopathology of fibrous dysplasia of bone in patients with activating mutations of the Gs alpha gene: site-specific patterns and recurrent histological hallmarks. J Pathol. 1999 Jan;187(2):249-58. PMID:10365102 2637. Rios JJ, Paria N, Burns DK, et al. Somatic gain-of-function mutations in PIK3CA in patients with macrodactyly. Hum Mol Genet. 2013 Feb 1;22(3):444-51. PMID:23100325 2638. Ritter J, Bielack SS. Osteosarcoma. Ann Oncol. 2010 Oct;21 Suppl 7:vii320-5. PMID:20943636 2639. Robinson C, Estrada A, Zaheer A, et al. Clinical and radiographic gastrointestinal abnormalities in McCune-Albright syndrome. J Clin Endocrinol Metab. 2018 Nov 1;103(11):4293-303. PMID:30124968 2640. Robinson DR, Wu YM, KalyanaSundaram S, et al. Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat Genet. 2013 Feb;45(2):180-5. PMID:23313952 2641. Robinson E, Neugut Al, Wylie P. Clinical aspects of postirradiation sarcomas. J Natl Cancer Inst. 1988 Apr 20;80(4):233-40. PMID:3280809 2642. Robson AM, Calonje E. Cutaneous perineurioma: a poorly recognized tumour often misdiagnosed as epithelioid histiocytoma. Histopathology. 2000 Oct;37(4):332-9. PMID:11012740 2643. Rochanawutanon M, Praneetvatakul P,

Laothamatas J, et al. Extraskeletal giant cell tumor of the larynx: case report and review of the literature. Ear Nose Throat J. 2011 May;90(5):226-30. PMID:21563092 2644. Rock MG, Sim FH, Unni KK, et al Secondary malignant giant-cell tumor of bone. Clinicopathological assessment of nineteen patients. J Bone Joint Surg Am. 1986 Sep;68(7):1073-9. PMID:3745247 2645. Rodriguez E, Sreekantaiah C, Gerald W, et al. A recurring t「anslocation, t(11；22) (p13;q11.2), characterizes intra-abdominal desmoplastic small「ound-cell tumors. Cancer Genet Cytogenet. 1993 Aug;69(1):17-21 PMID:8374894 2646. Rodriguez-Peralto JL, Lopez-Barea F, Gonzalez-Lopez J, et al. Case report 821: parosteal ossifying lipoma of femur. Skeletal Radiol. 1994 Jan;23(1):67-9. PMID:8160042 2647. Rohrich M, Koelsche C, Schrimpf D, et al. Methylation-based classification of benign and malignant peripheral nerve sheath tumors. Acta Neuropathol. 2016 Jun;131(6):877-87 PMID:26857854 2648. Roitman PD, Jauk F, Farfalli GL, et al. Denosumab-treated giant cell tumor of bone. Its histologic spectrum and potential diagnostic pitfalls. Hum Pathol. 2017 May;63:89-97 PMID:28235628 2649. Rojnueangnit K, Xie J, Gomes A, et al. High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecti ng p.Arg 1809: genotype-phenotype correlation. Hum Mutat. 2015Nov;36(11):105263. PMID:26178382 2650. Romeo S, Bovee JV, Grogan SP, et al. Chondromyxoid fibroma resembles in vitro chondrogenesis, but differs in expression of signalling molecules. J Pathol. 2005 Jun;206(2):135-42. PMID:15880456 2651. Romeo S, Bovee JV, Kroon HM, et al. Malignant fibrous histiocytoma and fibrosarcoma of bone: a re-assessment in the light of currently employed morphological, immunohistochemical and molecular approaches. Virchows Arch. 2012 Nov;461 (5):561-70. PMID:23001328 2652. Romeo S, Eyden B, Prins FA, et al. TGF-beta1 drives partial myofibroblastic differentiation in chondromyxoid fibroma of bone. J Pathol. 2006 Jan;208(1):26-34. PMID:16278817 2653. Romeo S, Hogendoorn PC, Dei Tos AP. Benign cartilaginous tumors of bone: from morphology to somatic and germ-line genetics. Adv Anat Pathol. 2009 Sep;16(5):307-15. PMID:19700940 2654. Ron E, Modan B, Boice JD Jr, et al. Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med. 1988 Oct 20;319(16):1033-9. PMID:3173432 2655. Ropke M, Boitze C, Neumann HW, et al. Genetic and epigenetic alterations in tumor progression in a dedifferentiated chondrosarcoma. Pathol Res P「act. 2003;199⑹:43774. PMID:12924447 2656. Rosario M, Kim HS, Yun JY, et al. Surveillance for lung metastasis from giant cell tumor of bone. J Surg Oncol. 2017 Dec;116(7):907-13. PMID:28650536 2657. Rose PS, Dickey ID, Wenger DE, et al. Periosteal osteosarcoma: long-term outcome and risk of late recurrence. Clin Orthop Relat Res. 2006 Dec;453(453):314-7. PMID:16906092 2658. Rosenberg AE. Pseudosarcomas of soft tissue. Arch Pathol Lab Med. 2008 Apr;132(4):579-86. PMID:18384209 2659. Rosenberg AE, Brown GA, Bhan AK, et al. Chondroid chordoma-a variant of chordoma. A morphologic and immunohistochemical study.

paybal：https://www.paypal.me/andy19801210 Am J Clin Pathol. 1994 Jan;101(1):36-41. PMID:7506477 2660. Rosenberg HS, Stenback WA, Spjut HJ. The fibromatoses of infancy and childhood. Perspect Pediatr Pathol. 1978;4:269-348. PMID:215963 2661. Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg. 1982 Sep;196⑶:305J5. PMID:7114936 2662. Rosenberg ZS, Lev S, Schmahmann S, et al. Osteosarcoma: subtle, rare, and misleading plain film features. AJR Am J Roentgenol. 1995 Nov;165(5):1209-14. PMID:7572505 2663. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse largeB-cell lymphoma. N Engl J Med. 2002 Jun 20;346(25):1937-47. PMID:12075054 2664. Ross DC. Epidemiology of Dupuytren's disease. Hand Clin. 1999 Feb; 15(1):53-62, vi. PMID:10050242 2665. Ross JA, Severson RK, Davis S, et al. Trends in the incidence of soft tissue sarcomas in the United States from 1973 through 1987. Cancer. 1993 Jul 15;72(2):486-90. PMID:8319178 2666. Rossi S, Fletcher CD. Angiosarcoma arising in hemangioma/vascular malformation: report of four cases and review of the literature. Am J Surg Pathol. 2002 Oct;26(10):1319-29. PMID:12360047 2667. Rossi S, Gasparotto D, Cacciatore M, et al. Neurofibromin C terminus-specific antibody (clone NFC) is a valuable tool for the identification of NF1-inactivated GISTs. Mod Pathol. 2018Jan;31(1):160-8. PMID:28862263 2668. Rossi S, Gasparotto D, Miceli R, et al. KIT, PDGFRA, and BRAF mutational spectrum impacts on the natural history of imatinib-naive localized GIST: a population-based study. Am J Surg Pathol. 2015 Jul;39(7):922-30. PMID:25970686 2669. Rossi S, Miceli R, Messerini L, et al. Natural history of imatinib-naive GISTs: a retrospective analysis of 929 cases with long­ term follow-up and development of a survival no mog ram based on mitotic in dex and size as continuous variables. Am J Surg Pathol. 2011 Nov;35(11):1646-56. PMID:21997685 2670. Rossi S, Orvieto E, Furlanetto 代 et al. Utility of the immunohistochemical detection of FLI-1 expression in round cell and vascular neoplasm using a monoclonal antibody. Mod Pathol. 2004 May;17(5):547-52. PMID:15001993 2671. Rossi S, Szuhai K, Ijszenga M, et al. EWSR1-CREB1 and EWSR1-ATF1 fusion genes in angiomatoid fibrous histiocytoma. Clin Cancer Res. 2007 Dec 15; 13(24):7322-8. PMID:18094413 2672. Rossleigh MA, Smith J, Yeh SD. Scintigraphic features of primary sacral tumors. J Nucl Med. 1986 May;27(5):627-30. PMID:3712078 2673. Rousseau A, Kujas M, van Effenteire R, et al. Primary intracranial myopericytoma: report of three cases and review of the literature. Neuropathol Appl Neurobiol. 2005 Dec;31 (6):641-8. PMID:16281913 2674. Rowland F, Call C, Mujtaba B, et al. Calcified leiomyoma of the deltoid: pathophysiology and imaging review. Skeletal Radiol. 2019Apr;48(4):625-8. PMID:30187111 2675. Rozeman LB, de Bruijn IH, Bacchini P, etal. Dedifferentiated peripheral chondrosarcomas: regulation of EXT-downstream molecules and differentiation-related genes. Mod Pathol. 2009 Nov;22(11):1489-98. PMID: 19734846 2676. Rozeman LB, Hameetman L,

Cleton-Jansen AM, et al. Absence of IHH and retention of PTHrP signalling in enchondromas and central chondrosarcomas. J Pathol. 2005 Mar;205(4):476-82. PMID:15685701 2677. Rozeman LB, Hameetman L, van Wezel T, et al. cDNA expression profiling of chondrosarcomas: Ollier disease resembles solitary tumours and alteration in genes coding for components of energy metabolism occurs with increasing grade. J Pathol. 2005 Sep;207(1):61-71. PMID:16007578 2678. Rozeman LB, Sangiorgi L, Briaire-de Bruijn IH, et al. Enchondromatosis (Ollier disease, Maffucci syndrome) is not caused by the PTHR1 mutation p.R150C. Hum Mutat. 2004 Dec;24(6):466-73. PMID:15523647 2679. Rozmaryn LM, Sadler AH, Dorfman HD. Intraosseous glomus tumor in the ulna. A case report. Clin Orthop Relat Res. 1987 Jul;(220):126-9. PMID:3036410 2680. Rubin BP, Antonescu CR, Gannon FH, et al. Protocol for the examination of specimens from patients with tumors of bone. Arch Pathol Lab Med. 2010 Apr; 134(4):e1-7. PMID:20367293 2681. Rubin BP, Cooper K, Fletcher CD, et al. Protocol for the examination of specimens from patients with tumors of soft tissue. Arch Pathol Lab Med. 2010 Apr;134(4):e31-9. PMID:20367297 2682. Rubin BP, Fletcher CD. Myxoid leiomyosarcoma of soft tissue, an underrecognized variant. Am J Surg Pathol. 2000 Jul;24(7):927-36. PMID:10895815 2683. Rubin BP, Singer S, Tsao C, et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res. 2001 Nov 15;61(22):8118-21. PMID:11719439 2684. Rubinstein JC, Visa A, Zhang L, et al. Primary low-grade fibromyxoid sarcoma of the kidney in a child with the alternative EWSR1CREB3L1 gene fusion. Pediatr Dev Pathol. 2014 Jul-Aug;17(4):321-6. PMID:24896634 2685. Rudisaile SN, Hurt MA, Santa Cruz DJ. Granular cell atypical fibroxanthoma. J Cutan Pathol. 2005 Apr;32(4):314-7. PMID:15769283 2686. Rudzinski ER, Anderson JR, Chi YY, et al. Histology, fusion status, and outcome in metastatic rhabdomyosarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2017 Dec;64(12):e26645. PMID:28521080 2687. Rudzinski ER, Anderson JR, Lyden ER, et al. Myogenin, AP2R, NOS-1, and HMGA2 are surrogate markers of fusion status in rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Am J Surg Pathol. 2014 May;38⑸:654-9. PMID:24618610 2688. Rudzinski ER, Lockwood CM, Stohr BA, et al. Pan-Trk immunohistochemistry identifies NTRK rearrangements in pediatric mesenchymal tumors. Am J Surg Pathol. 2018 Jul;42(7):927-35. PMID:29683818 2689. Rudzinski ER, Teot LA, Anderson JR, et al. Dense pattern of embryonal rhabdomyosarcoma, a lesion easily confused with alveolar rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Am J Clin Pathol. 2013Jul;140⑴:82-90. PMID:23765537 2690. Rueckert J, Devitt K, Kalof A, et al. "Lipoblastoma^^ has a nice ring to it. J Assoc Genet Technol. 2018;44(2):45-8. PMID:29897891 2691. Ruggieri P, Sim FH, Bond JR, et al. Malignancies in fibrous dysplasia. Cancer. 1994 Mar1;73(5): 1411-24. PMID:8111708 2692. Russell WO, Cohen J, Enzinger F, et al. A clinical and pathological staging system for soft tissue sarcomas. Cancer. 1977 Oct;40(4): 1562-70. PMID:907970 2693. Ruszczak Z, Mayer da Silva A, Orfanos

CE. Angioproliferative changes in clinically noninvolved, perilesional skin in AIDSassociated Kaposi's sarcoma. Derma⑹ogica. 1987;175(6):270-9. PMID:3691903 2694. Rutkowski P, Van Glabbeke M, Rankin CJ, et al. Imatinib mesylate in advanced dermatofibrosarcoma protuberans: pooled analysis of two phase II clinical trials. J Clin Oncol. 2010 Apr 1;28(10):1772-9. PMID:20194851 2695. Rybak LD, Abramovici L, Kenan S, et al. Cortico-medullary continuity in bizarre parosteal osteochondromatous proliferation mimicking osteochondroma on imaging. Skeletal Radiol. 2007 Sep;36(9):829-34. PMID:17437102 2696. Rybak LD, Rosenthal DI, Wittig JC. Chondroblastoma: radiofrequency ablation­ alternative to surgical resection in selected cases. Radiology. 2009 May;251 (2):599-604. PMID:19304917 2697. Rydholm A. Management of patients with soft-tissue tumors. Strategy developed at a regional oncology center. Acta Orthop Scand S叩pl. 1983;203:13-77. PMID:6581679 2698. Rydholm A, Berg NO. Size, site and clinical incidence of lipoma. Factors in the differential diagnosis of lipoma and sarcoma. Acta Orthop Scand. 1983 Dec;54(6):929-34. PMID:6670522 2699. Rydholm A, Gustafson P, Rooser B, et al. Limb-sparing surgery without radiotherapy based on anatomic location of soft tissue sarcoma. J Clin Oncol. 1991 Oct;9(10):175765. PMID:1919628 2700. Ryman W, Bale P. Recurring digital fibromas of infancy. Australas J Dermatol. 1985 Dec;26⑶:113-7. PMID:3835952 2701. Saab ST, McClain CM, Coffin CM. Fibrous hamartoma of infancy: a clinicopathologic analysis of 60 cases. Am J Surg Pathol. 2014 Mar;38(3):394^101. PMID:24525510 2702. Saada-Bouzid E, Burel-Vandenbos F, Ranchere-Vince D, et al. Prognostic value of HMGA2, CDK4, and JUN amplification in well-differentiated and dedifferentiated liposarcomas. Mod Pathol. 2015 Nov;28(11):1404-14. PMID:26336885 2703. Sachdeva MP, Goldblum JR, Rubin BP, et al. Low-fat and fat-free pleomorphic lipomas: a diagnostic challenge. Am J Dermatopathol. 2009 Jul;31 (5):423-6. PMID:19542913 2704. Sadri N, Barroeta J, Pack SD, et al. Malignant round cell tumor of bone with EWSR1-NFATC2 gene fusion. Virchows Arch. 2014Aug;465⑵:233-9. PMID:24993903 2705. Saggio I, Remoli C, Spica E, et al. Constitutive expression of Gsa(R201C) in mice produces a heritable, direct replica of human fibrous dysplasia bone pathology and demonstrates its natural history. J Bone Miner Res. 2014 Nov;29(11):2357-68. PMID:24764158 2706. Saiag P, GrobJJ.Lebbe C, etal. Diagnosis and treatment of dermatofibrosarcoma protuberans. Europea n consensus-based interdisciplinary guideline. Eur J Cancer. 2015 Nov;51 (17):2604-8. PMID:26189684 2707. Sait SF, Danzer E, Ramirez D, et al. Spontaneous regression in a patient with infantile fibrosarcoma. J Pediatr Hematol Oncol. 2018 May;40(4):e253-5. PMID:29200168 2708. Saito T. Glomus tumor of the penis. Int J Urol. 2000 Mar;7(3):115-7. PMID:10750892 2709. Sakakibara N, Seki T, Maru A, et al. Benign fibrous histiocytoma of the kidney. J Urol. 1989 Dec; 142(6):1558-9. PMID:2555573 2710. Sakamoto A, Imamura S, Matsumoto Y, et al. Bizarre parosteal osteochondromatous proliferation with an inversion of chromosome 7. Skeletal Radiol. 2011 Nov;40(11):1487-90. PMID:21509435 2711. Sakamoto A, Oda Y, Itakura E, et

al. H-, K-, and N-ras gene mutation in atypical fibroxanthoma and malignant fibrous histiocytoma. Hum Pathol. 2001 Nov;32(11):1225-31. PMID:11727262 2712. Sakamoto A, Oda Y, Itakura E, et al. Immunoexpression of ultraviolet photoproducts and p53 mutation analysis in atypical fibroxanthoma and superficial malignant fibrous histiocytoma. Mod Pathol. 2001 Jun;14⑹:5818. PMID:11406660 2713. Sakamoto A, Oda Y, Oshiro Y, et al. Immunoexpression of neurofibromin, S-100 protein, and leu-7 and mutation analysis of the NF1 gene at codon 1423 in osteofibrous dysplasia. Hum Pathol. 2001 Nov;32(11):124551.PMID:11727265 2714. Sakamoto A, Tanaka K, Yoshida T, et al. Nonossifying fibroma accompanied by pathological fracture in a 12-year-old runner. J Orthop Sports Phys Ther. 2008 Jul;380):4348. PMID:18591758 2715. Sakamoto A, Yamamoto H, Yoshida T, et al. Desmoplastic fibroblastoma (collagenous fibroma) with a specific breakpoint of 11q12. Histopathology. 2007 Dec;51 (6):859-60. PMID:17894801 2716. Sakharpe A, Lahat G, Gulamhusein T, et al. Epithelioid sarcoma and unclassified sarcoma with epithelioid features: clinicopathological variables, molecular markers, and a new experimental model. Oncologist. 2011;16(4):512-22. PMID:21357725 2717. Salamah MM, Hammoudi SM, Sadi AR. Infantile myofibromatosis. J Pediatr Surg. 1988 Oct;23(10):975-7. PMID:3236168 2718. Salas S, Chibon F, Noguchi T, et al. Molecular characterization by array comparative genomic hybridization and DNA sequencing of 194 desmoid tumors. Genes Chromosomes Cancer. 2010 Jun;49(6):560-8. PMID:20232483 2719. Salas S, Dufresne A, Bui B, et al. Prognostic factors influencing progression-free survival determined from a series of sporadic desmoid tumors: a wait-and-see policy according to tumor presentation. J Clin dncol. 2011 Sep 10;29(26):3553-8. PMID:21844500 2720. Salas S, Resseguier N, Blay JY, et al. Prediction of local and metastatic recurrence in solitary fibrous tumor: construction of a risk calculator in a multicenter cohort from the French Sarcoma Group (FSG) database. Ann Oncol. 2017 Aug 1;28(8):1979-87. PMID:28838212 2721. Saleh G, Evans HL, Ro JY, et al. Extraskeletal myxoid chondrosarcoma. A clinicopathologic study of ten patients with long-term follow-叩.Cancer. 1992 Dec 15;70(12):2827-30. PMID:1451062 2722. Salenave S, Boyce AM, Collins MT, et al. Acromegaly and McCune-Albright syndrome. J Clin Endocrinol Metab. 2014 Jun;99(6):195569. PMID:24517150 2723. Salib C, Edelman M, Lilly J, et al. USP6 gene rearrangement by FISH analysis in cranial fasciitis: a report of three cases. Head Neck Pathol. 2019 Feb 13. PMID:30758758 2724. Salinas-Souza C, De Andrea C, Bihl M, et al. GNAS mutations are not detected in parosteal and low-grade central osteosarcomas. Mod Pathol. 2015 Oct;28(10):1336-42. PMID:26248895 2725. Salomao DR, Nascimento AG. Plexiform fibrohistiocytic tumor with systemic metastases: a case report. Am J Surg Pathol. 1997 Apr;21 (4):469-76. PMID:9130995 2726. Salzer-Kuntschik M, Delling G, Beron G, et al. Morphological grades of regression in osteosarcoma after polychemotherapy - study COSS 80. J Cancer Res Clin Oncol. 1983;106 Suppl:21-4. PMID:6577010

References

585

paybal：https://www.paypal.me/andy19801210 2727. Samols MA, Skalsky RL, Maldonado AM, et al. Identification of cellular genes targeted by KSHV-encoded microRNAs. PLoS Pathog. 2007 May 11;3(5):e65. PMID:17500590 2728. Sandberg AA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: liposarcoma. Cancer Genet Cytogenet. 2004 Nov;155(1):1-24. PMID:15527898 2729. Sandberg AA, Bridge JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. Dermatofibrosarcoma protuberans and giant cell fibroblastoma. Cancer Genet Cytogenet. 2003 Jan 1 ;140(1 ):112. PMID:12550751 2730. Sanerkin NG, Mott MG, Roylance J. An unusual intraosseous lesion with fibroblastic, osteoclastic, osteoblastic, aneurysmal and fibromyxoid elements. "Solid^, variant of aneurysmal bone cyst Cancer. 1983 Jun 15;51(12):2278-86. PMID:6850506 2731. Sanfilippo R, Miceli R, Grosso F, et al. Myxofibrosarcoma: prognostic factors and survival in a series of patients treated at a single institution. Ann Surg Oncol. 2011 Mar;18⑶:720-5. PMID:20878245 2732. Sanghavi S, WahegaonkarA, Panchwagh Y, et al. Parosteal osteosarcoma of the distal radius mimicking an osteochond「oma-a diagnostic misadventure. J Hand Surg Am. 2017 Dec;42(12):1038.e1-10. PMID:28917546 2733. Sanjay BK, Sim FH, Unni KK, etal. Giant­ cell tumours of the spine. J Bone Joint Surg Br. 1993 Jan;75(1 ):148-54. PMID:8421014 2734. Sant DW, Margraf RL, Stevenson DA, et al. Evaluation of somatic mutations in tibial pseudarthrosis samples in neurofibromatosis type 1. J Med Genet. 2015 Apr;52(4):256-61. PMID:25612910 2735. Santarelli R, De Marco R, Masala MV, etal. Direct correlation between human herpesvirus-8 seroprevalence and classic Kaposi's sarcoma incidence in northern Sardinia. J Med Virol. 2001 Oct;65⑵:368-72. PMID: 11536246 2736. Santeusanio G, Bombonati A, Tarantino U, et al. Multifocal epithelioid angiosarcoma of bone: a potential pitfail in the differential diagnosis with metastatic carci noma Appl Immunohistochem Mol Morphol. 2003 Dec;11(4):359-63. PMID:14663364 2737. Santiago T, Clay MR, Allen SJ, et al. Recurrent BCOR internal tandem duplication and BCOR or BCL6 expression distinguish primitive myxoid mesenchymal tumor of infancy from congenital infantile fibrosarcoma. Mod Pathol. 2018 Feb;31 (2):374. PMID:29430000 2738. Santonja C, Martin-Hita AM, Dotor A, et al. Intimal angiosarcoma of the aorta with tumour embolisation causing mesenteric ischaemia. Report of a case diagnosed using CD31 immunohistochemistry in an intestinal resection specimen. Virchows Arch. 2001 Apr;438(4):404-7. PMID:11355177 2739. Sapi Z, Papp G, Szendroi M, et al. Epigenetic regulation of SMARCB1 by miR206, -381 and -671-5p is evident in a variety of SMARCB1 immunonegative soft tissue sarcomas, while miR-765 appears specific for epithelioid sarcoma. A miRNA study of 223 soft tissue sarcomas. Genes Chromosomes Cancer. 2016 Oct;55(10):786-802. PMID:27223121 2740. Sara AS, Evans HL, Benjamin RS. Malignant melanoma of soft parts (clear cell sarcoma). A study of 17 cases, with emphasis on prognostic factors. Cancer. 1990 Jan 15;65(2):367-74. PMID:2295060 2741. Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: metaanalysis of individual data. Lancet. 1997 Dec 6:350(9092):1647-54. PMID:9400508 2742. Sareen A, D'souza MM, Reddy

586

References

KB, et al. Genochondromatosis type I: a clinicoradiological study of four family members. Am J Med Genet A. 2015 Nov; 167A( 11 ):2758-66. PMID:26174433 2743. Sarma DP, Hoffmann EO. Infantile digital fibroma-like tumor in an adult. Arch Dermatol. 1980 May; 116(5):578-9. PMID:7377793 2744. Sarungbam J, Agaram N, Hwang S, etal. Symplastic/pseudoanaplastic giant cell tumor of the bone. Skeletal Radiol. 2016 Jul;45(7):92935. PMID:27020452 2745. Sato K, Kubota T, Yoshida K, et al. Intracranial extraskeletal myxoid chondrosarcoma with special reference to lamellar inclusions in the rough endoplasmic reticulum. Acta Neuropathol. 1993;86(5):525-8. PMID:8310804 2746. Sato K, Ueda Y, Miwa S, et al. Low-grade maligna nt soft-tissue perineurioma: interphase fluorescence in situ hybridization. Pathol Int. 2008 Nov;58(11):718-22. PMID:18844938 2747. Savage SA, Mirabello L. Using epidemiology and genomics to understand osteosarcoma etiology. Sarcoma. 2011;2011:548151. PMID:21437228 2748. Sawada S, Honda M, Kamide R, et al. Three cases of subungual glomus tumors with von Recklinghausen neurofibromatosis. J Am Acad Dermatol. 1995 Feb;32(2 Pt 1):277-8. PMID:7829715 2749. Sawyer JR, Sammartino G, Baker GF, et al. Clonal chromosome aberrations in a case of nodular fasciitis. Cancer Genet Cytogenet. 1994 Sep;76(2):154-6. PMID7923068 2750. Sawyer JR, Tryka AF, Lewis JM. A novel reciprocal chromosome translocation t(11;22) (p13;q12) in an intraabdominal desmoplastic small round-cell tumor. Am J Surg Pathol. 1992 Apr;16(4):41 仁6. PMID:1314522 2751. Schaefer IM, Dong F, Garcia EP, et al. Recurrent SMARCB1 inactivation in epithelioid malignant peripheral nerve sheath tumors. Am J Surg Pathol. 2019 Jun;43(6):835-43. PMID:30864974 2752. Schaefer IM, Fletcher CD. Malignant peripheral nerve sheath tumor (MPNST) arising in diffuse-type neurofibroma: clinicopathologic characterization in a series of 9 cases. Am J Surg Pathol. 2015 S即;39(9): 1234^11. PMID:25929351 2753. Schaefer IM, Fletcher CD. Myxoid variant of so-called angiomatoid "malignant fibrous histiocytoma": clinicopathologic characterization in a series of 21 cases. Am J Surg Pathol. 2014 Jun;38(6):816-23. PMID:24503754 2754. Schaefer IM, Fletcher CD, Hornick JL. Loss of H3K27 trimethylation distinguishes malignant peripheral nerve sheath tumors from histologic mimics. Mod Pathol. 2016 Jan;29(1):4-13.PMID:26585554 2755. Schaefer IM, Marino-EnriquezA, Fletcher JA. What is new in gastrointestinal stromal tumor? Adv Anat Pathol. 2017 Sep;24(5):25967. PMID:28632504 2756. Schaefer IM, Strobel P, ThihaA, etal. Soft tissue perineurioma and other unusual tumors in a patient with neurofibromatosis type 1. Int J Clin Exp Pathol. 2013 Nov 15;6(12):3003-8. PMID:24294391 2757. Schaefer IM, Wang Y, Liang CW, et al. MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation. Nat Commun. 2017 Mar 8;8:14674. PMID:28270683 2758. Schaison F, Anract P, Coste F, et al. [Chondrosarcoma secondary to multiple cartilage diseases. Study of 29 clinical cases and review of the literature]. Rev Chir Orthop Repar Appar Mot. 1999 Dec;85(8):834-45. French. PMID:10637885 2759. Schajowicz F, Gallardo H. Epiphysial

chondroblastoma of bone. A clinico-pathological study of s仪ty-nine cases. J Bone Joint Surg Br. 1970 May;52(2):205-26. PMID:5445403 2760. Scheier M, Ramoni A, Alge A, et al. Congenital fibrosarcoma as cause for fetal anemia: prenatal diagnosis and in ute「o treatment. Fetal Diagn Ther. 2008;24(4):434-6. PMID:19018145 ' 2761. Scheipl S, Barnard M, Cottone L, et al. EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen. J Pathol. 2016 Jul;239(3):320-34. PMID:27102572 2762. Scheithauer BW, Amrami KK, Folpe AL, et al. Synovial sarcoma of nerve. Hum Pathol. 2011 Apr;42(4):568-77. PMID:21295819 2763. Schellenberg GD, Miki T, Yu CE, et al. Werner syndrome. In: Valle D, Beaudet AL, Vogelstein B, et al., editors. Scriver's online metabolic and molecular bases of inherited disease. 8th ed. New York (NY): McGraw-Hill; 2011. 2764. Schenker K, Blumer S, Jaramillo D, et al. Epithelioid hemangioma of bone: radiologic and magnetic resonance imaging characteristics with histopathological correlation. Pediatr Radiol. 2017 Nov;47(12):1631-7. PMID:28721475 2765. Schindeler A, Little DG. Recent insights into bone development, homeostasis, and repair in type 1 neurofibromatosis (NF1). Bone. 2008 Apr;42(4):616-22. PMID:18248783 2766. Schlittenbauer T, Rieker R, Amann K, et al. Recurrent adult-type rhabdomyoma: a rare differential diagnosis of "swellings in the masticatory muscle". J Craniofac Surg. 2013;24(5):e504-7. PMID:24163862 2767. Schmale GA, Conrad EU 3rd, Raskind WH. The natural history of hereditary multiple exostoses. J Bone Joint Surg Am. 1994 Jul;76(7):986-92. PMID:8027127 2768. Schmidt H, Bartel F, Kappler M, et al. Gains of 13q are correlated with a poor prognosis in liposarcoma. Mod Pathol. 2005 May; 18(5):638-44. PMID:15540119 2769. Schneider K, Zelley K, Nichols KE, et al. Li-Fraumeni syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1999 Jan 19 [updated 2013 Apr 11], PMID:20301488 2770. Schneider N, Fisher C, Thway K. Ossifying fibromyxoid tumor: morphology, genetics, and differential diagnosis. Ann Diagn Pathol. 2016 Feb;20:52-8. PMID:26732302 2771. Schneider N, Hallin M, Thway K. STAT6 loss in dedifferentiated solitary fibrous tumor. Int J Surg Pathol. 2017 Feb;25(1):58-60. PMID:27189111 2772. Schneiderman BA, Kliethermes SA, Nystrom LM. Survival in mesenchymal chondrosarcoma varies based on age and tumor location: a survival analysis of the SEER database. Clin Orthop Relat Res. 2017 Mar;475(3):799-805. PMID:26975384 2773. Schneider-Stock R, Boitze C, Lasota J, et al. High prognostic value of p16INK4 alterations in gastrointestinal stromal tumors. J Clin Oncol. 2003 May 1;21(9):1688-97. PMID:12721243 2774. Schneider-Stock R, Walter H, Radig K, et al. MDM2 amplification and loss of heterozygosity at Rb and p53 genes: no simultaneous alterations in the oncogenesis of liposarcomas. J Cancer Res Clin Oncol. 1998;124(10):532-40. PMID:9829856 2775. Schneppenheim R, Fruhwald MC, Gesk S, et al. Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet. 2010 Feb 12;86(2):279-84. PMID:20137775 2776. Schoenmakers EF, Wanschura S, Mols

R, et al. Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours. Nat Genet. 1995 Aug;10(4):436-44. PMID:7670494 2777. Schoffski P, Wozniak 代 Kasper B, et al Activity and safety of crizotinib in patients with alveolar soft part sarcoma with rearrangement of TFE3: European Organization for Research and Treatment of Cancer (EORTC) phase || trial 90101 'CREATE1. Ann Oncol. 2018 Mar 1；29(3):758-65. PMID:29216400 2778. Scholfield DW, Sadozai 乙 Ghali C, et al. Does osteofibrous dysplasia progress to adamantinoma and how should they be treated? Bone Joint J. 2017 Mar;99-B⑶:409—6 PMID:28249983 2779. Schoolmeester JK, Xing D, Keeney GL, etal. Genital rhabdomyoma of the lower female genital tract: a study of 12 cases with molecular cytogenetic findings. Int J Gynecol Pathol. 2018 Jul;37⑷:349-55. PMID:28700439 2780. Schrader KA, Nelson TN, De Luca A, et al. Multiple granular cell tumors are an associated feature of LEOPARD syndrome caused by mutation in PTPN11. Clin Genet 2009 Feb;75(2): 185-9. PMID:19054014 2781. Schrage YM, Briaire-de Bruijn IH, de Miranda NF, et al. Kinome profiling of chondrosarcoma reveals SRC-pathway activity and dasatinib as option for treatment. Cancer Res. 2009 Aug 1;69(15):6216-22 PMID:19602594 2782. Schrage YM, Lam S, Jochemsen AG, et al. Central chondrosarcoma progression is associated with pRb pathway alterations: CDK4 down-regulation and p16 overexpression inhibit cell growth in vitro. J Cell Mol Med. 2009 Sep;13(9A):2843-52. PMID:18624751 2783. Schultz K, Rosenberg AE, Ebb DH, et al. Lower-extremity lymphangiomatosis. A case report with a seventeen-year follow-up. J Bone Joint Surg Am. 2005 Jan;87(1):162-7. PMID:15634828 2784. Schulz B, Altendorf-Hofmann A, Kirchner T, et al. Loss of CD34 and high IGF2 are associated with malignant transformation in solitary fibrous tumors. Pathol Res Pract. 2014 Feb;210(2):92-7. PMID:24360568 2785. Schwab JH, Antonescu CR, Athanasian EA, et al. A comparison of intcamedullary and juxtacortical low-grade osteogenic sarcoma. Clin Orthop Relat Res. 2008 Jun;466(6):131822. PMID:18425560 2786. Schwartz ED, Hurst RW, Sinson G, et al. Complete regression of intracranial arteriovenous malformations. Surg Neurol. 2002 Aug;58(2):139^47, discussion 147. PMID:12453655 2787. Schwartz HS, Unni KK, Pritchard DJ. Pigmented villonodular synovitis. A retrospective review of affected large joints. Clin Orthop Relat Res. 1989 Oct;(247):243-55. PMID:2791393 278& Schwartz HS, Walker R. Recognizable magnetic resonance imaging characteristics of intramuscular myxoma. Orthopedics. 1997 May;20(5):431-5. PMID:9172250 2789. Schwartz HS, Zimmerman NB, Simon MA, et al. The malignant potential of enchondromatosis. J Bone Joint Surg Am. 1987 Feb;69(2):269-74. PMID:3805090 2790. Schwartz JC, Cech TR, Parker RR. Biochemical properties and biological functions of FET proteins. Annu Rev Biochem. 2015;84:355-79. PMID:25494299 2791. Schwartz PE, Hui P, McCarthy S. Hormonal therapy for aggressive angiomyxoma: a case report and proposed management algorithm. J Low Genit Tract Dis. 2014Apr;18(2):E55-61.PMID:24402356 2792. Schwartz RA, Dabski C, Dabska M. The Dabska tumor: a thirty・yea「

paybal：https://www.paypal.me/andy19801210 retrospect. Dermatology. 2000;201(1 ):1-5. PMID:10971050 2793. Schweizer L, Koelsche C, Sahm F, et al. Meningeal hemangiope「icytoma and solitary fibrous tumors carry the NAB2-STAT6 fusion and can be diagnosed by nuclear expression of STAT6 protein. Acta Neuropathol. 2013 May;125(5):651-8. PMID:23575898 2794. Schwetye KE, Pfeifer JD, Duncavage EJ. MED12 exon 2 mutations in uterine and extrauterine smooth muscle tumors. Hum Pathol. 2014 Jan;45(1):65-70. PMID:24196187 2795. Scinicariello F, Dolan MJ, Nedelcu I, etal. Occurrenee of human papillomavirus and p53 gene mutations in Kaposi's sarcoma. Virology. 1994 Aug 15;203(1 ):153-7. PMID:8030271 2796. Sciot R, Akerman M, Dal Cin P, et al. Cytogenetic analysis of subcutaneous angiolipoma: further evidence supporting its difference from ordinary pure lipomas: a report of the CHAMP Study Group. Am J Surg Pathol. 1997Apr;21(4):441-4. PMID:9130991 2797. Sciot R, Bekaert J. Spindle cell lipoma with extramedullary haematopoiesis. Histopathology. 2001 Aug;39(2):215-6. PMID:11493343 2798. Sciot R, Dal Cin P, Fletcher C, et al. t(9;22)(q22-31;q11-12) is a consistent marker of extraskeletal myxoid chondrosarcoma: evaluation of three cases. Mod Pathol. 1995 Sep;8(7):765-8. PMID:8539235 2799. Sciot R, Dorfman H, Brys P, et al. Cytogenetic-morphologic correlations in aneurysmal bone cyst, giant cell tumor of bone and combined lesions. A report from the CHAMP study group. Mod Pathol. 2000 Nov; 13(11):1206-10. PMID:11106078 2801. Sebenik M, Ricci A Jr, DiPasquale B, et al. Undifferentiated intimal sarcoma of large systemic blood vessels: report of 14 cases with immunohistochemical profile and review of the literature. Am J Surg Pathol. 2005 Sep;29(9):1184-93. PM ID: 16096408 2802. Sebro R, DeLaney T, Homicek F, et al. Differences in sex distribution, anatomic location and MR imaging appearance of pediatric compared to adult chordomas. BMC Med Imaging. 2016 Sep 8;16(1):53. PMID:27609115 2803. Secondino S, Grazioli V, Valentino F, et al. Multimodal approach of pulmonary artery intimal sarcoma: a single-institution experience. Sarcoma. 2017;2017:7941432. PMID:28912665 2804. Segal NH, Pavlidis P, Antonescu CR, et al. Classification and subtype prediction of adult soft tissue sarcoma by functional genomics. Am J Pathol. 2003 Aug;163⑵:691 -700. PMID:12875988 2805. Seguier-Lipszyc E, Baazov A, Fichman S, et al. Current management of lipoblastoma. Eur J Pediatr. 2018 Feb; 177(2):237-41. PMID:29243188 2806. Seijas R, Ares O, Sierra J, et al. Oncogenic osteomalacia: two case reports with surprisingly different outcomes. Arch Orthop Trauma Surg. 2009 Apr;129(4):533-9. PMID:19125258 2807. Seiler R, Ohrstrom LM, Eppenberger P, et al. The earliest known case of frontal sinus osteoma in man. Clin Anat. 2019 Jan;32(1 ):105-9. PMID:30324624 2808. Seiter K, Qureshi A, Liu D, et al. Severe toxicity following induction chemotherapy for acute myelogenous leukemia in a patient with Werner's syndrome. Leuk Lymphoma. 2005 Jul;46(7):1091-5. PMID:16019564 2809. Seki M, Nishimura R, Yoshida K, et al. Integrated genetic and epigenetic analysis defines novel molecular subgro 叩 s in rhabdomyosarcoma. Nat Commun. 2015 Jul 3;6:7557. PMID:26138366

2810. Sekimizu M, Yoshida A, Mitani S, et al. Frequent mutations of genes encoding vacuolar H+ -ATPase components in granular cell tumors. Genes Chromosomes Cancer. 2019 Jun;58(6):373-80. PMID:30597645 2811. Sekoranja D, Bostjancic E, Salapura V, et al. Primary aneurysmal bone cyst with a novel SPARC-USP6 translocation identified by next­ generatio n sequencing. Cancer Genet. 2018 Dec;228-229:12-6. PMID:30553465 2812. Selby DM, Stocker JT, Ishak KG. Angiosarcoma of the liver in childhood: a clinicopathologic and follow-up study of 10 cases. Pediatr Pathol. 1992 JulAug;12(4):485-98. PMID:1409148 2813. Selfe J, Olmos D, Al-Saadi R, et al. Impact of fusion gene status versus histology on risk-stratification for rhabdomyosarcoma: retrospective analyses of patients on UK trials. Pediatr Blood Cancer. 2017 Jul;64(7):e26386. PMID:28035744 2814. Semmelink HJ, Pruszczynski M.Wiersmavan Tilburg 代 et al. Cytokeratin expression in chondroblastomas. Histopathology. 1990 Mar;16(3):257-63. PMID:1692005 、 2815. Sergi C, Zwerschke W. Osteogenic sarcoma (osteosarcoma) in the elderly: tumor delineation and predisposing conditions. Exp Gerontol. 2008 Dec;43(12):1039-43. PMID:18845233 2816. Setsu N, Miyake M, Wakai S, et al. Primary retroperitoneal myxoid liposarcomas. Am J Surg Pathol. 2016 Sep;40(9):1286-90. PMID:27158758 2817. Sferopoulos NK, Kotakidou R, Petropoulos AS. Myositis ossificans in children: a review. Eur J Orthop Surg Traumatol. 2017 May;27(4):491-502. PMID:28275867 *1 & Sforza-Huffman C. Cytology of fibrous 28 hamartoma of infancy: a helpful approach for an un common soft tissue lesi on. Acta Cytol. 2008 Mar-Apr;52⑵:123. PMID:18499982 2819. Shabb N, Sneige N, Fanni叩 CV, et al. Fine-needle aspiration cytology of alveolar soft-part sarcoma. Diagn Cytopathol. 1991;7(3):293-8. PMID:1879268 2820. Shadan FF, Mascarello JT, Newbury RO, et al. Supernume「ary ring chromosomes derived from the long arm of chromosome 12 as the primary cytogenetic anomaly in a rare soft tissue chondroma. Cancer Genet Cytogenet. 2000 Apr15;118(2):144-7. PMID:10748295 2821. Shah KK, McHugh JB, Folpe AL, et al. Dermatofibrosarcoma protuberans of distal extremities and acral sites: a clinicopathologic analysis of 27 cases. Am J Surg Pathol. 2018 Mar;42(3):413-9. PMID:29240584 2822. Shakked RJ, Geller DS, Gorlick R, et al. Mesenchymal chondrosarcoma: clinicopathologic study of 20 cases. Arch Pathol Lab Med. 2012 Jan;136(1):61-75. PMID:22208489 2823. Shalaby A, Presneau N,Ye H, et al. The role of epidermal growth factor receptor in chordoma pathogenesis: a potential therapeutic target. J Pathol. 2011 Feb;223(3):336-46. PMID:21171079 2824. Shang Leen SL, Fisher C, Thway K. Composite hemangioendothelioma: clinical and histologic features of an enigmatic entity. Adv Anat Pathol. 2015 Jul;22(4):254-9. PMID:26050262 2825. Shao L, Mardis N, Nopper A, et al. Giant cell tumor of bone in a child with Goltz syndrome. Pediatr Dev Pathol. 2013 JulAug;16(4):308-11. PMID:23530933 2826. Shapiro F, Simon S, Glimcher MJ. Hereditary multiple exostoses. Anthropometric, roentgenographic, and clinical aspects. J Bone Joint Surg Am. 1979 Sep;61(6A):815-24. PMID:225330 2827. Sharif S, Ferner R, Birch JM, et al. Second primary tumors in neurofibromatosis

1 patients treated for optic glioma: substantial risks after radiotherapy. J Clin Oncol. 2006 Jun 1;24(16):2570-5. PMID:16735710 2828. Sharma P, Shakya U, Sayami G, et al. Lipoblastoma: an unusual tumour of the left ventricle. Eur J Cardiothorac Surg. 2016 May;49(5):e147-8. PMID:26819289 2829. Shekhtman O, Gorozhanin V, Shishkina L. A rare case of brain angiolipoma imitating arteriovenous malformation: differential diagnosis, surgical treatment, and literature review. World Neurosurg. 2018 Jun;114:264-8. PMID:29614355 2830. Shelekhova KV, Kazakov DV, Hes O, et al. Phosphaturic mesenchymal tumor (mixed connective tissue variant): a case report with spectral analysis. Virchows Arch. 2006 Feb;448(2):232-5. PMID:16447065 2831. Shen LY, Amin SM, Chamlin SL, et al. Varied presentations of pediatric lipoblastoma: case series and review of the literature. Pediatr Dermatol. 2017 Mar;34(2):180-6. PMID:28111780 2832. Shen SH, Steinbach LS, Wang SF, et al. Primary leiomyosarcoma of bone. Skeletal Radiol. 2001 Oct;30(10):600-3. PMID:11685485 2833. Sheppard DG, Libshitz HI. Post-radiation sarcomas: a review of the clinical and imaging features in 63 cases. Clin Radiol. 2001 Jan;56(1):22-9. PMID:11162693 2834. Shern JF, Chen L, Chmielecki J, et al. Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov. 2014 Feb;4(2):216-31. PMID:24436047 2835. Shern JF, Yohe ME, Khan J. Pediatric rhabdomyosarcoma. Crit Rev Oncog. 2015:20(3-4):227-43. PMID:26349418 2836. Sheth DS, Yasko AW, Raymond AK, et al. Conventional and dedifferentiated parosteal osteosarcoma. Diagnosis, treatment, and outcome. Cancer. 1996 Nov 15;78(10):213645. PMID:8918422 2837. Sheth S, Li X, Binder S, et al. Differential gene expression profiles of neurothekeomas and nerve sheath myxomas by microarray analysis. Mod Pathol. 2011 Mar;24(3):343-54. PMID:21297585 2838. Shi E, Chmielecki J, Tang CM, et al. FGFR1 and NTRK3 actionable alterations in "wild-type" gastrointestinal stromal tumors. J Transl Med. 2016 Dec 14;14(1):339. PMID:27974047 2839. Shiba S, Imaoka H, Shioji K, et al. Clinical characteristics of Japanese patients with epithelioid hemangioendothelioma: a multicenter retrospective study. BMC Cancer. 2018 Oct 19;18(1):993. PMID:30340559 2840. Shibayama T, Okamoto T, Nakashima Y, et al. Screening of BCOR-CCNB3 sarcoma using immunohistochemistry for CCNB3: a clinicopathological report of three pediatric cases. Pathol Int. 2015 Aug;65(8):410-4. PMID:26037154 2841. Shibuya R, Matsuyama A, Shiba E, et al. CAMTA1 is a useful immunohistochemical marker for diagnosing epithelioid haemangioendothelioma. Histopathology. 2015 Dec;67(6):827-35. PMID:25879300 2842. Shih AR, Chebib I, Deshpande V, et al. Molecular characteristics of poorly differentiated chordoma. Genes Chromosomes Cancer. 2019 Nov;58(11):804-8. PMID:31135077 2843. Shih AR, Cote GM, Chebib I, et al. Clinicopathologic characteristics of poorly differentiated chordoma. Mod Pathol. 2018 Aug;31(8):1237-45. PMID:29483606 2844. Shim HS, Choi YD, Cho NH. Malignant glomus tumor of the urinary bladder. Arch

Pathol Lab Med. 2005 Jul;129(7):940-2. PMID:15974822 2845. Shimada T, Mizutani S, Muto T, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA. 2001 May 22;98(11):6500-5. PMID:11344269 2846. Shimada T, Urakawa I, Yamazaki Y, et al. FGF-23 transgenic mice dem onstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporte「 type Ila. Biochem Biophys Res Commun. 2004 Feb 6;314⑵:409-14. PMID:14733920 2847. Shimizu S, Hashimoto H, Enjoji M. Nodular fasciitis: an analysis of 250 patients. Pathology. 1984 Apr;16(2):161-6. PMID:6462780 ' 2848. Shinkai T, Masumoto K, Ono K, et al. A case of unusual his⑹ogy of infantile lipoblastoma confirmed by PLAG1 rearrangement. Surg Case Rep. 2015 Dec;1(1):42. PMID:26943407 2849. Shlien A, Baskin B, Achatz Ml, et al. A comm on molecular mechanism underlies two phenotypically distinct 17p13.1 microdeletion syndromes. Am J Hum Genet. 2010 Nov 12;87(5):631-42. PMID:21056402 2850. Shlien A, Tabori U, Marshall CR, et al. Excessive genomic DNA copy number variation in the Li-Fraumeni cancer predisposition syndrome. Proc Natl Acad Sci USA. 2008 Aug 12;105(32):11264-9. PMID:18685109 2851. Shmookler BM, Enzinger FM. Pleomorphic lipoma: a benign tumor simulating liposarcoma. A clinicopathologic analysis of 48 cases. Cancer. 1981 Jan 1;47(1 ):126-33. PMID:7459800 2852. Shmookler BM, Enzinger FM, Weiss SW. Giant cell fibroblastoma. A juvenile form of dermatofibrosarcoma protuberans. Cancer. 1989 Nov 15;64(10):2154-61. PMID:2804904 2853. Shon W, Folpe AL, Fritchie KJ. ERG expression in chondrogenic bone and soft tissue tumours. J Clin Pathol. 2015 Feb;68(2):125-9. PMID:25378537 2854. Shugart RR, Soule EH, Johnson EW Jr. Glomus tumor. Surg Gynecol Obstet. 1963 Sep;117:334-40. 2855. Side L, Taylor B, Cayouette M, et al. Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders. N Engl J Med. 1997 Jun 12;336(24):1713-20. PMID:9180088 2856. Sidwell RU, Rouse P, Owen RA, et al. Granular cell tumor of the scrotum in a child with Noonan syndrome. Pediatr Dermatol. 2008 May-Jun;25(3):341-3. PMID:18577039 2857. Siegal GP. Primary tumors of bone. In: Stocker JT, Askin FB, editors. Pathology of solid tumors in children. London (UK): Chapman & Hall Medical; 1998. pp. 183-212. 2858. Siegel HJ, Rock MG. Occult phosphaturic mesenchymal tumor detected by Tc-99m sestamibi scan. Clin Nucl Med. 2002 Aug;27(8):608-9. PMID:12170016 2859. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013 Jan;63(1):11-30. PMID:23335087 2860. Siitonen HA, Sotkasiira J, Biervliet M, et al. The mutation spectrum in RECQL4 diseases. Eur J Hum Genet. 2009 Feb;17(2):151-8. PMID:18716613 2861. Silve C, Juppner H. Ollier disease. Orphanet J Rare Dis. 2006 Sep 22;1:37. PMID:16995932 2862. Simanshu DK, Nissley DV, McCormick F. RA8 proteins and their regulators in human disease. Cell. 2017 Jun 29;170(1):17-33. PMID:28666118 2863. Simmons AD, Musy MM, Lopes CS, etal. A direct interaction between EXT proteins and

Refere nces

587

paybal：https://www.paypal.me/andy19801210 glycosyltransferases is defective in hereditary multiple exostoses. Hum Mol Genet. 1999 Nov;8(12):2155-64. PMID:10545594 2864. Simon MP, Pedeutour F, Sirvent N, et al. Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nat Genet. 1997 Jan;15(1):95-8. PMID:8988177 2865. Simons A, Schepens M, Jeuken J, et al. Frequent loss of 9p21 (p16(INK4A)) and other genomic imbalances in human malignant fibrous histiocytoma. Cancer Genet Cytogenet. 2000 Apr 15F8⑵:89-9& PMID:10748288 2866. Sinclair TJ, Thorson CM, Alvarez E, et al. Pleomorphic myxoid liposarcoma in an adolesce nt with Li-Fraumeni syndrome. Pediatr Surg Int. 2017 May;33(5):631-5. PMID:28160093 2867. Singer S, Antonescu CR, Riedel E, et al. Histologic subtype and margin of resection predict pattern of recurrence and survival for retroperitoneal liposarcoma. Ann Surg. 2003 S即;238(3):358-70, discussion 370-1. PMID:14501502 2868. Singer S, Demetri GD, Baldini EH, et al. Management of soft-tissue sarcomas: an overview and update. Lancet Oncol. 2000 Oct; 1:75-85. PMID:11905672 2869. Singer S, Socci ND, Ambrosini G, et al. Gene expression profiling of liposarcoma identifies distinct biological types/subtypes and potential therapeutic targets in welldifferentiated and dedifferentiated liposarcoma. Cancer Res. 2007 Jul 15;67(14):6626-36. PMID:17638873 2870. Singhi AD, Montgomery EA. Colorectal granular cell tumor: a clinicopathologic study of 26 cases. Am J Surg Pathol. 2010 Aug;34(8):1186-92. PMID:20661017 2871. Sinha S, Mundy C, Bechtold T, et al. Unsuspected osteochondroma-like outgrowths in the cranial base of hereditary multiple exostoses patients and modeling and treatment with a BMP antagonist in mice. PLoS Genet. 2017 Apr 26;13(4):e1006742. PMID:28445472 2872. Sio TT, Vu CC, Sohawon S, et al. Extraskeletal osteosarcoma: an international Rare Cancer Network study. Am J Clin Oncol. 2016 Feb;39(1):32-6. PMID:24401667 2873. Sioletic S, Dal Cin P, Fletcher CD, et al. Well-differentiated and dedifferentiated liposarcomas with prominent myxoid stroma: analysis of 56 cases. Histopathology. 2013 Jan;62(2):287-93. PMID:23020289 2874. Sirohi D, Smith SC, Epstein JI, et al. Pericytic tumors of the kidney-a clinicopathologic analysis of 17 cases. Hum Pathol. 2017Jun;64:106-17. PMID:28438616 2875. Sirvent N, Coindre JM, Maire G, et al. Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in diagnosing adipocytic lesions 日nd comparison with immunohistochemistry and real-time PCR. Am J Surg Pathol. 2007 Oct;31 (10):1476-89. PMID: 17895748 2876. Sirvent N, Maire G, Pedeutour F. Genetics of dermatofibrosarcoma protuberans family of tumors: from ring chromosomes to tyrosine kinase inhibitor treatment. Genes Chromosomes Cancer. 2003 May;37(1):1-19. PMID:12661001 2877. Sissons HA, Steiner GC, Dorfman HD. Calcified spherules in fibro-osseous lesions of bone. Arch Pathol Lab Med. 1993 Mar;117(3):284-90. PMID:8442673 2878. Sjogren H, Meis-Kindblom J, Kindblom LG, et al. Fusion of the EWS-related gene TAF2N to TEC in extraskeletal myxoid chondrosarcoma. Cancer Res. 1999 Oct 15；59(20):5064-7. PMID:10537274

588

References

2879. Sjogren H, Meis-Kindblom JM, Orndal C, et al. Studies on the molecular pathogenesis of extraskeletal myxoid chondrosarcomacytogenetic, molecular genetic, and cDNA microarray analyses. Am J Pathol. 2003 Mar;162(3):781-92. PMID:12598313 2880. Sjogren H, Orndal C, Tingby O, et al. Cytogenetic and spectral karyotype analyses of benign and malignant cartilage tumours. Int J Oncol. 2004 Jun;24 ⑹385-91. PMID:15138578 2881. Sjogren H, Wedell B, Meis-Kindblom JM, et al. Fusion of the NH2-terminal domain of the basic helix-loop-helix protein TCF12 to TEC in extraskeletal myxoid chondrosarcoma with translocation t(9;15)(q22;q21). Cancer Res. 2000 Dec 15;60(24):6832-5. PMID:11156374 2882. Skalova A, Michal M, Simpson RH. Newly described salivary gland tumors. Mod Pathol. 2017 Jan;30 s1:S27-43. PMID:28060365 2883. Skalova A, Weinreb I, Hyrcza M, et al. Clear cell myoepithelial carcinoma of salivary glands showing EWSR1 rearrangement: molecular analysis of 94 salivary gland carcinomas with prominent clear cell component. Am J Surg Pathol. 2015 Mar;39(3):338-4& PMID:25581728 2884. Skapek SX, Anderson J, Barr FG, et al. PAX-FOXO1 fusion status drives unfavorable outcome for children with rhabdomyosarcoma: a children's oncology group report. Pediatr Blood Cancer. 2013 Sep;60(9):1411-7. PMID:23526739 2885. Skapek SX, Ferrari A, Gupta AA, et al. Rhabdomyosarcoma. Nat Rev Dis Primers. 2019 Jan 7;5(1):1. PMID:30617281 2886. Skeletal Lesions In terobserver Correlation among Expert Diagnosticians (SLICED) Study Giwp. Reliability of histopathologic and radiologic grading of cartilaginous neoplasms in long bones. J Bone Joint Surg Am. 2007 Oct;89(10):2113-23. PMID:17908885 2887. Slater DN, Cotton DW, Azzopardi JG. Oncocytic glomus tumour: a new variant. Histopathology. 1987 May; 11(5):523-31. PMID:3038728 2888. Smeets MF, DeLuca E, Wall M, et al. The Rothmund-Thoms on syndrome helicase RECQL4 is essential for hematopoiesis. J Clin Invest. 2014 Aug;124(8):3551-65. PMID:24960165 2889. Smida J, Baumhoer D, Rosemann M, et al. Genomic alterations and allelic imbalances are strong prognostic predictors in osteosarcoma. Clin Cancer Res. 2010 Aug 15;16(16):4256-67. PMID:20610556 2890. Smida J, Xu H, Zhang Y, et al. Genome­ wide analysis of somatic copy number alterations and chromosomal breakages in osteosarcoma. Int J Cancer. 2017 Aug 15;141(4):816-28. PMID:28494505 2891. Smith A, Orchard D. Infantile myofibromatosis: two families supporting autosomal dominant inheritance. Australas Dermatol. 2011 Aug;52 ⑶ 04-7. J PMID:21834820 2892. Smith DM, Mahmoud HH, Jenkins JJ 3rd, et al. Myofibrosarcoma of the head and neck in children. Pediatr Pathol Lab Med. 1995 MayJun;15⑶:403「8. PMID:8597827 2893. Smith GM, Johnson GD, Grimer RJ, et al. Trends in presentation of bone and soft tissue sarcomas over 25 years: little evidence of earlier diagnosis. Ann R Coll Surg Engl. 2011 Oct;93⑺:542-7. PMID:22004638 2894. Smith J, Botet JF, Yeh SD. Bone sarcomas in Paget disease: a study of 85 patients. Radiology. 1984 Sep;152(3):583-90. PMID:6235535 ' 2895. Smith ME, Fisher C, Weiss SW. Pleomorphic hyalinizing angiectatic tumor of

soft parts. A low-grade neoplasm resembling neurilemoma. Am J Surg Pathol. 1996 Jan;20(1):21-9. PMID:8540605 2896. Smith SC, Buehler D, Choi EY, etal. CICDUX sarcomas demonstrate frequent MYC amplification and ETS-family transcription factor expression. Mod Pathol. 2015 Jan;28(1):57-68. PMID:24947144 2897. Smith SC, Gooding WE, Elkins M, et al. Solitary fibrous tumors of the head and neck: a multi-institutional clinicopathologic study. Am J Surg Pathol. 2017 Dec;41 (12):1642-56/ PMID:28877055 2898. Smith TA, Easley KA, Goldblum JR. Myxoid/round cell liposarcoma of the extremities. A clinicopathologic study of 29 cases with particular attention to extent of round cell liposarcoma. Am J Surg Pathol. 1996 Feb;20⑵:171-80. PMID:8554106 2899. Snyder EL, Sandstrom DJ, Law K, et al. c-Jun amplification and overexpression are oncogenic in liposarcoma but not always sufficient to inhibit the adipocytic differentiation programme. J Pathol. 2009 Jul;218(3):292300. PMID:19449367 2900. Sobreira NL, Cirulli ET, Avramopoulos D, et al. Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. PLoS Genet. 2010 Jun 17;6(6):e1000991. PMID:20577567 2901. Soder S, Inwards C, Muller S, et al. Cell biology and matrix biochemistry of chondromyxoid fibroma. Am J Clin Pathol. 2001 Aug;116(2):271-7. PMID:11488075 2902. Soler JM, Piza G, Aliaga F. Special characteristics of osteoid osteoma in the proximal phalanx. J Hand Surg Br. 1997 Dec;22(6):793-7. PMID:9457591 2903. Solomon DA, Antonescu CR, Link TM, et al. Hemosideroticfibrolipomatous tumor, notan entirely benign entity. Am J Surg Pathol. 2013 Oct;37(10):1627-30. PMID:24025526 2904. Somerhausen NS, Fletcher CD. Diffusetype giant cell tumor: clinicopathologic and immunohistochemical analysis of 50 cases with extraarticular disease. Am J Surg Pathol. 2000 Ap「;24⑷:479-92. PMID:10757395 2905. Somers GR, Gupta AA, Doria AS, et al. Pediatric undifferentiated sarcoma of the soft tissues: a clinicopathologic study. Pediatr Dev Pathol. 2006 Mar-Apr;9(2):132-42. PMID:16822084 2906. Song B, Ryu HJ, Lee C, et al. Intraosseous hibernoma: a rare and unique intraosseous lesion. J Pathol Transl Med. 2017 Sep;51 (5):499-504. PMID:28827513 2907. Song W, Suurmeijer AJH, Bollen SM, et al. Soft tissue aneurysmal bone cyst: s仪 new cases with imaging details, molecular pathology, and review of the literature. Skeletal Radiol. 2019 Jul;48(7):1059-67. PMID:30603771 2908. Song W, van den Berg E, Kwee TC, et al. Low-grade central fibroblastic osteosarcoma may be differentiated from its mimicker desmoplastic fibroma by genetic analysis. Clin Sarcoma Res. 2018 Aug 23;8:16. PMID:30159138 2909. Sontag LW, Pyle SI. The appearance and nature of cyst-like areas in distal femoral metaphyses of children. Am J Roentgenol RadiatTher. 1941;46:185-8. 2910. Sood N, Khandelia BK. Superficial CD34-positive fibroblastic tumor: a new entity; case report and review of literature. Indian J Pathol Microbiol. 2017 Jul-Sep;60(3):377-80. PMID:28937375 2911. Sordillo PP, Hajdu SI, Magill GB, et al. Extraosseous osteogenic sarcoma. A review of 48 patients. Cance匚 1983 Feb 15;51 (4):72734. PMID:6571801 2912. Sorrell AD, Espenschied CR, Culver JO, et al. Tumor protein p53 (TP53) testing and

Li-Fraumeni syndrome: current status of clinical applications and future directions. Mol Diagn Ther. 2013 Feb;仃⑴3-47. PMID:23355100 2913. Sotoda Y, Hirooka S, Kohi M, et al. Intramuscular hemangioma in the right ventricle. Gen Thorac Cardiovasc Surg. 2008 Feb;56⑵:85-7. PMID:18297465 2914. Soule EH. Proliferative (nodular) fasciitis. Arch Pathol. 1962 Jun;73:437-44 PMID:13915406 2915. Soule EH, Pritchard DJ. Fibrosarcoma in infants and children: a review of 110 cases. Cancer. 1977 Oct;40(4):1711-21 PMID:561651 2916. Spanier SS, Shuster JJ, Vander Griend RA. The effect of local extent of the tumor on prognosis in osteosarcoma. J Bone Joint Surg Am. 1990Jun;72(5):643-53. PMID:2355025 2917. Specht K, Sung YS, Zhang L, et al. Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1rearranged Ewing sarcomas: further evidence toward distinct pathologic entities. Genes Chromosomes Cancer. 2014 Jul;53(7):622-33 PMID:24723486 2918. Specht K, Zhang L, Sung YS, et al. Novel BCOR-MAML3 and ZC3H7B-BCOR gene fusions in undifferentiated small blue round cell sarcomas. Am J Surg Pathol. 2016 Apr;40(4):433-42. PMID:26752546 2919. Speer AL, Schofield DE, Wang KS, et al. Contemporary management of lipoblastoma. J Pediatr Surg. 2008 Jul;43(7):1295-300. PMID:18639685 2920. Speetjens FM.de Jong Y, Gelderblom H,et al. Molecular on cogenesis of chondrosarcoma: impact for targeted treatment. Curr Opin Oncol. 2016 Jul;28(4):314-22. PMID:27166664 2921. Spiker AM, Rotter BZ, Chang B, et al. Clinical presentation of intra-articular osteoid osteoma of the hip and preliminary outcomes after arthroscopic resection: a case series. J Hip Preserv Surg. 2017 Dec 28;5(1):88-99. PMID:29423256 2922. Spillane AJ, Fisher C, Thomas JM. Myxoid liposarcoma-the frequency and the natural history of nonpulmonary soft tissue metastases. Ann Surg Oncol. 1999 Jun;6(4):389-94. PMID:10379861 2923. SpougeAR, Thain LM. Osteoid osteoma: MR imaging revisited. Clin Imaging. 2000 JanFeb;24(1 ):19-27. PMID:11120413 2924. Squire JA, Pei J, Marrano P, et al. High-resolution mapping of amplifications and deletions in pediatric osteosarcoma by use of CGH analysis of cDNA microarrays. Genes Chromosomes Cancer. 2003 Nov;38(3):21525. PMID:14506695 2925. Sreekantaiah C, Leong SP, Davis JR, et al. Cytogenetic and flow cytometric analysis of a clear cell chondrosarcoma. Cancer Genet Cytogenet. 1991 Apr;52(2): 193-9. PMID:2021921 2926. Sreekantaiah C, Leong SP, Karakousis CP, et al. Cytogenetic profile of 109 lipomas. Cancer Res. 1991 Jan 1;51 (1):422-33. PMID:1988102 2927. Srinivasan S, Krishnan V, Ali SZ, et al. "Swirl sign" of aggressive angiomyxoma-a lesser known diagnostic sign. Clin Imaging. 2014 Sep-Oct;38(5):751-4. PMID:24852676 2928. Staals EL, Bacchini P, Bertoni F. Dedifferentiated central chondrosarcoma. Cancer. 2006 Jun 15;106(12):2682-91. PMID:16691621 2929. Staals EL, Bacchini P, Bertoni F. High­ grade surface osteosarcoma: a review of 25 cases from the Rizzoli Institute. Cancer. 2008 Apr 1;112(7):1592-9. PMID:18300258 2930. Staals EL, Bacchini P, Mercuri M, et al. Dedifferentiated chondrosarcomas arising

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paybal：https://www.paypal.me/andy19801210 in preexisting osteochondromas. J Bone Joint Surg Am. 2007 May;89(5):987-93. PMID:17473135 2931. Staats P, Tavora F, Burke AP. Intimal sarcomas of the aorta and iliofemoral arteries: a clinicopathological study of 26 cases. Pathology. 2014 Dec;46(7):596-603. PMID:25393249 2932. Stacchiotti S, Palassini E, Sanfilippo R, et al. Gemcitabine in advanced angiosarcoma: a retrospective case series analysis from the Italian Rare Cancer Network. Ann Oncol. 2012 Feb;23(2):501-8. PMID:21464156 2933. Stacy GS, Lo R, Montag A. Infarctassociated bone sarcomas: multimodality imaging findings. AJR Am J Roentgenol. 2015 Oct;205(4):W432-41. PMID:26397350 2934. Stancheva-lvanova MK, Wuyts W, van Hui E, et al. Clinical and molecular studies of EXT1/EXT2 in Bulgaria. J Inherit Metab Dis. 2011 Aug;34⑷:9仃一21. PMID:21499719 2935. Steele CD, Tarabichi M, Oukrif D, et al. Undifferentiated sarcomas develop through distinct evolutionary pathways. Cancer Cell. 2019 Mar 18;35(3):441-456.e8. PMID:30889380 2936. Steelman C, Katzenstein H, Parham D, et al. Unusual presentation of congenital infantile fibrosarcoma in seven infants with moleculargenetic analysis. Fetal Pediatr Pathol. 2011;30(5):329-37. PMID:21843073 2937. Steeper TA, Rosai J. Aggressive angiomyxoma of the female pelvis and perineum. Report of nine cases of a distinctive type of gynecologic soft-tissue neoplasm. Am J Surg Pathol. 1983 Jul;7⑸:463-75. PMID:6684403 2938. Steffner RJ, Jang ES. Staging of bone and soft-tissue sarcomas. J Am Acad Orthop Surg. 2018 Jul 1;26(13):e269-78. PMID:29781819 2939. Stelow EB, Murad FM, Debol 8M, et al. A limited immunocytochemical panel for the distinction of subepithelial gastrointesti nal mesenchymal n eoplasms sampled by endoscopic ultrasound-guided fine-needle aspiration. Am J Clin Pathol. 2008 Feb;129(2):219-25. PMID:18208801 2940. Stelow EB, Yaziji H. Immunohistochemistry, carcinomas of unknown primary, and incidence rates. Semin Diagn Pathol. 2018 Mar;35(2):143-52. PMID:29224972 2941. Stemm M, Beck C, Mannem R, et al. Dedifferentiated chondrosarcoma of bone with prominent rhabdoid component. Ann Diagn Pathol. 2017Jun;28:7-11. PMID:28648942 2942. Stemmermann GN, Stout AP. Elastofibroma dorsi. Am J Clin Pathol. 1962 May;37:499-506. PMID:13916810 2943. Stemmer-Rachamimov AO, Xu L, Gonzalez-Agosti C, et al. Universal absence of merlin, but not other ERM family members, in schwannomas. Am J Pathol. 1997 Dec;151 (6):1649-54. PMID:9403715 2944. Stenman G, Andersson H, Mandahl N, et al. Translocation t(9;22)(q22;q 12) is a primary cytogenetic abnormality in extraskeletal myxoid chondrosarcoma. Int J Cancer. 1995 Aug 9;62⑷:398702. PMID:7635565 2945. Stenman G, Kindblom LG, Angervall L. Reciprocal translocation t(12;22)(q13;q13) in clear-cell sarcoma of tendons and aponeuroses. Genes Chromosomes Cancer. 1992 Ma「;4⑵:122-7. PMID:1373311 2946. Stevenson DA, Zhou H, Ashrafi S, et al. Double inactivation of NF1 in tibial pseudarthrosis. Am J Hum Genet. 2006 Jul;79(1):143-8. PMID:16773574 2947. Stewart DR, Brems H, Gomes AG, et al. Jaffe-Campanacci syndrome, revisited: detailed clinical and molecular analyses determine

whether patients have neurofibromatosis type t coincidental manifestations, or a distinct disorder. Genet Med. 2014 Jun;16⑹:448—59. PMID:24232412 2948. Stewart DR, Pemov A, Van Loo P, et al. Mitotic recombination of chromosome arm 17q as a cause of loss of heterozygosity of NF1 in neurofibromatosis type 1 -associated glomus tumors. Genes Chromosomes Cancer. 2012 May;51 (5):429-37. PMID:22250039 2949. Stewart DR, Sloan JL, Yao L, et al. Diagnosis, management, and complications of glomus tumours of the digits in neurofibromatosis type 1. J Med Genet. 2010 Aug;47(8):525-32. PMID:20530151 2950. Stickens D, Clines G, Burbee D, et al. The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Nat Genet. 1996 Sep;14(1):25-32. PMID:8782816 2951. Stinco G, Governatori G, Mattighello P, et al. Multiple cutaneous neoplasms in a patient with Rothmund-Thomson syndrome: case report and published work review. J Dermatol. 2008 Mar;35(3):154-61, PMID:18346259 2952. Stockman DL, Ali SM, He J, et al. Sclerosing epithelioid fibrosarcoma presenting as intraabdominal sarcomatosis with a novel EWSR1-CREB3L1 gene fusion. Hum Pathol. 2014 Oct;45(10):2173-8. PMID:25123073 2953. Stockman DL, Hornick JL, Deavers MT, et al. ERG and FLI1 protein expression in epithelioid sarcoma. Mod Pathol. 2014 Apr;27(4):496-501. PMID:24072183 2954. Stojadinovic A, Leung DH, Hoos A, et al. Analysis of the prognostic significance of microscopic margins in 2,084 localized primary adult soft tissue sarcomas. Ann Surg. 2002 Mar;23503):424—34. PMID:11882765 2955. Stojanov IJ, Marino-Enriquez A, Bahri N, et al. Lipomas of the oral cavity: utility of MDM2 and CDK4 in avoiding overdiagnosis as atypical lipomatous tumor. Head Neck Pathol. 2019 Jun;13(2):169-76. PMID:29748845 2956. Stoll LM, Li QK. Cytology of 佃e-needle aspiration of inflammatory myofibroblastic tumor. Diagn Cytopathol. 2011 Sep;39(9):66372. PMID:20730898 2957. Stomp W, Reijnierse M, Kloppenburg M, et al. Prevalence of cartilaginous tumours as an incidental finding on MRI of the knee. Eur Radiol. 2015 Dec;25(12):3480-7. PMID:25994192 2958. Stone JJ, Prasad NK, Laumonerie P, et al. Recurrent desmoid-type fibromatosis associated with underlying neuromuscular choristoma. J Neurosurg. 2018 Aug 1:1-9. PMID:30168738 2959. Storlazzi CT, Mertens F, Mandahl N, etal. A novel fusion gene, SS18L1/SSX1, in synovial sarcoma. Genes Chromosomes Cancer. 2003 Jun;37(2):195-200. PMID:12696068 2960. Storlazzi CT, Wozniak A, Panagopoulos I, et al. Rearrangement of the COL12A1 and COL4A5 genes in subungual exostosis: molecular cytogenetic deli neation of the tumor­ specific translocation t(X;6)(q 13-14;q22). Int J Cancer. 2006 Apr 15;118(8):1972-6. PMID:16284948 2961. Stowe IB, Mercado EL, Stowe TR, et al. A shared molecular mechanism underlies the human rasopathies Legius syndrome and neurofibromatosis-1. Genes Dev. 2012 Jul 1;26(13):1421-6. PMID:22751498 2962. Stratakis CA, Carney JA. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J Intern Med. 2009 Jul;266(1):43-52. PMID:19522824 2963. Stratton MR, Moss S, Warren W, et al. Mutation of the p53 gene in human soft tissue

sarcomas: association with abnormalities of the RB1 gene. Oncogene. 1990 Sep;5(9):1297301. PMID:2216456 2964. Strauss DC, Qureshi YA, Hayes AJ, et al. The role of core needle biopsy in the diagnosis of suspected soft tissue tumours. J Surg Oncol. 2010 Oct1;102(5):523-9. PMID:20872955 2965. Strotman PK, Reif TJ, Kliethermes SA, et al. Dedifferentiated chondrosarcoma: a survival analysis of 159 cases from the SEER database (2001-2011). J Surg Oncol. 2017 Aug;116(2):252-7. PMID:28420036 2966. Struhl S, Edelson C, Pritzker H, et al. Solitary (unicameral) bone cyst. The fallen fragment sign revisited. Skeletal Radiol. 1989;18(4):261-5. PMID:2781324 2967. Strutto n G, Weedon D. Acroangiodermatitis. A simulant of Kaposi's sarcoma. Am J Dermatopathol. 1987 Apr;9(2):85-9. PMID:3504113 2968. Sturm D, Orr BA, Toprak UH, et al. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell. 2016 Feb 25:164(5):1060-72. PMID:26919435 2969. Sturt NJ, Gallagher MC, Bassett P, et al. Evidence for genetic predisposition to desmoid tumours in familial adenomatous polyposis independent of the germline APC mutation. Gut. 2004 Dec;53(12):1832-6. PMID:15542524 2970. Subbiah V, Lamhamedi-Cherradi SE, Cuglievan B, et al. Multimodality treatment of desmoplastic small round cell tumor: chemotherapy and complete cytoreductive surgery improve patient survival. Clin Cancer Res. 2018 Oct 1;24(19):4865-73. PMID:29871905 2971. Subhawong TK, Winn A, Shemesh SS, et al. F-18 FDG PET differentiation of benign from malignant chondroid neoplasms: a systematic review of the literature. Skeletal Radiol. 2017 Sep;46(9):1233-9. PMID:28608242 2972. Subramaniam MM, Um XY, Ven kateswara n K, etal. Dediffere ntiated solitary fibrous tumour of the nasal cavity: the first case reported with molecular characterization of a TP53 mutation. Histopathology. 2011 Dec;59(6):1269-74. PMID:22026427 2973. Suerink M, Ripperger T, Messiaen L, et al. Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testi叩 a child without malignancy. J Med Genet. 2019 Feb;56⑵:53-62. PMID:30415209 2974. Sugita S, Arai Y, Aoyama T, et al. NUTM2A-CIC fusion small round cell sarcoma: a genetically distinct variant of CIC-rearranged sarcoma. Hum Pathol. 2017 Jul;65:225-30. PMID:28188754 2975. Sugita S, Arai Y, Tonooka A, etal. A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma. Am J Surg Pathol. 2014 Nov;38(11):1571-6. PMID:25007147 2976. Sugita S, Hirano H, Kikuchi N, et al. Diagnostic utility of FOSB immunohistochemistry in pseudomyogenic hemangioendothelioma and its histological mimics. Diagn Pathol. 2016 Aug 11;11(1):75. PMID:27515856 2977. Sugiura Y, Nagaishi M, Takano I, et al. Convexity dural chondroma: a case report with pathological and molecular analysis. Clin Neuropathol. 2015 Jan-Feb;34(1):13-8. PMID:25250651 2978. Suh YG, Suh CO, Kim JS, et al. Radiotherapy for solitary plasmacytoma of bone and soft tissue: outcomes and prognostic factors. Ann Hematol. 2012 Nov;91(11):178593. PMID:22752147 2979. Suijker J, Baelde HJ, Roelofs H, et al. The oncometabolite D-2-hydroxyglutarate

induced by mutant IDH1 or-2 blocks osteoblast differentiation in vitro and in vivo. Oncotarget. 2015 Jun 20;6(17):14832-42. PMID:26046462 2980. SukovWR, 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 Radiol. 2008 Apr;37(4):321-7. PMID:18265974 2981. Sullivan LM, Folpe AL, Pawel BR, et al. Epithelioid sarcoma is associated with a high percentage of SMARCB1 deletions. Mod Pathol. 2013 Mar;26 03):385-92. PMID:23060122 2982. Sullivan RJ, Meyer JS, Dormans JP, et al. Diagnosing aneurysmal and unicameral bone cysts with magnetic resonance imaging. Clin Orthop Relat Res. 1999 Sep;(366):186-90. PMID:10627734 2983. Sultan I, Qaddoumi I, Rodriguez-Galindo C, et al. Age, stage, and radiotherapy, but not primary tumor site, affects the outcome of patients with malignant rhabdoid tumors. Pediatr Blood Cancer. 2010 Jan;54(1):35-40. PMID:19798737 2984. Sultan I, Rodriguez-Galindo C, Saab R, et al. Comparing children and adults with synovial sarcoma in the Surveillance, Epidemiology, and End Results program, 1983 to 2005: an analysis of 1268 patients. Cancer. 2009 Aug 1;115(15):3537-47. PMID:19514087 2985. Sumegi J, Nishio J, Nelson M, et al. A novel t(4;22)(q31;q12) produces an EWSR1-SMARCA5 fusion in extraskeletal Ewing sarcoma/primitive neuroectodermal tumor. Mod Pathol. 2011 Mar;24(3):333-42. PMID:21113140 2986. Sumegi J, Streblow R, Frayer RW, et al. Recurrent t(2;2) and t(2;8) translocations in rhabdomyosarcoma without the canonical PAX-FOXO1 fuse PAX3 to members of the nuclear receptor transcriptional coactivator family. Genes Chromosomes Cancer. 2010 Mar;49(3):224-36. PMID:19953635 2987. Sumiyoshi K, Tsuneyoshi M, Enjoji M. Myositis ossificans. A clinicopathologic study of 21 cases. Acta Pathol Jpn. 1985 Sep;35(5):1109-22. PMID:3866484 2988. Sun W, Chatterjee B, Shern JF, et al. Relationship of DNA methylation to mutational changes and transcriptional organ izati on in fusion-positive and fusion-negative rhabdomyosarcoma. Int J Cancer. 2019 Jun 1;144(11):2707-17. PMID:30565669 2989. Sun W, Chatterjee B, Wang Y, et al. Distinct methylation profiles characterize fusion-positive and fusion-negative rhabdomyosarcoma. Mod Pathol. 2015 Sep;28(9):1214-24. PMID:26226845 2990. Sun Y, Zhu L, Chang X, et al. Clinicopathological features and treatment analysis of rare aggressive angiomyxoma of the female pelvis and perineum - a retrospective study. Pathol Oncol Res. 2017 Jan;23(1):1317. PMID:27571990 2991. Sundaram M, Falbo S, McDonald D, etal. Surface osteomas of the appendiculacskeleton. AJR Am J Roentgenol. 1996 Dec;167(6):152933. PMID:8956591 2992. Sundaram M, McGuire MH, Herbold DR, et al. High signal intensity soft tissue masses on T1 weighted pulsing sequences. Skeletal Radiol. 1987:16(1):30-6. PMID:3823958 2993. Sundaram M, Totty WG, Kyriakos M, et al. Imaging findings in pseudocystic osteosarcoma. AJR Am J Roentgenol. 2001 Mar;176(3):783-8. PMID:11222226 2994. Suneja R, Grimer RJ, Belthur M, et al. Chondroblastoma of bone: long-term results and functional outcome after intralesional

References

589

paybal：https://www.paypal.me/andy19801210 curettage. J Bone Joint Surg Br. 2005 Jul;87(7):974-8. PMID:15972914 2995. Sung MS, Lee GK, Kang HS, et al. Sacrococcygeal chordoma: MR imaging in 30 patients. Skeletal Radiol. 2005 Feb;34⑵：8794. PMID: 15480648 2996. Sunitsch S, Gilg MM, Kashofer K, et al. Detection of GNAS mutations in intramuscular I cellular myxomas as diagnostic tool in the class币cation of myxoid soft tissue tumors. Diagn Pathol. 2018 Aug 15;13(1):52. PMID:30111377 2997. S叩erti-Furga 代 Spranger J, Nishimura G. Enchondromatosis revisited: new classification with molecular basis. Am J Med Genet C Semin Med Genet. 2012 Aug 15;160C⑶:154-64. PMID:22791316 2998. Surabhi VR, Garg N, Frumovitz M, et al. Aggressive angiomyxomas: a comprehensive imaging review with clinical and histopathologic correlation. AJR Am J Roentgenol. 2014 Jun;202(6):1171-8. PMID:24848813 2999. Suresh S, Saifuddin A. Radiological appearances of appendicula「osteosarcoma: a comprehensive pictorial review. Clin Radiol. 2007 Apr;62(4):314-23. PMID:17331824 3000. Susam-Sen H, Yalcin B, Kutluk T, et al. Lipoblastoma in children: review of 12 cases. Pediatr Int. 2017 May;59(5):545-50. PMID:28083971 3001. Suster S, Fisher C. Immunoreactivity for the human hematopoietic progenitor cell antigen (CD34) in lipomatous tumors. Am J Surg Pathol. 1997 Feb;21(2):195-200. PMID:9042286 3002. Suster S, Moran CA, Koss MN. Epithelioid hemangioendothelioma of the anterior mediastinum. Clinicopathologic, immunohistochemical, and ultrastructural analysis of 12 cases. Am J Surg Pathol. 1994 Sep;18(9):871-81. PMID:8067508 3003. Suster S, Wong TY, Moran CA. Sarcomas with combined features of liposarcoma and leiomyosarcoma. Study of two cases of an unusual soft-tissue tumor showing dual lineage differentiation. Am J Surg Pathol. 1993 Sep;17(9):905-11. PMID:8352375 3004. Suurmeijer AJH, Dickson BC, Swanson D, et al. A novel group of spindle cell tumors defined by S100 and CD34 co-expression shows recurrent fusions involving RAFI, BRAF, and NTRK1/2 genes. Genes Chromosomes Cancer. 2018 Dec;57(12):611-21. PMID:30276917 3005. Suurmeijer AJH, Song W, Sung YS, et al. Novel recurrent PHF1-TFE3 fusions in ossifying fibromyxoid tumors. Genes Chromosomes Cancer. 2019 Sep;58(9):643-9. PMID:3O92O7O8 3006. Suzuki H, Yamashiro K, Takeda H, et al. Adult rhabdomyoma of the extremity. Int J Surg Pathol. 2014Oct;22(7):634-9. PMID:24021898 3007. Suzuki-Inoue K, Tsukiji N, Shirai T, et al. Platelet CLEC-2: roles beyond hemostasis. Semin Thromb Hemost. 2018 Mar;44(2):12634. PMID:28992650 3008. Svajdler M, Michal M, Martlnek P, et al. Fibro-osseous pseudotumor of digits and myositis ossificans show consistent COL1A1USP6 rearrangement: a clinicopathological and genetic study of 27 cases. Hum Pathol. 2019 Jun;88:39-47. PMID:30946936 3009. Swaby MG, Evans HL, Fletcher CD, et al. Dermatofibrosarcoma protuberans with unusual sarcomatous transformation: a series of 4 cases with molecular confirmation. Am J Dermatopathol. 2011 Jun;33(4):354-60. PMID:21478726 3010. Sweet DE, Vinh TN, Devaney K. Cortical osteofibrous dysplasia of long bone and its relationship to adamantinoma. A clinicopathologic study of 30 cases. Am J Surg

590

References

Pathol. 1992 Mar;16(3):282-90. PMID:1599019 3011. Swerdlow SH, Campo E, Harris NL, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon (France): International Agency for Research on Cancer; 2017. (WHO classification of tumours series, 4th rev. ed.; vol. 2). https://publications. iarc.fr/556. 3012. Szuhai K, de Jong D, Leung WY, et al. Transactivating mutation of the MYOD1 gene is a frequent event in adult spindle cell rhabdomyosarcoma. J Pathol. 2014 Feb;232⑶:300-7. PMID:24272621 3013. Szuhai K, Ijszenga M, de Jong D, et al. The NFATc2 gene is involved in a novel cloned translocation in a Ewing sarcoma variant that couples its function in immunology to oncology. Clin Cancer Res. 2009 Apr 1;15(7):2259-6& PMID:19318479 3014. Szuhai K, IJszenga M, Tanke HJ, et al. Detection and molecular cytogenetic characterization of a novel ring chromosome in a histological variant of Ewing sarcoma. Cancer Genet Cytogenet. 2007 Jan 1;172(1):12-22. PMID:17175374 3015. Szuhai K, Jennes I, de Jong D, et al. Tiling resolution array-CGH shows that somatic mosaic deletion of the EXT gene is causative in EXT gene mutation negative multiple osteochondromas patients. Hum Mutat. 2011 Feb;32(2):E2036-49. PMID:21280143 3016. Szurian K, Kashofer K, Liegl-Atzwanger B. Role of next-generation sequencing as a diagnostic tool for the evaluation of bone and soft-tissue tumors. Pathobiology. 2017;84(6):323-38. PMID:28817827 3017. Szymanska J, Mandahl N, Mertens F, et al. Ring chromosomes in parosteal osteosarcoma contain sequences from 12q1315: a combined cytogenetic and comparative genomic hybridization study. Genes Chromosomes Cancer. 1996 May; 16(1 ):31-4. PMID:9162194 3018. Tabareau-Delalande F, Collin C, Gomez-Brouchet A, et al. Diagnostic value of investigating GNAS mutations in fibro-osseous lesions: a retrospective study of 91 cases of fibrous dysplasia and 40 other fibro-osseous lesions. Mod Pathol. 2013 Jul;26(7):911-21. PMID:23370769 3019. Tabone MD, Terrier P, Pacquement H, et al. Outcome of radiation-related osteosarcoma after treatment of childhood and adolesce nt cancer: a study of 23 cases. J Clin On col. 1999 Sep; 17(9):2789-95. PMID:10561354 3020. Tabori U, Nanda S, Druker H, et al. Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome. Cancer Res. 2007 Feb 15;67(4) :1415-8.PMID:仃308077 3021. Taconis WK, Mulder JD. Fibrosarcoma and malignant fibrous histiocytoma of long bones: radiographic features and grading. Skeletal Radiol. 1984;11 ⑷:237"5. PMID:6328676 3022. Tahiri Y, Xu L, Kanevsky J, et al. Lipofibromatous hamartoma of the median nerve: a comprehensive review and systematic approach to evaluation, diagnosis, and treatment. J Hand Surg Am. 2013 Oct;38(10):2055-67. PMID:23684521 3023. Tajima S, Fukayama M. Fibroblast growth factor receptor 1 (FGFR1) expression in phosphaturic mesenchymal tumors. Int J Clin Exp Pathol. 2015 Aug 1;8(8):9422-7. PMID:26464698 3024. Tajima S, Takanashi Y, Koda K. Enlarging cystic lymphangioma of the mediastinum in an adult: is this a neoplastic lesion related to the recently discovered PIK3CA mutation? Int J Clin Exp Pathol. 2015 May 1;8(5):5924-8. PMID:26191320

3025. Takahashi Y, Imamura T, Irie H, et al. Myolipoma of the retroperitoneum. Pathol Int. 2004 Jun;54(6):460-3. PMID:15144408 3026. Takahashi Y, Oda Y, Kawaguchi K, et al. Altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma. Mod Pathol. 2004 Jun;17⑹:660-9. PMID:15098008 3027. Takahashi Y, Oda Y, Yamamoto H, et al. Fibrocartilaginous mesenchymoma arising in the pubic bone: a case report. Pathol Int. 2013 Ap「;63⑷:226-9. PMID:23692424 3028. Takata H, Ikuta Y, Ishida O, et al. Treatment of subungual glomus tumour. Hand Surg. 2001 Jul;6(1):25-7. PMID:11677663 3029. Takeuchi K, Soda M, Togashi Y, et al. Pulmonary inflammatory myofibroblastic tumor expressing a novel fusion, PPFIBP1-ALK: reappraisal of anti-ALK immunohistochemistry as a tool for novel ALK fusion identification. Clin Cancer Res. 2011 May 15;17(10):3341-8. PMID:21430068 3030. Takiff H, Calabria R, Yin L, et al. Mesenteric cysts and intra-abdominal cystic lymphangiomas. Arch Surg. 1985 Nov;120(11):1266-9. PMID:4051731 3031. Talbot C, Khan T, Smith M. Infantile digital fibromatosis. J Pediatr Orthop B. 2007 Mar;16(2):110-2. PMID:17273037 3032. Tallegas M, Miquelestorena-Standley E, Labit-Bouvier C, et al. IDH mutation status in a series of 88 head and neck chondrosarcomas: different profile between tumors of the skull base and tumors involving the facial skeleton and the laryngotracheal tract. Hum Pathol. 2019 Feb;84:183-91. PMID:30296521 3033. Tallini G, Dorfman H, Brys P, et al. Correlation between clinicopathological features and karyotype in 100 cartilaginous and chordoid tumours. A report from the Chromosomes and Morphology (CHAMP) Collaborative Study Group. J Pathol. 2002 Feb;196(2):194-203. PMID:11793371 3034. Tallon B, Beer TW. MITF positivity in atypical fibroxanthoma: a diagnostic pitfall. Am J Dermatopathol. 2014 Nov;36(11):888-91. PMID:25238448 3034A. Tamborini E, Casieri P, Miselli F, et al. Analysis of potential receptor tyrosine kinase targets in intimal and mural sarcomas. J Pathol. 2007 Jun;212(2):227-35. PMID:17471466 3035. Tan CS, Loh HL, Foo MW, et al. EpsteinBarr virus-associated smooth muscle tumors after kidney transplantation: treatment and outcomes in a single center. Clin Transplant. 2013 Jul-Aug;27(4):E462-8. PMID:23682851 3036. Tan D, Kraybill W, Cheney RT, et al. Retiform hemangioendothelioma: a case report and review of the literature. J Cutan Pathol. 2005 Oct;32(9):634-7. PMID:16176302 3037. Tan MC, Brennan MF, Kuk D, et al. Histology-based classification predicts pattern of recurrence and improves risk stratification in primary retroperitoneal sarcoma. Ann Surg. 2016 Mar;263(3):593-600. PMID:25915910 3038. Tanaka M, Kato K, Gomi K, et al. Perivascular epithelioid cell tumor with SFPQ/ PSF-TFE3 gene fusion in a patient with advanced neuroblastoma. Am J Surg Pathol. 2009 Sep;33(9):1416-20. PMID:19606011 3039. Tanaka T, Fumino S, Shirai T, et al. Mesenchymal hamartoma of the chest wall in a 10-year-old girl mimicking malignancy: a case report. Skeletal Radiol. 2019 Apr;48(4):643-7. PMID:30374636 3040. Tanas MR, Ma S, Jadaan FO, et al. Mechanism of action of a WWTRI(TAZ)CAMTA1 fusion oncoprotein. Oncogene. 2016 Feb 18;35(7):929-38. PMID:25961935 3041. Tanas MR, Sboner A, Oliveira AM, et al. Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma.

8ci Transl Med. 2011 Aug 31;3(98)-98ra82 PMID:21885404 3042. Tang TT, Segura AD, Oechler HW, et al. Inflammatory myofibrohistiocytic proliferation simulating sarcoma in children. Cancer 1990 Apr 1;65(7):1626-34. PMID:2311072 3043. Tang W, Robles Al, Beyer RP, et al. The Werner syndrome RECQ helicase targets G4 DNA in human cells to modulate transcription. Hum Mol Genet. 2016 May 15;25(10) 2060-9 PMID:26984941 3044. Tani E, Wejde J, Astrom K, et al. FNA cytology of solitary fibrous tumors and the diagnostic value of STAT6 immunocytochemistry. Cancer Cytopathol 2018 Jan;126(1):36-43. PMID:28914981 3045. Tanner HC Jr, Dahlin DC, Childs DS Jr. Sarcoma complicating fibrous dysplasia. Probable role of radiation therapy. Oral Surg Oral Med Oral Pathol. 1961 Jul; 14:837-46 PMID:13775207 3046. Tantcheva-Poor I, Marathovouniotis N, Kutzner H, et al. Vascular congenital dermatofibrosarcoma protuberans: a new his⑹ogical variant of dermatofibrosarcoma protuberans. Am J Dermatopathol. 2012 Jun;34(4):e46-9. PMID:22257899 3047. Tap WD, Eilber FC, Ginther C, et al. Evaluation of well-differentiated/ de-differentiated liposarcomas by highresolution oligonucleotide array-based comparative genomic hybridization. Genes Chromosomes Cancer. 2011 Feb;50⑵:95112. PMID:21117066 3048. Tardio JC, Machado I, Alemany I, et al. Solitary fibrous tumor of the vulva: report of 2 cases, including a de novo dedifferentiated solitary fibrous tumor diagnosed after molecular demonstration of NAB2-STAT6 gene fusion. Int J Gynecol Pathol. 2018 Nov;37⑹:547-53. PMID:28968297 3049. Tardio JC, Pinedo F, Aramburu JA, et al. Clear cell atypical fibroxanthoma: clinicopathological study of 6 cases and review of the literature with special emphasis on the differential diagnosis. Am J Dermatopathol. 2016 Aug;38(8):586-92. PMID:26848640 3050. Tarkkanen M, Bohling T, Gamberi G, et al. Comparative genomic hybridization of lowgrade central osteosarcoma. Mod Pathol. 1998 May;11(5):421-6. PMID:9619593 3051. Tarpey PS, Behjati S, Cooke SL, et al. Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma. Nat Genet. 2013Aug;45(8):923-6. PMID:23770606 3052. Tarpey PS, Behjati S, Young MD, et al. The driver landscape of sporadic chordoma. Nat Commun. 2017 Oct 12;8(1):890. PMID:29026114 3053. Tateishi U, Hasegawa T, Onaya H, etal. Myxoin佃mmatory fibroblastic sarcoma: MR appearance and pathologic correlation. AJR Am J Roentgenol. 2005 Jun;184(6):1749-53. PMID:15908525 3054. Tateishi U, Yamaguchi U, Seki K, et al. Glut-1 expression and enhanced glucose metabolism are associated with tumour grade in bone and soft tissue sarcomas: a prospective evaluation by [18F]fluorodeoxyglucose positron emission tomography. Eur J Nucl Med Mol Imaging. 2006 Jun;33(6):683-91. PMID:16506050 3055. Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open­ label, phase 2 trial. Lancet Oncol. 2017 Nov;18(11):1493-501.PMID:28988646 3056. Taylor AJ, Stewart ET, Dodds WJ. Gastrointestinal lipomas: a radiologic and pathologic review. AJR Am J Roentgenol. 1990 Dec;155(6):1205-10. PMID:2122666

paybal：https://www.paypal.me/andy19801210 3057. Taylor BS, Barretina J, Socci ND, et al. Functional copy-number alterations in cancer. PLoS One. 2008 S即 11;3(9):e3179. PMID:18784837 3058. Taylor JG 6th, Cheuk AT, Tsang PS, et al. Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models. J Clin Invest. 2009 Nov;119(11 ):3395-407. PMID:19809159 3059. Templeton SF, Solomon AR Jr. Spindle cell lipoma is strongly CD34 positive. An immunohistochemical study. J Cutan Pathol. 1996 Dec;23(6):546-50. PMID:9001985 3060. ten Heuvel SE, Hoekstra HJ, Bastiaannet E, et al. The classic prognostic factors tumor stage, tumor size, and tumor grade are the strongest predictors of outcome in synovial sarcoma: no role for SSX fusion type or ezrin expression. Appl Immunohistochem Mol Morphol. 2009 May; 17(3):189-95. PMID:18997619 3061. Teoh KH, Watts AC, Chee YH, et al. Predictive factors for recurrence of simple bone cyst of the proximal humerus. J Orthop Surg (Hong Kong). 2010 Aug;18⑵:215-9. PMID:20808015 3061A. Teramura Y, Yamazaki Y, Tanaka M, et al. Case of mesenchymal tumor with the PPP6R3-USP6 fusion, possible nodular fasciitis with malignant transformation. Pathol I nt. 2019 Dec;69(12):706-9. PMID:31538390 3062. Terrier-Lacombe MJ, Guillou L, Maire G, et al. Dermatofibrosarcoma protuberans, giant cell fibroblastoma, and hybrid lesions in children: clinicopathologic comparative analysis of 28 cases with molecular data-a study from the French Federation of Cancer Centers Sarcoma Group. Am J Surg Pathol. 2003 Jan;27(1):27-39. PMID:12502925 3063. Thakur JS, Diwana VK, Sharma S, et al. Calcifying (juvenile) aponeurotic fibroma of the scalp. Ear Nose Throat J. 2011 Oct;90(10):E14-6. PMID:22033965 3064. Thampi S, Matthay KK, Boscardin WJ, et al. Clinical features and outcomes differ between skeletal and extraskeletal osteosarcoma. Sarcoma. 2014;2014:902620. PMID:25294959 3065. Thomas RM, Sobin LH. Gastrointestinal cancer. Cancer. 1995 Jan 1;75(1 S叩pl): 15470. PMID:8000994 3066. Thompson LD, Gyure KA. Extracranial sinonasal tract meningiomas: a clinicopathologic study of 30 cases with a review of the literature. Am J Surg Pathol. 2000 May;24(5):640-50. PMID: 10800982 3067. Thompson LDR, Jo VY, Agaimy A, et al. Sinonasal tract alveolar rhabdomyosarcoma in adults: a clinicopathologic and immunophenotypic study of fifty-two cases with emphasis on epithelial immunoreactivity. Head Neck Pathol. 2018 Jun;12(2):181-92. PMID:28875443 3068. Thum C, Hollowood K, Birch J, et al. Aberrant Melan-A expression in atypical fibroxa nthomaa nd un differentiated pleomorphic sarcoma of the skin. J Cutan Pathol. 2011 Dec;38(12):954-60. PMID:22050092 3069. Thum C, Husain EA, Mulholland K, et al. Atypical fibroxanthoma with pseudoangiomatous features: a histological and immunohistochemical mimic of cutaneous angiosarcoma. Ann Diagn Pathol. 2013 Dec;17(6):502-7. PMID:24080496 3070. Thway K, Fisher C. Angiomatoid fibrous histiocytoma: the current status of pathology and genetics. Arch Pathol Lab Med. 2015 May;139(5):674-82. PMID:25927151 3071. Thway K, Hayes A, leremia E, et al. Heterologous osteosarcomatous and rh abdomyosarcomatous elements in

dedifferentiated solitary fibrous tumor: further support for the concept of dedifferentiation in solitary fibrous tumor. Ann Diagn Pathol. 2013 Oct; 17(5):457-63. PMID:23040384 3072. Thway K, Jones RL, Noujaim J, et al. Epithelioid sarcoma: diagnostic features and genetics. AdvAnat Pathol. 2016 Jan;23(1):419. PMID:26645461 3073. Tian L, Cui CY, Lu SY, et al. Clinical presentation and CT/MRI findings of alveolar soft part sarcoma: a retrospective single­ center analysis of 14 cases. Acta Radiol. 2016 Apr;57(4):475-80. PMID:26231949 3074. Tiet TD, Hopyan S, Nadesan P, et al. Constitutive hedgehog signaling in chondrosarcoma up-regulates tumor cell proliferation. Am J Pathol. 2006 Jan;168(1):321-30. PMID:16400033 3075. Tinat J, Bougeard G, Baert-Desurmont S, et al. 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol. 2009 Sep 10;27(26):e108-9, author reply e110. PMID:19652052 3076. Tirabosco R, Mangham DC, Rosenberg AE, et al. Brachyury expression in extra-axial skeletal and soft tissue chordomas: a marker thatdistinguishes chordoma from mixed tumor/ myoepithelioma/parachordoma in soft tissue. Am J Surg Pathol. 2008 Apr;32⑷:572-80. PMID:18301055 3077. Tirode F, Surdez D, Ma X, etal. Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations. Cancer Discov. 2014 Nov;4(11):1342-53. PMID:25223734 3078. Titgemeyer C, Grois N, Minkov M, et al. Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. Med Pediatr Oncol. 2001 Aug;37⑵:108-14. PMID:11496348 3079. Tognon C, Knezevich SR, Huntsman D, et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002 Nov;2(5):367-76. PMID:12450792 3080. Togo T, Araki E, Ota M, et al. Fibrous hamartoma of infancy in a patient with Williams syndrome. Br J Dermatol. 2007 May;156(5): 1052-5. PMID:17326745 3081. Tokano H, Sugimoto T, Noguchi Y, et al. Sequential computed tomography images demonstcating characteristic changes in fibrous dysplasia. J Laryngol O⑹.2001 Sep;115(9):757-9. PMID:11564313 3082. Toki S, Wakai S, Sekimizu M, et al. PAX7 immunohistochemical evaluation of Ewing sarcoma and other small round cell tumours. Histopathology. 2018 Oct;73(4):645-52. PMID:29920735 3083. Tokita M, Kennedy SR, Risques RA, et al. Werner syndrome through the lens of tissue and tumour genomics. Sci Rep. 2016 Aug 25;6:32038. PMID:27559010 3084. Toledo RA. Genetics of pheochromocytomas and paragangliomas: an overview on the recently implicated genes MERTK, MET, fibroblast growth factor receptor 1, and H3F3A. Endocrinol Metab Clin North Am. 2017 Jun;46⑵:459-89. PMID:28476232 3085. Toledo RA, Qin Y, Cheng ZM, et al. Recurrent mutations of chromatin­ remodeling genes and kinase receptors in pheochromocytomas and paragangliomas. Clin Cancer Res. 2016 May 1;22(9):2301-10. PMID:26700204 3086. Toll AD, Wakely PE Jr, Ali S乙 Acral myxoinflammatory fibroblastic sarcoma: cytopathologic findings on fine-needle aspiration. Acta Cytol. 2013;57⑵:134-8. PMID:23406831 3087. Tomaszewski MM, Lupton GP. Atypical fibroxanthoma. An unusual variant with

osteoclast-like giant cells. Am J Surg Pathol. 1997 Feb0⑵:213-8. PMID:9042289 3088. Tomesello ML, Biryahwaho B, Downing R, et al. Human herpesvirus type 8 variants circulating in Europe, Africa and North America in classic, endemic and epidemic Kaposi *s sarcoma lesions during pre-AIDS and AIDS era. Virology. 2010 Mar 15;398(2):280-9. PMID:20079510 3089. Toro JR, Travis LB, Wu HJ, et al. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978-2001: an analysis of 26,758 cases. Int J Cancer. 2006 Dec 15; 119(12):2922-30. PMID:17013893 3090. Torres FX, Kyriakos M. Bone infarctassociated osteosarcoma. Cancer. 1992 Nov 15;70(10):2418-30. PMID:1423172 3091. Torres-Mora J, Dry S, Li X, et al. Malignant melanotic schwannian tumor: a clinicopathologic, immunohistochemical, and gene expression profiling study of 40 cases, with a proposal for the reclassification of ■'melanotic schwannoma". Am J Surg Pathol. 2014 Jan;38(1):94-105. PMID:24145644 3092. Torres-Mora J, Ud Din N, Ahrens WA, et al. Pseudolipoblastic perineurioma: an unusual morphological variant of perineurioma that may simulate liposarcoma. Hum Pathol. 2016 Nov;57:22-7. PMID:27395366 3093. Tostar U, Malm CJ, Meis-Kindblom JM, et al. Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. J Pathol. 2006 Jan;208(1):17-25. PMID:16294371 3094. Totoki Y, Yoshida A, Hosoda F, et al. Unique mutation portraits and frequent COL2A1 gene alteration in chondrosarcoma. Genome Res. 2014 Sep;24(9):1411-20. PMID:25024164 3095. Tran TAN, Linos K, Carlson JA, et al. A primary cutaneous vascular neoplasm with histologic features of anastomosing hemangioma. J Cutan Pathol. 2019 May;46(5):353-7. PMID:30666666 3096. Trassard M, Le Doussal V, Bui BN, et al. Angiosarcoma arising in a solitary schwannoma (neurilemoma) of the sciatic nerve. Am J Surg Pathol. 1996 Nov;20(11):1412-7. PMID:8898847 3097. Trattner A, Hodak E, David M, et al. The appearance of Kaposi sarcoma during corticosteroid therapy. Cancer. 1993 Sep 1;72(5):1779-83. PMID:8348508 3098. Trautmann M, Cyra M, Isfort I, et al. Phosphatidylinositol-3-kinase (PI3K)/ Akt signaling is functionally essential in myxoid liposarcoma. Mol Cancer Ther. 2019 Apr;18(4):834-44. PMID:30787173 3099. Travis JA, Bridge JA. Significance of both numerical and structural chromosomal abnormalities in clear cell sarcoma. Cancer Genet Cytogenet. 1992 Dec;64⑵H04-6. PMID:1486557 3100. Trembath DG, Dash R, Major NM, et al. Cytopathology of mesenchymal chondrosarcomas: a report and comparison of four patients. Cancer. 2003 Aug 25;99(4):2116. PMID:12925982 3101. Trindade F, Tellechea O, Torrelo A, et al. Wilms tumor 1 expression in vascular neoplasms and vascular malformations. Am J Dermatopathol. 2011 Aug;33(6):569-72. PMID:21697701 3102. Trkova M, Prochazkova K, Krutilkova V, et al. Telomere length in peripheral blood cells of germline TP53 mutation carriers is shorter than that of normal individuals of corresponding age. Cancer. 2007 Aug 1;110⑶:694-702. PMID:17567834

3103. Trobaugh-Lotrario AD, Finegold MJ, Feusner JH. Rhabdoid tumors of the liver: rare, aggressive, and poorly responsive to standard cytotoxic chemotherapy. Pediatr Blood Cancer. 2011 Sep;57(3):423-8. PMID:21744471 3104. Trojani M, Contesso G, Coindre JM, et al. Soft-tissue sarcomas of adults; study of pathological prognostic variables and definition of a histopathological grading system. Int J Cancer. 1984 Jan 15;33(1):37-42. PMID:6693192 3105. Trombetta D, Magnusson L, von Steyern FV, et al. Translocation t(7;19) (q22;q13)-a recurrent chromosome aberration in pseudomyogenic hemangioendothelioma? Cancer Genet. 2011 Apr;204(4):211-5. PMID:21536240 3106. Troum S, Dalton ML, Donner RS, et al. Multifocal mesenchymal hamartoma of the chest wall in infancy. J Pediatr Surg. 1996 May;31 (5):713-5. PMID:8861490 3107. Tsang WY, Chan JK, Chow LT, et al. Perineurioma: an uncommon soft tissue neoplasm distinct from localized hypertrophic neuropathy and neurofibroma. Am J Surg Pathol. 1992Aug;16(8):756-63. PMID:1497116 3108. Tsang WY, Chan JK, Lee KC, et al. Aggressive angiomyxoma. A report of four cases occurring in men. Am J Surg Pathol. 1992 Nov;16(11):1059-65. PMID:1471726 3109. Tsuda M, Davis IJ, Argani P, et al. TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition. Cancer Res. 2007 Feb 1;67(3):919-29. PMID:17283122 3110. Tsuda Y, Ogura K, Hakozaki M, et al. Mesenchymal chondrosarcoma: a Japanese Musculoskeletal Oncology G「o叩(JMOG) study on 57 patients. J Surg Oncol. 2017 May;115(6):760-7. PMID:29044531 3111. Tsuji K, Ishikawa Y, Imamura T. Technique for differentiating alveolar soft part sarcoma from other tumors in paraffin-embedded tissue: comparison of immunohistochemistry for TFE3 and CD147 and of reverse transcription polymerase chain reaction for ASPSCR1 ・ TFE3 fusion transcript. Hum Pathol. 2012 Mar;43(3):356-63. PMID:21835426 3112. Tsujimura T, Sakaguchi K, Aozasa K. Phosphaturic mesenchymal tumor, mixed connective tissue variant (oncogenic osteomalacia). Pathol Int. 1996 Mar;46⑶:23841.PMID:10846577 3113. Tsukamoto S, Righi A, Vanel D, et al. Development of high-grade osteosarcoma in a patient with recurrent giant cell tumor of the ischium while receiving treatment with denosumab. Jpn J Clin Oncol. 2017 Nov 1;47(11):1090-6. PMID:29048579 3114. Tsukamoto Y, Futani H, Kihara T, et al. An extremely rare case of primary malignancy in giant cell tumor of bone, arising in the right femur and harboring H3F3A mutation. Pathol Res Pract. 2018 Sep;214(9):1504-9. PMID:29970305 3115. Tsuneyoshi M, Dorfman HD, Bauer TW. Epithelioid hemangioendothelioma of bone. A clinicopathologic, ultrastructural, and immunohistochemical study. Am J Surg Pathol. 1986 Nov;10(11):754-64. PMID:2430475 3116. Tsuzuki T, Magi-Galluzzi C, Epstein JI. ALK-1 expression in inflammatory myofibroblastic tumor of the urinary bladder. Am J Surg Pathol. 2004 Dec;28(12):1609-14. PMID:15577680 3117. Tucker MA, D'Angio GJ, Boice JD Jr, et al. Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med. 1987 S即 3;317(10):588-93. PMID:3475572 3118. Turcotte RE. Giant cell tumor of bone. Orthop Clin North Am. 2006 Jan;37(1):35-51.

Refere nces

591

paybal：https://www.paypal.me/andy19801210 PMID:16311110 3119. Turcotte RE, Kurt AM, Sim FH, et al. Chondroblastoma. Hum Pathol. 1993 Sep;24(9):944-9. PMID:8253461 3120. Turner JH, Richmon JD. Head and neck rhabdomyosarcoma: a critical analysis of population-based incidence and survival data. Otolaryngol Head Neck Surg. 2011 Dec;145(6):967-73. PMID:21873599 3121. Ud Din N, Ahmad Z, Zreik R, et al. Abdominopelvic and retroperitoneal low-grade fibromyxoid sarcoma: a clinicopathologic study of 13 cases. Am J Clin Pathol. 2018 Jan 29;149⑵H28—34. PMID:29385413 3122. Ud Din N, Zhang P, Sukov WR, et al. Spindle cell lipomas arising at atypical locations. Am J Clin Pathol. 2016 Oct; 146(4):487-95. PMID:27686175 3123. Ueda T, Araki N, Mano M, et al. Frequent expression of smooth muscle markers in maligna nt fibrous histiocytoma of bone. J Clin Pathol. 2002 Nov;55(11):853-8. PMID:12401825 3124. Ueno-Yokohata H, Okita H, Nakasato K, et al. Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney. Nat Genet. 2015 Aug;47(8):861-3. PMID:26098867 3125. Ugurel S, Mentzel T, Utikal J, et al. Neoadjuvant imatinib in advanced primary or locally recurrent dermatofibrosarcoma protuberans: a multicenter phase II DeCOG trial with long-term follow-up. Clin Cancer Res. 2014 Jan 15;20(2):499-510. PMID:24173542 3126. UICC [Internet]. Geneva (Switzerland): Union for International Cancer Control; 2019. TNM Publications and Resources; updated 2019 Feb 4. Available from: https://www.uicc. org/resources/t nm/publications-resources. 3127. Ulano A, Bredella MA, Burke P, et al. Disting uishing untreated osteoblastic metastases from enostoses using CT attenuation measurements. AJR Am J Roentgenol. 2016 Aug;207⑵:362-8. PMID:27101076 3128. Unni KK, Dahlin DC, Beabout JW. Periosteal osteogenic sarcoma. Cancer. 1976 May;37⑸:2476-85. PMID:1063059 3129. Unni KK, Dahlin DC, Beabout JW, et al. Chondrosarcoma: clear-cell variant. A report of sixteen cases. J Bone Joint Surg Am. 1976 Jul;58(5):676-83. PMID:932066 、 3130. Unni KK, Inwards CY, Bridge JA, et al. Tumors of the bones and joints. Washington, DC: American Registry of Pathology; 2005. (AFIP atlas of tumor pathology, series 4; fascicle 2). 3131. Unni KK, Inwards CY, editors. Benign vascular tumors. In: Dahlin's bone tumours: general aspects and data on 10,165 cases. 6th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2010. pp. 262-71. 3132. Unni KK, Inwards CY, editors. Dahlin's bone tumours: general aspects and data on 10,165 cases. 6th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2010. 3133. Unni KK, Inwards CY, editors. Osteosarcoma. In: Dahlin's bone tumours: general aspects and data on 10,165 cases. 6th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2010. pp. 122-68. 3134. Upadhyaya M, Huson SM, Davies M, et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. 2007 Jan;80(1):140-51. PMID:仃160901 3135. Uppal S, Aviv H, Patterson F, et al. Alveolar soft part sarcoma-reciprocal translocation between chromosome 17q25

592

Refere nces

and Xp11, Report of a case with metastases at presentation and review of the literature. Acta Orthop Belg. 2003 Apr;69⑵:*I82 -7. PMID:12769020 3136. Uramoto N, Furukawa M, Yoshizaki T. Malignant phosphaturic mesenchymal tumor, mixed connective tissue variant of the tongue. Auris Nasus Larynx. 2009 Feb;36(1):104-5. PMID:18329207 3137. Urbina F, Sazunic I, Murray G. Infantile systemic hyalinosis or juvenile hyaline fibromatosis? Pediatr Dermatol. 2004 MarApr;21 (2):154-9. PMID:15078358 343& Ushijima M, Hashimoto H, Tsuneyoshi M, et al. Giant cell tumor of the tendon sheath (nodular tenosynovitis). A study of 207 cases to compare the large joint group with the comm on digit group. Cancer. 1986 Feb 15;57(4):875-84. PMID:3943019 3139. Ushijima M, Tsuneyoshi M, Enjoji M. D 叩 uytren type fibromatoses. A clinicopathologic study of 62 cases. Acta Pathol Jpn. 1984Sep;34(5):991-1001. PMID:6507097 3140. Uusitalo E, Leppavirta J, Koffert A, et al. Incidence and mortality of neurofibromatosis: a total population study in Finland. J Invest Dermatol. 2015 Mar;135⑶:904-6. PMID:25354145 3141. Uusitalo E, Rantanen M, Kallionpaa RA, etal. Distinctive cancer associations in patients with neurofibromatosis type 1. J Clin Oncol. 2016 Jun 10;34(17):1978-86. PMID:26926675 3142. Vakil-Adli A, Zandieh S, Hochreiter J, et al. Synovial hemangioma of the knee joint in a 12-year-old boy: a case report. J Med Case Rep. 2010 Apr 12;4:105. PMID:20385009 3143. Valery PC, Laversanne M, Bray F. Bone cancer incidence by morphological subtype: a global assessment. Cancer Causes Control. 2015Aug;26(8):1127-39. PMID:26054913 3144. Vallat-Decouvelaere AV, Dry SM, Fletcher CD. Atypical and malignant solitary fibrous tumors in extrathoracic locations: evidence of their comparability to intra-thoracic tumors. Am J Surg Pathol. 1998 Dec;22(12):1501-11. PMID:9850176 3145. Vallat-Decouvelaere AV, Wassef M, Lot G, et al. Spinal melanotic schwannoma: a tumour with poor prognosis. Histopathology. 1999 Dec;35⑹:558-66. PMID:10583580 、 3146. Valls J, Ottolenghi CE, Schajowicz F. Epiphyseal chondroblastoma of bone. J Bone Joint Surg Am. 1951 Oct;33-A(4):997-1009. PMID:14880556 3147. Van Antwerp ME, Chen DG, Chang C, et al. A point mutation in the MyoD basic domain imparts c-Myc-like properties. Proc Natl Acad Sci USA 1992 Oct 1;89(19):9010-4. PMID:1329087 3148. van Beerendonk HM, Rozeman LB, Taminiau AH, et al. Molecular analysis of the INK4A/INK4A-ARF gene locus in conventional (central) chondrosarcomas and enchondromas: indication of an important gene for tumour progression. J Pathol. 2004 Mar;202(3):35966. PMID:14991902 3149. van de Rijn M, Barr FG, Xiong QB, et al. Poorly differentiated synovial sarcoma: an analysis of clinical, pathologic, and molecular genetic features. Am J Surg Pathol. 1999 Jan;23(1):106-12. PMID:9888710 3150. Van den Berg E, MolenaarWM, Hoekstra HJ, et al. DNA ploidy and karyotype in recurrent and metastatic soft tissue sarcomas. Mod Pathol. 1992 Sep;5(5):505-14. PMID:1344814 3151. van den Berg H, Kroon HM, Slaar A, et al. Incidenee of biopsy-proven bone tumors in children: a report based on the Dutch pathology registration "PALGA”. J Pediatr Orthop. 2008 Jan-Feb;28( 1):29-35. PMID:18157043 3152. van der Graaf WTA, Orbach D, Judson IR, et al. Soft tissue sarcomas in adolescents and

young adults: a comparison with their paediatric and adult counterparts. Lancet Oncol. 2017 Mar;18(3):e166-75. PMID:28271871 3153. van der Heijden L, van de Sande MA, van der Geest IC, et al. Giant cell tumors of the sacrum-a nationwide study on midterm results in 26 patients after intralesional excision. Eur Spine J. 2014 Sep;23(9):1949-62. PMID:24614982 3154. van der Maten J, Blaauwgeers JL, Sutedja TG, et al. G「anula「cell tumors of the tracheobronchial tree. J Thorac Cardiovasc Surg. 2003 Sep;126(3):740-3. PMID:14502147 3155. Van der Woude HJ, Hazelbag HM, Bloem JL, et al. MRI of adamantinoma of long bones in correlation with histopathology. AJR Am J Roentgenol. 2004 Dec;183(6):1737-44. PMID:15547221 3156. Van Dievel J, Sciot R, Delcroix M, et al. Single-center experience with intimal sarcoma, an ultra-orphan, commonly fatal mesenchymal malignancy. Oncol Res Treat. 2017;40(6):3539. PMID:28501860 3157. Van Dorpe J, Sciot R, De Vos R, et al. Neuromuscular choristoma (hamartoma) with smooth and striated muscle component: case report with immunohistochemical and ultrastructural analysis. Am J Surg Pathol. 1997 S即;21 (9):1090-5. PMID:9298886 3158. van Gaal JC, Flucke UE, Roeffen MH, et al. Anaplastic lymphoma kinase aberrations in rhabdomyosarcoma: clinical and prognostic implications. J Clin Oncol. 2012 Jan 20；30(3):308-15. PMID:22184391 3159. Van Geertruyden J, Lorea P, Goldschmidt D, et al. Glomus tumours of the hand. A retrospective study of 51 cases. J Hand Surg Br. 1996Apr;21 ⑵:257-60. PMID:8732413 、 3160. van Houdt WJ, Wei IH, Kuk D, et al. Yield of colonoscopy in identification of newly diagnosed desmoid-type fibromatosis with underlying familial adenomatous polyposis. Ann Surg Oncol. 2019 Mar;26⑶:765-71. PMID:30610557 3161. van Houdt WJ, Westerveld CM, Vrijenhoek JE, et al. Prognosis of solitary fibrous tumors: a multicenter study. Ann Surg Oncol. 2013 Dec;20(13):4090-5. PMID:24052313 3162. van IJzendoorn DG, de Jong D, Romagosa C, et al. Fusion events lead to truncation of FOS in epithelioid hemangioma of bone. Genes Chromosomes Cancer. 2015 Sep;54(9):565-74. PMID:26173738 3163. van IJzendoorn DGP, Forghany 乙 Liebelt F, et al. Functional analyses of a human vascular tumor FOS variant identify a novel degradation mechanism and a link to tumorigenesis. J Biol Chem. 2017 Dec 29;292(52):21282-90. PMID:29150442 3164. van IJzendoorn DGP, Sleijfer S, Gelderblom H, et al. Telatinib is an effective targeted therapy for pseudomyogenic hemangioendothelioma. Clin Cancer Res. 2018 Jun 1;24(11):2678-87. PMID:29511030 3165. van Oosterwijk JG, Herpers B, Meijer D, et al. Restoration of chemosensitivity for doxorubicin and cisplatin in chondrosarcoma in vitro: BCL-2 family members cause chemoresistance. Ann Oncol. 2012 Jun;23(6):1617-26. PMID:22112972 3166. van Oosterwijk JG, Meijer D, van Ruler MA, et al. Screening for potential targets for therapy in mesenchymal, clear cell, and dedifferentiated chondrosarcoma reveals Bcl-2 family members and TGF0 as potential targets. Am J Pathol. 2013 Apr; 182(4):1347-56. PMID:23415961 3167. van Praag Veroniek VM, Rueten-Budde AJ, Ho V, et al. Incidence, outcomes and prognostic factors during 25 years of treatment of chondrosarcomas. Surg Oncol. 2018 Sep;27⑶:402-8. PMID:30217294

3168. van Roggen JF, van Unnik JA, Briaire-de Bruijn IH, et al. Aggressive angiomyxoma: a clinicopathological and immunohistochemical study of 11 cases with long-term follow-up. Virchows Arch. 2005 Feb;446(2): 157-63 PMID:15735978 3169. van Unnik JA, Coindre JM, Contesso C, et al. Grading of soft tissue sarcomas: experience of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 1993;29A(15):2089-93 PMID:8297645 3170. van den Berg H, van Rijn RR, Merks JH. Management of tumors of the chest wall in childhood: a review. J Pediatr Hematol Oncol. 2008 Mar;30(3):214-21. PMID:18376284 3171. van der Walt JD, Ryan JF. Parosteal osteogenic sarcoma of the hand Histopathology. 1990 Jan;16(1)75-8 PMID:2307417 3172. Vandevenne JE, De Schepper AM, De Beuckeleer L, et al. New concepts in understanding evolution of desmoid tumors: MR imaging of 30 lesions. Eur Radiol 1997;7(7):1013-9. PMID:9265665 3173. Vanel D, Picci P, De Paolis M, et al. Radiological study of 12 high-grade surface osteosarcomas. Skeletal Radiol. 2001 Dec;30(12):667-71. PMID:11810163 3174. Vanel D, Tcheng S, Contesso G, et al. The radiological appearances of telangiectatic osteosarcoma. A study of 14 cases. Skeletal Radiol. 1987;16(3):196-200. PMID:3473690 3175. Vang R, Kempson RL. Perivascular epithelioid cell tumor (PEComa1) of the uterus: a subset of HMB-45-positive epithelioid mesenchymal neoplasms with an uncertain relationship to pure smooth muscle tumors. Am J Surg Pathol. 2002 Jan;26(1):1-13. PMID:11756764 3176. van Hemel BM, Suurmeijer AJ. Effective application of the methanol-based PreservCyt(™) fixative and the Cellient(™) automated cell block processor to diagnostic cytopathology, immunocytochemistry, and molecular biology. Diagn Cytopathol. 2013 Aug;41 (8):734^1. PMID:23444168 3177. van IJzendoorn DGP, Bovee JVMG. Vascular tumors of bone: the evolvement of a classification based on molecular developments. Surg Pathol Clin. 2017 Sep;10(3):621-35. PMID:28797505 3178. Van Maldergem L, Piard J, Larizza L, et al. Baller-Gerold syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 2007 Aug 13 [updated 2018 Apr 19]. PMID:20301383 3179. van Roggen JF, McMenamin ME, Fletcher CD. Cellular myxoma of soft tissue: a clinicopathological study of 38 cases confirming indolent clinical behaviour. Histopathology. 2001 Sep;39(3):287-97. PMID:11532040 3180. Varadhachary GR, Abbruzzese JL, Lenzi R. Diagnostic strategies for unknown primary cancer. Cancer. 2004 May 1;100(9):1776-85. PMID:15112256 3182. Varela-Duran J, Oliva H, Rosai J. Vascular leiomyosarcoma: the malignant counterpart of vascular leiomyoma. Cancer. 1979 Nov;44(5):1684-91. PMID:498039 3183. Vasconcelos C, Cunha TM, Felix A. Lipoleiomyoma of the peritoneum. Acta Radiol. 2007 Feb;48(1):10-2. PMID:17325918 3184. Velagaleti GV, Tapper JK, Panova NE, et al. Cytogenetic findings in a case of nodular fasciitis of subclavicular region. Cancer Genet Cytogenet. 2003 Mar;141 (2):160-3. PMID:12606136 3185. Vellios F, Baez J, Shumacker HB. Lipoblastomatosis: a tumor of fetal fat different from hibernoma; report of a case, with observations on the embryogenesis of

paybal：https://www.paypal.me/andy19801210 human adipose tissue. Am J Pathol. 1958 NovDec;34⑹:竹49-59. PMID:13583102 3186. Vencio EF, Reeve CM, Unni KK, et al. Mesenchymal chondrosarcoma of the jaw bones: clinicopathologic study of 19 cases. Cancer. 1998 Jun 15;82(12):2350-5. PMID:9635527 3187. Venkatraman L, Goepel JR, Steele K, et al. Soft tissue, pelvic, and urinary bladder leiomyosarcoma as second neoplasm following hereditary retinoblastoma. J Clin Pathol. 2003 Ma「;56⑶:233-6. PMID:12610106 3188. Verbeke SL, Bertoni F, Bacchini P, et al. Active TGF-卩 signaling and decreased expression of PTEN separates angiosarcoma of bone from its soft tissue counterpart. Mod Pathol. 2013 S 即;26(9):1211-21. PMID:23599148 3189. Verbeke SL, Bertoni F, Bacchini P, et al. Distinct histological features characterize primary angiosarcoma of bone. Histopathology. 2011 Jan;58(2):254-64. PMID:21323951 3190. Verbeke SL, Bovee JV. Primary vascular tumors of bone: a spectrum of entities? I nt J Clin Exp Pathol. 2011 Aug 15;4(6):541-51. PMID:21904630 3191. Verbeke SL, de Jcmg D, Bertoni F, et al. Array CGH analysis identifies two distinct subgro ups of primary an giosarcoma of bone. Genes Chromosomes Cancer. 2015 Feb;54⑵:72-81. PMID:25231439 3192. Verbeke SL, Fletcher CD, Alberghini M, et al. A reappraisal of hemangiopericytoma of bone; analysis of cases reclassified as synovial sarcoma and solitary fibrous tumor of bone. Am J Surg Pathol. 2010 Jun;34⑹:777-83. PMID:20421780 3193. Verdegaal SH, Bovee JV, Pansuriya TC, et al. Incidence, predictive factors, and prognosis of chondrosarcoma in patients with Ollier disease and Maffucci syndrome: an international multicenter study of 161 patients. Oncologist. 2011;16(12):1771-9. PMID:22147000 3194. Verelst SJ, Hans J, Hanselmann RG, et al. Genetic instability in primary leiomyosarcoma of bone. Hum Pathol. 2004 Nov;35(11):1404-12. PMID:15668899 3195. Vergel De Dios AM, Bond JR, Shives TC, et al. Aneurysmal bone cyst. A clinicopathologic study of 238 cases. Cancer. 1992 Jun 15;69(12):2921-31. PMID:1591685 3196. Vermaat JS, Pals ST, Younes A, et al. Precision medicine in diffuse large B-cell lymphoma: hitting the target. Haema⑹ogica. 2015Aug;100(8):989-93. PMID:26314080 3197. Vermaat M, Vanel D, Kroon HM, et al. Vascular tumors of bone: imaging findings. Eur J Radiol. 2011 Jan;77(1):13-8. PMID:20828961 3198. Verschoor AJ, Bovee JVMG, Mastboom MJL, et al. Incidenee and demographics of giant cell tumor of bone in the Netherlands: first nationwide Pathology Registry study. Acta Orthop. 2018 Oct;89(5):570-4. PMID:29987945 3199. Versteege I, Sevenet N, Lange J, et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature. 1998 Jul 9;394(6689):203-6. PMID:9671307 3200. Viale G, Doglioni C, Iuzzolino P, et al. Infantile digital fibromatosis-like tumour (inclusion body fibromatosis) of adulthood: report of two cases with ultrastructural and immunocytochemical findings. Histopathology. 1988 Apr; 12⑷:415-24. PMID:2836293 3201. Villani A, Shore A, Wasserman JD, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-叩 of a prospective observational study. Lancet Oncol. 2016 Sep; 17(9): 1295-305. PMID:27501770 3202. Viskochil D, Buchberg AM, Xu G, et al. Deletions and a translocation interrupt a cloned

gene at the neurofibromatosis type 1 locus. Cell. 1990 Jul13;62(1):187-92. PMID:1694727 3203. Vissers LE, Fano V, Martinelli D, et al. Whole-exome sequenci叩 detects somatic mutations of IDH1 in metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA). Am J Med Genet A. 2011 Nov; 155A( 11 ):2609-16. PMID:22025298 3204. Vokuhl C, Oyen F, Haberle B, et al. Small cell undifferentiated (SCUD) hepatoblastomas: all malignant rhabdoid tumors? Genes Chromosomes Cancer. 2016 Dec;55(12):92531.PMID:27356182 3205. Voltaggio L, Murray R, Lasota J, et al. Gastric schwannoma: a clinicopathologic study of 51 cases and critical review of the literature. Hum Pathol. 2012 May;43(5):650-9. PMID:22137423 3206. von Mehren M, Randall RL, Benjamin RS, et al. Soft Tissue Sarcoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl ComprCanc Netw. 2018 May;16(5):53663. PMID:29752328 3207. Vortmeyer AO, Glasker S, Mehta GU, et al. Somatic GNAS mutation causes widespread and diffuse pituitary disease in acromegalic patients with McCune-Albright syndrome. J Clin Endocrinol Metab. 2012 Jul;97(7):2404-13. PMID:22564667 3208. Voth H, Landsberg J, Hinz T, et al. Management of dermatofibrosarcoma protuberans with fibrosarcomatous transformation: an evidence-based review of the literature. J Eur Acad Dermatol Venereol. 2011 Dec;25(12): 1385-91. PMID:21645124 3209. Vuillemin-Bodaghi V, Parlier-Cuau C, Cywiner-Gole nze「C, etal. Multifocal osteoge nic sarcoma in Paget's disease. Skeletal Radiol. 2000 Jun;29(6):349-53. PMID:10929418 3210. Vujovic S, Henderson S, Presneau N, et al. Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas. J Pathol. 2006 Jun;209(2):157-65. PMID:16538613 3211. WaaijerCJ, Winter MG, Reijnders CM, et al. Intronic deletion and duplication proximal of the EXT1 gene: a novel causative mechanism for multiple osteochondromas. Genes Chromosomes Cancer. 2013 Apr;52(4):431-6. PMID:23341036 3212. Wada N, Ito T, Uchi H, et al. Superficial CD34-positive fibroblastic tumor: a new case from Japan. J Dermatol. 2016Aug;43(8):934-6. PMID:26946226 3213. Wagner AJ, Remillard SP, Zhang YX, et al. Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors. Mod Pathol. 2013 Feb;26⑵:289-94. PMID:22955521 3214. Wakely PE Jr, McDermott JE, Ali SZ. Cytopathology of alveolar soft part sarcoma: a report of 10 cases. Cancer. 2009 Dec 25;117(6):500-7. PMID:19787801 3215. Wakely PE Jr, Price WG, Frable WJ. Sternomastoid tumor of infancy (fibromatosis colli): diagnosis by aspiration cytology. Mod Pathol. 1989 Jul;2(4):378-81. PMID:2762289 3216. Walavalkar V, Fischer AH, Owens CL. Cytologic diagnosis of metastatic alveolar rhabdomyosarcoma to the thyroid gland by fineneedle aspiration. Acta Cytol. 2014;58⑶:28892. PMID:24513670 3217. Walcott-Sapp S, Tang E, Kakar S, et al. Resection of the largest reported hepatic small vessel neoplasm. Hum Pathol. 2018 Aug;78:159-62. PMID:29366622 3218. Walczak BE, Johnson CN, Howe BM. Myositis ossificans. J Am Acad Orthop Surg. 2015 Oct;23(10):612-22. PMID:26320160 3219. Walker EA, Murphey MD, Fetsch JF. Imaging characteristics of tenosynovial and bursal chondromatosis. Skeletal Radiol. 2011

Mar;40(3):317-25. PMID:20711779 3220. Wallace MR, Marchuk DA, Andersen LB, et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science. 1990 Jul 13;249(4965):181-6. PMID:2134734 3221. Wallis LA, Asch T, Maisel BW. Diffuse skeletal hemangiomatosis: report of two cases and review of literature. Am J Med. 1964 Oct;37:545-63. PMID:14215843 3222. Waiterhouse DO, Pappo AS, Meza JL, et al. Shorter-duration therapy using vincristine, dactinomycin, and lower-dose cyclophosphamide with or without radiotherapy for patients with newly diagnosed low-risk rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. J Clin Oncol. 2014 Nov 1;32(31):3547-52. PMID:25267746 3223. Walther C, Hofvander J, Nilsson J, et al. Gene fusion detection in formalin-fixed paraffinembedded benign fibrous histiocytomas using fluorescence in situ hybridization and RNA sequencing. Lab Invest. 2015 Sep;95(9):10716. PMID:26121314 3224. Walther C, Tayebwa J, Lilljebjorn H, et al. A novel SERPINE1-FOSB fusion gene results in transcriptional up-regulation of FOSB in pseudomyogenic haema ngioendothelioma. J Pathol. 2014 Apr;232⑸:534-40. PMID:24374978 3225. Wan YCE, Liu J, Chan KM. Histone H3 mutations in cancer. Curr Pharmacol Rep. 2018;4(4):292-300. PMID:30101054 3226. Wang G, Tucker T, Ng TL, et al. Fineneedle aspiration of soft tissue myoepithelioma. Diagn Cytopathol. 2016 Feb;44(2):152-5. PMID:26644362 3227. Wang GY, Thomas DG, Davis JL, et al. EW8R1-NFATC2 translocation-associated sarcoma clinicopathologic findings in a rare aggressive primary bone or soft tissue tumor. Am J Surg Pathol. 2019 Aug;43(8):1112-22. PMID:30994538 3228. Wang H, Jacobson A, Harmon DC, et al. Prognostic factors in alveolar soft part sarcoma: a SEER analysis. J Surg Oncol. 2016 Apr;113(5):581-6. PMID:26804150 3229. Wang J, Zhu XZ, Zhang RY. [Malignant granular cell tumor: a clinicopathologic analysis of 10 cases with review of literature], Zhonghua Bing Li Xue Za Zhi. 2004 Dec;33(6):497-502. Chinese. PMID:15634442 3230. Wang L, Bhargava R, Zheng T, et al. Undifferentiated small round cell sarcomas with rare EWS gene fusions: identification of a novel EWS-SP3 fusion and of additional cases with the EWS-ETV1 and EWS-FEV fusions. J Mol Diagn. 2007 Sep;9(4):498-509. PMID:17690209 3231. Wang L, Mo⑹ T, Khanin R, et al. Identification ofa novel, recurrent HEY1-NCOA2 fusion in mesenchymal chondrosarcoma based on a genome-wide screen of exon-level expression data. Genes Chromosomes Cancer. 2012 Feb;51 ⑵:127-39. PMID:22034177 3232. Wang L, Ren W, Zhou X, et al. Pleomorphic liposarcoma: a clinicopathological, immunohistochemical and molecular cytogenetic study of 32 additional cases. Pathol Int. 2013 Nov;63(11):523-31. PMID:24274714 3233. Wang L, Zehir A, Sadowska J, et al. Consistent copy number changes and recurrent PRKAR1A mutations distinguish melanotic schwannomas from melanomas: SNP-array and next generation sequencing analysis. Genes Chromosomes Cancer. 2015 Aug;54(8):463-71. PMID:26031761 3234. Wang LL, Gannavarapu A, Kozinetz CA, et al. Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J

Natl Cancer Inst. 2003 May 7;95(9):669-74. PMID:12734318 3235. Wang LL, Levy ML, Lewis RA, et al. Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients. Am J Med Genet. 2001 Jul 22;102(1):11-7. PMID:11471165 3236. Wang LL, Perlman EJ, Vujanic GM, et al. Desmoplastic small round cell tumor of the kidney in childhood. Am J Surg Pathol. 2007 Apr;31 ⑷:576-84. PMID:17414105 3237. Wang LL, Pion SE. Rothmund-Thomson syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1999 Oct 6 [updated 2019 Jan 3]. PMID:20301415 3238. Wang R, Lu YJ, Fisher C, et al. Characterization of chromosome aberrations associated with soft-tissue leiomyosarcomas by twenty-four-color karyotyping and comparative genomic hybridizatio n analysis. Genes Chromosomes Cancer. 2001 May;31 (1):54-64. PMID:11284036 3239. Wang WL, Bones-Valentin RA, Prieto VG, et al. Sarcoma metastases to the skin: a clinicopathologic study of 65 patients. Cancer. 2012 Jun 1;118(11):2900-4. PMID:21989966 3240. Wang WL, Evans HL, Meis JM, et al. FUS rearrangements are rare in 'pure' sclerosing epithelioid fibrosarcoma. Mod Pathol. 2012 Jun;25(6):846-53. PMID:22388756 3241. Wang WL, Mayordomo E, Zhang W, et al. Detection and characterization of EWSR1/ ATF1 and EWSR1/CREB1 chimeric transcripts in clear cell sarcoma (melanoma of soft parts). Mod Pathol. 2009 Sep;22(9):1201-9. PMID:19561568 3242. Wang WL, Nero C, Pappo A, et al. CTNNB1 genotyping and APC screening in pediatric desmoid tumors: a proposed algorithm. Pediatr Dev Pathol. 2012 SepOct;15(5):361-7. PMID:22372443 3243. Wang WL, Patel NR, Caragea M, et al. Expression of ERG, an Ets family transcription factor, identifies ER&rearranged Ewing sarcoma. Mod Pathol. 2012 Oct;25(10):137883. PMID:22766791 3244. Wang WL, Torres-Cabala C, Curry JL, et al. Metastatic atypical fibroxanthoma: a series of 11 cases including with minimal and no subcutaneous involvement. Am J Dermatopathol. 2015 Jun;37(6):455-61. PMID:25590287 3245. Wang X, Asmann YW, EricksonJohnson MR, et al. High-resolution genomic mapping reveals consistent amplification of the fibroblast growth factor receptor substrate 2 gene in well-differentiated and dedifferentiated liposarcoma. Genes Chromosomes Cancer. 2011 Nov;50(11):849-58. PMID:21793095 3246. Wang X, Haswell JR, Roberts CW. Molecular pathways: SWI/SNF (BAF) complexes are frequently mutated in cancer­ mechanisms and potential therapeutic insights. Clin Cancer Res. 2014 Jan 1;20(1):21-7. PMID:24122795 3247. Wang Y, Marino-Enriquez A, Bennett RR, et al. Dystrophin is a tumor suppressor in human cancers with myogenic programs. Nat Genet. 2014 Jun;46(6):601-6. PMID:24793134 3248. Warren M, Turpin BK, Mark M, et al. Un differentiated myxoid lipoblastoma with PLAG1-HAS2 fusion in an infant; morphologically mimicking primitive myxoid mesenchymal tumor of infancy (PMMTI)diagnostic importance of cytogenetic and molecular testing and literature review. Cancer Genet. 2016 Jan-Feb;209(1-2):21-9. PMID:26701195 3249. Warren M, Xu D, Li X. Gene fusions PAFAH1B1-USP6 and RUNX2-USP6 in aneurysmal bone cysts identified by next

Refere nces

593

paybal：https://www.paypal.me/andy19801210 generation sequencing. Cancer Genet. 2017 Apr;212-213:13-8. PMID:28449806 3250. Warsame R, Gertz MA, Lacy MQ, et al. Trends and outcomes of modern staging of solitary plasmacytoma of bone. Am J Hematol. 2012Jul;87⑺:647-51. PMID:22549792 3251. Watanabe K, Suzuki T. Epithelioid fibrosarcoma of the ovary. Virchows Arch. 2004 Oct;445(4):410-3. PMID:15322876 3252. Waters BL, Panagopoulos I, Allen EF. Genetic characterization ofangiomatoid fibrous histiocytoma identifies fusion of the FUS and ATF-1 genes induced by a chromosomal translocation involving bands 12q13 and 16p11. Cancer Genet Cytogenet. 2000 Sep;121(2):109-16. PMID:11063792 3253. Watson 8, Perrin V, Guillemot D, et al. Transcriptomic definition of molecular subgroups of small round cell sarcomas. J Pathol. 2018 May;245(1):29-40. PMID:29431183 3254. Weatherby RP, Dahlin DC, Ivins JC. Postradiation sarcoma of bone: review of 78 Mayo Clinic cases. Mayo Clin Proc. 1981 May;56(5):294-306. PMID:6939953 3255. Weber DM. Solitary bone and extramedullary plasmacytoma. Hematology Am Soc Hematol Educ Program. 2005;373-6. PMID:16304406 3256. Weber MA, Papakonstantinou O, Nikodinovska VV, et al. Ewing's sarcoma and primary osseous lymphoma: spectrum of imaging appearances. Semin Musculoskelet Radiol. 2019 Feb;23(1):36-57. PMID:30699452 3257. Webster P, Wujanto L, Fisher C, et al. Malignancies confined to disused arteriovenous fistulae in renal transplant patients: an important differential diagnosis. Am J Nephrol. 2011;34(1):42-8. PMID:21659738 3258. Wegert J, Vokuhl C, Collord G, et al. Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants. Nat Commun. 2018 Jun 18;9(1):2378. PMID:29915264 3259. Wehrli BM, Weiss SW, Yandow S, et al. Gardner-associated fibromas (GAF) in young patients: a distinct fibrous lesion that identifies unsuspected Gardner syndrome and risk for fibromatosis. Am J Surg Pathol. 2001 May;25(5):645-51. PMID:11342777 3260. Wei S, Dumas A, Zhang PJ, et al. Palisading and Verocay body-prominent dermatofibrosarcoma protuberans: a case report. Pathol Res Pract. 2016 Feb;212(2):1457. PMID:26725533 3261. Wei S, Pan Z, Siegal GP, et al. Complex analysis of a recurrent pleomorphic hyalinizing angiectatic tumor of soft parts. Hum Pathol. 2012 Jan;43(1):121-6. PMID:21733556 3262. Weibolt VM, Buresh CJ, Roberts CA, et al. Involvement of 3q21 in nodular fasciitis. Cancer Genet Cytogenet. 1998 Oct 15;106(2):177-9. PMID:9797787 3263. Weidner N, Santa Cruz D. Phosphaturic mesenchymal tumors. A polymorphous group causing osteomalacia or rickets. Cancer. 1987 Apr 15;59(8): 1442-54. PMID:3545439 3264. Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: a fatal attraction. Nat Rev Cancer. 2011 Jun;11 (6):411-25. PMID:21593787 3265. Weingertner N, Neuville A, Chibon F, et al. Myxoid liposarcoma with heterologous components: dedifferentiation or metaplasia? A FISH-documented and CGH-documented case report. Appl Immunohistochem Mol Morphol. 2015 Mar;23(3):230-5. PMID:25747531 3266. Weinstein LS, Shenker A, Gejman PV, et al. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med. 1991 Dec 12;325(24):1688-95. PMID:1944469

594

References

3267. Weiss A, Khoury JD, Hoffer FA, et al. Telangiectatic osteosarcoma: the St. Jude Children's Research Hospital's experience. Cancer. 2007 Apr 15;109(8):1627-37. PMID:17351949 3268. Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carci noma. Cancer. 1982 Sep 1;50(5):970-81. PMID:7093931 3269. Weiss SW, Ishak KG, Dail DH, et al. Epithelioid hemangioendothelioma and related lesions. Semin Diagn Pathol. 1986 Nov;3⑷：259-87. PMID:3303234 3270. Weiss SW, Rao VK. Well-differentiated liposarcoma (atypical lipoma) of deep soft tissue of the extremities, retroperitoneum, and miscellaneous sites. A follow-up study of 92 cases with analysis of the incidence of "dedifferentiation". Am J Surg Pathol. 1992 Nov;16(11):1051-8. PMID:1471725 3271. Welborn J, Fenner S, Parks R. Angioleiomyoma: a benign tumor with karyotypic aberrations. Cancer Genet Cytogenet. 2010 Jun;199(2):147-8. PMID:20471520 3272. Wenger DE, Wold LE. Benign vascular lesions of bone: radiologic and pathologic features. Skeletal Radiol. 2000 Feb;29(2):6374. PMID:10741493 3273. Wenger DE, Wold LE. Malignant vascular lesions of bone: radiologic and pathologic features. Skeletal Radiol. 2000 Nov;29(11):619-31. PMID:11201031 3274. West DS, Dogan A, Quint PS, et al. Clonally related follicular lymphomas and Langerhans cell neoplasms: expanding the spectrum of transdifferentiation. Am J Surg Pathol. 2013 Jul;37(7):978-86. PMID:23759932 3275. West RB, Corless CL, Chen X, et al. The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol. 2004 Jul;165(1):107-13. PMID:15215166 3276. West RB, Harvell J, Linn SC, et al. Apo D in soft tissue tumors: a novel marker for dermatofibrosarcoma protuberans. Am J Surg Pathol. 2004 Aug;28(8):1063-9. PMID:15252314 3277. West RB, Rubin BP, Miller MA, et al. A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proc Natl Acad Sci USA. 2006 Jan 17;103 ⑶:6905. PMID:16407111 3278. Westacott D, Kannu P, Stimec J, et al. Osteofibrous dysplasia of the tibia in children: outcome without resection. J Pediatr Orthop. 2017 Dec 8. PMID:29227372 3279. Wettach GR, Boyd LJ, Lawee HJ, et al. Cytogenetic analysis of a hemosiderotic fibrolipomatous tumor. Cancer Genet Cytogenet. 2008 Apr 15;182(2):140-3. PMID:18406878 3280. Whimster IW. The pathology of lymphangioma circumscriptum. Br J Dermatol. 1976 May;94(5):473-86. PMID:1268059 3281. White W, Shiu MH, Rosenblum MK, etal. Cellular schwannoma. A clinicopathologic study of 57 patients and 58 tumors. Cancer. 1990 Sep 15;66(6) :1266-75. PMID:2400975 3282. WHO Classification of Tumours Editorial Board. Digestive system tumours. Lyon (France): International Agency for Research on Cancer; 2019. (WHO classification of tumours series, 5th ed.; vol. 1). https://publications.iarc. fr/579. 3283. Wick MR, Ritter JH, Dehner LP. Malignant rhabdoid tumors: a clinicopathologic review and conceptual discussion. Semin Diagn Pathol. 1995 Aug;12(3):233-48. PMID:8545590 3284. Wick MR, Siegal GP, Unni KK, et al. Sarcomas of bone complicating osteitis

deformans (Paget's disease): fifty years' experience. Am J Surg Pathol. 1981 Jan;5(1):47-59. PMID:6941703 3285. Wicklund CL, Pauli RM, Johnston D, et al. Natural history study of hereditary multiple exostoses. Am J Med Genet. 1995 Jan 2;55(1):43-6. PMID:7702095 3286. Widemann BC. Current status of sporadic and neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors. Curr Oncol Rep. 2009 Jul;11(4):322-8. PMID:19508838 3287. Widhe B, Widhe T. Initial symptoms and clinical features in osteosarcoma and Ewing sarcoma. J Bone Joint Surg Am. 2000 May;82(5):667-74. PMID:10819277 3288. Wiegand S, Eivazi B, Barth PJ, et al. Pathogenesis of lymphangiomas. Virchows Arch. 2008 Jul;453(1):1-& PMID:18500536 3289. Wierdl M.Tsurkan L, Chi L, et al. Targeting ALK in pediatric RMS does not induce antitumor activity in vivo. Cancer Chemother Pharmacol. 2018Aug;82(2):251-63. PMID:29855693 3290. Wile AG, Evans HL, Romsdahl MM. Leiomyosarcoma of soft tissue: a clinicopathologic study. Cancer. 1981 Aug 15;48(4):1022-32. PMID:7272926 3291. Wilken JJ, Meier FA, Kornstein MJ. Kaposiform hemangioe ndothelioma of the thymus. Arch Pathol Lab Med. 2000 Oct; 124(10):1542-4. PMID:11035594 3292. Wilkerson BW, Crim JR, Hung M, et al. Characterization of synovial sarcoma calcification. AJR Am J Roentgenol. 2012 Dec;199(6):W730-4. PMID:23169746 3293. Willems SM, Debiec-Rychter M, Szuhai K, et al. Local recurrenee of myxofibrosarcoma is associated with increase in tumour grade and cytogenetic aberrations, suggesting a multistep tumour progression model. Mod Pathol. 2006 Mar;19(3):407-16. PMID:16415793 3294. Willems SM, Mohseny AB, Balog C, et al. Cellular/intvmuscular myxoma and grade I myxofibrosarcoma are characterized by distinct genetic alterations and specific composition of their extracellular matrix. J Cell Mol Med. 2009 Jul;13⑺:1291-301. PMID:19320777 3295. Willeumier JJ, van der Hoeven NM, Bollen L, etal. Epidermal growth factor receptor mutations should be considered as a prognostic factor for survival of patients with pathological fractures or painful bone metastases from non-small cell lung cancer. Bone Joint J. 2017 Apr;99-B⑷:516-21. PMID:28385942 3296. William J, Laskin W, Nayar R, et al. Diagnosis of phosphaturic mesenchymal tumor (mixed connective tissue type) by cytopathology. Diagn Cytopathol. 2012 Aug;40 Suppl 2:E109-13. PMID:22927293 3297. Williams A, Bartie G, Sumathi VP, et al. Detection of ASPL/TFE3 fusion transcripts and the TFE3 antigen in formalin-fixed, paraffinembedded tissue in a series of 18 cases of alveolar soft part sarcoma: useful diagnostic tools in cases with unusual histological features. Virchows Arch. 2011 Mar;458(3):291300. PMID:21279521 3298. Williamson D, Missiaglia E, de Reynies A, et al. Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol. 2010 May 1;28(13):2151-8. PMID:20351326 3299. Winter L, Langrehr J, Hanninen EL. Primary angiosarcoma of the abdominal aorta: multi-row computed tomography. Abdom Imaging. 2010 Aug;35(4):485-7. PMID:19462198 3300. Wittkop B, Davies AM, Mangham DC. Primary synovial chondromatosis and synovial chondrosarcoma: a pictorial review. Eur Radiol. 2002Aug;12(8):2112-9. PMID:12136332

3301. Wojcik J, Rosenberg AE, Bredella MA, et al. Denosumab-treated giant cell tumor of bone exhibits morphologic overlap with malignant giant cell tumor of bone. Am J Surg Pathol 2016 Jan;40(1):72-80. PMID:26414220 ' 3302. Wojcik JB, Bellizzi AM, Dal Cin P, et al Primary sclerosing epithelioid fibrosarcoma of bone: analysis of a series. Am J Surg Pathol 2014 Nov;38(11):1538-44. PMID:24921641 3303. Wold LE, Unni KK, Beabout JW, et al. Dedifferentiated parosteal osteosarcoma, j Bone Joint Surg Am. 1984 Jan;66(1) *53-9 PMID:6581170 3304. Wold LE, Unni KK, Beabout JW, et al. Hemangioendothelial sarcoma of bone Am J Surg Pathol. 1982 Jan;6(1):59-70 PMID:7200731 3305. Wong NL. Fine needle aspiration cytology of pseudosarcomatous reactive proliferative lesions of soft tissue. Acta Cytol. 2002 NovDec;46(6):1049-55. PMID:12462081 3306. Wong YP, Chia WK, Low SF, et al. Dendritic fibromyxolipoma: a variant of spindle cell lipoma with extensive myxoid change, with cytogenetic evidence. Pathol Int. 2014 Jul;64(7):346-51. PMID:25047505 3307. Wood LD, Noe M, Hackeng W, et al. Patients with McCune-Albright syndrome have a broad spectrum of abnormalities in the gastrointestinal tract and pancreas. Virchows Arch. 2017 Apr;470(4):391-400 PMID:28188442 3308. Woodruff JM, Godwin TA, Erlandson RA, et al. Cellular schwannoma: a variety of schwannoma sometimes mistaken for a malignant tumor. Am J Surg Pathol. 1981 Dec;5(8):733-44. PMID:7337161 3309. Woodruff JM, Scheithauer BW, KurtkayaYapicier O, et al. Congenital and childhood plexiform (multinodular) cellular schwannoma: a troublesome mimic of malignant peripheral nerve sheath tumor. Am J Surg Pathol. 2003 Oct;27(10):1321-9. PMID:14508393 3310. Woodruff JM, Selig AM, Crowley K, et al. Schwannoma (neurilemoma) with malignant transformation. A rare, distinctive peripheral nerve tumor. Am J Surg Pathol. 1994 Sep;18(9):882-95. PMID:8067509 3311. Worch J, Cyrus J, Goldsby R, et al. Racial differences in the incidence of mesenchymal tumors associated with EWSR1 translocation. Cancer Epidemiol Biomarkers Prev. 2011 Mar;20(3):449-53. PMID:21212061 3312. Wu CC, Shete S, Amos Cl, et al. Joint effects of germ-line p53 mutation and sex on cancer risk in Li-Fraumeni syndrome. Cancer Res. 2006 Aug 15;66(16):8287-92. PMID:16912210 3313. Wu CT, Inwards CY, O'Laughlin S, et al. Chondromyxoid fibroma of bone: a clinicopathologic review of 278 cases. Hum Pathol. 1998 May;29(5):438-46. PMID:9596266 3314. Wu H, Bui MM, Zhou L, et al. Phosphaturic mesenchymal tumor with an admixture of epithelial and mesenchymal elements in the jaws: clinicopathological and immunohistochemical analysis of 22 cases with literature review. Mod Pathol. 2019 Feb;32Q:189—204. PMID:30206408 3315. Wu J, Brinker DA, Haas M, et al. Primary alveolar soft part sarcoma (ASPS) of the breast: report of a deceptive case with xanthomatous features confirmed by TFE3 immunohistochemistry and electron microscopy. Int J Surg Pathol. 2005 Jan;13(1):81-5. PMID:15735860 3316. Wu J, Tian W, Tian G, et al. An investigation of PIK3CA mutations in isolated macrodactyly. J Hand Surg Eur Vol. 2018 Sep;43(7):756-60. PMID:29661094 3317. Wunder JS, Eppert K, Burrow SR, et al. Co-amplification and overexpression of CDK4,

paybal：https://www.paypal.me/andy19801210 SAS and MDM2 occurs frequently in human parosteal osteosarcomas. Oncogene. 1999 Jan 21;18(3):783-8. PMID:9989829 3318. Wurlitzer F, Ayala L, Romsdahl M. Extraosseous osteogenic sarcoma. Arch Surg. 1972 Nov;105(5):691-5. PMID:4507677 3319. Wurtz LD, Peabody TD, Simon MA Delay in the diagnosis and treatment of primary bone sarcoma of the pelvis. J Bone Joint Surg Am. 1999 Mar;81 (3):317-25. PMID:10199269 3320. Wuyts W, Cleiren E, Homfray T, et al. The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500). J Med Genet. 2000 Dec;37(12):916-20. PMID:11106354 3321. Wuyts W, Van Hui W, Wauters J, et al. Positional cloning of a gene involved in hereditary multiple exostoses. Hum Mol Genet. 1996 Oct;5(10):1547-57. PMID:8894688 3322. Xia L, Chen Y, Geng N, et al. Multifocal myopericytoma in the maxillofacial region: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010 Feb;109(2):e59-62. PMID:20123399 3323. Xie GP, Jiang N, Liang CX, et al. Pigmented villonodular synovitis: a retrospective multicenter study of 237 cases. PLoS One. 2015 Mar 23;10(3):e0121451. PMID:25799575 3324. Xie GP, Song HJ, Jiang N.etal. Periosteal osteosarcoma and Marfan's syndrome: a case report and literature review. Oncol Lett. 2016 Jan;11(1):311-5.PMID:26870209 3325. Xu J, Li D, Xie L, et al. Mesenchymal chondrosarcoma of bone and soft tissue: a systematic review of 107 patients in the past 20 years. PLoS One. 2015 Apr 7;10(4):e0122216. PMID:25849226 3326. Yadav R, Sharma MC, Malgulwar PB, et al. Prognostic value of MIB-1, p53, epidermal growth factor receptor, and INI1 in childhood chordomas. Neuro Oncol. 2014 Mar;16(3):37281.PMID:24305715 3327. Yamada Y, Kinoshita I, Kenichi K, et al. Histopathological and genetic review of phosphaturic mesenchymal tumours, mixed connective tissue variant. Histopathology. 2018 Feb;72⑶:460-71. PMID:28858396 、 3328. Yamada Y, Kinoshita I, Kohashi K, et al. HIF-1a, MDM2, CDK4, and p16 expression in ischemic fasciitis, focusing on its ischemic condition. VirchowsArch.2017 Jul;471(1):11722. PMID:28477272 3329. Yamada Y, Kuda M, Kohashi K, et al. His⑹ogical and immunohistochemical characteristics of undifferentiated small「ound cell sarcomas associated with CIC-DUX4 and BCOR-CCNB3 fusion genes. Virchows Arch. 2017 Apr;470(4):373-80. PMID:28197724 3330. Yamada Y, Yamamoto H, Kohashi K, et al. Histological spectrum of angiofibroma of soft tissue: histological and genetic analysis of 13 cases. Histopathology. 2016 Sep;69⑶:45969. PMID:26845637 3331. Yamaguchi T, Dorfman HD. Radiographic and histologic patterns of calcification in chondromyxoid fibroma. Skeletal Radiol. 1998 Oct;27(10):559-64. PMID:9840392 3332. Yamaguchi T, Imada H, lida S, et al. Notochordal tumors: an update on molecular 阳 thology with therapeutic implications. Surg Pathol Clin. 2017 Sep;10⑶:637-56. PMID:28797506 3333. Yamaguchi T, Iwata J, Sugihara 8, et al. Distinguish!ng benign notochordal cell tumors from vertebral chordoma. Skeletal Radiol. 2008 Apr;37 ⑷:291—9.PMID:18188556 3334. Yamaguchi T, Suzuki S, Ishiiwa H, et al. Intraosseous benign notochordal cell tumours: overlooked precursors of classic chordomas? Histopathology. 2004 Jun;44(6):597-602.

PMID:15186275 3335. Yamaguchi U, Hasegawa T, HiroseT.etal. Sclerosing perineurioma: a clinicopathological study of five cases and diagnostic utility of immunohistochemical staining for GLUT1. Virchows Arch. 2003 Aug;443(2):159-63. PMID:12836021 3336. Yamamoto H, Handa M, Tobo T, et al. Clinicopathological features of primary leiomyosarcoma of the gastrointestinal tract following recognition of gastrointestinal stromal tumours. Histopathology. 2013 Aug;63(2):194207. PMID:23763337 3337. Yamamoto H, Iwasaki T, Yamada Y, et al. Diagnostic utility of histone H3.3 G34W, G34R, and G34V mutant-specific antibodies for giant cell tumors of bone. Hum Pathol. 2018 Mar;73:41-50. PMID:29241742 3338. Yamamoto H, Kohashi K, Oda Y, et al. Absence of human herpesvirus-8 and EpsteinBarr virus in inflammatory myofibroblastic tumor with anaplastic large cell lymphoma kinase fusion gene. Pathol Int. 2006 Oct;56(10):58490. PMID:16984614 3339. Yamamoto H, Yoshida A, Taguchi K, etal. ALK, ROS1 and NTRK3 gene rearrangements in inflammatory myofibroblastic tumours. Histopathology. 2016 Jul;69(1 ):72-83. PMID:26647767 3340. Yamashita K, Fletcher CD. PEComa presenting in bone: clinicopathologic analysis of 6 cases and literature review. Am J Surg Pathol. 2010 Nov;34⑴):1622-9. PMID:20975340 3341. Yamashita K, Kohashi K, Yamada Y, et al. Osteogenic differentiation in dedifferentiated liposarcoma: a study of 36 cases in comparison to the cases without ossification. Histopathology. 2018Apr;72(5):729-38. PMID:29076540 3342. Yamashita K, Kohashi K, Yamada Y, et al. Primary extraskeletal osteosarcoma: a clinicopathological study of 18 cases focusing on MDM2 amplification status. Hum Pathol. 2017 May;63:63-9. PMID:28235629 3343. Yamato M, Ikota H, Hanakita J, et al. Intradural extramedullary spinal nerve sheath myxoma: a report of two cases. Brain Tumor Pathol. 2014 Jan;31(1):57-61.PMID:23306964 3344. Yamazaki F, Nakatani F, Asano N, et al. Novel NTRK3 fusions in fibrosarcomas of adults. Am J Surg Pathol. 2019 Apr;43(4):52330,PMID:30520818 3345. Yan AC, Chamlin SL, Liang MG, et al. Congenital infantile fibrosarcoma: a masquerader of ulcerated hemangioma. Pediatr Dermatol. 2006 Jul-Aug;23(4):330-4. PMID:16918626 3346. Yang CY, Liau JY, Huang WJ, et al. Targeted next-generation sequencing of cancer genes identified frequent TP53 and ATRX mutations in leiomyosarcoma. Am J Transl Res. 2015 Oct 15;7(10):2072-81. PMID:26692951 3347. Yang FC, Ingram DA, Chen S, et al. Nf1dependent tumors require a microenvironment containing Nf1 +/- and c-kit-d即endent bone marrow. Cell. 2008 Oct 31;135(3):437-48. PMID:18984156 3348. Ya ng J, Du X, Chen K, et al. Genetic aberrations in soft tissue leiomyosarcoma. Cancer Lett. 2009 Mar 8;275(1):1-8. PMID:18649996 3349. Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol. 1998 Jan;16(1):197-203. PMID:9440743 3350. Yang L, Chen Y, Cui T, et al. Identification of biomarkers to distinguish clear cell sarcoma from malignant melanoma. Hum Pathol. 2012 Sep;43(9):1463-70. PMID:22406360 3351. Yang L, Tang W. Pelvic lipomatosis with ureteral calculi managed by flexible

ureteroscopy: a case report. Medicine 但 altimore). 2019 Jan;98 ⑷:"4265. PMID:30681625 3352. Yang S, Zheng X, Lu C, et al. Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase. Genes Dev. 2016 Jul 15;30(14):1611-6. PMID:27474439 3353. Yang SH, LeBoit PE. Angiomatous kaposi sarcoma: a variant that mimics hemangiomas. Am J Dermatopathol. 2014 Mar;36(3):229-37. PMID:24067801 3354. Yang XR, Ng D, Alcorta DA, et al. T (brachyury) gene duplication confers major susceptibility to familial chordoma. Nat Genet. 2009 Nov;41(11):1176-8. PMID:19801981 3355. Yang Yj Damron TA, Ambrose JL. Diagnosis of chondroid lipoma by fine-needle aspiration biopsy. Arch Pathol Lab Med. 2001 Sep;125(9):1224-6. PMID:11520278 3356. Yap YS, Munusamy P, Um C, et al. Breast cancer in women with neurofibromatosis type 1 (NF1): a comprehensive case series with molecular insights into its aggressive phenotype. Breast Cancer Res Treat. 2018 Oct;171 (3):719-35. PMID:29926297 3357. Yarmish G, Klein MJ, Landa J, et al. Imaging characteristics of primary osteosarcoma: nonconventional subtypes. Radiographics. 2010 Oct;30(6):1653-72. PMID:21071381 3358. Yasuda T, Perry KD, Nelson M, et al. Alveolar rhabdomyosarcoma of the head and neck region in older adults: genetic characterization and a review of the literature. Hum Pathol. 2009 Mar;40 ⑶:341-8. PMID:18973919 3359. Yau DTW, Chan JKC, Bao S, et al. Bone sarcoma with EWSR1-NFATC2 fusion: sarcoma with varied morphology and amplification of fusion gene distinct from Ewing sarcoma. Int J Surg Pathol. 2019 Aug;27(5):561-7. PMID:30714449 3360. Ye ZX, Yang C, Chen MJ, et al. Juxtaarticular myxoma of the temporomandibular joint. J Craniofac Surg. 2015 Nov;26(8):e695-6. PMID:26594976 3361. Yi ES, Shmookler BM, Malawer MM, et al. Well-differentiated extraskeletal osteosarcoma. A soft-tissue homologue of parosteal osteosarcoma. Arch Pathol Lab Med. 1991 Sep;115(9):906-9. PMID:1929787 3362. Yi J, Lee YH, Kim SK, et al. Response evaluation of giant-cell tumor of bone treated by denosumab: histogram and texture analysis of CT images. J Orthop Sci. 2018 May;23(3):5707. PMID:29429890 3363. Yi X, Wang J, Zhang Y, et al. Renal solitary fibrous tumor/hemangiopericytoma: computed tomography findings and clinicopathologic features. Abdom Radiol (NY). 2019 Feb;44(2):642-51. PMID:30225611 3364. Yohe ME, Gryder BE, Shern JF, et al. MEK inhibition induces MYOG and remodels super­ enhancers in RAS-driven rhabdomyosarcoma. Sci Transl Med. 2018 Jul 4;10(448):eaan4470. PMID:29973406 3365. Yokoyama R, Tsuneyoshi M, Enjoji M, et al. Prognostic factors of malign ant fibrous histiocytoma of bone. A clinical and histopathologic analysis of 34 cases. Cancer. 1993 Sep 15;72(6):1902-8. PMID:8364866 3366. Yong M, Raza AS, Greaves TS, et al. Fine-needle aspiration of a pleomorphic lipoma of the head and neck: a case report. Diagn Cytopathol. 2005 Feb;32(2):110-3. PMID:15637670 3367. Yoo HJ, Hong SH, Choi JY, et al. Differentiating high-grade from low-grade chondrosarcoma with MR imaging. Eur Radiol. 2009 Dec;19(12):3008-14. PMID:19547983 3368. Yoshida A, Arai Y, Kobayashi E, et al. CIC break-apart fluorescence in-situ

hybridization misses a subset of CIC-DUX4 sarcomas: a clinicopathological and molecular study. Histopathology. 2017 Sep;71(3):461-9. PMID:28493604 ' 3369. Yoshida A, Asano N, Kawai A, et al. Differential SALL4 immunoexpressio n in malignant rhabdoid tumours and epithelioid sarcomas. Histopathology. 2015 Jan;66(2):252-61. PMID:24827994 3370. Yoshida A, Goto K, Kodaira M, et al. CIC-rearranged sarcomas: a study of 20 cases and comparisons with Ewing sarcomas. Am J Surg Pathol. 2016 Mar;40(3):313-23. PMID:26685084 3371. Yoshida A, Tsuta K, Ohno M, et al. STAT6 immunohistochemistry is helpful in the diagnosis of solitary fibrous tumors. Am J Surg Pathol. 2014Apr;38⑷:552-9. PMID:24625420 3372. Yoshida A, Ushiku T, Motoi T, et al. Immunohistochemical analysis of MDM2 and CDK4 distinguishes low-grade osteosarcoma from benign mimics. Mod Pathol. 2010 Sep;23(9):1279-88. PMID:20601938 3373. Yoshida A, Ushiku T, Motoi T, etal. MDM2 and CDK4 immunohistochemical coexpression in high-grade osteosarcoma: correlation with a dedifferentiated subtype. Am J Surg Pathol. 2012 Mar;36(3):423-31. PMID:22301501 3374. Yoshida A, Ushiku T, Motoi T, et al. Well-differentiated liposarcoma with lowgrade osteosarcomatous component: an underrecognized variant. Am J Surg Pathol. 2010 Sep;34(9):1361-6. PMID:20697254 3375. Yoshida H, Miyachi M, Ouchi K, et al. Identification of COL3A1 and RAB2A as novel translocation partner genes of PLAG1 in lipoblastoma. Genes Chromosomes Cancer. 2014 Jul;53⑺:606-11. PMID:24700772 3376. Yoshida KI, Nakano Y, Honda-Kitahara M, et al. Absence of H3F3A mutation in a subset of maligna nt giant cell tumor of bone. Mod Pathol. 2019 Dec;32(12):1751-61. PMID:31285528 3377. Yoshimoto T, Tanaka M, Homme M, et al. CIC-DUX4 induces small round cell sarcomas distinct from Ewing sarcoma. Cancer Res. 2017 Jun 1;77(11):2927-37. PMID:28404587 3378. Young JR, Sternbach S, Willinger M, et al. The etiology, evaluation, and management of plantar fibromatosis. Orthop Res Rev. 2018 Dec17;11:1-7. PMID:30774465 3379. Younga J, Mott M, Hammoud ZT. Venous hemangioma presenting as a s叩erio「sulcus tumor. Ann Thorac Surg. 2010 Dec;90(6):20335. PMID:21095359 3380. Youssefian L, Vahidnezhad H, Touati A, et al. The genetic basis of hyaline fibromatosis syndrome in patients from a consanguineous background: a case series. BMC Med Genet. 2018 May 25;19(1):87. PMID:29801470 3381. Yu Y, Demierre MF, Mahalingam M. Anaplastic Kaposi's sarcoma: an uncommon histologic phe notype with an aggressive clin ical course. J Cutan Pathol. 2010 Oct;37(10):108891,PMID:19638066 3382. Zagars GK, Ballo MT, Pisters PW, et al. Prognostic factors for patients with localized soft-tissue sarcoma treated with conservation surgery and radiation therapy: an analysis of 1225 patients. Cancer. 2003 May 15;97(10):2530-43. PMID:12733153 3383. Zahm SH, Fraumeni JF Jr. The epidemiology of soft tissue sarcoma. Semin Oncol. 1997 Oct;24(5):504-14. PMID:9344316 3384. Zambrano E, Nose V, Perez-Atayde AR, et al. Distinct chromosomal rearrangements in subungual (Dupuytren) exostosis and bizarre parosteal osteochondromatous proliferation (Nora lesion). Am J Surg Pathol. 2004 Aug;28(8):1033-9. PMID:15252309 3385. Zamecnik M, Michal M. Angiomatous spindle cell lipoma: report of three cases with immunohistochemical and ultrastructural study

Refere nces

595

paybal：https://www.paypal.me/andy19801210 and reappraisal of former 'pseudoangiomatous' variant. Pathol Int. 2007 Jan;57(1):26-31. PMID:17199739 3386. Zamecnik M, Michal M. EMA+ cells in dermatofibrosarcoma protuberans. A study of 11 tumors suggesting perineurial cell differentiation. Cesk Patol. 2002 Apr;38(2):5562. PMID:12426982 3387. Zamecnik M, Michal M, Simpson RH, et al. Ossifying fibromyxoid tumor of soft parts: a report of 17 cases with emphasis on unusual histological features. Ann Diagn Pathol. 1997 Dec;1(2)73-81. PMID:9869828 3388. Zamolyi RQ, Souza P, Nascimento AG, et al. Intraabdominal myositis ossificans: a report of 9 new cases. Int J Surg Pathol. 2006 Jan;14(1):37-41.PMID:16501833 3389. Zehetgruber H, Bittner B, Gruber D, et al. Prevalence of aneurysmal and solitary bone cysts in young patients. Clin Orthop Relat Res. 2005 Oct;439(439):136-43. PMID:16205152 3390. Zelger B, Weinlich G, Zelger B. Perineuroma. A frequently unrecognized entity with emphasis on a plexiform variant. Adv Clin Path. 2000 Jan;4(1):25-33. PMID:10936896 3391. Zelger BW, Zelger BG, Plorer A, et al. Dermal spindle cell lipoma: plexiform and nodular variants. Histopathology. 1995 Dec;27(6):533-40. PMID:8838333 、 3392. Zhang H, Macdonald WD, EricksonJohnson M, et al. Cytogenetic and molecular cytogenetic findings of intimal sarcoma. Cancer Genet Cytogenet. 2007 Dec;179(2):146-9. PMID:18036403 3393. Zhang HY, Yang GH, Chen HJ, et al. Clinicopathological, immunohistochemical, 3nd ultrastructural study of 13 cases of melanotic schwannoma. Chin Med J (Engl). 2005 Sep 5;118(17):1451-61. PMID:16157048

596

Refere nces

3394. Zhang J, Walsh MF, Wu G, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2015 Dec 10;373(24):2336-46. PMID:26580448 3395. Zhang L, Smyrk TC, Young WF Jr, et al. Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases. Am J Surg Pathol. 2010 Jan;34(1):5364. PMID:19935059 3396. Zhang M, Wang Y, Jones S, et al. Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. Nat Genet. 2014 Nov;46(11):1170-2. PMID:25305755 3397. Zhang Y, Paz Mejia A, Temple HT, et al. Squamous cell carcinoma arising in dedifferentiated chondrosarcoma proved by isocitrate dehydrogenase mutatio n analysis. Hum Pathol. 2014 Jul;45(7):1541-5. PMID:24792622 3398. Zhang YX, van Oosterwijk JG, Sicinska E, et al. Functional profiling of receptor tyrosine kin ases and down stream signaling in huma n chondrosarcomas identifies pathways for rational targeted therapy. Clin Cancer Res. 2013 Jul 15;19(14):3796-807. PMID:23714727 3399. Zhao C, Gao X, Yang J, et al. Surgical management and outcome of spinal alveolar soft part sarcoma (ASPA): a case series of five patients and literature review. World J Surg Oncol. 2017 Feb 6;15(1):39. PMID:28166791 3399A. Zhao J, Roth J, Bode-Lesniewska B, et al. Combined comparative genomic hybridization and genomic microarray for detection of gene amplifications in pulmonary artery intimal sarcomas and adrenocortical tumors. Genes Chromosomes Cancer. 2002 May;34(1):48-57. PMID:11921282

3400. Zhao Z, Paquette C, Shah AA, et al. Fine needle aspiration cytology of diffuse-type tenosynovial giant cell tumors. Acta Cytol. 2017;61(2):160-4. PMID:28324880 3401. Zhao Z, Yin Y, Zhang J, et al. Spindle cell/sclerosing rhabdomyosarcoma: case series from a single institution emphasizing morphology, immunohistochemistry and follow-up. Int J Clin Exp Pathol. 2015 Nov 1;8(11):13814-20. PMID:26823695 3402. Zheng L, Tang H, Chen X, et al. Paratesticular fetal-type rhabdomyoma in a 12-year-old boy: a case report and literature review. Urology. 2013 Nov;82(5):1150-2. PMID:23768526 3403. Zhou P, Zhang H, Bu H, et al. Paravertebral glomangiomatosis. Case report. J Neurosurg. 2009 Aug;111 (2):272-7. PMID:19267531 ' 3404. Zhou Q, Lu L, Fu Y, et al. Epithelioid hemangioma of bone: a report of two special cases and a literature review. Skeletal Radiol. 2016 Dec;45(12):1723-7. PMID:27660230 3405. Zhu G, Benayed R, Ho C, et al. Diagnosis of known sarcoma fusions and novel fusion partners by targeted RNA sequencing with identification of a recurrent ACTB-FOSB fusion in pseudomyogenic hemangioendothelioma. Mod Pathol. 2019 May;32(5):609-20. PMID:30459475 3406. Zillmer DA, Dorfman HD. Chondromyxoid fibroma of bone: thirty-six cases with clinicopathologic correlation. Hum Pathol. 1989 Oct;20(10):952-64. PMID:2793160 3407. Zreik RT, Carter JM, Sukov WR, et al. TGFBR3 and MGEA5 rearrangements are much more common in "hybrid" hemosiderotic fibrolipomatous tumor-myxoinflammatory fibroblastic sarcomas than in classical

myxoinflammatory fibroblastic sarcomas: a morphological and fluorescence in situ hybridization study. Hum Pathol. 2016 Jul;53:14-24. PMID:26980036 3408. Zreik RT, Fritchie KJ. Morphologic spectrum of desmoid-type fibromatosis. Am J Clin Pathol. 2016 Mar;145(3):332-40 PMID:27124915 3409. Zucman J, Delattre O, Desmaze C, et al. EWS and ATF-1 gene fusion induced' by t(12;22) translocation in malignant melanoma of soft parts. Nat Genet. 1993 Aug;4(4):341-5 PMID:8401579 3410. Zukerberg LR, Nickoloff BJ, Weiss SW. Kaposiform hemangioendothelioma of infancy and childhood. An aggressive neoplasm associated with Kasabach-Merritt syndrome and lymphangiomatosis. Am J Surg Pathol. 1993Apr;17(4):321-8. PMID:8494101 3411. Zuntini M, Pedrini E, Parra A, et al. Genetic models of osteochondroma onset and neoplastic progression: evidence for mechanisms alternative to EXT genes inactivation. Oncogene. 2010 Jul 1;29(26):3827-34. PMID:20418910 3412. Zuo QY, Wang H, Li W, et al. Treatment and outcomes of tumor-induced osteomalacia associated with phosphaturic mesenchymal tumors: retrospective review of 12 patients. BMC Musculoskelet Disord. 2017 S 即 21;18(1):403. PMID:28934935 3413. Zurick AO 3rd, Lenge De Rosen V, Tan CD, et al. Pulmonary artery intimal sarcoma masquerading as pulmonary embolism. Circulation. 2011 Sep 6;124(10):1180-1. PMID:21900097

paybal：https://www.paypal.me/andy19801210

Refere nces

597

paybal：https://www.paypal.me/andy19801210 Subject index Bold page numbers indicate the main discussion(s) of the topic.

Numbers and symbols

aneurysmal bone cyst (ABC)

512

17-OH-progesterone

a-ketoglutarate a-Klotho

397-398, 404, 406, 408,

354, 502

angiofibroma

291

50, 75, 84, 88-89, 91-92, 94-95,

p-catenin

113, 224, 250-251, 334, 357, 382, 385,

atypical lipomatous tumour / well-

437-439, 459,

2, 29, 72, 80-83, 104, 107

angioleiomyoma angiolipoma

A

angiomatosis

abdominal fibromatosis

neurofibromatous neoplasm of uncertain

3, 6, 183, 186-187

biological potential (AN/ANNUBP)

2, 6-7, 23-24, 145-146

83, 238

3,

ACP5

503, 506, 508

acquired tufted haemangioma

acral fibromyxoma

2, 156

3, 78-79, 266-267

B

angiosarcoma

3-4, 6-7, 9-11,23, 159,

B2M

164-166, 174,

176-178, 231,256, 269,

ACTB

152, 170

338, 343, 389, 430, 432,

ACTH

516

503-504, 507

adamantinoma

338, 341-344, 460-466

adamanti no ma, dediffere ntiated

338,

adult fibrosarcoma

64, 503

BCLAF1

82-83

2,

96, 101, 124, 176, 191,219, 233, 376,

227

ARID1B

227

ARID5B

224

SeeALDH1A1

ALDH1A1

ASPL

110-111, 196, 206, 212, 487, 490-491

alkaline phosphatase

3, 51,

3, 11,

297-299 518

Subject index

BLM

338,

150-151

405, 503, 523, 527

BMP

357, 393, 518

110

BOC

21

40

bone infarction

ATP6AP2

240-241

brachyury

179

340, 420

343, 371,377, 449-450, 452-453,

455, 457

BRAF

40, 196, 224, 319, 406

340, 343, 353, 355, 358,

338, 346-350

blue rubber bleb naevus syndrome

272, 278, 300, 302

240-241

199

405, 503, 523

Bloom syndrome

297-299

338,

370-377, 379,

382, 452, 509, 517-518

489-491

408

Birt-Hogg-Dube syndrome

proliferation (BPOP)

306

See ASPSCR1

ATP6AP1

3, 249, 251

316

BEST3

bizarre parosteal osteochondromatous

147-148

atypical cartilaginous tumour (ACT)

224

anaplastic large cell lymphoma (ALCL)

598

ATM

ATRX

124

anastomosing haemangioma

ATF1

449-450

choristoma (NMC)

2, 143, 147,

278, 290, 300-301

ATIC

201,203-208, 405

alveolar soft part sarcoma (ASPS)

AMER1

(BNCT)

benign triton tumour / neuromuscular

BGLAP

ASPSCR1 ATF

341,441

alveolar rhabdomyosarcoma (ARMS)

AMACR

benign notochordal cell tumour

83

ASCL1

106

201,

502-503

arteriovenous haemangioma

(AVM/H)

ALDH1

ALX4

484

149

16, 90

274

Beckwith-Wiedemann syndrome

arteriovenous malformation/haemangioma

503

alcohol

ALK

BCORL1

494,497,499

ARID1A

434

AKT1

364 202, 224, 274, 319, 322-323, 327,

333-335

203

ARNT

32-33

BCOR

57, 88, 91-92, 94, 393, 503

arginase-1 (ARG1)

3, 198-200

166

AKT

334, 487, 491

ANTXR2

ARAF

AIDS-associated Kaposi sarcoma (KS)

AIP

291,304, 376, 389, 491

BCL6

APC

122-123

adult rhabdomyoma AHRR

BCL2

152, 170, 398, 428

13

199, 504

503

AP-2P

515-516

504, 523

Ban nay a n—Riley—Ruvalcaba syndrome

basal cell naevus syndrome

218

AP-1

463-466 adenylyl cyclase

434-436,

488

Baller-Gerold syndrome

ANTXR1

ANO1

368-369

224

3, 25, 187, 312-313, 505

angiomyxoma

2, 86-87

503

AXIN2

2, 78-79

2, 34-35

tumour

147, 149, 165, 180, 426-427

angiomyofibroblastoma

2, 93

234,

254, 256 atypical spindle cell / pleomorphic lipomatous

angiomyolipoma

ABL1

14, 36-38, 343

atypical neurofibroma / atypical

10,271-273

ACVR2A

differentiated liposarcoma

(ALT/WDLPS)

angiomatoid fibrous histiocytoma (AFH)

398, 423, 473, 518

ACVR1

32, 34, 36-40, 45-47, 81, 343

467-468, 471, 473

285

a-SMA

50, 53, 142,

285, 338, 342, 359-360, 364, 384,

111

5A4

2, 14, 26,

atypical lipomatous tumour (ALT)

512

androstenedione

atypical fibroxanthoma (AFX)

3, 268-270

116-117, 119-120, 180-181,

220-221,283, 288, 301,487, 493-494,

497, 499, 503

BRCA1

224, 406

BRCA2

57, 406

paybal：https://www.paypal.me/andy19801210 290

BRD9

503

BUB1B

Budd-Chiari syndrome

Burkitt lymphoma

195

338, 489-490

Buschke-Ollendorff syndrome

393, 503

C C9orf92

26

C11orf95

C19

135, 408, 487-488, 493

338-344, 352-356, 358, 360-361,363,

CD56

22, 207, 285, 487-488

369-390, 406-407, 413, 415-416,

CD57

244

418, 425, 443, 453, 455, 471,481-482,

CD61

157

503-504, 507-509, 517-518, 525-526

CD63

137, 241

CD68

135, 241,270, 272, 443, 477, 493,

chondrosarcoma, dedifferentiated

343-344, 358,

CD79B

calcifying aponeurotic fibroma

2, 74-75, 97

26, 66, 194, 197, 314

CD99

487, 491

338, 340, 343-344, 378,

chordoma

449_457> 504-505

491

75, 270, 272-273, 291,311,324-326,

chordoma, dedifferentiated

328, 331-332, 334, 386, 408

66, 111, 123, 187, 279, 283

CD117

See KIT

CHRND

calretinin

241,299, 331

CD138

328,487-488

chromogranin

CD147

297, 299

chromothripsis

CD163

135, 263, 265, 496

CD207

See CDC5L

279, 296, 310

3, 165, 172-174, 431-433

CAMTA1

capillary haemangioma CARD11

147, 426

491

CDC5

cardiofaciocutaneous syndrome

Carney complex

503

231,258-259, 365-367,

504

CDH11 CDK4

Camey-Stratakis syndrome CARS

110

CASR

57

cathepsin K

217, 504

299

143, 149, 165,

180, 285, 426-427, 506-507

CIC-rearranged sarcoma

224, 405

CITED2

438

CK1

465

174, 484 174, 296, 465

401-402, 406, 411-412, 415, 417

CK13

465

CK14

461,465 461,465

124

CDKN1C

201,503

CK17

CDKN2A

44, 124, 196, 206, 220, 224, 234,

CK18

174, 218, 384, 465

236, 254-255, 316, 318, 323, 327, 374,

CK19

296,461,465

376, 383, 405, 425, 481

CK20

484

124, 196, 487

CCND2

196, 331,487

CCND3

487

CDX1

318

CEA

124, 206, 234, 236, 254-255, 318,

CDKN2B

327

387 256

clear cell sarcoma (CCS)

cellular angiofibroma

2, 29, 72, 80-81

491

cellular angiolipoma

491

cellular epithelioid haemangioma

CD4

491

central atypical cartilaginous tumour /

CD5

487, 491

2, 23

CLTC

157 110-111,481

clusteri n c-Met

270, 276, 487, 491

CD14

496

CD19

487-488

CD20

487-488, 490-491

CHEK1

40

CD23

487

CHEK2

224, 503

COL1A1

CD24

128, 130

CHIC2

CD30

491

CHMP2B

CD31

151, 153, 155, 157-158, 160-161,

chondroblastoma

CD34

2, 22, 30, 35, 56, 60, 72-73, 77, 79,

81,83-85, 87-89, 97, 99, 102-103, 107-

108, 114-115, 120, 123, 125, 138, 151,

(ACT/CS1)

370

375

317 283

223, 33& 341-342,

359-361,383-384, 438, 443, 493 chondroid chordoma chondroid lipoma

chondroma

338, 451,453

2, 27-28

3, 217, 222-223, 338, 342,

351-353, 355, 369, 382 223, 338, 343, 368-369, 506

153, 155-158, 160-161, 165, 167, 174,

chondromatosis

177, 181, 183, 197, 218, 229, 234-236,

chondromesenchymal hamartoma of chest

238-239, 244, 253, 256, 262, 265, 267, 270, 281,283, 287-288, 291, 296, 298,

328, 427, 430, 432, 435

wall

338, 458-459

chondromyxoid fibroma 362-364

135

297

CD10

central chondrosarcoma, grades 2

CMG2

See ANTXR2

CNBP

438

CNC1

See PRKAR1A

CNC2

259, 366

53, 98-101, 103, 438

COL1A2

21

COL2A1

376, 506

COL3A1

21

COL6A3

101

COL12A1

346, 364

collagen IV

181,236, 244

collagen VI

64

Complexity Index in Sarcomas

(CINSARC)

12

composite haemangioendothelioma (CHE)

285, 338, 342, 360,

3, 11,300-302,

334 CLEC2

2, 152

chondrosarcoma, grade 1

and 3

338, 342-344,

360-361,383-384

CD2

427, 430, 432, 435

239, 246, 253

claudin-1

clear cell chondrosarcoma

CD3

165, 167, 170, 174, 177-178, 270, 408,

322-323, 330, 332

3, 211,213, 319

CK8

333-335

493-494, 496, 499

176, 319, 322-323, 327, 330-332, 434

CIC

206, 208, 224, 267, 316, 320, 376, 382,

CCND1

CD1a

36, 195, 318, 363, 405-406,

CK7

CCNB3

CCNE1

20乙 215, 484

26, 32, 35-36, 38-41,46, 196,

CDK6

cavernous haemangioma

214

512

405

CDC5L

338, 343,

454-455

calponin

CAM5.2

338,

388-390, 425, 443, 455,

471, 481-482, 518

CD79a, CD79A

5, 308

caldesmon

487-488

496

28

3, 223, 285, 303-305,

chondrosarcoma

CD38 CD45

congenital

2, 160, 163-165 3, 20-21,59, 61,96-97, 100,

119, 145, 147, 154, 157, 182, 190, 211,

Subject index

599

paybal：https://www.paypal.me/andy19801210 epithelioid haemangioma

213, 233, 309, 329, 366, 458, 512, 520,

DHEAS

522

diastase

64, 298-299, 311,367

DICER1

201,503

congenital spindle cell

rhabdomyosarcoma

COPS3

224

cortisol

512

201, 503

DLG2

Cowden syndrome

13, 248, 504

DMD

36, 40

CPS1

484 2, 49-50

C-reactive protein

CREB

epithelioid inflammatory myofibroblastic sarcoma (EIMS)

110, 341

epithelioid sarcoma (ES)

224

DOG1

218, 220, 360

DUX4

330-331

DVL2

312

484-485, 510 ERBB2 (HER2)

EBNA2

127-128, 130

EBV

130

EBV-associated smooth muscle

CREM

CSF1

134-136

136

91-92, 94-95, 202, 250-251,

CTNNB1

422-423, 438 334-335

cyclin D1

334-335, 434, 487-488

cystic lymphangioma

ETS

ectopic meningioma

111

247-248

ETV1

331

ETV4

331-332

EGF

74-75, 96

ETV5

331

ETV6

110,119-121

60, 96, 106, 202, 224, 316,

European Society for Medical Oncology

(ESMO)

106

EI24

40

EIF1

438

343-344, 404, 408, 466, 483

2, 57-58

19, 28, 83, 87, 103, 128, 131, 153, 174,

188, 211,213, 272-273, 278-279, 300-

246, 248, 250, 253, 256, 270, 272-273,

302, 304-306, 308, 319, 323, 325-329,

DCTN1

110

386, 408, 430, 432, 435, 450, 453, 465

42-44, 48, 316

denosumab

embryonal rhabdomyosarcoma (ERMS)

441,443, 445-446

dermal nerve sheath myxoma

dermatofibrosarcoma protuberans (DFSP)

2,

3,

exostoses

503-504

EXT1

pleomorphic

22, 25-26, 35, 50, 52, 56, 72-73, 79,

EML4

517

357-358, 373-374, 382, 502-503,

517-519 EXT2

3, 201

2, 76-77

tumour

6, 9, 201-204, 206-208, 210, 213-215,

EMILIN2

98-103, 123

desmin

425, 456-457

EWSR1 -SMAD3-positive fibroblastic

embryonal rhabdomyosarcoma (ERMS),

243-244

2, 42-44, 48, 76-77, 128, 130, 132,

EWSR1

177, 197, 229, 234-236, 238-239, 244-

276, 279, 291-292, 296, 307, 310-311,

227

9, 11,291-292, 319,

322-327,331-332, 334-335, 340-341,

224

DDR1

342

Ewing sarcoma

DAXX2

DDIT3

406

319, 323-326

254-255

EMA

354, 506, 508

233, 497, 521

EED

elastofibroma

155, 160, 165, 167, 174, 432,

435-436

D5F3

3, 214-215

EGR1

2, 154, 159

ERK

ESR1

376, 452-453

D

D-2-HG

191-192,

ectomesenchymoma

EGFR (HER1)

cyclin B3

D2-40

435

487, 491

301

CSF1R

270, 285, 296, 325, 331,427, 430, 432,

190-192

EBV-encoded small RNA (EBER)

130

CRTC1

165, 167, 170-171, 173-174, 177-178,

7, 182, 190-192, 478-479, 491

tumour

76-77, 151, 153, 157-158, 160-161,

ERG

191

127-128, 130, 132

274, 503

338, 492,

495-497, 499

405

CREB3L2

CREBBP

510

494

Erdheim-Chester disease (ECD)

E2F3

CREB3L1

CREB3L3

26, 79, 81, 189, 201,267, 371,406, 479,

ER

E

425

2, 124, 126

2-3, 11, 169, 272,

294-296, 319

104

ERBB3

272-273, 301

CREB3L

2, 45

epithelioid myxofibrosarcoma

130, 220

272, 301

CREB1

2, 109-111

epithelioid liposarcoma

406

Doege-Potter syndrome

cranial fasciitis

343,

428-430

35

DNMT3A

395

CPM

epithelioid haemangioma of bone

338,

489-491 DLEU1

2, 152-153, 338,

396, 432

diffuse large B-cell lymphoma (DLBCL)

3, 211

Costello syndrome

COX-2

512

357-358, 373-374, 502-503, 517-519

extra-abdominal desmoid

101

2, 93

extra-articular synovial chondromatosis

110, 119

emperipolesis

117, 498-499

extrarenal rhabdoid tumour

183-184, 187, 189, 192-194, 197, 199,

enchondroma

338, 342, 351-355, 370-372,

extraskeletal myxoid chondrosarcoma

203-204, 207-208, 210, 212-215, 218,

250, 262, 267, 270, 272-273, 276, 279, 291,299, 307-308, 314, 317, 328, 386,

desmoplastic fibroma

2, 67, 69-70

338, 401-402,

411-412, 422-423, 425, 471 desmoplastic small round cell tumour (DSRCT)

600

3, 306-308

Subject index

enchondromatosis

341,353-355, 371-372,

EPC1

3, 303-305

extraskeletal osteosarcoma

54, 224-225,

526

376, 503-504, 506-507, 509

EP400

389, 425, 455, 479, 481

desmoplastic fibroblastoma

(EMC)

375-376, 381,503-504, 506-509

368

296, 309-311

81,83, 92, 97, 111, 113, 120, 125, 135,

274

F

164, 274

epithelioid haemangioendothelioma

3,

163-165, 172-175, 338 epithelioid haemangioendothelioma of

bone

431-433

factor VIIl-related antigen 432, 435

factor XII la FARP1

481

496

177, 427, 430,

paybal：https://www.paypal.me/andy19801210 499

FAS

496

fascin

FAT1

516

H3-3A

141,361,407, 442, 445-446, 481-482

FUS

42-44, 48, 127-128, 130, 211,272,

H3-3B

360-361,383, 407, 445, 481-482

269

FBXW7 FET

FSH

278-279, 325-329, 425

202

43, 323, 325

G

285-286

FGF3

167

GAP

FGF4

167

Gardner fibroma

FGF8

283

Gardner syndrome

GAB1

284-286, 472, 481,515-516

FGFR1

106, 206, 220, 222, 285-286, 405,

191-192

484

222

GATA3

GCDFP-15

FGFR4

202, 206

GDP

503

343,

470-471

fibromatosis

2, 50, 67-69

2, 61-62

fibro-osseous pseudotumour of digits

(FP)

229, 239, 244, 256, 279, 305, 328,

fibrosarcoma

2, 13, 18, 59-60, 109, 198,

247-249, 266, 338, 449, 458-459, 471,

2, 60, 98-99 141,285, 338,

440-445,

503, 520

21

HAS2

96

HBEGF 141-142, 270

h-caldesmon

224, 316

181, 183-184, 187, 189, 192,

197, 218, 291,314, 425, 479, 481

180, 503

glomangioma

119-123, 128-132,

2, 109,

3, 117, 280-283

hamartoma

448, 482, 504-505

GLMN

50, 53-54, 350

haemosiderotic fibrolipomatous tumour

(HFLT)

516

GLI1

3, 179-180

hedgehog

199, 224, 334, 357, 376, 513, 518

Hep Par-1

484

glomangiomatosis

3, 179-180

heparan sulfate

181,211,285, 287, 338, 402, 424-425,

glomangiomyoma

3, 179-180

HEY1

385, 387

471,480, 525-526

glomulin

HHV8

7, 160, 166-168,487

fibrosarcoma of bone fibrous dysplasia

424, 480

461, 468,

471-474, 503, 514-516

28, 207, 324, 364

glypican-3 (GPC3) GNA14

hibernoma

2, 31-33, 338, 342, 475-477

high-grade surface osteosarcoma

311

high-molecular-weight cytokeratin

151

Hippo pathway

445, 447-448, 480

GNAS

261, 263-265, 341,343, 402, 423,

histone

461,471,473-474, 502-503, 516

153, 165, 170, 174, 325, 386, 427, 430,

FLI1

432, 435 FLT4

FOS

152-153, 170, 261,395-396, 398-399,

408, 428-430, 461

441

3, 196, 240-242, 270,

504 GRM1 Gsa

152-153, 169-171,398-399, 428-430

FOSB

granular cell tumour

338, 489-490, 493

426

363-364

473, 502, 515-516

106, 224, 274, 344, 354, 508

2, 16-17, 166, 190-192, 489

HIV

HLA-DR HMB45

493

301-302, 312-313 HMGA1

14

HMGA2

13-14, 25-26, 32, 36, 41, 188, 202,

222, 266-267, 316

GSK3B

224

HNRNPA1

67, 69, 152, 428

GSTP1

57

Hodgkin disease

FOSL2

152, 42& 438

GTF2I

FOXO1

206

GTP

FOXO4

206, 331

GTPase

515, 521

515, 521

French Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) 41,44, 293, 344

FRMD6

FRS2

364

36, 41

8, 11,

HOX

334

HPV

484

HR AS

HTRA1

H H19 H3.3 H3.3B

2, 16

26, 187, 231,241,259-260, 270,

FOSL1

83

296, 484

124, 173, 432

HIV lipodystrophy

Gorlin-Goltz syndrome

74-76, 110, 222, 285-286, 368-369

FN1

267

Gorham-Stout syndrome

176, 503

follicular lymphoma

GnRH

338,

412-413, 415, 417-418

151, 157

GNAQ

199

31,342, 475-477

406

HIC1

137-138, 244, 271-273, 318, 440, 443, FLCN

357, 502, 518

hibernoma of bone

10, 148, 157, 236, 239, 246, 253

GLUT1 glycogen

2, 59-60

2-3, 6, 10, 124,

fibrous histiocytoma

3, 179-182, 187, 503-504,

520-521

401-402, 411-412, 419, 421, 423, 438,

fibrous hamartoma of infancy

180

glomus tumour

261,285, 33& 341,

120, 128, 131,

137-138, 180, 183, 192, 255, 408

giant cell tumour of soft tissue

fibromatosis colli

343, 426-430

haemangiopericytoma-like

343-344, 360, 389, 407, 438,

88-91, 93-96, 111, 120, 123, 249-251, 422, 503

179-180, 271,280, 285, 338, 343, 396,

haemangioma of bone

484

giant cell tumour of bone

2, 4, 8, 10, 49, 55, 61-66, 75,

147-153,

156-157, 164-165, 167, 169, 176,

426-430, 432, 503-509

giant cell fibroblastoma

fibroma of tendon sheath

3, 5,

386 GHRH

2, 23, 143, 145,

haemangioma

521

GFAP

23-24, 53, 56, 265, 280, 407-408

fibrocartilaginous mesenchymoma

7, 94, 251, 391,393, 503

7, 10, 12, 216-221,503-505, 520-521

357,487,518

2-3, 156-157,

338, 430-433

2, 84, 88-89, 503

GATA2

FGFR3

FH

227, 229, 255-257, 288, 389

159-161, 163-165, 169-170, 172-176,

233, 521

FGFR2

fibrin

See H3-3B

haemangioendothelioma

83

gastrointestinal stromal tumour (GIST)

448

See H3-3A

H3F3B

H3K27me3

FGF1

FGF23

H3F3A

110 338, 489

201-202, 214, 269, 442, 503

227

hybrid nerve sheath tumour

3, 252

201,503 344, 360-361,383, 438, 441-446, 481

360

ICR1

503

Subject index

601

paybal：https://www.paypal.me/andy19801210 IDH

351-352, 355, 372, 377-378, 389-390,

juvenile xanthogranuloma

36-48, 81, 124, 318, 320, 343, 510-511 liposarcoma, dedifferentiated (DDLPS)

188

389-390, 406, 471, 482, 502-503, 506,

KANSL1

508-509

Kaposi sarcoma (KS)

Kasabach-Merritt phenomenon (KMP)

487

IgG

kataegis

104, 106, 201

lgG4

499

290

487, 490, 493

KDM2B

493

KDR

IgM

487

Ki-67

IHH

376

KIT

immunodeficiency

6-7, 100, 102, 190-192,

487

implant-related osteosarcoma

167, 180, 202, 220, 269, 448, 487,

lymphangioma

lymphangiomatosis

2,

156-158

LZTR1

228

227

M

LATS2

227

M component

145-146, 149

intramuscular haemangioma intramuscular lipoma

2, 23, 145

leiomyosarcoma (LMS) of bone

2, 49-50

LEMD3

487-488, 491

LEUTX

346

LH

2, 55-56

isocitrate dehydrogenase

354, 371,378,

502, 507

35

50

JAK2

106

juvenile hyaline fibromatosis

Subject index

338,

maligna nt lymphoma, no n-Hodgki n

338, 489

231,258-260

malignant peripheral nerve sheath tumour 3, 6-7, 10-11, 227, 229-231,

Li-Fraumeni syndrome (LFS)

7, 36, 38,

malignant triton tumour

47, 195, 201, 341,404, 502-503, 505,

MAML2

510-513

mammaglobin 2, 20-22, 97

lipofibromatosis

2, 6-7,

lipoma of bone

254-258, 291-292, 389,

504, 520-521,525-526

2, 20 2, 96-9乙 287-288

13-15, 18, 20-21, 23, 25,

27-32, 34-37, 43, 72, 80, 266, 338, 468,

2, 63-64

176, 502-504, 506-509

malignant lymphoma, lymphoblastic

233-236, 239,

484

MAP2K1

147, 494, 497, 499, 503

MAP2K3

224

MAP3K5

40

MAPK

124, 219, 240, 448, 492, 494-495,

497, 499, 508, 521

MAX

475-477

lipoma-like liposarcoma

255-257

164, 334

marginal zone B-cell lymphoma

475-477, 503-504

40, 152, 170, 428, 461

487

Maffucci syndrome

(MPNST)

278

lipoma

520

240, 504

331

lipoblastomatosis 441,447-448,

487

MAFB

(MMNST)

393, 503

lipoblastoma

Jaffe-Campanacci syndrome

343-344,

516

LIFR

MAFA

malignant melanotic nerve sheath tumour

LEOPARD syndrome

IRS4

486, 488

487

489

478

IRF4

JAK-1

193-197, 211, 216, 270,

481, 503, 510-511,525-526

3, 211-212

387

ischaemic fasciitis

3, 6, 8-10, 21,

316-317, 338, 343-344, 389, 425, 478,

intraosseous spindle cell

intravascular fasciitis

181, 189-190,

261-265, 472, 515

rhabdomyosarcoma

3, 186, 188-190, 266, 503, 526

leiomyosarcoma (LMS)

2, 13-14

intramuscular myxoma

MAF

341,512

leiomyoma

3, 315-317

intramuscular angioma

602

452

LYVE1

LATS1

LDH

206

intimal sarcoma

JUN

338,

LYST

360, 492-496, 499

See SMAFICB1

ITM2B

502-503,

Langerhans cell histiocytosis (LCH)

241

IRF2BP2

487-491,493, 510, 512

137

517-518

481

INO80D

2, 154-155, 162

6, 159, 164, 166, 176-178

328, 338-339, 40& 420, 483,

lymphoma

64

Langer-Giedion syndrome

419-420

41,109-111

INI1

lymphoedema

LAMTOR1

3, 182

312

2, 154-155, 159, 161, 165,

167

494, 497, 499

laminin

ING1

224, 406

KRAS

419

inflammatory myofibroblastic tumour (IMT)

14

LSAMP

lymphangioleiomyomatosis

2, 119-121,287

inhibin

LPP

278

infantile fibrosarcoma (IFS)

112-

113, 423

227, 229, 236, 487, 491,493

L

2, 127-132,

low-grade myofibroblastic sarcoma

216-221,305, 316-31 乙 435, 487, 503

2, 65-66

infarct-related osteosarcoma

338, 343, 400-402, 423, 473

230

176, 434, 503

inclusion body fibromatosis

infantile myofibromatosis

(LGCOS)

KLF17

487-488, 491

immunoglobulin (Ig)

191,479

low-grade fibromyxoid sarcoma

503

274

IGH

110, 119-120, 152, 288, 428, 527

LMP1

low-grade central osteosarcoma

KDM2A

IGK

LMNA

406

KCNQ1OT1

487

156-158

188

KAT6B

206, 405

IGF2

2,

8, 14, 26, 36-41, 45-46, 343

2, 156-158

(KHE)

406, 471,482, 502-503, 506, 508-509

IGF1R

liposarcoma, well-differentiated (WDLPS)

kaposiform haemangioendothelioma

371-372, 376, 378, 380-383, 387, 390,

2, 8,

39-4^ 46-48, 124, 318, 320

2, 4, 7, 23, 147,

166-167, 280

341, 343, 354-355, 358, 361, 369,

IDH2

2, 6, 8-11, 14, 21-22, 26-27, 34,

liposarcoma

K

369, 371-372, 376-378, 380-383, 387,

2, 18-19

2, 13, 16-19

lipomatosis

341, 343, 352, 354-355, 358, 361,

IDH1

IgA

lipomatosis of nerve

495

264-265

juxta-articular myxoma

415, 508

2, 36

338, 489

220

Mazabraud syndrome

261,341,472, 503, 515

paybal：https://www.paypal.me/andy19801210 152, 428

MBNL1

341,

472-473, 502-503, 514-516

124, 224, 267, 316-317, 320, 327,

2, 16-17

343, 350, 382, 389, 401-402, 405-406, 411-413, 415, 417, 423, 434, 471,512

neurofibroma

344,

408

MYC

3, 10, 228, 232-236, 252-256,

521

neurofibromatosis

176-178, 191,211,331,405, 434, 487,

491

252, 254-256, 288, 447-448, 502, 504,

MYCN

206, 208

520-521

274

MYD88

MED12

188, 319

MYF4

See myogenin

neurothekeoma

MEF2A

364

MYH9

49

NF1

MEK

211, 213

melan-A

301-302,314

319, 408, 482-484, 488, 512, 525-526

MEN1

MYODI-mutant spindle cell / sclerosing

46, 125, 256, 259, 269, 300-302,

melanoma

32-33, 504

rhabdomyosarcoma

3, 211, 213

myoepithelial carcinoma

3, 277-279

myofibroblastic sarcoma

457, 525-526

247

343-344, 385-387

MET

119

119-120, 206,461

metachondromatosis

504, 506-509, 518

207, 219, 224, 233, 236, 269,

methylation

318, 354, 360, 387, 406, 456, 508

MIDI

159

MIR17HG

206, 208

MIR584F1

119

mismatch repair cancer syndrome MITF

MMSET

3, 182-186

NSD2

NSE

2, 6, 10, 39-40, 46, 117,

360,487

215, 241,305 3, 120, 122, 287-289, 425

NTRK

124-126, 135, 262-263, 270, 319, 482,

NTRK1

119-121, 124, 288

525-526

NTRK2

119, 288

NTRK3

110-111, 119-122, 220, 288, 425

3, 303-305

2, 10, 21,27,

NTRK-rearranged spindle cell neoplasm

2, 47-48

myxoinflammatory fibroblastic sarcoma

2, 116-117, 280, 283

(MIFS)

3, 243-244, 261-265, 365, 472,

myxoma

3,

287-288

503-504, 515

28

50, 52, 75, 95, 111, 181, 199, 203, 212,

301,516

N

2, 84

nuchal fibroma NUT

331

NUTM1

331

NUTM2A

331

NUTM2B

334

O 104, 106-108

NAB2

OGA

484

napsin A

NBN

oculoectodermal syndrome

502

NADPH

OMD

481,504

ncBAF

43, 96, 101, 124, 158, 176, 191,219,

NCOA1

206

NCOA2

3, 82-83, 211, 213, 385, 387

233,376 128, 130-132, 276, 425

MUC5AC

331

43, 125, 236, 256, 290

290

nerve sheath myxoma nestin

447-448

117, 280-281,283

Ollier disease

504

MTAP

mucin

303-305 202, 269, 301,376, 380, 487, 494,

497, 499

2, 50, 52-54, 225, 412,

mTOR

MUC4

201,240, 504

180-181

170

214, 311

MSH

338, 340, 445,

283

NR AS

myxoid pleomorphic liposarcoma

3, 277-279

214

MRTFB MSA

504

2, 49-54, 67, 95

312

NOTCH

42-44, 46-48

See NSD2

MNF116

MRLN

2, 25-26

myxoid liposarcoma (MLPS)

See MAP2K3

MKK3

NONO

NR4A3

myxoid chondrosarcoma

241,270, 301,314, 328

mixed tumour

484

NPM3

myxofibrosarcoma

Milroy disease

325, 328, 331

NKX3-1

212-215, 272, 307, 317, 328, 386, 455,

myositis ossificans

504

50, 487

NKX2-2

481

myopericytoma

233, 489

253

NF-kB

Noonan syndrome

503

12

MIB1

microenvironment

319, 326-329

19, 203, 229, 232, 236, 244-246, 250,

447-448, 520

199, 202-204, 206-208, 210,

myolipoma

See OGA

MGEA5

NFP

non-ossifying fibroma (NOF)

214

myogenin

7, 226-228, 230-231,238, 406, 504

NFATC2

3, 120, 182, 185

myofibromatosis MYOG

338, 343, 458, 470-471

mesoblastic nephroma

2, 29, 71-72, 80

3, 182-185

myofibroma

338,

NF2

nodular fasciitis

myofibroblastoma

227, 238

mesenchymal chondrosarcoma

mesenchymoma

2, 109-110,

112-113, 423

meningothelial hamartoma merlin (NF2)

3, 277-279

myoepithelioma

3, 226, 228, 238, 247-248, 453,

meningioma

254-257, 448, 502, 504, 520-521

3, 199, 203-204, 206-208, 210-

214, 272, 307, 317, 328, 386, 481

97, 236, 259, 301,314, 524

243-244

7, 10, 46, 124, 180, 193, 201-202, 217, 219-220, 224, 232-234, 236, 238,

196

MYOD1

219, 233, 255, 502, 521

neurofibromin

364

MYOCD

46, 187, 241,259-260, 270,

melanin

487, 491

MYO1E

220, 233, 521

7, 176, 180, 201,217,

226-227, 230, 232, 236, 238, 240,

MEAF6

MEIS1

2, 163,

165

Musculoskeletal Tumor Society (MSTS)

15, 26, 32, 35-36, 38-41,46, 48,

MDM2

haemangioendothelioma (CHE)

379, 502-503, 517-518 multiple symmetrical lipomatosis

297, 299

MCT1

357-358, 373,

multiple osteochondromas

McCune-Albright syndrome (MAS)

502-504, 506-509

438

ORF73

167

ossifying fibromyxoid tumour (OFMT)

3, 243-244

241

neuroendocrine composite

3,

274-276 osteoblastoma

338, 393, 395-399, 407-408,

438 osteocalcin

408

Subject index

603

paybal：https://www.paypal.me/andy19801210 osteochondroma

338, 341-342, 346, 348,

356-358,373-374, 379-380, 411-

350,

412, 502-503, 507, 517-519, 525-526 osteochondromyxoma

338, 365-366, 504

osteofibrous dysplasia (OFD)

338, 342-343,

PDL1

PORCN

389

POT1

137

PDPN

PEA3

PEComa

312-314

2, 16

PPP2R1B

338, 341-342, 394-399,

perineurioma/schwannoma

252

PPP6R3

periosteal chondroma

osteosarcoma

perivascular epithelioid tumour

408

osteoprotegerin

3, 7, 54, 107, 212, 224-225,

291, 323, 338-344, 350, 358, 361, 377-378, 380, 382, 384, 389,

399-421,

423, 425, 438-439, 445-446, 473,

PGI2

522-526

PHH3

osteosarcoma, extraskeletal

3, 224

395

441

22, 229, 234-236, 255, 376, 382-383,

3,

p53

p63

haemangioendothelioma

PSF

36, 38, 124, 236, 269-270, 304, 376,

PKC

137, 515

PTBP1

PAFAH1B1

340, 419-421,

57

PAK

124

(PI LA)

217, 441,504

parosteal osteosarcoma

225, 338, 343-344,

350, 382, 401, 410-413, 415, 417

319,326-329 130, 487, 490-491

PAX8

484

PBX1

278

pleomorphic sarcoma

3,

164

318-320, 338, 341,343, 389,

402, 405, 421,425, 455,

480-481,504, 2, 10,

PMP22

PDGFD

101, 103

PMS2

Subject index

RAC

21

124

RAD51B

3, 245

21

radiation-associated sarcoma

RAF

419-420

220, 233

288

RANBP2

110-111

441

RAPADILINO syndrome

3, 226, 228, 230

504, 523

119, 124, 176, 201-202, 219-220, 233,

240, 499, 502, 508, 521 RASSF1 RASSF1A

RB1

224

406 See RASSF1

7, 29-30, 35, 47, 72-73, 80-81, 87, 124, 195-196, 220, 224, 318, 341,376, 379,

504

podoplanin

R

RAS

plexiform solitary circumscribed neuroma

98-101, 103

216-221,316-317,504

3, 228, 232-236,

253-256, 520-521

(SCN)

406

176

PTPRB

RANK

plexiform schwannoma

504, 506, 508

PTPN11

RAF1

525-526

PDGFB

504, 506, 508

508

PTHrP

RAB2A 3, 6, 39-41,46, 124,

139-140

203

508

PTH

2, 9, 41,45-48, 81

126, 135, 196-197, 209-210, 255, 269,

plexiform neurofibroma

188, 278

P-cadherin

PDGFRA

29-30, 72, 80

plexiform fibrohistiocytic tumour

206

PCH2

280-281, 283

pleomorphic rhabdomyosarcoma

281,285,

199, 504

13, 195, 202, 224, 248, 318, 435, 504

PTH1R

209-210, 525-526

2, 160-162

paraganglioma

PBX3

338, 486-488

pleomorphic liposarcoma

90

papillary intralymphatic angioendothelioma

164

PTEN

176

pleomorphic lipoma (PL)

palmar fibromatosis

PAX7

PLCG1

(PHAT) of soft parts

PAH

PAX5

90-91

169-170

See SFPQ

PTCH1

pleomorphic hyalinizing angiectatic tumour

441, 489, 504-505

PATZ1

plantar fibromatosis

plasmacytoma of bone

438

Paget disease of bone (PDB)

604

484

515

21-22, 188, 278-279

508

pseudomyoge nic

366, 515

248, 270, 279, 461, 465, 484

PD1

19, 154, 176, 202, 224, 497

PKA

PLAG1

2, 51-52

484

PIP2

379, 383, 389, 434, 442, 502, 511-513

2, 51-52, 55-56

155-158, 160-161,432

PSAP

484

434, 436, 484 p40

PROX1

PSA

43, 96, 202, 219, 233, 434, 452

PIK3CA

248

protein tyrosine phosphatase

406

284-286

p16

23

proliferative myositis

12

PI3K

234

137

PRKD2

proliferative fasciitis

phosphaturic mesenchymal tumour (PMT)

P

PRKCD

progesterone

274, 276

PHLDA2

137

PRKCB

giant cell tumour syndrome

110, 231,258-260, 366, 504

PRKAR1A

phaeochromocytoma-paraganglioma and

PHF1

489

bone

3, 312

395

PGE2

481,483-484, 503-505, 510-511,518,

p14ARF

primary non-Hodgkin lymphoma of

380, 382, 412, 414-41 & 421

508

osteopontin

114-115, 319

PRDM10 338, 342-343, 350,

periosteal osteosarcoma

391,393, 503

334 254-255, 521

PRC2

338, 352, 355,

40 50

PRC1.1

358, 381-382, 415

408

502-503,

26, 79, 81, 189, 267, 479, 510

PR

338, 342, 351-352,

355,382 periosteal chondrosarcoma

503-504 osteonectin

110

252

338, 341-342, 391-399, 408,

osteopoikilosis

278, 319

PPFIBP1

perineurioma/neurofibroma

408

osteoma

POU5F1

33& 343, 461-466

adamantinoma

osteoid osteoma

504

517-518

3, 19, 236-238, 252-253

perineurioma

406

504

Potocki-Shaffer syndrome

331

pelvic lipomatosis

460-466 osteofibrous dysplasia (OFD)-like

poly (ADP-ribose) polymerase (PARP)

96, 101, 110, 182, 184

PDGFRB

155-161, 167, 174, 465

382, 387, 405-406, 434, 479, 481, 484, 504

paybal：https://www.paypal.me/andy19801210 35

RCBTB2

secondary peripheral chondrosarcoma,

484

RCCm

grades 2 and 3

receptor tyrosine kinase

96, 176, 219, 285,

289, 461

SETD2

405, 523, 527

RECQ

SERPINE1

See BLM

SH3BP2

RECQL4

405, 502, 504, 522-524

SH3PXD2A

182, 184

2,

SIX3

159-160, 163-165

retinoblastoma

504 227

simple bone cyst

retiform haemangioendothelioma

7, 195, 405, 419-421, 502, 504

106

retinoic acid receptor

SMAD

50, 438

STAT6

104, 106-108, 138, 425

STRN

2, 16-17

481

STK24

338, 341,467-469

124

425

122

STRN3

338, 345-347,

subungual exostosis

499

SLC29A3

425

STAT3

steroid lipomatosis

420

304

SKP2

323

STARD13

sickle cell disease

96, 110

RET

248, 285

290, 292

STAG2

360

312

SFPQ

292

SSTR2A

SSX

170

RECQL3

RELA

379

SS18L1

76

349-350, 358

3, 197, 210, 279, 294-296, 299,

SMAD3

2, 76-77

succinate dehydrogenase

304-305, 307, 309-311, 456-45乙 504

SMAD4

484

superficial CD34-positive fibroblastic

rhabdoid

rhabdoid tumour

3, 294-296, 309-311,

small cell osteosarcoma (SCOS)

456-457, 504

rhabdomyoma

338,

3, 198-200, 249-250,

2, 114-115

tumour

SUZ12

403-404, 406-409

254-255, 521

SMARCA2

234

SWI/SNF

SMARCA4

224, 294, 310, 319, 504

synaptophysin

201-215,

SMARCA5

319

synovial chondromatosis

231,389, 412, 481,483, 503-505, 510-511,

SMARCB1

228, 230, 255-257, 276,

synovial haemangioma

504-505

rhabdomyosarcoma

3, 6, 9, 11, 107,

525-526 RICTOR

ROS1

278-279, 294-296, 305, 309-311, 343,

124

96, 110-111

Rosai-Dorfman disease (RDD)

338,

498—499

294

SMARCC2

294

405,

419, 502, 504, 522-524, 527

potential

3, 190 3, 222-223, 369

RRBP1

110-111

RUNX2

224, 405-406, 408, 438, 441

3,

2, 41, 104-108,

123, 138, 291-292, 425 486-

488

311

sarcoma botryoides

201

sarcoma with BCOR genetic alterations

322-

225, 285, 334-335, 40& 415, 425,

442, 481

schwannoma

telomerase

360, 386

tenos ynovial giant cell turn our

SOX10

sclerosing liposarcoma

2, 36, 40

sclerosing perineurioma

3, 237-239

testosterone

319

TET 441

secondary osteosarcoma

338, 419-421

2, 14, 29-30, 32,

34-35, 72, 80

SQSTM1

119, 504

512

3, 211, 213 3, 172-175, 241, 274, 276, 297-299,

312, 314, 431-433

2-3, 29, 34-35, 72,

spindle cell rhabdomyosarcoma

521

3, 211-213 3, 318

TFG

110, 119, 304

TGF-a

96

TGF-p

76, 393, 434

TGFB

389

TGFBR3

117, 280-281, 283

THRAP3

438

thyroglobulin

484

TIE1

176

sec on dary peripheral atypical cartilaginous

SRC

376

TLE1

290, 292, 334

tumour/ch on drosarcoma, grade 1

SRF

28, 182, 184, 211

TNFRSF11A

505

TNFRSF11B

408

(ACT/CS1)

373-374, 517

SS18

290, 292

2, 67, 116,

304

TFE3

80, 211-213, 320

SPRED1

110

318

40, 43, 106, 108, 224, 269, 318

TFCP2

408, 438

SPARC

spindle cell sarcoma, undifferentiated

216-221,504

SEC31L1

TERT

279, 288, 301-302, 328, 484 SP3

338,

133-136

241-242, 253, 256-257, 259-260, 270,

spindle cell lipoma (SCL)

128-132, 425

SDH

228-229, 231-232, 236, 239,

rhabdomyosarcoma

2,

176, 505

TEK

504

See merlin (NF2)

sclerosing epithelioid fibrosarcoma

211

338, 489-491

403-404, 406-409, 439

spindle cell / sclerosing

252-254, 258

schwannomin

TEAD1

199, 224, 334, 513

SP7 transcription factor

3, 72, 226-231, 235-236, 240,

304

SOX9

See TSPAN31

SATB2

TCF12

SOS1

323,333-335

SAS

364

343, 449-450, 452, 457, 504

TBXT

telangiectatic osteosarcoma (TAEOS)

sonic hedgehog

SALL4

304, 325

T-cell lymphoma

solitary fibrous tumour (SFT)

solitary plasmacytoma of bone (SPB)

S

3, 6, 9-11,290-293,

see TBXT

TBL1XR1

245-246 3, 318

T

TAF15

solitary circumscribed neuroma (SCN)

326, 329

round cell sarcoma, undifferentiated

223, 343, 368-369 143

T

soft tissue chondroma

round cell sarcoma with EWSR1-non-ETS

165, 207, 215, 305, 311,484

334, 423, 425, 464, 466, 525-526

smooth muscle turn our of uncertain malignant

Rothmund-Thomson syndrome (RTS)

fusions

SMARCC1

290, 294-295, 310

synovial sarcoma (SS)

386, 456-457, 504

216-217

Subject index

605

paybal：https://www.paypal.me/andy19801210 U

499

TNFRSF6

7, 43-44, 46, 106, 124, 167, 176,

TP53

WIF1

ubiquitin UCP1

269, 312, 318, 323, 341, 376, 389-390,

ultrasound

TPM3

110-111, 119, 121, 288

TPM4

110

TPR

TR

undifferentiated sarcoma

318-319, 330, 389, 420, 445-446 49-50, 53-54, 67, 350, 438-439

USP6

USP9X

119-120, 288

3, 41,46, 105,

See THRAP3

Trevor disease

124

120-121,288-289

TRPS1

148, 189, 306-308, 331-332

406

WWOX

WWTR1 -3, 152, 172-174, 428, 431-433

xanthogranuloma

YAP1

405

3, 172-175, 318, 431-433

VEGFR2

See KDR

YEATS2

VEGFR3

160-162, 176

YEATS4

36

YWHAE

110, 334

venous haemangioma

v-Fos

518

Y

493, 497

VE1

2, 148-149

452, 505

VGLL2

3, 211, 213

Z

TSC2

312, 314, 452, 505

VGLL3

117, 124, 283, 318

ZBTB16

36, 316, 417

TSSC3

TTF1

See PHLDA2

25, 59, 312, 452, 505

tuberous sclerosis

tufted angioma (TA) Turner syndrome tyrosinase

VHL

505

VIM

152, 428

vimentin

484

VMP1

248, 270, 465

154

W Werner syndrome (WS) 523, 525-527

606

Subject index

ZNF444

278

ZNF687

441,505

ZNF9

481

405, 419, 502, 505,

40 152, 428

ZFP36

156-158

259

376

398

TSC1

TSPAN31

495-497

240-241

V-ATPase

VEGFA

301

TRIM11

TRK

358, 518

516

TRIO

405, 502, 505, 523, 525, 527

WT1

X

V

367, 508

TRAP150

TRH

WRN

438

493

TRAP

59

91,94, 224, 334, 357, 382, 385, 398,

473, 518

10, 21-22, 61, 119, 396, 512,

514, 516

404-406, 414, 442, 465, 481,487, 491, 502, 505, 510-513

WNT

32, 477

195-196, 201-202, 206, 220, 224, 268-

406

Williams syndrome

152, 429, 432

See CNBP

paybal：https://www.paypal.me/andy19801210 The World Health Organization Classification of Tumours Female reproductive organs

Haematopoietic and lymphoid tissues

Kurman RJ, Carcangiu ML, Herrington CS, et al., editors. WHO

Swerdlow SH, Campo E, Harris NL, et al., editors. WHO

classification of tumours of female reproductive organs. Lyon

classification of tumours of haematopoietic and lymphoid tissues.

(France): International Agency for Research on Cancer; 2014.

Lyon (France): Inter national Agency for Research on Cancer; 2017.

(WHO classification of tumours series, 4th ed.; vol. 6).

(WHO classification of tumours series, 4th rev. ed.; vol. 2).

https://publications.iarc.fr/16.

https://publications.iarc.fr/556.

Lung, pleura, thymus and heart

Skin

Travis WD, Brambilla E, Burke AP, et al., editors. WHO classification

Eider DE, Massi D, Scolyer RA, et al., editors. WHO classification

of tumours of the lung, pleura, thymus and heart. Lyon (France):

of skin tumours. Lyon (Franee):丨nternational Agency for Research

International Agency for Research on Cancer; 2015. (WHO

on Cancer; 2018. (WHO classification of tumours series, 4th ed.;

classification of tumours series, 4th ed.; vol. 7).

vol. 11).

https://publications.iarc.fr/17.

https://publications.iarc.fr/560.

Urinary system and male genital organs

Eye

Moch H, Humphrey PA, Ulbright TM, et al., editors. WHO

Grossniklaus HE, Eberhart CG, Kivela TT, editors. WHO

classification of tumours of the urinary system and male genital

classification of tumours of the eye. Lyon (France): International

organs. Lyon (Fra nee): Inter national Agency for Research on

Agency for Research on Cancer; 2018. (WHO classification of

Cancer; 2016. (WHO classification of tumours series, 4th ed.; vol. 8).

tumours series, 4th ed.; vol. 12).

https://publications.iarc.fr/540 .

https://publications.iarc.fr/561.

Central nervous system

Digestive system

Louis DN, Ohgaki H, Wiestler OD, et al., editors. WHO classification

WHO Classification of Tumours Editorial Board. Digestive system

of tumours of the central nervous system. Lyon (Franee):

tumours. Lyon (France): International Agency for Research on

International Agency for Research on Cancer; 2016. (WHO

Cancer; 2019. (WHO classification of tumours series, 5th ed.; vol. 1).

classification of tumours series, 4th rev. ed.; vol. 1).

https://publications.iarc.fr/579.

https://publications.iarc.fr/543 .

Breast Head and neck

WHO Classification of Tumours Editorial Board. Breast tumours.

El-Naggar AK, Chan JKC, Grandis JR, et al., editors. WHO

Lyon (France): International Agency for Research on Cancer; 2019.

classification of head and neck tumours. Lyon (France):

(WHO classification of tumours series, 5th ed.; vol. 2).

Intemational Agency for Research on Cancer; 2017. (WHO

https://publications.iarc.fr/581.

classification of tumours series, 4th ed.; vol. 9). https://publications.iarc.fr/548.

Soft tissue and bone WHO Classification of Tumours Editorial Board. Soft tissue and

En docrine orga ns

bone tumours. Lyon (France): International Agency for Research on

Lloyd RV, Osamura RY, Kloppel G, et al., editors. WHO

Cancer; 2020. (WHO classification of tumours series, 5th ed.; vol. 3).

classification of tumours of endocrine organs. Lyon (France):

https://publications.iarc.fr/588.

lnte「national Agency for Research on Cancer; 2017. (WHO

classification of tumours series, 4th ed.; vol. 10). https://publicatio ns. iarc.fr/554.

Previous volumes in the series

Subject index

607

paybal：https://www.paypal.me/andy19801210 The WHO Classification of Turn ours Soft Tissue and Bone Tumours is the third volume in the 5th edition of the WHO series on the classification of human tumours. This series (also known as the WHO Blue Books) is regarded as the gold standard for the diagnosis of tumours and comprises a unique synthesis of histopathological diagnosis with digital and molecular pathology. These authoritative and concise reference books provide indispensable international standards for anyone invoIved in the care of patie nts with cancer or in cancer r esearch, un derpi nning in dividual patient treatment as well as research into all aspects of cancer causation, prevention, therapy, and education. Whafs new in this edition?

The 5th edition, guided by the WHO Classification of Tumours Editorial Board, will establish a single coherent cancer classification presented across a collection of individual volumes organized on the basis of anatomical site (digestive system, breast, soft tissue and bone, etc.) and structured in a systematic manner, with each tumour type listed within a taxonomic classification: site, category, family (class), type, and subtype. In each volume, the entities are now listed from benign to malignant and are described under an updated set of headi ngs, in eluding histopathology, diagnostic molecular pathology, staging, and easy-to-read essential and desirable diagnostic criteria. Who should read this book?

• • • • • •

Pathologists On colog ists Cancer researchers Surgeons Epidemiologists Cancer registrars

This volume • • • •

Prepared by 208 authors and editors Contributors from arou nd the world More than 1200 high-quality images More than 3400 references

WHO Classification of Tumours Online •

The content of this renowned classification series is now also available in a convenient digital format: https://tumourclassificatio n.iarc.who.int

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9789283 245025

ISBN 978-92-832-4502-5