THIRD EDITION

ii
 Third Edition

Matthew R. Lindberg, MD
Associate Professor of Pathology
University of Arkansas for Medical Sciences
Little Rock, Arkansas

iii
 DIAGNOSTIC PATHOLOGY: SOFT TISSUE TUMORS, THIRD EDITION ISBN: 978-0-323-66110-2

Copyright © 2019 by Elsevier. All rights reserved.

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Notices
Practitioners and researchers must always rely on their own experience and knowledge in
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Because of rapid advances in the medical sciences, in particular, independent verification of
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iv
 Dedication
To my wonderful wife, Rani, for her love, support, and infinite patience during
the course of putting together this book. Also, to the excellent team of editors
and coauthors with whom I have been very privileged to work. Many, many
thanks for your hard work and high standards.

MRL

v
vi
Contributing Authors
David Cassarino, MD, PhD
Dermatopathologist
Staff Pathologist
Los Angeles Permanente Medical Center
Los Angeles, California

Jerad M. Gardner, MD
Associate Professor of Pathology and Dermatology
Dermatopathology Fellowship Program Director
University of Arkansas for Medical Sciences
Little Rock, Arkansas

David Lucas, MD
Professor and Director of Anatomic Pathology
University of Michigan
Ann Arbor, Michigan

Charles Matthew Quick, MD

Associate Professor of Pathology
University of Arkansas for Medical Sciences
Little Rock, Arkansas

Kandi Stallings-Archer, MD
Assistant Professor of Pathology
University of Arkansas for Medical Sciences
Little Rock, Arkansas

Additional Contributing Authors

Jessica M. Comstock, MD
Cyril Fisher, MD, DSc, FRCPath
Jonathan B. McHugh, MD
L. Jeffrey Medeiros, MD
Thomas Mentzel, MD
Elizabeth A. Montgomery, MD
Amitabh Srivastava, MD
Lester D. R. Thompson, MD
Khin Thway, MD, FRCPath

vii
viii
 Preface
The field of soft tissue pathology continues to grow and change, with new diagnostic
entities, immunohistochemical antibodies, and molecular tests introduced seemingly every
month. The 3rd edition of Diagnostic Pathology: Soft Tissue Tumors strives to incorporate
this new knowledge in the form of new chapters, updated text, and additional high-quality
histologic images.

Since the publication of the 2nd edition, several new entities have been described in the
scientific literature, including atypical spindle cell lipomatous tumor, superficial CD34-
positive fibroblastic tumor, and BCOR-rearranged sarcoma. Chapters dedicated to each of
these entities (as well as others) have been added in this new edition. Existing chapters
devoted entirely to immunohistochemistry and molecular testing have also been updated
to reflect recent discoveries in this span, and many individual chapters have seen a variety
of text and gallery improvements. In particular, several galleries have been modified by
swapping in new images that better reflect the extensive morphologic spectrum of soft
tissue pathology.

As before, the 3 innovative “Approach to Diagnosis” chapters are still included in this new
edition. Using a combination of clinical information, overall histologic pattern, and specific
histologic findings, these chapters can aid the struggling pathologist in developing a
thoughtful differential diagnosis for even some of the more challenging or unusual soft
tissue cases. I hope you find these unique additions helpful in your own practice, both now
and for many years to come.

Lastly, as always, owners of Diagnostic Pathology: Soft Tissue Tumors, 3rd edition, receive
online access to all information and images contained in this text, plus much more. Enjoy!

Matthew R. Lindberg, MD
Associate Professor of Pathology
University of Arkansas for Medical Sciences
Little Rock, Arkansas

ix
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Acknowledgments
Lead Editor
Joshua Reynolds, PhD

Text Editors
Arthur G. Gelsinger, MA
Rebecca L. Bluth, BA
Nina I. Bennett, BA
Terry W. Ferrell, MS
Megg Morin, BA

Image Editors
Jeffrey J. Marmorstone, BS
Lisa A. M. Steadman, BS

Illustrations
Richard Coombs, MS
Lane R. Bennion, MS
Laura C. Wissler, MA

Art Direction and Design

Tom M. Olson, BA

Production Coordinators
Emily C. Fassett, BA
John Pecorelli, BS

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xii
 Sections
SECTION 1: Soft Tissue Introduction

SECTION 2: Diagnostic Approach to Soft Tissue Tumors

SECTION 3: Tumors of Adipose Tissue

SECTION 4: Fibroblastic/Myofibroblastic Lesions

SECTION 5: Pediatric Fibroblastic/Myofibroblastic Tumors

SECTION 6: Fibrohistiocytic, Histiocytic, and Dendritic Cell Tumors

SECTION 7: Smooth Muscle Tumors

SECTION 8: Pericytic (Perivascular) Tumors

SECTION 9: Tumors of Skeletal Muscle

SECTION 10: Vascular Tumors (Including Lymphatics)

SECTION 11: Chondroosseous Tumors

SECTION 12: Peripheral Nerve Sheath Tumors

SECTION 13: Genital Stromal Tumors

SECTION 14: Tumors of Mesothelial Cells

SECTION 15: Hematopoietic Tumors in Soft Tissue

SECTION 16: Tumors of Uncertain Differentiation

SECTION 17: Undifferentiated/Unclassified Sarcomas

SECTION 18: Mesenchymal Tumors of Gastrointestinal Tract

SECTION 19: Other Entities

xiii
 TABLE OF CONTENTS

74 Hibernoma
SECTION 1: SOFT TISSUE INTRODUCTION Matthew R. Lindberg, MD
INTRODUCTION AND OVERVIEW 78 Myelolipoma
Matthew R. Lindberg, MD
4 Gross Examination 80 Lipoblastoma
Matthew R. Lindberg, MD Matthew R. Lindberg, MD
6 Grading and Staging 84 Atypical Spindle Cell Lipomatous Tumor
Matthew R. Lindberg, MD Matthew R. Lindberg, MD
ANCILLARY TECHNIQUES INTERMEDIATE, LOCALLY AGGRESSIVE
12 Soft Tissue Immunohistochemistry 88 Atypical Lipomatous Tumor/Well-Differentiated
Matthew R. Lindberg, MD Liposarcoma
18 Molecular Features of Soft Tissue Tumors Matthew R. Lindberg, MD
Matthew R. Lindberg, MD
MALIGNANT
SECTION 2: DIAGNOSTIC APPROACH TO
SOFT TISSUE TUMORS 94 Dedifferentiated Liposarcoma
Matthew R. Lindberg, MD
OVERVIEW 100 Myxoid Liposarcoma
Matthew R. Lindberg, MD
22 Biopsy and Resection of Soft Tissue Tumors
106 Pleomorphic Liposarcoma
Matthew R. Lindberg, MD
Matthew R. Lindberg, MD
CLINICAL APPROACH
SECTION 4:
26 Age- and Location-Based Approach to Diagnosis FIBROBLASTIC/MYOFIBROBLASTIC
Matthew R. Lindberg, MD LESIONS
HISTOLOGIC APPROACH BENIGN
28 Pattern-Based Approach to Diagnosis 114 Nodular Fasciitis
Matthew R. Lindberg, MD Matthew R. Lindberg, MD
36 Feature-Based Approach to Diagnosis 120 Proliferative Fasciitis/Myositis
Matthew R. Lindberg, MD Matthew R. Lindberg, MD
124 Ischemic Fasciitis
SECTION 3: TUMORS OF ADIPOSE TISSUE Matthew R. Lindberg, MD
126 Myositis Ossificans
BENIGN
Matthew R. Lindberg, MD
46 Lipoma 130 Fibroosseous Pseudotumor of Digit
Matthew R. Lindberg, MD David Lucas, MD and Elizabeth A. Montgomery, MD
52 Lipomatosis of Nerve 134 Fibroma of Tendon Sheath
Jerad M. Gardner, MD David Lucas, MD
54 Synovial Lipomatosis 140 Desmoplastic Fibroblastoma
Matthew R. Lindberg, MD David Cassarino, MD, PhD and Khin Thway, MD, FRCPath
56 Angiolipoma 142 Elastofibroma
Jerad M. Gardner, MD Matthew R. Lindberg, MD
60 Spindle Cell/Pleomorphic Lipoma 144 Angiofibroma of Soft Tissue
Matthew R. Lindberg, MD Matthew R. Lindberg, MD
66 Chondroid Lipoma 148 Mammary-Type Myofibroblastoma
Matthew R. Lindberg, MD Matthew R. Lindberg, MD
70 Myolipoma 152 Intranodal Palisaded Myofibroblastoma
Jerad M. Gardner, MD Matthew R. Lindberg, MD

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 TABLE OF CONTENTS
156 Pleomorphic Fibroma 254 Fibromatosis Colli
David Cassarino, MD, PhD Kandi Stallings-Archer, MD and Cyril Fisher, MD, DSc,
158 Dermatomyofibroma FRCPath
David Cassarino, MD, PhD 256 Gardner Fibroma
160 Storiform Collagenoma Jerad M. Gardner, MD
David Cassarino, MD, PhD
162 Keloid INTERMEDIATE (LOCALLY AGGRESSIVE)
David Cassarino, MD, PhD 258 Lipofibromatosis
164 Nuchal-Type Fibroma Kandi Stallings-Archer, MD and Elizabeth A. Montgomery,
Matthew R. Lindberg, MD MD
260 Giant Cell Fibroblastoma
INTERMEDIATE (LOCALLY AGGRESSIVE) Matthew R. Lindberg, MD
166 Palmar/Plantar Fibromatosis
Matthew R. Lindberg, MD INTERMEDIATE (RARELY METASTASIZING)
168 Desmoid-Type Fibromatosis 264 Infantile Fibrosarcoma
Matthew R. Lindberg, MD Matthew R. Lindberg, MD
INTERMEDIATE (RARELY METASTASIZING) SECTION 6: FIBROHISTIOCYTIC,
174 Dermatofibrosarcoma Protuberans HISTIOCYTIC, AND DENDRITIC CELL
Matthew R. Lindberg, MD TUMORS
184 Solitary Fibrous Tumor
Matthew R. Lindberg, MD BENIGN
192 Low-Grade Myofibroblastic Sarcoma 270 Dermatofibroma and Fibrous Histiocytoma
Matthew R. Lindberg, MD David Cassarino, MD, PhD
196 Inflammatory Myofibroblastic Tumor 276 Deep Benign Fibrous Histiocytoma
Matthew R. Lindberg, MD Matthew R. Lindberg, MD
202 Myxoinflammatory Fibroblastic Sarcoma 278 Localized-Type Tenosynovial Giant Cell Tumor
Matthew R. Lindberg, MD David Lucas, MD
210 Superficial CD34(+) Fibroblastic Tumor 284 Diffuse-Type Tenosynovial Giant Cell Tumor
Matthew R. Lindberg, MD David Lucas, MD
290 Cellular Neurothekeoma
MALIGNANT Jerad M. Gardner, MD and Cyril Fisher, MD, DSc, FRCPath
214 Adult-Type Fibrosarcoma 294 Xanthomas
Jerad M. Gardner, MD Matthew R. Lindberg, MD
216 Myxofibrosarcoma 298 Solitary (Juvenile) Xanthogranuloma
Matthew R. Lindberg, MD David Cassarino, MD, PhD and Elizabeth A. Montgomery,
222 Low-Grade Fibromyxoid Sarcoma MD
Matthew R. Lindberg, MD 300 Reticulohistiocytoma
232 Sclerosing Epithelioid Fibrosarcoma David Cassarino, MD, PhD
Matthew R. Lindberg, MD 304 Deep Granuloma Annulare
Jerad M. Gardner, MD
SECTION 5: PEDIATRIC 306 Rheumatoid Nodule
FIBROBLASTIC/MYOFIBROBLASTIC Jerad M. Gardner, MD
TUMORS 308 Langerhans Cell Histiocytosis
Matthew R. Lindberg, MD
BENIGN 310 Extranodal Rosai-Dorfman Disease
240 Fibrous Hamartoma of Infancy Matthew R. Lindberg, MD
Matthew R. Lindberg, MD 314 Crystal-Storing Histiocytosis
244 Calcifying Aponeurotic Fibroma Matthew R. Lindberg, MD and Elizabeth A. Montgomery,
Matthew R. Lindberg, MD MD
248 Calcifying Fibrous Tumor
Kandi Stallings-Archer, MD and Elizabeth A. Montgomery, INTERMEDIATE (RARELY METASTASIZING)
MD 316 Plexiform Fibrohistiocytic Tumor
250 Inclusion Body Fibromatosis Matthew R. Lindberg, MD
Matthew R. Lindberg, MD 320 Giant Cell Tumor of Soft Tissue
252 Hyaline Fibromatosis Syndrome David Lucas, MD
Kandi Stallings-Archer, MD, Elizabeth A. Montgomery,
MD, and Cyril Fisher, MD, DSc, FRCPath

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 TABLE OF CONTENTS
MALIGNANT MALIGNANT
324 Histiocytic Sarcoma 380 Embryonal Rhabdomyosarcoma
Matthew R. Lindberg, MD Matthew R. Lindberg, MD
326 Follicular Dendritic Cell Sarcoma 386 Alveolar Rhabdomyosarcoma
Matthew R. Lindberg, MD Matthew R. Lindberg, MD
328 Interdigitating Dendritic Cell Sarcoma 392 Spindle Cell Rhabdomyosarcoma
Matthew R. Lindberg, MD, L. Jeffrey Medeiros, MD, and Matthew R. Lindberg, MD
Cyril Fisher, MD, DSc, FRCPath 396 Sclerosing Rhabdomyosarcoma
Matthew R. Lindberg, MD
SECTION 7: SMOOTH MUSCLE TUMORS 400 Pleomorphic Rhabdomyosarcoma
Jerad M. Gardner, MD
BENIGN 404 Epithelioid Rhabdomyosarcoma
332 Smooth Muscle Hamartoma Matthew R. Lindberg, MD
Jerad M. Gardner, MD
334 Superficial Leiomyoma SECTION 10: VASCULAR TUMORS
Jerad M. Gardner, MD and Jonathan B. McHugh, MD (INCLUDING LYMPHATICS)
338 Deep Leiomyoma
Matthew R. Lindberg, MD BENIGN
408 Papillary Endothelial Hyperplasia
INTERMEDIATE David Cassarino, MD, PhD and Amitabh Srivastava, MD
342 Epstein-Barr Virus-Associated Smooth Muscle Tumor 410 Bacillary Angiomatosis
David Lucas, MD David Cassarino, MD, PhD
412 Congenital Hemangioma
MALIGNANT Kandi Stallings-Archer, MD
416 Infantile Hemangioma
344 Leiomyosarcoma
Kandi Stallings-Archer, MD
Matthew R. Lindberg, MD
420 Lobular Capillary Hemangioma
SECTION 8: PERICYTIC (PERIVASCULAR) Matthew R. Lindberg, MD
TUMORS 422 Epithelioid Hemangioma
Matthew R. Lindberg, MD
BENIGN 426 Spindle Cell Hemangioma
Jerad M. Gardner, MD
352 Glomus Tumors (and Variants)
430 Intramuscular Hemangioma
Thomas Mentzel, MD and Matthew R. Lindberg, MD
Matthew R. Lindberg, MD and Jonathan B. McHugh, MD
358 Myopericytoma
434 Hobnail Hemangioma
Matthew R. Lindberg, MD and Thomas Mentzel, MD
David Cassarino, MD, PhD
362 Myofibroma and Myofibromatosis
436 Acquired Tufted Angioma
Matthew R. Lindberg, MD
David Cassarino, MD, PhD
366 Angioleiomyoma
438 Microvenular Hemangioma
Matthew R. Lindberg, MD
David Cassarino, MD, PhD
SECTION 9: TUMORS OF SKELETAL 440 Sinusoidal Hemangioma
David Cassarino, MD, PhD
MUSCLE
442 Glomeruloid Hemangioma
BENIGN David Cassarino, MD, PhD
444 Angiomatosis
370 Focal Myositis David Lucas, MD
Matthew R. Lindberg, MD and Cyril Fisher, MD, DSc, 446 Lymphangioma
FRCPath David Cassarino, MD, PhD
372 Adult Rhabdomyoma 450 Massive Localized Lymphedema
Matthew R. Lindberg, MD Matthew R. Lindberg, MD
374 Fetal Rhabdomyoma 452 Atypical Vascular Lesion
Matthew R. Lindberg, MD David Lucas, MD
376 Genital Rhabdomyoma
Matthew R. Lindberg, MD INTERMEDIATE (LOCALLY AGGRESSIVE)
378 Cardiac Rhabdomyoma
Matthew R. Lindberg, MD 454 Kaposiform Hemangioendothelioma
David Lucas, MD

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 TABLE OF CONTENTS
INTERMEDIATE (RARELY METASTASIZING) INTERMEDIATE
456 Papillary Intralymphatic Angioendothelioma 556 Melanotic Schwannoma
David Cassarino, MD, PhD Matthew R. Lindberg, MD
458 Retiform Hemangioendothelioma
David Cassarino, MD, PhD MALIGNANT
460 Composite Hemangioendothelioma 558 Malignant Peripheral Nerve Sheath Tumor
David Lucas, MD Matthew R. Lindberg, MD
462 Pseudomyogenic Hemangioendothelioma 566 Epithelioid Malignant Peripheral Nerve Sheath
Matthew R. Lindberg, MD Tumor
Matthew R. Lindberg, MD
MALIGNANT 570 Ectomesenchymoma
466 Epithelioid Hemangioendothelioma Matthew R. Lindberg, MD and Cyril Fisher, MD, DSc,
Matthew R. Lindberg, MD and Thomas Mentzel, MD FRCPath
470 Angiosarcoma
Matthew R. Lindberg, MD SECTION 13: GENITAL STROMAL
476 Kaposi Sarcoma TUMORS
Jerad M. Gardner, MD and Thomas Mentzel, MD 574 Fibroepithelial Stromal Polyp
Matthew R. Lindberg, MD
SECTION 11: CHONDROOSSEOUS 576 Angiomyofibroblastoma
TUMORS Matthew R. Lindberg, MD
BENIGN 580 Cellular Angiofibroma
Matthew R. Lindberg, MD
486 Soft Tissue Chondroma 584 Deep (Aggressive) Angiomyxoma
David Lucas, MD Matthew R. Lindberg, MD
492 Synovial Chondromatosis
David Lucas, MD SECTION 14: TUMORS OF MESOTHELIAL
CELLS
MALIGNANT
496 Extraskeletal Osteosarcoma BENIGN
David Lucas, MD 590 Adenomatoid Tumor
500 Extraskeletal Mesenchymal Chondrosarcoma Matthew R. Lindberg, MD
David Lucas, MD 592 Multicystic Peritoneal Mesothelioma
Matthew R. Lindberg, MD
SECTION 12: PERIPHERAL NERVE 594 Well-Differentiated Papillary Mesothelioma
SHEATH TUMORS David Lucas, MD and Cyril Fisher, MD, DSc, FRCPath
BENIGN MALIGNANT
506 Solitary Circumscribed Neuroma 598 Malignant Mesothelioma
Jerad M. Gardner, MD Matthew R. Lindberg, MD and Cyril Fisher, MD, DSc,
508 Schwannoma FRCPath
Matthew R. Lindberg, MD
522 Neurofibroma SECTION 15: HEMATOPOIETIC TUMORS
Matthew R. Lindberg, MD IN SOFT TISSUE
530 Perineurioma
Matthew R. Lindberg, MD 606 Solitary Extramedullary Plasmacytoma
536 Hybrid Nerve Sheath Tumor Matthew R. Lindberg, MD
Matthew R. Lindberg, MD 608 Myeloid Sarcoma
540 Granular Cell Tumor Matthew R. Lindberg, MD
Matthew R. Lindberg, MD 610 Lymphoma of Soft Tissue
546 Dermal Nerve Sheath Myxoma Matthew R. Lindberg, MD and Khin Thway, MD, FRCPath
David Lucas, MD
550 Ganglioneuroma SECTION 16: TUMORS OF UNCERTAIN
Matthew R. Lindberg, MD DIFFERENTIATION
554 Neuromuscular Choristoma BENIGN
David Lucas, MD
614 Intramuscular Myxoma
Matthew R. Lindberg, MD

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 TABLE OF CONTENTS
618 Juxtaarticular Myxoma 728 Undifferentiated Round Cell Sarcoma With CIC-DUX4
Matthew R. Lindberg, MD and Khin Thway, MD, FRCPath Translocation
620 Superficial Angiomyxoma David Lucas, MD
Jerad M. Gardner, MD 734 BCOR-CCNB3 Fusion-Positive Sarcoma
624 Acral Fibromyxoma David Lucas, MD
Matthew R. Lindberg, MD
626 Pleomorphic Hyalinizing Angiectatic Tumor SECTION 18: MESENCHYMAL TUMORS
Matthew R. Lindberg, MD and Cyril Fisher, MD, DSc, OF GASTROINTESTINAL TRACT
FRCPath 740 Benign Neural Gastrointestinal Polyps
630 Aneurysmal Bone Cyst of Soft Tissue Matthew R. Lindberg, MD
Matthew R. Lindberg, MD 744 Gastrointestinal Stromal Tumor
632 Ectopic Hamartomatous Thymoma Matthew R. Lindberg, MD
Matthew R. Lindberg, MD 760 Gastrointestinal Schwannoma
Matthew R. Lindberg, MD
INTERMEDIATE (LOCALLY AGGRESSIVE)
762 Gastrointestinal Smooth Muscle Neoplasms
634 Hemosiderotic Fibrolipomatous Tumor Matthew R. Lindberg, MD
Matthew R. Lindberg, MD 766 Inflammatory Fibroid Polyp
Matthew R. Lindberg, MD
INTERMEDIATE (RARELY METASTASIZING) 770 Gangliocytic Paraganglioma
636 Atypical Fibroxanthoma Matthew R. Lindberg, MD
David Cassarino, MD, PhD 772 Plexiform Fibromyxoma
642 Angiomatoid Fibrous Histiocytoma Matthew R. Lindberg, MD
Matthew R. Lindberg, MD 776 Malignant Gastrointestinal Neuroectodermal Tumor
650 Ossifying Fibromyxoid Tumor Matthew R. Lindberg, MD
Matthew R. Lindberg, MD
656 Myoepithelioma of Soft Tissue SECTION 19: OTHER ENTITIES
Matthew R. Lindberg, MD
664 Phosphaturic Mesenchymal Tumor
BENIGN
Matthew R. Lindberg, MD 782 Amyloidoma
Matthew R. Lindberg, MD
MALIGNANT 784 Ganglion Cyst
666 Synovial Sarcoma Matthew R. Lindberg, MD
Matthew R. Lindberg, MD 786 Tumoral Calcinosis
678 Epithelioid Sarcoma Matthew R. Lindberg, MD
Matthew R. Lindberg, MD 788 Idiopathic Tumefactive Fibroinflammatory Lesions
684 Alveolar Soft Part Sarcoma Matthew R. Lindberg, MD
Matthew R. Lindberg, MD 792 Cardiac Myxoma
688 Clear Cell Sarcoma Matthew R. Lindberg, MD
Jerad M. Gardner, MD 796 Cardiac Fibroma
692 Perivascular Epithelioid Cell Tumor (PEComa) Matthew R. Lindberg, MD
Matthew R. Lindberg, MD 798 Congenital Granular Cell Epulis
700 Desmoplastic Small Round Cell Tumor Matthew R. Lindberg, MD
Matthew R. Lindberg, MD 800 Nasopharyngeal Angiofibroma
706 Extraskeletal Ewing Sarcoma Matthew R. Lindberg, MD, Lester D. R. Thompson, MD,
Kandi Stallings-Archer, MD and Cyril Fisher, MD, DSc, and Cyril Fisher, MD, DSc, FRCPath
FRCPath 804 Sinonasal Glomangiopericytoma
712 Extraskeletal Myxoid Chondrosarcoma Matthew R. Lindberg, MD and Jonathan B. McHugh, MD
David Lucas, MD 810 Ectopic Meningioma
716 Extrarenal Rhabdoid Tumor Matthew R. Lindberg, MD
Matthew R. Lindberg, MD 812 Glial Heterotopia
720 Intimal Sarcoma Matthew R. Lindberg, MD
Jerad M. Gardner, MD
INTERMEDIATE
SECTION 17: 814 Paraganglioma
UNDIFFERENTIATED/UNCLASSIFIED Matthew R. Lindberg, MD
SARCOMAS 822 Peripheral Hemangioblastoma
724 Undifferentiated Pleomorphic Sarcoma Matthew R. Lindberg, MD
Matthew R. Lindberg, MD 824 Melanotic Neuroectodermal Tumor of Infancy
Matthew R. Lindberg, MD

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826 Ependymoma of Soft Tissue
Matthew R. Lindberg, MD

MALIGNANT
828 Metastatic Tumors to Soft Tissue Sites
Matthew R. Lindberg, MD
832 Neuroblastoma and Ganglioneuroblastoma
Kandi Stallings-Archer, MD, Jessica M. Comstock, MD, and
Cyril Fisher, MD, DSc, FRCPath
842 Extraaxial Soft Tissue Chordoma
Jerad M. Gardner, MD
844 Undifferentiated Embryonal Sarcoma of Liver
Matthew R. Lindberg, MD
846 Primary Pulmonary Myxoid Sarcoma
David Lucas, MD
850 Biphenotypic Sinonasal Sarcoma
Matthew R. Lindberg, MD
854 Spindle Epithelial Tumor With Thymus-Like
Differentiation
Matthew R. Lindberg, MD
856 Low-Grade Endometrial Stromal Sarcoma
Charles Matthew Quick, MD and Khin Thway, MD,
FRCPath

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THIRD EDITION
 SECTION 1

Soft Tissue Introduction

Introduction and Overview

Gross Examination 4
Grading and Staging 6

Ancillary Techniques
Soft Tissue Immunohistochemistry 12
Molecular Features of Soft Tissue Tumors 18
 Gross Examination
Soft Tissue Introduction

• Note any orientation provided by surgeon (e.g., stitches,

INTRODUCTION
Overview
• Thorough but focused gross examination is vital
component of overall evaluation and diagnostic work-up of
soft tissue tumors
• Common errors (e.g., undersampling, inappropriate
sampling, not inking margins) can severely hamper or
preclude accurate diagnosis, pathologic staging, and
subsequent clinical planning
• Review of patient clinical history and information prior to
gross examination is strongly recommended
CLINICAL FINDINGS
History
• Review any available clinical notes or operative report
○ Note age of patient and clinical presentation of tumor
○ Note if patient has prior history of tumor in same
anatomic location, nearby, or elsewhere
• Determine whether tumor has been previously biopsied or
treated or if there is established diagnosis
Imaging
• Review any pertinent radiographs, CT, or MR scans
○ Determine if tumor is homogeneous or heterogeneous
○ Identify any notable structures involved (e.g., large nerve
trunk)
○ Determine whether radiologist favors benign or
malignant process
• Note anatomic location (e.g., thigh, neck, retroperitoneum,
finger)
• Note tissue plane (i.e., superficial/subcutaneous vs.
deep/intramuscular)
GROSSING PROCEDURE
External Examination
• Specimen should be weighed and measured in 3
dimensions
• Describe external appearance and shape of mass
strip of overlying skin, large nerves)
○ Skin is often excised to remove previous biopsy tract
with rest of specimen
• Ink peripheral margins of specimen
○ Oriented tumors often require inking with up to 6
different colors
○ Unoriented tumors may be inked in 1 color
Sectioning and Internal Evaluation
• Serially section ("bread loaf") mass in 1-cm thick sections,
perpendicular to long axis of specimen
• Lay out all slabs of tumor and examine cut surfaces
• Describe appearance of cut surface and note areas of
different coloration &/or texture
○ Common colors: Tan, white, gray, red, brown
○ Common textures: Firm/fibrous, fleshy,
gelatinous/glistening, fatty
• Note any areas of hemorrhage &/or necrosis
○ Quantify necrosis (none, ≤ 50%, or > 50%)
○ Highly necrotic tumors should be placed in formalin to fix
and to minimize fragmentation
• Take representative fresh tissue for possible ancillary
techniques or treatment protocols (may be snap frozen)
Sampling
• Standard approach is to take 1 section per cm of greatest
tumor dimension (margin sections counted separately)
○ e.g., 16-cm tumor gets 16 blocks with 1 tissue piece in
each or 8 blocks with 2 tissue pieces in each
○ Fewer sections may be submitted for large tumors with
diffuse homogeneous appearance
• Inked margins, specifically close (< 2 cm) margins, should be
sampled with perpendicular sections
• Sections should be taken from all distinctive areas (e.g.,
fibrous, gelatinous, fleshy, etc.)
○ Sections taken at interface between different areas can
provide very useful histologic information
• Obviously necrotic areas should be minimally sampled
○ These areas often represent high-grade morphologies
and are generally less useful diagnostically

External Examination Specimen Inking

(Left) The gross appearance of
a soft tissue tumor specimen
varies depending on the type
of surgery, but many tumors
(especially sarcomas) are
removed with at least a thin
rim of surrounding soft tissue.
If the tumor has been
previously sampled by core
biopsy, the biopsy tract ﬉ and
skin strip are often removed as
well. (Right) Although known
benign soft tissue tumors are
often excised without
orientation by the surgeon,
sarcomas often arrive oriented
by stitches and require inking,
as depicted, for satisfactory
margin evaluation.

4
 Gross Examination
Serial Sectioning
Evaluation of Cut Surface
Large Homogeneous Tumors
Soft Tissue Introduction
Evaluation of Cut Surface
(Left) After external
examination and inking of the
soft tissue tumor specimen, it
should be serially sectioned in
~ 1-cm slices. After all sections
are laid out, the margins
should be assessed and
sampled, and the appearance
of the cut surfaces should be
evaluated with any variations
noted. (Right) The cut surface
of a soft tissue tumor may
show a variety of appearances
(e.g., fibrous ﬈, fleshy, fatty,
gelatinous ﬊), and all
distinctive areas should be
noted and sampled. Transition
areas should be particularly
targeted.
Documentation of Necrosis
(Left) Gross photo of a
dedifferentiated liposarcoma
shows a mixture of fibrous ﬈
and fleshy ﬇ areas
representing the high-grade
component. The minimal, well-
differentiated component ﬉
may be easily mistaken for
normal fat and ignored.
(Right) It is important to assess
and document the amount of
necrosis ſt present during
gross examination, as it may
be useful in subsequent
grading of the tumor. Of note,
sometimes nonnecrotic,
degenerative, edematous, or
myxoid areas may be mistaken
for necrosis grossly.
En Bloc Radical Resection Specimen
(Left) Some larger soft tissue
tumors show a similar
homogeneous cut surface on
all gross slices without areas
of variation, as is seen in this
gross photo of a lipoma. The
"1 section per cm" rule may be
relaxed in this situation.
(Right) Soft tissue tumors that
arise in body cavities
(particularly the
retroperitoneum) can grow to
incredible sizes and may
require radical surgical
resection and debulking. This
gross photo shows a
dedifferentiated liposarcoma
with renal ſt involvement.
5
 Grading and Staging
Soft Tissue Introduction

GRADING AND STAGING SYSTEMS Overall Histologic Grade

• Summation of 3 individual scores indicates grade
Grading System ○ Grade 1 (low grade): Total score 2 or 3
• French FNCLCC system most commonly utilized ○ Grade 2 (intermediate grade): Total score 4 or 5
Staging System ○ Grade 3 (high grade): Total score 6, 7, or 8
• TNM system (AJCC Cancer Staging Manual, 8th edition) Limitations
• Grading schemata apply best to fully excised specimens
HISTOLOGIC FEATURES EVALUATED IN that have not been preoperatively treated with
GRADING (FNCLCC) neoadjuvant therapies
Method ○ Only minimum grade can be applied to limited (biopsy)
sample
• Assign following 3 independent scores based upon
○ Sarcomas treated preoperatively with chemotherapy
particular histologic parameters
&/or radiation cannot be accurately graded
○ Differentiation
• For some sarcomas, grade is automatically defined by
○ Mitotic rate
histologic subtype
○ Necrosis
○ Always grade 1 (low grade)
• 3 independent scores are totaled to determine histologic
– Well-differentiated LPS
grade of sarcoma
– Conventional dermatofibrosarcoma protuberans
Degree of Cellular Differentiation – Infantile fibrosarcoma
• Score 1: Sarcomas closely resembling normal, adult ○ Always grade 3 (high grade)
mesenchymal tissue – Ewing sarcoma
○ Well-differentiated examples of liposarcoma (LPS) – High-grade myxoid LPS (formerly round cell LPS)
○ Leiomyosarcoma – Pleomorphic LPS
○ Malignant peripheral nerve sheath tumor (MPNST) – Dedifferentiated LPS
○ Others – Extraskeletal osteosarcoma
• Score 2: Sarcoma for which histologic typing is certain – Mesenchymal chondrosarcoma
○ Myxofibrosarcoma – Desmoplastic small round cell tumor
○ Myxoid LPS (excluding cellular/round cell) – Extrarenal rhabdoid tumor
○ Conventional leiomyosarcoma ○ Not formally graded but often managed as high grade
○ MPNST – Alveolar soft part sarcoma
○ Others – Clear cell sarcoma
• Score 3: Embryonal or undifferentiated sarcomas, synovial – Epithelioid sarcoma
sarcoma, or sarcoma of uncertain type – Extraskeletal myxoid chondrosarcoma
○ Dedifferentiated LPS – Angiosarcoma
○ Pleomorphic LPS – Embryonal and alveolar rhabdomyosarcoma
○ High-grade myxoid LPS (formerly round cell LPS)
Additional Considerations
○ Most rhabdomyosarcoma
○ Ewing sarcoma • Some mesenchymal neoplasms have unique criteria for
histologic grading (or risk assessment) and do not routinely
○ Mesenchymal chondrosarcoma
utilize FNCLCC system
○ Extraskeletal osteosarcoma
○ Epithelioid hemangioendothelioma
○ Pleomorphic leiomyosarcoma 
○ Gastrointestinal stromal tumor
○ Pleomorphic MPNST
○ Solitary fibrous tumor
○ Undifferentiated pleomorphic sarcoma
○ Ossifying fibromyxoid tumor
Mitotic Rate (Mitoses per 10 HPF) ○ PEComa
• Score 1: 0-9
• Score 2: 10-19
• Score 3: > 19
○ Count total number in 10 successive HPF (40x objective)
in most mitotically active areas
○ Avoid ulcerated, necrotic, or hypocellular areas
Percentage of Microscopic Tumor Necrosis
• Score 0: No necrosis
• Score 1: Necrosis < 50% total tumor volume
• Score 2: Necrosis ≥ 50% total tumor volume
○ Tumor necrosis should be evaluated at macroscopic and
microscopic levels

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 Grading and Staging

Soft Tissue Introduction

Soft Tissue Sarcoma Staging (TNM System) for Trunk and Extremities
Pathologic Staging Category Description
Primary Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor ≤ 5 cm in greatest dimension
T2 Tumor > 5 cm and ≤ 10 cm in greatest dimension
T3 Tumor > 10 cm and ≤ 15 cm in greatest dimension
T4 Tumor > 15 cm in greatest dimension
Regional Lymph Nodes (N)
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
Distant Metastasis (M)
M1 Distant metastasis [specify site(s), if known]

All tables adapted from 8th edition AJCC Staging Forms (2018). Nx designation not used for soft tissue tumors.

Soft Tissue Sarcoma Staging (TNM System) for Retroperitoneum

Pathologic Staging Category Description
Primary Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor ≤ 5 cm in greatest dimension
T2 Tumor > 5 cm and ≤ 10 cm in greatest dimension
T3 Tumor > 10 cm and ≤ 15 cm in greatest dimension
T4 Tumor > 15 cm in greatest dimension
Regional Lymph Nodes (N)
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
Distant Metastasis (M)
M1 Distant metastasis [specify site(s), if known]

Soft Tissue Sarcoma Staging (TNM System) for Orbit

Pathologic Staging Category Description
Primary Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor ≤ 2 cm in greatest dimension
T2 Tumor > 2 cm in greatest dimension without invasion of bony walls or globe
T3 Tumor of any size with invasion of bony walls
T4 Tumor of any size with invasion of globe or periorbital structures, including eyelid, conjunctiva,
temporal fossa, nasal cavity, paranasal sinuses, &/or central nervous system
Regional Lymph Nodes (N)
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
Distant Metastasis (M)
M1 Distant metastasis [specify site(s), if known]

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 Grading and Staging
Soft Tissue Introduction

Soft Tissue Sarcoma Staging (TNM System) for Abdomen and Thoracic Organs
Pathologic Staging Category Description
Primary Tumor (T)
TX Primary tumor cannot be assessed
T1 Tumor is organ confined
T2 Tumor extension into tissue beyond organ
T2a Tumor invades serosa or visceral peritoneum
T2b Tumor extends beyond serosa (mesentery)
T3 Tumor invades another organ
T4 Multifocal involvement
T4a Multifocal (2 sites)
T4b Multifocal (3-5 sites)
T4c Multifocal (> 5 sites)
Regional Lymph Nodes (N)
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
Distant Metastasis (M)
M1 Distant metastasis [specify site(s), if known]

All tables adapted from 8th edition AJCC Staging Forms (2017).

Soft Tissue Sarcoma Staging (pTNM System) for Head and Neck
Pathologic Staging Category Description
Primary Tumor (T)
TX Primary tumor cannot be assessed
T1 Tumor ≤ 2 cm
T2 Tumor > 2 to ≤ 4 cm
T3 Tumor > 4 cm
T4 Tumor with invasion of adjoining structures
T4a Tumor with orbital invasion, skull base/dural invasion, invasion of central compartment viscera,
involvement of facial skeleton, or invasion of pterygoid muscles
T4b Tumor with brain parenchymal invasion, carotid artery encasement, prevertebral muscle invasion,
or central nervous system involvement via perineural spread
Regional Lymph Nodes (N)
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
Distant Metastasis (M)
M1 Distant metastasis [specify site(s), if known]

Additional Descriptors (pTNM system)

Descriptor Meaning
Prefix
y Tumor is being staged post therapy (i.e., neoadjuvant chemotherapy, radiation therapy, or
both chemotherapy and radiation)
r Tumor is recurrent (must follow documented disease-free interval)
Suffix
m Multiple primary tumors involving single site

Example: ypT3(m)N0 in pathologic stage T3 sarcoma, multifocal, treated with neoadjuvant therapy prior to resection.

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 Grading and Staging

Soft Tissue Introduction

Anatomic Stage/Prognostic Groups (Trunk and Extremities)
Stage Tumor Node Metastasis Grade (G)
Stage IA T1 N0 M0 G1 or GX (low grade)
Stage IB T2 N0 M0 G1 or GX (low grade)
T3 N0 M0 G1 or GX (low grade)
T4 N0 M0 G1 or GX (low grade)
Stage II T1 N0 M0 G2 or G3 (high grade)
Stage IIIA T2 N0 M0 G2 or G3 (high grade)
Stage IIIB T3 N0 M0 G2 or G3 (high grade)
T4 N0 M0 G2 or G3 (high grade)
Stage IV Any T N1 M0 Any G
Any T Any N M1 Any G

All tables adapted from 8th edition AJCC Staging Forms (2017). GX: Grade cannot be assessed; M0: No distant metastasis.

Anatomic Stage/Prognostic Groups (Retroperitoneum)

Stage Tumor Node Metastasis Grade (G)
Stage IA T1 N0 M0 G1 or GX (low grade)
Stage IB T2 N0 M0 G1 or GX (low grade)
T3 N0 M0 G1 or GX (low grade)
T4 N0 M0 G1 or GX (low grade)
Stage II T1 N0 M0 G2 or G3 (high grade)
Stage IIIA T2 N0 M0 G2 or G3 (high grade)
Stage IIIB T3 N0 M0 G2 or G3 (high grade)
T4 N0 M0 G2 or G3 (high grade)
Stage IV Any T N1 M0 Any G
Any T Any N M1 Any G

No formal stage groupings exist for head and neck, orbit, abdominal visceral organs, and thoracic visceral organ sites.

9
 Grading and Staging
Soft Tissue Introduction

T1 (TNM Staging) T1 (TNM Staging)

(Left) Axial graphic of the
thigh shows a T1 soft tissue
sarcoma ﬈. By definition,
these tumors are ≤ 5 cm in
greatest dimension. The
previous "a" and "b"
designations used to denote
superficial (T1a) and deep
localization (T1b) are no
longer utilized. (Right) Axial
graphic of the thigh shows a
T1 soft tissue sarcoma ﬈
measuring < 5 cm. Though
once designated "pT1b" in
previous staging schema due
to its deep/subfascial
involvement, this tumor would
now be staged purely as T1.

T2 (TNM Staging) T3 (TNM Staging)

(Left) Axial graphic of the
thigh shows a T2 soft tissue
sarcoma ﬈. By definition,
these tumors measure 5-10 cm
in greatest dimension.
Localization above or below
the fascia is no longer taken
into account. (Right) Axial
graphic of the thigh shows a
T3 soft tissue sarcoma ﬈. By
definition, these tumors
measure 10-15 cm in greatest
dimension. Although the
tumor arises in the muscle, it
does not affect the staging
designation.

T4 (TNM Staging) Anatomic/Prognosis Stage IA Group

(Left) Axial graphic of the
thigh shows a T4 soft tissue
sarcoma ﬈. By definition,
these tumors measure > 15 cm
in greatest dimension. (Right)
Axial graphic and MR show an
anatomic stage IA soft tissue
sarcoma ﬈ of the extremity.
By definition, the tumor is < 5
cm, histologically low grade,
and no metastases (nodal or
distant) are present. If this
tumor were > 5 cm, it would
be grouped as IB.

10
 Grading and Staging
Anatomic/Prognosis Stage II Group
Anatomic/Prognosis Stage IV Group
Anatomic/Prognosis Stage IV Group
Soft Tissue Introduction
Anatomic/Prognosis Stage IIIB Group
(Left) Axial graphic and MR of
the extremity show a stage II
soft tissue sarcoma ﬈. These
lesions are G2 or G3 (high
grade) and all measure < 5 cm
in greatest dimension. No
metastases are present.
(Right) Axial graphic and MR
of the extremity show a stage
IIIB soft tissue sarcoma ﬈.
These tumors are G2 or G3
(high grade), and all measure
> 10 cm in greatest dimension.
No nodal metastases are
present. If this same tumor
measured between 5-10 cm, it
would be grouped as IIIA.
Anatomic/Prognosis Stage III Group
(Left) Axial graphic through
the low pelvis shows inguinal
adenopathy ﬉. The presence
of involved lymph nodes,
though uncommon in sarcoma,
makes this stage IV disease.
The primary tumor can be any
size or histologic grade. (Right)
Axial MR with contrast shows
an abnormal gluteus maximus
muscle ſt, which was
infiltrated with tumor. Note
the prominent inguinal
adenopathy ﬊, making this a
stage IV sarcoma.
Anatomic/Prognosis Stage IV Group
(Left) Coronal graphic through
the lungs demonstrates
multiple bilateral pulmonary
metastases ﬉ from a soft
tissue sarcoma. The presence
of distant metastases makes
this stage IV disease. In this
setting, the size and histologic
grade of the primary tumor
are irrelevant. (Right) This
chest radiograph in a patient
with a malignant nerve sheath
tumor shows multiple
pulmonary metastases ﬈ and
a large malignant effusion ﬉
filling the left hemithorax.
11
 Soft Tissue Immunohistochemistry
Soft Tissue Introduction

Commonly Used Antibodies in Soft Tissue Pathology

Antibody Name Main Diagnostic Utility Specific Notes or Caveats
ALK1 Inflammatory myofibroblastic tumor (IMT), epithelioid fibrous 50-60% of IMTs; occasionally seen in other tumors,
histiocytoma, angiomatoid fibrous histiocytoma including rhabdomyosarcoma and neuroblastoma
β-catenin Nuclear expression in fibromatosis (50-75% of cases) Nuclear expression occasionally seen in other tumors,
limiting specificity; cytoplasmic expression nonspecific
Brachyury Chordoma Nuclear expression specific for notochordal origin
Caldesmon Smooth muscle neoplasms, glomus, perivascular epithelioid cell Similar to desmin; can also be expressed in GIST
tumor (PEComa)
Calponin Smooth muscle neoplasms, myoepithelioma; myofibroblastic Relatively nonspecific; better markers available
lesions
Calretinin Malignant mesothelioma Also common in synovial sarcoma and schwannoma
CD163 Histiocytic proliferations Truly histiocyte specific; superior to CD68
CD21 Follicular dendritic cell sarcoma Absent in interdigitating dendritic cell sarcoma
CD31 Vascular lesions (endothelial marker) Pitfall: Weak granular expression in histiocytes
CD34 Dermatofibrosarcoma protuberans, solitary fibrous tumor (SFT), Always use in conjunction with morphology; diffuse
spindle cell lipoma, cellular angiofibroma, mammary-type expression is usually significant; weak &/or focal
myofibroblastoma, vascular lesions, epithelioid sarcoma expression is often nonspecific
CD45 Hematolymphoid proliferations (including lymphoma) Can be negative in lymphoblastic lymphomas
CD56 Limited applications due to lack of specificity Usually negative in Ewing sarcoma and lymphoblastic
lymphomas but expressed in many other small round
blue cell tumors, including poorly differentiated
synovial sarcoma; nonspecific in spindle cell lesions.
CD68 Histiocytic proliferations, fibrous histiocytomas, granular cell Lacks specificity (lysosome specific instead of histiocyte
tumor specific); CD163 is superior
CD99 Ewing sarcoma (strong, diffuse membranous expression) Caveat: Many other small round blue cell tumors may
show patchy, focal, &/or weak expression; always
negative in neuroblastoma
CD117 (C-kit) Gastrointestinal stromal tumor (GIST) Highest specificity in GI tract; can also be seen in clear
cell sarcoma, melanoma, PEComa, Kaposi sarcoma
CDK4 Atypical lipomatous tumor/well-differentiated liposarcoma, Nuclear expression; negative in lipoma and most other
dedifferentiated liposarcoma pleomorphic sarcomas; best utilized in conjunction with
MDM2
Claudin-1 Perineurioma May be seen focally in low-grade fibromyxoid sarcoma
Clusterin Follicular dendritic cell sarcoma Absent in interdigitating dendritic cell sarcoma
D2-40 (podoplanin) Lymphatic lesions; malignant mesothelioma Lacks specificity for lymphatic endothelium
Desmin Myogenic tumors, angiomatoid fibrous histiocytoma, Good screening marker for myogenic differentiation;
desmoplastic small round cell tumor (DSRCT), can be focally expressed in myofibroblastic tumors
angiomyofibroblastoma
DOG1 GIST Helpful second-line marker in GISTs that are CD117(-)
EMA Perineurioma, synovial sarcoma, epithelioid sarcoma, Limited utility due to nonspecificity; can also be seen in
myoepithelioma, ectopic meningioma low-grade fibromyxoid sarcoma
ERG Vascular neoplasms Nuclear expression; more specific than FLI-1
ER and PR Angiomyofibroblastoma, cellular angiofibroma, aggressive Expressed in mammary/gynecologic carcinomas
(deep) angiomyxoma, deep smooth muscle neoplasms
FLI-1 Vascular tumors, Ewing sarcoma Nuclear expression; similar to but less specific than
ERG; may also be expressed in lymphocytes,
lymphoblastic lymphoma, and other tumors
Factor XIII Fibrous histiocytoma (dermatofibroma) Stains intralesional histiocytes; limited utility as better
markers are available
FOSB Pseudomyogenic hemangioendothelioma, epithelioid Nuclear expression
hemangioma
GFAP Myoepithelioma, schwannoma, soft tissue ependymoma, Limited utility due to better markers available
gastrointestinal schwannoma
GLUT1 Infantile hemangioma, perineurioma Negative in congenital hemangioma, kaposiform

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 Soft Tissue Immunohistochemistry

Soft Tissue Introduction

Commonly Used Antibodies in Soft Tissue Pathology (Continued)
Antibody Name Main Diagnostic Utility Specific Notes or Caveats
hemangioendothelioma, and vascular malformations
H3K27me3 Malignant peripheral nerve sheath tumor (MPNST) Only loss of nuclear expression counts
HHV8 (LANA) Kaposi sarcoma Highly useful; nuclear expression
HMB-45 Melanoma, PEComa, clear cell sarcoma, melanotic schwannoma Can be negative or focally positive; often best used in
panel of melanocytic markers
INI1 (SMARCB1) Epithelioid sarcoma, malignant extrarenal rhabdoid tumor Only loss of nuclear expression counts; subset of
epithelioid MPNST, malignant myoepithelioma, and
extraskeletal myxoid chondrosarcoma show loss
Keratins Evidence of epithelial differentiation (epithelioid sarcoma, Caveat: Must always exclude carcinoma; can also be
synovial sarcoma, DSRCT, myoepithelioma, others) expressed in some epithelioid vascular tumors
MDM2 Atypical lipomatous tumor/well-differentiated liposarcoma, Nuclear expression; negative in lipoma and most other
dedifferentiated liposarcoma pleomorphic sarcomas
Melan-A (MART-1) Melanoma, PEComa, clear cell sarcoma, melanotic schwannoma Can be negative; best used in panel of melanocytic
markers; may also be focally expressed in epithelioid
GIST
MiTF Melanoma, PEComa, cellular neurothekeoma, clear cell sarcoma Nuclear expression; also expressed in granular cell
tumor; occasionally positive in histiocytes
MUC4 Low-grade fibromyxoid sarcoma, sclerosing epithelioid Also seen in subset of ossifying fibromyxoid tumor
fibrosarcoma
Muscle-specific actin Myogenic tumors, PEComa Similar to desmin
(HHF-35)
MyoD1 Rhabdomyoma, rhabdomyosarcomas, rhabdomyoblastic Only nuclear expression should be considered positive
elements
Myogenin (Myf4) Rhabdomyoma, rhabdomyosarcomas, rhabdomyoblastic Only nuclear expression should be considered positive
elements
NB84 Neuroblastoma Not entirely specific; occasionally seen focally in Ewing
sarcoma and several other small round blue cell tumors
Retinoblastoma (Rb) Spindle cell lipoma, cellular angiofibroma, mammary-type Only loss of nuclear expression is significant
protein myofibroblastoma, atypical spindle cell lipomatous tumor
S100 protein Schwannoma, neurofibroma, hybrid nerve sheath tumor, Always use in conjunction with morphology and panel
MPNST, melanoma, myoepithelioma, ossifying fibromyxoid of other immunostains
tumor, extranodal Rosai-Dorfman disease, others
SATB2 Extraskeletal osteosarcoma Nuclear expression; expressed in any osteoblastic cell
(not specific for osteosarcoma)
Smooth muscle actin Smooth muscle, myofibroblasts, glomus, PEComa Pattern of expression helpful (diffuse cytoplasmic vs.
wispy submembranous)
SOX10 Melanoma, peripheral nerve sheath tumors, MPNST, Nuclear expression; shows very similar sensitivity,
myoepithelioma specificity, and tissue distribution to S100 protein; does
not mark histiocytes; notable for expression in basal-
type breast carcinoma
STAT6 SFT Nuclear expression; appears highly specific for SFT
Synaptophysin Paraganglioma, neuroblastoma Can be expressed in some cases of extraskeletal
myxoid chondrosarcoma and alveolar
rhabdomyosarcoma
TdT Lymphoblastic lymphoma Assists in diagnosis of CD45(-) lymphoblastic
lymphomas
TFE3 Alveolar soft part sarcoma, granular cell tumor Also expressed in subsets of PEComa and epithelioid
hemangioendothelioma
TLE1 Synovial sarcoma Strong, diffuse nuclear expression; focal &/or weak
expression is nonspecific
Vimentin Generally not helpful in most situations (widespread expression) Extremely nonspecific overall but may be useful as
marker of antigen preservation
WT1 Mesothelioma, desmoplastic small round cell tumor, Nuclear expression; for DSRCT, antibodies recognizing
adenomatoid tumor, CIC-DUX4 sarcoma carboxy-terminus must be utilized

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 Soft Tissue Immunohistochemistry
Soft Tissue Introduction

Immunohistochemical Panel for Selected Spindle Cell Tumors in Soft Tissue

Tumor
Cellular angiofibroma
Dermatofibrosarcoma
protuberans (DFSP)
Fibromatosis
Inflammatory
myofibroblastic tumor
Leiomyosarcoma
Low-grade
myofibroblastic
sarcoma
Low-grade fibromyxoid -
sarcoma
Malignant peripheral
nerve sheath tumor
(MPNST)
Mammary-type
myofibroblastoma
Neurofibroma
Nodular fasciitis
Perivascular epithelioid -
cell tumor (PEComa)
Perineurioma
Schwannoma
Solitary fibrous tumor
Spindle cell lipoma
Spindle cell
rhabdomyosarcoma
Synovial sarcoma
Keratin S100 SMA Desmin CD34 Other Markers
Protein
- - - - +++ Loss of nuclear Rb protein expression
- - - - +++ CD34 expression decreased or absent in
fibrosarcomatous DFSP
- - +/- - - Nuclear β-catenin expression in majority of tumors
+/- - +++ +/- - ALK1(+) in over 50% of cases
- - +++ +/- - Caldesmon (+); occasional focal keratin (+)
- - +/- +/- - Nuclear atypia, desmin (+), and absence of nuclear β-
catenin favors this diagnosis over fibromatosis
- +/- - - MUC4 most specific marker; focal EMA expression
common
- +/- - - +/- S100(+) and SOX10(+) usually focal or patchy; desmin
expression seen in rhabdomyoblastic elements; loss of
nuclear H3L27me3 expression also seen
- - - +++ +++ Loss of nuclear Rb protein expression
- +++ - - +++ Contains mixture of S100(+) Schwann cells, CD34(+)
stromal cells, and EMA/claudin-1 (+) perineurial cells
- - +++ - - Rare focal desmin (+)
- +++ +/- - Myomelanocytic immunophenotype with additional
variable expression of HMB-45, melan-A, &/or MITF
- - - - +/- EMA(+), claudin-1 (+), GLUT1(+)
- +++ - - +/- CD34 expression usually subcapsular; focal keratin (+)
in retroperitoneal schwannomas
- - - - +++ Nuclear STAT6(+) is highly specific
- - - - +++ Loss of nuclear Rb protein expression
- - +/- +++ - Myogenin (+), MYOD1(+)
+++ +/- - - - TLE1(+); also expresses CD56 and calretinin

(+++) = typically positive; (+/-) = variably positive or negative; (-) = typically negative.

Immunohistochemical Panel for Selected Highly Pleomorphic Soft Tissue Tumors

Tumor Keratin S100 SMA Desmin Myogenin MDM2/ Notes
Protein CDK4
Dedifferentiated - - +/- - - +++ Most common in retroperitoneum
liposarcoma
Malignant - - +++ +/- - - Variable melanocytic marker expression
perivascular
epithelioid cell tumor
(PEComa)
Pleomorphic - - +++ +/- - - Should show morphologic features of smooth
leiomyosarcoma muscle differentiation
Melanoma - +++ - - - - Also SOX10(+); variable melanocytic markers
Pleomorphic - - +/- +++ +++ +/- Myogenin (+) often focal
rhabdomyosarcoma
Sarcomatoid +++ - +/- - - - p63(+) and p40(+) in squamous cell carcinoma
carcinoma
Undifferentiated - - +/- - - - Diagnosis of exclusion
pleomorphic sarcoma

(+++) = typically positive; (+/-) = variably positive or negative; (-) = typically negative.

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 Soft Tissue Immunohistochemistry

Soft Tissue Introduction

Immunohistochemical Panel for Large, Epithelioid Cell Tumors in Soft Tissue
Tumor Keratin S100 SMA Desmin CD34 HMB-45 INI1 TFE3 Notes
Protein
Alveolar soft part - - +/- +/- - - Retained +++ May show significant nuclear
sarcoma pleomorphism
Epithelioid +/- - - - +++ - Retained - Also positive for CD31 and ERG
angiosarcoma
Epithelioid +/- - - - +++ - Retained Subset Also positive for CD31 and ERG
hemangio-
endothelioma
Epithelioid - +++ - - - - Lost (50%) - Mosaic (patchy) loss of nuclear
malignant INI1 expression
peripheral nerve
sheath tumor
(MPNST)
Epithelioid +++ - - - +/- - Lost - Negative for p63 and CD31
sarcoma
Extrarenal +++ - - - - - Lost - May also appear as small round
rhabdoid tumor blue cell tumor
Granular cell - +++ - - - - Retained +++ Prominent granular cytoplasm
tumor
Melanoma - +++ - - - +++ Retained - Other melanocytic markers
(melan-A, MITF, tyrosinase)
Myoepithelioma +++ +++ +/- +/- - - Retained - Also expresses calponin;
variable GFAP, p63
Perivascular - - +++ +/- - +++ Retained Subset Can also express caldesmon,
epithelioid cell melan-A, MITF
tumor (PEComa)
Poorly +++ - - - - - Retained - p63 for squamous cell
differentiated carcinoma; various markers for
carcinoma adenocarcinoma (TTF-1, pax-8,
Hep-Par1, etc.)

(+++) = typically positive; (+/-) = variably positive or negative; (-) = typically negative.

Immunohistochemical Panel for Selected Small Round Blue Cell Tumors

Tumor Keratin CD99 NB84 CD45 Desmin Myogenin Synaptophysin Other Markers
Alveolar +/- - - - +++ +++ +/- Also MyoD1(+)
rhabdomyosarcoma
Desmoplastic small +++ +/- +/- - +++ (dot) - +/- WT1(+) if antibody recognizes
round cell tumor carboxy-terminus
Ewing sarcoma +/- +++ +/- - - - +/- FLI-1(+); notably CD56(-)
Extrarenal rhabdoid +++ +/- - - - - +/- Characteristic loss of nuclear
tumor INI1
Lymphoma - +/- - +++ - - - TdT(+) to help exclude CD45(-)
lymphoblastic lymphomas
Melanoma - - - - - - - S100(+), SOX10(+); variable
melanocytic
Neuroblastoma - - +++ - - - +++ Notable CD99 negativity
Poorly differentiated +/- +++ - - - - - TLE1(+); also commonly
synovial sarcoma expresses CD56
Small cell +++ - - - - - +++ TTF-1(+)
neuroendocrine
carcinoma

(+++) = typically positive; (+/-) = variably positive or negative; (-) = typically negative.

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 Soft Tissue Immunohistochemistry
Soft Tissue Introduction

Immunohistochemical Panel for Spindle Cell Tumors in GI Tract

Tumor Keratin S100 CD117 DOG1 CD34 SMA Desmin Notes
Protein (C-kit)
Desmoid fibromatosis - - - - - +/- - Nuclear β-catenin (+) in majority;
extrinsic to GI tract
Ganglioneuroma - +++ - - - - - Contains ganglion cells
Gastrointestinal - - +++ +++ +++ +/- - Most common overall
stromal tumor (GIST)
Granular cell tumor - +++ - - -- - - Prominent granular cytoplasm;
also epithelioid/polygonal tumor
cells
Hybrid nerve sheath - +++ - -- +/- - - Also expresses perineurial
tumor markers (e.g., EMA, claudin-1)
Inflammatory fibroid - - - - +++ - - Submucosal
polyp
Inflammatory +/- - - - - +++ +/- ALK1(+) in majority; typically
myofibroblastic extrinsic to GI tract
tumor
Kaposi sarcoma - - +/- - +++ - - Also HHV8(+), CD31(+), and ERG
Leiomyoma - - - - - +++ +++ More common than GIST in
esophagus
Leiomyosarcoma - - - - - +++ +/- Often pleomorphic
Perineurioma (polyp) - - - - +/- - - EMA(+), claudin-1 (+)
Plexiform - - - - - +++ - Arises in gastric antrum;
fibromyxoma conspicuous plexiform growth
Schwannoma - +++ - - - - - Peripheral lymphoid cuff
Solitary fibrous tumor - - - - +++ - - Nuclear STAT6(+)

(+++) = typically positive; (+/-) = variably positive or negative; (-) = typically negative.

Immunohistochemical Panel for Epithelioid Tumors in GI Tract

Tumor Keratin S100 CD117 DOG1 SMA HMB45 Notes
Protein (C-kit)
Epithelioid - - +++ +++ - - Also CD34(+); occasionally CD117 can be
gastrointestinal negative; rare focal melan-A; some tumors are
stromal tumor pleomorphic and resemble carcinoma or
(GIST) melanoma
Glomus tumor - - - - +++ - Can resemble epithelioid GIST
Malignant - +++ - - - - Variable expression of synaptophysin, NB84,
gastrointestinal CD56; negative for CD99 and melan-A
neuroectodermal
tumor
Melanoma - +++ +/- - - +++ Also expresses other melanocytic markers
Perivascular - - +/- - +++ +++ Can also express caldesmon, melan-A, MITF
epithelioid cell
tumor (PEComa)
Poorly +++ - - - - - Should always be excluded clinically,
differentiated histologically, &/or immunohistochemically
carcinoma
Poorly +/- - - - - - Strong diffuse nuclear TLE1 expression;
differentiated molecular analysis in difficult cases
synovial sarcoma
SDH-deficient GIST - - +++ +++ - - Loss of cytoplasmic SDHB protein expression
diagnostic (subset also shows loss of SDHA
protein)

(+++) = typically positive; (+/-) = variably positive or negative; (-) = typically negative.

16

Selected Soft Tissue Tumors With Prominent CD34 Expression
Tumor
Acral fibromyxoma
Angiosarcoma
Atypical spindle cell lipomatous tumor
Cellular angiofibroma
Deep benign fibrous histiocytoma
Dermatofibrosarcoma protuberans
Elastofibroma
Epithelioid hemangioendothelioma
Epithelioid hemangioma
Epithelioid sarcoma
Fibrous hamartoma of infancy
Gastrointestinal stromal tumor
Giant cell fibroblastoma
Hemosiderotic fibrolipomatous tumor
Kaposiform hemangioendothelioma
Kaposi sarcoma
Mammary-type myofibroblastoma
Myeloid sarcoma
Neurofibroma
Perineurioma
Pleomorphic hyalinizing angiectatic
tumor
Solitary fibrous tumor
Spindle cell/pleomorphic lipoma
Superficial CD34(+) fibroblastic tumor
*Rarely, prominent CD34(+) reported in various other tumors, including dedifferentiated liposarcoma, retroperitoneal leiomyosarcoma, myxofibrosarcoma,
and myxoinflammatory fibroblastic sarcoma.
Soft Tissue Immunohistochemistry
Soft Tissue Introduction
Helpful Clues to Diagnosis
Location (hands or feet, often subungual); generally bland spindle cells within myxoid to fibrous stroma;
loss of nuclear Rb expression
Location (scalp, breast, etc.); evidence of vasoformation with infiltrative or dissecting growth; CD31(+),
ERG(+)
Loose fascicles of bland spindle cells in myxoid to fibrous stroma; variable number of mono- and
multivacuolated lipoblasts with atypical nuclei; loss of nuclear Rb expression; negative for MDM2/CDK4
Usually genital region; hyalinized vessels; neural-like cytomorphology; desmin (-); loss of nuclear Rb
expression
Well circumscribed, often with fibrous capsule; storiform growth pattern; admixed chronic inflammatory
infiltrate common; ectatic vasculature
Dermal/subcutaneous tumor; prominent storiform growth pattern; honeycomb-like fat infiltration;
contains COL1A1-PDGFB fusion
Location (infrascapular deep soft tissue); affects older/elderly women; contains abnormal coarse,
fragmented, beaded elastic fibers
Characteristic myxohyaline matrix; angiocentricity; blister cells; CD31(+); ERG(+)
Location (head, distal extremities); abundant lymphocytes and eosinophils; vasoformation present;
CD31(+); CD34(+)
Location (distal extremity in classic type); nests of eosinophilic epithelioid cells, often with central necrosis;
keratin (+); loss of nuclear INI1 expression
Affect infants; organoid growth pattern with 3 distinct components; diffuse CD34 expression only in
collagenized pseudoangiomatous (or neurofibroma-like) areas
Arises in muscularis propria of GI tract or rarely omentum/mesentery; CD117(+), DOG1(+)
Common in children; often on trunk; irregular clefts lined by multinucleated cells; may contain areas of
DFSP; CD31(-); contains COL1A1-PDGFB fusion
Location (often distal lower extremity); adult women; abundant mature adipose tissue and hemosiderin;
TGFBR3 &/or MGEA3 rearrangements
Occurs in children; associated with clinical Kasabach-Merritt syndrome; cannonball growth pattern with
glomeruloid structures
Hemorrhage common; clinical scenario (e.g., AIDS); lymph node involvement; HHV8(+); CD31(+)
Genital region or extremities; features coarse collagen bundles; vasculature usually not prominent;
additionally desmin (+); loss of nuclear Rb expression
Clinical context (acute myeloid leukemia); myeloperoxidase (+); negative for vascular markers
Often cutaneous or originating from deeper nerve; admixed CD34(+) stromal cells with S100(+) Schwann
cells
Low-grade cytology; whorling growth; usually EMA(+), claudin-1 (+)
Location (often distal lower extremity); characteristic hyalinized/fibrin-lined vasculature; pleomorphic
nuclei with pseudoinclusions; hemosiderin
Prominent ectatic staghorn vasculature; conspicuous stromal collagen; "patternless" architectural pattern;
nuclear STAT6(+)
Classic distribution (neck, back, shoulders); adipose tissue component usually conspicuous, but not always;
floret cells in pleomorphic lipoma; desmin (-); loss of nuclear Rb expression
Prominent nuclear pleomorphism, often bizarre; macronucleoli; patchy keratin (+)
17
 Molecular Features of Soft Tissue Tumors
Soft Tissue Introduction
Diagnostically Useful Molecular and Cytogenetic Findings
Histologic Classification
Acral fibromyxoma
Alveolar rhabdomyosarcoma
Alveolar soft part sarcoma
Aneurysmal bone cyst of soft tissue
Angiofibroma of soft tissue
Angiosarcoma
Atypical spindle cell lipomatous tumor
Atypical lipomatous tumor
Angiomatoid fibrous histiocytoma
Cellular angiofibroma
Chondroid lipoma
Clear cell sarcoma
Dedifferentiated liposarcoma
Deep aggressive angiomyxoma
Dermatofibrosarcoma protuberans (DFSP)
Desmoid-type fibromatosis
Desmoplastic fibroblastoma
Desmoplastic small round cell tumor
Epithelioid hemangioendothelioma
Epithelioid hemangioma
Epithelioid fibrous histiocytoma
Epithelioid sarcoma
Ewing sarcoma
Extrarenal rhabdoid tumor
18
Key Abnormality Comment
Loss of 13q12 (RB1) Similar to spindle cell lipoma and related
lesions
t(2;13)(q35;q14) with PAX3-FOXO1 fusion Most common (60% of cases)
t(1;13)(p36;q14) with PAX7-FOXO1 fusion
der(17)t(X;17)(p11;q25) with ASPSCR1-TFE3 fusion Same gene fusion present in subset of
distinctive pediatric renal cell carcinoma
17p13 rearrangements Involves USP6 gene
t(5;8)(p15;q13) with AHRR-NCOA2 fusion
Amplification of 8q24 (MYC) Characteristic of tumors arising in
association with radiation or
lymphedema
Loss of 13q14 (RB1) Similar to spindle cell lipoma, cellular
angiofibroma, mammary-type
myofibroblastoma, acral fibromyxoma
Ring form of chromosome 12; amplification of MDM2, Same tumor as well-differentiated
CDK4, CPM liposarcoma
t (2;22)(q33;q12) with EWSR1-CREB1 fusion t(2;22) most common (90% of cases);
t(12;22)(q13;q12) with EWSR1-ATF1 fusion also present in clear cell sarcoma and
malignant gastrointestinal
neuroectodermal tumor
t(12;16)(q13;p11) with FUS-ATF1 fusion Uncommon variant
Loss of 13q14 (RB1) Same abnormality in mammary-type
myofibroblastoma and spindle
cell/pleomorphic lipoma
t(11;16)(q13;p13) with C11orf95-MKL2 fusion
t(12;22)(q13;q12) with EWSR1-ATF1 fusion t(12;22) most common (90% of cases);
t(2;22)(q33;q12) with EWSR1-CREB1 fusion also present in angiomatoid fibrous
histiocytoma and malignant
gastrointestinal neuroectodermal
tumor
Ring form of chromosome 12, amplification of MDM2, Also present in atypical lipomatous
CDK4, CPM by FISH analysis tumor/well-differentiated liposarcoma
Rearrangements of 12q14.3 Involves HMGA2
t(17;22)(q21;q13) with COL1A1-PDGFB fusion Also present in giant cell fibroblastoma
Novel PDGFD fusion with COL6A3 or EMILIN2 Uncommon
CTNNB1 (β-catenin gene) mutations in sporadic lesions APC mutations in tumors arising within
setting of Gardner syndrome
11q12 rearrangements Recurrent t(2;11)(q31;q12) reported
t(11;22)(p13;q12) with EWSR1-WT1 fusion
t(1;3)(p36.3;q23-25) with WWTR1-CAMTA1 fusion Nearly all cases
t(x;11)(p11;q22) with YAP1-TFE3 fusion Minor subset
FOS rearrangements (14q24.3)
2p23 (ALK gene) rearrangements Most cases
22q11-12 abnormalities Inactivation of SMARCB1 (a.k.a. INI1 or
SNF5)
t(11;22)(q24;q12) with EWSR1-FLI1 fusion Most common (85% of cases)
t(21;22)(q22;q12) with EWSR1-ERG Variants
t(2;22)(q33;q12) with EWSR1-FEV
t(7;22)(p22;q12) with EWSR1-ETV1
t(17;22)(q21;q12) with EWSR1-ETV4
Very rare fusions involving FUS
Deletion of 22q11.2 Inactivation of SMARCB1 (a.k.a. INI1 or
SNF5)
 Molecular Features of Soft Tissue Tumors
Diagnostically Useful Molecular and Cytogenetic Findings (Continued)
Histologic Classification
Extraskeletal myxoid chondrosarcoma
Gastrointestinal stromal tumor
Giant cell fibroblastoma
Hemosiderotic fibrolipomatous tumor
Hibernoma
Infantile fibrosarcoma
Inflammatory myofibroblastic tumor
Intramuscular myxoma
Intranodal palisaded myofibroblastoma
Lipoblastoma
Low-grade fibromyxoid sarcoma
Mammary-type myofibroblastoma
Myoepithelioma of soft tissue
Myxoid liposarcoma
Malignant gastrointestinal neuroectodermal
tumor
Myxoinflammatory fibroblastic sarcoma
Nodular fasciitis
Ossifying fibromyxoid tumor
PEComa
Pleomorphic hyalinizing angiectatic tumor
Pseudomyogenic (epithelioid sarcoma-like)
hemangioendothelioma
Solitary fibrous tumor
Spindle cell/pleomorphic lipoma
Synovial sarcoma
BCOR-CCNB3 fusion-positive sarcoma
Tenosynovial giant cell tumor
CIC-DUX4 translocation sarcoma
Well-differentiated liposarcoma
Key Abnormality
t(9;22)(q22;q12) with EWSR1-NR4A3 fusion
t(9;17) with TAF15-NR4A3
t(9;15) with TCF12-NR4A3
t(9;3) with TFG-NR4A3
KIT, PDGFRA mutations
t(17;22)(q21;q13) with COL1A1-PDGFB fusion
t(1;10)(p22;q24) with TGFBR3-MGEA5 fusion
11q13 rearrangements
t(12;15)(p13;q26) with ETV6-NTRK3 fusion
2p23 rearrangements
GNAS gene mutations
CTNNB1 (β-catenin gene) mutations
8q11-13 rearrangements
t(7;16)(q33;p11) with FUS-CREB3L2
t(11;16)(p11;p11) with FUS-CREB3L1
Loss of 13q14 (RB1)
t(6;22)(p12;q12) with EWSR1-POU5F1 fusion
t(1;22)(q23;q12) with EWSR1-PBX1 fusion
t(19;22)(q13;q12) with EWSR1-ZNF444 fusion
t(12;16)(q13;p11) with FUS-DDIT3 fusion
t(12;22)(q13;q12) with EWSR1-DDIT3 fusion
t(2;22)(q33;q12) with EWSR1-CREB1 fusion
t(12;22)(q13;q12) with EWSR1-ATF1 fusion
t(1;10)(p22;q24) with TGFBR3-MGEA5 fusion
t(17;22)(p13;q13) with MYH9-USP6 fusion
6p21 rearrangements
Deletion of 16p
TFE3 rearrangements
t(1;10)(p22;q24) with TGFBR3-MGEA5 fusion
t(7;19)(q22;q13) with SERPINE1-FOSB fusion
12q13 aberrations withNAB2-STAT6 fusion
Loss of 13q14 (RB1)
t(X;18)(p11;q11) involving SS18 (SYT) gene
X chromosome (paracentric inversion)
t(1;2)(2p;13q) with CSF1-COL6A3 fusion
t(4;19)(q35;q13.1)
t(10;19)(q26;3q13)
Ring form of chromosome 12; amplification of MDM2,
CDK4, CPM
Soft Tissue Introduction
Comment
Most common
All variant translocations associated
with more aggressive course (high-
grade morphology, rhabdoid cells)
Rare: Mutations in SDH subunit genes
(usually SDHB) or NF1
Also present in DFSP
Identical aberration seen in cellular
mesoblastic nephroma of kidney
Results in ALK gene fusion
Involves PLAG1
Most common (65-70% of cases); also
present in some cases of sclerosing
epithelioid fibrosarcoma
Rare
Same as spindle cell/pleomorphic
lipoma and cellular angiofibroma
50% of cases
Rare
Most common (95% of cases)
Rare
Also seen in clear cell sarcoma and
angiomatoid fibrous histiocytoma
Controversial; also present in
hemosiderotic fibrolipomatous tumor
and pleomorphic hyalinizing angiectatic
tumor
Involves PHF1
Loss of TSC2
Minor subset of cases
Also found hemosiderotic
fibrolipomatous tumor
Intrachromosomal rearrangement
Also present in myofibroblastoma and
cellular angiofibroma
Fusions between SS18 and SSX1 (most
common), SSX2, or SSX4 (rare)
Other fusions described (BCOR-MAML3)
Both localized and diffuse forms
Both translocations result in CIC-DUX4
fusion
Same tumor as atypical lipomatous
tumor
19
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 SECTION 2

Diagnostic Approach to Soft Tissue Tumors

Overview
Biopsy and Resection of Soft Tissue Tumors 22

Clinical Approach
Age- and Location-Based Approach to Diagnosis 26

Histologic Approach
Pattern-Based Approach to Diagnosis 28
Feature-Based Approach to Diagnosis 36
 Biopsy and Resection of Soft Tissue Tumors
Diagnostic Approach to Soft Tissue Tumors
OVERVIEW
General Points
• Variety of diagnostic procedures are currently available to
surgeons and clinicians to evaluate soft tissue tumors
○ Initial tumor tissue sampling may or may not be sought,
depending on overall impression of tumor biologic
potential derived from synthesis of clinical features and
imaging characteristics
– Tumors that appear likely benign are often surgically
excised without sampling or followed clinically
– Tumors that appear likely malignant or potentially
malignant are usually sampled preoperatively
□ With increasing frequency, soft tissue tumors are
sampled initially by core needle biopsy, fine-needle
aspiration (FNA), or limited biopsy due to minimal
morbidity to patient
□ Nondiagnostic results may reflex into larger open
surgical biopsy with intraoperative frozen section
evaluation or even outright resection, depending
on clinical impression of tumor biology
□ Successful diagnosis usually leads to local excision,
wide resection with margins, or preoperative
adjuvant chemotherapy &/or radiation
• Smaller specimens are generally more challenging to
evaluate due to sampling problems and issues related to
immunohistochemistry
○ Underdiagnosis often poses greater risk than
overdiagnosis
○ Misclassification is possible if several different tumors
share morphologic overlap
Types of Specimens
• Core needle biopsy
○ Very small sample of tumor/lesion
○ Popular due to minimal risk of morbidity to patient
○ May be done in outpatient setting for superficial lesions
or under CT guidance for deep or visceral lesions
• FNA
○ Very small sample of tumor/lesion
Core Needle Biopsy
(Left) Collecting tissue by core
needle biopsy has become
popular due to both the ease
of performance and minimal
morbidity to the patient as
compared with open surgical
biopsy. Despite the limited
tissue sample, a diagnosis is
often possible with careful
histologic evaluation and
judicious use of ancillary
techniques. (Right) Cell block
collected from a fine-needle
aspiration (FNA) can also be
used for diagnosis. However,
tissue is often heavily
fragmented and scant, as
depicted.
22
○ Aspiration allows for immediate evaluation of sampling
adequacy (success or failure of attaining diagnostic
tissue) with added benefit of cell block for histologic and
immunohistochemical evaluation
○ Popular due to minimal risk of morbidity to patient
• Open surgical biopsy
○ Small sample of tumor/lesion but generally contains
more intact tissue than core needle biopsy or FNA
○ Tissue may be sent for intraoperative frozen section
consultation or just permanent sectioning
○ Smaller risk of underdiagnosis or misdiagnosis compared
to needle biopsy and FNA
• Local excision
○ Entire tumor available for histologic evaluation
○ Surgical focus is on removal of tumor and not achieving
rim of uninvolved soft tissue
○ Standard approach for benign, superficial tumors that
are not believed to be locally aggressive
• Resection with margins
○ Includes wide resection and radical resection
– Radical resection often contains extensive normal
tissue or, in cases of intraabdominal, intrathoracic, or
retroperitoneal tumors, may contain organs involved
by tumor
○ Entire tumor available for histologic evaluation
○ Standard approach for locally aggressive benign tumors
(e.g., fibromatosis), deep (subfascial) tumors, and
sarcomas
○ May be performed following chemotherapy &/or
radiation to improve resectability and decrease potential
morbidity
BIOPSY SPECIMENS
General Histologic Approach
• Ensure that lesional tissue is present
• Evaluate histologic growth pattern and architecture in
conjunction with cytologic features of tumor cells
○ Looks for histologic clues that suggest specific
differentiation (e.g., lipoblasts)
• Assess mitotic activity and presence or absence of necrosis
Fine-Needle Aspiration
 Biopsy and Resection of Soft Tissue Tumors
• Utilize ancillary studies (e.g., immunohistochemistry,
molecular analysis) as needed
• If constellation of features is classic for particular tumor,
diagnosis can be made
• If clear diagnosis cannot be made, determine whether
tumor appears benign, low-grade malignant, or high-grade
malignant
○ Even in absence of clear diagnosis, this information is
helpful to guide surgical/clinical planning
Caveats
• Always exclude carcinoma, melanoma, lymphoma, and
mesothelioma before committing to mesenchymal
diagnosis
• At times, actual tumor does not get sampled
○ Some tumors may incite prominent peripheral host
fibroblastic or inflammatory reaction that is
inadvertently sampled
○ Normal subcutaneous fat adjacent to tumor may be
sampled and mistaken for lipomatous tumor
• Be wary of sampling issues related to biopsy evaluation
○ Tumors that appear low grade on biopsy may contain
higher grade areas upon resection
– Particularly important in tumors of adipocytic and
neural origin
○ Tumors that appear as nonspecific high-grade
pleomorphic sarcomas on biopsy often can be more
specifically classified on resection
– e.g., dedifferentiated liposarcoma, pleomorphic
liposarcoma, extraskeletal osteosarcoma
– Diagnosis "undifferentiated pleomorphic sarcoma"
should not be made on biopsy, as it is diagnosis of
exclusion
• Awareness of particular idiosyncrasies of soft tissue
pathology is very important
○ Sarcomas may appear paradoxically bland and therefore
benign
– e.g., low-grade fibromyxoid sarcoma, myxoid
liposarcoma, myxoid synovial sarcoma
○ Benign tumors may show histologic features that
suggest malignancy
– e.g., nodular fasciitis, proliferative fasciitis/myositis,
cellular schwannoma
• Only commit to clear diagnosis on biopsy if it is well
supported
○ In general, conservative diagnosis on biopsy better
serves patient
Reporting
• Every effort should be taken to establish clear diagnosis
(and histologic grade, if applicable) on biopsy
○ Modern ancillary techniques are making this much easier
for pathologists
○ Margin status cannot be evaluated
• If clear diagnosis cannot be established, descriptive
diagnosis can help guide surgical/clinical planning
○ e.g., benign fibroblastic lesion
○ e.g., low-grade myxoid neoplasm, favor benign
○ e.g., high-grade pleomorphic sarcoma, not further
classified
• Descriptive comment is highly recommended in many cases
to discuss differential diagnosis options
Diagnostic Approach to Soft Tissue Tumors
○ e.g., "Although these findings are suggestive of a low-
grade neoplasm, such as an intramuscular myxoma, a
low-grade sarcoma, such as low-grade fibromyxoid
sarcoma or low-grade myxofibrosarcoma, cannot be
excluded in this limited sample."
○ e.g., "Although the histologic features are consistent
with a neurofibroma, given the large size of the lesion
clinically, the possibility of an unsampled malignant
component cannot be excluded in this limited sample."
RESECTION SPECIMENS
General Histologic Approach
• Surgical removal without neoadjuvant therapy
○ If tumor has been sampled previously, review original
biopsy (if available) and confirm diagnosis and adequacy
of sampling
– If diagnosis is established or confirmed, assure
accuracy of histologic grade (if applicable)
□ Tumors diagnosed as "low grade" on biopsy may
contain higher grade areas in resection specimen
– Ancillary techniques (e.g., immunohistochemistry,
molecular analysis) may be utilized as needed
○ If tumor has not been sampled previously, evaluate all
histologic sections of tumor to establish diagnosis
– Ancillary techniques may be utilized as needed
○ Evaluate margin status (mainly sarcomas and locally
aggressive benign tumors)
• Surgical removal following neoadjuvant therapy
○ If tumor has been sampled previously, review original
biopsy (if available) and confirm diagnosis
○ Determine whether diagnosis can be established or
confirmed on resection (may not be possible due to
treatment effect)
– Overall histologic picture depends heavily upon
biologic response of tumor to therapy
□ Tumors may be extensively necrotic, inflamed, &/or
fibrotic/hyalinized
□ Tumor cells may become markedly pleomorphic
and atypical, including bizarre cytomorphologies
○ Document approximate percentage of residual tumor
viability
○ Evaluate margin status
Caveats
• Despite all efforts, small percentage of soft tissue tumors
defy classification after resection
○ Distinction between benign, low-grade malignant, and
high-grade malignant should be goal in these cases
○ Always ensure carcinoma, melanoma, lymphoma, and
mesothelioma have been excluded before committing
to soft tissue diagnosis
• Care is warranted when attempting to classify soft tissue
tumor treated preoperatively with chemotherapy/radiation
○ Tumors that are usually cytologically monomorphic may
appear pleomorphic following therapy
○ Cytoplasmic vacuolizations may be prominent, mimicking
lipoblastic differentiation
○ Ancillary techniques are unreliable following
chemotherapy/radiation and should not be utilized
23
 Biopsy and Resection of Soft Tissue Tumors
Diagnostic Approach to Soft Tissue Tumors
Reporting
• Surgical pathology reports for soft tissue resections should
contain tumor diagnosis, histologic grade (if applicable),
and margin status (if appropriate)
○ Additional staging information (e.g., size) can be included
as checklist
• For tumors that cannot be definitively classified after all
options are exhausted, descriptive diagnosis can be utilized
○ e.g., low-grade myxoid sarcoma, not otherwise specified
(NOS)
○ e.g., epithelioid malignant mesenchymal neoplasm, favor
high-grade sarcoma
• For tumors treated with neoadjuvant therapy prior to
resection
○ High-grade sarcoma with extensive therapy effect (20%
tumor viability)
SPECIAL TOPICS
Intraoperative Frozen Section Consultation for
Diagnosis
• May be requested by surgeon in certain scenarios
○ Tumor has not been sampled previously
○ To confirm previous biopsy diagnosis
○ Tumor was sampled previously by biopsy but no specific
diagnosis was attained
○ Tumor with previous benign or low-grade biopsy
diagnosis, and there is clinical concern for unsampled,
higher grade component
• Intraoperative diagnosis or confirmation of diagnosis can be
sought to confirm surgical/clinical treatment plan
○ Variability exists between individual surgeons
– May continue with resection plans for benign or low-
grade malignancies
– May halt further surgery and administer neoadjuvant
therapy if high-grade malignancy
• In many instances, specific soft tissue diagnosis cannot be
made by frozen section evaluation
○ Most helpful information pathologist can provide:
Whether tumor appears benign, low-grade malignant, or
high-grade malignant
– Exercise caution when calling soft tissue tumor
"benign" on frozen section
□ Use of term "low grade" recommended over
"benign," unless benignity is absolutely certain
□ Some low-grade sarcomas can be easily mistaken
for benign tumors on frozen section, which can
lead to inappropriately conservative treatment
○ If diagnosis cannot be made on frozen section, and
alternative descriptive interpretation cannot be
comfortably provided by pathologist, it is appropriate to
document presence of satisfactory lesional tissue and
defer to evaluation of permanent sections
○ Examples of appropriate frozen section interpretations
– Low-grade spindle cell proliferation
– High-grade sarcoma
– Spindle cell sarcoma, favor low grade
– Tumor present, defer to permanents
– Malignant neoplasm, defer to permanents
24
Evaluation by Ancillary Testing
• Immunohistochemistry
○ Wide array of antibodies available today has made it
easier for pathologists to make confident soft tissue
diagnoses on limited tissue samples
○ It is recommended that every attempt be made to
establish diagnosis or limited differential by routine
histology
○ When needed, limited screening panel of
immunohistochemical stains is helpful for supporting (or
excluding) diagnoses
– Specific screening panels vary depending on
pathologist's comfort level with soft tissue pathology
○ Common 5-stain screening panel: Keratin, S100 protein,
SMA, desmin, CD34
– Provides reasonably broad coverage
– Can be modified with additional stains as necessary
depending upon histologic/clinical context
○ Recommendations and caveats
– Always confirm that external and internal controls are
functioning properly
– Examine entire slide and all tissue fragments
– Know what constitutes positive staining for each
antibody (e.g., nuclear, cytoplasmic, membranous
expression)
– If stain appears positive, confirm that actual cells of
interest are staining
– Important: On very limited tissue sample, negative
staining for particular antibody may not reflect status
of entire tumor
□ e.g., myogenin expression in embryonal
rhabdomyosarcoma can be patchy and focal
• Molecular analysis
○ Representative paraffin tissue block can be used for
variety of sophisticated testing (e.g., FISH, RT-PCR)
Expert Consultation
• Pathologists who are experienced in evaluation of soft
tissue tumors may be consulted to review case
• Common reasons
○ Primary pathologist is uncomfortable with &/or has
limited experience in soft tissue pathology
○ Surgeon, primary care provider, or patient may request
2nd opinion
– Histologic diagnosis is at odds with clinical impression
– Diagnosis of very rare or unusual tumor is rendered
○ Newer immunohistochemical antibodies or molecular
tests are not readily available to primary pathologist
• Sending 1 or more paraffin tissue blocks along with slides
for ancillary testing can be helpful
○ Ideal blocks contain well-processed tissue and minimal to
no necrosis
– Blocks containing areas of lower grade histology are
more likely to show diagnostically useful antigen
expression than blocks containing predominantly
high-grade pleomorphic morphology
• Inclusion of recent clinical history, imaging reports, and
surgical notes can also provide useful information
 Biopsy and Resection of Soft Tissue Tumors
High-Grade Pleomorphic Sarcoma
Low-Grade Spindle Cell Neoplasm
Posttherapy Changes
Diagnostic Approach to Soft Tissue Tumors
Well-Differentiated Adipocytic Neoplasms
(Left) On core needle biopsy, it
may be difficult to distinguish
one high grade pleomorphic
sarcoma from another,
particularly if discriminatory
immunohistochemical stains
or molecular tests are not
available to the pathologist.
Fortunately, in many cases,
designation of "high-grade
sarcoma" is often sufficient.
(Right) Care should be taken in
classifying well-differentiated
adipocytic neoplasms on
limited biopsy, as atypical
lipomatous tumor/well-
differentiated liposarcoma can
contain large areas resembling
conventional lipoma.
Deceptively Bland Sarcoma
(Left) Classification of low-
grade spindle cell neoplasms
on limited biopsy can be
challenging without ancillary
tests mainly because some
low-grade sarcomas can
closely resemble benign
entities morphologically. This
H&E shows a core biopsy
specimen of a low-grade
fibromyxoid sarcoma
mimicking a benign neural or
fibroblastic neoplasm. (Right)
This H&E depicts a largely
myxoid synovial sarcoma. On a
limited biopsy specimen, this
tumor could easily be
mistaken for a benign or low-
grade process.
Immunohistochemistry
(Left) If a specific diagnosis is
not established prior to
neoadjuvant therapy,
definitive classification of a
soft tissue sarcoma may not
be possible due to therapy-
related histologic changes,
including bizarre nuclear
atypia, stromal fibrosis, and
edema. IHC and molecular
analysis are also largely
unhelpful in this setting.
(Right) Care must always be
taken with IHC performed on
limited tissue. One pitfall is
focal tumor antigen
expression ﬉ (e.g., myogenin,
shown) that is not present on
biopsy.
25
 Age- and Location-Based Approach to Diagnosis
Diagnostic Approach to Soft Tissue Tumors

DIRECTIONS Infants, Children, or Adolescents (< 20 Years Old)

How to Use These Guides
• The following guides are neither comprehensive nor
perfect and are meant to serve only as a starting point for
working up a suspected mesenchymal neoplasm
• Includes entities that are most commonly or classically
associated with particular clinical and histologic findings
Specific Directions for This Guide
• For each site and associated age range listed below, a
selection of most commonly or characteristically associated
diagnoses are provided
• Compile an assortment of potential diagnoses from the
guide using age of patient and provided tumor site from
your particular case
• Compare this selection to those created from the other 2
approach chapters in this section
• Overlapping diagnoses derived from these 3 distinct
approaches are highest yield and should be your focus
• Once high-yield diagnoses have been identified, specific
entity chapters should be directly consulted for detailed
information and image galleries
○ In particular, the Differential Diagnosis sections should
be fully utilized to broaden search and increase chances
of securing the correct diagnosis
Important Caveat
• Always exclude carcinoma, melanoma, lymphoma, and
mesothelioma before committing to a mesenchymal
diagnosis
AGE-BASED APPROACH
Infancy (< 3 Years Old)
• Fibrous hamartoma of infancy
• Inclusion body fibromatosis
• Infantile fibrosarcoma
• Lipoblastoma
• Lipofibromatosis
• Myofibroma
• Angiomatosis
• Calcifying aponeurotic fibroma
• Dabska tumor (infants and children)
• Embryonal rhabdomyosarcoma
• Extrarenal rhabdoid tumor (infants and children)
• Fibromatosis
• Gardner fibroma
• Giant cell fibroblastoma
• Kaposiform hemangioendothelioma (infants and children)
Adolescents to Young Adults (~ 10 to 35 Years Old)
• Alveolar rhabdomyosarcoma
• Alveolar soft part sarcoma
• Angiomatoid fibrous histiocytoma
• Desmoplastic small round cell tumor (and children)
• Epithelioid sarcoma (classic type)
• Fibromatosis
• Inflammatory myofibroblastic tumor
• Low-grade fibromyxoid sarcoma
• Myxoid liposarcoma
• Plexiform fibrohistiocytic tumor
• Synovial sarcoma
Young to Middle-Aged Adults (~ 20 to 50 Years Old)
• Clear cell sarcoma
• Dermatofibrosarcoma protuberans
• Epithelioid hemangioendothelioma
• Epithelioid sarcoma (proximal type)
• Fibroma of tendon sheath
• Fibromatosis
• Hibernoma
• Leiomyosarcoma
• Low-grade myofibroblastic sarcoma
• Myositis ossificans
• Myxoinflammatory fibroblastic sarcoma
• Nodular fasciitis
• Pseudomyogenic hemangioendothelioma
• Tenosynovial giant cell tumor (both localized and diffuse
types)

Inclusion Body Fibromatosis Dedifferentiated Liposarcoma

(Left) Some mesenchymal
neoplasms show a striking
predilection for very specific
age groups and very specific
anatomic locations. For
example, inclusion body
fibromatosis (a.k.a. infantile
digital fibromatosis) most
frequently arises in the digits
of infants. (Right)
Dedifferentiated liposarcoma
is the most common
pleomorphic sarcoma of the
retroperitoneum and should
always be at the top of the
differential diagnosis for
retroperitoneal tumors in
older adults.

26
 Age- and Location-Based Approach to Diagnosis

Diagnostic Approach to Soft Tissue Tumors

Middle-Aged to Older Adults (~ 40 to 65 Years Old) Head and Neck
• Atypical lipomatous tumor/well-differentiated liposarcoma • Alveolar soft part sarcoma (infants and children)
• Dedifferentiated liposarcoma • Atypical fibromyxoma
• Desmoplastic fibroblastoma • Cellular neurothekeoma
• Extraskeletal myxoid chondrosarcoma • Ectopic meningioma
• Extraskeletal osteosarcoma • Embryonal rhabdomyosarcoma
• Hemosiderotic fibrolipomatous tumor • Epithelioid hemangioma
• Intramuscular myxoma • Paraganglioma
• Mammary-type myofibroblastoma • Rhabdomyoma (adult and fetal types)
• Ossifying fibromyxoid tumor • Solitary circumscribed neuroma
• Proliferative fasciitis/myositis • Spindle cell rhabdomyosarcoma
• Sclerosing epithelioid fibrosarcoma
Retroperitoneum
• Spindle cell/pleomorphic lipoma
• Dedifferentiated liposarcoma
Older and Elderly Adults (> 50 Years Old) • Desmoid fibromatosis
• Atypical fibroxanthoma • Extrarenal rhabdoid tumor
• Elastofibroma • Ganglioneuroma
• Ischemic fasciitis • Inflammatory myofibroblastic tumor
• Myxofibrosarcoma • Leiomyosarcoma
• Pleomorphic liposarcoma • PEComa
• Pleomorphic rhabdomyosarcoma • Schwannoma (cellular variant)
• Undifferentiated pleomorphic sarcoma • Well-differentiated liposarcoma
Trunk, Shoulders, and Back
LOCATION-BASED APPROACH
• Dermatofibrosarcoma protuberans
Distal Extremities • Desmoid fibromatosis
• Calcifying aponeurotic fibroma • Elastofibroma
• Clear cell sarcoma • Lipoblastoma
• Epithelioid sarcoma (classic type) • Proliferative myositis
• Fibromatosis • Spindle cell/pleomorphic lipoma
• Hemosiderotic fibrolipomatous tumor
• Lipofibromatosis GASTROINTESTINAL MESENCHYMAL
• Palmar/plantar fibromatosis TUMORS (MOST COMMON BY LOCATION)
• Pleomorphic hyalinizing angiectatic tumor
Esophagus
Fingers and Toes • Leiomyoma (mural)
• Acral fibromyxoma • Granular cell tumor
• Dermal nerve sheath myxoma
Stomach
• Epithelioid hemangioma
• Fibroma of tendon sheath • Gastrointestinal stromal tumor
• Glomus tumor • Inflammatory fibroid polyp
• Inclusion body fibromatosis • Schwannoma
• Localized-type tenosynovial giant cell tumor Small Bowel
• Myxoinflammatory fibroblastic sarcoma • Gastrointestinal stromal tumor
• Soft tissue chondroma • Inflammatory fibroid polyp
Genital Region and Groin Colorectum
• Angiomyofibroblastoma • Leiomyoma (polyp; nonmural)
• Cellular angiofibroma • Gastrointestinal stromal tumor
• Deep (aggressive) angiomyxoma
• Genital rhabdomyoma MESENCHYMAL TUMORS INVOLVING LYMPH
• Intranodal palisaded myofibroblastoma NODES (MOST COMMON)
• Mammary-type myofibroblastoma
Metastasis
• Spindle cell rhabdomyosarcoma (paratesticular)
• Epithelioid sarcoma
Mesentery/Omentum/Peritoneum • Clear cell sarcoma
• Desmoid fibromatosis • Rhabdomyosarcomas
• Desmoplastic small round cell tumor
Nodal Primary
• Gastrointestinal stromal tumor
• Inflammatory myofibroblastic tumor • Kaposi sarcoma
• Intranodal palisaded myofibroblastoma

27
 Pattern-Based Approach to Diagnosis
Diagnostic Approach to Soft Tissue Tumors

DIRECTIONS MONOMORPHIC SPINDLE CELL PATTERNS

How to Use These Guides Monomorphic Spindle Cells Arranged in Sheets
• These guides are neither comprehensive nor perfect and • Angiomatoid fibrous histiocytoma
are meant to serve only as starting point for working up • Infantile fibrosarcoma
suspected mesenchymal neoplasm • Solitary fibrous tumor
• They include entities that are most commonly or classically • Synovial sarcoma
associated with particular histologic patterns in soft tissue
Monomorphic Spindle Cells Featuring Hyper- and
Specific Directions for This Guide Hypocellular Areas
• Following list of histologic patterns has been generated • Low-grade fibromyxoid sarcoma
using combination of cell types (spindle or epithelioid), • Malignant peripheral nerve sheath tumor (MPNST)
cytologic features (monomorphism vs. pleomorphism), and
• Schwannoma
various stromal characteristics (e.g., myxoid, prominent
• Solitary fibrous tumor
vasculature)
• Synovial sarcoma
• For each histologic pattern listed below, selection of more
commonly or characteristically associated diagnoses are Monomorphic Spindle Cells Arranged in Bundles or
provided Fascicles
• Compile assortment of potential diagnoses from each • Angioleiomyoma
guide using main histologic pattern(s) from your particular
• Deep leiomyoma
case
• Fibromatosis
• Compare this selection to those created from other 2
• Fibrous hamartoma of infancy
approach chapters
• Inclusion body fibromatosis
• Overlapping diagnoses derived from these 3 distinct
• Infantile fibrosarcoma
approaches are highest yield and should be your focus
• Kaposi sarcoma
• Once high-yield diagnoses have been identified, specific
entity chapters should be directly consulted for detailed • Leiomyosarcoma
information and image galleries • Lipofibromatosis
○ In particular, differential diagnosis sections should be • Mammary-type myofibroblastoma
fully utilized to broaden search and increase chances of • Plexiform fibrohistiocytic tumor
securing correct diagnosis • Schwannoma
• Solitary circumscribed neuroma
Important Caveats
• Always exclude carcinoma, melanoma, lymphoma, and Monomorphic Spindle Cells Arranged in Cellular
mesothelioma before committing to mesenchymal Herringbone Fascicles
diagnosis • Adult-type fibrosarcoma
• Always exclude gastrointestinal stromal tumor when tumor • Fibrosarcomatous dermatofibrosarcoma protuberans
arises within abdominal cavity or pelvis (DFSP)
○ Can demonstrate almost any morphologic pattern • Infantile fibrosarcoma
• MPNST
• Spindle cell rhabdomyosarcoma

Monomorphic Spindle Cells: Sheets

Monomorphic Spindle Cells: Sheets (Syncytia)
(Left) A sheet-like pattern
tends to feature diffuse
growth of spindle cells
without obvious directional
orientation, however, areas of
bundled or fascicular growth
are not uncommon. This
pattern is common in synovial
sarcoma (shown) and solitary
fibrous tumor. (Right) Sheets
of spindled cells can also have
a syncytial appearance in
which cytoplasmic borders are
inconspicuous, and
independent cell nuclei appear
to share the same cytoplasm.
This appearance is common in
angiomatoid fibrous
histiocytoma.

28
 Pattern-Based Approach to Diagnosis
• Synovial sarcoma
Monomorphic Spindle Cells Arranged in Storiform or
Whorled Architecture
• Deep benign fibrous histiocytoma
• Dermatofibroma (fibrous histiocytoma)
• Dermatofibrosarcoma protuberans
• Follicular dendritic cell sarcoma
• Hybrid nerve sheath tumor
• Inclusion body fibromatosis
• Low-grade fibromyxoid sarcoma
• Low-grade myofibroblastic sarcoma
• Nodular fasciitis
• Perineurioma
Monomorphic Spindle Cells Arranged in Multinodular
or Plexiform Architecture
• Granular cell tumor
• Plexiform fibrohistiocytic tumor
• Plexiform neurofibroma
• Plexiform schwannoma
• Solitary circumscribed neuroma
Monomorphic Spindle Cells Arranged in Reticular or
Microcystic Pattern
• Extraskeletal myxoid chondrosarcoma
• Myoepithelioma
• Perineurioma (variant)
• Schwannoma (variant)
Monomorphic Spindle Cells Within Myxoid Stroma
• Acral fibromyxoma
• Deep (aggressive) angiomyxoma
• Dermal nerve sheath myxoma
• Dermatofibrosarcoma protuberans (myxoid type)
• Desmoid fibromatosis
• Embryonal rhabdomyosarcoma
• Hybrid nerve sheath tumor
• Inflammatory myofibroblastic tumor
• Intramuscular myxoma
• Leiomyosarcoma (variant)
• Low-grade fibromyxoid sarcoma
• Myxoid liposarcoma
• Neurofibroma
• Nodular fasciitis
• Perineurioma
• Proliferative fasciitis/myositis
• Synovial sarcoma
• Spindle cell lipoma
Monomorphic Spindle Cells Within Collagenous,
Hyalinized, or Sclerotic Stroma
• Acral fibromyxoma
• Calcifying fibrous tumor
• Cellular angiofibroma
• Desmoplastic fibroblastoma
• Elastofibroma
• Fibroma of tendon sheath
• Fibromatosis
• Inflammatory myofibroblastic tumor
• Low-grade fibromyxoid sarcoma
Diagnostic Approach to Soft Tissue Tumors
• Low-grade myofibroblastic sarcoma
• Neurofibroma
• Nodular fasciitis
• Perineurioma
• Sclerosing rhabdomyosarcoma
• Solitary fibrous tumor
Monomorphic Spindle Cells Amidst Prominent
Stromal Vasculature
• Angiofibroma of soft tissue
• Angioleiomyoma
• Deep (aggressive) angiomyxoma
• Dermatofibrosarcoma protuberans (myxoid type)
• Low-grade fibromyxoid sarcoma
• Myopericytoma
• Myxoid liposarcoma
• Schwannoma
• Solitary fibrous tumor
Monomorphic Spindle Cells Associated With Mature
Adipose Tissue
• Angiomyofibroblastoma
• Cellular angiofibroma
• Elastofibroma
• Fibrous hamartoma of infancy
• Hemosiderotic fibrolipomatous tumor
• Lipoblastoma
• Lipofibromatosis
• Mammary-type myofibroblastoma
• Myolipoma
• Solitary fibrous tumor (variant)
• Spindle cell lipoma
PLEOMORPHIC SPINDLE CELL PATTERNS
Pleomorphic Spindle Cells Arranged in Sheets
• Angiosarcoma
• Dedifferentiated liposarcoma
• Extraskeletal osteosarcoma
• Pleomorphic liposarcoma
• Pleomorphic rhabdomyosarcoma
• Superficial CD34(+) fibroblastic tumor
• Undifferentiated pleomorphic sarcoma
Pleomorphic Spindle Cells Arranged in Fascicles
• Dedifferentiated liposarcoma
• Leiomyosarcoma
• MPNST
• Pleomorphic rhabdomyosarcoma
• Undifferentiated pleomorphic sarcoma
Pleomorphic Spindle Cells Within Myxoid Stroma
• Ancient schwannoma
• Atypical neurofibroma
• Dedifferentiated liposarcoma
• Embryonal rhabdomyosarcoma (anaplastic)
• Giant cell fibroblastoma
• MPNST
• Myxofibrosarcoma
• Myxoinflammatory fibroblastic sarcoma
• Well-differentiated liposarcoma (variant)
29
 Pattern-Based Approach to Diagnosis
Diagnostic Approach to Soft Tissue Tumors

Pleomorphic Spindle Cells Within Collagenous, Epithelioid Cells Within Myxoid Stroma
Hyalinized, or Sclerotic Stroma • Epithelioid hemangioendothelioma
• Atypical lipomatous tumor/well-differentiated liposarcoma • Epithelioid MPNST
• Giant cell fibroblastoma • Extraskeletal myxoid chondrosarcoma
• Myxoinflammatory fibroblastic sarcoma • Glomus tumor
• Undifferentiated pleomorphic sarcoma • Myoepithelioma of soft tissue
• Myxofibrosarcoma (variant)
Pleomorphic Spindle Cells Arranged in Storiform
• Soft tissue chondroma (variant)
Architecture
• Dedifferentiated liposarcoma Epithelioid Cells Within Collagenous, Hyalinized, or
• Myxofibrosarcoma (high grade) Sclerotic Stroma
• Pleomorphic liposarcoma • Desmoplastic small round cell tumor
• Undifferentiated pleomorphic sarcoma • Epithelioid sarcoma
• Myoepithelioma of soft tissue
Pleomorphic Spindle Cell Amidst Prominent Stromal
• Perineurioma (variant)
Vasculature
• Sclerosing epithelioid fibrosarcoma
• Myxofibrosarcoma • Tenosynovial giant cell tumor (both types)
• Pleomorphic hyalinizing angiectatic tumor
• Solitary fibrous tumor (malignant) Epithelioid Cells Associated With Prominent Stromal
• Undifferentiated pleomorphic sarcoma Vasculature
• Alveolar soft part sarcoma
EPITHELIOID CELL PATTERNS • Angiomyofibroblastoma
Epithelioid Cells Arranged in Nests or Lobules • Glomus tumor
• Paraganglioma
• Alveolar rhabdomyosarcoma
• PEComa
• Alveolar soft part sarcoma
• Cellular solitary fibrous tumor (formerly
• Cellular neurothekeoma
hemangiopericytoma)
• Clear cell sarcoma
• Desmoplastic small round cell tumor Epithelioid Cells Associated With Adipose Tissue
• Epithelioid MPNST • Angiomyofibroblastoma
• Epithelioid sarcoma (classic type) • Chondroid lipoma
• Glomus tumor • Hibernoma
• Granular cell tumor
• Myoepithelioma of soft tissue OTHER PATTERNS
• Paraganglioma Mixed Epithelioid and Spindle Cells
• Perivascular epithelioid cell tumor (PEComa)
• Angiomyofibroblastoma
Epithelioid Cells Arranged in Cords or Trabeculae • Epithelioid sarcoma
• Ossifying fibromyxoid tumor • Leiomyoma
• Mammary-type myofibroblastoma (epithelioid variant) • Malignant mesothelioma (biphasic)
• Myoepithelioma of soft tissue • Myoepithelioma of soft tissue
• Sclerosing epithelioid fibrosarcoma • PEComa
• Plexiform fibrohistiocytic tumor
Epithelioid Cells Arranged in Sheets (Abundant
• Schwannoma
Cytoplasm)
• Synovial sarcoma (biphasic)
• Adult rhabdomyoma
• Alveolar soft part sarcoma Checkerboard Skeletal Muscle Pattern
• Epithelioid angiosarcoma • Intramuscular hemangioma
• Epithelioid sarcoma (proximal type) • Intramuscular lipoma
• Extrarenal rhabdoid tumor • Intramuscular myxoma
• Tenosynovial giant cell tumor (both types) • Low-grade myofibroblastic sarcoma
• Proliferative myositis
Epithelioid Cells Arranged in Sheets (Minimal/Scant
Cytoplasm) Nuclear Palisading
• Alveolar rhabdomyosarcoma • Dermatofibroma (fibrous histiocytoma)
• Ewing sarcoma • Leiomyoma
• Extrarenal rhabdoid tumor • Leiomyosarcoma
• Extraskeletal mesenchymal chondrosarcoma • MPNST
• Infantile fibrosarcoma • Schwannoma
• Neuroblastoma • Synovial sarcoma
• Synovial sarcoma (poorly differentiated)

30
 Pattern-Based Approach to Diagnosis
Monomorphic Spindle Cells: Hypocellular
and Hypercellular Areas
Monomorphic Spindle Cells: Cellular
Herringbone Fascicles
Monomorphic Spindle Cells: Multinodular
or Plexiform Architecture
Diagnostic Approach to Soft Tissue Tumors
Monomorphic Spindle Cells: Bundles or
Fascicles
(Left) A mixed light and dark
pattern due to alternating
areas of low ﬊ and high ﬉
cellularity is often best
appreciated at low
magnification. This pattern is
commonly seen in
schwannoma and MPNST.
(Right) Classic bundled or
fascicular growth features
cells oriented in parallel
groups. Directionality is more
conspicuous than is usually
seen in the sheet-like pattern,
and bundles/fascicles may
intersect or be organized in
different directions. This
image shows fibrous
hamartoma of infancy.
Monomorphic Spindle Cells: Storiform or
Whorled Architecture
(Left) A herringbone pattern is
created when spindle cells
within adjacent fascicles are
oriented in roughly the same
direction yet appear to slope
away from each other. This
orientation results in a wide V-
shaped or chevron
morphology. (Right) A
storiform pattern is
manifested by spindled cells
that appear to radiate
outward from a central point,
often with a vague swirling or
whorling, similar to a
pinwheel. This pattern is most
closely associated with DFSP
but may be seen in a variety of
other tumors.
Monomorphic Spindle Cells: Reticular or
Microcystic Pattern
(Left) Plexiform growth is
characterized by discrete
globular &/or serpiginous
nodules of tumor cells. It tends
to be most common in neural
tumors, including plexiform
neurofibroma and plexiform
schwannoma (shown). (Right)
A reticular pattern is created
by thin spindled or stellate
cells arranged such that
cytoplasmic extensions appear
to interconnect in a net-like or
sieve-like fashion. Acellular
microcystic ﬈ spaces in
between cells are also seen.
31
 Pattern-Based Approach to Diagnosis
Diagnostic Approach to Soft Tissue Tumors

Monomorphic Spindle Cells: Myxoid Monomorphic Spindle Cells: Myxoid

Stroma Stroma (Cellular)
(Left) Myxoid stroma is very
common in soft tissue tumors,
particularly spindled lesions
that are cytologically
monomorphic. This pattern is
inherent to some tumors (e.g.,
intramuscular myxoma) but is
often seen in variants of other
tumors (e.g., spindle cell
lipoma, DFSP). (Right) Some
tumors, such as myxoid
liposarcoma (shown) or low-
grade fibromyxoid sarcoma,
may feature areas of
increased cellularity. However,
significant nuclear
pleomorphism is absent.

Monomorphic Spindle Cells: Collagenous, Monomorphic Spindle Cells: Prominent

Hyalinized, Sclerotic Stroma Stromal Vasculature (Large)
(Left) Some monomorphic
spindle cell tumors
characteristically feature a
conspicuous collagenous
stroma that may or may not
show prominent hyalinization
or dense sclerosis. Tumor cells
may show fascicular,
storiform, or haphazard
arrangements. (Right) Large,
dilated or ectatic blood vessels
﬈ are relatively common as a
focal finding in soft tissue
tumors. Although these
vessels are not usually
prominent, some tumors
(particularly solitary fibrous
tumor) are notable exceptions.

Monomorphic Spindle Cells: Prominent Monomorphic Spindle Cells: Adipose

Stromal Vasculature (Small) Tissue Component
(Left) Smaller capillary
vascular channels ﬈ are
conspicuous in some lesions,
perhaps most notably myxoid
liposarcoma. (Right) Although
mature adipose tissue may be
present in a tumor as a result
of infiltration, some lesions
feature fat as a true
component of the tumor.
Examples include spindle cell
lipoma and mammary-type
myofibroblastoma.

32
 Pattern-Based Approach to Diagnosis
Pleomorphic Spindle Cells: Bundles and
Pleomorphic Spindle Cells: Sheets
Pleomorphic Spindle Cells: Collagenous,
Pleomorphic Spindle Cells: Myxoid Stroma
Pleomorphic Spindle Cells: Storiform or
Whorled Architecture
Diagnostic Approach to Soft Tissue Tumors
Fascicles
(Left) Diffuse, cellular sheets
of highly pleomorphic cells are
typical of many high-grade
sarcomas, including
undifferentiated pleomorphic
sarcoma, dedifferentiated
liposarcoma, and high-grade
myxofibrosarcoma. (Right)
Fascicular and bundled growth
patterns can also be present in
pleomorphic spindle cell
neoplasms, particularly
leiomyosarcoma and MPNST.
Pleomorphic cells within a
herringbone growth pattern is
often MPNST.
Hyalinized, or Sclerotic Matrix
(Left) Significant
pleomorphism within a
prominent myxoid stroma is
most frequently associated
with myxofibrosarcoma;
however, it can also be seen in
dedifferentiated and
pleomorphic types of
liposarcoma. (Right)
Pleomorphism within a
prominent collagenous matrix
is often associated with
various high-grade sarcomas;
however, it can also be the
pattern of sclerosing well-
differentiated liposarcoma
(shown).
Pleomorphic Spindle Cells: Prominent
Stromal Vessels
(Left) The pattern of
pleomorphic spindle cells
arranged in whorls or
storiform arrays is rather
nonspecific and can be seen in
a variety of often
morphologically similar high-
grade sarcomas. (Right) A
prominent nonneoplastic
stromal vasculature ﬊ is a
feature of some pleomorphic
spindle cell neoplasms,
including both low-grade (e.g.,
pleomorphic hyalinizing
angiectatic tumor, shown) and
higher grade (e.g.,
myxofibrosarcoma) tumors.
33
 Pattern-Based Approach to Diagnosis
Diagnostic Approach to Soft Tissue Tumors

Epithelioid Cells: Nests or Lobules Epithelioid Cells: Cords or Trabeculae

(Left) Nested or lobular
patterns are common in
epithelioid neoplasms. Some
tumors, such as alveolar soft
part sarcoma (shown), may
also show a central loss of
cellular cohesion ﬉ imparting
a pseudoalveolar appearance.
(Right) Distinct, linear
arrangements of epithelioid
cells may be seen within a
myxoid, fibromyxoid, or
fibrous stroma.
Myoepithelioma and ossifying
fibromyxoid tumor (shown)
are examples.

Epithelioid Cells: Sheets (Abundant Epithelioid Cells: Sheets (Minimal/Scant

Cytoplasm) Cytoplasm)
(Left) Tumors that show a
diffuse sheet-like arrangement
of epithelioid cells are often
high grade and feature
marked cytologic atypia and
mitotic activity. This
morphology can closely mimic
carcinoma or melanoma.
(Right) Tumors with sheets of
smaller epithelioid cells with
minimal cytoplasm appear
very blue or basophilic due to
increased cell density. These
neoplasms are often referred
to as small, round, blue cell
tumors.
Immunohistochemistry is often
necessary for diagnosis.

Epithelioid Cells: Collagenous, Hyalinized,

Epithelioid Cells: Myxoid Stroma or Sclerotic Stroma
(Left) The pattern of
epithelioid cells within a
myxoid stroma is distinctive
but not generally common.
Examples of tumors include
myoepithelioma, extraskeletal
myxoid chondrosarcoma, and
epithelioid MPNST. (Right)
Epithelioid cells within a
collagenous stroma should
always lead to consideration
of sclerosing epithelioid
fibrosarcoma (shown),
however, this pattern can also
be seen in myoepithelioma,
epithelioid sarcoma, and
others.

34
 Pattern-Based Approach to Diagnosis
Epithelioid Cells: Prominent Stromal
Vasculature
Mixed Spindle and Epithelioid Cells
Checkerboard Skeletal Muscle Pattern
Diagnostic Approach to Soft Tissue Tumors
Epithelioid Cells: Adipose Tissue
Component
(Left) Sheets or nests of
epithelioid cells arranged
around a prominent
vasculature ﬈ (either small or
larger vessels) are classically
associated with glomus tumor
but can also be seen in cellular
solitary fibrous tumor
(previously
hemangiopericytoma) and
others. (Right) Adipose tissue
can be an integral part of
some epithelioid soft tissue
tumors but is generally
uncommon. Examples include
angiomyofibroblastoma
(shown) and chondroid lipoma.
Spindle and Epithelioid Cells
(Left) Some soft tissue tumors
feature a mixture of spindled
﬉ and epithelioid ﬊ tumor
cells, either as discrete
components or closely
admixed. Examples include
synovial sarcoma and
epithelioid sarcoma (shown).
(Right) Plexiform
fibrohistiocytic tumor is a
neoplasm that may feature
predominantly spindled cells in
bundles/fascicles,
predominantly epithelioid cells
in nests, or a mixture of the 2
patterns (shown).
Nuclear Palisading
(Left) Although any
intramuscular neoplasm can
show infiltration of normal
skeletal muscle, some tumors
characteristically feature cells
growing between fibers ﬈,
imparting a checkerboard
pattern. Examples include
proliferative myositis and low-
grade myofibroblastic
sarcoma. (Right) Linear rows
of nuclei (or cells) ﬈ typify a
palisading pattern, as shown.
Although classically
associated with neural tumors,
this pattern can also be seen
in nonneural tumors including
leiomyoma, GIST, and synovial
sarcoma.
35
 Feature-Based Approach to Diagnosis
Diagnostic Approach to Soft Tissue Tumors

DIRECTIONS CYTOLOGIC FEATURES

How to Use These Guides Clear Cells
• These guides are neither comprehensive nor perfect and • Alveolar soft-part sarcoma
are meant to serve only as starting point for working up • Clear cell sarcoma
suspected mesenchymal neoplasm • Desmoplastic small round cell tumor
• They include entities that are most commonly or classically • Ewing sarcoma
associated with particular clinical and histologic findings • Myoepithelioma
Specific Directions for This Guide • Myoepithelial carcinoma
• This list contains variety of distinctive histologic features • PEComa
ranging from unique nuclear and cellular morphologies to • Sclerosing epithelioid fibrosarcoma
specific stromal components Granular Cells
○ Each listed feature is more commonly or • Adult rhabdomyoma
characteristically associated with some soft tissue
• Alveolar soft-part sarcoma
tumors and not others
• Chondroid lipoma
• For each histologic feature listed below, selection of most
• Congenital granular cell epulis
commonly or characteristically associated diagnoses are
provided • Extranodal Rosai-Dorfman disease
• Compile assortment of potential diagnoses from guide • Granular cell tumor
using particular feature(s) from your particular case • Hibernoma
○ Compare this selection to those created from other 2 • Leiomyoma
approach chapters • PEComa
○ Overlapping diagnoses derived from these 3 distinct Hobnail Cells
approaches are highest yield and should be your primary
• Epithelioid hemangioma
focus
• Hobnail hemangioma
• Once high-yield diagnoses have been identified, chapters
on specific entities should be directly consulted for detailed • Papillary intralymphatic angioendothelioma (Dabska)
information and image galleries • Retiform hemangioendothelioma
○ In particular, differential diagnosis sections should be Rhabdoid Cells
fully utilized to broaden search and increase chances of • Angiomatoid fibrous histiocytoma
securing correct diagnosis
• Desmoplastic small round cell tumor
Important Caveat • Epithelioid malignant peripheral nerve sheath tumors
• Always exclude carcinoma, melanoma, lymphoma, and (MPNST)
mesothelioma before committing to mesenchymal • Epithelioid sarcoma
diagnosis • Extrarenal rhabdoid tumor
• Always consider GIST for tumors in abdomen, pelvis, and • Extraskeletal myxoid chondrosarcoma
retroperitoneum • Myoepithelial carcinoma
• Pseudomyogenic hemangioendothelioma
• Synovial sarcoma (poorly differentiated)

Clear Cells Granular Cells

(Left) Soft tissue tumors
featuring cells with clear
cytoplasm include
myoepithelioma, PEComa, and
alveolar soft-part sarcoma
(shown), among others. Unlike
epithelial neoplasms, clear cell
change in mesenchymal
tumors is usually focal or
patchy and rarely diffuse.
(Right) Cells with prominent
granular, eosinophilic
cytoplasm are most commonly
associated with granular cell
tumor but can also be seen in
congenital granular cell epulis
(shown), PEComa, hibernoma,
and adult rhabdomyoma.

36
 Feature-Based Approach to Diagnosis

Diagnostic Approach to Soft Tissue Tumors

Rhabdomyoblastic Elements Prominent Neutrophils
• Dedifferentiated liposarcoma • Dedifferentiated liposarcoma (rare)
• MPNST (a.k.a. malignant Triton tumor) • Myxoinflammatory fibroblastic sarcoma
• Rhabdomyosarcomas • Pseudomyogenic hemangioendothelioma
• Superficial angiomyxoma
Paranuclear Vacuoles
• Intranodal palisaded myofibroblastoma Prominent Plasma Cells
• Leiomyoma • Extranodal Rosai-Dorfman disease
• Leiomyosarcoma • Inflammatory myofibroblastic tumor
• Kaposi sarcoma
Vacuolated Cells (Nonlipoblast)
• Chondroid lipoma MULTINUCLEATED CELLS
• Epithelioid hemangioma
• Epithelioid hemangioendothelioma Entrapped Atrophic Skeletal Muscle Fibers
• Hibernoma • Desmoid fibromatosis
• Myoepithelioma (parachordoma) • Intramuscular hemangioma
• Myxofibrosarcoma • Intramuscular lipoma
• Myxoinflammatory fibroblastic sarcoma Floret-Like Tumor Cells
• Spindle cell hemangioma
• Atypical lipomatous tumor/well-differentiated liposarcoma
• Peripheral hemangioblastoma
• Giant cell fibroblastoma
• Myxofibrosarcoma
INFLAMMATORY COMPONENT
• Pleomorphic lipoma
Prominent Eosinophils
Various Multinucleated Giant Cells
• Epithelioid hemangioma
• Alveolar rhabdomyosarcoma
• Inflammatory myofibroblastic tumor
• Calcifying aponeurotic fibroma
• Myxoinflammatory fibroblastic sarcoma
• Clear cell sarcoma
• Solitary (juvenile) xanthogranuloma
• Dermatofibroma (fibrous histiocytoma)
Prominent Foamy Histiocytes • Extraskeletal osteosarcoma
• Schwannoma • Giant cell tumor of soft tissue
• Dermatofibroma (fibrous histiocytoma) • Myxoinflammatory fibroblastic sarcoma
• Tenosynovial giant cell tumor (both types) • Nodular fasciitis (including intravascular variant)
• PEComa
Prominent Lymphocytes
• Phosphaturic mesenchymal tumor
• Angiomatoid fibrous histiocytoma (peripheral cuff)
• Plexiform fibrohistiocytic tumor
• Cellular schwannoma (peripheral cuff)
• Tenosynovial giant cell tumor (both types)
• Dendritic cell sarcomas
• Soft tissue chondroma (chondroblastoma-like variant)
• Epithelioid hemangioma (peripheral cuff)
• Solitary (juvenile) xanthogranuloma
• EBV-associated smooth muscle tumor
• Undifferentiated pleomorphic sarcoma
• Extranodal Rosai-Dorfman disease
• Inflammatory myofibroblastic tumor NUCLEAR FEATURES
• Kaposi sarcoma
• Retiform hemangioendothelioma Grooves
• Soft tissue chondroma (chondroblastoma-like variant)
Prominent Mast Cells
• Spindle cell lipoma
• Acral fibromyxoma • Tenosynovial giant cell tumor (both types)
• Cellular angiofibroma
• Mammary-type myofibroblastoma Prominent Nucleoli
• Pleomorphic hyalinizing angiectatic tumor • Alveolar soft-part sarcoma
• Solitary fibrous tumor • Clear cell sarcoma
• Spindle cell lipoma • Dendritic cell sarcomas
• Synovial sarcoma • Epithelioid angiosarcoma
• Epithelioid sarcoma (proximal type)
Prominent Mixed Inflammation
• Epithelioid MPNST
• Dedifferentiated liposarcoma • Extrarenal rhabdoid tumor
• Leiomyosarcoma (inflammatory variant) • Inflammatory myofibroblastic tumor
• Myxoinflammatory fibroblastic sarcoma • Myoepithelial carcinoma
• Well-differentiated liposarcoma (inflammatory variant) • Myxoinflammatory fibroblastic sarcoma
• Superficial CD34-positive fibroblastic tumor • Proliferative fasciitis/myositis
• Superficial CD34-positive fibroblastic tumor

37
 Feature-Based Approach to Diagnosis
Diagnostic Approach to Soft Tissue Tumors

Pseudoinclusions • Myxoinflammatory fibroblastic sarcoma

• Pleomorphic hyalinizing angiectatic tumor • Pleomorphic hyalinizing angiectatic tumor
• Paraganglioma • Schwannoma
• Superficial CD34-positive fibroblastic tumor • Tenosynovial giant cell tumor (both types)

Smudgy Nuclei Stromal Microcystic Spaces

• Ancient schwannoma • Lipoblastoma
• Atypical lipomatous tumor/well-differentiated liposarcoma • Myxoid liposarcoma
• Atypical neurofibroma • Nodular fasciitis
• Inflammatory myofibroblastic tumor
• Ischemic fasciitis STRUCTURES
• Massive localized lymphedema Nodular Eosinophilic Structures
• Myxoinflammatory fibroblastic sarcoma • Intranodal palisaded myofibroblastoma
• Low-grade fibromyxoid sarcoma
STROMAL FINDINGS • Schwannoma (neuroblastoma-like variant)
Blood-Filled Spaces True Epithelial Elements
• Aneurysmal bone cyst of soft tissue • Ectopic hamartomatous thymoma
• Aneurysmal dermatofibroma (fibrous histiocytoma) • Myoepithelioma (mixed tumor)
• Angiomatoid fibrous histiocytoma • Synovial sarcoma (biphasic)
• Giant cell tumor of soft tissue
Calcification VASCULATURE
• Calcifying aponeurotic fibroma Curvilinear Vessels
• Calcifying fibrous pseudotumor • Myxofibrosarcoma
• Leiomyoma • Low-grade fibromyxoid sarcoma
• Melanotic schwannoma
• Phosphaturic mesenchymal tumor ("grungy" calcification)
Ectatic Staghorn Vasculature
• Synovial sarcoma • Deep benign fibrous histiocytoma
• Infantile fibrosarcoma
Cleft-Like Spaces • Glomus tumor
• Fibroma of tendon sheath • Leiomyosarcoma
• Fibrous hamartoma of infancy • Myopericytoma/myofibroma
• Giant cell fibroblastoma • Paraganglioma
• Sclerosing rhabdomyosarcoma • Solitary fibrous tumor
• Solitary circumscribed neuroma • Synovial sarcoma
• Spindle cell lipoma (angiomatous variant)
• Tenosynovial giant cell tumor, diffuse type
Perivascular Cellularity
• Low-grade fibromyxoid sarcoma
Extravasated Red Blood Cells • Myxofibrosarcoma
• Intranodal palisaded myofibroblastoma • MPNST
• Kaposi sarcoma
• Nodular fasciitis
Perivascular Hyalinization
• Cellular angiofibroma
Keloidal Collagen • PEComa
• Desmoid fibromatosis • Pleomorphic hyalinizing angiectatic tumor
• Keloid • Schwannoma
• Nodular fasciitis • Solitary fibrous tumor
• Solitary fibrous tumor
Perivascular Tumor Cell Viability
Peripheral Bone Formation • Ewing sarcoma
• Aneurysmal bone cyst of soft tissue • Gastrointestinal stromal tumor
• Myositis ossificans • MPNST
• Ossifying fibromyxoid tumor
Plexiform Capillary Vasculature
Pigment (Various) • Atypical spindle cell lipomatous tumor
• Aneurysmal dermatofibroma (fibrous histiocytoma) • Lipoblastoma
• Angiomatoid fibrous histiocytoma • Myxoid liposarcoma
• Dermatofibrosarcoma protuberans (Bednar type) • Superficial angiomyxoma
• Giant cell tumor of soft tissue • Well-differentiated liposarcoma (myxoid variant)
• Hemosiderotic fibrolipomatous tumor
• Melanotic schwannoma

38
 Feature-Based Approach to Diagnosis

Diagnostic Approach to Soft Tissue Tumors

Hobnail Cells Rhabdoid Cells
(Left) Hobnail cells are plump
endothelial cells ﬉ that
project independently into a
vascular lumen (also referred
to as matchstick or tombstone
cells). (Right) Rhabdoid cells
feature a large, eosinophilic,
and often glassy
intracytoplasmic inclusion ﬈
with an eccentrically located
nucleus. Nucleoli are often
prominent. Although
classically associated with
extrarenal rhabdoid tumors,
these cells are now known to
be featured in a variety of
other high-grade sarcomas,
including epithelioid sarcoma.

Paranuclear Vacuoles Vacuolated Cells

(Left) Small, clear paranuclear
vacuoles ﬈ can be seen in
smooth muscle neoplasms,
particularly leiomyoma and
leiomyosarcoma, but also
gastrointestinal stromal tumor
and intranodal palisaded
myofibroblastoma. (Right)
Vacuolated tumor cells may
feature 1, several, or
numerous intracytoplasmic
vacuoles. A single vacuole ﬉
(if any at all) is most typical of
vascular tumors, such as
epithelioid
hemangioendothelioma
(shown), epithelioid
hemangioma, or spindle cell
hemangioma.

Multivacuolated Cells Brown Fat Cells

(Left) Multivacuolated tumor
cells ﬈ often resemble true
lipoblastic cells and may be
referred to as
pseudolipoblasts. Unlike true
lipoblasts, however, the
cytoplasm contains mucin
instead of lipid. (Right) Brown
fat cells ﬊ are
characteristically
hypervacuolated, as depicted.
In hibernomas, these cells are
often associated with other
cells ﬉ featuring finely
granular eosinophilic
cytoplasm. Hibernoma-like
cells may also be occasionally
seen in myxoid liposarcoma or
lipoblastoma.

39
 Feature-Based Approach to Diagnosis
Diagnostic Approach to Soft Tissue Tumors

Prominent Lymphocytic Infiltrate Lymphocytic Cuff

(Left) A mild lymphocytic
infiltrate is common in soft
tissue tumors and is entirely
nonspecific. A prominent
infiltrate is a common finding
in some entities, such as
inflammatory myofibroblastic
tumor (IMT) and the dendritic
cell sarcomas. (Right) Several
tumors are well known to
feature a conspicuous, patchy
lymphoid cuff st, including
angiomatoid fibrous
histiocytoma, cellular forms of
schwannoma, and epithelioid
hemangioma. Consideration of
lymphoma or a nodal
metastasis is possible when
this cuff is prominent.

Neutrophilic Infiltrate Prominent Plasma Cell Infiltrate

(Left) A prominent
neutrophilic infiltrate ﬈ is
generally uncommon in soft
tissue tumors; however, it can
be a striking finding in a few
entities, particularly
pseudomyogenic (epithelioid
sarcoma-like)
hemangioendothelioma.
(Right) A prominent infiltrate
of plasma cells ﬈ is a
common and classic finding in
IMT but can be seen in other
tumors, including extranodal
Rosai-Dorfman disease.

Entrapped Skeletal Muscle Cells Floret-Like Multinucleated Cells

(Left) Entrapped benign
skeletal myocytes ﬉ are a
relatively common finding in
intramuscular hemangioma
and intramuscular lipoma.
Note the grape-like clustering
of small nuclei and dark
eosinophilic cytoplasm. (Right)
Floret-like tumor cells ﬈ with
hyperchromatic nuclei
arranged radially around the
periphery of part of the cell
are best recognized as a
feature of pleomorphic
lipoma; however, they can also
be seen in some sarcomas,
including well-differentiated
liposarcoma and
myxofibrosarcoma (shown).

40
 Feature-Based Approach to Diagnosis

Diagnostic Approach to Soft Tissue Tumors

Osteoclast-Like Giant Cells
Wreath-Like Giant Cells
(Left) Osteoclast-like
multinucleated giant cells ﬈
are seen in a variety of soft
tissue neoplasms, both benign
and malignant, and feature a
variable number of uniform
nuclei arranged randomly
within the cytoplasm. (Right)
Some tumors feature
multinucleated giant cells
with nuclei arranged
peripherally in a wreath-like
arrangement ﬉. This type of
giant cell morphology is more
commonly associated with
clear cell sarcoma and
alveolar rhabdomyosarcoma.

Nuclear Grooves Prominent Nucleoli

(Left) Nuclear grooves ﬈ or
clefts are rarely striking but
can be seen upon close
cytologic inspection in some
tumors, including spindle cell
lipoma, tenosynovial giant cell
tumors, and angiomatoid
fibrous histiocytoma (shown).
(Right) Prominent nucleoli ﬈
are generally nonspecific;
however, diffusely prominent
uniform nucleoli are more
characteristic of some entities,
including clear cell sarcoma
and epithelioid MPNST.
Ganglion cell-like
myofibroblasts in proliferative
fasciitis/myositis also feature
prominent nucleoli.

Macronucleoli Nuclear Pseudoinclusions

(Left) A small group of
mesenchymal neoplasms are
well known to feature
prominent basophilic or
eosinophilic macronucleoli ﬉
(reminiscent of viral infection),
including myxoinflammatory
fibroblastic sarcoma. (Right)
Nuclear pseudoinclusions ﬊,
or intranuclear cytoplasmic
invaginations, are often
conspicuous in some tumors,
including pleomorphic
hyalinizing angiectatic tumor,
superficial CD34-positive
fibroblastic tumor, and
paraganglioma, and they may
be eosinophilic or pale/clear.

41
 Feature-Based Approach to Diagnosis
Diagnostic Approach to Soft Tissue Tumors

Smudgy Nuclei Cleft-Like Spaces

(Left) Enlarged, poorly defined
hyperchromatic nuclei ﬈ with
smudgy chromatin can be seen
in tumors, such as atypical
lipomatous tumor (well-
differentiated liposarcoma)
and some forms of IMT
(shown) and likely represent
degenerative changes. This
finding can also be seen in
some benign neural and
smooth muscle tumors. (Right)
Cleft-like spaces are
commonly seen in fibroma of
the tendon sheath (shown)
and solitary circumscribed
neuroma and may represent
thin vessels ﬊ or artifactual
spaces.

Pseudovascular Cleft-Like Spaces Keloidal Collagen

(Left) Some tumors can
feature irregular cleft-like
spaces ﬈ lined by
hyperchromatic mono- or
multinucleated cells, including
giant cell fibroblastoma
(shown) and fibrous
hamartoma of infancy. These
areas can resemble a vascular
neoplasm. (Right) Thick,
brightly eosinophilic, and
glassy collagen fibers or
bundles ﬈ can be seen in
lesions other than keloids,
including nodular fasciitis,
desmoid fibromatosis (shown),
and solitary fibrous tumor.

Stromal Microcystic Spaces Nodular Eosinophilic Structures

(Left) Discrete microcystic
spaces ﬈ are most
characteristic of myxoid
liposarcoma (shown) but can
also be seen much less
commonly in myxoid areas of
some tumors, such as
lipoblastoma. This finding is
also common in nodular
fasciitis; however, the spaces
are irregular, resembling torn
tissue paper. (Right) Nodular
eosinophilic structures ﬈ are
most typically associated with
morphologic variants of low-
grade fibromyxoid sarcoma
and schwannoma but can very
rarely be seen in other tumors.

42
 Feature-Based Approach to Diagnosis
Prominent Ectatic, Staghorn Vasculature
Perivascular Cellularity
Perivascular Tumor Cell Viability
Diagnostic Approach to Soft Tissue Tumors
Curvilinear Vasculature
(Left) Scattered, irregularly
shaped and dilated vascular
spaces ﬉ (a.k.a. staghorn or
hemangiopericytoma-like
vessels) can be prominent in
some tumors, the most well
known of which is solitary
fibrous tumor. (Right) Thin-
walled capillary blood vessels
﬈ lined by inflammatory cells
and tumor cells and arranged
in linear and curving arrays
(curvilinear) are a
characteristic feature of
myxofibrosarcoma but can
also be seen in myxoid regions
of low-grade fibromyxoid
sarcoma (LGFMS).
Perivascular Hyalinization
(Left) Some tumors
characteristically show an
increase in tumor cell density
﬈ around stromal blood
vessels, as depicted in this case
of MPNST. Other tumors
include myxofibrosarcoma and
LGFMS. (Right) Stromal vessels
lined or rimmed by dense,
acellular collagen ﬈ or fibrin
are seen in tumors, such as
schwannoma, solitary fibrous
tumor, and cellular
angiofibroma and represent
degenerative changes.
Plexiform Capillary Vasculature
(Left) In the setting of
extensive geographic necrosis
(and less commonly extensive
degenerative changes), some
tumors can show retained cell
viability only around stromal
vessels ﬉, creating a
distinctive peritheliomatous
appearance, as depicted in this
case of GIST. This finding can
also be seen in MPNST. (Right)
A delicate ramifying,
arborizing, or plexiform
capillary vasculature ﬈ is
characteristic of myxoid
liposarcoma (shown) but can
also be seen in myxoid areas of
lipoblastoma or well-
differentiated liposarcoma.
43
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 SECTION 3

Tumors of Adipose Tissue

Benign
Lipoma 46
Lipomatosis of Nerve 52
Synovial Lipomatosis 54
Angiolipoma 56
Spindle Cell/Pleomorphic Lipoma 60
Chondroid Lipoma 66
Myolipoma 70
Hibernoma 74
Myelolipoma 78
Lipoblastoma 80
Atypical Spindle Cell Lipomatous Tumor 84

Intermediate, Locally Aggressive

Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma 88

Malignant
Dedifferentiated Liposarcoma 94
Myxoid Liposarcoma 100
Pleomorphic Liposarcoma 106
 Lipoma

KEY FACTS
Tumors of Adipose Tissue

TERMINOLOGY MICROSCOPIC
• Benign neoplasm of mature adipocytes (white fat) • Lobules and sheets of mature adipocytes with minimal size
variation and no nuclear atypia
CLINICAL ISSUES
• May show fat necrosis, myxoid changes, or other
• Very common (most common soft tissue tumor overall) degenerative features
• Superficial lipomas are most common in upper back, • Variants: Fibrolipoma, myxolipoma, intramuscular lipoma,
shoulder, neck, and abdomen lipoma with osseous or cartilaginous metaplasia
○ Rarely may be multiple
• Surgical excision is generally curative ANCILLARY TESTS
○ Intramuscular lipoma can recur (15% rate) • Aberrations involving locus at 12q13-15 are most common
• Lipomatosis • No amplification of MDM2
○ Diffuse &/or regional overgrowth of mature adipose TOP DIFFERENTIAL DIAGNOSES
tissue
• Atypical lipomatous tumor/well-differentiated liposarcoma
MACROSCOPIC • Spindle cell lipoma
• Well circumscribed, often lobulated with thin capsule • Lipomatosis of nerve
• Yellow, greasy cut surface with very thin to no fibrous septa • Myxoid liposarcoma
• Hibernoma (lipoma-like variant)

Lipoma LIpoma, Cut Surface

(Left) A lipoma is surrounded
by a thin, delicate, and
transparent capsule ſt and is
often highly lobulated. It is
also often taken out by the
surgeon piecemeal. (Right) The
cut surface of a lipoma is
yellow, homogeneous, and
greasy. Note the thin, delicate
fibrous septa ﬇, which
separate the tumor into
lobules. Some variants may
show myxoid areas or small
foci of hemorrhage.

Mature Adipose Tissue Mature Adipose Tissue

(Left) A conventional lipoma is
composed of lobules and
sheets of mature adipocytes
(white fat). Small to medium-
sized vessels ﬈ are often
scattered in the background
but are usually not prominent.
(Right) The mature adipocytes
of a lipoma usually vary little
in size from one another. Thin
fibrous septa ﬈ are
commonly seen separating the
lobules; however, thicker,
more fibrotic septa may be
present along with fat
necrosis in traumatized
tumors.

46
 Lipoma
TERMINOLOGY
Definitions
• Benign neoplasm of mature adipocytes (white fat)
CLINICAL ISSUES
Epidemiology
• Incidence
○ Very common (most common soft tissue tumor overall)
○ More common in obese people
• Age
○ Wide range (40-60 years most common)
○ Rare < 20 years
Site
• Superficial lipomas are most common in upper back,
shoulder, neck, and abdomen
○ Rare in hands, feet, lower legs, and face
• Deep lipomas may arise in deep soft tissues as well as
thorax, mediastinum, pelvis, and, rarely, retroperitoneum
○ May also occur near bone (periosteal/parosteal lipoma)
• Intramuscular lipoma is most common within large muscles
of thigh, upper arm, and shoulder
• Mature adipose tissue proliferation within synovium of
large joint (synovial lipoma or lipoma arborescens) may
clinically simulate diffuse-type tenosynovial giant cell
tumor/pigmented villonodular synovitis
Presentation
• Painless mass
○ Larger lesions may be painful
• May be multiple (5% of cases)
○ Range in number from several to hundreds
○ Predilection for upper arm, shoulder, and back in older
men
○ May be hereditary in 30% of cases (familial multiple
lipomas)
○ Multiple lipomas can occur in various syndromes,
including Cowden, Proteus, and Fröhlich
Treatment
• Surgical excision is curative
Prognosis
• Recurrences are rare
• Higher recurrence rate in intramuscular lipoma (15%)
Clinical Variants
• Lipomatosis
○ Diffuse &/or regional overgrowth of mature adipose
tissue
– Not same as multiple discrete lipomas
○ Subtypes: Diffuse, symmetric, pelvic, steroid, and HIV-
associated lipodystrophy
○ Adipose tissue often appears poorly marginated,
resulting in tendency toward recurrence
○ Significant growth may lead to obstruction of regional
structures (larynx, ureter, bowel, etc.)
○ Cytologically and morphologically similar to conventional
lipoma, except may show infiltration of muscle or
regional structures
Tumors of Adipose Tissue
MACROSCOPIC
General Features
• Well circumscribed, often lobulated
• Thin, delicate capsule
• Yellow, greasy cut surface
• Myxoid change, focal hemorrhages, bone, or cartilage may
be evident
• Infiltrative margins may be present in intramuscular cases
Size
• Usually 2-10 cm
• Deep and intramuscular lipomas are often larger
MICROSCOPIC
Histologic Features
• Lobules and sheets of mature adipocytes
○ In small samples, adipocytes are often indistinguishable
from normal, nonlesional fat
• Minimal variation in adipocyte size
• Bland nuclei are small and often peripherally flattened
○ May appear absent
○ May show small intranuclear vacuoles (Lochkern change)
• Small to medium-sized vessels sparsely distributed
throughout tumor
○ May be more prominent in atrophic lipomas
• Thin, discontinuous fibrous bands with collagen may be
present, particularly in larger lesions
• Degenerative changes, including foci of fat necrosis,
myxoid change, or hemorrhage, are not uncommon
○ Fat necrosis may be extensive in some cases
• Ischemic changes, infarction, and cystic degeneration may
be present, particularly in traumatized lipomas
Morphologic Variants
• Fibrolipoma
○ Contains variably prominent fibrous tissue and septa
with abundant collagen
○ Extensively fibrous examples ("sclerotic lipoma") have
predilection for hands and scalp of young men
• Myxolipoma
○ Prominent/diffuse stromal myxoid change in otherwise
conventional lipoma
○ May also show prominent vascular component (so-called
angiomyxolipoma)
• Lipoma with cartilaginous metaplasia (chondrolipoma)
○ Additional component of mature cartilage
• Lipoma with osseous metaplasia (osteolipoma)
○ Additional component of mature bone
• Intramuscular lipoma
○ Often much larger than subcutaneous forms
○ Variable amounts of admixed mature skeletal muscle
fibers, most prominent at periphery
– Imparts checkerboard appearance at low
magnification
– Often infiltrative margins
○ Atrophic skeletal muscle fibers, if present, often mimic
atypical stromal cells ("smudge cells") of atypical
lipomatous tumor (ALT)/well-differentiated liposarcoma
47
 Lipoma
Tumors of Adipose Tissue
ANCILLARY TESTS
Immunohistochemistry
• Mature adipocytes express S100 protein
• MDM2(-), CDK4(-)
Genetic Testing
• Majority of lipomas have abnormal karyotype
○ Aberrations involving 12q13-15 (most cases)
– t(3;12)(q27-28;q13-15) most common translocation
○ Also aberrations involving 6p21-23, 13q11-12, and
12q22-24
• No amplification of MDM2
DIFFERENTIAL DIAGNOSIS
Atypical Lipomatous Tumor/Well-Differentiated
Liposarcoma
• Often larger and more deeply seated than lipoma but may
occur in subcutaneous tissue (ALT)
• Contain variably thickened fibrous septa containing atypical
stromal cells ("smudge cells")
○ Atypical stromal cells may be extremely focal
• Lipoblasts may or may not be present and are not required
for diagnosis
• May arise intramuscularly and show similar myoinfiltrative
checkerboard pattern as in intramuscular lipoma
• MDM2(+) and CDK4(+) by IHC
• MDM2 amplification by FISH
• In retroperitoneum, well-differentiated liposarcoma is far
more common than lipoma
Spindle Cell Lipoma
• Predilection for upper arms, shoulders, and posterior neck
• Classically contains "ropey" collagen and population of
bland, spindled fibroblastic cells
• Myxoid stroma is common and may be extensive
• Mast cells common
• CD34(+) spindle cells
• Loss of nuclear Rb expression by IHC
Myxoid Liposarcoma
• Plexiform chicken wire capillary vascular pattern
• Variable numbers of early lipoblasts and maturing
adipocytes
• Generally more cellular than myxolipoma
• DDIT3 rearrangements
Hibernoma
• Often occurs in younger patients than conventional lipoma
• Most common in thigh but can occur in variety of sites
• Contains multivacuolated "brown fat" cells
○ May be very focal (lipoma-like hibernoma)
• Karyotypic aberrations involving 11q13-21
Lipomatosis of Nerve
• Children and young adults
• Predominantly affects hand, wrist, forearm
• May be associated with macrodactyly
• Mature adipose tissue infiltrating around and between
nerve branches and along perineurium
48
Diffuse-Type Neurofibroma
• Infiltrative growth within connective and adipose tissues
• Neural element may be sparse compared to adipocytic
component
• S100(+) spindle cells
• Often show pseudomeissnerian bodies
Intramuscular Hemangioma
• May contain abundant mature adipose tissue, mimicking
intramuscular lipoma
• Most patients < 30 years of age
• Contains prominent benign capillary or large vessel vascular
component
• Significant recurrence rate (~ 50%)
Chondroid Lipoma
• Contains regions of myxoid or sclerotic lipoblastic
differentiation that superficially resemble cartilage
• Lacks mature cartilage and contains numerous lipoblasts
• May contain large zones of relatively unremarkable-
appearing mature adipose tissue
DIAGNOSTIC CHECKLIST
Pathologic Interpretation Pearls
• Most examples are clinically superficial/subcutaneous
• Homogeneous, yellow cut surface and lacking prominent,
thick fibrous septations
• Adipocytes are mature and nuclei lack enlargement,
irregularity, and hyperchromasia
• Fat necrosis and atrophic skeletal muscle fibers may mimic
atypical stromal cells of well-differentiated
liposarcoma/ALT
SELECTED REFERENCES
1. Michal M et al: Dysplastic lipoma: a distinctive atypical lipomatous neoplasm
with anisocytosis, focal nuclear atypia, p53 overexpression, and a lack of
mdm2 gene amplification by FISH; a report of 66 cases demonstrating
occasional multifocality and a rare association with retinoblastoma. Am J
Surg Pathol. 42(11):1530-40, 2018
2. Stojanov IJ et al: Lipomas of the oral cavity: utility of MDM2 and CDK4 in
avoiding overdiagnosis as atypical lipomatous tumor. Head Neck Pathol.
ePub, 2018
3. Agaimy A: Anisometric cell lipoma: Insight from a case series and review of
the literature on adipocytic neoplasms in survivors of retinoblastoma
suggest a role for RB1 loss and possible relationship to fat-predominant
("fat-only") spindle cell lipoma. Ann Diagn Pathol. 29:52-56, 2017
4. Manor E et al: Oral lipoma: analysis of 58 new cases and review of the
literature. Ann Diagn Pathol. 15(4):257-61, 2011
5. Macarenco RS et al: Retroperitoneal lipomatous tumors without cytologic
atypia: are they lipomas? A clinicopathologic and molecular study of 19
cases. Am J Surg Pathol. 33(10):1470-6, 2009
6. Sakurai H et al: Intrathoracic lipomas: their clinicopathological behaviors are
not as straightforward as expected. Ann Thorac Surg. 86(1):261-5, 2008
7. Laskin WB et al: Sclerotic (fibroma-like) lipoma: a distinctive lipoma variant
with a predilection for the distal extremities. Am J Dermatopathol.
28(4):308-16, 2006
8. Gaskin CM et al: Lipomas, lipoma variants, and well-differentiated
liposarcomas (atypical lipomas): results of MRI evaluations of 126
consecutive fatty masses. AJR Am J Roentgenol. 182(3):733-9, 2004
9. Tardío JC et al: Angiomyxolipoma (vascular myxolipoma) of subcutaneous
tissue. Am J Dermatopathol. 26(3):222-4, 2004
10. Willén H et al: Comparison of chromosomal patterns with clinical features in
165 lipomas: a report of the CHAMP study group. Cancer Genet Cytogenet.
102(1):46-9, 1998
11. Zelger BG et al: Sclerotic lipoma: lipomas simulating sclerotic fibroma.
Histopathology. 31(2):174-81, 1997
12. Fletcher CD et al: Intramuscular and intermuscular lipoma: neglected
diagnoses. Histopathology. 12(3):275-87, 1988
 Lipoma

Tumors of Adipose Tissue

Mature Adipocytes Lochkern Nuclear Change
(Left) A lipoma is composed
entirely of mature white fat.
The adipocyte nucleus ﬊ is
bland, small, and typically
compressed against the
periphery of the cell by the
large fat vacuole. Of note,
most adipocytes appear to
lack a nucleus as a result of 2D
tissue sectioning. (Right)
Adipocytes showing nuclear
vacuolization (or Lochkern
change) is relatively common
and may be mistaken for
multivacuolated lipoblasts.
The vacuoles (usually 1 or 2)
are not external to the nucleus
as would be seen in lipoblasts.

Stromal Myxoid Change Fat Necrosis

(Left) Focal stromal myxoid
change is a common finding in
lipomas, particularly ones that
have been traumatized. Fat
necrosis is often present
elsewhere. (Right) Fat necrosis
is represented by foamy
histiocytes surrounding and
reacting to damaged
adipocytes. Not uncommonly,
the histiocytes are
multinucleated, and the
apparent hyperchromasia
caused by nuclear overlap ﬈
may raise concern for an
atypical lipomatous
tumor/well-differentiated
liposarcoma.

Focal Fat Necrosis Fibrolipoma

(Left) Fat necrosis presents in
a wide variety of histologic
patterns, and the constituent
histiocytes are commonly
misidentified as lipoblasts or
atypical cells indicative of an
atypical lipomatous
tumor/well-differentiated
liposarcoma, particularly when
focal and isolated. (Right) A
lipoma containing abundant
fibrous tissue and collagen is
appropriately designated as a
fibrolipoma. Examples with
extensive fibrosis have been
referred to as sclerotic
lipomas.

49
 Lipoma
Tumors of Adipose Tissue

Abundant Collagen Bundles of Collagen

(Left) Fibrolipomas often
contain an abundance of
collagen in the form of
apparent septa or ill-defined
aggregates. The exact amount
of collagen varies from one
case to the next. (Right) Some
cases of fibrolipoma show
well-demarcated bundles of
collagen ﬈ cut in cross
section. This morphology may
be easily confused with the
smooth muscle bundles of a
myolipoma when diffuse or
even neural elements when
focal.

Fibrolipoma Stromal Myxoid Change

(Left) This example of an
otherwise conventional
fibrolipoma contains foci of
thickened collagen bundles
similar to what is seen in
spindle cell lipoma. The
distinction in such cases is
largely academic. (Right) A
lipoma that demonstrates
extensive and diffuse stromal
myxoid change is
appropriately classified as a
myxolipoma. If a component
of bland spindle cells is also
present, a diagnosis of spindle
cell lipoma is more
appropriate.

Myxolipoma Osseous Metaplasia

(Left) Compared to a myxoid
spindle cell lipoma,
myxolipoma lacks a
component of bland spindle
cells as well as "ropey"
collagen. The myxoid stroma is
largely acellular. Although not
seen in this H&E, prominent
vessels may also be seen (so-
called angiomyxolipoma).
(Right) Metaplastic bone
formation in a lipoma may be
focal or extensive and is often
first evident at the time of
gross examination.

50
 Lipoma

Tumors of Adipose Tissue

Cartilaginous Metaplasia Intramuscular Lipoma
(Left) Cartilaginous
metaplasia in a lipoma may be
isolated or associated with
foci of metaplastic bone. Not
uncommonly, the background
adipose tissue shows increased
fibrosis and collagen or
myxoid stromal change.
(Right) Intramuscular or
intermuscular lipomas
typically show bundles of
mature skeletal muscle
intermixed to some degree
with the elements of mature
adipose tissue.

Checkerboard Pattern Mature Skeletal Muscle

(Left) The adipose tissue
component of intramuscular
lipoma is often highly
intermixed with the skeletal
muscle bundles and
demonstrates the classic
alternating checkerboard
appearance. (Right) The
skeletal muscle bundles in an
intramuscular lipoma are
composed of mature
myocytes. They may be
present focally in some tumors
and extensively in others.

Atrophic Skeletal Muscle Atrophic Myocytes

(Left) Atrophic skeletal muscle
fibers ﬈ are commonly
identified in cases of
intramuscular lipoma,
although the extent of this
finding may be very focal. This
finding is not specific to
lipomas and may be seen in
other intramuscular tumors.
(Right) Atrophic myocytes
characteristically contain
bright pink cytoplasm and
numerous small, overlapping
nuclei in a cluster of grapes
configuration ﬈. It is
important to not confuse
these cells with atypical
stromal cells ("smudge cells")
of liposarcoma.

51
 Lipomatosis of Nerve

KEY FACTS
Tumors of Adipose Tissue

TERMINOLOGY IMAGING
• Increased fibrofatty tissue infiltrating and surrounding • Coaxial cable-like (axial view) and spaghetti-like (coronal
nerves view) appearances due to linear nerve bundles encased in
• Synonym: Fibrolipomatous hamartoma of nerve fat
CLINICAL ISSUES MACROSCOPIC
• Predominantly in children, often congenital • Sausage-shaped mass
○ Some in young adults up to 30 years; rare in older adults • Yellow-white fibroadipose tissue surrounds and distends
• Median nerve and digital branches most common (80%) nerve
○ Symptoms often similar to compression neuropathy or MICROSCOPIC
carpal tunnel syndrome
• Mature adipose and fibrous tissue infiltrate nerve
• Slowly progressive swelling/mass of palm (if median nerve
○ Individual nerve bundles separated and encased by fat
affected)
• Marked epineurial and perineurial fibrous thickening
• Macrodactyly present in 30%
• Concentric hyperplasia of perineurium
• Biopsy not needed if classic MR findings
○ Complete excision usually contraindicated because of TOP DIFFERENTIAL DIAGNOSES
potential nerve damage • Lipoma of nerve
• Good prognosis when conservatively managed • Neuroma

Nerve Surrounded by Fat and Fibrosis Perineurial Hyperplasia

(Left) In this H&E of
lipomatosis of nerve
(fibrolipomatous hamartoma),
a small, solitary nerve bundle
﬇ is surrounded by concentric
layers of dense fibrosis st,
mature adipose tissue ﬊, and
a thick layer of epineurial
fibrosis ﬈. (Right) At higher
magnification, nerve bundles
with perineurial hyperplasia
are separated from one
another by fibrous tissue and
mature fat.

Frequent Involvement of Median Nerve Appearance on Axial MR

(Left) In this gross photograph
of lipomatosis of nerve, the
median nerve is markedly
enlarged and distended by
pale yellow-white adipose
tissue. (Courtesy T. Al-Jabri,
MD.) (Right) The median nerve
﬈ is massively enlarged on
this axial T1 MR and has an
appearance likened to a cross
section of a coaxial cable.
Multiple individual nerve
bundles (dark) are divided
from one another by
intervening fibroadipose tissue
(light). (Courtesy Dr. A,
Lawson, Radiopaedia.org.)

52
 Lipomatosis of Nerve

Tumors of Adipose Tissue

TERMINOLOGY Size
• Variable, up to 10 cm length of nerve may be involved
Synonyms
• Fibrolipomatous hamartoma of nerve MICROSCOPIC
• Neural fibrolipoma, neurolipomatosis
Histologic Features
• Fatty infiltration of median nerve
• Mature adipose and fibrous tissue infiltrate nerve
Definitions ○ Individual nerve bundles separated and encased by fat
• Increased fibrofatty tissue infiltrating and surrounding • Marked epineurial and perineurial fibrous thickening
nerves • Concentric hyperplasia of perineurium
• Nerves can become atrophic in longstanding cases
CLINICAL ISSUES • Rare metaplastic bone formation
Epidemiology
• Age DIFFERENTIAL DIAGNOSIS
○ Predominantly in children, often congenital Lipoma of Nerve
○ Some in young adults up to 30 years; rare in older adults • Circumscribed and confined within nerve
Site • Fat does not entrap and separate individual nerve bundles
• Median nerve and digital branches most common (80%) Neuroma
○ Affects palmar surface of hand, wrist, forearm, digits • Increased number of nerve bundles, disorganized and
• Rarely ulnar, radial, sciatic, peroneal, or cranial nerve; any tangled together
nerve can be involved • Minimal fatty component
• Vast majority are unilateral
Lipomatosis
Presentation • Histologically similar; clinical information is key to
• Slowly progressive swelling/mass of palm (if median nerve distinction
affected) • May have secondary nerve involvement but primarily lesion
• Paresthesia and dysesthesia of skin/subcutis or muscle
○ Symptoms often similar to compression neuropathy or
Neurofibromatosis Type 1
carpal tunnel syndrome
• Macrodactyly (digital gigantism, macrodystrophia • Also may cause macrodactyly
lipomatosa) in 30% • Expanded nerve in neurofibromatosis type 1 (NF1) may
○ Can be congenital and progressive grossly resemble lipomatosis of nerve
○ Increased growth of bone and soft tissue of affected ○ Histologically easy to distinguish by typical features of
digit neurofibroma and lack of fat
• Other distinct clinical features of NF1 not usually seen in
Treatment lipomatosis of nerve
• Biopsy not needed if MR findings are classic
• Complete excision usually contraindicated because of SELECTED REFERENCES
potential nerve damage 1. Prasad NK et al: A new pattern of lipomatosis of nerve: case report. J
• Surgical decompression (e.g., carpal tunnel release) or Neurosurg. 126(3):933-7, 2017
debulking may reduce symptoms 2. Chiaradia G et al: Precalcaneal congenital fibrolipomatous hamartoma:
report of 2 cases. J Pediatr Surg. 46(3):e11-2, 2011
• For macrodactyly, may remove deformed digit
3. Al-Jabri T et al: Lipofibromatous hamartoma of the median nerve. J Orthop
Prognosis Surg Res. 5:71, 2010
4. Chiang CL et al: MRI diagnosis of fibrolipomatous hamartoma of the median
• Good prognosis when conservatively managed nerve and associated macrodystrophia lipomatosa. J Chin Med Assoc.
73(9):499-502, 2010
5. Flann S et al: Precalcaneal congenital fibrolipomatous hamartoma. Clin Exp
IMAGING Dermatol. 34(4):495-6, 2009
MR Findings 6. Bisceglia M et al: Neural lipofibromatous hamartoma: a report of two cases
and review of the literature. Adv Anat Pathol. 14(1):46-52, 2007
• Fusiform enlargement of affected nerve segment 7. Jain TP et al: Fibrolipomatous hamartoma of median nerve. Australas Radiol.
• Coaxial cable-like (axial view) and spaghetti-like (coronal 51 Spec No.:B98-B100, 2007
view) appearances due to linear nerve bundles encased in 8. Razzaghi A et al: Lipofibromatous hamartoma: review of early diagnosis and
treatment. Can J Surg. 48(5):394-9, 2005
fat 9. Al-Qattan MM: Lipofibromatous hamartoma of the median nerve and its
associated conditions. J Hand Surg [Br]. 26(4):368-72, 2001
MACROSCOPIC 10. Marom EM et al: Fibrolipomatous hamartoma: pathognomonic on MR
imaging. Skeletal Radiol. 28(5):260-4, 1999
General Features 11. Berti E et al: Fibrolipomatous hamartoma of a cranial nerve. Histopathology.
24(4):391-2, 1994
• Sausage-shaped mass
12. Amadio PC et al: Lipofibromatous hamartoma of nerve. J Hand Surg [Am].
• Yellow-white fibroadipose tissue surrounds and distends 13(1):67-75, 1988
nerve 13. Silverman TA et al: Fibrolipomatous hamartoma of nerve. A clinicopathologic
analysis of 26 cases. Am J Surg Pathol. 9(1):7-14, 1985

53
 Synovial Lipomatosis

KEY FACTS
Tumors of Adipose Tissue

TERMINOLOGY IMAGING
• Benign, likely reactive, subsynovial proliferation of mature • Effusion
adipose tissue • Synovial hypertrophy with villous projections showing
○ May arise independently or in association with chronic signal intensity of normal fat
joint disease
MACROSCOPIC
• Synonyms: Lipoma arborescens, synovial lipoma
• Yellow, fatty-appearing tissue
CLINICAL ISSUES
MICROSCOPIC
• Wide age range
• Knee most common site • Proliferation of mature adipose tissue beneath synovial
membrane
• Pain and swelling of affected joint
• Synovium characteristically shows villous appearance
○ Secondary synovial lipomatosis arises in setting of joint
disease, most commonly osteoarthritis • Variable chronic inflammatory cell infiltrate
• Treatment: Arthroscopic or open synovectomy TOP DIFFERENTIAL DIAGNOSES
• Benign • Diffuse-type tenosynovial giant cell tumor
• Low risk of local recurrence • Atypical lipomatous tumor
• Untreated lesions can lead to degenerative changes within • Hoffa disease
affected joint • Rheumatoid arthritis

Synovial Lipomatosis Villous Appearance

(Left) Synovial lipomatosis,
a.k.a. synovial lipoma or
lipoma arborescens, is a
benign proliferation of
subsynovial adipose tissue.
Grossly and intraoperatively,
the lesion ﬉ appears as
yellow, fatty tissue, often with
a villiform external contour.
(Courtesy R. Nicholas, MD.)
(Right) At low magnification,
synovial lipomatosis shows
abundant mature adipose
tissue filling the subsynovial
connective tissue. A villiform
synovial architecture is often
conspicuous.

Subsynovial Mature Adipose Tissue Mature Adipose Tissue

(Left) The adipose tissue
present in synovial lipomatosis
is mature and devoid of atypia.
A variable chronic
inflammatory infiltrate is
present in many cases. The
overlying synovium ﬈ may be
unremarkable, hyperplastic, or
inflamed. (Right) The mature
adipose tissue of synovial
lipomatosis is
indistinguishable from
conventional lipoma at high
magnification. Small blood
vessels ﬉ are common as
well.

54
 Synovial Lipomatosis

Tumors of Adipose Tissue

TERMINOLOGY MICROSCOPIC
Synonyms Histologic Features
• Synovial lipoma • Proliferation of mature adipose tissue beneath synovial
• Lipoma arborescens membrane
• Villous lipomatous proliferation of synovial membrane • Synovium characteristically shows villous appearance
○ May show reactive hyperplasia
Definitions
• Generally lacks hemorrhage and hemosiderin pigment
• Benign, likely reactive, subsynovial proliferation of mature • Variable chronic inflammatory cell infiltrate
adipose tissue
○ May arise independently or in association with chronic DIFFERENTIAL DIAGNOSIS
joint disease
Diffuse-Type Tenosynovial Giant Cell Tumor
CLINICAL ISSUES • Villonodular proliferation of epithelioid cells
Epidemiology • Sheet-like growth common
• Hemosiderin and foamy macrophages
• Incidence
• Fat typically absent
○ Rare
• Age Atypical Lipomatous Tumor/Well-Differentiated
○ Wide range Liposarcoma
– Rare in children and adolescents • Large, lobular, expansile mass
• Sex • Rarely presents as intraarticular disease
○ Male predominance • Combined MDM2(+) and CDK4(+) by
Site immunohistochemistry
• MDM2 amplification
• Knee most common
• Atypical stromal fibroblasts ("smudge cells")
• Other sites
○ Ankle Hoffa Disease
○ Wrist • Affects knee
○ Elbow • Hypertrophy of infrapatellar fat pad, related to prior
○ Hip trauma
• Occasionally bilateral Rheumatoid Arthritis
Presentation • Positive serologies for antirheumatoid factor
• Pain and swelling of affected joint • Prominent lymphoplasmacytic synovial and subsynovial
• Secondary synovial lipomatosis arises in setting of joint infiltrate
disease, most commonly osteoarthritis
○ Associated with joint disease, most commonly SELECTED REFERENCES
osteoarthritis 1. Kim S et al: An intra-articular synovial lipoma of the hip, possibly causing
osteoarthritis: a case report and review of the literature. Skeletal Radiol.
Treatment 47(5):717-721, 2018
• Arthroscopic or open synovectomy 2. Kulkarni HG et al: Lipoma arborescens - eyes see what mind knows! J Orthop
Case Rep. 7(5):59-62, 2017
Prognosis 3. Tsifountoudis I et al: Lipoma arborescens of the knee: report of three cases
and review of the literature. Case Rep Med. 2017:3569512, 2017
• Benign 4. Miladore N et al: Synovial lipomatosis: a rare cause of knee pain in an
• Untreated lesions can lead to degenerative changes within adolescent female. World J Orthop. 6(3):369-73, 2015
affected joint 5. Sailhan F et al: Bilateral lipoma arborescens of the knee: a case report. J
Bone Joint Surg Am. 93(2):195-8, 2011
• Low risk of local recurrence 6. Chae EY et al: Lipoma arborescens of the glenohumeral joint causing bone
erosion: MRI features with gadolinium enhancement. Skeletal Radiol.
IMAGING 38(8):815-8, 2009
7. Martín S et al: Diagnostic imaging of lipoma arborescens. Skeletal Radiol.
MR Findings 27(6):325-9, 1998
8. Soler T et al: Lipoma arborescens of the knee: MR characteristics in 13 joints.
• Effusion J Comput Assist Tomogr. 22(4):605-9, 1998
• Synovial hypertrophy with villous projections showing
signal intensity of normal fat

MACROSCOPIC
General Features
• Yellow, fatty-appearing tissue

55
 Angiolipoma

KEY FACTS
Tumors of Adipose Tissue

TERMINOLOGY MACROSCOPIC
• Benign tumor consisting of mature adipocytes and thin- • Circumscribed, yellow-red nodule
walled blood vessels with intraluminal fibrin thrombi • Typically < 2 cm in size
ETIOLOGY/PATHOGENESIS MICROSCOPIC
• Majority are sporadic; rare familial cases • Admixture of mature adipocytes and capillary-sized blood
vessels
CLINICAL ISSUES
○ Hallmark: Fibrin thrombi within vessels
• Commonly in young adults
• Vascularity often more prominent in periphery
○ Male predominance
• No nuclear atypia in adipocytic or endothelial components
• Forearm, trunk, and upper arm most common sites
• Morphologic variant: Cellular angiolipoma
• Painful tender subcutaneous nodules
○ Often multiple TOP DIFFERENTIAL DIAGNOSES
• Treatment: Simple surgical excision • Lipoma
• Excellent prognosis • Intramuscular hemangioma
○ Local recurrence very rare • Kaposi sarcoma
○ No risk of malignant transformation • Spindle cell hemangioma
• Angiomyolipoma (PEComa family)

Angiolipoma Abundant Adipose Tissue

(Left) Angiolipoma is
composed of both vascular ﬈
and mature adipocytic ﬊
components admixed together
in varying proportions. They
are often small circumscribed
lesions, as seen here. (Right)
This angiolipoma is
predominantly composed of
adipose tissue. The focal
vascular component is present
as clusters of small vessels
near the periphery ﬈ and
near the thin fibrous septa ﬉.

Peripheral Vascular Component Characteristic Fibrin Thrombi

(Left) The focal vascular
component of angiolipoma is
present as clusters of small
vessels near the periphery of
the mass ﬈. The remainder of
the lesion is composed of
mature adipocytes ﬈. (Right)
Bright pink fibrin thrombi ﬈
are present in small clustered
capillary vessels. This is the
hallmark feature of
angiolipoma.

56
 Angiolipoma

Tumors of Adipose Tissue

TERMINOLOGY DIFFERENTIAL DIAGNOSIS
Definitions Lipoma
• Benign tumor composed of mature adipocytes and • Mass composed of mature adipose tissue
clustered small blood vessels with intraluminal fibrin ○ May have increased single vessels but lacks clustered
thrombi vessels and fibrin thrombi
• Lipomas possess various translocations of chromosome
ETIOLOGY/PATHOGENESIS 12q or 6p
Unknown • Fat-predominant angiolipoma may mimic lipoma
○ Even 1 cluster of small vessels with microthrombi is
• Majority are sporadic
diagnostic of angiolipoma
• Rare familial predilection (5%)
Intramuscular Hemangioma
CLINICAL ISSUES • Previously known as "infiltrating angiolipoma"
Epidemiology • Large infiltrative lesion in deep muscle (not in subcutis)
• Age • Often has adipose tissue and large thick-walled vessels
○ Most common in young adults ○ Lacks clustered small vessels with luminal thrombi
○ Rare in children or in adults > 50 years ○ May have organizing thrombi in large vessels
• Sex Kaposi Sarcoma
○ Male predominance • More spindled and fascicular endothelial proliferation
Site • Blood-filled slit-like spaces and extravasated RBCs
• Forearm, trunk, and upper arm most common sites • Plasma cells almost always present
• Rare on scalp or face • PAS(+) hyaline globules, but no fibrin thrombi
• HHV8(+) endothelial cells
Presentation
Angiomyolipoma (PEComa Family)
• Painful subcutaneous nodule, often multiple (in 2/3 of
cases) • Spindle cells with pale/granular pink cytoplasm
• HMB-45 &/or MART-1(+) plus smooth muscle actin &/or
Treatment desmin (+)
• Simple surgical excision • Vessels are large caliber and thick walled
Prognosis • Vanishingly rare in subcutis or peripheral soft tissue

• Excellent: Benign Spindle Cell Hemangioma

○ Very low risk of local recurrence • Painful multiple subcutaneous nodules in extremities
○ No known risk of malignant transformation • Unlike cellular angiolipoma, spindle cell hemangioma has:
○ Large, cavernous vascular spaces
MACROSCOPIC ○ Cellular zones of spindled and epithelioid endothelial
Gross Features cells and clustered endothelial vacuoles resembling
miniature adipocytes
• Well circumscribed
○ Large calcified thrombi (phleboliths), but lacks clustered
• Yellow-red nodules small vessels with luminal thrombi
• Typically < 2 cm in size
DIAGNOSTIC CHECKLIST
MICROSCOPIC
Pathologic Interpretation Pearls
Histologic Features
• Mature adipocytes
• 2 components present in varying proportions • Clusters of capillary-sized vessels
○ Mature adipocytes • Fibrin microthrombi in vessels
○ Clustered capillary-sized vessels with fibrin thrombi
– Vascularity often more prominent in periphery SELECTED REFERENCES
• No nuclear atypia in adipocytic or endothelial components
1. Hofvander J et al: Frequent low-level mutations of protein kinase D2 in
Morphologic Variant angiolipoma. J Pathol. 241(5):578-82, 2017
2. Sheng W et al: Cellular angiolipoma: a clinicopathological and
• Cellular angiolipoma immunohistochemical study of 12 cases. Am J Dermatopathol. 35(2):220-5,
○ Vascular component predominates 2013
3. Sciot R et al: Cytogenetic analysis of subcutaneous angiolipoma: further
evidence supporting its difference from ordinary pure lipomas: a report of
ANCILLARY TESTS the CHAMP Study Group. Am J Surg Pathol. 21(4):441-4, 1997
4. Fletcher CD et al: Correlation between clinicopathological features and
Immunohistochemistry karyotype in lipomatous tumors. A report of 178 cases from the
• Immunostains not useful for diagnosis Chromosomes and Morphology (CHAMP) Collaborative Study Group. Am J
Pathol. 148(2):623-30, 1996
5. Hunt SJ et al: Cellular angiolipoma. Am J Surg Pathol. 14(1):75-81, 1990

57
 Angiolipoma
Tumors of Adipose Tissue

Fibrin Thrombi Abundant Fibrin Thrombi

(Left) Fibrin thrombi within
capillary lumina ﬈ are pink
and amorphous. (Right) The
capillaries in angiolipoma
often have a lobular
arrangement and may appear
reminiscent of a hemangioma
in some cases; however, pink
fibrin thrombi are present in
many of the lumina ﬈ in
angiolipoma.

Moderate Cellularity Kaposi-Like Cellularity

(Left) More cellular vascular
areas are admixed with
mature adipose tissue in this
angiolipoma. The vascularity is
still enhanced at the
peripheral aspect of the mass.
(Right) Spindled endothelial
cells and pericytes appear to
infiltrate into mature adipose
tissue. This more cellular and
spindled pattern can mimic
Kaposi sarcoma; however,
note the characteristic fibrin
thrombi ﬈.

Fibrin Thrombi Focal Spindled Morphology

(Left) Capillary lumina with
bland endothelial cells can be
appreciated at high power in
the cellular zones. Fibrin
thrombi ﬈ are present, unlike
in Kaposi sarcoma. (Right)
Angiolipoma may have
spindled cellular foci, but
there are still small well-
formed vessels ﬊. The
spindled cells are endothelial
and pericytic (perivascular
modified smooth muscle cells).
Both cell types are bland and
lack nuclear atypia or
significant mitotic activity in
angiolipoma.

58
 Angiolipoma
Cellular Angiolipoma
Tightly Packed Capillary Channels
Well-Formed Vessels
Tumors of Adipose Tissue
Lobular Arrangement
(Left) The cellular variant of
angiolipoma is composed
almost entirely of densely
packed small blood vessels.
There is very little adipose
component within the mass.
(Right) There is often a lobular
arrangement of vessels in
cellular angiolipoma. Focal
adipocytes ﬈ appear to be
entrapped between the
vascular lobules, which may
give a false impression of
aggressive infiltrative growth.
Numerous Thrombi
(Left) Vascular zones in
cellular angiolipoma are
composed of tightly packed,
well-formed small vessels.
(Right) Numerous fibrin
thrombi ﬈ are present within
the lumina of the vessels,
helping to establish the
diagnosis of angiolipoma.
Bland Cytology
(Left) The vessels in a cellular
angiolipoma are well formed
and lined by bland endothelial
cells. (Right) The endothelial
cells here are bland and
uniform. The presence of
intraluminal fibrin thrombi in
cellular angiolipoma is helpful
in distinguishing it from Kaposi
sarcoma.
59
 Spindle Cell/Pleomorphic Lipoma

KEY FACTS
Tumors of Adipose Tissue

CLASSIFICATION • Yellow-tan cut surface with variable gray-white &/or myxoid

• Benign adipocytic tumor with variable admixture of spindle foci
cells, "ropey" collagen, mature adipose tissue, and MICROSCOPIC
multinucleate tumor giant cells
• Variable admixture of bland spindle cells, "ropey" collagen,
• Spindle cell lipoma and pleomorphic lipoma (PL) are mature adipose tissue, myxoid stroma, and mast cells
morphologic variations of same neoplasm
○ PL contains multinucleated tumor cells
CLINICAL ISSUES • Morphologic variants: Fat free, fat poor, angiomatous
• Most common in older (> 50 years) men ANCILLARY TESTS
• Most arise in shoulder, posterior neck, or back
• CD34(+); loss of nuclear retinoblastoma expression
○ Tumors in women more likely to arise in atypical
• Molecular: Deletion of RB1 (13q14)
locations
• Treatment: Conservative surgical excision only TOP DIFFERENTIAL DIAGNOSES
• Benign; excellent prognosis • Atypical lipomatous tumor
MACROSCOPIC • Neurofibroma
• Cellular angiofibroma
• Well-circumscribed subcutaneous (or less commonly
• Mammary-type myofibroblastoma
dermal) mass
• Atypical spindle cell lipomatous tumor
• Solitary fibrous tumor

Spindle Cell Lipoma Spindle Cell Lipoma

(Left) Like conventional
lipomas, spindle cell (SCL) and
pleomorphic lipomas (PL) have
a homogeneous, yellow cut
surface. Both tumors also
often show subtle, gray-white
foci ﬊ that are firm in
consistency and correlate
histologically with spindle cell
areas containing "ropey"
collagenous matrix. (Right) At
low power, SCL is composed of
a mixture of adipose tissue
and a variable myxoid to
collagenous stroma containing
bland spindle cells.

"Ropey" Collagen and Mast Cells Bland Spindle Cells

(Left) Blocky bundles and
strips of collagen ("ropey"
collagen) are a consistent
finding in SCL/PL and a helpful
diagnostic feature. Mast cells
﬈ are also very commonly
identified. (Right) The lesional
cells of SCL are cytologically
bland and show bipolar or
stellate cytoplasmic processes.
Nuclear grooves may be
identified in some cases ﬈.
Mitoses are rare.

60
 Spindle Cell/Pleomorphic Lipoma

Tumors of Adipose Tissue

TERMINOLOGY MICROSCOPIC
Abbreviations Histologic Features
• Spindle cell lipoma (SCL) • SCL and PL exist as 2 ends of single morphologic spectrum
• Pleomorphic lipoma (PL) ○ Some tumors show morphology of SCL exclusively and
some show morphology of PL exclusively
Definitions
○ Tumors demonstrating intermixed features or discrete
• Benign adipocytic tumor with variable admixture of spindle areas of both SCL and PL are common
cells, "ropey" collagen, and mature adipose tissue • SCL
○ PL additionally contains multinucleated tumor giant cells ○ Variable admixture of 3 components
• SCL and PL are considered morphologic variations on same – Uniform, bland spindle cell proliferation
entity
□ Bipolar to stellate cytoplasmic projections
□ May cluster together akin to "schools of fish" or
CLINICAL ISSUES show nuclear palisading
Epidemiology □ May show nuclear grooves
• Age □ Mitotic figures rare to absent
○ Typically in older age group (> 50 years) – Mature adipocytes
○ Very rare < 20 years – Bundles of "ropey" collagen fibers
• Sex ○ Myxoid stroma is common and may be extensive
○ Strong male predilection ○ Mast cells are very common and nearly constant finding
– Dermal SCL appears to be more common in women • PL
○ Characterized by variable numbers of multinucleated
Site giant cells with dense eosinophilic cytoplasm and
• Most occur superficially in subcutaneous tissue or dermis peripherally arranged nuclei (floret cells)
○ Exceptionally rare in deep soft tissues – Also cells with "smudgy" nuclei &/or nuclear
• Shoulder, posterior neck, and back most common (80% of pseudoinclusions
cases) ○ Bland spindled cells, "ropey" collagen, mast cells, and
○ Atypical locations: Face, oral cavity, trunk, extremities adipose tissue also usually present
– In women, SCL more likely to arise in these locations ○ Mitotic figures rare to absent (may be atypical)
Presentation ○ May contain lipoblasts
• Very similar to conventional lipoma Morphologic Variants
○ Painless, slow-growing mass • Fat-free or fat-poor SCL
○ Often present for long duration ○ Minimal to no mature adipose tissue component
• Rarely arise in multiple sites (synchronous or ○ May show abundant collagen, abundant myxoid stroma,
metachronous) or predominantly spindle cells
○ May be familial ○ Fat-free and fat-poor forms of PL also exist
Treatment • Pseudoangiomatoid SCL
○ Also described as angiomatous SCL
• Conservative surgical excision
○ Contains prominent slit-like to ectatic cleavage spaces
Prognosis (sometimes lined by endothelial cells)
• Benign; excellent prognosis ○ Nodules or lobules of tumor may appear to float in
• Local recurrence is very rare empty space
• Atypical findings in SCL/PL, such as lipoblasts and very rare ○ May also show prominent myxoid stroma or minimal
abnormal mitoses, do not appear to affect behavior mature adipose tissue
○ Can be combined with fat-free or fat-poor morphology
MACROSCOPIC
ANCILLARY TESTS
General Features
Immunohistochemistry
• Well circumscribed
○ Dermal tumors usually less circumscribed • Strong, diffuse CD34(+) in spindled or multinucleated cells
• Yellow-tan cut surface • Loss of nuclear retinoblastoma (Rb) expression
• Subtle, gray-white foci correlate with spindle cell foci • Generally S100 protein, smooth muscle actin, and desmin (-)
• May show focal myxoid areas or be extensively gelatinous ○ Rare cases with S100(+) or desmin (+) spindle cells
• Very rare multinodular, plexiform growth pattern Molecular Genetics
Size • Characteristic deletion (monoallelic or biallelic) of RB1 on
• Usually 3-5 cm (rarely > 10 cm) 13q14
○ Identical deletion present in mammary-type
myofibroblastoma and cellular angiofibroma
• No MDM2 amplification

61
 Spindle Cell/Pleomorphic Lipoma
Tumors of Adipose Tissue
DIFFERENTIAL DIAGNOSIS
Atypical Lipomatous Tumor/Well-Differentiated
Liposarcoma
• Usually large tumors
• Commonly arise in deep locations [especially
retroperitoneum in well-differentiated liposarcoma
(WDLPS)]
• "Ropey" collagen bundles and mast cells are not typical
features
• MDM2(+), CDK4(+) by IHC
○ Rare cases of SCL show focal expression
• Amplification of MDM2 by FISH in most cases
Neurofibroma
• Presence of bland spindle cells with intermixed adipose
tissue in SCL may suggest diffuse-type neurofibroma
• "Ropey" collagen bundles in myxoid background in SCL may
suggest plexiform neurofibroma
• S100(+) in most spindle cells
• CD34(+) component of admixed fibroblastic cells
Cellular Angiofibroma
• Most cases occur in lower external genital tract in women
○ May also occur in men in same general region
• Can show morphologic overlap with SCL
○ Hyalinized vessels common in cellular angiofibroma
• Strong CD34(+)
• Loss of nuclear Rb expression
• Deletion of RB1 on 13q14
Mammary-Type Myofibroblastoma
• Histologically identical to myofibroblastoma of breast
• Short fascicles of monomorphic spindle cells in collagenous
stroma
• Can show morphologic overlap with SCL
○ Thickened, coarse collagen bundles are characteristic
feature of myofibroblastoma
• Strong CD34(+), desmin (+)
• Loss of nuclear Rb expression
• Deletion of RB1 on 13q14
Atypical Spindle Cell Lipomatous Tumor
• Predilection for upper and lower extremities
• Nearly 1/2 of cases arise in deep soft tissue
• Nuclear hyperchromasia and lipoblasts common
• Generally lacks "ropey" collagen bundles
Solitary Fibrous Tumor
• Prominent ectatic "staghorn" vascular network in most
cases
• "Ropey" collagen bundles are not feature
• Diffusely CD34(+) in vast majority of cases
• May also show intratumoral adipose tissue (lipomatous
solitary fibrous tumor)
Myxoid Liposarcoma
• Usually affects younger age group than SCL/PL
• Often strikingly lobular growth pattern
• Usually shows prominent delicate plexiform capillary
vascular pattern
• Uni- and multivacuolated lipoblasts are common
62
• May contain cellular ("round cell") foci
• CD34(-)
• Characteristic t(12;16) in most cases
Dermatofibrosarcoma Protuberans
• Usually occurs in younger individuals than SCL/PL
• Monomorphic spindle cells arranged in broad or tight
storiform pattern
• May be focally or extensively myxoid
• Prominent infiltration of peripheral adipose tissue or
skeletal muscle (honeycomb infiltration)
• Mast cells uncommon
• Diffuse CD34(+) in vast majority of cases
• t(17;22) with COL1A1-PDGFB fusion
Giant Cell Fibroblastoma
• Most common in children < 6 years
• Multinucleated stromal giant cells lining pseudovascular
spaces/clefts
○ Tumors with inconspicuous pseudovascular spaces can
resemble PL
• CD34(+)
• t(17;22) with COL1A1-PDGFB fusion
SELECTED REFERENCES
1. McCarthy AJ et al: Tumours composed of fat are no longer a simple
diagnosis: an overview of fatty tumours with a spindle cell component. J Clin
Pathol. 71(6):483-92, 2018
2. Creytens D 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. 41(11):1443-1455, 2017
3. Ko JS et al: Spindle cell lipomas in women: a report of 53 cases. Am J Surg
Pathol. 41(9):1267-1274, 2017
4. Mariño-Enriquez A et al: Atypical spindle cell lipomatous tumor:
clinicopathologic characterization of 232 cases demonstrating a
morphologic spectrum. Am J Surg Pathol. 41(2):234-244, 2017
5. Michal M et al: Lipoblasts in spindle cell and pleomorphic lipomas: a close
scrutiny. Hum Pathol. 65:140-6, 2017
6. Ud Din N et al: Spindle cell lipomas arising at atypical locations. Am J Clin
Pathol. 146(4):487-95, 2016
7. Cheah A et al: Spindle cell/pleomorphic lipomas of the face: an under-
recognized diagnosis. Histopathology. 66(3):430-7, 2015
8. Creytens D et al: Atypical spindle cell lipoma: a clinicopathologic,
immunohistochemical, and molecular study emphasizing its relationship to
classical spindle cell lipoma. Virchows Arch. 465(1):97-108, 2014
9. Chen BJ 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.
36(8):1119-28, 2012
10. Wood L et al: Cutaneous CD34+ spindle cell neoplasms: Histopathologic
features distinguish spindle cell lipoma, solitary fibrous tumor, and
dermatofibrosarcoma protuberans. Am J Dermatopathol. 32(8):764-8, 2010
11. Sachdeva MP et al: Low-fat and fat-free pleomorphic lipomas: a diagnostic
challenge. Am J Dermatopathol. 31(5):423-6, 2009
12. Billings SD et al: Diagnostically challenging spindle cell lipomas: a report of
34 "low-fat" and "fat-free" variants. Am J Dermatopathol. 29(5):437-42, 2007
13. Fanburg-Smith JC et al: Multiple spindle cell lipomas: a report of 7 familial
and 11 nonfamilial cases. Am J Surg Pathol. 22(1):40-8, 1998
14. Hawley IC et al: Spindle cell lipoma--a pseudoangiomatous variant.
Histopathology. 24(6):565-9, 1994
15. Shmookler BM et al: Pleomorphic lipoma: a benign tumor simulating
liposarcoma. A clinicopathologic analysis of 48 cases. Cancer. 47(1):126-33,
1981
16. Enzinger FM et al: Spindle cell lipoma. Cancer. 36(5):1852-9, 1975
 Spindle Cell/Pleomorphic Lipoma

Tumors of Adipose Tissue

"Ropey" Collagen Thick Collagen Bundles
(Left) The characteristic
"ropey" collagen bundles ﬈ of
SCL/PL vary widely in extent
and distribution. Thin, wispy
fibers ﬊ are often present as
well and may be the
predominant form of collagen
in some cases. (Right) In some
cases of SCL, the collagen
fibers have a thickened and
organized appearance,
reminiscent of mammary-type
myofibroblastoma, a tumor
that appears to be
histogenetically related to
SCL.

Prominent Collagen Haphazard Components

(Left) Some cases of SCL show
prominent stromal collagen,
such as in this example where
the "ropey" fibers are densely
packed in together. (Right)
Many cases of SCL show a
haphazard, disorganized
distribution of bipolar and
stellate spindle cells with
"ropey" or wispy collagen. This
morphology may lead to
consideration of a peripheral
nerve sheath tumor like
neurofibroma.

Myxoid Stroma Myxoid Spindle Cell Lipoma

(Left) SCL may show a
markedly abundant myxoid
stroma and overall striking
hypocellularity that is
suggestive of a myxoma or
myxolipoma. Identification of
a discrete component of
scattered bland spindle cells is
helpful, as are foci of "ropey"
collagen. (Right) This case of
myxoid SCL showed a relative
paucity of adipocytes. This
variant has been described as
"fat poor" or "fat free."

63
 Spindle Cell/Pleomorphic Lipoma
Tumors of Adipose Tissue

Nuclear Palisading Fat-Free and Fat-Poor Variant

(Left) Nuclear palisading is not
an uncommon finding in
myxoid SCL, but it is usually
not extensive. Many cases,
however, show small clusters
or linear arrangements of
tumor cells, akin to schools of
fish. (Right) In some cases of
SCL, there is little to no
mature adipose tissue. These
cases can be very challenging
to diagnose; however, the
characteristic spindle cells and
collagen bundles are helpful
clues, as is possibly the clinical
presentation.

Fat-Free Variant Fat-Free Variant

(Left) The cellularity of fat-
poor and fat-free SCL may be
strikingly increased in some
cases, resulting in the lesion
looking nothing like an
adipocytic tumor. (Right)
Despite the cellularity, the
cytologic features of this fat-
free variant of SCL are not
worrisome for malignancy,
and mitotic figures are
inconspicuous or absent. Note
the mast cell ﬈.

Pseudoangiomatoid Variant Pseudoangiomatoid Spindle Cell Lipoma

(Left) The unusual
pseudoangiomatoid variant of
SCL demonstrates slit-like to
markedly dilated cleavage
spaces associated with the
otherwise characteristic
features of SCL. (Right) Some
cases of the
pseudoangiomatoid SCL
variant show nodules of tumor
"floating" in relatively empty
spaces, as depicted. Red blood
cells may also be seen in these
spaces. This particular
example was highly myxoid as
well.

64
 Spindle Cell/Pleomorphic Lipoma
Endothelial Lining
Pleomorphic Lipoma
Rare Multivacuolated Lipoblasts
Tumors of Adipose Tissue
Pleomorphic Lipoma
(Left) A conspicuous
endothelial lining ﬈ can
sometimes be identified in
pseudoangiomatoid SCL,
suggesting that
"angiomatous" might be a
better term. A CD31
immunostain will highlight the
endothelial cells. (Right) PL is
essentially the same neoplasm
as SCL. Accordingly, many
features of SCL are often
present in PL, including bland
spindle cells and "ropey"
collagen bundles. Notably,
there is also a variably
prominent population of
multinucleated tumor giant
cells termed floret cells ﬈.
Floret Tumor Cells
(Left) Some cases of PL are
mostly adipocytic with
scattered foci of myxoid
stroma containing the
diagnostic findings. Examples
such as these may at first
resemble a myxolipoma or
liposarcoma. Occasional cases
of PL are fat poor or fat free.
(Right) The floret cell defines
the morphology of PL. These
cells have eosinophilic
cytoplasm and contain
multiple hyperchromatic
nuclei often arranged in a
peripheral distribution,
resembling that of a floral
arrangement.
Diffuse CD34 Expression
(Left) Multivacuolated
lipoblasts ﬉ may be rarely
encountered in otherwise
typical cases of PL. Similarly, a
scattered atypical mitotic
figure may also rarely be
identified. Neither of these
findings appears to alter the
usual benign clinical course of
these neoplasms. (Right) CD34
expression is strong, diffuse,
and consistent in both SCL and
PL and stains both the spindle
cells and the multinucleated
floret cells. S100 protein is
expressed in adipocytes but is
generally negative in the
lesional cells.
65
 Chondroid Lipoma

KEY FACTS
Tumors of Adipose Tissue

TERMINOLOGY ○ Some nonvacuolated tumor cells have granular

• Benign mesenchymal neoplasm composed of lipoblastic
cells and mature adipocytes within myxochondroid matrix
CLINICAL ISSUES
• Very rare
• Adults (20-40 years most common)
• Strong female predilection (4:1)
• Slow-growing, painless mass
• Most common in proximal limbs and limb girdles
○ Also trunk, head and neck
• Occurs in both superficial and deep tissues
• Simple complete excision is curative
MICROSCOPIC
• Well circumscribed, often encapsulated
• Nests, sheets, and cords of uni- and multivacuolated round
cells
eosinophilic cytoplasm
○ Classic multivacuolated lipoblasts common
• Myxochondroid to hyalinized matrix
• Variable mature adipose tissue component
• Interspersed thick- and thin-walled vessels with variable
hemorrhage and hemosiderin deposition
ANCILLARY TESTS
• Variable S100 protein (+) in lipoblast-like cells
• Characteristic chromosomal translocation
○ t(11;16)(q13;p12-13) with C11orf95-MKL2 fusion
TOP DIFFERENTIAL DIAGNOSES
• Soft tissue chondroma
• Atypical lipomatous tumor/well-differentiated liposarcoma
• Myxoid liposarcoma
• Extraskeletal myxoid chondrosarcoma
• Myoepithelioma of soft tissue

Chondroid Lipoma Sharp Circumscription

(Left) Chondroid lipoma is
classically a very well-
circumscribed lesion with a
multilobulated and yellow to
tan cut surface. As in other
forms of lipoma, foci of
hemorrhage may be identified.
(Right) Chondroid lipoma is
usually sharply delineated
from adjacent tissues and may
or may not be encapsulated. It
can occur in both superficial
and deep soft tissues, the
latter evidenced in this case by
the presence of surrounding
mature skeletal muscle ﬈.

Multilobulated Growth Classic Appearance

(Left) Most cases of chondroid
lipoma show a multilobulated
growth pattern with each
lobule delineated by a thin or
thick fibrous septa. Dilated
blood vessels ﬈ are also
abundant and conspicuous in
this tumor. (Right) The classic
image of chondroid lipoma
shows a mixture of rounded
eosinophilic cells with 1 to
several intracytoplasmic
vacuoles deposited in a
myxochondroid matrix. Some
cells, however, are not
vacuolated.

66
 Chondroid Lipoma

Tumors of Adipose Tissue

TERMINOLOGY ANCILLARY TESTS
Definitions Immunohistochemistry
• Benign mesenchymal neoplasm composed of lipoblastic • Variable S100 protein (+) in lipoblast-like cells
cells and mature adipocytes within myxochondroid matrix • Rarely focal keratin (+)
• Smooth muscle actin, HMB-45, EMA (-)
CLINICAL ISSUES
Genetic Testing
Epidemiology • Characteristic chromosomal translocation
• Incidence ○ t(11;16)(q13;p12-13) with C11orf95-MKL2 fusion
○ Very rare • No amplification of MDM2 or CDK4
• Age
○ Adults (20-40 years most common) DIFFERENTIAL DIAGNOSIS
• Sex
Soft Tissue Chondroma
○ Strong female predilection (4:1)
• Occurs in fingers, toes, hands, feet
Site • Contains true hyaline cartilage
• Predominantly proximal limbs and limb girdles • Lacks adipocytic component
• Also trunk, head and neck (particularly oral cavity)
Atypical Lipomatous Tumor/Well-Differentiated
• Occurs in both superficial and deep soft tissue
Liposarcoma
Presentation • Often large, slowly growing
• Painless, slowly enlarging mass • Lobules of atypical fat separated by thick fibrous
○ History of recent enlargement in 1/2 of cases septa containing atypical "smudgy" stromal cells
Treatment • Multivacuolated lipoblasts may be few, absent, or
numerous
• Simple complete excision • May show prominent myxoid stroma
Prognosis • MDM2 amplification
• Benign Myxoid Liposarcoma
• Does not recur or metastasize • Bland spindle cell component
• Plexiform capillary vascular pattern (staghorn vessels)
MACROSCOPIC • Cellular (round cell) myxoid liposarcoma has larger, ovoid
General Features cells with monomorphic nuclei
• Well circumscribed and frequently encapsulated • Characteristic t(12;16) translocation involving FUS and
• Tan-yellow cut surface; occasionally with hemorrhagic foci DDIT3

Size Extraskeletal Myxoid Chondrosarcoma

• 1.5-11.0 cm (median: 4.0 cm)
MICROSCOPIC
Histologic Features
• Well circumscribed
• Often lobulated with fibrous septa
• Nests, sheets, and cords of uni- and multivacuolated
epithelioid cells
○ Cells may appear to be in lacunar spaces (chondrocyte-
like)
○ Some nonvacuolated tumor cells have granular
eosinophilic cytoplasm
○ No significant nuclear atypia or mitotic activity
• Classic multivacuolated lipoblasts common
• Myxochondroid matrix
○ May be hyalinized
• Variable mature adipose tissue component
• Interspersed thick- and thin-walled vessels with variable
hemorrhage and hemosiderin deposition
• Can show fibrosis, calcification, metaplastic bone
• Often larger, slowly growing, and infiltrative
• Anastomosing cords of spindled to stellate cells in
prominent myxoid stroma
• No adipose tissue or lipoblasts
• Characteristic translocations involving NR4A3
Myoepithelioma of Soft Tissue
• Lacks lipoblasts
• Most cases show diffuse keratin (+) &/or S100 protein (+)
• Variable expression of SMA, EMA, calponin, GFAP, desmin
SELECTED REFERENCES
1. Flucke U et al: Presence of C11orf95-MKL2 fusion is a consistent finding in
chondroid lipomas: a study of eight cases. Histopathology. 62(6):925-30,
2013
2. Thway K et al: Chondroid lipoma: an update and review. Ann Diagn Pathol.
16(3):230-4, 2012
3. de Vreeze RS et al: Delineation of chondroid lipoma: an
immunohistochemical and molecular biological analysis. Sarcoma.
2011:638403, 2011
4. Ballaux F et al: Chondroid lipoma is characterized by t(11;16)(q13;p12-13).
Virchows Arch. 444(2):208-10, 2004
5. Kindblom LG et al: Chondroid lipoma: an ultrastructural and
immunohistochemical analysis with further observations regarding its
differentiation. Hum Pathol. 26(7):706-15, 1995
6. Meis JM et al: Chondroid lipoma. A unique tumor simulating liposarcoma
and myxoid chondrosarcoma. Am J Surg Pathol. 17(11):1103-12, 1993

67
 Chondroid Lipoma
Tumors of Adipose Tissue

Eosinophilic Cells Chondroid Morphology

(Left) The constituent cell of
chondroid lipoma is small and
round, contains abundant
eosinophilic cytoplasm, and
has a small, bland nucleus
with irregular contours. Focal
enlargement ﬈ may be seen,
but significant nuclear
pleomorphism is not typically
a feature. (Right) Chondroid
lipoma resembles a
cartilaginous tumor in part
due to the presence of cells ﬈
with cytoplasmic vacuoles
surrounding the nucleus that
create a compressed
peripheral rim of eosinophilic
cytoplasm, simulating a
chondrocyte within a lacuna.

Univacuolated Cells Rare Spindling of Tumor Cells

(Left) Most cells of chondroid
lipoma contain at least 1
cytoplasmic vacuole. In the
cells that contain only 1 ﬈,
the nucleus may be
compressed at the periphery,
reminiscent of a signet ring
cell. When prominent, this
morphology may be confused
with carcinoma. (Right) Vague
spindling of tumor cells is a
rare and generally focal
finding in chondroid lipoma
and may lead to confusion
with pleomorphic lipoma or
even forms of liposarcoma.

Multivacuolated Lipoblasts Mature Adipose Tissue

(Left) Some of the
multivacuolated tumor cells of
chondroid lipoma are
morphologically
indistinguishable from the
classic multivacuolated
lipoblasts encountered in
forms of liposarcoma. They
vary in number from sparse to
numerous but are usually
quite abundant. (Right) A
component of mature adipose
tissue is almost always
identified in chondroid lipoma,
but the distribution varies
from focal to extensive. In the
latter setting, limited sampling
may lead to diagnostic error.

68
 Chondroid Lipoma
Mature Adipose Tissue
Myxoid Stroma
Degenerative Changes
Tumors of Adipose Tissue
Myxoid Stroma
(Left) In some cases of
chondroid lipoma, the
constituent tumor cells form
small aggregates or nests
within a background of
abundant mature adipose
tissue. (Right) Myxoid stroma
is a common and relatively
consistent feature of
chondroid lipoma.
Hyalinized Stroma
(Left) In some heavily myxoid
cases of chondroid lipoma, the
overall appearance of
scattered, small, bland tumor
cells associated with adipose
tissue and multivacuolated
lipoblast-like cells may closely
resemble a myxoid
liposarcoma. However,
chondroid lipoma does not
demonstrate a delicate,
plexiform vascular network.
(Right) Foci of hyalinization
are often intermingled with
myxoid zones in chondroid
lipoma; however, they are
usually not prominent. In rare
cases, the stroma is almost
entirely hyalinized.
Conspicuous Vasculature
(Left) This particular case of
chondroid lipoma contained
abundant degenerative
changes, including prominent
sclerosis, central ischemia, and
perivascular hyalinization ﬉.
A small aggregate of tumor
cells ﬊ can be identified at
the center. (Right) Thin- to
thick-walled dilated blood
vessels ﬉ are a common
finding in chondroid lipoma
and are often easily identified.
They may be associated with
stromal hemorrhage as well as
hemosiderin deposition and
fibrosis.
69
 Myolipoma

KEY FACTS
Tumors of Adipose Tissue

TERMINOLOGY ○ Muscle & fat evenly intermixed throughout tumor (sieve-

• Benign soft tissue neoplasm composed of mature adipose like appearance)
tissue & smooth muscle ○ Majority show smooth muscle predominance
• Scattered thin-walled vessels are often present but lack
CLINICAL ISSUES thick-walled muscular arteries
• Adults; peak 5th-6th decades • Lack cytologic atypia
• Female predilection • Mitoses very rare or absent
• Most occur in retroperitoneum, pelvis, inguinal region, &
ANCILLARY TESTS
abdominal wall
• Excellent prognosis • Smooth muscle markers (actins, desmin, calponin, H-
caldesmon) (+) in spindle cell component
MACROSCOPIC • Estrogen receptor (+) (86%) & HMGA2 (+) (60%)
• Intraabdominal tumors often large (mean: 10-15 cm) • HMB-45, MART-1, CD34, & S100 protein (-)
MICROSCOPIC TOP DIFFERENTIAL DIAGNOSES
• Mixture of mature adipose tissue & smooth muscle • Angiomyolipoma (PEComa)
○ Smooth muscle component is usually arranged in short • Leiomyoma with fatty metaplasia/degeneration
fascicles • Dedifferentiated liposarcoma (with low-grade morphology)
○ Adipose component consists of mature adipocytes • Spindle cell lipoma

Myolipoma Sieve-Like Appearance

(Left) Myolipoma is composed
of an even admixture of
smooth muscle and mature
adipose tissue, imparting a
sieve-like appearance. Most
tumors have a predominance
of smooth muscle, as
demonstrated here in this
example from the
retroperitoneum. (Right)
Eosinophilic smooth muscle
cells intercalate between
mature adipocytes in
myolipoma. Hypocellular
sclerotic and edematous areas
are also present ﬈. (Courtesy
T. Bocklage, MD and R. Berry,
MD.)

Vague Fascicle Formation Desmin Expression

(Left) Vague fascicle
formation ﬈ by smooth
muscle cells is often seen in
myolipoma. Note also the
component of mature adipose
tissue. (Courtesy T. Bocklage,
MD and R. Berry, MD.) (Right)
The smooth muscle
component of myolipoma
displays strong, diffuse desmin
expression. (Courtesy T.
Bocklage, MD and R. Berry,
MD.)

70
 Myolipoma

Tumors of Adipose Tissue

○ No lipoblasts or floret-type giant cells
TERMINOLOGY
• Background sclerosis or chronic inflammation may be
Synonyms prominent
• Extrauterine lipoleiomyoma • Lacks thick-walled muscular arteries; scattered thin-walled
vessels often present 
Definitions • Similar appearance to uterine lipoleiomyoma but unrelated
• Benign soft tissue neoplasm composed of mature adipose • Rare unusual features may be present focally
tissue & smooth muscle ○ Hypercellular fascicles, degenerative nuclear atypia,
round cell morphology, hemosiderin deposition,
CLINICAL ISSUES metaplastic bone/cartilage, eosinophil infiltrates
Epidemiology
• Incidence ANCILLARY TESTS
○ Rare Immunohistochemistry
• Age • Smooth muscle markers (actins, desmin, calponin, H-
○ Adults; peak in 5th-6th decades caldesmon) (+) in spindle cell component
• Sex • Estrogen receptor (+) (86%) & HMGA2(+) (60%)
○ Female predilection • HMB-45, MART-1, CD34, & S100 protein (-)
Site • MDM2 & CDK4 (-)
• Most occur in retroperitoneum, pelvis, inguinal canal, & In Situ Hybridization
abdominal wall • Rearrangements of HMGA2 gene
• Less often occurs in extremities (subcutaneous or deep) ○ Also seen in conventional lipomas & uterine leiomyomas
Presentation
DIFFERENTIAL DIAGNOSIS
• Painless mass
• May be incidentally discovered if deep Angiomyolipoma (PEComa)
• Granular or clear plump/epithelioid smooth muscle cells
Treatment
spin off of thick-walled muscular vessels
• Complete surgical excision is treatment of choice • Express HMB-45 &/or MART-1 with actin &/or desmin
Prognosis Leiomyoma With Fatty Metaplasia/Degeneration
• Excellent prognosis • Focal rather than uniform (sieve-like) distribution of fat
• Very low risk of recurrence after complete excision throughout muscle component of tumor 
• No metastatic potential • Fatty degeneration common in uterine leiomyomas, seen in
subset of subcutaneous leiomyomas
MACROSCOPIC
Dedifferentiated Liposarcoma (Low-Grade
General Features Morphology)
• Circumscribed & typically encapsulated • Can have myogenic differentiation & thus mimic myolipoma
• Yellow to tan-white depending on relative amounts of fat & • Diagnostic, large, hyperchromatic, atypical spindle cells
muscle present in adipocytic component
• More white-gray, firm, & whorled cut surface if muscle • Spindle cell component displays atypia & mitotic activity
component predominates
• Often HMGA2 (+) (like myolipoma)
Size • MDM2 & CDK4 amplification by FISH (unlike myolipoma)
• Intraabdominal tumors often large (mean: 10-15 cm) Spindle Cell Lipoma
○ Usually much smaller when superficially located
• Exceedingly rare in retroperitoneum & pelvis
• May also have sieve-like admixture of fat & spindle cells
MICROSCOPIC
○ Spindle cells are not smooth muscle by H&E & IHC
Histologic Features – No eosinophilic fibrillary cytoplasm or paranuclear
• Mixture of variable amounts of mature adipose tissue & vacuoles
smooth muscle – Myoid markers usually (-)
○ Majority show smooth muscle predominance
○ Muscle & fat evenly intermixed throughout tumor (sieve- SELECTED REFERENCES
like appearance) 1. Fukushima M et al: Myolipoma of soft tissue: clinicopathologic analysis of 34
• Smooth muscle component composed of elongated cases. Am J Surg Pathol. 41(2):153-160, 2017
spindle cells with abundant eosinophilic fibrillary cytoplasm 2. Panagopoulos I et al: Fusion of the HMGA2 and C9orf92 genes in myolipoma
with t(9;12)(p22;q14). Diagn Pathol. 11:22, 2016
○ Usually arranged in short intersecting fascicles 3. Michal M: Retroperitoneal myolipoma. A tumour mimicking retroperitoneal
○ May have paranuclear vacuoles angiomyolipoma and liposarcoma with myosarcomatous differentiation.
○ Lack cytologic atypia Histopathology. 25(1):86-8, 1994
4. Meis JM et al: Myolipoma of soft tissue. Am J Surg Pathol. 15(2):121-5, 1991
○ Mitoses very rare or absent
• Adipose component consists of mature adipocytes
71
 Myolipoma
Tumors of Adipose Tissue

Fat Predominant Tumors Smooth Muscle Predominant Tumors

(Left) Some myolipomas, such
as this pelvic tumor, have a
predominance of mature
adipose tissue. The smooth
muscle component
intercalates between mature
adipocytes. (Right) In some
areas, the myogenic
component of myolipoma may
predominate. Bland smooth
muscle cells are arranged into
long fascicles similar to a
leiomyoma. There is no atypia,
and mitotic activity is minimal.
Scattered mast cells are
present in this case ﬈.
(Courtesy T. Bocklage, MD and
R. Berry, MD.)

Myolipoma Hypocellular Edematous Areas

(Left) At low power,
myolipoma has a well-
circumscribed border ﬈ and
lacks a capsule. Smooth
muscle may predominate at
the periphery, as depicted,
with the bulk of the tumor
interior composed of fat.
(Right) Mature adipocytes are
evenly distributed in a sieve-
like pattern throughout the
pink smooth muscle
component of myolipoma.
Hypocellular edematous areas
are also present ﬈. (Courtesy
T. Bocklage, MD and R. Berry,
MD.)

Edematous Foci Thin-Walled Vessels

(Left) Smooth muscle cells
with intervening edema ﬊ are
seen on this H&E. (Courtesy T.
Bocklage, MD and R. Berry,
MD.) (Right) Dilated, thin-
walled vessels ﬊ are typical
of myolipoma, but medium-
sized muscular arteries, as
would be seen in
angiomyolipoma (PEComa),
are not present.

72
 Myolipoma

Tumors of Adipose Tissue

Foci of Sclerosis Foci of Sclerosis
(Left) Intermediate-power H&E
shows evenly dispersed
adipose tissue and short
fascicles of smooth muscle,
the typical appearance of
myolipoma. Focal areas of
sclerosis can be seen ﬉.
(Right) The smooth muscle
cells and mature adipocytes
that comprise myolipoma lack
atypia and mitotic activity.
Background sclerosis may be
present ﬉. (Courtesy T.
Bocklage, MD and R. Berry,
MD.)

Fascicle Formation Focal Round Cell Morphology

(Left) Short fascicles of
elongated spindle cells with
oval, cytologically bland nuclei
and abundant eosinophilic
fibrillary cytoplasm are seen in
myolipoma, similar to
leiomyoma. (Right) Rare cases
of myolipoma contain foci of
tumor cells featuring a small
round cell morphology
(bottom left) rather than the
usual spindling. These cells are
cytologically banal, and the
finding is of no clinical or
prognostic significance.

Minimal Atypia and Mitotic Activity Sclerotic and Edematous Areas

(Left) The smooth muscle cells
of myolipoma lack atypia and
significant mitotic activity.
Mast cells ﬊ are also present
on this H&E. (Courtesy T.
Bocklage, MD and R. Berry,
MD.) (Right) Hypocellular
areas ﬈ of sclerosis and
edema may be present in
myolipoma, as depicted.
(Courtesy T. Bocklage, MD and
R. Berry, MD.)

73
 Hibernoma

KEY FACTS
Tumors of Adipose Tissue

TERMINOLOGY MICROSCOPIC
• Benign lipomatous tumor composed of lobules of cells • Lobulated tumor composed of mixture of cell types in
resembling brown fat varying proportions
○ Polygonal cells with granular eosinophilic cytoplasm,
CLINICAL ISSUES
multivacuolated cells, univacuolated adipocytes
• Age: 20-40 years most common • Small, bland, central nuclei ± nucleoli
• Painless, slow-growing mass • Stromal vessels are common & may be prominent
• Most common in thigh, upper trunk, & neck • Morphologic variants: Lipoma-like, myxoid, spindle cell
○ Subcutaneous (most common) or intramuscular
• Treatment: Simple surgical excision ANCILLARY TESTS
• Benign; very rare recurrences • Variable S100 protein (+)
• Molecular: Rearrangements of 11q13-21
MACROSCOPIC
• Circumscribed, lobulated lesion TOP DIFFERENTIAL DIAGNOSES
• Tan-yellow to yellow-brown, greasy cut surface • Normal brown fat
• Mean size: 9.3 cm • Lipoblastoma
• Atypical lipomatous tumor/well-differentiated liposarcoma

Hibernoma Multivacuolated Cells

(Left) Hibernoma is a benign
lipomatous neoplasm
composed of cells resembling
brown fat. This classic case
shows a mixture of granular
eosinophilic cells ﬈,
multivacuolated cells ﬊, &
scattered univacuolated
mature adipocytes ﬉. (Right)
The multivacuolated cells ﬈
usually contain innumerable
lipid droplets & resemble
multivacuolated lipoblasts,
however, the latter have
enlarged, hyperchromatic, &
scalloped nuclei. The
eosinophilic cells ﬊ get their
coloration from numerous
mitochondria.

Prominent Vacuoles Lipoma-Like Hibernoma

(Left) Multivacuolated cells
can be prominent & diffuse in
some cases of hibernoma.
Such cases often resemble the
multivacuolated lipoblasts of
atypical lipomatous
tumor/well-differentiated
liposarcoma. Enlarged,
scalloped nuclei are absent in
hibernoma, however. (Right)
Occasional cases of hibernoma
show predominantly
univacuolated white fat cells
with only scattered
multivacuolated ﬊ &
eosinophilic granular cells.
These tumors may be easily
misclassified as conventional
lipoma.

74
 Hibernoma

Tumors of Adipose Tissue

• Spindle cell
TERMINOLOGY
○ Hybrid features of hibernoma & spindle cell lipoma
Synonyms – Hibernoma cells, thick collagen bundles, mast cells,
• Fetal lipoma mature fat
• Lipoma of embryonic fat ○ Rare
– Found in posterior neck or scalp
Definitions
• Benign lipomatous tumor composed of lobules of cells ANCILLARY TESTS
resembling brown fat
Immunohistochemistry
CLINICAL ISSUES • Variable S100 protein (+)
• Spindle cell variant is often CD34(+)
Epidemiology
• UCP1(+) in brown fat cells
• Age
○ 20-40 years most common Molecular Genetics
○ Rare in children & elderly > 60 years • Rearrangements of 11q13-21 common & characteristic
• Concomitant deletions of tumor suppressor genes AIP &
Site
MEN1
• Subcutaneous (most common) or intramuscular
• Most common in thigh DIFFERENTIAL DIAGNOSIS
○ Also neck, arm, trunk, back, shoulder, & retroperitoneum
Normal Brown Fat
– Rarely breast, kidney, or mediastinum
• More abundant in children & young adults than older adults
Presentation • Usually found in neck, axilla, mediastinum, & paraspinal
• Painless, slow-growing mass regions
Treatment • No discrete mass lesion
• Simple surgical excision Lipoblastoma
Prognosis • May contain brown fat cells
• Usually occurs in infants (< 3 years of age)
• Benign
• Prominent lobularity with myxoid stroma & lipoblasts
• Recurrences are very rare
• PLAG1 gene rearrangements
MACROSCOPIC Atypical Lipomatous Tumor/Well-Differentiated
General Features Liposarcoma
• Circumscribed, lobulated lesions • Atypical "smudge" cells in thickened fibrous septa
• Tan-yellow to yellow-brown, greasy cut surface • True lipoblasts with hyperchromatic scalloped nuclei may
be present
Size • MDM2 amplification by FISH
• Range: 1-24 cm (mean: 9.3 cm)
Granular Cell Tumor
MICROSCOPIC • Diffuse cytoplasmic granularity
• No multivacuolated cells
Histologic Features • Diffuse S100 protein (+)
• Lobulated tumor composed of mixture of cell types in
varying proportions Myxoid Liposarcoma
○ Polygonal cells with granular eosinophilic cytoplasm • Delicate, plexiform vascular pattern; lipoblasts common
○ Multivacuolated cells with numerous lipid droplets • Hibernoma-like cells uncommon
○ Univacuolated adipocytes • Characteristic t(12;16) or t(12;22)
• Medium-sized stromal vessels are common & may be
prominent SELECTED REFERENCES
• Small, bland, central nuclei ± nucleoli 1. Greenbaum A et al: Hibernoma: diagnostic and surgical considerations of a
• Mitotic figures are rare rare benign tumour. BMJ Case Rep. 2016, 2016
2. Vassos N et al: Deep-seated huge hibernoma of soft tissue: a rare differential
Morphologic Variants diagnosis of atypical lipomatous tumor/well differentiated liposarcoma. Int J
Clin Exp Pathol. 6(10):2178-84, 2013
• Lipoma-like 3. Manieri M et al: Morphological and immunohistochemical features of brown
○ Mostly univacuolated adipocytes adipocytes and preadipocytes in a case of human hibernoma. Nutr Metab
Cardiovasc Dis. Oct;20(8):567-74, 2010
○ Eosinophilic granular & multivacuolated cells are sparse 4. Chirieac LR et al: Characterization of the myxoid variant of hibernoma. Ann
○ Most common in thigh Diagn Pathol. 10(2):104-6, 2006
• Myxoid 5. Furlong MA et al: The morphologic spectrum of hibernoma: a
clinicopathologic study of 170 cases. Am J Surg Pathol. 25(6):809-14, 2001
○ Predominantly occurs in male patients
– In head & neck
○ Constituent cells separated by acellular myxoid stroma
75
 Hibernoma
Tumors of Adipose Tissue

Prominent Eosinophilic Cells Vasculature

(Left) Hibernoma with sheets
of eosinophilic cells can
resemble granular cell tumor
or even oncocytoma.
Intracytoplasmic material ﬉
resembling mucin can also be
seen focally in some cases.
(Right) Hibernoma often has a
lobulated appearance at low
magnification. These tumors
are highly vascular as well, as
evidenced by the prominent
large blood vessels ﬉ seen in
most cases. Small lymphoid
aggregates ﬊ may be present
as well.

Angiomatous Pattern Myxoid Hibernoma

(Left) Hibernoma can show
areas with apparent
hypervascularity, producing
the appearance of cell clusters
floating within clear spaces. In
some cases, an endothelial
lining can be appreciated.
(Right) A rare variant of
hibernoma features myxoid
stromal change that may be
diffuse. Scattered
multivacuolated cells ﬈ &
mature adipocytes can be
identified. Identification of
other more typical areas of
hibernoma is helpful.

Myxoedematous Stroma Spindle Cells in Hibernoma

(Left) In some cases of myxoid
hibernoma, the stroma is less
blue & myxoid & more pale &
edematous. Note the
scattered tumor cells ﬈.
(Right) Hybrid tumors with
features of hibernoma &
spindle cell lipoma have been
described, & most arise in the
posterior neck & shoulder
region. As expected, the
spindle cells in such lesions are
often CD34(+).

76
 Hibernoma

Tumors of Adipose Tissue

Skeletal Muscle Cluster Morphology
(Left) Most cases of hibernoma
arise within the subcutaneous
fat of the extremity or neck,
however, occasional tumors
are more deeply located &
may involve skeletal muscle
﬉. (Right) In some cases,
clusters of hibernoma cells ﬉
may retract from each other,
resembling a pattern often
seen in mucinous epithelial
tumors. Note the gaping
vascular spaces ﬈, a common
feature of hibernoma.

Frozen Section of Hibernoma Infarcted Hibernoma

(Left) Unlike white fat, which
is very difficult to freeze &
section adequately, brown fat
cells with abundant
mitochondria can often be
visualized on frozen section,
making a preliminary
diagnosis possible. (Right) This
case of a large hibernoma
showed a centralized zone of
infarction. In some of the
interface areas, the dense
eosinophilic appearance is
somewhat reminiscent of
hyalinized zones in chondroid
lipoma.

Focal Calcification Mitochondria

(Left) As in other fatty tumors,
calcification ﬈ may be
present in hibernoma,
particularly in the setting of
local trauma, but it is rare. Fat
necrosis & a multinucleated
giant cell reaction can also
rarely be seen. (Right) Electron
micrograph of hibernoma
shows numerous tightly
packed mitochondria
displaying transverse cristae
﬊. There are also small
electron-dense lysosomes ﬉ &
lipid droplets ſt.

77
 Myelolipoma

KEY FACTS
Tumors of Adipose Tissue

TERMINOLOGY • Yellow-tan cut surface with red-gray areas

• Benign, likely neoplastic proliferation composed of mature • Most are < 5 cm but may be larger
fat and hematopoietic tissues MICROSCOPIC
ETIOLOGY/PATHOGENESIS • Sharply circumscribed, often with rim of adrenal cortex
• Most are idiopathic • Mature adipose tissue without atypia or lipoblasts
• Some associated with various endocrine neoplasms or • Mature bone marrow hematopoietic elements
hyperhormonal states ○ All 3 cell lines (myeloid, erythroid, megakaryocytic)
represented
CLINICAL ISSUES • Rare findings: Metaplastic bone, myxoid change
• Older adults, usually > 40 years
• Most common in adrenal gland TOP DIFFERENTIAL DIAGNOSES
○ Extraadrenal locations rare • Extramedullary hemopoiesis
• Most are incidental findings and asymptomatic • Conventional lipoma
• Treatment: Surgical excision or clinically follow • Well-differentiated liposarcoma
• Benign; overall excellent prognosis • Myeloid sarcoma (granulocytic sarcoma)
• Adrenocortical adenoma
MACROSCOPIC
• Well-circumscribed nodule

Myelolipoma Hematopoietic Elements and Fat

(Left) Myelolipoma is a benign
tumor that usually arises in
the adrenal gland and rarely in
other sites. There is a sharp
demarcation between the
adrenal cortex and the
underlying lesion ﬈. The
cortex is often thinned;
however, this patient had
adrenocortical hyperplasia ﬇,
which may be seen in some
cases. (Right) The
hematopoietic component of
myelolipoma consists of all 3
cell lines (erythroid, myeloid,
and megakaryocytic ﬈). Note
the admixed mature
adipocytes ﬇.

Mature Adipose Tissue Rare Metaplastic Bone

(Left) The mature adipose
tissue component often
predominates in myelolipoma,
and no atypical
adipocytic/stromal nuclei or
lipoblasts are present. In some
cases, the hematopoietic
elements ﬈ may be sparse
and easily overlooked. (Right)
Metaplastic bone is an unusual
finding in adrenal
myelolipoma. Note peripheral
adrenal cortical tissue ﬊,
mature bone ﬈, and fatty
hematopoietic lesional tissue
st.

78
 Myelolipoma

Tumors of Adipose Tissue

TERMINOLOGY MICROSCOPIC
Definitions Histologic Features
• Benign, likely neoplastic proliferation composed of mature • Sharply circumscribed, often with rim of adrenal cortex
fat and hematopoietic tissues • Mature adipose tissue without atypia or lipoblasts
• Mature bone marrow hematopoietic elements
ETIOLOGY/PATHOGENESIS ○ May be extensive or sparse
Idiopathic ○ All 3 cell lines (myeloid, erythroid, megakaryocytic)
represented
• Most cases
○ Lymphoid foci may be present
Associated Conditions • Rare findings: Metaplastic bone, myxoid change
• Hormonally active endocrine neoplasms
○ Adrenocortical adenoma, adrenocortical carcinoma, ANCILLARY TESTS
pheochromocytoma Molecular Genetics
• Hypercortisolic or hyperaldosteronic states
• Reports of t(3;21)(q25;p11) translocation
○ Adrenal cortical hyperplasia, Conn syndrome, 21-
• Nonrandom X chromosome inactivation
hydroxylase deficiency
• Obesity
DIFFERENTIAL DIAGNOSIS
CLINICAL ISSUES Extramedullary Hemopoiesis
Epidemiology • Typically arises in patients with myeloproliferative disease
or severe anemia
• Incidence
• Multiple deposits common
○ Rare
• Often associated with splenomegaly
• Age
○ Older adults, usually > 40 years Conventional Lipoma
• Sex • Encapsulated
○ M=F • Lacks bone marrow elements
Site Well-Differentiated Liposarcoma
• Most common in adrenal gland • Lacks myeloid elements
• Extraadrenal locations rare • Variably thickened fibrous septa containing enlarged,
○ Retroperitoneum, presacral region, mediastinum, others hyperchromatic stromal cells
• May contain lipoblasts
Presentation
• Most are incidental findings and asymptomatic Myeloid Sarcoma
• Large lesions may cause abdominal symptoms • Generally lacks fatty component
○ Massive acute hemorrhage in rare cases • Sheets of primitive myeloid cells
• Usually occurs in association with acute leukemia
Treatment
• Surgical excision is curative Adrenocortical Adenoma
• Small lesions may be followed without surgery • Expansile proliferation of adrenocortical cells
• Lacks adipose tissue and bone marrow elements
Prognosis
• Benign SELECTED REFERENCES
• Excellent prognosis
1. Decmann Á et al: Adrenal myelolipoma: a comprehensive review. Endocrine.
○ Very rare spontaneous rupture and hemorrhage 59(1):7-15, 2018
reported 2. Littrell LA et al: Extra-adrenal myelolipoma and extramedullary
hematopoiesis: imaging features of two similar benign fat-containing
presacral masses that may mimic liposarcoma. Eur J Radiol. 93:185-194,
IMAGING 2017
Radiographic Findings 3. Shi Q et al: Primary mediastinal myelolipoma: a case report and literature
review. J Thorac Dis. 9(3):E219-E225, 2017
• Circumscribed lucent mass, often in adrenal gland 4. Ramirez M et al: Adrenal myelolipoma: to operate or not? A case report and
review of the literature. Int J Surg Case Rep. 5(8):494-496, 2014
MACROSCOPIC 5. Suárez-Peñaranda JM et al: Unusual forms of adrenal and extra-adrenal
myelolipomas. Int J Surg Pathol. 22(5):473-477, 2014
General Features 6. Goltz JP et al: [Ruptured giant myelolipoma of the adrenal gland with acute
retroperitoneal hemorrhage.] Rofo. 181(5):485-7, 2009
• Well-circumscribed nodule 7. Bishop E et al: Adrenal myelolipomas show nonrandom X-chromosome
• Yellow-tan cut surface with red-gray areas inactivation in hematopoietic elements and fat: support for a clonal origin of
myelolipomas. Am J Surg Pathol. 30(7):838-43, 2006
Size 8. Chang KC et al: Adrenal myelolipoma with translocation (3;21)(q25;p11).
Cancer Genet Cytogenet. 134(1):77-80, 2002
• Usually small, and most are < 5 cm 9. Sanders R et al: Clinical spectrum of adrenal myelolipoma: analysis of 8
• Rare examples are large (giant myelolipoma) tumors in 7 patients. J Urol. 153(6):1791-3, 1995

79
 Lipoblastoma

KEY FACTS
Tumors of Adipose Tissue

TERMINOLOGY
• Well-circumscribed, benign, lobular lipomatous neoplasm
with resemblance to fetal adipose tissue
○ Deep tumors with infiltrative borders may be designated
"diffuse lipoblastoma" or "lipoblastomatosis"
CLINICAL ISSUES
• Majority occur in first 3 years of life
• 2:1 male predominance
• Trunk and extremities most common
○ May involve mediastinum, retroperitoneum, viscera
• Treatment: Complete surgical excision
• Benign; excellent prognosis
• Local recurrence likely related to incomplete excision
MACROSCOPIC
• Pale tan-yellow, variably gelatinous cut surface
• Usually 2-6 cm
MICROSCOPIC
• Most are well circumscribed and lobular
• Lobules of immature adipocytes in various states of
development, separated by fibrous septa
○ Spindle/stellate cells, univacuolated and multivacuolated
lipoblasts
• Myxoid stromal change is common
• Delicate capillary vasculature often present
• Recurrent tumors often show evidence of maturation
(lipoma-like)
ANCILLARY TESTS
• Molecular: Rearrangement of 8q11-13 (PLAG1)
TOP DIFFERENTIAL DIAGNOSES
• Myxoid liposarcoma
• Lipoma
• Lipoblastoma-like tumor of vulva

Lipoblastoma Fibrous Septa

(Left) Lipoblastoma is a benign
adipocytic neoplasm that is
most commonly identified in
the first 3 years of life. At low
magnification, it is
characterized by a prominent
lobularity imparted by
extensive fibrous septation.
Foci of myxoid change ﬈ are
also evident. (Right) In some
cases of lipoblastoma, the
fibrous septa are very thick,
although the overall lobularity
is retained. Rarely, the fibrous
tissue may predominate over
the fat component, suggesting
a fibroblastic process.

Immature Fat Immature Fat

(Left) The presence of
immature fat is definitional
for lipoblastoma and is
characterized by lipoblasts in
various stages of
development. The more
primitive foci often show
myxoid stroma and are most
common at the periphery of
the lobules ﬈. (Right)
Lipocytes are seen in all stages
of development, including
spindled preadipocytes, small
signet ring-like univacuolated
lipoblasts ﬈, multivacuolated
lipoblasts, and large mature-
appearing adipocytes ﬊.

80
 Lipoblastoma

Tumors of Adipose Tissue

○ Mature adipocytes may be seen, particularly near center
TERMINOLOGY of lobules
Synonyms ○ No significant nuclear atypia
• Fetal lipoma; embryonic lipoma ○ Mitoses rare to absent
• Myxoid stromal change is common and may be focal or
Definitions extensive
• Well-circumscribed, benign, lobular lipomatous neoplasm ○ Stromal mucin pools may be seen
with resemblance to fetal adipose tissue • Delicate capillary vasculature often present
○ Deep tumors with infiltrative borders may be designated ○ Often conspicuous and plexiform in myxoid areas
"diffuse lipoblastoma" or "lipoblastomatosis" • Rare findings: Collagen deposition, hibernoma-like cells,
chondroid metaplasia, extramedullary hematopoiesis,
CLINICAL ISSUES multinucleated cells
Epidemiology • Diffuse lipoblastoma (lipoblastomatosis)
• Age ○ Deep variant with infiltrative growth with less
○ Majority occur in first 3 years of life pronounced lobular pattern
– Rare in older children and adolescents ○ Entrapped skeletal muscle may be seen
– Very rare in adults • Recurrent tumors often show evidence of maturation
• Sex ○ Increased proportion of mature adipose tissue; may be
○ 2:1 male predominance indistinguishable from lipoma or fibrolipoma

Site ANCILLARY TESTS

• Most frequent in trunk and extremities Molecular Genetics
○ Subcutaneous tissue (most common)
• Rearrangement of 8q11-13 involving PLAG1 gene common
○ Deep/intramuscular (diffuse
○ Fusion partner genes include HAS2, COL1A2,
lipoblastoma/lipoblastomatosis)
RAD51B, COL3A1, RAB2A
• May also arise in head/neck region, mediastinum,
retroperitoneum, mesentery, visceral organs
DIFFERENTIAL DIAGNOSIS
Presentation Myxoid Liposarcoma
• Painless, slow- or rapidly growing mass
• Rare in first 10 years of life
• Subset of patients have central nervous system disorders
• More likely to arise in deep soft tissue
○ e.g., developmental delays, seizures, autism, congenital
• Lobular but generally less septated than lipoblastoma
malformations
• Hypercellular or "round cell" areas with nuclear atypia in
Treatment some cases
• Complete surgical excision • Characterized by t(12;16) or t(16;22) with DDIT3
rearrangements
Prognosis • Lacks rearrangements of PLAG1 (8q11-13)
• Benign; excellent outcome
Lipoma
• Local recurrences not uncommon, particularly in diffuse,
infiltrative forms • Occurs in older patient population than lipoblastoma
○ Likely related to incomplete excision • Lacks lipoblasts and myxoid stroma with plexiform capillary
vasculature
MACROSCOPIC Lipoblastoma-Like Tumor of Vulva
General Features • Rare; recently described
• Pale tan-yellow cut surface with variable myxoid or • Affects adults; arises in vulva or groin
gelatinous quality • Loss of nuclear Rb expression (often in mosaic pattern)
• Almost all reported cases lack PLAG1 rearrangement
Size
• Usually 2-6 cm SELECTED REFERENCES
○ Rare cases > 10 cm
1. Abdul-Ghafar J et al: Lipoblastoma: a clinicopathologic review of 23 cases
from a major tertiary care center plus detailed review of literature. BMC Res
MICROSCOPIC Notes. 11(1):42, 2018
2. Schoolmeester JK et al: Lipoblastoma-like tumor of the vulva: a
Histologic Features clinicopathologic, immunohistochemical, fluorescence in situ hybridization
and genomic copy number profiling study of seven cases. Mod Pathol. ePub,
• Most are lobular and well circumscribed 2018
• Lobules of immature adipocytes separated by variably 3. Kok KY et al: Lipoblastoma: clinical features, treatment, and outcome. World
thickened fibrous septa J Surg. 34(7):1517-22, 2010
○ Immature adipocytes 4. Coffin CM et al: Lipoblastoma (LPB): a clinicopathologic and
immunohistochemical analysis of 59 cases. Am J Surg Pathol. 33(11):1705-
– Spindled or stellate cells (preadipocytes), small signet 12, 2009
ring-like univacuolated lipoblasts, multivacuolated 5. Collins MH et al: Lipoblastoma/lipoblastomatosis: a clinicopathologic study
lipoblasts of 25 tumors. Am J Surg Pathol. 21(10):1131-7, 1997

81
 Lipoblastoma
Tumors of Adipose Tissue

Gross Appearance Capillary Vasculature

(Left) Lipoblastomas have a
glistening, pale yellow, lobular
appearance with interlobular
fibrous septation ﬊, which
may also be apparent on gross
examination. (Right)
Lipoblastoma contains a
variably prominent, delicate,
branching capillary vascular
network ﬈ very similar to
that seen in myxoid
liposarcoma. Note the
presence of conspicuous
bland, spindled preadipocytes,
also reminiscent of myxoid
liposarcoma.

Delicate Capillary Vasculature Maturing Fat

(Left) The capillary network of
lipoblastoma is usually most
prominent in areas of myxoid
change and may occasionally
be striking. (Right) In most
cases of lipoblastoma, the
adipocytes near the center of
a lobule are more mature than
those at the periphery. Note,
however, the variation in size,
a feature not generally seen in
conventional lipoma.

Cellular Foci Cellular Foci

(Left) Rare cases of
lipoblastoma may show an
increase in lobule cellularity,
raising concerns for myxoid
liposarcoma; however, more
conventional morphology is
often seen in other fields. FISH
analysis may be helpful in
difficult cases. (Right) Cellular
foci in lipoblastoma are
characterized by a
proliferation of very bland,
uniform spindled cells
associated with delicate
capillaries. The very young age
of the patient is often a major
clue to avoiding a misdiagnosis
of myxoid liposarcoma in these
cases.

82
 Lipoblastoma

Tumors of Adipose Tissue

Myxoid Stroma Stromal Mucin Pools
(Left) Occasionally,
lipoblastoma may show
extensive myxoid stromal
change, as depicted. A more
conventional area can be seen
in the upper left. (Right)
Stromal mucin pools are
present in some cases of
lipoblastoma and are
morphologically reminiscent
of pulmonary edema in the
lung. In general, however, this
feature is more commonly
identified in myxoid
liposarcoma than
lipoblastoma.

Multivacuolated Cells Diffuse Lipoblastoma

(Left) Multivacuolated
lipoblasts, similar to what can
be seen in myxoid liposarcoma
and atypical lipomatous
tumor, can also be seen in
lipoblastoma. (Right) Diffuse
lipoblastoma (or
lipoblastomatosis) is almost
indistinguishable histologically
from solitary lipoblastoma;
however, the former is less
lobular, more infiltrative, and
more likely to involve muscle
(shown). It is also more likely
to be incompletely excised and
recur.

Maturing Lipoblastoma Maturing Lipoblastoma

(Left) Fat maturation has been
well documented in recurrent
cases of lipoblastoma, as
evidenced by the presence of
mostly mature adipose tissue
with minimal to no primitive
fat or myxoid component.
Note the prominent lobularity
and fibrous septa. (Right) This
area of a recurrent
lipoblastoma with maturation
is indistinguishable from
conventional lipoma at high
magnification.

83
 Atypical Spindle Cell Lipomatous Tumor

KEY FACTS
Tumors of Adipose Tissue

TERMINOLOGY MICROSCOPIC
• Low-grade atypical spindle cell neoplasm with adipocytic • Vaguely lobular, unencapsulated lesion, often with ill-
differentiation defined or infiltrative peripheral border
• Synonyms: Spindle cell liposarcoma, fibrosarcoma-like • Relatively uniform spindle cell proliferation
lipomatous neoplasm, atypical spindle cell lipoma ○ Variable nuclear atypia and hyperchromasia
CLINICAL ISSUES • Mature adipocytic component ± lipoblasts
○ Uni-, bi-, and multivacuolated lipoblasts frequent
• Wide age range (mean: 54 years)
• Myxoid to collagenous stroma
• Slowly growing mass or swelling
• Mitoses rare; no necrosis
• Majority arise in limbs and limb girdles
○ Also head/neck, trunk, genital region ANCILLARY TESTS
• May arise in superficial or deep soft tissue • Variable CD34 and S100 protein expression
• Treatment: Complete surgical excision • Loss of nuclear Rb expression in 50%
• Low risk of local recurrence (~ 10%) • No MDM2 amplification
• No reports of malignant progression
TOP DIFFERENTIAL DIAGNOSES
MACROSCOPIC • Spindle cell lipoma
• Median size: 5 cm • Atypical lipomatous tumor
• Mammary-type myofibroblastoma

Atypical Spindle Cell Lipomatous Tumor Adipocytic Component

(Left) Atypical spindle cell
lipomatous tumor (ASCLT) is
an unusual low-grade
adipocytic neoplasm
composed of variably atypical
spindle cells and lipoblasts
within a collagenous to
myxoid stroma. It has also
been described as "spindle cell
liposarcoma" and
"fibrosarcoma-like lipomatous
neoplasm." (Right) Adipocytic
differentiation is a consistent
feature of ASCLT and takes
the form of mature adipocytes
± lipoblasts ﬉.

Lipoblast Cytomorphology Absence of MDM2 Nuclear Expression

(Left) Univacuolated and
bivacuolated lipoblasts are a
common finding in ASCLT and
display cytomorphologies that
can resemble either an ice
cream cone ﬉ or hourglass
﬈, respectively. (Right) Unlike
atypical lipomatous
tumor/well-differentiated
liposarcoma, ASCLT does not
show MDM2 gene
amplification nor does it show
coexpression of MDM2 and
CDK4 by
immunohistochemistry. This is
a helpful distinguishing
feature of the tumor.

84
 Atypical Spindle Cell Lipomatous Tumor

Tumors of Adipose Tissue

• Myxoid to collagenous stroma
TERMINOLOGY
○ Wispy collagen may be seen, but "ropey" bundles rare
Abbreviations • Mitoses rare; necrosis absent
• Atypical spindle cell lipomatous tumor (ASCLT)
ANCILLARY TESTS
Synonyms
• Spindle cell liposarcoma Immunohistochemistry
• Fibrosarcoma-like lipomatous neoplasm • Variable CD34(+) in majority of cases
• Atypical spindle cell lipoma • Spindle cells may be S100(+) &/or focally desmin (+)
• Loss of nuclear Rb expression in 50%
Definitions • MDM2/CDK4 coexpression (-)
• Low-grade atypical spindle cell neoplasm with adipocytic
differentiation Molecular Genetics
• Heterozygous deletion of RB1 in subset of cases
CLINICAL ISSUES • No amplification of MDM2
Epidemiology
DIFFERENTIAL DIAGNOSIS
• Age
○ Wide range (mean: 54 years) Spindle Cell/Pleomorphic Lipoma
• Sex • Absence of infiltrative growth
○ Male predominance • Most are subcutaneous, affecting neck, back, or shoulders
• Spindle cell component lacks nuclear atypia
Site
• Characteristic "ropey" collagen bundles
• Majority arise in limbs and limb girdles
○ Mostly commonly hands, feet, thigh Atypical Lipomatous Tumor/Well-Differentiated
• May arise in superficial or deep soft tissue Liposarcoma
• Also head/neck, trunk, genital region • Retroperitoneum common site
• Rarely mediastinum, retroperitoneum, other • Lacks well-developed spindle cell component
• MDM2/CDK4 overexpression by IHC
Presentation
• MDM2 amplification
• Slowly growing mass or swelling
• May be present for years Dedifferentiated Liposarcoma (Low Grade)
• Retroperitoneum common site
Treatment
• Higher grade zones often present
• Complete surgical excision • MDM2/CDK4 overexpression by IHC
Prognosis • MDM2 amplification
• Low risk of local recurrence (~ 10%) Mammary-Type Myofibroblastoma
• No reports of malignant progression • Well-circumscribed lesions
• Usually CD34(+) and desmin (+)
MACROSCOPIC • Mature adipose tissue, if present, lacks lipoblasts
Size
Dermatofibrosarcoma Protuberans
• Wide range (0.5-28.0 cm)
• Conspicuous storiform growth pattern common
○ Median: 5.0 cm
• "Honeycomb" infiltration of subcutaneous fat
• t(17;22) with COL1A1-PDGFB fusion
MICROSCOPIC
Histologic Features SELECTED REFERENCES
• Vaguely lobular, unencapsulated lesion, often with ill- 1. Creytens D et al: "Atypical" pleomorphic lipomatous tumor: a
defined peripheral border clinicopathologic, immunohistochemical and molecular study of 21 cases,
emphasizing its relationship to atypical spindle cell lipomatous tumor and
○ Infiltration of adjacent tissue common suggesting a morphologic spectrum (atypical spindle cell/pleomorphic
• Wide range in cellularity (often low to moderate) lipomatous tumor). Am J Surg Pathol. 41(11):1443-1455, 2017
• Relatively uniform spindle cell proliferation 2. Mariño-Enriquez A et al: Atypical spindle cell lipomatous tumor:
clinicopathologic characterization of 232 cases demonstrating a
○ Variable nuclear atypia and hyperchromasia morphologic spectrum. Am J Surg Pathol. 41(2):234-244, 2017
○ May show bizarre, hyperchromatic, multinucleated cells 3. Creytens D et al: Atypical spindle cell lipoma: a clinicopathologic,
– Floret-like cells can resemble those of pleomorphic immunohistochemical, and molecular study emphasizing its relationship to
classical spindle cell lipoma. Virchows Arch. 465(1):97-108, 2014
lipoma 4. Deyrup AT et al: Fibrosarcoma-like lipomatous neoplasm: a reappraisal of so-
– Some cases referred to in literature as "atypical called spindle cell liposarcoma defining a unique lipomatous tumor
pleomorphic lipomatous tumor" unrelated to other liposarcomas. Am J Surg Pathol. 37(9):1373-8, 2013
5. Mentzel T et al: Well-differentiated spindle cell liposarcoma ('atypical spindle
• Adipocytic component cell lipomatous tumor') does not belong to the spectrum of atypical
○ Variably sized, mature adipocytes lipomatous tumor but has a close relationship to spindle cell lipoma:
clinicopathologic, immunohistochemical, and molecular analysis of six cases.
○ Uni-, bi-, &/or multivacuolated lipoblasts frequent Mod Pathol. 23(5):729-36, 2010

85
 Atypical Spindle Cell Lipomatous Tumor
Tumors of Adipose Tissue

Peripheral Border Infiltrative Periphery

(Left) At low power, ASCLT
often shows a vaguely lobular
growth pattern with most
cases demonstrating an ill-
defined peripheral margin
(often infiltrative). However, a
minority of cases are well
circumscribed, as depicted.
(Right) This case of ASCLT
arose in the quadriceps muscle
and showed obvious
infiltration of adjacent
skeletal muscle ﬈. FISH
analysis was negative for
MDM2 gene amplification.

Variation in Cellularity Myxoid Stroma

(Left) Cellularity is variable in
ASCLT with most cases falling
on the low end of the
spectrum. Some cases can
show areas of moderate to
high cellularity and
architectural organization,
mimicking low-grade
dedifferentiated liposarcoma.
(Right) Stromal myxoid change
is common in ASCLT. Note the
minimal to mild nuclear atypia
in the spindled tumor cells and
also the univacuolated
lipoblasts ﬈.

Collagenous Stroma Sparse to Absent Mitotic Activity

(Left) Stromal collagen can be
prominent in ASCLT, as
depicted. Delicate wisps or
bundles of collagen fibers can
be seen in some cases,
creating morphologic overlap
with spindle cell lipoma.
(Right) Mitotic figures ﬉ are
generally challenging to find
in ASCLT and may be
completely absent in
histologic sections.
Coagulative tumor necrosis is
never seen.

86
 Atypical Spindle Cell Lipomatous Tumor
Delicate Capillary Vasculature
Mature Adipose Tissue
S100 Protein Expression
Tumors of Adipose Tissue
Lipoblastic Differentiation
(Left) Some cases of ASCLT
may show a delicate,
arborizing capillary network
similar to myxoid liposarcoma.
This finding, if present, is
generally focal and not as
extensive as that typically
seen in myxoid liposarcoma.
(Right) Although the number
of lipoblasts varies widely
from one case to the next,
they may be a prominent
finding in ASCLT, as depicted
in this hematoxylin and eosin.
Cellular, Nonlipogenic Areas
(Left) Mature adipose tissue is
a common feature of ASCLT,
and the adipocytes often show
variation in size. Hematoxylin
and eosin also shows scattered
univacuolated lipoblasts
between the larger mature
adipocytes. (Right) In some
cases of ASCLT, there may be
a decrease or absence of
lipogenic tissue associated
with an increase in cellularity.
This finding may lead to
consideration of
dedifferentiation; however,
MDM2 gene amplification is
absent as is coexpression of
MDM2 and CDK4 by
immunohistochemistry.
Atypical Pleomorphic Lipomatous Tumor
(Left) Expression of S100 is
common in ASCLT and can
show positivity in both lesional
spindle cells and lipoblasts
(red chromogen here). (Right)
Cases of ASCLT may also show
bizarre, hyperchromatic,
multinucleated, floret-like
cells ﬉, reminiscent of
pleomorphic lipoma. These
tumors have been recently
described in the literature as
"atypical pleomorphic
lipomatous tumor" and appear
to be histogenetically related
to ASCLT. Note also the
multivacuolated lipoblast ﬈.
87
 Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma

KEY FACTS
Tumors of Adipose Tissue

TERMINOLOGY
• Locally aggressive mesenchymal neoplasm composed of
atypical adipocytes and demonstrating at least focal
nuclear atypia in adipocytes &/or stromal cells
CLINICAL ISSUES
• Most common form of liposarcoma (40-45% of cases)
• Most occur in middle-aged to elderly adults
• Extremities, retroperitoneum, abdominal cavity,
paratesticular region, mediastinum
• Treatment: Complete surgical excision with negative
margins
• Anatomic site is most important prognostic factor
○ Low risk of recurrence and dedifferentiation in
extremities
○ More significant risk of recurrence/dedifferentiation in
body cavities
• No metastatic potential
MICROSCOPIC
• Sheets and lobules of relatively mature adipocytes of
varying sizes
• Thickened, irregular fibrous bands or septa common
• Stromal &/or adipocyte nuclear atypia characteristic
• Lipoblasts vary in number and may be absent
• Rarely may show prominent myxoid stroma
• Other subtypes: Sclerosing, inflammatory, myxoid
ANCILLARY TESTS
• Overexpression of nuclear MDM2 and CDK4 by IHC
• Molecular: MDM2 amplification
• Supernumerary ring and giant marker chromosomes
TOP DIFFERENTIAL DIAGNOSES
• Lipoma
• Pleomorphic lipoma
• Atypical spindle cell lipomatous tumor
• Dedifferentiated liposarcoma

Atypical Lipomatous Tumor Atypical Lipomatous Tumor

(Left) Atypical lipomatous
tumor (ALT) is generally well
circumscribed and often shows
a variable tan to yellow, firm
to fatty cut surface. Well-
differentiated liposarcoma
(WDLPS) is an alternate term
for the same entity. (Right)
This image shows the classic
morphologic appearance of
ALT: Thickened fibrous bands
containing atypical stromal
cells and lobules of adipose
tissue containing variable
numbers of multivacuolated
lipoblasts.

Thickened Fibrous Bands Fibrosis With Atypical Stromal Cells

(Left) Most cases of
ALT/WDLPS characteristically
show irregular expansion of
fibrous septa/bands between
lobules of adipocytes;
however, in some cases they
may be sparse. Atypical
stromal cell nuclei ﬈ can
often be appreciated from low
power. (Right) Fibrosis in
ALT/WDLPS may be seen
within the adipocytic lobules
as patchy splotches or
irregular deposits, as depicted.
Note the atypical stromal cell
nuclei ﬊.

88
 Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma
TERMINOLOGY
Abbreviations
• Atypical lipomatous tumor (ALT)
• Well-differentiated liposarcoma (WDLPS)
Synonyms
• Atypical lipoma (obsolete)
Definitions
• Locally aggressive mesenchymal neoplasm composed of
atypical adipocytes and demonstrating at least focal
nuclear atypia in adipocytes &/or stromal cells
○ Histologic subtypes: Adipocytic (lipoma-like), sclerosing,
inflammatory, myxoid
– Spindle cell liposarcoma is now considered to be
distinct from ALT/WDLPS
□ Described in literature as "atypical spindle cell
lipomatous tumor" or "fibrosarcoma-like
lipomatous neoplasm"
• Terms "atypical lipomatous tumor" and "well-differentiated
liposarcoma" are synonyms for same neoplasm
○ "Well-differentiated liposarcoma" is best utilized only for
tumors occurring within body cavities (retroperitoneum,
mediastinum, abdominopelvic sites) or paratesticular
region
– Due to significant morbidity in these sites; also,
increased risk of dedifferentiation
CLINICAL ISSUES
Epidemiology
• Incidence
○ Most common form of liposarcoma (40-45% of cases)
• Age
○ Most occur in middle-aged to elderly adults
○ Extremely rare in childhood
Site
• Overall, most frequently arise in deep soft tissues of
extremities
○ May also arise in subcutaneous tissue and very rarely in
skin
• Also common in retroperitoneum, abdominal cavity,
paratesticular region, mediastinum
• Less frequent in head/neck area
• Subtype site predilections
○ Sclerosing subtype most common in retroperitoneum
and spermatic cord
○ Inflammatory subtype most common in
retroperitoneum
Presentation
• Slow-growing, painless, deep-seated mass
• Retroperitoneal tumors may only be discovered after
attaining significant growth (> 20 cm)
Treatment
• Complete surgical excision with negative margins
• Surgical debulking for large, multifocal
retroperitoneal/intraabdominal tumors
○ May require partial or complete resection of
intraabdominal organs
Tumors of Adipose Tissue
Prognosis
• Anatomic site of occurrence is most important prognostic
factor
○ Tumors in surgically amenable locations (e.g.,
extremities)
– Recur only rarely after complete excision with clearly
negative margins
○ Intraabdominal, retroperitoneal, mediastinal, or
paratesticular tumors
– Often recur locally and may cause significant
morbidity and lead to death
□ Long-term mortality rate in retroperitoneal WDLPS
up to 80%
• Risk of dedifferentiation
○ Very rare in extremities (< 2%)
○ Much higher in retroperitoneum (> 20%)
– May arise de novo or in recurrences
• No metastatic potential for ALT/WDLPS unless
dedifferentiation is present
MACROSCOPIC
General Features
• Well-circumscribed, lobular
• Variable yellow, fatty to tan-gray cut surface
• Thickened fibrous bands may be evident grossly
• Fat necrosis may be seen in larger tumors
Sections to Be Submitted
• Sampling very important in well-differentiated tumors
• 1 section submitted per cm of greatest linear dimension
• Focus sampling on firm or tan-gray areas
Size
• Wide size range (usually > 5 cm)
○ May grow to enormous sizes (> 20 cm), particularly in
retroperitoneum and abdominal cavity
MICROSCOPIC
Histologic Features
• Sheets and lobules of relatively well-differentiated
adipocytes
○ Adipocytes show significant variation in size and shape
– Usually show at least focal nuclear hyperchromasia
and atypia
• Variably prominent, thickened, irregular fibrous bands or
septa
○ Often contain atypical, nonlipogenic fibroblastic cells
– 1 or several enlarged, hyperchromatic nuclei
– Variable amphophilic to eosinophilic cytoplasm
– May show indistinct nuclear &/or cytoplasmic
membranes ("smudge cells")
– May show floret-like morphology
• Lipoblasts may be seen but are not essential for diagnosis
(as they may be absent)
○ Usually multivacuolated
○ Hyperchromatic nuclei that are compressed and
indented/scalloped by vacuoles
○ Significant nuclear pleomorphism/atypia absent
• Atypical cells may be present within walls of larger stromal
blood vessels
89
 Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma
Tumors of Adipose Tissue
• Prominent stromal collagenization/hyalinization in some
tumors (sclerosing subtype)
○ Minimal adipocytic component
○ Atypical stromal cells often frequent
○ Chronic inflammatory infiltrate may be seen
• Dense stromal chronic inflammatory infiltrate in some
tumors (inflammatory subtype)
○ Mainly lymphocytes, plasma cells
○ Scattered atypical stromal cells and lipoblasts
○ Often edematous stroma
• Myxoid stromal changes in some cases
○ May be prominent and extensive
• Heterologous differentiation rare
○ Bone, cartilage, smooth muscle, or skeletal muscle
ANCILLARY TESTS
Immunohistochemistry
• S100 protein (+) in adipocytes and lipoblasts
• Nuclear MDM2(+) and CDK4(+) in majority
○ Pitfall: Nuclear expression in reactive histiocytes (fat
necrosis)
• Nuclear Rb expression intact
Cytogenetics
• Characteristic supernumerary ring and giant marker
chromosomes
○ Contain amplified sequences originating from 12q14-15
region
Molecular Genetics
• MDM2 amplification
○ Also, CDK4, CPM, HMGA2, FRS2, and YEATS4 frequently
coamplified
○ Can be detected by FISH, PCR, array CGH
DIFFERENTIAL DIAGNOSIS
Lipoma
• Most are smaller than ALT/WDLPS, but some can grow to
very large sizes
• Lacks atypical stromal cells with irregular, hyperchromatic,
pleomorphic nuclei
• Usually lacks significant variation in size and shape of
adipocytes
• Generally no lipoblasts
• Negative for MDM2 and CDK4 by IHC
• No amplification of MDM2
Pleomorphic Lipoma
• Usually small lesions, often subcutaneous
• Variable number of floret-like cells
• Ropey collagen and scattered mast cells common
• Loss of nuclear Rb expression by IHC
• No MDM2 amplification
Atypical Spindle Cell Lipomatous Tumor
• Previously known as spindle cell liposarcoma
• Bland spindle cells within fibrous to myxoid stroma
• Variable adipocytic differentiation, often with univacuolar
lipoblasts
• Negative for MDM2 and CDK4 by IHC
90
• Loss of nuclear Rb expression by IHC in over 50% of cases
• No amplification of MDM2
Dedifferentiated Liposarcoma
• Cellular, usually nonlipogenic sarcoma with wide
morphologic spectrum
○ Component of WDLPS may be present
• Positive for MDM2, CDK4 by IHC
• Shows MDM2 amplification
Hibernoma
• Variably prominent component of brown fat
• Enlarged atypical stromal cells rare
• No MDM2 amplification
Idiopathic Retroperitoneal Fibrosis
• Often bilateral, with impingement of ureters and
subsequent hydronephrosis
• Lacks atypical stromal cells of WDLPS
• No MDM2 amplification
Massive Localized Lymphedema
• Large superficial pseudotumor in morbidly obese patients
• Often show retention but expansion of overall architecture
of subcutaneous tissue
• Reactive fibroblast nuclei may simulate atypical stromal
cells of ALT/WDLPS
• No MDM2 amplification
Myxoid Liposarcoma
• Prominent arborizing "chicken-wire" capillary vasculature;
stromal mucin cysts common
• Lacks atypical stromal cells of ALT/WDLPS
• Characteristic t(12;16) in most cases, with DDIT3 fusion
SELECTED REFERENCES
1. Kammerer-Jacquet SF et al: Differential diagnosis of atypical lipomatous
tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma:
utility of p16 in combination with MDM2 and CDK4 immunohistochemistry.
Hum Pathol. 59:34-40, 2017
2. Mariño-Enriquez A et al: Atypical spindle cell lipomatous tumor:
clinicopathologic characterization of 232 cases demonstrating a
morphologic spectrum. Am J Surg Pathol. 41(2):234-44, 2017
3. Dei Tos AP: Liposarcomas: diagnostic pitfalls and new insights.
Histopathology. 64(1):38-52, 2014
4. Deyrup AT 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. 37(9):1373-8, 2013
5. Sioletic S et al: Well-differentiated and dedifferentiated liposarcomas with
prominent myxoid stroma: analysis of 56 cases. Histopathology. 62(2):287-
93, 2013
6. Piperi E et al: Well-differentiated liposarcoma/atypical lipomatous tumor of
the oral cavity: report of three cases and review of the literature. Head Neck
Pathol. 6(3):354-63, 2012
7. Aleixo PB et al: Can MDM2 and CDK4 make the diagnosis of well
differentiated/dedifferentiated liposarcoma? An immunohistochemical
study on 129 soft tissue tumours. J Clin Pathol. 62(12):1127-35, 2009
8. 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.
31(1):1-14, 2007
9. Sirvent N et al: Detection of MDM2-CDK4 amplification by fluorescence in
situ hybridization in 200 paraffin-embedded tumor samples: utility in
diagnosing adipocytic lesions and comparison with immunohistochemistry
and real-time PCR. Am J Surg Pathol. 31(10):1476-89, 2007
10. Binh MB 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. 29(10):1340-7, 2005
 Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma
Atypical Stromal Cells
Atypical Adipocyte Nuclei
Occasional Vascular Changes Atrophic Skeletal Muscle Fibers
Tumors of Adipose Tissue
Floret-Like Cells
(Left) Atypical stromal cells ﬈
are a key finding in
ALT/WDLPS but vary widely in
number and distribution from
case to case. The nuclei are
characteristically enlarged,
irregular, and hyperchromatic
and sometimes show a
"smudgy" quality. These cells
are usually most easily
identified within the fibrous
areas of ALT/WDLPS. (Right)
Frequently, the atypical
stromal cells of ALT/WDLPS
show a floret-like morphology
﬈ similar to the cells seen in
pleomorphic lipoma and some
other tumors.
Fat Necrosis
(Left) Atypical adipocytic
nuclei ﬈ may also be seen in
ALT/WDLPS. The enlargement
and hyperchromasia
distinguish them from benign
nuclei with vacuolated
Lochkern change. (Right) Fat
necrosis (particularly
overlapping histiocyte nuclei
﬉) in a lipoma may lead to
the overcalling of nuclear
atypia and a subsequent
misdiagnosis of ALT/WDLPS.
However, true ALT/WDLPS
can also contain fat necrosis.
Note the true atypical stromal
cell ﬊ within the adjacent
fibrous band, which helps
support the diagnosis.
(Left) Rare cases of
ALT/WDLPS show atypical
cells ﬈ within the muscular
walls of stromal vessels. These
cases also frequently contain a
component of heterologous
smooth muscle (so-called
lipoleiomyosarcoma). (Right)
Intramuscular adipocytic
tumors may contain foci of
atrophic skeletal muscle
fibers, which should not be
confused with true atypical
cells of ALT/WDLPS. These
cells ﬈ often show dense
eosinophilic cytoplasm and
clustering/overlapping of
numerous small rounded
nuclei.
91
 Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma
Tumors of Adipose Tissue

Multivacuolated Lipoblasts Cellular Fibrous Bands

(Left) Multivacuolated
lipoblasts are a common but
numerically variable finding in
ALT/WDLPS; however, they
can be absent in some cases
and are therefore not required
to make the diagnosis. They
are identified by multiple
intracytoplasmic fat vacuoles
that compress and
indent/scallop the
hyperchromatic adipocyte
nuclei ﬈. (Right) The fibrous
septa or bands of ALT/WDLPS
may be quite cellular, as
depicted, and should not be
taken as evidence of
dedifferentiation.

Fibrosis Sclerosing Subtype

(Left) In some cases of
ALT/WDLPS, stromal fibrosis is
more extensive and diffuse.
Note the variation in size of
the adipocytes in ALT/WDLPS,
another common finding in
this tumor. (Right) Examples
of ALT/WDLPS with extensive
stromal fibrosis and collagen
that contain a minimal
lipogenic component are
sometimes referred to as the
sclerosing type. Note the
hypocellularity that, along
with the essentially absent
mitotic activity, distinguishes
this morphology from true
dedifferentiation.

Rare Thickened Collagen Bundles Myxoid Stroma

(Left) Thickened or even
"ropey" collagen bundles are a
rare finding in ALT/WDLPS
and are more suggestive of
spindle cell or pleomorphic
lipoma. However, in large
tumors, MDM2 (or related)
testing should be performed
to aid in the diagnosis. (Right)
Myxoid stroma is seen in a
subset of ALT/WDLPS and may
lead to serious consideration
of other myxoid neoplasms,
including myxoid liposarcoma.
Other more conventional
areas and features of
ALT/WDLPS are usually
present. Molecular techniques
can also be utilized.

92
 Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma
Rare Arborizing Capillary Vasculature
Inflammatory Subtype
CT Scan
Tumors of Adipose Tissue
Chronic Inflammation
(Left) An arborizing capillary
vasculature, similar to that
seen in myxoid liposarcoma,
may be seen rarely in
ALT/WDLPS. Note the
hyperchromatic atypical
stromal cells ﬈. (Right)
Lymphoid aggregates or
collections of chronic
inflammatory cells may be
seen in ALT/WDLPS. Rarely,
this chronic inflammatory
component is very prominent
(inflammatory-type
ALT/WDLPS).
Rare Brown Fat Component
(Left) The inflammatory
subtype of ALT/WDLPS shows
a prominent chronic
inflammatory infiltrate and
only scattered atypical
stromal cells &/or
multivacuolated lipoblasts ﬈.
(Right) A component of brown
fat (top of image) is a rare
finding in ALT/WDLPS but may
lead to misdiagnosis as
hibernoma. Molecular testing
can be helpful in such cases.
MDM2 Amplification
(Left) This abdominal CT scan
shows a large, well-
differentiated liposarcoma ﬈
surrounding and almost
encasing the right kidney st.
Despite its size, no
dedifferentiated component
was identified histologically.
(Right) In situ hybridization
FISH analysis shows MDM2
amplification, a characteristic
feature of ALT/WDLPS (and
also dedifferentiated
liposarcoma). Note numerous
green signals in an analyzed
tumor cell nucleus.
93
 Dedifferentiated Liposarcoma

KEY FACTS
Tumors of Adipose Tissue

TERMINOLOGY MACROSCOPIC
• Malignant, generally nonlipogenic sarcoma of variable • Well-demarcated, large mass with variable cut surface
histologic grade often arising in association with • Important to sample thoroughly
identifiable component of atypical lipomatous tumor
(ALT)/well-differentiated liposarcoma (WDLPS) MICROSCOPIC
• Classic appearance shows abrupt or gradual transition from
CLINICAL ISSUES ALT/WDLPS to nonlipogenic, cellular sarcoma
• Dedifferentiation occurs in up to 10% of ALT/WDLPS • Nonlipogenic component shows broad morphologic
○ Vast majority (90%) arise de novo spectrum (often high grade)
• Middle-aged to elderly adults • Mitotic rate > 5 per 10 HPF
• Most common in retroperitoneum/abdominal cavity
ANCILLARY TESTS
○ Also spermatic cord, trunk, extremities, head/neck
• Treatment: Complete surgical resection with negative • Diffuse nuclear MDM2(+) and CDK4(+)
margins • Molecular: Overexpression of MDM2
• Anatomic location is most important prognostic factor TOP DIFFERENTIAL DIAGNOSES
• Local recurrence in ~ 40% of cases • Undifferentiated pleomorphic sarcoma
• Distant metastases observed in 15-20% of cases • Myxofibrosarcoma
• Pleomorphic liposarcoma

Dedifferentiated Liposarcoma Dedifferentiated Liposarcoma

(Left) The cut surface of
dedifferentiated liposarcoma
(DDLPS) varies in appearance
depending upon the exact
composition of the tumor.
Lipogenic ﬈ and nonlipogenic
﬊ (dedifferentiated)
components are often readily
distinguished from one
another by differences in color
and consistency. (Right)
DDLPS may appear entirely or
almost entirely composed of
fibrous or fleshy nonlipogenic
sarcoma ﬊. Sampling of
peripheral fatty tissue ſt to
detect a minor lipogenic
component is important.

Abrupt Transition Gradual Transition

(Left) This classic example of
DDLPS shows a transition
from a well-differentiated
liposarcoma component (right)
to a nonlipogenic sarcoma
component (left). This
transition may appear abrupt,
as shown, with a sharp
demarcation between the 2
components. (Right) The
transitional interface in classic
DDLPS may be more gradual
and less abrupt, as depicted,
with atypical fat cells admixed
with otherwise nonlipogenic
sarcoma.

94
 Dedifferentiated Liposarcoma
TERMINOLOGY
Abbreviations
• Dedifferentiated liposarcoma (DDLPS)
Definitions
• Malignant, generally nonlipogenic sarcoma of variable
histologic grade often arising in association with
identifiable component of atypical lipomatous tumor
(ALT)/well-differentiated liposarcoma (WDLPS)
CLINICAL ISSUES
Epidemiology
• Incidence
○ Relatively common form of liposarcoma
○ Vast majority (90%) arise de novo
– Minority develop in local recurrences of ALT/WDLPS
○ Dedifferentiation occurs in up to 10% of ALT/WDLPS
– Probably represents time-dependent phenomenon
• Age
○ Middle-aged to elderly adults
Site
• Most common in retroperitoneum and abdominal cavity
• Also spermatic cord, trunk, extremities, head/neck region
• Most tumors arise in deep soft tissue
○ Rarely subcutaneous
Presentation
• Large, painless mass
• May be incidentally discovered in retroperitoneum
• In limbs, may present as longstanding mass that exhibits
recent increase in size
Treatment
• Complete surgical resection with negative margins
• Surgical debulking for large, multifocal
retroperitoneal/intraabdominal tumors
○ May require partial or complete resection of
intraabdominal organs
Prognosis
• Anatomic location is most important prognostic factor
○ Retroperitoneal/intraabdominal tumors exhibit worst
clinical behavior
• Local recurrence in ~ 40% of cases
○ Nearly all retroperitoneal tumors recur with long-term
follow-up
• Distant metastases observed in 15-20% of cases
○ Less frequent than typically seen in other adult-type
pleomorphic sarcomas
• Overall mortality 25-30% at 5-year follow-up
○ Likely higher rate with long-term follow-up
• Amount &/or histologic grade of dedifferentiated
component generally shows no prognostic importance
○ However, in retroperitoneal tumors, high-grade
morphology has been associated with decreased survival
• Presence of myogenic (especially rhabdomyoblastic)
differentiation in retroperitoneal tumors has been
associated with significantly decreased survival rates
• Epithelioid morphology (particularly when prominent)
portends more aggressive clinical course
Tumors of Adipose Tissue
MACROSCOPIC
General Features
• Well demarcated, large, uni- or multinodular
• Dedifferentiated areas are often tan-gray-white with firm
or fleshy cut surface
• Well-differentiated components, if present, are yellow and
fatty
• Hemorrhage &/or necrosis common
Sections to Be Submitted
• Sections of both dedifferentiated and well-differentiated
components must be sampled thoroughly
○ 1 section per cm of greatest linear tumor dimension
• If well-differentiated component is not obvious, sampling
of peripheral adipose tissue is important
Size
• Often large (> 5 cm)
○ Retroperitoneal/intraabdominal tumors may be
enormous
MICROSCOPIC
Histologic Features
• Classic appearance is transition from ALT/WDLPS to
(usually) nonlipogenic, cellular sarcoma
○ ALT/WDLPS may be adipocytic (lipoma-like), sclerosing,
or inflammatory subtypes
○ Transition may be abrupt or gradual
○ Component of ALT/WDLPS may be focal or absent
• Nonlipogenic sarcoma component shows very broad
morphologic spectrum and may be high or low histologic
grade
○ Many tumors show mixture of patterns
○ Cellular, pleomorphic morphology
– Resembles undifferentiated pleomorphic sarcoma
and other adult-type pleomorphic sarcomas
○ Prominent myxoid stroma morphology
– Usually resembles intermediate- to high-grade
myxofibrosarcoma
□ Pleomorphic, multinucleated tumor cells and
curvilinear stromal vasculature
– Rare focal areas may resemble myxoid liposarcoma
○ Fascicular spindle cell morphology
– Variable nuclear atypia and pleomorphism
□ May appear low grade and resemble fibromatosis
– Variable hyalinized stroma
○ Storiform, meningothelial-like morphology
– Resembles neural proliferation or
dermatofibrosarcoma protuberans
– May be associated with metaplastic bone formation
○ Inflammatory morphology
– Abundant neutrophilic infiltrate
– Also plasma cells, lymphoid infiltrate
○ Epithelioid morphology
– Diffuse, sheet-like growth
– Rhabdoid cells may be apparent; rare acinar-like
epithelial structures
95
 Dedifferentiated Liposarcoma
Tumors of Adipose Tissue
– Often resemble carcinoma, melanoma,
mesothelioma, or other sarcomas with epithelioid
morphology
– Some areas may be indistinguishable from alveolar
rhabdomyosarcoma
□ Identical immunophenotype as well (desmin,
myogenin)
○ Rare homologous lipoblastic morphology
– Contains lipoblasts or pleomorphic lipoblasts
□ Occurring throughout lesion or in aggregates away
from interface with ALT/WDLPS component
– Can closely resemble pleomorphic liposarcoma
○ Hemangiopericytoma-like vasculature may be prominent
in rare cases
• Mitotic rate > 5 per 10 HPF
• Necrosis common
• Heterologous differentiation present in up to 10% of cases
○ Myogenic (rhabdomyoblastic, leiomyomatous),
osteosarcoma, chondrosarcoma
ANCILLARY TESTS
Immunohistochemistry
• Diffuse nuclear MDM2(+) and CDK4(+) in majority
• Variable SMA, desmin, CD34
• Intact nuclear INI1 expression
• Nuclear H3K27me3 expression usually intact
○ Rarely lost, often in tumors with heterologous elements
• Heterologous elements in nonlipogenic areas can be
highlighted by pertinent markers
○ e.g., desmin (+), myogenin (+) in rhabdomyoblastic
elements
• Generally keratin and S100 protein (-)
○ Rare cases feature anomalous keratin expression (usually
focal or patchy)
– Often seen in epithelioid DDLPS
Molecular Genetics
• Similar to changes seen in ALT/WDLPS
○ Supernumerary ring and giant marker chromosomes
○ Amplified sequences originating from 12q13-15 region
– Overexpression of MDM2, CDK4, &/or HMGA2
detectable by FISH
• Rare DDIT3 gene amplification
○ May be associated with myxoid liposarcoma-like
morphology &/or homologous lipoblastic differentiation
DIFFERENTIAL DIAGNOSIS
Undifferentiated Pleomorphic Sarcoma
• Very rare in retroperitoneum
○ Most retroperitoneal tumors with undifferentiated
pleomorphic sarcoma morphology are actually DDLPS
• Lacks component of ALT/WDLPS
• Generally less morphologically heterogeneous than DDLPS
• No MDM2 amplification
Myxofibrosarcoma
• Very rare in retroperitoneum/abdomen
• Lacks component of ALT/WDLPS
• No MDM2 amplification
96
Pleomorphic Liposarcoma
• May arise in retroperitoneum
• Lacks component of ALT/WDLPS
• No MDM2 amplification
Well-Differentiated Liposarcoma
• May contain cellular areas, but mitotic activity is low to
absent
• Lacks overtly fibrous or fleshy appearance grossly
Atypical Spindle Cell Lipomatous Tumor
• Lacks significant cytologic atypia
• Mitotic figures scarce or absent
• No MDM2 amplification
Myxoid Liposarcoma
• Very rare in retroperitoneum/abdomen
• Lacks component of ALT/WDLPS
• No MDM2 amplification
• Characteristic t(12;16)
Malignant Peripheral Nerve Sheath Tumor
• Fascicles of spindle cells with tapering nuclei; rarely
markedly pleomorphic
• Characteristic perivascular cellularity in many cases
• May show origin from benign peripheral nerve sheath
tumor (e.g., neurofibroma)
• May contain heterologous elements
• No MDM2 amplification
Leiomyosarcoma
• Diffuse smooth muscle cytology (eosinophilic cytoplasm,
cigar-shaped nuclei, etc.)
• Diffuse SMA(+)
• Variable desmin (+), caldesmon (+)
• No MDM2 amplification
SELECTED REFERENCES
1. Agaimy A et al: Dedifferentiated liposarcoma composed predominantly of
rhabdoid/epithelioid cells: a frequently misdiagnosed highly aggressive
variant. Hum Pathol. 77:20-7, 2018
2. Makise N et al: Dedifferentiated liposarcoma with epithelioid/epithelial
features. Am J Surg Pathol. 41(11):1523-31, 2017
3. Thway K et al: Dedifferentiated liposarcoma: updates on morphology,
genetics, and therapeutic strategies. Adv Anat Pathol. 23(1):30-40, 2016
4. Gronchi A et al: Myogenic differentiation and histologic grading are major
prognostic determinants in retroperitoneal liposarcoma. Am J Surg Pathol.
39(3):383-93, 2015
5. Liau JY et al: Dedifferentiated liposarcoma with homologous lipoblastic
differentiation: expanding the spectrum to include low-grade tumours.
Histopathology. 62(5):702-10, 2013
6. Ghadimi MP et al: Diagnosis, management, and outcome of patients with
dedifferentiated liposarcoma systemic metastasis. Ann Surg Oncol.
18(13):3762-70, 2011
7. Thway K et al: Dedifferentiated liposarcoma with meningothelial-like whorls,
metaplastic bone formation, and CDK4, MDM2, and p16 expression: a
morphologic and immunohistochemical study. Am J Surg Pathol. 35(3):356-
63, 2011
8. Lucas DR et al: Dedifferentiated liposarcoma with inflammatory
myofibroblastic tumor-like features. Am J Surg Pathol. 34(6):844-51, 2010
9. Mariño-Enríquez A 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. 34(8):1122-31, 2010
10. Sirvent N et al: Detection of MDM2-CDK4 amplification by fluorescence in
situ hybridization in 200 paraffin-embedded tumor samples: utility in
diagnosing adipocytic lesions and comparison with immunohistochemistry
and real-time PCR. Am J Surg Pathol. 31(10):1476-89, 2007
 Dedifferentiated Liposarcoma
Pleomorphic Morphology
Low-Grade Myxoid Morphology
Fascicular Morphology
Tumors of Adipose Tissue
Myxofibrosarcoma-Like Morphology
(Left) A common morphologic
appearance in DDLPS is that
of a high-grade, cellular
pleomorphic sarcoma. Out of
context, this morphology is
indistinguishable from that of
an undifferentiated
pleomorphic sarcoma. (Right)
A prominent myxoid
morphology with distinct
stromal vessels is common in
DDLPS and may closely
simulate myxofibrosarcoma;
however, the latter is very rare
in the retroperitoneum in
contrast to DDLPS.
Spindled Morphology
(Left) Some myxoid
nonlipogenic areas of DDLPS
are cytologically low grade
and may lead to consideration
of other myxoid tumors, such
as myxoid liposarcoma or low-
grade fibromyxoid sarcoma.
Identification of more
conventional, higher grade
areas is useful. (Right) Tumor
cells may be spindled and
loosely fascicular in DDLPS.
This morphology may lead to
consideration of other
diagnoses, including
leiomyosarcoma and
malignant peripheral nerve
sheath tumor.
Low-Grade Fascicular Morphology
(Left) Fascicular growth may
be well developed in DDLPS
and show a herringbone
architecture, as shown,
leading to consideration of
entities like leiomyosarcoma
and fibrosarcoma. (Right)
Spindled, fascicular areas in
DDLPS may be cytologically
low grade, imparting an
appearance suggestive of
fibromatosis or a variety of
low-grade sarcomas.
97
 Dedifferentiated Liposarcoma
Tumors of Adipose Tissue

Sclerotic Matrix Storiform Morphology

(Left) Some cases of DDLPS
may contain focal or
prominent regions of
hyalinized/sclerotic matrix.
The overall fascicular growth,
presence of mitoses, and lack
of fat help distinguish this
pattern from sclerosing
ALT/WDLPS. (Right) A
storiform growth pattern is
not uncommon in DDLPS and
may superficially resemble
tumors such as
dermatofibrosarcoma
protuberans, perineurioma, or
follicular dendritic cell
sarcoma.

Whorled Morphology Inflammatory Component

(Left) A peculiar,
meningothelial-like whorling
growth may be seen in rare
cases of DDLPS. This pattern
has been associated with
metaplastic bone formation in
some cases. (Right) A chronic
inflammatory component may
be seen in DDLPS and often
consists of plasma cells and
lymphocytes. In conjunction
with a fascicular morphology,
this finding may suggest
inflammatory myofibroblastic
tumor.

Abundant Neutrophils Epithelioid Morphology

(Left) Occasional cases of
DDLPS show a prominent
neutrophilic infiltrate and may
not be readily identifiable as a
liposarcoma. This finding is
most frequently seen in the
retroperitoneum. Detection of
MDM2/CDK4 overexpression
or amplification can be very
helpful. (Right) An epithelioid
morphology in DDLPS, though
rare, is well described and can
mimic carcinoma, melanoma,
and other sarcomas with an
epithelioid appearance.
Rhabdoid change, as seen in
this H&E, is also possible.

98
 Dedifferentiated Liposarcoma
Heterologous Elements
Myogenin
Homologous Lipoblastic Differentiation
Tumors of Adipose Tissue
Rhabdomyosarcoma-Like Areas
(Left) Heterologous
differentiation is seen in up to
10% of cases of DDLPS.
Rhabdomyoblasts ﬈ are one
of many types of elements and
may be highlighted with
desmin and myogenin
immunostains. (Right) Rare
cases of DDLPS can show
epithelioid areas that closely
resemble alveolar
rhabdomyosarcoma (ARMS),
including cytoplasmic clearing
and scattered
rhabdomyoblasts. Further, IHC
staining supports
rhabdomyoblastic
differentiation.
Heterologous Elements
(Left) Epithelioid DDLPS with
areas resembling ARMS show
diffuse myogenin expression,
similar to actual ARMS.
Demonstration of classic
WDLPS zones or MDM2 gene
amplification is often required
to make the diagnosis of
DDLPS. (Right) Heterologous
osteosarcoma &/or
chondrosarcoma may be seen
in some cases of DDLPS, as
shown. Additional types of
elements include
leiomyosarcoma and, rarely,
angiosarcoma.
Unusual Morphologies
(Left) Rare cases of DDLPS
contain lipoblastic
differentiation within the
high-grade dedifferentiated
component and is considered
by some as homologous
differentiation. The
morphology often closely
resembles pleomorphic
liposarcoma. (Right) A variety
of unusual morphologies can
be noted in DDLPS, including
ones that resemble cellular
myxoid liposarcoma or even
hemangioblastoma. This case
(shown) features microcysts
and abundant cytoplasmic
eosinophilic globules.
99
 Myxoid Liposarcoma

KEY FACTS
Tumors of Adipose Tissue

TERMINOLOGY MICROSCOPIC
• Malignant neoplasm composed of primitive nonlipogenic • Typically shows lobular growth pattern
mesenchymal cells and variable number of lipoblasts set in • Abundant myxoid stroma
prominent myxoid stroma with characteristic branching • Characteristic delicate, arborizing capillary vasculature
capillary vasculature • Small spindled, stellate, and ovoid nonlipogenic tumor cells
CLINICAL ISSUES • Uni-, bi-, and multivacuolated lipoblasts frequently present
• Accounts for ~ 30-35% of all liposarcomas • Mitoses generally scarce
• Most occur in young to middle-aged adults • Progression to hypercellular or round cell areas may be
present
• Usually arise in deep soft tissue of extremities
• Treatment: Complete surgical resection with negative ANCILLARY TESTS
margins • Molecular: Characteristic t(12;16) with FUS-DDIT3 fusion
• Local recurrence in ~ 30% of cases
• Metastatic risk varies by histologic grade (< 10% up to 60%) TOP DIFFERENTIAL DIAGNOSES
○ Presence of hypercellular (round cell) areas is most • Atypical lipomatous tumor/well-differentiated liposarcoma
important histologic predictor of outcome • Myxofibrosarcoma
• Lipoblastoma
MACROSCOPIC
• Low-grade fibromyxoid sarcoma
• Usually large (median 10-12 cm) • Intramuscular myxoma

Myxoid Liposarcoma Lobular Growth

(Left) Grossly, myxoid
liposarcoma (MLPS) typically
shows a glistening, gelatinous
cut surface; however, more
cellular, high-grade areas
often appear more firm and
gray-white ﬈. Thorough
sampling of this neoplasm is
critical for proper histologic
grading. (Right) Lobular
growth is a typical feature of
MLPS, and lobules may be
separated by hypocellular,
pink fibrous zones. Although
not shown in this image, an
increase in cellularity may be
present at the periphery of
these lobules.

Abundant Myxoid Stroma Bland Cytologic Features

(Left) Myxoid liposarcoma is
characterized in most cases by
an abundant myxoid stroma,
particularly in low-grade
areas; however, this stroma
becomes less conspicuous in
hypercellular, higher grade
areas. (Right) The lesional cells
of MLPS are spindled, stellate,
or ovoid and usually contain
small, bland nuclei. Mitoses
are often scarce. With very
rare exceptions, nuclear
pleomorphism is not a feature
of MLPS and should prompt
consideration of other
diagnoses.

100
 Myxoid Liposarcoma
TERMINOLOGY
Abbreviations
• Myxoid liposarcoma (MLPS)
Synonyms
• Round cell liposarcoma (high-grade MLPS)
Definitions
• Malignant neoplasm composed of primitive nonlipogenic
mesenchymal cells and variable number of lipoblasts set in
prominent myxoid stroma with characteristic branching
capillary vasculature
○ Use of term "round cell liposarcoma" no longer
advocated (2013 WHO classification)
– Current recommendation: High-grade MLPS
CLINICAL ISSUES
Epidemiology
• Incidence
○ Accounts for ~ 30-35% of all liposarcomas
○ Represents 5-10% of all sarcomas in adults
○ Most common form of liposarcoma in children and
adolescents
• Age
○ Most occur in young to middle-aged adults (usually 20-50
years)
○ Rare in children
Site
• Deep soft tissue of extremities
○ Majority of cases arise within musculature of thigh
○ Rarely in subcutaneous tissue
• Exceptionally rare in retroperitoneum and body cavities
○ More likely to be primary well-differentiated liposarcoma
or metastatic MLPS from somatic soft tissue site
Presentation
• Painless, slow-growing, deep-seated mass
• May present with synchronous or metachronous multifocal
disease
○ Likely represent hematogenous soft tissue metastases
rather than distinctly separate tumors
Treatment
• Complete surgical resection with negative margins
• Radiotherapy may reduce risk of local recurrence
• Trabectedin may be effective in treating metastatic MLPS
Prognosis
• Local recurrence in ~ 30% of cases
• Most frequent sites of metastasis include other soft tissue
sites, bone, retroperitoneum, lungs
○ Metastatic risk varies by histologic grade
– Low-grade tumors have < 10% risk
– Higher-grade tumors have significantly increased risk
(40-60%)
• Presence of hypercellular (round cell) areas is most
important histologic predictor of outcome
○ > 5% hypercellularity is associated with unfavorable
outcome (considered high grade)
Tumors of Adipose Tissue
– Some studies recommend cutoff of 25% to consider
high grade
• Other adverse prognostic factors: Age (> 45 years),
presence of coagulative necrosis, p53 overexpression, TP53
and CDKN2A mutations
• Overall mortality rate 25-40%
MACROSCOPIC
General Features
• Well circumscribed, multinodular
• Homogeneous, gelatinous cut surface in low-grade lesions
• Higher grade lesions are often tan-white and firm or fleshy
• Macroscopic evidence of necrosis uncommon
Size
• Usually large (median 10-12 cm)
Sections to Be Submitted
• Thorough sampling is necessary to adequately estimate
percentage of hypercellular or round cell component, if
present
MICROSCOPIC
Histologic Features
• Typically shows lobular growth pattern
○ Often increased cellularity at periphery of lobules
• Characteristic abundant myxoid stroma
○ May show areas of mucin pooling (pulmonary edema-like
pattern)
• Characteristic delicate, arborizing capillary vasculature
(chicken-wire pattern)
• Small spindled, stellate, and ovoid nonlipogenic tumor cells
with scant cytoplasm
○ Bland nuclei with fine chromatin and inconspicuous
nucleoli
– General absence of nuclear pleomorphism
□ Exception: Very rare multinucleated cells
○ Mitoses generally scarce
• Uni-, bi-, and multivacuolated lipoblasts frequently present
○ Vary widely in number from case to case; may be sparse
○ Often most numerous at periphery of lobules or around
stromal blood vessels
○ Some are highly vacuolated with eosinophilic, granular
cytoplasm (hibernoma-like cells)
• Other findings: Interstitial hemorrhage, mature adipose
tissue, stromal hyalinization (often following radiotherapy),
rare foci of cartilaginous differentiation
• Progression to hypercellular or round cell areas
○ Nests or solid sheets of back-to-back &/or overlapping
cells
– Nuclei often larger and more hyperchromatic; may
show more conspicuous nucleoli
– Mitoses and apoptotic cells more frequent
○ Characteristic arborizing vasculature less conspicuous
but present
○ Lipoblasts and stromal mucin pools may be present
○ Percentage of reportable hypercellular/round cell
component varies from 5% to > 80%
○ Round cell areas may rarely show corded growth in
hyalinized matrix
101
 Myxoid Liposarcoma
Tumors of Adipose Tissue

• Lacks lipoblasts
ANCILLARY TESTS
• Characteristic t(7;16) with FUS-CREB3L2 fusion
Immunohistochemistry
Lipoblastoma-Like Tumor of Vulva
• Best utilized to exclude other entities
• Rare; only affect vulva
• Variable S100 protein (+)
• Striking lobularity
○ May highlight lipoblasts or show focal expression in
round cell areas • Loss of nuclear Rb expression by IHC
• Negative for keratin, CD34, SMA, desmin • Lacks DDIT3 fusions
• Usually negative for MDM2 and CDK4 (rare focal nuclear Extraskeletal Myxoid Chondrosarcoma
expression) • Small spindled, stellate, or round eosinophilic tumor cells
Molecular Genetics arranged in clusters and cords
• Characteristic recurrent t(12;16)(q13;p11) involving DDIT3 • Lacks lipoblasts and arborizing capillary vascular pattern
(CHOP) and FUS genes • Variable S100 protein (+) in minority of cases
○ Vast majority of cases (90-95%) • Characteristic NR4A3 gene arrangements
• Infrequent variant t(12;22)(q13;q12) involving DDIT3 and Dermatofibrosarcoma Protuberans (Myxoid Variant)
EWSR1
• Infiltrative dermal/subcutaneous neoplasm
• Also, activating PIK3CA mutations or homozygous loss of
• Diffuse infiltration of preexisting structures and adjacent
PTEN in some tumors
soft tissue (honeycomb pattern)
• TP53 mutations in 1/3 of cases, independent of histologic
• Lacks lipoblasts
grade
• Vascular network and absence of nuclear pleomorphism
may somewhat resemble that of MLPS
DIFFERENTIAL DIAGNOSIS
• Diffuse CD34(+) expression
Atypical Lipomatous Tumor/Well-Differentiated • Characteristic COL1A1-PDGFB gene fusion
Liposarcoma
Synovial Sarcoma (Poorly Differentiated)
• May contain focal to extensive zones of myxoid stromal
• May resemble hypercellular round cell areas of MLPS
change
• Often shows areas of cellular fascicular growth
• Contains scattered enlarged, hyperchromatic stromal cells
(including floret-like cells) • Lacks lipoblasts and arborizing capillary vasculature of MLPS
• Variably thickened fibrous bands • Variable keratin (+) &/or EMA(+), often focal
• Absence of delicate, arborizing vasculature in most cases • Diffuse nuclear TLE1 expression by immunohistochemistry
• Most show MDM2(+) and CDK4(+) by • Characteristic t(X;18) involving SS18 (SYT)
immunohistochemistry Ewing Sarcoma
• MDM2 amplification • Lacks lipoblasts and arborizing capillary vascular pattern of
• Lacks DDIT3 fusions MLPS
Myxofibrosarcoma • Usually strong, membranous CD99(+)
• Generally affects older age group than MLPS • Most contain EWSR1 translocation
• Nuclear pleomorphism and atypia are characteristic ○ No rearrangement of DDIT3 (CHOP)
• Lacks true lipoblasts
○ May contain pseudolipoblasts (vacuolated fibroblastic
SELECTED REFERENCES
tumor cells containing mucin) 1. Chowdhry V et al: Myxoid liposarcoma: treatment outcomes from
chemotherapy and radiation therapy. Sarcoma. 2018:8029157, 2018
• Elongated curvilinear vessels of myxofibrosarcoma are
2. Muratori F et al: Myxoid liposarcoma: prognostic factors and metastatic
different from delicate arborizing vasculature of MLPS pattern in a series of 148 patients treated at a single institution. Int J Surg
• Lacks DDIT3 fusions Oncol. 2018:8928706, 2018
3. Bekers EM et al: Myxoid liposarcoma of the foot: a study of 8 cases. Ann
Lipoblastoma Diagn Pathol. 25:37-41, 2016
4. Iwasaki H et al: Extensive lipoma-like changes of myxoid liposarcoma:
• Most common in infancy and early childhood morphologic, immunohistochemical, and molecular cytogenetic analyses.
• PLAG1 rearrangements Virchows Arch. 466(4):453-64, 2015
• Lacks molecular signature of MLPS 5. Hoffman A et al: Localized and metastatic myxoid/round cell liposarcoma:
clinical and molecular observations. Cancer. 119(10):1868-77, 2013
Intramuscular Myxoma 6. Gronchi A et al: Phase II clinical trial of neoadjuvant trabectedin in patients
with advanced localized myxoid liposarcoma. Ann Oncol. 23(3):771-6, 2012
• Often smaller, well-circumscribed tumors 7. Moreau LC et al: Myxoid\round cell liposarcoma (MRCLS) revisited: an
• Lacks lipoblasts and arborizing capillary vascular pattern of analysis of 418 primarily managed cases. Ann Surg Oncol. 19(4):1081-8, 2012
MLPS 8. de Vreeze R et al: Multifocal myxoid liposarcoma--metastasis or second
primary tumor?: a molecular biological analysis. J Mol Diagn. 12(2):238-43,
• Lacks DDIT3 fusions 2010
9. ten Heuvel SE et al: Clinicopathologic prognostic factors in myxoid
Low-Grade Fibromyxoid Sarcoma liposarcoma: a retrospective study of 49 patients with long-term follow-up.
• Bland fibrous zones punctuated by more cellular and Ann Surg Oncol. 14(1):222-9, 2007
vascularized myxoid nodules 10. Orvieto E et al: Myxoid and round cell liposarcoma: a spectrum of myxoid
adipocytic neoplasia. Semin Diagn Pathol. 18(4):267-73, 2001
• Lacks delicate arborizing capillary channels of MLPS

102
 Myxoid Liposarcoma
Arborizing Capillary Vasculature
Lipoblasts
Rare Multinucleated Cells
Tumors of Adipose Tissue
Arborizing Capillary Vasculature
(Left) The stromal vascular
network of MLPS is highly
characteristic and composed
of delicate, arborizing or
ramifying, thin-walled
capillary channels. This
pattern may be referred to as
chicken-wire or crow's feet.
(Right) Rarely, in some areas
the arborizing vasculature of
MLPS may appear more
prominent secondary to
increased perivascular cell
density and may raise the
possibility of
myxofibrosarcoma or low-
grade fibromyxoid sarcoma.
Sparse Lipoblasts
(Left) Lipoblasts are a common
finding in MLPS and are often
univacuolated ﬊ (resembling
signet-ring cells) or
bivacuolated. Multivacuolated
forms are also seen. Lipoblasts
vary widely in number and
distribution and show a
tendency to cluster around
stromal blood vessels. (Right)
This image of MLPS was taken
from a case that showed a
nicely developed "chicken-
wire" vasculature but a
relatively low number of
lipoblasts. In a limited biopsy,
absence of lipoblasts should
never exclude the possibility of
MLPS.
Hibernoma-Like Cells
(Left) Very rare cases of MLPS
may show scattered cells with
nuclear pleomorphism or
multinucleation ﬉. This
finding does not appear to
affect prognosis. (Right) Some
cases of MLPS contain highly
vacuolated lipogenic cells ﬊
with eosinophilic, granular
cytoplasm. These cells
resemble those of hibernoma.
More characteristic lipoblasts
﬈ and stromal mucin pools
st are also seen.
103
 Myxoid Liposarcoma
Tumors of Adipose Tissue

Stromal Mucin Pools Stromal Mucin Pools

(Left) The formation of
stromal mucin pools ﬈ is a
relatively common finding in
MLPS and has been described
as a pulmonary edema-like or
lymphangioma-like pattern.
The size of the pools vary from
small to quite large. (Right)
Rare cases of MLPS show
confluence of mucin pools and
formation of large cystic
structures, which may be so
large as to be apparent at the
time of gross examination.

Mature Adipose Tissue Stromal Hyalinization

(Left) Small, scattered foci of
mature adipose tissue are not
uncommon in MLPS; however,
a dominant component of
mature fat, as depicted, is
much less frequent and may
lead to underdiagnosis as a
myxolipoma or spindle cell
lipoma. (Right) Stromal
hyalinization is often present
in cases of MLPS treated
preoperatively with radiation;
however, it can be seen in
untreated tumors as well,
albeit less frequently. Note
the intact capillary
vasculature ﬊ and scattered
lipoblasts ﬈.

S100 Protein Expression Transitional Areas

(Left) S100 protein expression
is generally limited to
lipoblasts and adipocytes in
MLPS and is not seen in
lesional spindled/ovoid cells.
However, focal expression
may be seen in hypercellular
round cell areas. (Right) Low-
grade MLPS is generally
hypocellular; however, a
modest increase in cellularity
is not uncommon. Note that,
unlike prognostically
significant hypercellular or
round cell areas, the nuclei in
these transitional areas do not
show marked crowding or
overlapping.

104
 Myxoid Liposarcoma

Tumors of Adipose Tissue

Hypercellularity Hypercellularity
(Left) Quantification of
hypercellularity in MLPS is
critical for histologic grading
and prognostication.
Hypercellular areas show
dense crowding of cells and
nuclei with limited or no
myxoid stroma. Note that the
arborizing capillary
vasculature ﬈ is still present
and identifiable but much less
conspicuous. (Right) Lipoblasts
﬊ may be seen in
hypercellular areas of MLPS
but are much less frequent
compared to lower grade
areas. Note that significant
nuclear pleomorphism is not a
feature of high-grade MLPS.

Cytology of Hypercellular Areas Mucin Pools in Hypercellular Areas

(Left) Although still lacking
significant pleomorphism, the
nuclei in high-grade areas of
MLPS are often rounder and
show greater atypia and more
conspicuous nucleoli than
those in lower grade areas.
Mitoses ﬈ are also more
frequent in these areas.
(Right) Similar to conventional
low-grade areas of MLPS,
high-grade areas may also
show formation of stromal
mucin pools ﬇. Along with
scattered lipoblasts, this
finding can be a helpful clue to
the diagnosis in diffusely
hypercellular or round cell
tumors.

Round Cell Morphology Round Cell Variations

(Left) Hypercellular areas in
high-grade MLPS may show a
prominent round cell
morphology, as shown, and
out of context can be easily
confused with a variety of
other round cell sarcomas and
nonmesenchymal neoplasms.
Ancillary studies are often
helpful in making the
diagnosis. (Right) Rare cases
of high-grade MLPS may
contain areas of round cells
embedded in a sclerotic or
hyalinized stroma, often
forming short cords.

105
 Pleomorphic Liposarcoma

KEY FACTS
Tumors of Adipose Tissue

TERMINOLOGY
• High-grade, pleomorphic sarcoma demonstrating evidence
of lipoblastic differentiation in absence of component of
well-differentiated liposarcoma or another line of
differentiation
CLINICAL ISSUES
• Least common variant of liposarcoma (5% of cases)
• Most common in patients > 50 years
• Deep soft tissues of extremities (75% of cases)
• Also trunk, retroperitoneum, other sites
• Treatment: Complete surgical resection with negative
margins
• Aggressive sarcoma with poor prognosis
○ Metastases in 30-50% of cases
MACROSCOPIC
• Usually large (median size: 8-10 cm)
MICROSCOPIC
• Lipoblasts (often pleomorphic) are characteristic and
requisite finding
○ Vary widely in number and distribution
• Multiple morphologic patterns in varying proportions
○ Cellular pleomorphic sarcoma (most common),
myxofibrosarcoma-like, epithelioid
• Mitoses and necrosis common in all patterns
ANCILLARY TESTS
• MDM2 and CDK4 (-)
• Molecular: Complex, nonspecific karyotypes
TOP DIFFERENTIAL DIAGNOSES
• Undifferentiated pleomorphic sarcoma
• Dedifferentiated liposarcoma
• Myxofibrosarcoma
• Poorly differentiated carcinoma

Pleomorphic Liposarcoma Pleomorphic Liposarcoma

(Left) A gross photograph of a
pleomorphic liposarcoma
(PLPS) shows an
intramuscular, partly necrotic
neoplasm with tan and gray-
white, firm cut surfaces. Most
examples are large with a
median size of 8-10 cm. (Right)
This typical example of PLPS
shows a variable number of
lipoblasts and pleomorphic
lipoblasts ﬊ scattered within
a background of cellular,
pleomorphic sarcoma. The
number of pleomorphic
lipoblasts vary considerably in
number and distribution from
case to case.

Pleomorphic Lipoblasts Atypical Mitotic Figures

(Left) Pleomorphic lipoblasts
are similar to conventional
multivacuolated lipoblasts,
except that the nuclei are
much larger, hyperchromatic,
and pleomorphic than what is
typically seen in lower grade
liposarcomas. Note that some
pleomorphic lipoblasts can
show bizarre nuclear atypia.
(Right) Mitotic figures are
often numerous in PLPS, and
atypical forms ﬊ are quite
common.

106
 Pleomorphic Liposarcoma

Tumors of Adipose Tissue

TERMINOLOGY MICROSCOPIC
Abbreviations Histologic Features
• Pleomorphic liposarcoma (PLPS) • Infiltrative periphery
• Lipoblasts (often pleomorphic) are characteristic and
Definitions
requisite finding
• High-grade, pleomorphic sarcoma demonstrating evidence ○ Enlarged, hyperchromatic nuclei scalloped by
of lipoblastic differentiation in absence of component of cytoplasmic vacuoles
well-differentiated liposarcoma or another line of
– Nuclear atypia may be extreme in some lipoblasts
differentiation
○ Vary widely in number from sparse and scattered to
abundant and sheet-like
CLINICAL ISSUES
• Multiple morphologic patterns in varying proportions
Epidemiology ○ Cellular pleomorphic sarcoma (most common)
• Incidence – Pleomorphic spindled, round, and polygonal cells
○ Rare □ Sheets, short fascicles, storiform arrays
– Least common variant of liposarcoma (5% of cases) – Severe nuclear atypia, multinucleation common
• Age – Numerous mitoses, including atypical forms
○ Most common in patients > 50 years – Intra- and extracellular eosinophilic droplets
• Sex (represent lysosomal structures) may be noted
○ Slight male predominance ○ Myxofibrosarcoma-like morphology
– Myxoid stroma containing prominent stromal
Site vasculature
• Deep soft tissues of extremities (75% of cases), most – Pleomorphic tumor cell nuclei, including
commonly thigh multinucleated floret-like cells
○ Less commonly arise in subcutaneous tissue – Scattered pleomorphic lipoblasts
○ Purely dermal lesions rare – Rare cystic and microcystic stromal changes
• Trunk and retroperitoneum less commonly involved ○ Epithelioid morphology
• Rare sites include mediastinum, paratesticular region, scalp, – Solid, cohesive sheets of epithelioid cells with clear to
abdominal/pelvic cavities eosinophilic cytoplasm
Presentation □ Can resemble clear cell renal cell carcinoma or
adrenocortical carcinoma
• Enlarging, firm, painless mass
– Pleomorphic lipoblasts scattered singly or in
• Often short preoperative history
aggregates
Treatment ○ Coagulative necrosis common in all patterns
• Complete surgical resection with negative margins
• Postoperative radiotherapy may be given for large, ANCILLARY TESTS
incompletely excised neoplasms Immunohistochemistry
Prognosis • Lipoblasts often S100 protein (+)
• Aggressive malignant neoplasm • Loss of nuclear Rb protein (by IHC) reported in one series
○ Local recurrence common • Epithelioid variant may show focal keratin (+) or EMA(+)
○ Metastases in 30-50% of cases • MDM2 and CDK4 (-)
– Most commonly to lungs Molecular Genetics
○ Overall 5-year survival: ~ 50-60%
• Complex, nonspecific chromosomal abnormalities
• Adverse prognostic factors
• Loss of RB1 in few reported cases
○ Age (> 60 years), nonextremity location, size (> 10 cm),
mitotic rate (> 10 per 10 HPF), and deeply situated DIFFERENTIAL DIAGNOSIS
tumors
Dedifferentiated Liposarcoma
MACROSCOPIC • Much more common in retroperitoneum than PLPS
General Features • Cellular, nonlipogenic sarcoma with range of morphologic
appearances
• Well defined and multinodular or irregular and infiltrative
○ Pleomorphic lipoblasts rare (only seen in "homologous"
• Tan-white-yellow cut surface with myxoid &/or necrotic foci
dedifferentiation)
Size • Most cases contain component of well-differentiated
• Usually large (median size: 8-10 cm) liposarcoma
○ Presence of this component essentially precludes
Sections to Be Submitted diagnosis of PLPS
• Thorough gross sampling is critical for accurate • MDM2 and CDK4 (+) by IHC
classification of PLPS • MDM2 amplification by FISH
○ Lipoblastic differentiation may be very focal
107
 Pleomorphic Liposarcoma
Tumors of Adipose Tissue

Undifferentiated Pleomorphic Sarcoma
• Usually cellular, high-grade, pleomorphic morphology
○ Can show significant morphologic overlap with PLPS
• No evidence of lipoblastic differentiation
○ Thorough gross sampling critical for correct classification
Myxofibrosarcoma
• More common in subcutaneous than deep tissue
• Multinodular growth
• No true lipoblastic component
○ But may contain fibroblastic "pseudolipoblasts"
• Can show significant morphologic overlap with PLPS
○ However, myxofibrosarcoma lacks lipoblastic
differentiation
Atypical Lipomatous Tumor/Well-Differentiated
Liposarcoma
• Sheets and lobules of low-grade, atypical adipocytes
separated by thickened fibrous septa containing atypical,
hyperchromatic stromal cells
• Lacks component of cellular, nonlipogenic pleomorphic
sarcoma
• Lacks pleomorphic lipoblasts
• Mitotic activity generally low
• MDM2 and CDK4 (+) by IHC
• MDM2 amplification by FISH
Silicone Granuloma
• Morphologic appearance may mimic sheets of lipoblasts
• History of silicone injection or implants present
• No atypical mitoses or coagulative necrosis
Myxoid Liposarcoma
• Young to middle-aged adults
• Fine, chicken-wire arborizing capillary vasculature
• Generally lacks degree of nuclear pleomorphism seen in
PLPS
• Lacks pleomorphic lipoblasts
• t(12;16) or t(12;22)
Poorly Differentiated Carcinoma
• Renal cell and adrenocortical carcinomas are most common
types on differential of epithelioid PLPS
• No evidence of lipoblastic differentiation
• More than focal expression of keratin, EMA, and other
epithelial markers
Metastatic Malignant Melanoma
• No evidence of lipoblastic differentiation
• S100 protein (+) in tumor cells
• Expression of melanocytic markers
SELECTED REFERENCES
1. Creytens D 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. 41(11):1443-55, 2017
2. Ramírez-Bellver JL et al: Primary dermal pleomorphic liposarcoma: utility of
adipophilin and MDM2/CDK4 immunostainings. J Cutan Pathol. 44(3):283-8,
2017
3. Mariño-Enríquez A et al: Dedifferentiated liposarcoma and pleomorphic
liposarcoma: a comparative study of cytomorphology and MDM2/CDK4
expression on fine-needle aspiration. Cancer Cytopathol. 122(2):128-37,
2014
4. Al-Zaid T et al: Dermal pleomorphic liposarcoma resembling pleomorphic
fibroma: report of a case and review of the literature. J Cutan Pathol.
40(8):734-9, 2013
5. Wang L et al: Pleomorphic liposarcoma: a clinicopathological,
immunohistochemical and molecular cytogenetic study of 32 additional
cases. Pathol Int. 63(11):523-31, 2013
6. Gardner JM et al: Cutaneous and subcutaneous pleomorphic liposarcoma: a
clinicopathologic study of 29 cases with evaluation of MDM2 gene
amplification in 26. Am J Surg Pathol. 36(7):1047-51, 2012
7. Ghadimi MP et al: Pleomorphic liposarcoma: clinical observations and
molecular variables. Cancer. 117(23):5359-69, 2011
8. Mariño-Enríquez A 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. 34(8):1122-31, 2010
9. Fiore M et al: Myxoid/round cell and pleomorphic liposarcomas: prognostic
factors and survival in a series of patients treated at a single institution.
Cancer. 109(12):2522-31, 2007
10. Singer S et al: Gene expression profiling of liposarcoma identifies distinct
biological types/subtypes and potential therapeutic targets in well-
differentiated and dedifferentiated liposarcoma. Cancer Res. 67(14):6626-
36, 2007
11. Idbaih A et al: Myxoid malignant fibrous histiocytoma and pleomorphic
liposarcoma share very similar genomic imbalances. Lab Invest. 85(2):176-81,
2005
12. Hornick JL et al: Pleomorphic liposarcoma: clinicopathologic analysis of 57
cases. Am J Surg Pathol. 28(10):1257-67, 2004
13. Panoussopoulos D et al: Focal divergent chondrosarcomatous
differentiation in a primary pleomorphic liposarcoma and expression of
transforming growth factor beta. Int J Surg Pathol. 12(1):79-85, 2004
14. Val-Bernal JF et al: Primary purely intradermal pleomorphic liposarcoma. J
Cutan Pathol. 30(8):516-20, 2003
15. Gebhard S 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.
26(5):601-16, 2002
16. Huang HY et al: Epithelioid variant of pleomorphic liposarcoma: a
comparative immunohistochemical and ultrastructural analysis of six cases
with emphasis on overlapping features with epithelial malignancies.
Ultrastruct Pathol. 26(5):299-308, 2002
17. Cai YC et al: Primary liposarcoma of the orbit: a clinicopathologic study of
seven cases. Ann Diagn Pathol. 5(5):255-66, 2001
18. Downes KA et al: Pleomorphic liposarcoma: a clinicopathologic analysis of 19
cases. Mod Pathol. 14(3):179-84, 2001
19. Meis-Kindblom JM et al: Cytogenetic and molecular genetic analyses of
liposarcoma and its soft tissue simulators: recognition of new variants and
differential diagnosis. Virchows Arch. 439(2):141-51, 2001
20. Oliveira AM et al: Pleomorphic liposarcoma. Semin Diagn Pathol. 18(4):274-
85, 2001
21. Dei Tos AP: Liposarcoma: new entities and evolving concepts. Ann Diagn
Pathol. 4(4):252-66, 2000
22. Miettinen M et al: Epithelioid variant of pleomorphic liposarcoma: a study of
12 cases of a distinctive variant of high-grade liposarcoma. Mod Pathol.
12(7):722-8, 1999
23. Dei Tos AP et al: Primary liposarcoma of the skin: a rare neoplasm with
unusual high grade features. Am J Dermatopathol. 20(4):332-8, 1998
24. Mertens F 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. 22(1):16-25, 1998
25. Schneider-Stock R et al: No correlation of c-myc overexpression and p53
mutations in liposarcomas. Virchows Arch. 433(4):315-21, 1998
26. Zagars GK et al: Liposarcoma: outcome and prognostic factors following
conservation surgery and radiation therapy. Int J Radiat Oncol Biol Phys.
36(2):311-9, 1996
27. Klimstra DS et al: Liposarcoma of the anterior mediastinum and thymus. A
clinicopathologic study of 28 cases. Am J Surg Pathol. 19(7):782-91, 1995
28. Azumi N et al: Atypical and malignant neoplasms showing lipomatous
differentiation. A study of 111 cases. Am J Surg Pathol. 11(3):161-83, 1987
29. Weiss LM et al: Ultrastructural distinctions between adult pleomorphic
rhabdomyosarcomas, pleomorphic liposarcomas, and pleomorphic
malignant fibrous histiocytomas. Hum Pathol. 15(11):1025-33, 1984

108
 Pleomorphic Liposarcoma
Cellular Pleomorphic Sarcoma Morphology
Eosinophilic Globules
Spindled Morphology
Tumors of Adipose Tissue
Marked Nuclear Pleomorphism
(Left) The most common
morphologic pattern in PLPS is
that of a high-grade, cellular
pleomorphic sarcoma.
Scattered areas of definite
lipoblastic differentiation ﬊
are required to distinguish
PLPS from other pleomorphic
sarcomas. (Right) Nuclear
pleomorphism is often
characteristically severe in
PLPS with numerous bizarre
and highly multinucleated
forms. Nuclear
pseudoinclusions ﬈ are also
common.
Abundant Globules
(Left) Intracellular or
extracellular eosinophilic
globules ﬊ are a feature of
some cases of PLPS but may
be focal. This finding is not
pathognomonic of PLPS,
however, and can be seen in
other tumors. (Right) This
example of PLPS shows diffuse
cytoplasmic eosinophilic
globules, creating a striking
morphologic appearance.
Spindled Morphology
(Left) As is the case with other
pleomorphic sarcomas, PLPS
may show areas that are more
spindled and fascicular and
less pleomorphic; however,
this morphology is usually not
prominent. A more
conventional pleomorphic
morphology was seen in most
other fields in the depicted
case. Note the focus of
lipoblastic differentiation
(upper left). (Right) There are
numerous small, lipid-laden
vacuoles in this H&E of PLPS,
many of which indent or
scallop the adjacent nuclei ﬉.
109
 Pleomorphic Liposarcoma
Tumors of Adipose Tissue

Coagulative Necrosis Sheets of Lipoblasts

(Left) Coagulative tumor
necrosis is a common finding
in PLPS and may appear as
small pockets or geographic
zones. Note the prominent
nuclear pleomorphism in this
H&E. (Right) In some cases of
PLPS, the tumor is
predominantly composed of or
contains large sheets made up
of almost entirely lipoblasts
and pleomorphic lipoblasts.
Note the atypical mitotic
figure ﬊.

Sheets of Lipoblasts Sheets of Pleomorphic Lipoblasts

(Left) This case of PLPS shows
extensive lipoblastic
differentiation and marked
variation in the size of the
lipoblasts. Note the focally
severe nuclear atypia ﬊.
(Right) This case of PLPS
contains extensive lipoblastic
differentiation and shows
numerous highly pleomorphic
lipoblasts ﬈ with marked
nuclear atypia.

Myxofibrosarcoma-Like Pattern Myxofibrosarcoma-Like Pattern

(Left) Another common
pattern in PLPS is that of
prominent myxoid stroma
containing conspicuous, thin-
walled curvilinear blood
vessels and scattered
pleomorphic cells, reminiscent
of intermediate- to high-grade
myxofibrosarcoma. (Right) In
some cases, the
myxofibrosarcoma-like
pattern of PLPS may be
histologically indistinguishable
from true myxofibrosarcoma.
Identification of true
lipoblastic differentiation ﬊
clarifies the issue.

110
 Pleomorphic Liposarcoma
Myxofibrosarcoma-Like Pattern
Epithelioid Morphology
Epithelioid Morphology
Tumors of Adipose Tissue
Cystic and Microcystic Changes
(Left) Areas resembling low-
grade myxofibrosarcoma are
uncommon in PLPS and are
usually associated with
morphologically higher grade
areas. Note the atypical
mitotic figure ﬊. (Right)
Stromal cystic changes ﬉,
similar to what is often in
myxoid liposarcoma, are
occasionally seen in PLPS.
Note the nuclear atypia ﬈
identifiable even at low
power.
Epithelioid Morphology
(Left) An epithelioid
morphology may be seen in
occasional cases of PLPS but is
the least common variant
pattern overall. These tumors
show diffuse, variably cohesive
sheets and lobules of rounded
cells, simulating an epithelial
neoplasm. (Right) The tumor
cells in epithelioid PLPS can
show granular, eosinophilic to
clear or foamy-appearing
cytoplasm, morphologically
suggesting a carcinoma, e.g.,
clear cell renal cell carcinoma
or adrenocortical carcinoma.
This confusion is most likely in
retroperitoneal tumors, given
the regional anatomy.
Unusual Epithelioid Cells
(Left) The epithelioid
cytomorphology and apparent
lobular or nested growth of
this variant of PLPS can lead
to confusion with a poorly
differentiated carcinoma, such
as renal cell carcinoma.
Lipoblastic differentiation ﬈
and IHC help make the
distinction. (Right) This
unusual case of epithelioid
PLPS shows atypical
epithelioid tumor cells with
abundant pale eosinophilic,
granular, and xanthomatous
cytoplasm. Note the
pleomorphic lipoblast ﬊.
111
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 SECTION 4

Fibroblastic/Myofibroblastic Lesions

Benign
Nodular Fasciitis 114
Proliferative Fasciitis/Myositis 120
Ischemic Fasciitis 124
Myositis Ossificans 126
Fibroosseous Pseudotumor of Digit 130
Fibroma of Tendon Sheath 134
Desmoplastic Fibroblastoma 140
Elastofibroma 142
Angiofibroma of Soft Tissue 144
Mammary-Type Myofibroblastoma 148
Intranodal Palisaded Myofibroblastoma 152
Pleomorphic Fibroma 156
Dermatomyofibroma 158
Storiform Collagenoma 160
Keloid 162
Nuchal-Type Fibroma 164

Intermediate (Locally Aggressive)

Palmar/Plantar Fibromatosis 166
Desmoid-Type Fibromatosis 168

Intermediate (Rarely Metastasizing)

Dermatofibrosarcoma Protuberans 174
Solitary Fibrous Tumor 184
Low-Grade Myofibroblastic Sarcoma 192
Inflammatory Myofibroblastic Tumor 196
Myxoinflammatory Fibroblastic Sarcoma 202
Superficial CD34(+) Fibroblastic Tumor 210

Malignant
Adult-Type Fibrosarcoma 214
Myxofibrosarcoma 216
Low-Grade Fibromyxoid Sarcoma 222
Sclerosing Epithelioid Fibrosarcoma 232
 Nodular Fasciitis

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY ○ No nuclear hyperchromasia or pleomorphism

• Self-limited, benign fibroblastic/myofibroblastic neoplasm
characterized in most cases by USP6-MYH9 gene fusion
○ Variants: Intravascular fasciitis, cranial fasciitis
CLINICAL ISSUES
• Wide range (most common: 20-40 years)
• Most common in extremities (particularly forearm), trunk,
and head and neck
• Usually in subcutaneous tissue
• Small tumor with rapid growth characteristic
• Treatment: Conservative surgical excision
• Excellent prognosis; local recurrence very rare
MACROSCOPIC
• Usually small (average: 2-3 cm)
MICROSCOPIC
• Plump, spindled fibroblasts and myofibroblasts
○ Variable mitotic rate; may be numerous
• Variable short fascicular and loose storiform growth
patterns
○ Overall cellularity varies widely
○ Loose, myxoid matrix is common; may be collagenous
• Extravasated erythrocytes, stromal lymphocytes, and
osteoclast-like giant cells common
ANCILLARY TESTS
• Molecular: USP6 gene rearrangement in most cases
○ USP6-MYH9 fusion most common
TOP DIFFERENTIAL DIAGNOSES
• Desmoid fibromatosis
• Inflammatory myofibroblastic tumor
• Proliferative fasciitis/myositis
• Leiomyosarcoma
• Pseudosarcomatous myofibroblastic proliferation

Nodular Fasciitis Nodular Fasciitis

(Left) Nodular fasciitis is a
benign self-limited
myofibroblastic neoplasm that
most commonly affects young
to middle-aged adults.
Although usually small (< 2-3
cm), most cases show rapid
growth, raising clinical
concerns for malignancy.
(Right) Most cases of nodular
fasciitis arise in the superficial
soft tissues and are well to
moderately circumscribed;
however, limited peripheral
soft tissue infiltration may be
present ſt. Occasional cases
are entirely intramuscular.

Myxoid Stroma Cytologic Features

(Left) A loose, myxoid stroma
is common in nodular fasciitis,
particularly in lesions that are
excised early. Tumor cells are
characteristically arranged
loosely in a haphazard fashion,
reminiscent of tissue culture
growth. (Right) Tumor cells in
nodular fasciitis are
cytologically myofibroblastic
with vesicular nuclei and 1 or
2 tiny nucleoli. Nuclear
hyperchromasia and
pleomorphism are not present.

114
 Nodular Fasciitis

Fibroblastic/Myofibroblastic Lesions
○ May rarely appear infiltrative
TERMINOLOGY
• Variable fibrous to myxoid cut surface
Synonyms
Size
• Pseudosarcomatous fasciitis
• Usually small (average: 2-3 cm)
Definitions ○ Very rarely > 5 cm
• Self-limited, benign fibroblastic/myofibroblastic neoplasm
characterized in most cases by recurrent USP6-MYH9 gene MICROSCOPIC
fusion
Histologic Features
○ May arise from small or medium-sized vessels
(intravascular fasciitis) • Usually well-demarcated peripheral border, but focal
infiltration common
○ May arise in scalp in infants and involve underlying skull
(cranial fasciitis) ○ Often shows limited peripheral extension along fibrous
septa between fat in subcutis or between skeletal
muscle fibers in deeper lesions
ETIOLOGY/PATHOGENESIS
• Plump, spindled fibroblasts and myofibroblasts
Trauma ○ Eosinophilic cytoplasm and vesicular nuclei with 1 or 2
• History of local trauma may be reported in minority (~ 15%) distinct nucleoli
of cases of nodular fasciitis ○ Resemble cells in granulation tissue or tissue culture
• Birth trauma has been associated with development of ○ No nuclear hyperchromasia or pleomorphism
cranial fasciitis ○ Variable mitotic rate
– Mitoses may be numerous
CLINICAL ISSUES – No atypical forms
Epidemiology • Variable short fascicular and loose storiform growth
patterns
• Incidence
○ Overall cellularity varies widely both within and between
○ Relatively common
cases
• Age
– May be alarmingly hypercellular
○ Wide range (most common: 20-40 years)
• Loose, myxoid matrix is common and often abundant
○ Cranial fasciitis usually arises in infants
○ More cellular areas may show loose, dyscohesive foci
• Sex
○ Older lesions are often less myxoid and more
○ Cranial fasciitis shows male predilection
collagenous and hypocellular
○ M = F in other forms
– May contain thickened, keloidal collagen fibers
Site • Extravasated erythrocytes and lymphocytes are frequent
• Most arise in subcutaneous tissue finding
○ Minority arise entirely within skeletal muscle ○ Also histiocytes, scattered or in small aggregates
○ Rarely in skin (intradermal fasciitis) • Osteoclast-like giant cells are not uncommon
• Most common in extremities (particularly forearm), trunk, • Frank intratumoral hemorrhage or cystic change is rare
and head and neck • Rare metaplastic bone formation (ossifying fasciitis or
• Rare in distal/acral extremities, joints, other sites fasciitis ossificans)
• Cranial fasciitis arises in periosteum of skull and involves ○ No zonal maturation in these lesions
adjacent soft tissue of scalp; may extend inward and • Necrosis rare (usually focal and centralized)
involves meninges • Cranial fasciitis shows similar morphology to conventional
nodular fasciitis
Presentation
○ May be more myxoid and show metaplastic bone
• Usually small, tender or nontender nodule or mass formation
• Rapid growth (several weeks to a few months)
characteristic Morphologic Variants
• Intravascular fasciitis
Treatment
○ Arises from small to medium-sized vessels, often veins
• Conservative surgical excision – Can be partly or entirely intravascular
Prognosis □ May show multinodular or plexiform growth in
latter
• Excellent
○ Often more solid than conventional nodular fasciitis
○ Local recurrence very rare
○ Osteoclast-like giant cells are often abundant
○ Can show spontaneous regression
• Does not metastasize or show malignant transformation
ANCILLARY TESTS
MACROSCOPIC Immunohistochemistry
General Features • SMA(+), often diffuse
• Rare desmin (+), usually focal
• Well marginated but unencapsulated
• Negative for keratin, S100 protein, CD34, nuclear β-catenin
115
 Nodular Fasciitis
Fibroblastic/Myofibroblastic Lesions
• CD68(+) in intralesional histiocytes
Molecular Genetics
• Recurrent USP6 gene rearrangement (17p13) in majority of
tumors
○ USP6-MYH9 fusion most common (60-80% of cases)
○ Many other fusion partners identified, including RRBP1,
COL6A2, CTNNB1
○ USP6 rearrangement also reported in aneurysmal bone
cyst, myositis ossificans, fibroosseous pseudotumor of
digit, and cellular fibroma of tendon sheath
DIFFERENTIAL DIAGNOSIS
Desmoid Fibromatosis
• Larger, infiltrative lesions
• Long, sweeping fascicles of fibroblasts/myofibroblasts
• Evenly distributed stromal collagen
• Some myxoid areas may resemble nodular fasciitis
• Nuclear β-catenin expression in 70% of cases
Inflammatory Myofibroblastic Tumor
• Chronic inflammatory component (particularly plasma cells)
• Usually larger size than nodular fasciitis
• ALK(+) in 50% of cases
• Lacks USP6 rearrangements
Proliferative Fasciitis/Myositis
• Histologically similar to nodular fasciitis
• Contains large, ganglion cell-like myofibroblasts
• Lacks USP6 rearrangement
Leiomyosarcoma
• Often larger tumors
• Intersected fascicles of eosinophilic cells with elongated,
blunted nuclei
• Nuclear pleomorphism and hyperchromasia common
• SMA(+), desmin (+), caldesmon (+)
Pseudosarcomatous Myofibroblastic Proliferation
• Histologically similar to nodular fasciitis
• Usually arises in mucosal sites, particularly bladder
• May be associated with prior trauma or surgery
• Keratin (+) common; also, SMA(+)
• Lack USP6 rearrangements
Dermatofibroma (Fibrous Histiocytoma)
• Most are small dermal lesions
• Generally lacks plump myofibroblastic cells
• Mixed chronic inflammatory component (lymphocytes,
plasma cells, foamy histiocytes) common
• Usually SMA(-)
Neurofibroma
• Small, hyperchromatic, wavy or buckled nuclei
• May have history of neurofibromatosis type 1
• S100 protein (+)
• SMA(-)
Fibroma of Tendon Sheath
• Occurs predominantly in acral locations (particularly finger)
• Cellular tumors can show overlap with nodular fasciitis
• Peripheral slit-like vessels common
116
Undifferentiated Pleomorphic Sarcoma
• Usually large, deep tumors
• Most common in older adults and elderly
• Overtly malignant cytologic atypia
• Atypical mitotic figures and coagulative necrosis
Angiomatoid Fibrous Histiocytoma
• Multinodular, often with peripheral lymphocytic cuff
• Centralized hemorrhagic foci common
• Variable desmin (+)
• EWSR1 gene translocation
Desmoplastic Fibroblastoma (Collagenous Fibroma)
• Usually very well circumscribed and markedly hypocellular
○ Spindled to stellate cells
Myositis Ossificans
• Presence of zonal maturation
○ Centralized fasciitis-like areas transitioning to mature
bone at periphery
• Also features USP6 rearrangement
Soft Tissue Aneurysmal Bone Cyst
• Features large, dilated, blood-filled spaces
• Peripheral rim of metaplastic bone
• Also features USP6 rearrangement
Low-Grade Myofibroblastic Sarcoma
• Usually highly infiltrative
• Enlarged, hyperchromatic nuclei present, at least focally
• SMA(+), often patchy; variable desmin (+)
Kaposi Sarcoma
• Typically found in immunocompromised patients (especially
AIDS patients)
• CD31(+), CD34(+), HHV8(+)
Myofibroma
• Most common in infants and children
• Myoid nodules with variably prominent
hemangiopericytoma-like vascular component
SELECTED REFERENCES
1. Erber R et al: 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. 473(3):351-60, 2018
2. Patel NR et al: USP6 activation in nodular fasciitis by promoter-swapping
gene fusions. Mod Pathol. 30(11):1577-88, 2017
3. Kumar E et al: Cutaneous nodular fasciitis with genetic analysis: a case series.
J Cutan Pathol. 43(12):1143-9, 2016
4. Shin C et al: USP6 gene rearrangement in nodular fasciitis and histological
mimics. Histopathology. 69(5):784-91, 2016
5. Oliveira AM et al: USP6-induced neoplasms: the biologic spectrum of
aneurysmal bone cyst and nodular fasciitis. Hum Pathol. 45(1):1-11, 2014
6. Chi AC et al: Intravascular fasciitis: report of an intraoral case and review of
the literature. Head Neck Pathol. 6(1):140-5, 2012
7. Erickson-Johnson MR et al: Nodular fasciitis: a novel model of transient
neoplasia induced by MYH9-USP6 gene fusion. Lab Invest. 91(10):1427-33,
2011
8. de Feraudy S et al: Intradermal nodular fasciitis: a rare lesion analyzed in a
series of 24 cases. Am J Surg Pathol. 34(9):1377-81, 2010
9. Weinreb I et al: Nodular fasciitis of the head and neck region: a
clinicopathologic description in a series of 30 cases. J Cutan Pathol.
36(11):1168-73, 2009
10. Hornick JL et al: Intraarticular nodular fasciitis--a rare lesion: clinicopathologic
analysis of a series. Am J Surg Pathol. 30(2):237-41, 2006
 Nodular Fasciitis
Cytologic Features
Extravasated Blood Cells
Stromal Collagen
Fibroblastic/Myofibroblastic Lesions
Stromal Dyscohesion
(Left) Mitotic figures ﬊ are
very common in nodular
fasciitis and naturally align
with the frequent rapid
growth seen clinically. In some
cases, mitoses are so
numerous that a sarcoma is
considered (or misdiagnosed).
However, importantly,
abnormal mitoses are not
seen. (Right) Stromal "tears"
or dyscohesive foci are a
common finding in nodular
fasciitis, as depicted. These
areas may be focal or
abundant.
Osteoclast-Like Giant Cells
(Left) Extravasated
erythrocytes ﬊ and chronic
inflammatory cells
(particularly lymphocytes ﬈)
are relatively common in
nodular fasciitis. Scattered
plasma cells may also be seen
in some tumors; however, they
are generally inconspicuous.
(Right) Multinucleated
osteoclast-like giant cells ﬈
are a frequent finding in
nodular fasciitis. They may be
identified singly or in small
clusters. Overlapping nuclei in
these cells may be mistaken
for nuclear pleomorphism.
Storiform Growth
(Left) As nodular fasciitis
progresses, the amount of
myxoid stroma often
decreases and stromal
collagen increases. The
lesional cells, in turn, start to
appear less haphazard and
somewhat more organized.
(Right) A storiform growth
pattern may be seen in some
cases of nodular fasciitis, as
depicted.
117
 Nodular Fasciitis
Fibroblastic/Myofibroblastic Lesions

Stromal Hyalinization Keloidal Collagen

(Left) Older lesions of nodular
fasciitis often show a greater
degree of stromal collagen
and subsequent hyalinization.
Cellularity is variable in these
cases, and myxoid zones may
or may not be present. (Right)
Focal keloidal collagen is not
uncommon in nodular fasciitis,
as depicted in this image. In
rare cases, it may be a
prominent finding.

Increased Cellularity Cellular Areas

(Left) Foci or zones of
increased cellularity and
organization ﬈ are not
uncommon in nodular fasciitis
and can easily lead to
consideration (or
misdiagnosis) of sarcoma.
Mitotic figures are usually
frequent as well, further
increasing the risk of
overdiagnosis. (Right) Nodular
fasciitis may show areas of
striking cellularity. Short
linear or curved fascicles or
bundles are common findings
in these areas. Mitoses are
common, but never abnormal.

Cellular Areas Origin in Muscle

(Left) Areas of increased
stromal collagen and
architectural organization in
nodular fasciitis, as shown in
this image, may lead to
consideration of fibromatosis
or a low-grade myofibroblastic
sarcoma. (Right) A minority of
cases of nodular fasciitis arise
entirely within muscle ﬊, as
depicted. Care must be taken
not to misidentify entrapped
atrophic skeletal muscle fibers
﬈ as pleomorphic
hyperchromatic tumor cells.

118
 Nodular Fasciitis

Fibroblastic/Myofibroblastic Lesions
Peripheral Extension Intravascular Fasciitis
(Left) Some cases of nodular
fasciitis, particularly those
that arise within skeletal
muscle, can show a nodular
morphology ﬈ at the
periphery of the tumor, which
may lead to consideration of a
malignant, invasive process.
(Right) Nodular fasciitis may
grow partially or entirely
within a vessel and is
recognized by the term
intravascular fasciitis. Note
the protrusion into an
endothelial-lined space ﬈. Of
note, osteoclast-like giant
cells ﬊ are often more
prominent in this variant.

Intravascular Growth Fibrous or Myxoid Stroma

(Left) Intravascular growth ﬈
may be identified within
vessels located around the
periphery of the tumor in some
cases, as seen here. The main
lesion had otherwise typical
features of nodular fasciitis.
(Right) Intravascular fasciitis
closely resembles
conventional nodular fasciitis
morphologically and can
feature a fibrous or myxoid
stroma. Cellularity can also
vary.

Intravascular Fasciitis, Trichrome Stain SMA Expression

(Left) A trichrome stain shows
an entirely intravascular
example of intravascular
fasciitis. Despite the occlusive
growth, this does not usually
result in any functional
impairment, and the lesion
presents as a mass clinically.
Veins or arteries can be
involved, and the lesional
tissue sometimes extends
through the vessel wall.
(Right) Strong staining with
smooth muscle actin (SMA) is
common in nodular fasciitis,
and expression is often
peripheral and
submembranous as seen in
other myofibroblastic lesions.

119
 Proliferative Fasciitis/Myositis

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY MICROSCOPIC
• Pseudosarcomatous myofibroblastic proliferation featuring • Shows many morphologic features of nodular fasciitis
ganglion-like cells and occurring in subcutaneous tissue • Additional component of large ganglion-like fibroblasts
(proliferative fasciitis) or intramuscularly (proliferative (hallmark)
myositis) ○ 1 or more nuclei, often eccentric with prominent
CLINICAL ISSUES macronucleoli
• Proliferative fasciitis in children is often more cellular and
• Middle-aged and older adults
mitotically active
○ Can arise in children (uncommon)
• Checkerboard growth pattern in proliferative myositis
• Fasciitis: Subcutaneous tissue of upper extremity
(particularly forearm), lower extremity, trunk ANCILLARY TESTS
• Myositis: Muscles of trunk, shoulder, upper arm • SMA(+)
• Rapidly growing, often tender mass • Desmin, keratin, S100 protein, myogenin (-)
• Treatment: Simple excision
TOP DIFFERENTIAL DIAGNOSES
• Benign; local recurrence very rare
• Nodular fasciitis
MACROSCOPIC • Embryonal rhabdomyosarcoma
• Poorly circumscribed, elongated mass, usually < 4 cm • Pleomorphic rhabdomyosarcoma
• Undifferentiated pleomorphic sarcoma

Proliferative Fasciitis Proliferative Fasciitis

(Left) Proliferative fasciitis
usually presents clinically as a
small but rapidly growing
subcutaneous mass. At low
magnification, it often tracks
along fibrous connective tissue
septa. (Right) Histologically,
proliferative fasciitis (and
myositis) shares many
similarities with nodular
fasciitis, including spindled to
stellate myofibroblastic cells
within a loose myxoid to
collagenous stroma.
Extravasated erythrocytes are
common.

Ganglion-Like Cells Ganglion-Like Cells

(Left) The hallmark of
proliferative fasciitis/myositis
is the presence of enlarged
epithelioid or polygonal cells
﬉ with basophilic or
amphophilic cytoplasm and
large, eccentric vesicular
nuclei with prominent
macronucleoli. These cells
resemble ganglion cells but
are actually fibroblasts.
(Right) Within any given case
of proliferative fasciitis, the
ganglion-like cells may be
distributed singly, in loose
clusters, or in aggregates. The
actual density varies from
microscopic field to field.

120
 Proliferative Fasciitis/Myositis

Fibroblastic/Myofibroblastic Lesions
○ Epithelioid cells with abundant amphophilic or basophilic
TERMINOLOGY cytoplasm
Definitions ○ Contain 1 or 2 vesicular nuclei, often eccentric with
• Pseudosarcomatous myofibroblastic proliferation featuring prominent macronucleoli
ganglion-like cells and occurring in subcutaneous tissue ○ Can form large aggregates or loose clusters
(proliferative fasciitis) or intramuscularly (proliferative • Proliferative fasciitis in children is often much more cellular
myositis) and mitotically active
○ May have acute inflammation and foci of necrosis
CLINICAL ISSUES • Checkerboard pattern of intramuscular growth in
Epidemiology proliferative myositis
• Older lesions may show stromal hyalinization
• Incidence
• Focal metaplastic bone formation rare
○ Rare
– Less common than nodular fasciitis ANCILLARY TESTS
• Age
○ Middle-aged and older adults Immunohistochemistry
– Can arise in children (uncommon) • SMA(+)
• Desmin, keratin, S100 protein, myogenin, MYOD1 (-)
Site
• Proliferative fasciitis DIFFERENTIAL DIAGNOSIS
○ Subcutaneous tissue of upper extremity (particularly
forearm), lower extremity, trunk Nodular Fasciitis
– May also arise in dermis or involve underlying fascia • More common in younger adults
• Proliferative myositis • Histologically similar to proliferative fasciitis/myositis
○ Muscles of trunk, shoulder, upper arm • Lacks ganglion-like cells
• Well circumscribed
Presentation • USP6 gene rearrangements
• Rapidly growing, often tender mass
• History of trauma reported in minority of cases Embryonal Rhabdomyosarcoma
• Usually involves genital region or head/neck of infants and
Treatment young children
• Simple excision • Mucosal tumors often show enhanced cellularity beneath
Prognosis epithelium (cambium layer)
• Usually malignant cytologic features
• Benign
• Desmin (+), myogenin (+)
• Usually no local recurrence, even with incomplete excision
Pleomorphic Rhabdomyosarcoma
MACROSCOPIC • Usually large, intramuscular, and in older adults
General Features • Markedly pleomorphic cells with numerous atypical mitoses
and necrosis
• Poorly circumscribed, elongated mass
• Desmin (+), myogenin (+)
○ Childhood tumors are often well circumscribed and
lobular Undifferentiated Pleomorphic Sarcoma
Size • Usually large, intramuscular, and in older adults
• Usually < 4 cm • Markedly pleomorphic cells with numerous atypical mitoses
and necrosis
MICROSCOPIC
SELECTED REFERENCES
Histologic Features
1. Wei N et al: Proliferative myositis in the right brachioradialis: a case report.
• Similar morphologic features to nodular fasciitis Exp Ther Med. 13(5):2483-2485, 2017
○ Plump, spindled, and stellate myofibroblasts in variably 2. Rosa G et al: A report of three cases of pediatric proliferative fasciitis. J Cutan
Pathol. 41(9):720-3, 2014
myxoid or collagenous stroma 3. Yamaga K et al: Proliferative fasciitis mimicking a sarcoma in a child: a case
– Myxoid tumors often have loose tissue culture report. J Dermatol. 41(2):163-7, 2014
appearance 4. Satter EK et al: Intradermal proliferative fasciitis on the finger. Am J
Dermatopathol. 37(3):246-8, 2013
– Vesicular nuclei with 1 or 2 small but conspicuous
5. Brooks JK et al: Intraoral proliferative myositis: case report and literature
nucleoli review. Head Neck. 29(4):416-20, 2007
– Mitotic activity often brisk; no atypical forms 6. Sasano H et al: Proliferative fasciitis of the forearm: case report with
○ Extravasated erythrocytes and stromal lymphocytic immunohistochemical, ultrastructural and DNA ploidy studies and a review
of the literature. Pathol Int. 48(6):486-90, 1998
infiltrate common 7. Meis JM et al: Proliferative fasciitis and myositis of childhood. Am J Surg
○ Older lesions may have abundant hyalinized collagen Pathol. 16(4):364-72, 1992
• Large ganglion-like fibroblasts (hallmark)

121
 Proliferative Fasciitis/Myositis
Fibroblastic/Myofibroblastic Lesions

Binucleation Pediatric Proliferative Fasciitis

(Left) Although most of the
ganglion-like cells in
proliferative fasciitis have
single nuclei, some may be
binucleated ﬈. This H&E
shows several of these variant
cells. Note also the loose
myxoid stroma with
extravasated erythrocytes.
(Right) Pediatric proliferative
fasciitis is often much more
cellular and less myxoid than
adult forms. This variant may
naturally raise concerns for
malignancy. A correct
diagnosis can usually be
derived from the clinical
presentation and
immunohistochemistry.

Pediatric Proliferative Fasciitis Pediatric Proliferative Fasciitis

(Left) Pediatric proliferative
fasciitis is more likely to show
increased mitotic activity than
the typical adult form. Two
mitotic figures ﬊ are shown
in this H&E. Importantly,
mitoses are almost never
atypical. If more than a rare
atypical figure is identified,
malignancy should be
carefully excluded. (Right)
Pediatric examples of
proliferative fasciitis may also
show pockets of acute
inflammation ﬈ as well as
foci of necrosis ﬊.

Stromal Hyalinization Proliferative Myositis

(Left) Occasionally, older
lesions may show stromal
hyalinization. Together with
the large, ganglion-like cells,
this feature may mimic osteoid
deposition and lead to
misdiagnosis as osteosarcoma.
(Right) Proliferative myositis is
essentially the intramuscular
counterpart to proliferative
fasciitis. Characteristically, the
proliferation splays out muscle
fibers, imparting a highly
infiltrative appearance.
Ganglion-like cells ﬈ can be
seen even at low
magnification.

122
 Proliferative Fasciitis/Myositis
Proliferative Myositis
Spindled Morphology
Cellular Foci
Fibroblastic/Myofibroblastic Lesions
Checkerboard Pattern
(Left) Just as in proliferative
fasciitis, proliferative myositis
characteristically contains
scattered ganglion-like cells
with prominent nucleoli. The
background stroma is loose
and myxoid, similar to nodular
fasciitis. (Right) When seen in
cross section, the splayed
muscle fibers appear to
alternate with the lesional
proliferation, imparting a
checkerboard morphologic
pattern.
Rare Metaplastic Bone
(Left) In some areas of
proliferative myositis, the
lesional fibroblasts may adopt
a subtle fascicular
morphology, reminiscent of
fibromatosis. Note, however,
the presence of a ganglion-like
cell ﬈. (Right) Foci of
metaplastic bone formation
﬊ may be seen in rare cases
of proliferative myositis (or
proliferative fasciitis). Note
also the checkerboard pattern
of muscle fibers.
Fasciitis/Myositis Mimics
(Left) Similar to proliferative
fasciitis, the ganglion-like cells
in proliferative myositis may
show areas of increased
cellular density. (Right)
Reactive myofibroblastic
proliferations, such as those
seen in the setting of
intraabdominal adhesions or
incarcerated hernias, may
closely mimic proliferative
fasciitis histologically.
However, there is often a
prominent component of
adipose tissue in reactive
adhesions, and the clinical
presentation is often very
different from that of
proliferative fasciitis.
123
 Ischemic Fasciitis

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY ○ Vascularized granulation tissue typically surrounds

• Pseudosarcomatous proliferation composed of zones of fat
and fibrinoid necrosis with ingrowth of capillaries, reactive
fibroblasts, and myofibroblasts
• Synonym: Atypical decubital fibroplasia
CLINICAL ISSUES
• Peak incidence: 70-90 years of age
• Most common in soft tissues overlying bony prominences
○ Hip, shoulder, chest wall, back, sacrum
• Many patients are immobilized or debilitated
• Treatment: Simple surgical excision
• Benign
○ Local recurrences rare
MICROSCOPIC
• Characteristic zonal appearance
○ Central fibrinoid necrosis/degeneration
necrotic foci
– Thin-walled capillary channels lined by plump, reactive
endothelial cells
– Reactive fibroblasts often enlarged with amphophilic
cytoplasm and variably prominent nucleoli
□ May resemble ganglion cells (ganglion cell-like
myofibroblast)
○ Peripheral soft tissue shows variable myxoid change,
fibrosis, fat necrosis
• Mitotic activity usually low but may be brisk
• Variable inflammatory infiltrate
TOP DIFFERENTIAL DIAGNOSES
• Proliferative fasciitis/myositis
• Nodular fasciitis
• Well-differentiated liposarcoma
• Myxofibrosarcoma (low grade)

Ischemic Fasciitis Vascularized Rim

(Left) Ischemic fasciitis (also
referred to as atypical
decubital fibroplasia)
classically shows a zonal
appearance with centralized
fibrinoid necrosis ﬈, mantled
by arcades of reactive
capillaries ﬊ admixed with
reactive myofibroblasts and
surrounding tissues. Adipose
tissue ﬉ often contains fat
necrosis and may be partially
infarcted. (Right) The
vascularized granulation
tissue-like rim ﬈ shows small,
reactive capillaries admixed
with reactive myofibroblasts.

Reactive Myofibroblasts Reactive Myofibroblasts

(Left) The reactive
myofibroblasts ﬈ of ischemic
fasciitis are often enlarged
and contain basophilic to
amphophilic cytoplasm.
Nucleoli may be inconspicuous
or prominent, the latter
sometimes resembling
ganglion cells. Mitoses vary in
number, and rare atypical
forms may be seen. (Right) In
some cases of ischemic
fasciitis, the myofibroblasts
appear bipolar or stellate with
hyperchromatic and "smudgy"
degenerative nuclei ﬈,
reminiscent of atypical
lipomatous tumor/well-
differentiated liposarcoma.

124
 Ischemic Fasciitis

Fibroblastic/Myofibroblastic Lesions
□ May resemble ganglion cells (ganglion cell-like
TERMINOLOGY myofibroblast)
Synonyms □ Nuclei may appear degenerative (hyperchromatic
• Atypical decubital fibroplasia and "smudgy")
○ Peripheral soft tissue around lesion shows variable
Definitions myxoid change, fibrosis, fat necrosis
• Pseudosarcomatous proliferation composed of zones of fat • Mitotic activity usually low but may be brisk
and fibrinoid necrosis with ingrowth of capillaries, reactive ○ Atypical mitoses rare
fibroblasts, and myofibroblasts • Variable inflammatory infiltrate
○ Usually lymphocytes and plasma cells, occasionally
CLINICAL ISSUES neutrophils
Epidemiology • Other findings: Extravasated erythrocytes, hemosiderin,
• Age vascular hyalinization/thrombosis
○ Peak incidence: 70-90 years
– Occasionally in younger adult patients ANCILLARY TESTS
• Sex Immunohistochemistry
○ Slight male predominance • Variable SMA(+), desmin (+), CD34(+)
Site • Keratin (-), S100 protein (-)
• Most common in soft tissues overlying bony prominences
DIFFERENTIAL DIAGNOSIS
○ Hip, shoulder, chest wall, back, and sacrum
• Usually deep subcutaneous tissue Nodular Fasciitis/Proliferative Fasciitis/Proliferative
○ May extend to involve dermis or underlying Myositis
fascia/muscle • Often occurs away from bony prominences
Presentation • Exuberant myofibroblastic proliferation with delicate
vessels, extravasated erythrocytes, scattered lymphocytes
• Painful or painless mass
○ More evenly cellular than ischemic fasciitis
○ Overlying skin usually not ulcerated
• Absence of zonal pattern with central fibrinoid necrosis
• Many patients are immobilized or debilitated
• Proliferative fasciitis/myositis: Randomly scattered or
○ Some patients have history of local trauma (including clustered myofibroblasts with eccentric nuclei and
previous surgical procedure) or chronic disease (e.g., prominent nucleoli (ganglion cell-like myofibroblasts)
osteoarthritis, COPD)
Well-Differentiated Liposarcoma
Treatment
• Often large, deep tumors of extremities or in
• Simple surgical excision retroperitoneum
Prognosis • Lobules of atypical fat separated by variably thickened
• Benign fibrous septa containing hyperchromatic "smudgy" cells
• Local recurrence is rare • Multivacuolated lipoblasts may be present
• Absence of zonal pattern with central fibrinoid necrosis
MACROSCOPIC • Minimal mitotic activity
• MDM2 gene amplification
General Features
• Ill-defined, tan-yellow mass with cut surface showing Myxofibrosarcoma (Low Grade)
variable necrosis and hemorrhage • Absence of zonal pattern (central fibrinoid necrosis with
surrounding reactive changes)
Size
• Nuclear pleomorphism often present, at least focally
• 1-10 cm
Epithelioid Sarcoma
MICROSCOPIC • Large nests of eosinophilic epithelioid cells, often with
central necrosis
Histologic Features
○ Malignant cytologic features
• Vaguely lobular configuration and generally hypocellular • Keratin (+), EMA(+), loss of INI1
• Characteristic zonal appearance
○ Central fibrinoid necrosis/degeneration SELECTED REFERENCES
– May show pseudocyst formation &/or infarcted fat
1. Yamada Y et al: HIF-1α, MDM2, CDK4, and p16 expression in ischemic
○ Vascularized granulation tissue typically surrounds fasciitis, focusing on its ischemic condition. Virchows Arch. 471(1):117-122,
necrotic foci 2017
– Thin-walled capillary channels lined by plump, reactive 2. Lehmer LM et al: Ischemic fasciitis: enhanced diagnostic resolution through
clinical, histopathologic and radiologic correlation in 17 cases. J Cutan
endothelial cells Pathol. 43(9):740-8, 2016
– Reactive fibroblasts often enlarged with amphophilic 3. Liegl B et al: Ischemic fasciitis: analysis of 44 cases indicating an inconsistent
cytoplasm and variably prominent nucleoli association with immobility or debilitation. Am J Surg Pathol. 32(10):1546-
52, 2008

125
 Myositis Ossificans

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY MACROSCOPIC
• Localized, self-limited, reactive fibroblastic lesion arising • Size range: 2-12 cm (mean: 5 cm)
intramuscularly and featuring bone in varying stages of
MICROSCOPIC
maturation
○ Biologically similar lesions occur in other specific sites • Well circumscribed
(e.g., fibroosseous pseudotumor of digit, panniculitis • Characteristic zonal appearance with peripheral maturation
ossificans) ○ Centralized proliferations of spindled fibroblasts and
myofibroblasts
ETIOLOGY/PATHOGENESIS – No nuclear atypia or atypical mitoses
• Many cases are associated with history of localized trauma ○ Areas with woven bone formation and peripheral
or injury maturation
CLINICAL ISSUES TOP DIFFERENTIAL DIAGNOSES
• Wide age range (most common around 30 years) • Extraskeletal osteosarcoma
• 3:2 male predominance • Nodular fasciitis
• Skeletal muscle of thigh, buttock, elbow, shoulder most • Aneurysmal bone cyst of soft tissue
common sites • Ossifying fibromyxoid tumor
• Treatment: Simple surgical excision
• Benign; rare local recurrence

Myositis Ossificans Zonal Maturation

(Left) Myositis ossificans (MO)
is a reactive, self-limiting
fibroblastic proliferation that
features bone in various
stages of maturation. It may
be confused both clinically and
histologically with a sarcoma.
(Right) The presence of zonal
maturation is a key feature of
MO. Lesions tend to show
gradual progression from
loose or cellular fibroblastic
zones ﬈ to areas containing
immature woven bone
formation ﬊ to more
peripheral areas of remodeling
and mature lamellar bone
formation.

Nodular Fasciitis-Like Areas Cellular Foci

(Left) The fibroblastic areas of
MO are often centralized
within the lesion and
commonly resemble nodular
fasciitis, as shown. The
cellularity of these areas
varies widely from loose and
sparse to strikingly dense.
(Right) Some fibroblastic areas
in MO may be alarmingly
cellular, usually in early
lesions, and mitotic figures
may be numerous.
Importantly, nuclei are
cytologically bland, and
mitoses are not abnormal.
Osteoclasts ﬈ are also a
common finding.

126
 Myositis Ossificans

Fibroblastic/Myofibroblastic Lesions
○ Centralized proliferations of spindled fibroblasts and
TERMINOLOGY myofibroblasts
Abbreviations – Often closely resembles nodular fasciitis
• Myositis ossificans (MO) – Variably cellular and myxoid
– Cells randomly oriented or in loose fascicles
Synonyms
– Bland, vesicular nuclei ± small nucleoli
• MO circumscripta/traumatica – Mitoses may be numerous but never atypical
Definitions – Vascularized stroma with extravasated erythrocytes,
• Localized, self-limited, reactive fibroblastic lesion arising fibrin, and lymphocytes
intramuscularly and featuring bone in varying stages of – Osteoclast-like giant cells are common
maturation ○ Peripheral portion with bone formation
○ Biologically similar lesions occur in other specific sites – Merges with cellular myofibroblastic portion
– Fibroosseous pseudotumor of digits (fingers and toes) – Irregular trabeculae of immature woven bone rimmed
– Panniculitis ossificans (subcutaneous adipose tissue) by osteoblasts
– Also in fascia and mesentery – Maturation into well-developed trabeculae of lamellar
bone at periphery of older lesions
ETIOLOGY/PATHOGENESIS □ Older lesions may be composed entirely of mature
bone ± hematopoietic elements
Injury – Cartilage uncommon but may be seen
• Many cases are associated with history of localized trauma • Zonal appearance poorly developed in some lesions
or injury
○ Patients with MO are often physically active ANCILLARY TESTS
In Situ Hybridization
CLINICAL ISSUES
• USP6 gene rearrangements
Epidemiology ○ Similar to nodular fasciitis and aneurysmal bone cyst
• Age
○ Wide age range (most common around 30 years) DIFFERENTIAL DIAGNOSIS
• Sex
Extraskeletal Osteosarcoma
○ Male predominance
• Often large masses in older adults
Site • Marked cytologic atypia, atypical mitoses
• Arise intramuscularly in areas prone to local trauma • Lacks zonal maturation of MO
○ Thigh, buttock, elbow, shoulder most common ○ Random deposits of osteoid and bone associated with
cytologically malignant cells
Presentation
• Rapidly growing, variably tender mass Nodular Fasciitis
• Most common in subcutaneous tissue
Treatment
• Usually lacks prominent bone formation
• Simple surgical excision • Early lesions of MO may be indistinguishable from nodular
Prognosis fasciitis
• Benign Aneurysmal Bone Cyst of Soft Tissue
○ Rare local recurrence • Large, centralized, cystic, hemorrhagic spaces
• Exceptionally rare reports of malignant transformation • Peripheral rim of bone common

IMAGING Ossifying Fibromyxoid Tumor

CT Findings • Uniform, generally rounded cells, often in lace-like pattern
• Incomplete, peripheral rim of mature bone in majority of
• Early lesions: Soft tissue fullness cases
• 2-6 weeks later: Flocculent calcifications and eventual • Usually S100 protein (+); some desmin (+)
development of bony shell (eggshell-like)
• PHF1 gene rearrangements
MACROSCOPIC SELECTED REFERENCES
Size 1. Bekers EM et al: Myositis ossificans - another condition with USP6
• 2-12 cm (mean: 5 cm) rearrangement, providing evidence of a relationship with nodular fasciitis
and aneurysmal bone cyst. Ann Diagn Pathol. 34:56-9, 2018
2. Sferopoulos NK et al: Myositis ossificans in children: a review. Eur J Orthop
MICROSCOPIC Surg Traumatol. 27(4):491-502, 2017
3. Sukov WR et al: Frequency of USP6 rearrangements in myositis ossificans,
Histologic Features brown tumor, and cherubism: molecular cytogenetic evidence that a subset
• Well circumscribed of "myositis ossificans-like lesions" are the early phases in the formation of
soft-tissue aneurysmal bone cyst. Skeletal Radiol. 37(4):321-7, 2008
• Characteristic zonal appearance with peripheral maturation

127
 Myositis Ossificans
Fibroblastic/Myofibroblastic Lesions

Myositis Ossificans: CT Scan Gross Appearance

(Left) CT through the left leg
shows a partial rim of bone ﬈
in this example of well-
developed MO. (Right) This
gross photo of MO shows a
circumscribed but not
encapsulated early lesion.
There are foci of hemorrhage
﬊ mainly in the center of the
lesion with adjacent, firm,
white-yellow tissue. Bone may
be grossly obvious in older
cases.

Zonal Maturation and Osteoblastic

Cytologic Features Rimming
(Left) The cytologic features of
MO are similar to those of
nodular fasciitis. The lesional
fibroblastic/myofibroblastic
cells are uniform and have
bland nuclear features.
Mitoses can be present (and
numerous) but are not
atypical. (Right) Evidence of
zonal maturation is a key
feature of MO. Woven bone
formation with a conspicuous
peripheral lining of
osteoblasts ﬈ is a typical
finding.

Osteoclastic Giant Cells Extravasated Red Blood Cells

(Left) Osteoclastic giant cells
are commonly seen in MO,
particularly in the centralized
portion of early proliferative
forms. In conjunction with the
myofibroblastic cells and
fibromyxoid stroma, the
appearance is similar to
nodular fasciitis. (Right)
Extravasated red blood cells
﬉ are common in the cellular,
proliferative portion of MO
and provide further
morphologic similarity to
nodular fasciitis.

128
 Myositis Ossificans
Cellular Proliferative Zones
Primitive Trabecular Morphology
Loose, Storiform Growth
Fibroblastic/Myofibroblastic Lesions
Osteoid Deposition and Immature Bone
(Left) MO is characterized by a
zoned proliferation of
myofibroblasts with a
peripheral rim of woven bone
﬊. This example has a highly
cellular central portion ﬈,
which may be worrisome for
sarcoma at low magnification.
(Right) Foci of osteoid
deposition with prominent
osteoblasts in MO can be
easily mistaken for a
malignant process. The overall
features of the lesion must be
taken into account, including
presence of zonal maturation
and absence of malignant
atypia.
Vascularity
(Left) Osteoid deposition and
immature bone formation can
form a ramifying, trabecular
pattern in MO. Osteoblastic
rimming is also common.
(Right) The proliferative
myofibroblastic zones of MO
are often well vascularized,
and myxoedematous change
around the stromal vessels ﬉
is not uncommon.
Mature Bone
(Left) Some cases of MO show
a proliferative zone featuring
bland myofibroblastic spindle
cells in a storiform
arrangement, as depicted
here. Osteoclastic giant cells
are not seen in this image.
(Right) In the later stages of
MO, mature bone ﬉ is more
prominent and well
developed. A residual
centralized and somewhat
more cellular proliferative
area ﬊ is still identifiable in
this image.
129
 Fibroosseous Pseudotumor of Digit

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY • Periosteal reaction common

• Reactive-appearing, ossifying fibroblastic proliferation of MACROSCOPIC
soft tissue typically affecting digits of hands and feet
• 0.5-5.6 cm; median: ~ 2.0 cm
• Florid reactive periostitis
MICROSCOPIC
ETIOLOGY/PATHOGENESIS
• Fasciitis-like spindle cell proliferation with active ossification
• Clonal transient neoplasm with USP6 rearrangement
• Myofibroblastic spindle and stellate cells with vesicular
CLINICAL ISSUES nuclei and amphophilic cytoplasm
• Fusiform swelling, often with erythema, pain, or ulceration • Ossification in various stages of maturation
• Rapid onset; weeks to months • Peripheral zonal osseous maturation present in 50%
• Proximal phalanx of hand most common site • Cartilage with endochondral ossification in some
• Rarely occurs beyond acral extremities TOP DIFFERENTIAL DIAGNOSES
• Benign, often self-limited • Extraskeletal osteosarcoma
• Simple excision usually curative • Myositis ossificans
IMAGING • Fracture callus
• Early lesions characterized by ill-defined soft tissue density • Bizarre parosteal osteochondromatous proliferation
• Older lesions with intralesional calcification

Fibroosseous Pseudotumor Low-Power Architecture

(Left) Fibroosseous
pseudotumor (FP) typically
presents as fusiform swelling
of a proximal phalanx of the
hand. This radiograph depicts
ill-defined soft tissue density
﬈ and periosteal reaction ﬉.
FP is also known as florid
reactive periostitis. (Right)
This scanning power
micrograph depicts a
circumscribed FP with lobular
architecture, areas of bone
formation ﬈, and loosely
textured edematous, myxoid
nodules ﬉. Bone formation in
FP is usually distributed
randomly as shown.

Myofibroblasts and Reactive Bone Osteoid and Woven Bone

(Left) FP consists of a fasciitis-
like proliferation of spindle-
shaped myofibroblasts ﬈
with vesicular nuclei and
abundant amphophilic
cytoplasm admixed with
reactive bone ﬈. The bone is
rimmed by osteoblasts ﬉. FP
is regarded as a reactive
nonneoplastic process. (Right)
Bone formation in FP typically
shows a zonal pattern of
maturation from osteoid to
bone. In this example,
eosinophilic osteoid ﬈
undergoes progressive
mineralization and
transformation into
trabeculae of woven bone ﬈.

130
 Fibroosseous Pseudotumor of Digit

Fibroblastic/Myofibroblastic Lesions
• Cellular areas alternate with less cellular fibromyxoid areas
TERMINOLOGY in lobular pattern
Abbreviations • Ossification at various stages of maturation
• Fibroosseous pseudotumor (FP) ○ Osteoid and wispy immature woven bone
○ Anastomosing trabeculae of woven bone rimmed by
Synonyms single layer of plump activated osteoblasts
• Florid, reactive periostitis of tubular bones of hands and ○ Mature lamellar bone
feet • Geographic areas of collagenous matrix in some
• Fasciitis ossificans • Cartilage with endochondral ossification in some
• Parosteal fasciitis
Cytologic Features
Definitions
• Myofibroblastic spindle and stellate cells with vesicular
• Reactive-appearing, ossifying fibroblastic proliferation of nuclei and amphophilic cytoplasm
soft tissue typically affecting digits of hands and feet
DIFFERENTIAL DIAGNOSIS
ETIOLOGY/PATHOGENESIS
Extraskeletal Osteosarcoma
Neoplastic
• Much larger tumor; very rare in digits
• Clonal transient neoplasm • Malignant cytoarchitectural features
• USP6 rearrangement
Myositis Ossificans
CLINICAL ISSUES • Larger tumor, involves skeletal muscle, proximal
extremities, and trunk
Epidemiology
• Well-defined peripheral zonal ossification
• Incidence
○ Rare; exact incidence unknown Fracture Callus
• Age • Reactive proliferation of woven bone, granulation tissue,
○ 5-75 years; median: ~ 35 years and reactive cartilage
• Sex • Radiographic evidence of fracture in most cases
○ Slight female predominance Bizarre Parosteal Osteochondromatous Proliferation
Site • Tubular bones of hands and feet, adherent to periosteum
• Hands, feet • Ossifying tumor with cartilage cap
○ Proximal phalanx of hand most common site • Spindle cell stroma, woven bone, and immature basophilic
○ Rarely occurs beyond acral extremities "blue" bone

Presentation Tenosynovial Giant Cell Tumor

• Fusiform swelling, often with erythema, pain, or ulceration • Common in fingers
• Rapid onset; weeks to months • Polymorphous population of epithelioid cells, osteoclastic
giant cells, macrophages, and xanthoma cells
Natural History • May have hyalinized collagenous matrix that mimics osteoid
• Benign, often self-limited
Giant Cell Tumor of Soft Tissue
Treatment • Identical histology to giant cell tumor of bone
• Surgical approaches • Ovoid or spindled stromal cells and numerous osteoclastic
○ Simple excision usually curative giant cells
• Often has peripheral rim of bone
IMAGING
Ossifying Fibromyxoid Tumor
General Features • Soft tissue tumor often with peripheral rim of bone
• Early lesions characterized by ill-defined soft tissue density • Ovoid mesenchymal cells arranged in cords and clusters
• Older lesions with intralesional calcification • Usually S100 protein (+)
• Periosteal reaction common • Myxohyaline matrix

MACROSCOPIC SELECTED REFERENCES

Size 1. Flucke U et al: Fibro-osseous pseudotumor of digits - expanding the
spectrum of clonal transient neoplasms harboring USP6 rearrangement.
• 0.5-5.6 cm; median: ~ 2.0 cm Ann Diagn Pathol. 35:53-5, 2018
2. Chaudhry IH et al: Fibro-osseous pseudotumor of the digit: a
MICROSCOPIC clinicopathological study of 17 cases. J Cutan Pathol. 37(3):323-9, 2010
3. Moosavi CA et al: Fibroosseous [corrected] pseudotumor of the digit: a
Histologic Features clinicopathologic study of 43 new cases. Ann Diagn Pathol. 12(1):21-8, 2008
• Fasciitis-like spindle cell proliferation with active ossification 4. Dupree WB et al: Fibro-osseous pseudotumor of the digits. Cancer.
58(9):2103-9, 1986

131
 Fibroosseous Pseudotumor of Digit
Fibroblastic/Myofibroblastic Lesions

Interconnecting Trabeculae of Osteoid Immature Bone

(Left) This medium-power
micrograph depicts irregular
interconnecting trabeculae of
osteoid ﬈ within myxoid
stromal background ﬈.
Spindle cells condense around
the osteoid ﬉. (Right) The
bone in FP varies from
immature woven bone ﬈ to
mature lamellar bone. In this
example, the bone arises
within thick seams of pale
osteoid matrix ﬈.

Osteoblastic Rimming Geographic Area of Fibrous Matrix

(Left) FP typically contains a
large amount of reactive-
appearing bone as shown by a
trabecula of immature woven
bone ﬈ rimmed by a single-
cell layer of plump activated
osteoblasts with abundant
basophilic granular cytoplasm
and eccentric nuclei ﬉.
(Right) Large geographic
sheets of collagenous matrix
﬈ in between spindle cell
areas ﬉ may be seen in FP as
depicted in this low-power
micrograph.

Fasciitis-Like Histology Myofibroblasts

(Left) The spindle cell
component of FP typically
resembles nodular fasciitis,
consisting of fascicles of
spindle-shaped myofibroblasts
with brisk mitotic activity ﬈
and extravasated red blood
cells ﬉. (Right) This high-
power micrograph illustrates
the cytologic features of
myofibroblasts in FP,
consisting of plump spindle
cells with abundant
amphophilic cytoplasm ﬈ and
vesicular nuclei with
prominent solitary nucleoli ﬉.

132
 Fibroosseous Pseudotumor of Digit
Fibroosseous Pseudotumor of Hand
Myxoid Area
Endochondral Ossification
Fibroblastic/Myofibroblastic Lesions
Hyalinized Collagen
(Left) Although the most
common site is within a
proximal phalanx of the hand,
FP affects other sites such as
the thenar compartment,
depicted in this radiograph by
an ill-defined soft tissue
density ﬈. Only rare examples
have been reported outside
the hands and feet. (Right)
Geographic zones of densely
hyalinized, pale eosinophilic
collagen ﬈ alternate with
spindle cell areas ﬈ as
illustrated by this low-power
micrograph.
Osteoid and Myxoid Matrix
(Left) Myxoid areas are
common in FP, consisting of
pale blue matrix containing
myofibroblasts with plump,
vesicular nuclei and abundant
amphophilic cytoplasm often
forming stellate-shaped cells
﬈. (Right) Low-power
micrograph depicts trabeculae
of eosinophilic osteoid matrix
﬉ surrounded by proliferating
spindle cells and osteoblasts
﬈ juxtaposed with a less
cellular area containing
abundant myxoid matrix ﬊.
Fibrocartilage
(Left) Reactive endochondral
ossification can sometimes be
present in FP. In this example,
fibrocartilage ﬈ merges with
woven bone ﬉, which
subsequently merges with a
collagenous spindle cell area
﬊, creating a distinctive zonal
architecture. (Right) This high-
power image depicts
fibrocartilage within an FP
consisting of chondrocytes in
cleared-out lacunar spaces ﬈
embedded within avascular,
pale blue cartilaginous matrix
containing bundles of
eosinophilic collagen ﬉.
133
 Fibroma of Tendon Sheath

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY MACROSCOPIC
• Benign fibrous nodule typically attached to tendon sheath • Well circumscribed
• White-tan
ETIOLOGY/PATHOGENESIS
• Uni- or multinodular
• Generally regarded as reactive, nonneoplastic process
• Hard, rubbery, or gelatinous
• Cellular fibroma of tendon sheath (FTS) has USP6 fusions,
• Median size: ~ 2.0 cm (range: 0.5-5.0 cm)
indicating benign neoplasm related to nodular fasciitis
MICROSCOPIC
CLINICAL ISSUES
• Well demarcated
• Median age: 30 years
• Attached to tendon sheath or tendon
• Painless mass
• Benign fibroblasts and myofibroblasts
• Slowly growing
• Slit-like vascular spaces
• Hand (80%)
• Cellular nodular fasciitis-like areas
○ Finger most common site
• Intraarticular fibroma (rare) TOP DIFFERENTIAL DIAGNOSES
○ Knee most common site • Nodular fasciitis
• Very low recurrence rate following complete excision • Superficial fibromatosis
• Localized tenosynovial giant cell tumor
• Desmoplastic fibroblastoma

Fibroma of Tendon Sheath Slit-Like Blood Vessels

(Left) Fibroma of tendon
sheath (FTS) typically presents
as a well-circumscribed soft
tissue nodule, most of which
occur in the finger. This
micrograph depicts a
circumscribed FTS ﬊ attached
to a synovial-lined tendon
sheath ﬈. (Right) Long, slit-
like blood vessels ﬈, usually
located at the periphery, is a
characteristic feature of FTS.
Note the dense collagenous
stroma and wide distribution
of plump spindle cells.

Gross Photograph Multinodular

(Left) Grossly, FTS presents as
a well-circumscribed, white-
tan nodule. It is often
multinodular, as shown, and
has a fibrous cut surface with
clefts ﬈. No intratumoral
hemorrhage or hemosiderin
pigment is evident, as would
be present in tenosynovial
giant cell tumor. (Right)
Multinodular architecture is
common in FTS, as depicted by
spindle cell nodules ﬈
separated by a dense fibrous
septum ﬊.

134
 Fibroma of Tendon Sheath

Fibroblastic/Myofibroblastic Lesions
• Uncommon findings
TERMINOLOGY
○ Nerve impingement
Abbreviations ○ Carpal tunnel syndrome
• Fibroma of tendon sheath (FTS) ○ Trigger finger
○ Bone erosion
Synonyms
• Tenosynovial fibroma Treatment
• Intraarticular fibroma • Complete surgical excision
Definitions Prognosis
• Benign fibrous nodule typically attached to tendon sheath • Excellent
○ Low recurrence rate
ETIOLOGY/PATHOGENESIS – Very low rate with good surgical technique and
Histogenesis complete excision
– Reexcision usually curative
• Generally regarded as reactive, nonneoplastic process
• Cellular FTS has USP6 fusions IMAGING
○ Indicating benign neoplasm related to nodular fasciitis
MR Findings
CLINICAL ISSUES • Focal nodular mass
Epidemiology • Variable signal
• No hemosiderin
• Incidence
○ Uncommon, exact incidence unknown MACROSCOPIC
• Age
○ Median: 30 years General Features
– Range: 5 months to 70 years • Well circumscribed
• Sex • Uni- or multinodular
○ Men outnumber women • White-tan
• Hard, rubbery
Site
• Some with gelatinous or cystic areas
• Upper extremities
○ Hand (80%) Size
– Finger most common site • Median: ~ 2.0 cm
□ Especially thumb and index and middle fingers ○ Range: 0.5-5.0 cm
– Palm
– Wrist MICROSCOPIC
○ Forearm Histologic Features
○ Biceps tendon • Well demarcated
• Lower extremities • Attached to tendon sheath or portion of tendon
○ Anterior knee • Benign fibroblasts and myofibroblasts
○ Ankle ○ Vesicular nucleus with single nucleolus
○ Foot ○ Abundant, finely granular, amphophilic cytoplasm
○ Toes ○ Bipolar and stellate forms
• Rare sites ○ Low mitotic rate in most
○ Medial canthal tendon • Variable fibrous to myxoid stroma
○ Thigh ○ Some tumors with densely hyalinized, fibrous stroma
○ Shoulder ○ Some with myxoid matrix or cystic areas
○ Back • Slit-like vascular spaces
○ Trunk ○ Characteristic feature of FTS
• Rare cases with multifocal involvement ○ Most prevalent at periphery
• Intraarticular fibroma ○ Lined by flattened endothelial cells
○ Rare • Cellular areas
○ Knee most common site ○ Most prevalent at periphery
○ Less common sites ○ May resemble nodular fasciitis
– Ankle ○ Diffusely cellular tumors are termed cellular FTS
– Wrist • Storiform areas in some tumors
– Acromioclavicular joint • Rare tumors with cellular pleomorphism
Presentation ○ May be referred to as pleomorphic FST
• Slowly growing • Rare tumors with chondroid and osseous metaplasia
• Painless mass
135
 Fibroma of Tendon Sheath
Fibroblastic/Myofibroblastic Lesions

ANCILLARY TESTS Benign Fibrous Histiocytoma

• Rare in fingers
Immunohistochemistry • Typically arises in dermis but can be more deeply seated
• SMA(+); may be focal • Well-defined storiform pattern
• Desmin (-) • More cellular than FTS
Molecular Testing • Plump spindle cells (fibrohistiocytic)
• Cellular FTS shows USP6 gene rearrangements • Multinucleated giant cells common
○ Suggest relationship to nodular fasciitis • Infiltrative growth with entrapment of dermal collagen

DIFFERENTIAL DIAGNOSIS SELECTED REFERENCES

1. Carter JM et al: USP6 genetic rearrangements in cellular fibroma of tendon
Nodular Fasciitis sheath. Mod Pathol. 29(8):865-9, 2016
• Rare in fingers 2. Al-Qattan MM: Fibroma of tendon sheath of the hand: a series of 20 patients
with 23 tumours. J Hand Surg Eur Vol. 39(3):300-5, 2014
• Usually arises from fascia 3. De Maeseneer M et al: Fibroma of the tendon sheath of the long head of the
• Less circumscribed biceps tendon. Skeletal Radiol. 43(3):399-402, 2014
• More cellular and mitotically active 4. Glover M et al: Intra-articular fibroma of tendon sheath arising in the
acromioclavicular joint. Skeletal Radiol. 43(5):681-6, 2014
• Cellular FTS often indistinguishable from nodular fasciitis
5. Jacobs E et al: Fibroma of tendon sheath located within Kager's triangle. J
○ Appears be clonal neoplasm related to nodular fasciitis Foot Ankle Surg. 53(2):208-11, 2014
with alternate USP6 fusions 6. Andrew N et al: Tendon sheath fibroma of the medial canthal tendon.
Ophthal Plast Reconstr Surg. 29(1):e1-2, 2013
Superficial Fibromatosis 7. Nason GJ et al: Fibroma of the peroneus longus tendon sheath in a child: a
case report. J Orthop Surg (Hong Kong). 21(3):387-90, 2013
• Arises from palmar or plantar fascia
8. Lucas DR: Tenosynovial giant cell tumor: case report and review. Arch Pathol
• Infiltrates surrounding tissue Lab Med. 136(8):901-6, 2012
• Dupuytren contracture in palmar tumors 9. Moretti VM et al: Tendon sheath fibroma in the thigh. Orthopedics.
35(4):e607-9, 2012
• Often nuclear β-catenin (+)
10. Kosuge D et al: Flexor tendon fibroma as a cause of wrist triggering and
○ FTS is negative carpal tunnel syndrome. J Hand Surg Eur Vol. 36(3):246-7, 2011
11. Park SY et al: Multiple fibromas of tendon sheath: unusual presentation. Ann
Localized Tenosynovial Giant Cell Tumor Dermatol. 23 Suppl 1:S45-7, 2011
• Synonym: Giant cell tumor of tendon sheath 12. Moretti VM et al: Fibroma of tendon sheath in the knee: a report of three
cases and literature review. Knee. 17(4):306-9, 2010
• Common in fingers
13. Ciatti R et al: Fibroma of tendon sheath located within the ankle joint
• Arises from tendon sheath capsule. J Orthop Traumatol. 10(3):147-50, 2009
• Stromal cells with round to reniform, eccentric nuclei 14. Laskin WB, Miettinen M, Fetsch JF: Infantile digital fibroma/fibromatosis: a
clinicopathologic and immunohistochemical study of 69 tumors from 57
• Osteoclastic giant cells patients with long-term follow-up. Am J Surg Pathol. 33(1):1-13, 2009
• Xanthoma cells 15. Gleason BC et al: Deep "benign" fibrous histiocytoma: clinicopathologic
• Hemosiderin-laden macrophages analysis of 69 cases of a rare tumor indicating occasional metastatic
potential. Am J Surg Pathol. 32(3):354-62, 2008
• Variable fibrosis
16. Le Corroller T et al: Mineralized fibroma of the tendon sheath presenting as
○ Markedly fibrotic tumors resemble FTS a bursitis. Skeletal Radiol. 37(12):1141-5, 2008
17. Carlson JW et al: Immunohistochemistry for beta-catenin in the differential
Desmoplastic Fibroblastoma diagnosis of spindle cell lesions: analysis of a series and review of the
• Synonym: Collagenous fibroma literature. Histopathology. 51(4):509-14, 2007
18. Fox MG et al: MR imaging of fibroma of the tendon sheath. AJR Am J
• Rare in fingers Roentgenol. 180(5):1449-53, 2003
• Arises in subcutis or skeletal muscle 19. Varallo VM et al: Beta-catenin expression in Dupuytren's disease: potential
• Well circumscribed role for cell-matrix interactions in modulating beta-catenin levels in vivo and
in vitro. Oncogene. 22(24):3680-4, 2003
• Larger size 20. Dal Cin P et al: Translocation 2;11 in a fibroma of tendon sheath.
• Stellate-shaped and bipolar myofibroblasts Histopathology. 32(5):433-5, 1998
21. Evans HL: Desmoplastic fibroblastoma. A report of seven cases. Am J Surg
Sclerosing Perineurioma Pathol. 19(9):1077-81, 1995
• Common in hands 22. Lamovec J et al: Pleomorphic fibroma of tendon sheath. Am J Surg Pathol.
15(12):1202-5, 1991
• Well-demarcated nodule 23. Pulitzer DR et al: Fibroma of tendon sheath. A clinicopathologic study of 32
• Whorling pattern cases. Am J Surg Pathol. 13(6):472-9, 1989
• Scant, ill-defined cytoplasm 24. Jablokow VR et al: Fibroma of tendon sheath. J Surg Oncol. 19(2):90-2, 1982
25. Chung EB et al: Fibroma of tendon sheath. Cancer. 44(5):1945-54, 1979
• EMA(+), GLUT1(+)
Inclusion Body Fibromatosis
• Usually in hands and feet
• Dome-shaped dermal nodule
• 1st year of life
○ Very rare in adults
• Infiltrating fascicles in dermis
• Cytoplasmic spherical inclusions

136
 Fibroma of Tendon Sheath
Fibroma of Tendon Sheath
Tendon Attachment
Well-Circumscribed Nodule
Fibroblastic/Myofibroblastic Lesions
Fibroma of Tendon Sheath
(Left) Typical low-power
appearance of FTS, depicting a
hypocellular, collagenous
tumor, which is sharply
demarcated and attached to
tenosynovium ﬈, is shown.
This tumor is traversed by a
muscular vein with artifactual
clefting ﬊. Note attached,
uninvolved skeletal muscle at
the edge ﬉. (Right) T1 MR
demonstrates a 1.6-cm, well-
circumscribed FTS ﬈ within
the flexor retinaculum of the
hand, situated superficial to a
flexor tendon ﬉. The nodule
is isointense with skeletal
muscle.
Multinodular Architecture
(Left) In some cases, FTS has
direct attachment to the
tendon ﬈. Note the lesional
tissue at the top of the stain.
(Right) This low-power
micrograph depicts an FTS
with a small, peripheral
nodule ﬈ separated from the
main lesion by a clefted space
﬉. In some cases, these
peripheral nodules may
separate completely and
become detached.
Multilobular Architecture
(Left) FTS varies from 0.5-5.0
cm. Small tumors, such as this
one, are uninodular and well
circumscribed, as depicted.
Despite the circumscription,
marginal or incomplete
excision may lead to local
recurrence in some cases.
(Right) Scanning power depicts
a dumbbell-shaped FTS
excised from a finger. Note the
relatively smooth outer border
of the lesion and lower
cellularity at the centers of
the nodules.
137
 Fibroma of Tendon Sheath
Fibroblastic/Myofibroblastic Lesions

Hyalinized Matrix Loose Collagenous Stroma

(Left) This hypocellular FTS
has abundant, hyalinized,
collagenous matrix associated
with widely dispersed spindle
cells and thin-walled,
curvilinear blood vessels ﬈.
The spindled fibroblasts are
devoid of nuclear atypia and
mitotic activity. (Right) This
FTS contains loosely textured
fibrous stroma consisting of
fibrillary collagen bundles
within edematous matrix and
a sparse population of uniform
myofibroblasts.

Dense Collagenous Stroma Peripheral Cellularity

(Left) FTS is often composed
of dense, fibrous stroma
consisting of mature collagen.
Note the widely dispersed
mature fibroblasts ﬈. In some
lesions, particularly older
ones, stromal hyalinization
may be diffuse. (Right) FTS
frequently shows increased
cellularity at the periphery ﬈,
while the center is
hypocellular and more
collagenous ﬉. This zonation
is often a useful clue to the
diagnosis.

Cellular Fibroma of Tendon Sheath Cellular Fibroma of Tendon Sheath

(Left) FTS can be partially or
exclusively composed of
hypercellular areas containing
fascicles and storiform arrays
of plump myofibroblastic
spindle cells, as depicted. This
morphology resembles cellular
foci in nodular fasciitis. (Right)
Cellular zones in FTS may
show a fascicular architecture,
raising concerns for a
sarcoma; however, the overall
lesion is usually small and well
circumscribed, and central
hypocellularity is often
present. Also, significant
nuclear atypia is not seen.

138
 Fibroma of Tendon Sheath
Resembling Nodular Fasciitis
Cystic Degeneration
Cellular Atypia
Fibroblastic/Myofibroblastic Lesions
Cytological Features
(Left) Cellular areas of FTS can
resemble nodular fasciitis, as
depicted by loosely textured
fascicles of myofibroblastic
spindle cells, myxoid pools ﬈,
and keloidal collagen ﬊.
(Right) The proliferating cells
in both conventional and
cellular FTS consist of bland
myofibroblasts with oval,
vesicular nuclei containing
single nucleoli and finely
granular, amphophilic
cytoplasm in bipolar and
stellate configurations, as
depicted.
Myxoid Matrix
(Left) Central cystic
degeneration can be found in
some FTS, as depicted by this
stellate-shaped area of
edematous myxoid matrix ﬈.
Other degenerative changes,
such as metaplastic bone or
cartilage, may be seen on
occasion. (Right) Myxoid
matrix consists of loosely
textured areas of edematous
mucoid material ﬈.
Cellularity in these areas is
often low.
Intraarticular Fibroma
(Left) This high-power H&E
illustrates activated
myofibroblasts with cellular
and nuclear pleomorphism in a
cellular FTS. Scattered, bizarre
pleomorphic cells may rarely
be a feature. (Right) Fibroma
(of tendon sheath) can
occasionally present as a
purely intraarticular mass, as
depicted by this T1 MR of a
3.4-cm mass ﬈ in the anterior
lateral ankle. The knee,
however, is the most common
site for intraarticular fibroma.
139
 Desmoplastic Fibroblastoma

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY • Patternless distribution of bland, spindled and stellate-

• Rare, benign fibrous soft tissue neoplasm occurring mainly shaped cells
in adult males, consisting of paucicellular arrays of stellate • Hypovascular fibrous or fibromyxoid stroma
and spindle-shaped fibroblasts • Mitotic figures rare; no necrosis
• a.k.a. collagenous fibroma ANCILLARY TESTS
CLINICAL ISSUES • Variably SMA(+)
• Usually in older adults (5th-6th decades) as slow-growing, • CD34, desmin, S100 (-)
painless mass • Cytogenetics: Reciprocal translocation t(2;11)(q31;q12)
• Male preponderance reported in few cases
• Most occur in subcutaneous tissue, but up to 25% involve TOP DIFFERENTIAL DIAGNOSES
skeletal muscle
• Fibromatosis
• Most common in proximal extremity
• Neurofibroma
MICROSCOPIC • Nodular fasciitis
• Generally well circumscribed, although may infiltrate • Elastofibroma
adjacent soft tissues • Fibroma of tendon sheath
• Characteristically hypocellular • Calcifying fibrous pseudotumor

Desmoplastic Fibroblastoma at Higher

Desmoplastic Fibroblastoma Magnification
(Left) Low-magnification
examination of a desmoplastic
fibroblastoma is shown. The
lesion is a well-circumscribed,
ovoid or fusiform mass. The
characteristic hypocellularity
is apparent at low power.
(Right) Higher magnification
of desmoplastic fibroblastoma
is shown. Although the tumor
is largely circumscribed, focal
infiltration of surrounding soft
tissue, including skeletal
muscle in this case, may be
seen ﬈.

Myxoid Stroma in Desmoplastic Spindled and Stellate Fibroblasts in

Fibroblastoma Desmoplastic Fibroblastoma
(Left) H&E of desmoplastic
fibroblastoma shows the
sparsely cellular nature of the
lesion. The stroma can be
myxoid ﬊ in some cases.
Although cells may be plump,
no true atypia is seen, and
mitotic figures are rare or
absent. (Right) High
magnification shows stroma
that is densely collagenous
and contains spindle and
stellate fibroblasts in
patternless distributions.
Vessels are inconspicuous.

140
 Desmoplastic Fibroblastoma

Fibroblastic/Myofibroblastic Lesions
TERMINOLOGY Genetic Testing
• Reciprocal translocation t(2;11)(q31;q12) reported in 2
Synonyms cases
• Collagenous fibroma ○ Same translocation has also been reported in 1 case of
Definitions fibroma of tendon sheath
○ 11q12 breakpoint in 2 other cases
• Rare, benign fibrous soft tissue neoplasm occurring mainly
in adult males and consisting of paucicellular arrays of
stellate and spindle fibroblasts
DIFFERENTIAL DIAGNOSIS
Fibromatosis
CLINICAL ISSUES • More infiltrative and cellular
Epidemiology • Cells in loose fascicles
• Age • Prominent vascular pattern and extravasated red blood
cells
○ All ages but particularly older adults (5th-6th decades)
• Sex Neurofibroma
○ M>F • Cell nuclei are usually angulated, wavy-appearing, or
Site schwannian
• Strongly S100 protein (+)
• Most occur in subcutaneous tissue
○ Up to 25% involve skeletal muscle Nodular Fasciitis (Late Stage)
• Most common in upper extremity (shoulder, upper arm, • Foci of increased cellularity
forearm) followed by lower extremity • Chronic inflammation, extravasated red cells
• Rare in head and neck
Elastofibroma
Presentation • Typically located in subscapular region
• Slow growing • Fragmented elastic fibers
• Painless mass
Fibroma of Tendon Sheath
Treatment • Peritendinous locations, particularly of hands
• Simple complete excision but not necessary given benign
behavior Calcifying Fibrous Pseudotumor
• Children and young adults
Prognosis • Psammomatous calcifications
• Benign; does not recur locally or metastasize • Lymphoplasmacytic infiltrate

MACROSCOPIC Low-Grade Fibromyxoid Sarcoma

• Often larger and more cellular; may show hyalinizing
General Features
rosette formation
• Firm, circumscribed, lobulated mass • MUC4(+)
• White or gray cut surface • Characteristic translocations t(7;16) and t(11;16)
• No necrosis or hemorrhage
Size SELECTED REFERENCES
• Often small (< 4 cm); range: 1.5-20.0 cm 1. Vasconcelos AC et al: Oral bilateral collagenous fibroma: a previously
unreported case and literature review. J Clin Exp Dent. 10(1):e96-e99, 2018
2. Hu SC et al: Dermal desmoplastic fibroblastoma presenting as a large sacral
MICROSCOPIC mass. Australas J Dermatol. 57(4):296-299, 2016
3. Tofuku Y et al: Case of collagenous fibroma (desmoplastic fibroblastoma)
Histologic Features with vascular hyperplasia in the boundary area detected by Doppler
• Generally well circumscribed, although may infiltrate sonography and histopathological examination. J Dermatol. 42(8):831-2,
2015
adjacent soft tissues
4. Nagaraja V et al: Desmoplastic fibroblastoma presenting as a parotid
• Sparsely cellular tumour: a case report and review of the literature. Head Neck Pathol.
• Patternless proliferation of bland spindle or stellate cells 7(3):285-90, 2013
5. Macchia G et al: FOSL1 as a candidate target gene for 11q12
• Hypovascular fibrous or fibromyxoid stroma rearrangements in desmoplastic fibroblastoma. Lab Invest. 92(5):735-43,
• Mitotic figures very rare; no necrosis 2012
6. Watanabe H et al: Desmoplastic fibroblastoma (collagenous fibroma). J
Dermatol. 35(2):93-7, 2008
ANCILLARY TESTS 7. Bernal K et al: Translocation (2;11)(q31;q12) is recurrent in collagenous
Immunohistochemistry fibroma (desmoplastic fibroblastoma). Cancer Genet Cytogenet. 149(2):161-
3, 2004
• Variable SMA(+) 8. Miettinen M et al: Collagenous fibroma (desmoplastic fibroblastoma): a
• CD34, desmin, S100 protein (-) clinicopathologic analysis of 63 cases of a distinctive soft tissue lesion with
stellate-shaped fibroblasts. Hum Pathol. 29(7):676-82, 1998
• Rare focal keratin expression 9. Evans HL: Desmoplastic fibroblastoma. A report of seven cases. Am J Surg
Pathol. 19(9):1077-81, 1995

141
 Elastofibroma

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY • Usually 3-10 cm

• Benign fibrous tumor containing abnormal elastic fibers MICROSCOPIC
within collagenous stroma admixed with variable
• Infiltrative, ill-defined lesion
component of mature adipose tissue
• Variable mixture of dense collagenous stroma and mature
ETIOLOGY/PATHOGENESIS adipose tissue
• May be associated with repetitive physical labor • Numerous thickened and fragmented elastic fibers within
collagenous stroma
CLINICAL ISSUES ○ Appear as beaded cords and individual rounded
• Usually > 50 years fragments of variable size
• Female predominance
ANCILLARY TESTS
• Most occur at inferior margin of scapula on chest wall
• Painless, slow-growing mass • Elastin stain highlights abnormal elastic fibers
• Treatment: Simple excision TOP DIFFERENTIAL DIAGNOSES
• Benign • Desmoid fibromatosis
MACROSCOPIC • Nuchal-type fibroma/Gardner fibroma
• Ill-defined, firm mass with admixed tan-white to yellow cut • Elastofibromatous change
surface • Fibrolipoma

Elastofibroma Dystrophic Elastic Fibers

(Left) Elastofibroma is a
benign infiltrative lesion that
classically occurs near the
inferior border of the scapula
and is composed of a variable
admixture of densely
collagenous tissue and mature
fat. (Right) The characteristic
finding in elastofibroma is the
presence of enlarged
fragments of abnormal elastic
fibers arranged as irregular
beaded cords ﬈ and solitary,
rounded structures ﬊ of
varying size.

Elastic Fiber Special Stain Edematous Stromal Change

(Left) Verhoeff van Gieson
histochemical stain nicely
highlights the abnormal
elastic fibers in elastofibroma
as dark, fragmented cords and
spherules. (Right) The fibrous
tissue in most cases of
elastofibroma are densely
collagenous, but occasional
areas show loose, edematous
change in which collagen
bundles admix with dystrophic
elastic fibers. Myxoid stromal
change can be seen as well.

142
 Elastofibroma

Fibroblastic/Myofibroblastic Lesions
TERMINOLOGY MICROSCOPIC
Synonyms Key Microscopic Features
• Elastofibroma dorsi • Infiltrative, ill-defined lesion
• Variable mixture of dense collagenous stroma with bland
Definitions
fibroblasts and mature adipose tissue
• Benign fibrous tumor containing abnormal elastic fibers ○ Stroma may be myxoid or edematous
within collagenous stroma admixed with variable
• Numerous thickened and fragmented elastic fibers within
component of mature adipose tissue
collagenous stroma
○ Appear as beaded cords and individual rounded
ETIOLOGY/PATHOGENESIS fragments of variable size
Environmental Exposure ○ Elastic fibers may be sparse and subtle in areas
• Some related to trauma or friction • May infiltrate and entrap skeletal muscle
○ Some cases reported in manual workers doing repetitive
physical labor ANCILLARY TESTS
○ Similar microscopic changes are found in 15% of Histochemistry
autopsies of older patients
• Elastic special stains highlights abnormal elastic fibers
• Radiation therapy may play role in development
Molecular Genetics
CLINICAL ISSUES • Nonrandom X chromosome inactivation or gains of Xq
Epidemiology • Recurrent chromosomal rearrangements in 1p and 7q
• Incidence
○ Rare
DIFFERENTIAL DIAGNOSIS
○ Vast majority are sporadic; some familial Desmoid Fibromatosis
• Age • More cellular than elastofibroma
○ Most  > 50 years • Parallel-aligned sweeping fascicles of myofibroblasts
• Sex • Nuclear β-catenin (+) in many cases
○ Female predominance
Nuchal-Type Fibroma/Gardner Fibroma
Site • Different anatomic distribution from elastofibroma
• Classically occur at inferior margin of scapula on chest wall • Predominantly dense collagen
○ Deep to muscles of back • Absence of abnormal elastic fibers
○ Can adhere to periosteum
Elastofibromatous Change
• Also described in other soft tissue sites
• Visceral locations include oral cavity, stomach, rectum, • Seen in gastrointestinal tract, usually colon or rectum
omentum • Often centered about elastotic submucosal vessels
• May resemble amyloid; Congo red (-)
Presentation
Fibrolipoma
• Slow-growing, often painless mass
• Most are solitary; occasionally bilateral • Different anatomic distribution from elastofibroma
• Lacks abnormal elastic fibers
Treatment
Atypical Lipomatous Tumor/Well-Differentiated
• Simple excision
Liposarcoma
Prognosis • Usually large tumors in extremity or retroperitoneum (well-
• Benign differentiated liposarcoma)
• Local recurrence is rare • Atypical stromal cells and adipocyte atypia often present
• No abnormal elastic fibers
MACROSCOPIC
General Features SELECTED REFERENCES
• Ill-defined, firm mass with admixed tan-white to yellow cut 1. Deveci MA et al: Elastofibroma dorsi: Clinical evaluation of 61 cases and
review of the literature. Acta Orthop Traumatol Turc. 51(1):7-11, 2017
surface
2. Giannotti S et al: Elastofibroma dorsi: case series of a rare benign tumour of
• Skeletal muscle infiltration or involvement of periosteum the back. Eur J Orthop Surg Traumatol. 23(6):643-5, 2013
not uncommon 3. Lococo F et al: Elastofibroma dorsi: clinicopathological analysis of 71 cases.
Thorac Cardiovasc Surg. 61(3):215-22, 2013
Size 4. Nishio J et al: Elastofibroma dorsi: diagnostic and therapeutic algorithm. J
Shoulder Elbow Surg. 21(1):77-81, 2012
• Usually 3-10 cm
5. Vincent J et al: Elastofibroma: cytomorphologic, histologic, and radiologic
findings in five cases. Diagn Cytopathol. 40 Suppl 2:E99-E103, 2012

143
 Angiofibroma of Soft Tissue

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY • Very prominent and complex stromal vasculature

• Low-grade fibrovascular neoplasm characterized by ○ Vessels range from small and thin-walled to medium and
recurrent chromosomal translocation large ectatic channels
• Stromal chronic inflammatory infiltrate common
CLINICAL ISSUES
ANCILLARY TESTS
• Occurs in superficial or deep soft tissues of extremities
(lower limb most common) • SMA, CD34, desmin usually (-) or at most focally positive
• Slow-growing, painless mass ○ CD34 highlights prominent vascular network
• Treatment: Simple conservative excision • Negative for S100 protein, STAT6
• Benign; recurrence very rare • Molecular: Recurrent t(5;8) (p15;q13) translocation
with AHRR-NCOA2 gene fusion
MACROSCOPIC
TOP DIFFERENTIAL DIAGNOSES
• Well circumscribed
• 1-12 cm (mean: 4.3 cm) • Low-grade fibromyxoid sarcoma
• Myxoid liposarcoma
MICROSCOPIC • Solitary fibrous tumor
• Very well circumscribed, often with fibrous capsule • Lobular capillary hemangioma (pyogenic granuloma)
• Bland, uniform spindle cells in variably myxoid to • Myxofibrosarcoma (low grade)
collagenous stroma

Soft Tissue Angiofibroma Soft Tissue Angiofibroma

(Left) Soft tissue angiofibroma
(STA) is a benign fibrovascular
neoplasm that most
commonly occurs in the
extremities, particularly the
lower limbs. It is often well
circumscribed, and > 1/2 of
cases display a fibrous capsule
﬈ of varying thickness.
(Right) STA appears to arise as
often in deep soft tissues
(subfascial or intramuscular
﬈) as it does in subcutaneous
tissue. Note the sharp
circumscription of the tumor,
which is a feature of most, but
not all, cases.

Variable Cellularity Prominent Vascular Network

(Left) At low magnification,
STA often shows regional
variation in cellularity (similar
to solitary fibrous tumor), and
the quality of the stroma
varies from myxoid to
collagenous. Note the
prominent vascularity, a
consistent feature of this
tumor. (Right) Although the
vessels vary widely in size in
STA, the typical case shows
numerous ramifying thin-
walled vascular channels. This
pattern is particularly striking
in myxoid or edematous zones,
as depicted.

144
 Angiofibroma of Soft Tissue

Fibroblastic/Myofibroblastic Lesions
TERMINOLOGY Molecular Genetics
• Recurrent t(5;8) (p15;q13) translocation resulting in fusion
Definitions of AHRR and NCOA2 genes
• Low-grade fibroblastic neoplasm featuring prominent and ○ NCOA2 detectable by FISH
complex stromal vasculature
DIFFERENTIAL DIAGNOSIS
CLINICAL ISSUES
Low-Grade Fibromyxoid Sarcoma
Epidemiology • Large, deeply situated mass
• Age • Alternating fibrous and myxoid zones
○ Wide range (median: 49 years) ○ Prominent vascularity is seen only in myxoid zones
• Sex • MUC4(+)
○ F:M (2:1) • FUS gene fusions (FUS-CREB3L2 most common)
Site Myxoid Liposarcoma
• Superficial or deep soft tissues of extremities (lower limb • Large, deeply situated mass
most common) • Prominent myxoid stroma with delicate plexiform capillary
○ Also back, pelvis, chest wall, and abdominal wall vascular network
Presentation • Uni- and multivacuolated lipoblasts are common
• Slow-growing, painless mass • DDIT3 gene fusions (DDIT3-FUS most common)

Treatment Solitary Fibrous Tumor

• Simple conservative excision • Prominent branching ectatic "staghorn" vasculature
○ Usually lack abundant small vessels
Prognosis • Diffuse CD34(+), STAT6(+)
• Benign
Lobular Capillary Hemangioma (Pyogenic
• Rarely recurs, even with incomplete excision
Granuloma)
MACROSCOPIC • Usually arise in head and neck, particularly oral and nasal
cavities
General Features • Usually small (< 2.5 cm)
• Well circumscribed • Lobulated growth pattern with small capillaries arranged
• Firm, rubbery cut surface around larger "feeder" vessels
Size Myxofibrosarcoma (Low Grade)
• 1-12 cm (mean: 4.3 cm) • Very infiltrative myxoid neoplasm in superficial soft tissues
of older adults
MICROSCOPIC • Usually conspicuous nuclear hyperchromasia and
Histologic Features pleomorphism
• Often shows thick-walled elongated curvilinear vessels with
• Generally well circumscribed; ± fibrous capsule
perivascular tumor cell accentuation
• Cellularity varies widely
• Bland, uniform spindled to stellate cells in variably myxoid Deep Benign Fibrous Histiocytoma
to collagenous stroma • Vasculature may be prominent and contain branching &/or
○ Rare degenerative mild nuclear atypia ectatic vessels
• Very prominent and complex stromal vasculature • Many cases contain stromal hyalinization, foamy histiocytes,
○ Vessels range from small and thin-walled to medium and &/or multinucleated giant cells
large ectatic "staghorn" channels • CD34(+) in most cases
○ Variable perivascular hyalinization or fibrosis
• Stromal chronic inflammatory infiltrate common SELECTED REFERENCES
• Extravasation of erythrocytes common 1. Bekers EM et al: Soft tissue angiofibroma: clinicopathologic,
• Mitoses rare immunohistochemical and molecular analysis of 14 cases. Genes
Chromosomes Cancer. 56(10):750-7, 2017
2. Yamada Y et al: Histological spectrum of angiofibroma of soft tissue:
ANCILLARY TESTS histological and genetic analysis of 13 cases. Histopathology. 69(3):459-69,
2016
Immunohistochemistry 3. Sugita S et al: Diagnostic utility of NCOA2 fluorescence in situ hybridization
• Focal EMA(+) in 1/2 of cases and STAT6 immunohistochemistry staining for soft tissue angiofibroma and
morphologically similar fibrovascular tumors. Hum Pathol. 45(8):1588-96,
• SMA, CD34, and desmin usually negative or at most focally 2014
positive 4. Edgar MA et al: Soft tissue angiofibroma: report of 2 cases of a recently
○ CD34 highlights prominent vascular network described tumor. Hum Pathol. 44(3):438-41, 2013
5. Mariño-Enríquez A et al: Angiofibroma of soft tissue: clinicopathologic
• Estrogen receptor expression reported in 1 series characterization of a distinctive benign fibrovascular neoplasm in a series of
• Negative for S100 protein, CD31, MUC4, STAT6 37 cases. Am J Surg Pathol. 36(4):500-8, 2012

145
 Angiofibroma of Soft Tissue
Fibroblastic/Myofibroblastic Lesions

Prominent Vascular Network Bland Fibroblastic Spindle Cells

(Left) An extensive, branching
vascular pattern is
characteristic of STA but can
also somewhat resemble the
capillary network of myxoid
liposarcoma; however, the
vessels are more numerous
and thicker walled in STA.
(Right) The tumor cells of STA
are bland, spindled, and
uniform with inconspicuous
cytoplasm. Rare degenerative
nuclear changes may be seen,
but significant nuclear atypia
is not seen.

Cellular Zones Chronic Inflammatory Infiltrate

(Left) Some areas of STA may
show a moderate to marked
increase in cellularity.
Importantly, the lesional cells
remain uniform and
cytologically bland, and foci of
more conventional
morphology are often present.
(Right) A variably brisk stromal
infiltrate of chronic
inflammatory cells,
particularly lymphocytes, is a
common finding in STA.
Lymphocytes may also form
small perivascular aggregates
﬊.

Chronic Inflammatory Infiltrate Stromal Collagen

(Left) In addition to
lymphocytes, scattered mast
cells ﬈, plasma cells, and
neutrophils may occasionally
be present in STA. (Right) Soft
tissue angiofibroma often
contains variably prominent,
fine or coarse stromal collagen
﬈. In some cases, this
collagenous stroma may be
quite dominant.

146
 Angiofibroma of Soft Tissue

Fibroblastic/Myofibroblastic Lesions
Collagenous Stroma Coarse Collagen Bundles
(Left) In areas of STA that
show prominent collagenous
stroma, the characteristic
vascular channels ﬈ are
present but are somewhat less
conspicuous. The orientation
of the collagen may also
impart a fascicular
morphologic appearance.
(Right) In some areas of STA,
the stromal collagen forms
more discrete, coarse bundles
﬈. The stroma in these areas
is often myxoid and
hypocellular.

Perivascular Hyalinization Ectatic "Staghorn" Vessels

(Left) Perivascular
hyalinization ﬈ (fibrosis or
collagen deposition) is a
common finding in STA but
can also be a feature in
several entities on the
differential diagnosis. (Right)
In addition to small and
medium vessels, large ectatic
channels are not uncommon in
STA and may show an
irregular "staghorn"
morphology. When prominent,
a diagnosis of solitary fibrous
tumor may be entertained;
however, STA is negative for
STAT6 and CD34.

Vascular Changes CD34 Immunostain

(Left) Various changes may
occur within the walls of the
blood vessels in STA, including
fibrinoid necrosis ﬈ and focal
thrombus formation. (Right)
The lesional cells of STA are
usually negative for SMA,
desmin, and CD34, or at most
are focally positive.
Endothelial markers (such as
CD31 and CD34) nicely
highlight the prominent
stromal vascular network, as
depicted.

147
 Mammary-Type Myofibroblastoma

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY MICROSCOPIC
• Benign fibroblastic/myofibroblastic neoplasm featuring • Composed of variably sized fascicles of bland spindled cells
hyalinized bundles of stromal collagen and variable ○ Tapered or ovoid banal nuclei and moderate eosinophilic
amounts of mature adipose tissue cytoplasm
○ Appears to form histogenetic continuum with spindle • Hyalinized bundles of stromal collagen are characteristic
cell lipoma and cellular angiofibroma • Variable mature adipose tissue component common
CLINICAL ISSUES • Stromal vasculature is generally inconspicuous
• Morphologic variant: Epithelioid myofibroblastoma
• Affects 4th-7th decades (mean age: 55 years)
• Most arise in subcutaneous tissue of inguinal/groin or ANCILLARY TESTS
vulvovaginal region • CD34(+), desmin (+)
• Slow-growing, often painless mass • SMA(+) in 30% of cases
• Treatment: Simple excision is usually curative • Loss of nuclear retinoblastoma protein expression
• Excellent prognosis • Molecular: Loss of 13q14 region characteristic
MACROSCOPIC TOP DIFFERENTIAL DIAGNOSES
• Well circumscribed, unencapsulated • Spindle cell lipoma
• Size range: 1-13 cm (median: 5.5 cm) • Cellular angiofibroma
• Solitary fibrous tumor

Mammary-Type Myofibroblastoma Mammary-Type Myofibroblastoma

(Left) Myofibroblastoma is a
benign fibroblastic neoplasm
of adults. Though originally
described in the breast, it also
occurs in extramammary soft
tissue sites, particularly the
inguinal and vulvovaginal
regions. Most tumors are well
circumscribed ﬈ but
unencapsulated, as shown.
(Right) The classic example of
myofibroblastoma is
composed of variably cellular
and sized fascicles of
cytologically bland spindle
cells within a stroma
containing coarse bundles of
collagen ﬈.

Bland Cytologic Features CD34 Expression

(Left) The tumor cells of
myofibroblastoma
demonstrate ovoid to
elongated bland nuclei, which
often contain a small
inconspicuous nucleolus.
Nuclear grooves ﬉ may
occasionally be seen. Mitotic
activity is generally low.
(Right) Diffuse CD34
expression is a characteristic
feature of myofibroblastoma
but can be seen in a variety of
other mesenchymal
neoplasms. In the rare
negative cases, Rb IHC can be
helpful (nuclear expression
lost in myofibroblastoma).

148
 Mammary-Type Myofibroblastoma

Fibroblastic/Myofibroblastic Lesions
• Hyalinized bundles of stromal collagen are characteristic
TERMINOLOGY
○ Some cases are paucicellular and show stromal sclerosis
Synonyms • Variable mature adipose tissue component
• Soft tissue myofibroblastoma • Stromal vasculature is generally inconspicuous
• Extramammary myofibroblastoma ○ Lacks prominent perivascular hyalinization and large
"staghorn" vessels
Definitions
• Stromal myxoid change common
• Benign fibroblastic/myofibroblastic neoplasm featuring • Necrosis absent
hyalinized bundles of stromal collagen and variable
amounts of mature adipose tissue Morphologic Variants
○ Histologically identical to myofibroblastoma of breast • Epithelioid myofibroblastoma
• Appears to form histogenetic continuum with spindle cell ○ Composed predominantly of small, rounded or
lipoma and cellular angiofibroma epithelioid tumor cells
○ Other features of myofibroblastoma often present
CLINICAL ISSUES
Epidemiology ANCILLARY TESTS
• Age Immunohistochemistry
○ Wide range (mean: 55 years) • CD34(+), desmin (+)
• Sex • SMA(+) in 30-40% of cases
○ Slight male predominance • Loss of nuclear retinoblastoma (Rb) protein expression
Site ○ Also seen in spindle cell lipoma and cellular angiofibroma
• Keratin, S100 protein, STAT6, myogenin, CD31 (-)
• Most arise in subcutaneous tissue
• Inguinal/groin, vulvovaginal, scrotal regions most common Molecular Genetics
extramammary sites • Loss of 13q14 region characteristic
• Extremities (lower > upper) and trunk ○ Monoallelic deletion of RB1 or FOXO1 genes by FISH
• Retroperitoneum, abdominal cavity, head/neck, viscera ○ Also seen in spindle cell lipoma and cellular angiofibroma
uncommon
• Appears to occur more frequently along "milk line" DIFFERENTIAL DIAGNOSIS
○ Line of potential breast tissue from axilla to inner groin
Spindle Cell Lipoma
Presentation • Most commonly arises in neck or back
• Slow-growing, often painless mass • Frequent myxoid areas
Treatment • CD34(+); usually desmin (-)
• Loss of 13q14 and nuclear Rb protein expression
• Simple excision is usually curative
Cellular Angiofibroma
Prognosis
• Most common in genital/inguinal region
• Excellent
• Stromal vessels more conspicuous and often hyalinized
• No significant risk of recurrence
• CD34(+); desmin (-)
• Does not metastasize
• Loss of 13q14 and nuclear Rb protein expression
MACROSCOPIC Solitary Fibrous Tumor
General Features • Characteristic prominent "staghorn" vasculature
• CD34(+), STAT6(+); desmin (-)
• Circumscribed lesion
• Nuclear Rb protein expression intact
• Firm, tan, yellow, or white whorled cut surface
• Characteristic NAB2-STAT6 gene fusion
Size
• 1-13 cm diameter (median: 5.5 cm) SELECTED REFERENCES
1. McCarthy AJ et al: Tumours composed of fat are no longer a simple
MICROSCOPIC diagnosis: an overview of fatty tumours with a spindle cell component. J Clin
Pathol. 71(6):483-92, 2018
Histologic Features 2. Howitt BE et al: Mammary-type myofibroblastoma: clinicopathologic
characterization in a series of 143 cases. Am J Surg Pathol. 40(3):361-7, 2016
• Well circumscribed, unencapsulated
3. Magro G et al: Mammary and vaginal myofibroblastomas are genetically
• Composed of variably sized fascicles of bland spindled cells related lesions: fluorescence in situ hybridization analysis shows deletion of
○ Tapered or ovoid banal nuclei and moderate eosinophilic 13q14 region. Hum Pathol. 43(11):1887-93, 2012
cytoplasm 4. Flucke U et al: Cellular angiofibroma: analysis of 25 cases emphasizing its
relationship to spindle cell lipoma and mammary-type myofibroblastoma.
– Rare nuclear atypia ± multinucleation (degenerative Mod Pathol. 24(1):82-9, 2011
changes) 5. McMenamin ME et al: Mammary-type myofibroblastoma of soft tissue: a
tumor closely related to spindle cell lipoma. Am J Surg Pathol. 25(8):1022-9,
○ May show focal epithelioid cytomorphology 2001
○ Rare nuclear palisading (neurilemmoma-like)
○ Mitoses rare
149
 Mammary-Type Myofibroblastoma
Fibroblastic/Myofibroblastic Lesions

Scanning Magnification Nuclear Palisading

(Left) At low power,
myofibroblastoma shows a
clean border with the
surrounding adipose tissue. No
capsule is present. This
particular case featured a
myxoid and palisaded
morphology. (Right) Nuclear
palisading in
myofibroblastoma is
distinctive but rare. Unlike
schwannoma,
myofibroblastoma is S100
negative and often
coexpresses CD34 and desmin.

Cellular and Myxoid Variants Rare Focal Atypia &/or Multinucleation

(Left) Myofibroblastoma can
also feature areas of increased
cellularity (left) or stromal
myxoid change (right). These
variations may be focal or
diffuse, depending on the
individual lesion. (Right) Rare
cases of myofibroblastoma
show focal degenerative
nuclear atypia, including
multinucleation ﬊. The rest
of the cells show the usual
bland cytologic features.

Mature Adipose Tissue Prominent Stromal Hyalinization

(Left) Most cases of
myofibroblastoma contain
some degree of mature
adipose tissue, as shown. In
some cases it can be extensive,
resembling a lipoma, though in
other cases it can be focal.
Note the presence of collagen
bundles ﬈, visible even at low
power. (Right) Some cases of
myofibroblastoma are
extensively hyalinized and
appear hypocellular, as shown
in this image. Note the
scattered mature adipocytes.

150
 Mammary-Type Myofibroblastoma
Prominent Stromal Hyalinization
Smooth Muscle Actin Expression
Epithelioid Variant: Cytology
Fibroblastic/Myofibroblastic Lesions
Desmin Expression
(Left) The tumor cells in
hyalinized cases of
myofibroblastoma are
cytologically similar to
conventional cases. Given the
prominent overall eosinophilia
of the lesion, a smooth muscle
tumor may be considered.
(Right) Desmin is expressed in
the majority of cases of
myofibroblastoma and may be
diffuse, patchy, or focal. In
some tumors, desmin is
negative.
Epithelioid Variant
(Left) Approximately 30-40%
of myofibroblastomas show
smooth muscle actin (SMA)
expression, often in a patchy
distribution. This finding can
be used for diagnostic support
in cases that are CD34(+) but
desmin (-). (Right) Epithelioid
cytomorphologic change is
uncommon but well
documented in mammary
myofibroblastoma and may be
focal or diffuse. This
morphology may also be seen
in extramammary soft tissue
sites.
Epithelioid Variant: Growth Patterns
(Left) The tumor cells of
epithelioid myofibroblastoma
are small and bland with
indistinct eosinophilic
cytoplasm. At lower
magnification, they can mimic
inflammatory cells
(particularly plasma cells).
(Right) Epithelioid
myofibroblastoma shows a
tendency to form cords or
linear arrays of tumor cells, as
depicted, mimicking
infiltrating carcinoma. This is
particularly problematic in
mammary cases but can also
be seen in extramammary
sites.
151
 Intranodal Palisaded Myofibroblastoma

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY • Uniform, elongated spindled cells in variably cellular

• Distinctive benign spindle cell tumor that occurs in lymph bundles, fascicles, and whorls
nodes, particularly within inguinal region ○ Nuclear palisading is common, particularly around
hyalinized blood vessels
CLINICAL ISSUES ○ Perinuclear vacuolization common
• Most common 45-55 years • Bland, uniform nuclei
• 2:1 male predominance • Frequent stromal microhemorrhages
• Most arise in inguinal lymph nodes ○ Hemosiderin pigment and extravasated erythrocytes
• Slow-growing, usually painless mass • Collagenous bodies are characteristic
• Treatment: Simple surgical excision
ANCILLARY TESTS
• Benign; local recurrences rare
• SMA(+)
MACROSCOPIC • Negative for S100, desmin, CD31, CD34, keratin, HMB-45
• Well circumscribed
TOP DIFFERENTIAL DIAGNOSES
• Usually < 5 cm in size
• Schwannoma
MICROSCOPIC • Kaposi sarcoma
• Rim of compressed residual lymph node tissue at periphery • Desmoid fibromatosis
• Lymph node metastasis

Intranodal Palisaded Myofibroblastoma Resemblance to Involved Lymph Node

(Left) Intranodal palisaded
myofibroblastoma (IPM) is a
distinctive benign spindle cell
tumor that shows a strong
predilection for inguinal lymph
nodes. This tumor is well
circumscribed, and
compressed residual nodal
tissue is usually seen at the
periphery ſt. (Right) A
peripheral rim ﬈ of
compressed residual lymph
node is usually easily
identifiable histologically in
IPM. The tumor ﬇ arises
centrally and is composed of
fascicles and whorls of spindle
cells.

Fibrous Pseudocapsule Nuclear Palisading

(Left) Most cases of IPM
demonstrate a fibrous or
collagenous pseudocapsule ﬈
at the interface between the
tumor ﬊ and the peripheral
residual nodal tissue (not
shown in this image). (Right)
The lesional cells of IPM are
uniform and spindled with
eosinophilic cytoplasm and
elongated, cytologically bland
nuclei. Some degree of nuclear
palisading is commonly
present in these tumors ﬊.

152
 Intranodal Palisaded Myofibroblastoma

Fibroblastic/Myofibroblastic Lesions
○ Can show occasional intranuclear pseudoinclusions,
TERMINOLOGY nuclear grooves
Synonyms ○ Mitoses usually infrequent
• Intranodal hemorrhagic spindle cell tumor with amianthoid • Finely collagenous to myxoedematous stroma with
fibers frequent microhemorrhages
• Solitary spindle cell tumor with myoid differentiation of ○ Often associated with hemosiderin pigment and
lymph node extravasated erythrocytes
○ Mild chronic inflammatory infiltrate may be present
Definitions
• Collagenous bodies are characteristic findings
• Distinctive benign spindle cell tumor that occurs in lymph ○ Variably sized bundles of acellular collagen, reminiscent
nodes, particularly within inguinal region of amianthoid fibers
○ Occasionally calcified
CLINICAL ISSUES • Rare findings: Metaplastic bone, extramedullary
Epidemiology hematopoiesis, focal "staghorn" vasculature
• Incidence
○ Rare ANCILLARY TESTS
• Age Immunohistochemistry
○ Most common 45-55 years • SMA(+)
• Sex • Negative for S100 protein, desmin, CD31, CD34, keratin,
○ 2:1 male predominance HMB-45
Site • Nuclear β-catenin (+), cyclin-D1 (+)
• Most arise in inguinal lymph nodes Molecular Genetics
• Rare cases reported in submandibular nodes, cervical • CTNNB1 gene mutations reported
nodes, and mediastinum
Presentation DIFFERENTIAL DIAGNOSIS
• Slow-growing, usually painless mass Schwannoma
• Usually solitary; very rarely multicentric • Rare in lymph nodes
Treatment • S100 protein (+); negative for SMA
• Simple surgical excision Kaposi Sarcoma
Prognosis • Often associated with history of immunosuppression
• CD34(+), CD31(+), ERG(+), D2-40(+), HHV8(+)
• Benign
• Negative for SMA
• Local recurrence is very rare
PEComa
MACROSCOPIC • Can show dyscohesive, fascicular morphology with stromal
General Features hemorrhage
• Does not arise in lymph nodes
• Well circumscribed, often with compressed residual nodal
tissue at periphery • SMA(+), HMB45(+), MART-1(+)
• Solid tan-red-brown cut surface Desmoid Fibromatosis
Size • Does not arise in lymph nodes
• Usually < 5 cm • Lacks nuclear palisading and amianthoid-like collagen fibers
Lymph Node Metastasis
MICROSCOPIC • Spindle cell carcinoma or spindle cell melanoma
Histologic Features • Clinical history of primary tumor
• Rim of compressed residual lymph node tissue at periphery • Immunohistochemistry may be necessary
○ Tumor is often separated from residual nodal tissue by
fibrocollagenous pseudocapsule SELECTED REFERENCES
• Uniform, elongated spindled cells in variably cellular 1. Agaimy A et al: CTNNB1 (β-catenin)-altered neoplasia: a review focusing on
bundles, fascicles, and whorls soft tissue neoplasms and parenchymal lesions of uncertain histogenesis.
Adv Anat Pathol. 23(1):1-12, 2016
○ Nuclear palisading is common, particularly around 2. Bhullar JS et al: Intranodal palisaded myofibroblastoma: a review of the
hyalinized blood vessels literature. Int J Surg Pathol. 21(4):337-41, 2013
○ Perinuclear artifactual clearing is common 3. Kandemir NO et al: Intranodal palisaded myofibroblastoma (intranodal
hemorrhagic spindle cell tumor with amianthoid fibers): a case report and
○ Fascicles may be collagenized and resemble fibromatosis literature review. Diagn Pathol. 5:12, 2010
○ Intracytoplasmic perinuclear pale eosinophilic globules 4. Nguyen T et al: Intranodal palisaded myofibroblastoma. Arch Pathol Lab
have been reported Med. 131(2):306-10, 2007
• Bland, uniform nuclei

153
 Intranodal Palisaded Myofibroblastoma
Fibroblastic/Myofibroblastic Lesions

Irregular Fascicular Growth Cellularity

(Left) A haphazard
organization of spindled cells
in fascicles is a common
morphology in IPM. Note also
the stromal and cellular
dyscohesion ﬈ associated
with hemorrhage, a prominent
finding in some tumors. (Right)
Fascicles of spindle cells vary
in length, cellularity, and
organization in IPM.
Prominent, well-developed,
and cellular fascicles, as seen
here, may lead to
consideration of a sarcoma.

Fibromatosis-Like Morphology Bland Nuclear Cytology

(Left) In some cases of IPM,
the fascicles are broad and
show increased collagen
deposition, imparting a similar
morphologic appearance to
fibromatosis. (Right) The
lesional cell nuclei of IPM are
elongated, uniform, and
cytologically bland. The nuclei
may also appear wavy (shown)
and can occasionally show
grooves or small, pale
pseudoinclusions ﬈.

Artifactual Clearing Extramedullary Hematopoiesis

(Left) Artifactual perinuclear
clearing ﬈ is a relatively
common finding in IPM but
varies widely in distribution
from case to case. This finding
is similar to that seen in some
spindled gastrointestinal
stromal tumors. (Right)
Extramedullary hematopoiesis
is an uncommon but
documented finding in IPM.
Note the presence of a
megakaryocyte ﬈.

154
 Intranodal Palisaded Myofibroblastoma
Microhemorrhages
Perivascular Collagen
Eosinophilic Collagen
Fibroblastic/Myofibroblastic Lesions
Perivascular Collagen
(Left) Stromal
microhemorrhages are
common and characteristic of
IPM, and associated
extravasated erythrocytes and
hemosiderin pigment are also
seen. At times, this
appearance of blood between
elongated eosinophilic cells
may closely simulate Kaposi
sarcoma. (Right) Perivascular
collagen deposition can be
seen in IPM, and some cases
show a diffuse lattice-like
arrangement when vessel
density increases.
Collagenous Bodies
(Left) This higher
magnification view shows
perivascular collagen
deposition in IPM, as
evidenced by hypocellular
eosinophilic zones around
centralized capillary channels.
(Right) Dense collagenous
bodies ﬊, resembling
amianthoid fibers, are another
characteristic finding seen in
many cases of IPM. They may
be focal and easily overlooked
or numerous and dominate the
histologic picture.
Myxoid Stromal Change
(Left) The eosinophilic
collagenous bodies in IPM
typically show a denser
centralized portion and a
lighter or paler periphery.
These bodies may also show
calcification in rare cases.
(Right) The stroma in IPM is
usually finely collagenous but
may also show myxoid or
edematous change.
Perinuclear vacuoles and
extravasated erythrocytes are
often prominent in these
areas.
155
 Pleomorphic Fibroma

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY • Lesional cells are predominantly spindle shaped with few

• Pleomorphic fibroma (PF) larger stellate and multinucleated cells
• Benign, dermal-based neoplasm composed of • Mitotic figures are rare or absent
pleomorphic-appearing myofibroblasts • Stroma typically is composed of hyalinized-appearing
collagen fibers
ETIOLOGY/PATHOGENESIS • Cells show enlarged, hyperchromatic nuclei with small
• Unknown; some cases may be related to ischemia, trauma, nucleoli and scant amounts of eosinophilic cytoplasm
or degenerative changes
ANCILLARY TESTS
CLINICAL ISSUES • CD34(+), SMA(+), and vimentin (+)
• Slow-growing skin nodule • Variable FXIIIA(+)
• Usually dome-shaped or polypoid-appearing
TOP DIFFERENTIAL DIAGNOSES
• May show local recurrence if incompletely excised
• Atypical fibroxanthoma
MACROSCOPIC • Dermatofibroma (fibrous histiocytoma)
• Size range: 0.4-1.6 cm • Fibrous papule (angiofibroma)
MICROSCOPIC • Sclerotic fibroma
• Well-circumscribed, dome-shaped, or polypoid hypocellular
proliferation of dermal spindle cells

Pleomorphic Fibroma Superficial Multinucleated Cells

(Left) Scanning magnification
shows a polypoid (skin-tag-
like) lesion with a fibromyxoid
stroma. The lesion is usually
solitary and occurs on the
trunk, head and neck region,
or extremities. (Right) Higher
magnification shows
multinucleated histiocytic cells
﬉ in the superficial dermis
with a background of fibrosis
and telangiectasia.

Cytologic Features CD34 Expression

(Left) High-power examination
shows a population of
enlarged, hyperchromatic-
staining, spindled ﬊, stellate,
and multinucleated cells set in
a fibromyxoid stroma. No
mitoses are seen. (Right) CD34
shows strong and diffuse
staining of the spindled and
multinucleated cells. This is in
contrast to atypical
fibroxanthoma and
dermatofibroma (fibrous
histiocytoma), which are often
negative for this antigen.

156
 Pleomorphic Fibroma
TERMINOLOGY
Abbreviations
• Pleomorphic fibroma (PF)
Definitions
• Benign, dermal-based neoplasm composed of
pleomorphic-appearing myofibroblasts
ETIOLOGY/PATHOGENESIS
Unknown
• Some cases may be related to ischemia, trauma, or
degenerative changes
CLINICAL ISSUES
Presentation
• Slow-growing skin papule or nodule
○ Usually dome-shaped or polypoid-appearing
○ Flesh colored and nonulcerated
• Typically occurs on trunk, extremities, or head and neck
region
Treatment
• Complete conservative excision is curative
Prognosis
• Benign tumors with excellent prognosis
• May show local recurrence if incompletely excised
MACROSCOPIC
Size
• Range: 0.4-1.6 cm
MICROSCOPIC
Histologic Features
• Well-circumscribed, dome-shaped, or polypoid hypocellular
proliferation of dermal spindle cells
• Lesional cells are predominantly spindle-shaped with
scattered larger stellate and multinucleated cells
• Cells show enlarged, hyperchromatic nuclei with small
nucleoli and scant amounts of eosinophilic cytoplasm
• Mitotic figures are rare or absent
○ No atypical mitoses should be seen
• Stroma typically composed of hyalinized-appearing
collagen fibers
○ Some cases show overlapping features with sclerotic
fibroma
– i.e., these cases show storiforming of hyalinized
collagen bundles with collagen clefts
• Myxoid areas may be present
○ Can be prominent/diffuse in some cases (myxoid PF)
ANCILLARY TESTS
Immunohistochemistry
• CD34(+), SMA(+), and vimentin (+)
• Variable FXIIIA(+), often weak
• Loss of Rb protein expression
Fibroblastic/Myofibroblastic Lesions
DIFFERENTIAL DIAGNOSIS
Atypical Fibroxanthoma
• Highly cellular and atypical-appearing, dermal-based tumor
associated with solar elastosis in head and neck region
• Mitotic figures are easily found in most cases, including
atypical forms
• Typically CD34(-), and nonspecific markers (including CD68,
CD10, and CD99) are usually (+)
Dermatofibroma (Fibrous Histiocytoma)
• Usually does not show degree of pleomorphism seen in PF,
although rare cases may (i.e., atypical dermatofibroma or
"dermatofibroma with monster cells")
• More typical dermatofibroma areas should be present at
periphery of tumor
○ Collagen trapping, histiocytoid cells, and overlying
epidermal hyperplasia are usually present
• Typically CD34(-), unlike PF
Fibrous Papule (Angiofibroma)
• Small, dome-shaped papule that shows dermal fibrosis and
increased blood vessels with telangiectasia
• Scattered, enlarged, mildly pleomorphic-appearing
fibroblasts may be present
• CD34(-), FXIIIA(+)
Sclerotic Fibroma
• Shows characteristic storiform pattern of thickened,
hyalinized-appearing collagen bundles with clefts between
them
• Some cases show overlapping features with PF with
population of enlarged, pleomorphic-appearing spindled
cells
○ Some authors believe that PF is variant of sclerotic
fibroma, but this is not universally accepted
DIAGNOSTIC CHECKLIST
Pathologic Interpretation Pearls
• Hypocellular dermal proliferation of spindled, stellate, and
multinucleated cells
• Cells appear pleomorphic and hyperchromatic but lack
mitotic activity
SELECTED REFERENCES
1. Tashakori M et al: Pleomorphic fibroma of the skin with MDM2
immunoreactivity: a potential diagnostic pitfall. J Cutan Pathol. 45(1):59-62,
2018
2. Hinds B et al: Loss of retinoblastoma in pleomorphic fibroma: an
immunohistochemical and genomic analysis. J Cutan Pathol. 44(8):665-71,
2017
3. Halteh P et al: Subungual pleomorphic fibroma: a case report and review of
the literature. Dermatol Online J. 22(11), 2016
4. Al-Zaid T et al: Pleomorphic fibroma and dermal atypical lipomatous tumor:
are they related? J Cutan Pathol. 40(4):379-84, 2013
5. Yadav Y et al: Cytomorphology of pleomorphic fibroma of skin: a diagnostic
enigma. J Cytol. 30(1):71-3, 2013
6. Mahmood MN et al: Solitary sclerotic fibroma of skin: a possible link with
pleomorphic fibroma with immunophenotypic expression for O13 (CD99)
and CD34. J Cutan Pathol. 30(10):631-6, 2003
7. Pitt MA et al: Myxoid cutaneous pleomorphic fibroma. Histopathology.
25(3):300, 1994
8. Kamino H et al: Pleomorphic fibroma of the skin: a benign neoplasm with
cytologic atypia. A clinicopathologic study of eight cases. Am J Surg Pathol.
13(2):107-13, 1989
157
 Dermatomyofibroma

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY MICROSCOPIC
• a.k.a. plaque-like dermal fibromatosis • Dermal-based spindle cell proliferation
• Myofibroblastic tumor with features overlapping with • Tumor is composed of broad fascicles of elongated
dermatofibroma monomorphic spindle cells oriented parallel to surface
○ Bland nuclei; palely eosinophilic cytoplasm
ETIOLOGY/PATHOGENESIS
• Overlying epidermal hyperplasia often present
• May be related to trauma in some cases
• Elastic fibers are typically increased in numbers and
CLINICAL ISSUES fragmented
• Rare, slow-growing plaque or nodule • Mitotic figures are rare and not atypical
○ Often red-brown in color ANCILLARY TESTS
• Usually occurs in young adult females • Variable SMA(+)
• No malignant potential but may continue to enlarge if not • CD34(-), MSA(-), desmin (-), S100 protein (-), and FXIIIA(-)
completely removed
TOP DIFFERENTIAL DIAGNOSES
MACROSCOPIC
• Dermatofibroma
• Small, dermal-based nodule
• Superficial (palmar/plantar) fibromatosis
• Usually 1-2 cm in size but occasionally much larger
• Leiomyoma
• Hypertrophic scar

Scanning Magnification of Higher Magnification of

Dermatomyofibroma Dermatomyofibroma
(Left) Dermatomyofibroma is
a dermal-based, plaque-like
spindle proliferation with
overlying epidermal
hyperplasia ﬇ and basilar
pigmentation, similar to a
dermatofibroma. (Right)
Higher magnification shows
the superficial portion of the
spindle cell proliferation
closely approaching the
epidermis. Note the parallel
arrangement and the
prominent eosinophilic-
staining cytoplasm of the
spindled cells ﬉.

High Magnification of
Dermatomyofibroma SMA Staining in Dermatomyofibroma
(Left) High magnification
shows the cytologic features
of dermatomyofibroma. The
lesion is composed of bland-
appearing, elongated,
eosinophilic-staining spindled
cells with inconspicuous to
small nucleoli ﬉. (Right) SMA
shows diffuse positivity in the
spindle cells of
dermatomyofibroma. Desmin
is typically negative.

158
 Dermatomyofibroma

Fibroblastic/Myofibroblastic Lesions
○ Uniform chromatin with small nucleoli
TERMINOLOGY
○ Palely eosinophilic cytoplasm, poorly delineated
Synonyms • Foci of collagen trapping may be present but not as
• Plaque-like dermal fibromatosis prominent as in dermatofibroma
• Mitotic figures are rare and not atypical
Definitions
• Elastic fibers are typically increased in numbers and
• Myofibroblastic tumor with many features similar to fragmented
dermatofibroma ○ Can highlight this with elastic stains

ETIOLOGY/PATHOGENESIS ANCILLARY TESTS

Unknown Immunohistochemistry
• May be related to trauma in some cases • Variable SMA(+)
• CD34(-), MSA(-), desmin (-), S100 protein (-), and FXIIIA(-)
CLINICAL ISSUES
Epidemiology DIFFERENTIAL DIAGNOSIS
• Incidence Dermatofibroma
○ Rare tumor • Lacks parallel orientation and muscle differentiation
• Age • Shows more prominent peripheral collagen trapping 
○ Usually occurs in young adults
• Sex Superficial (Palmar/Plantar) Fibromatosis
○ M:F = 1:8 • Occurs in hands or feet
• Nodular growth, rather than plaque-like
Site
• Typically present in shoulder and axillary regions Leiomyoma
○ Also present in trunk, head and neck • Shows more clear-cut smooth muscle differentiation with
strong SMA, MSA, and desmin expression
Presentation • Fascicles of spindle cells not typically oriented parallel to
• Slow-growing indurated plaque or nodule epidermis
○ Often red-brown in color
• Rarely may present as multiple lesions
Hypertrophic Scar
• Dense proliferation of collagen with vertically oriented
Treatment vessels
• Complete surgical excision is curative, but not necessary, • Adnexal structures are lost as opposed to
given benign nature of these tumors dermatomyofibroma
Prognosis Dermatofibrosarcoma Protuberans
• Excellent • Plaque-like variant of dermatofibrosarcoma protuberans
○ No malignant potential but may continue to enlarge if can show histologic features similar to dermatomyofibroma
not completely removed • Strong CD34(+), SMA(-)
• Does not generally recur, even if incompletely excised
SELECTED REFERENCES
MACROSCOPIC 1. Borucki R et al: Fluorescence microscopy for the evaluation of elastic tissue
patterns within fibrous proliferations of the skin on hematoxylin-eosin-
General Features stained slides. J Am Acad Dermatol. ePub, 2018
• Small, dermal-based nodule 2. Lima LAF et al: Multiple dermatomyofibromas. An Bras Dermatol. 93(2):268-
270, 2018
Size 3. Ma JE et al: Dermatomyofibromas arising in children: report of two new
cases and review of the literature. Pediatr Dermatol. 34(3):347-351, 2017
• Usually 1-2 cm in size but occasionally much larger
4. Cano Martínez N et al: Dermatomyofibroma mimicking granuloma annulare.
Dermatol Online J. 17(6):3, 2011
MICROSCOPIC 5. Gomez-Moyano E et al: Two cases of dermatomyofibroma (plaque-like
dermal fibromatosis). Int J Dermatol. 49(8):914-7, 2010
Histologic Features 6. Mentzel T et al: Dermatomyofibroma: clinicopathologic and
• Dermal-based, plaque-like spindle cell proliferation immunohistochemical analysis of 56 cases and reappraisal of a rare and
distinct cutaneous neoplasm. Am J Dermatopathol. 31(1):44-9, 2009
○ Usually located in reticular dermis but may show 7. Mortimore RJ et al: Dermatomyofibroma: a report of two cases, one
involvement of superficial subcutis occurring in a child. Australas J Dermatol. 42(1):22-5, 2001
○ Adnexal structures are usually preserved 8. Mentzel T et al: Dermatomyofibroma: additional observations on a
distinctive cutaneous myofibroblastic tumour with emphasis on differential
○ Often see overlying epidermal hyperplasia (similar to diagnosis. Br J Dermatol. 129(1):69-73, 1993
dermatofibroma) 9. Cooper PH: Dermatomyofibroma: a case of fibromatosis revisited. J Cutan
• Tumor is composed of broad fascicles of elongated Pathol. 19(2):81-2, 1992
monomorphic spindle cells 10. Kamino H et al: Dermatomyofibroma. A benign cutaneous, plaque-like
proliferation of fibroblasts and myofibroblasts in young adults. J Cutan
○ Fascicles often run in parallel to epidermis Pathol. 19(2):85-93, 1992
○ Nuclei bland and tapered

159
 Storiform Collagenoma

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY MICROSCOPIC
• Synonym: Sclerotic fibroma • Composed of thickened, hyalinized-appearing collagen
• Benign, dermal-based fibroblastic proliferation bundles in storiform/whorled pattern
○ Prominent clefts often seen between collagen bundles
ETIOLOGY/PATHOGENESIS
• Cells are typically small, bland, spindled to stellate
• May be related to trauma fibroblasts
• Some cases may represent regressed dermatofibromas • Occasional cases may show large, bizarre-appearing cells
• Multiple lesions are associated with Cowden syndrome, (pleomorphic sclerotic fibroma)
consistent with genetic influence ○ These cells do not show infiltrative features or increased
CLINICAL ISSUES mitotic activity
• May occur at any age, including infants and elderly ANCILLARY TESTS
• Excellent prognosis; may locally recur but no metastatic • FXIIIA(+), vimentin (+), focal CD34(+)
potential
• Present most commonly on face, extremities, and trunk TOP DIFFERENTIAL DIAGNOSES
• Dermatofibroma
MACROSCOPIC
• Pleomorphic fibroma
• Typically 0.5-3.0 cm in size • Collagenous fibroma
• Dermal nodule with firm, yellow-tan surface • Acral fibrokeratoma (subungual and periungual fibroma)

Intermediate Magnification of Sclerotic

Sclerotic Fibroma at Low Magnification Fibroma
(Left) Scanning magnification
view of sclerotic fibroma
shows a dermal-based,
symmetric-appearing nodular
spindle cell proliferation with
storiforming ﬉ of collagen.
(Right) Intermediate-power
examination shows prominent
areas of storiforming and
clefting artifact between the
collagen bundles st.

Sclerotic Fibroma at High Magnification FXIIIA Expression

(Left) High-power
magnification shows spindled
fibroblasts ſt without nuclear
atypia in a dense fibrous
stroma with a few scattered
small lymphocytes ﬊. (Right)
FXIIIA immunohistochemistry
shows staining of scattered
spindle cells ﬈ in sclerotic
fibroma (storiform
collagenoma).

160
 Storiform Collagenoma

Fibroblastic/Myofibroblastic Lesions
TERMINOLOGY ANCILLARY TESTS
Synonyms Immunohistochemistry
• Sclerotic fibroma • FXIIIA(+), vimentin (+), focal CD34(+)
• Ki-67 may highlight few scattered nuclei, but overall
Definitions
proliferative rate is low
• Benign, dermal-based fibroblastic proliferation with
storiforming collagen DIFFERENTIAL DIAGNOSIS
ETIOLOGY/PATHOGENESIS Dermatofibroma
• Typically does not show prominent storiforming of
Unknown
collagen, although it may be focally present in rare cases
• May be related to trauma • Areas of conventional dermatofibroma with collagen
• Some cases may represent regressed dermatofibromas trapping and histiocytic cells should be present
• Some cases are genetic ○ Some cases may show overlapping features, leading
○ Multiple lesions are associated with Cowden syndrome some investigators to believe that sclerotic fibromas are
(PTEN mutations, associated with multiple hamartomas involuting dermatofibromas
and tricholemmomas)
Pleomorphic Fibroma
CLINICAL ISSUES • Clinically resembles skin tag
• Pleomorphic cells are more prominent, and storiforming
Epidemiology
pattern of collagen should be absent
• Age
○ May occur at any age, including infants and elderly Collagenous Fibroma
• Sex • Usually subcutaneous tumors with only rare dermal
○ Occurs in both males and females involvement
• Densely collagenous or fibromyxoid stroma; lacks
Site prominent storiforming of collagen
• Present most commonly on face, extremities, and trunk
Acral Fibrokeratoma (Subungual and Periungual
Presentation Fibroma)
• Slow-growing, flesh-colored papule or nodule • Usually shows overlying hyperkeratosis and acanthosis
Treatment • Proliferation of thick collagen bundles, often vertically
oriented
• Complete conservative excision is curative
Prognosis DIAGNOSTIC CHECKLIST
• Excellent; may locally recur but no metastatic potential Pathologic Interpretation Pearls
• Dermal nodule of thickened, hyalinized-appearing collagen
MACROSCOPIC bundles in storiform/whorled pattern
General Features
• Dermal nodule with firm, yellow-tan surface SELECTED REFERENCES
1. Ebadian M et al: Dermoscopy of a solitary storiform collagenoma. Dermatol
Size Pract Concept. 8(2):120-122, 2018
• Typically 0.5-3.0 cm 2. Shi KY et al: Late-stage nodular erythema elevatum diutinum mimicking
sclerotic fibroma. J Cutan Pathol. 45(1):94-96, 2018
3. Kieselova K et al: Multiple sclerotic fibromas of the skin: an important clue
MICROSCOPIC for the diagnosis of Cowden syndrome. BMJ Case Rep. 2017, 2017
Histologic Features 4. Val-Bernal JF et al: Sclerotic fibroma (storiform collagenoma)-like stroma in a
fibroadenoma of axillary accessory breast tissue. J Cutan Pathol. 39(8):798-
• Circumscribed, unencapsulated dermal nodule 802, 2012
• Composed of thickened, hyalinized-appearing collagen 5. Nakashima K et al: Solitary sclerotic fibroma of the skin: morphological
characterization of the 'plywood-like pattern'. J Cutan Pathol. 35 Suppl 1:74-
bundles in storiform/whorled pattern 9, 2008
○ Prominent clefts often seen between collagen bundles 6. González-Vela MC et al: Sclerotic fibroma-like dermatofibroma: an
(so-called plywood or fingerprint pattern) uncommon distinctive variant of dermatofibroma. Histol Histopathol.
20(3):801-6, 2005
• Cells are typically small, bland, spindled to stellate 7. Chen TM et al: Pleomorphic sclerotic fibroma: a case report and literature
fibroblasts review. Am J Dermatopathol. 24(1):54-8, 2002
• Occasional cases may show large, bizarre-appearing cells 8. Martín-López R et al: Pleomorphic sclerotic fibroma. Dermatology.
198(1):69-72, 1999
(pleomorphic sclerotic fibroma), similar to pleomorphic
9. Pujol RM et al: Solitary sclerotic fibroma of the skin: a sclerotic
fibroma dermatofibroma? Am J Dermatopathol. 18(6):620-4, 1996
○ These cells do not show infiltrative features or increased 10. Requena L et al: Multiple sclerotic fibromas of the skin. A cutaneous marker
mitotic activity of Cowden's disease. J Cutan Pathol. 19(4):346-51, 1992
11. Rapini RP et al: Sclerotic fibromas of the skin. J Am Acad Dermatol. 20(2 Pt
• Pacinian collagenoma is rare variant with "onion-skin" 1):266-71, 1989
mimicking pacinian corpuscle

161
 Keloid

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY MACROSCOPIC
• Synonym: Scar with keloidal collagen • Large, nodular, dermal-based lesion with firm, white cut
• Reactive/reparative proliferation with prominent thickened surface
and hyalinized, eosinophilic-staining bundles of collagen
MICROSCOPIC
extending beyond original biopsy/wound site
• Dense proliferation of thickened, hyalinized-appearing
CLINICAL ISSUES collagen bundles in dermis
• Scar that grows beyond original biopsy/wound site • Decreased vessels compared to conventional and
• Often erythematous, pruritic lesions with predilection for hypertrophic scars
earlobe in black patients • Increased numbers of stromal fibroblasts, lymphocytes, and
• Most common in patients < 30 years mast cells are usually present
• Typically follows ear piercing or other trauma by a few • May be background of conventional or hypertrophic scar
months with smaller collagen bundles and perpendicular vessels
• Direct injection of steroids is often 1st-line treatment TOP DIFFERENTIAL DIAGNOSES
• Complete excision, accompanied by concurrent steroid
• Hypertrophic scar
injections or radiotherapy to decrease risk of recurrence
• Desmoplastic melanoma
• Persistence and recurrence are common, but there is no
risk of malignancy • Nodular fasciitis

Keloid Low Magnification

(Left) This keloid forms a
polypoid skin lesion and
displays dense dermal
collagen, especially in the
center of the lesion ﬉. Note
the mild epidermal
hyperplasia. Commonly, the
epidermis overlying a keloidal
scar is atrophic-appearing.
(Right) Keloids usually are
dome-shaped or polypoid skin
lesions, which show dense,
thickened dermal collagen
bundles, often with areas of
hypertrophic scar ﬊. Note the
overlying irregular epidermal
hyperplasia in this example.

Dense Dermal Scarring Ectatic Vessels

(Left) Intermediate
magnification shows the
superficial aspects of a keloid.
Note the dermal scarring with
telangiectasia ﬈ and
prominent thickened,
hyalinized-appearing collagen
bundles ﬉. (Right) Higher
magnification of the
superficial portion of a keloid
shows telangiectatic vessels
surrounded by hyalinized,
eosinophilic-staining collagen
bundles ﬉.

162
 Keloid

Fibroblastic/Myofibroblastic Lesions
○ Superficial telangiectatic vessels often present
TERMINOLOGY
○ Associated with mild, chronic inflammation
Synonyms • Overlying epidermis may show atrophy or acanthosis
• Scar with keloidal collagen • Increased fibroblasts, lymphocytes, and mast cells are
usually present
Definitions
• Reactive/reparative proliferation with prominent thickened DIFFERENTIAL DIAGNOSIS
and hyalinized, eosinophilic-staining bundles of collagen
extending beyond original biopsy/wound site Hypertrophic Scar
• Lacks characteristic hyalinized collagen bundles of keloid
ETIOLOGY/PATHOGENESIS • Has more small, perpendicularly oriented vessels; lacks
telangiectasia
Unknown, Possibly Genetic
• Overlapping cases often seen; may be diagnosed as
• Fibroblasts from keloids show decreased apoptosis hypertrophic scar with keloidal collagen
• Many cytokines implicated in stimulating fibroblasts, • Clinically not as elevated as keloid
including TNF-α, TGF-β1, IL-1α, IL-1β, IL-6, IL-15
Desmoplastic Melanoma
CLINICAL ISSUES • Unlikely but rarely may enter differential diagnosis if no
Epidemiology history of trauma or previous biopsy/surgery
• Reexcision specimens of desmoplastic melanoma may
• Age show keloidal collagen
○ Most common in patients < 30 years • Usually S100(+)
• Ethnicity ○ Pitfall: Increased numbers of S100(+) dermal dendritic
○ More common in black patients; least common in white cells may be seen in scars
patients – Should not show spindled morphology of
Site desmoplastic melanoma cells
• Earlobe is most common site Nodular Fasciitis
○ Typically follows ear piercing or other trauma by a few • May rarely show focal keloidal collagen
months • Background shows classic features of nodular fasciitis with
Presentation loose, tissue culture appearance, mucin, and vessels
• Mass lesion most common • Zonation with cellular, myxoid, and more fibrous areas
• Scar that grows beyond confines of original wound
• Often erythematous, pruritic lesions with predilection for DIAGNOSTIC CHECKLIST
earlobe in black patients Pathologic Interpretation Pearls
• Potentially disfiguring • Nodular, elevated lesion compared to adjacent skin
Treatment • Thickened, hyalinized, eosinophilic collagen bundles
• Surgical approaches • Often see background of hypertrophic scar
○ Complete excision, accompanied by concurrent steroid
injections or radiotherapy to decrease risk of recurrence SELECTED REFERENCES
• Drugs 1. Chen ZY et al: The mechanisms of β-catenin on keloid fibroblast cells
proliferation and apoptosis. Eur Rev Med Pharmacol Sci. 22(4):888-95, 2018
○ Direct injection of steroids is often 1st-line treatment 2. Lee HJ et al: Recent understandings of biology, prophylaxis and treatment
strategies for hypertrophic scars and keloids. Int J Mol Sci. 19(3):E711, 2018
Prognosis
3. Zhong L et al: Identification and integrated analysis of microRNA expression
• Persistence and recurrence are common, but there is no profiles in keloid. J Cosmet Dermatol. 17(5):917-24, 2018
risk of malignancy 4. Shi C et al: The pivotal role of inflammation in scar/keloid formation after
acne. Dermatoendocrinol. 9(1):e1448327, 2017
5. Halim AS et al: Keloid scarring: understanding the genetic basis, advances,
MACROSCOPIC and prospects. Arch Plast Surg. 39(3):184-9, 2012
6. Iqbal SA et al: Identification of fibrocytes from mesenchymal stem cells in
General Features keloid tissue: a potential source of abnormal fibroblasts in keloid scarring.
• Large, nodular, dermal-based lesion with firm, white cut Arch Dermatol Res. 304(8):665-71, 2012
surface 7. Shih B et al: Comparative genomic hybridisation analysis of keloid tissue in
Caucasians suggests possible involvement of HLA-DRB5 in disease
pathogenesis. Arch Dermatol Res. 304(3):241-9, 2012
MICROSCOPIC 8. Zhang G et al: Analyses of CDC2L1 gene mutations in keloid tissue. Clin Exp
Dermatol. 37(3):277-83, 2012
Histologic Features 9. Gauglitz GG et al: Hypertrophic scarring and keloids: pathomechanisms and
• Dense proliferation of thickened, hyalinized collagen current and emerging treatment strategies. Mol Med. 17(1-2):113-25, 2011
10. Wolfram D et al: Hypertrophic scars and keloids--a review of their
bundles in dermis pathophysiology, risk factors, and therapeutic management. Dermatol Surg.
• May be background of conventional or hypertrophic scar 35(2):171-81, 2009
with smaller collagen bundles and perpendicular vessels 11. Butler PD et al: Current progress in keloid research and treatment. J Am Coll
Surg. 206(4):731-41, 2008
• Decreased vessels compared to conventional and
12. Köse O et al: Keloids and hypertrophic scars: are they two different sides of
hypertrophic scars the same coin? Dermatol Surg. 34(3):336-46, 2008

163
 Nuchal-Type Fibroma

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY • Mean size: 3 cm

• Benign pseudotumor composed of abundant collagen and MICROSCOPIC
showing predilection for posterior neck
• Poorly circumscribed, unencapsulated
ETIOLOGY/PATHOGENESIS • Arises in dermis and subcutaneous tissue
• Up to 1/2 of patients with nuchal-type fibroma also have • Abundant haphazardly arranged thickened collagen
diabetes bundles
○ Elastic fibers present but often scant
CLINICAL ISSUES • Markedly hypocellular, with scant admixed bland spindle
• Most common in young to middle-aged adults (20-50 years) cells
○ Rare in children • Entrapment of mature adipose tissue, nerve twigs, and
○ Strong male predominance cutaneous adnexal structures
• Posterior neck region most common
TOP DIFFERENTIAL DIAGNOSES
○ Infrequently arises in upper back area, extremities, face
• Treatment: Simple surgical excision • Gardner fibroma
• Local recurrence common • Nuchal fibrocartilaginous pseudotumor
• Elastofibroma
MACROSCOPIC • Fibrolipoma
• Poorly delineated, firm mass • Solitary fibrous tumor

Nuchal-Type Fibroma Poor Margination

(Left) Nuchal-type fibroma
(NTF) is a benign pseudotumor
of young to middle-aged
adults that shows a
predilection for the posterior
neck. At low power, it appears
as a paucicellular lesion
composed predominantly of
abundant thick collagen
bundles. (Right) Most cases of
NTF are poorly marginated
and often show an irregular or
infiltrative interface with the
surrounding dermis,
subcutaneous fat, and
underlying skeletal muscle ﬊.

Entrapment of Adipose Tissue, Vessels,

Abundant Thick Collagen Bundles and Nerves
(Left) Hypocellularity is the
rule in NTF, and the lesion is
composed of thick bundles of
collagen with scattered bland
fibroblastic spindle cells (often
only identifiable by their
nuclei ﬈). (Right) Entrapment
of normal structures and
tissue is a frequent finding in
NTF. This image shows mature
adipose tissue (most common),
but blood vessels and nerve
twigs are also seen with some
regularity.

164
 Nuchal-Type Fibroma

Fibroblastic/Myofibroblastic Lesions
• Abundant haphazardly arranged thickened collagen
TERMINOLOGY bundles
Abbreviations ○ Bundles may appear to intersect
• Nuchal-type fibroma (NTF) ○ Elastic fibers present but often scant
• Markedly hypocellular, with scant admixed bland spindle
Synonyms cells
• Nuchal fibroma • Entrapment of mature adipose tissue, nerve twigs, and
• Collagenosis nuchae cutaneous adnexal structures
Definitions
ANCILLARY TESTS
• Benign pseudotumor composed of abundant collagen and
showing predilection for posterior neck Immunohistochemistry
• CD34(+) in spindle cells
ETIOLOGY/PATHOGENESIS • Negative for SMA, desmin, and nuclear β-catenin
Disease Association
• Up to 1/2 of patients with NTF also have diabetes
DIFFERENTIAL DIAGNOSIS
○ NTF histologically resembles scleroderma-like process Gardner Fibroma
seen in this disease • Mainly affects children (< 10 years)
• Most associated with familial adenomatous
CLINICAL ISSUES polyposis/Gardner syndrome
Epidemiology • Nuclear β-catenin (+)
• Incidence Nuchal Fibrocartilaginous Pseudotumor
○ Rare • History of trauma often present
• Age • Arises in nuchal ligament but involves surrounding soft
○ Most commonly 20-50 years tissues
○ Rare in children • Fibrocartilaginous composition
• Sex
○ Strong male predominance
Elastofibroma
• Predominantly arises near inferior border of scapula
Site • Contains dystrophic, "beaded" elastic fibers
• Posterior neck region most common
• Infrequently arises in upper back area
Fibrolipoma
• Rare cases described in extremities and face • Well-circumscribed lesion
• Abundant mature adipose tissue component
Presentation • Fibrocollagenous bands or septa
• Solitary, painless mass
○ Rarely multifocal
Solitary Fibrous Tumor
• Prominent ectatic "staghorn" vasculature
Treatment • More cellular than NTF
• Simple surgical excision • Striking, diffuse CD34(+)
Prognosis
SELECTED REFERENCES
• Excellent
• Local recurrence common 1. Gong Y et al: Nuchal-type fibroma of the shoulder: a case report and review
of the literature. Oncol Lett. 11(6):4152-4, 2016
• No metastasis or malignant transformation 2. Kim DH et al: Multiple nuchal-type fibromas on the scalp: a case report. Ann
Dermatol. 27(2):194-6, 2015
MACROSCOPIC 3. LeBlanc KG Jr et al: Multiple nuchal fibromas in a 2-year-old without Gardner
syndrome. Pediatr Dermatol. 28(6):695-6, 2011
General Features 4. Samadi DS et al: Nuchal fibroma: a clinicopathological review. Ann Otol
Rhinol Laryngol. 109(1):52-5, 2000
• Poorly delineated, firm mass 5. Laskin WB et al: Nuchal fibrocartilaginous pseudotumor: a clinicopathologic
• White-gray cut surface study of five cases and review of the literature. Mod Pathol. 12(7):663-8,
1999
Size 6. Michal M et al: Nuchal-type fibroma: a clinicopathologic study of 52 cases.
Cancer. 85(1):156-63, 1999
• Mean: 3 cm
7. O'Connell JX et al: Nuchal fibrocartilaginous pseudotumor: a distinctive soft-
tissue lesion associated with prior neck injury. Am J Surg Pathol. 21(7):836-
MICROSCOPIC 40, 1997
8. Balachandran K et al: Nuchal fibroma. A clinicopathological study of nine
Histologic Features cases. Am J Surg Pathol. 19(3):313-7, 1995
• Poorly circumscribed, unencapsulated
• Arises in dermis and subcutaneous tissue
○ Often superficially involves underlying skeletal muscle

165
 Palmar/Plantar Fibromatosis

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY MACROSCOPIC
• Locally infiltrative but nonmetastasizing fibroblastic • Usually < 3 cm
proliferation arising from aponeurosis of hand or foot
MICROSCOPIC
○ Similar proliferations may occur on knuckles (knuckle
pads) or penile shaft (Peyronie disease) • Nodules of uniform, elongated, spindled fibroblasts in long,
• Synonyms "sweeping" fascicles
○ Palmar fibromatosis: Dupuytren contracture ○ Cellularity varies with age of lesion
○ Plantar fibromatosis: Ledderhose disease • Variably collagenous stroma with compressed, thin-walled
stromal vessels
CLINICAL ISSUES
ANCILLARY TESTS
• Palmar: Palm of hand in middle-aged to older adults
• SMA(+), desmin (variable)
• Plantar: Plantar aponeurosis in children to young adults
• Keratin (-), S100(-), CD34(-)
• Solitary or multiple firm nodules
• Treatment TOP DIFFERENTIAL DIAGNOSES
○ Complete surgical excision of involved • Desmoid fibromatosis
aponeurosis/fascia, if possible • Leiomyoma
○ Collagenase clostridium histolyticum injections are • Synovial sarcoma (monophasic)
effective alternative • Malignant peripheral nerve sheath tumor
• Benign, but significant rate of local recurrence

Palmar Fibromatosis Bland Cytology

(Left) Superficial fibromatosis
is characterized by nodules
and fascicles of uniform
fibroblasts with a collagenous
stroma. It most commonly
arises in the palm of the hand
or plantar aspect of the foot.
Origin from fascia or
aponeurosis may be
histologically evident. (Right)
All forms of superficial
fibromatosis show uniformly
bland, spindled fibroblastic
cells with small nuclei. The
cells are often plumper in
earlier lesions, and older
lesions contain more abundant
collagen. Compressed vascular
spaces ﬈ are also common.

Epithelioid Morphology Plantar Fibromatosis

(Left) It is important to note
that the spindled fascicles of
fibromatosis may appear
epithelioid when viewed in
cross section. Perinuclear
clearing is often also evident
in this morphology. (Right)
Some cases of superficial
fibromatosis may show
alarming hypercellularity,
particularly when in the foot
(plantar). Mitoses ﬈ may be
present in any form of
fibromatosis but are never
atypical.

166
 Palmar/Plantar Fibromatosis

Fibroblastic/Myofibroblastic Lesions
TERMINOLOGY MICROSCOPIC
Synonyms Histologic Features
• Palmar fibromatosis: Dupuytren contracture • Nodules of uniform, elongated, spindled fibroblasts in long,
• Plantar fibromatosis: Ledderhose disease "sweeping" fascicles
○ Monomorphic nuclei devoid of nuclear atypia
Definitions
– May appear wavy
• Locally infiltrative but nonmetastasizing fibroblastic ○ Mitotic figures may be present
proliferation arising from aponeurosis of hand or foot
• Variably collagenous stroma with compressed thin-walled
○ Similar proliferations may occur on knuckles (knuckle stromal vessels
pads) or penile shaft (penile fibromatosis or Peyronie
• Cellularity varies with age of lesion
disease)
○ In general, plantar fibromatosis is hypercellular
• Scattered, multinucleated giant cells or metaplastic bone or
CLINICAL ISSUES
cartilage may be present
Epidemiology ○ Mainly plantar forms
• Incidence • No necrosis
○ Palmar fibromatosis most common of superficial
fibromatoses ANCILLARY TESTS
• Age Immunohistochemistry
○ Palmar: Middle-aged to older adults
• SMA(+), desmin (variable)
○ Plantar: Children to young adults
• Nuclear β-catenin (+) in up to 50% of cases but often focal
• Sex
• Keratin (-), S100(-), CD34(-)
○ Strong male predominance
Site DIFFERENTIAL DIAGNOSIS
• Palmar: Dermis and underlying fascia of palm of hand, Desmoid Fibromatosis
particularly ulnar aspect
• Occurs in sites other than hands, feet, and penis
• Plantar: Within plantar aponeurosis, often in nonweight-
○ Usually abdominal wall, muscles of extremities,
bearing areas
abdominal mesentery
Presentation • Large, highly infiltrative tumors
• Palmar • Nuclear β-catenin (+) more common and more diffuse
○ Small nodules or string-like indurations • Mutations in APC and CTNNB1
○ Contractures may result, usually of 4th/5th digits Leiomyoma
○ Bilateral palmar involvement in 50% of cases
• Uncommon in hands and feet
○ May occur in association with other forms of superficial
• Bundles and fascicles of eosinophilic spindled cells with
fibromatosis
blunt-ended nuclei
• Plantar
• Strong, diffuse SMA(+) and desmin (+)
○ Solitary or multiple firm nodules
○ Contractures are rare Synovial Sarcoma (Monophasic)
• Usually highly cellular but cytologically monomorphic
Treatment
• Focal keratin (+) &/or EMA(+)
• Limited or complete surgical excision of involved
• Nuclear TLE1(+)
aponeurosis/fascia
• Collagenase clostridium histolyticum injections are Malignant Peripheral Nerve Sheath Tumor
effective alternative • Usually large tumors; may arise from nerve or neurofibroma
Prognosis • Focal S100(+) in many cases
• SMA(-), desmin (-)
• Benign
• Significant rate of local recurrence
SELECTED REFERENCES
MACROSCOPIC 1. Sanjuan-Cerveró R et al: Efficacy and adverse effects of collagenase use in
the treatment of Dupuytren's disease: a meta-analysis. Bone Joint J. 100-
General Features B(1):73-80, 2018
2. Peimer CA et al: Dupuytren contracture recurrence following treatment
• Firm, tan/gray nodules with collagenase clostridium histolyticum (CORDLESS [Collagenase Option
for Reduction of Dupuytren Long-Term Evaluation of Safety Study]): 5-Year
Size Data. J Hand Surg Am. 40(8):1597-605, 2015
• Usually < 3 cm 3. Karabeg R et al: Results of surgery treatment of Dupuytren's contracture in
115 patients. Med Arch. 66(5):329-31, 2012
4. Zgonis T et al: Plantar fibromatosis. Clin Podiatr Med Surg. 22(1):11-8, 2005
5. Montgomery E et al: Superficial fibromatoses are genetically distinct from
deep fibromatoses. Mod Pathol. 14(7):695-701, 2001

167
 Desmoid-Type Fibromatosis

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY
• Intermediate (locally aggressive) but nonmetastasizing
myofibroblastic neoplasm that is characterized by
infiltrative growth and tendency toward local recurrence
CLINICAL ISSUES
• Most are sporadic; 10% familial
• Wide age range (most common in young to middle-aged
adults)
• Extraabdominal and intraabdominal tumors
• Mesenteric tumors can be associated with familial
adenomatous polyposis (FAP)/Gardner syndrome
• Usually large, painless, slow-growing mass
• Treatment
○ Surgical excision with preservation of function, radiation,
or nonsurgical medical therapy
• Benign; does not metastasize
○ Significant rate of local recurrence
MACROSCOPIC
• Variable size range (usually 5-10 cm)
MICROSCOPIC
• Very infiltrative
• Uniform, bland, spindled cells in long, "sweeping" fascicles
• Prominent stromal collagen; occasional myxoid change
• Small to medium blood vessels with perivascular edema
ANCILLARY TESTS
• Nuclear β-catenin (+) in ~ 75% of cases
• SMA(+), MSA(+), focal desmin (+), S100 protein (-), CD117(-)
TOP DIFFERENTIAL DIAGNOSES
• Low-grade myofibroblastic sarcoma
• Low-grade dedifferentiated liposarcoma
• Fibrous scar
• Sclerosing mesenteritis/idiopathic retroperitoneal fibrosis
• Nodular fasciitis

Desmoid Fibromatosis Fascicular Growth

(Left) Desmoid fibromatosis is
a locally aggressive tumor that
most often occurs in young to
middle-aged adults. They are
generally large, and most
show a firm, tan-white cut
surface. This tumor in the
shoulder has eroded into the
scapula; however, typically
fibromatoses do not erode
bone. (Right) Histologically,
the classic example of
fibromatosis shows
collagenous stroma containing
long fascicles of fibroblasts
that appear to stream from
one end of the microscopic
field to the other.

Loose Storiform Growth Bland Cytology

(Left) In addition to fascicular
architecture, a loose storiform
growth pattern is common in
desmoid fibromatosis. Stromal
blood vessels ﬈ are a
conspicuous feature of this
tumor, and the vascular
lumina may appear
compressed or dilated. (Right)
The fibroblasts of fibromatosis
are uniform and cytologically
bland. Nuclei are vesicular and
contain 1 to a few tiny nucleoli
﬈. Mitoses vary in number
but are never atypical.

168
 Desmoid-Type Fibromatosis

Fibroblastic/Myofibroblastic Lesions
TERMINOLOGY Prognosis
• Benign; does not metastasize
Synonyms • Prone to local recurrence
• Aggressive fibromatosis ○ Higher risk associated with younger age, mesenteric or
• Desmoid tumor head/neck location, and particularly FAP/Gardner
• Musculoaponeurotic fibromatosis syndrome
Definitions • Rare deaths due to compromise of local vital structures
• Intermediate (locally aggressive) but nonmetastasizing
MACROSCOPIC
myofibroblastic neoplasm that is characterized by
infiltrative growth and tendency toward local recurrence General Features
• Poorly circumscribed, firm
CLINICAL ISSUES • Tan-white, gritty, fibrous or gelatinous cut surface
Epidemiology Size
• Incidence • Variable range (usually 5-10 cm)
○ Less common than superficial (palmar/plantar) ○ Intraabdominal tumors often > 10 cm
fibromatosis
○ Most are sporadic; 10% familial MICROSCOPIC
• Age
Histologic Features
○ Wide range (most common in young to middle-aged
adults) • Majority of cases show infiltration of adjacent adipose
• Sex tissue or skeletal muscle
○ Female predominance • Uniform, spindled to stellate cells in long, "sweeping"
– Puberty to 40 years of age fascicles or loose, vague storiform arrays
○ Male = female ○ Small vesicular nuclei with 1 or several tiny nucleoli
– Later adulthood ○ Mitotic activity varies
– Pediatric population ○ Absence of nuclear pleomorphism and atypical mitotic
figures
Site • Collagenous stroma
• Extraabdominal ○ May appear sparse in cellular areas or abundant in
○ Shoulder, chest wall, back, thigh, head/neck hyalinized lesions
○ Anterior abdominal wall – Some cases with keloidal collagen fibers
• Intraabdominal – Heavily hyalinized tumors may show vague nodular
○ Mesentery, retroperitoneum, pelvis growth
• Very rare in hands and feet ○ Occasional extensive myxoid or edematous stromal
changes
Presentation – Most common in mesenteric and pelvic tumors
• Usually large, painless, slow-growing mass – Often associated with microhemorrhages and
• Abdominal wall fibromatosis classically occurs in pregnant extravasated erythrocytes
women or within year following childbirth • Small to medium-sized stromal blood vessels
• Intraabdominal fibromatosis ○ Often show perivascular edema
○ Asymptomatic, vague abdominal pain or symptoms ○ Ectatic, thin-walled, staghorn or hemangiopericytoma-
related to adjacent organ involvement (small bowel, like vessels with perivascular hyalinization can be seen in
ureter, bladder, etc.) intraabdominal tumors
○ ~ 50% of cases associated with prior trauma or surgical • Metaplastic ossification or calcification rare
procedure
○ Mesenteric fibromatosis can occur within setting of ANCILLARY TESTS
familial adenomatous polyposis (FAP), Gardner
syndrome Immunohistochemistry
• May rarely arise in surgical scar (cicatricial fibromatosis) • SMA(+), MSA(+), focal desmin (+)
• CD34, h-caldesmon, S100 protein, CD117, STAT6 (-)
Treatment
• Nuclear β-catenin (+) in ~ 75% of cases
• Symptomatic tumors
○ Surgical excision with preservation of function Molecular Genetics
– Reexcision of recurrences • Somatic mutations in β-catenin CTNNB1 gene on 3p21
– Radiation, chemotherapy, hormone therapy ± NSAIDs (sporadic tumors)
for unresectable lesions • Inactivating germline mutations in APC gene on 5q21-q22
• Asymptomatic tumors may be followed clinically or treated (tumors in FAP/Gardner syndrome)
medically to stabilize

169
 Desmoid-Type Fibromatosis
Fibroblastic/Myofibroblastic Lesions
DIFFERENTIAL DIAGNOSIS
Low-Grade Myofibroblastic Sarcoma
• Highly infiltrative
• Most arise in head/neck or extremities
• Displays at least focal nuclear atypia
• Nuclear β-catenin (-)
Low-Grade Dedifferentiated Liposarcoma
• Most common in retroperitoneum
• May feature component of well-differentiated liposarcoma
• MDM2 (+) and CDK4 (+) by IHC
• MDM2 amplification by FISH
Fibrous Scar
• Site of previous trauma or surgical procedure
○ Caveat: Rare cases of fibromatosis arise in scar tissue
• Usually lacks infiltrative growth pattern
• Nuclear β-catenin (-)
Sclerosing Mesenteritis/Idiopathic Retroperitoneal
Fibrosis
• Middle-aged to older adults
• Prominent chronic inflammatory component (particularly
plasma cells), often with fat necrosis
• Less cellular and fascicular than fibromatosis
• Nuclear β-catenin (-)
Nodular Fasciitis
• May show morphologic overlap with highly myxoid
fibromatosis
• Small, rapidly growing, well-circumscribed lesion
• Usually lacks long, "sweeping" fascicles
• Nuclear β-catenin (-)
Proliferative Fasciitis/Myositis
• Features enlarged, ganglion cell-like myofibroblasts
• Fasciitis background can mimic myxoid fibromatosis
Low-Grade Fibromyxoid Sarcoma
• Hypocellular collagenous zones with myxoid foci
• Usually lacks long, "sweeping" fascicles
• MUC4(+), rare focal SMA(+)
• FUS gene translocations
Gastrointestinal Stromal Tumor (Spindle Cell Type)
• Arises from muscularis propria of gastrointestinal tract
• Usually lacks long, "sweeping" fascicles
• CD117(+), DOG1(+), CD34(+)
• KIT or PDGFRA mutation
Inflammatory Myofibroblastic Tumor
• Mesentery common location in pediatric age group
• Usually abundant inflammatory cells (plasma cells,
lymphocytes)
• ALK(+) or ALK gene rearrangments in 50%
• SMA(+), nuclear β-catenin (-)
Leiomyoma
• Well circumscribed, expansile
• Smooth muscle cytologic features
• SMA(+), desmin (+)
• Nuclear β-catenin (-)
170
Deep (Aggressive) Angiomyxoma
• May show morphologic overlap with highly myxoid pelvic
desmoids
• Lacks fascicular growth seen in fibromatosis
• Desmin (+), CD34 (variable); nuclear β-catenin (-)
SELECTED REFERENCES
1. Bekers EM et al: Multifocal occurrence of extra-abdominal desmoid type
fibromatosis - a rare manifestation. A clinicopathological study of 6 sporadic
cases and 1 hereditary case. Ann Diagn Pathol. 35:38-41, 2018
2. Koike H et al: Is immunohistochemical staining for β-catenin the definitive
pathological diagnostic tool for desmoid-type fibromatosis?: a multi-
institutional study. Hum Pathol. ePub, 2018
3. Agaimy A et al: CTNNB1 (β-Catenin)-altered neoplasia: a review focusing on
soft tissue neoplasms and parenchymal lesions of uncertain histogenesis.
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4. Carter JM et al: CTNNB1 mutations and estrogen receptor expression in
neuromuscular choristoma and its associated fibromatosis. Am J Surg
Pathol. 40(10):1368-74, 2016
5. Huss S et al: β-catenin (CTNNB1) mutations and clinicopathological features
of mesenteric desmoid-type fibromatosis. Histopathology. 62(2):294-304,
2013
6. Barak S et al: Immunoreactivity for calretinin and keratins in desmoid
fibromatosis and other myofibroblastic tumors: a diagnostic pitfall. Am J
Surg Pathol. 36(9):1404-9, 2012
7. Bertani E et al: Recurrence and prognostic factors in patients with aggressive
fibromatosis. The role of radical surgery and its limitations. World J Surg
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8. Bo N et al: Analysis of β-catenin expression and exon 3 mutations in pediatric
sporadic aggressive fibromatosis. Pediatr Dev Pathol. 15(3):173-8, 2012
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type fibromatosis after radiation therapy. Hum Pathol. 43(9):1418-24, 2012
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receptor and nonreceptor tyrosine kinases. Hum Pathol. 43(10):1711-8,
2012
11. Dumont AG et al: A nonrandom association of gastrointestinal stromal
tumor (GIST) and desmoid tumor (deep fibromatosis): case series of 28
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resected fibromatosis of the breast. Histopathology. 60(2):347-56, 2012
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Med. 114(8):832-5, 1990
 Desmoid-Type Fibromatosis
Characteristic Vasculature
Stromal Myxoid Change
Stellate Cells
Fibroblastic/Myofibroblastic Lesions
Haphazard Cellular Arrangement
(Left) The stromal blood
vessels of fibromatosis are
often elongated and
compressed between lesional
fascicles. It is common to see a
slight rim of perivascular
clearing (edema ﬈) that may
contain scattered chronic
inflammatory cells. (Right) In
some foci of desmoid
fibromatosis, the cellular
organization is less fascicular
and storiform and more
haphazard. This appearance is
more common in
myxedematous areas. Note
the characteristic vessels ﬈
with mild perivascular edema.
Fasciitis-Like Morphology
(Left) Myxoid or edematous
stromal change is not
uncommon in desmoid
fibromatosis and varies from
focal to diffuse. This change is
particularly common in
mesenteric lesions. (Right)
Extensive myxoid stromal
change and a loose
arrangement of lesional cells
may impart an appearance
similar to nodular fasciitis or
inflammatory myofibroblastic
tumor. Extravasated
erythrocytes ﬈ further add to
the morphologic overlap.
Myxocollagenous Stroma
(Left) In some myxedematous
cases of desmoid fibromatosis,
the lesional cells appear
stellate as well as spindled. In
hypocellular examples, this
morphology may resemble
desmoplastic fibroblastoma.
(Right) Occasional cases of
desmoid fibromatosis show
alternating or swirling
collagenous and
myxedematous layers. This
low-power appearance may
raise concerns for low-grade
fibromyxoid sarcoma.
171
 Desmoid-Type Fibromatosis
Fibroblastic/Myofibroblastic Lesions

Epithelioid Cytomorphology Large, Ectatic Blood Vessels

(Left) Similar to superficial
forms of fibromatosis, in
desmoid tumors, an epithelioid
morphology may be apparent
if spindled fascicles are cut
and viewed in cross section. A
perinuclear rim of clearing ﬈
is often also seen in many of
the cells. (Right) Dilated
staghorn or
hemangiopericytoma-like
stromal vessels with
perivascular hyalinization may
be seen in desmoid
fibromatosis, particularly
intraabdominal tumors. This
finding may be quite
prominent in some cases.

Sclerotic Stroma Vague Nodular Growth

(Left) Extensive stromal
hyalinization or sclerosis may
be seen in desmoid
fibromatosis. These cases are
often very hypocellular. Note
the dilated blood vessel ﬈.
(Right) In addition to
characteristic "streaming"
fascicular growth, some cases
of desmoid fibromatosis show
formation of vague nodules
﬈. The nodules are often
highly collagenous and
hypocellular and may show
artifactual clefting ﬊.

Keloidal Collagen Stromal Microhemorrhage

(Left) Thick, glassy bundles of
keloidal collagen are seen in
some cases of desmoid
fibromatosis. This finding is
particularly common in
intraabdominal tumors.
(Right) Stromal
microhemorrhages are a
variable finding in desmoid
fibromatosis. They are often
focal and associated with
myxoid stromal change but
rarely may be somewhat
prominent.

172
 Desmoid-Type Fibromatosis
Metaplastic Bone Formation
Infiltration of Fat and Skeletal Muscle
Wispy SMA Expression
Fibroblastic/Myofibroblastic Lesions
Infiltrative Growth
(Left) Rare cases of desmoid
fibromatosis contain focal
stromal calcification or
formation of metaplastic
bone. (Right) Desmoid
fibromatosis is generally a
highly infiltrative and locally
aggressive neoplasm.
Depending upon the exact
location of the tumor,
infiltration of fat or muscle is
often easily identified at the
periphery.
Entrapped Myocytes
(Left) H&E shows a desmoid
tumor with extensive
infiltration of both adipose
tissue ﬈ and skeletal muscle
﬊. Note the checkerboard
pattern of myoinfiltration in
this case, a finding similar to
what is usually seen in
proliferative myositis. (Right)
In intramuscular tumors,
entrapped atrophic or
regenerative skeletal muscle
fibers may show compressed
nuclei and mimic pleomorphic
fibroblastic nuclei ﬈. This
phenomenon is similar to what
can be seen in other
intramuscular neoplasms.
Nuclear β-Catenin Expression
(Left) SMA expression is
common in desmoid
fibromatosis and classically
manifests as fine, "wispy"
cytoplasmic positivity. This is
in contrast to leiomyoma,
which shows strong, diffuse
cytoplasmic expression. (Right)
Abnormal nuclear localization
of β-catenin is seen in ~ 70%
of cases of desmoid
fibromatosis. Cytoplasmic
expression is commonly seen
in a variety of other tumors
and is entirely nonspecific.
Only nuclear expression
counts in supporting the
diagnosis.
173
 Dermatofibrosarcoma Protuberans

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY
• Locally aggressive, low-grade, superficial fibroblastic
sarcoma characterized in most cases by COL1A1-PDGFB
gene fusion
○ May show progression to higher grade neoplasm with
increased metastatic risk [fibrosarcomatous
dermatofibrosarcoma protuberans (DFSP)]
CLINICAL ISSUES
• Young to middle-aged adults
• Most common in trunk and proximal extremities
• Persistent, slow-growing, plaque-like or protuberant
nodular/multinodular cutaneous mass
• Treatment: Complete surgical excision with widely negative
(2-3 cm) margins
• Local recurrences common (up to 50% of cases)
• Metastases extremely rare (< 0.5%)
○ 10-15% risk in tumors with fibrosarcomatous changes
MICROSCOPIC
• Diffuse infiltration of dermis and subcutis
○ Honeycomb pattern of fat infiltration
• Uniform spindled cells characteristically arranged in
storiform or whorled growth pattern
• Variable myxoid stromal change
• Fibrosarcomatous DFSP
○ More cellular zones with fascicular growth
○ Increased cytologic atypia and mitotic activity
ANCILLARY TESTS
• Diffuse CD34(+)
• COL1A1-PDGFB fusion in most cases
○ Subset with PDGFD rearrangements
TOP DIFFERENTIAL DIAGNOSES
• Dermatofibroma (fibrous histiocytoma)
• Perineurioma
• Deep benign fibrous histiocytoma

Dermatofibrosarcoma Protuberans Infiltrative Growth Patterns

(Left) Dermatofibrosarcoma
protuberans (DFSP) is a
distinctive, superficial, low-
grade sarcoma with a
tendency toward local
recurrence. It is characterized
clinically by an exophytic,
plaque-like or multinodular
growth in most cases. (Right)
At low magnification, DFSP
often shows diffuse dermal
and subcutaneous
involvement with
characteristic infiltration of
subcutaneous fat ﬈ by
neoplastic cells that grow
along fibrous septa ﬊.

Nodular Pattern Storiform Architecture

(Left) Some cases of DFSP are
more clearly nodular and
multinodular, as depicted;
however, infiltrative
properties are still readily
apparent as evidenced by
infiltration of subcutaneous
fat ﬈. (Right) A tight
storiform or pinwheel growth
pattern (tumor cells radiating
or spiraling out from a
common center) is highly
characteristic of DFSP,
although not pathognomonic.

174
 Dermatofibrosarcoma Protuberans

Fibroblastic/Myofibroblastic Lesions
○ Multiple protuberances are often seen in recurrent cases
TERMINOLOGY
• Firm, gray-white cut surface
Abbreviations • Usually no tumor necrosis
• Dermatofibrosarcoma protuberans (DFSP) • Rare tumors arise in subcutaneous tissue
Definitions Size
• Locally aggressive, low-grade, superficial fibroblastic • Wide size range (average: 5 cm)
sarcoma characterized in most cases by COL1A1-PDGFB ○ May grow to considerable sizes
gene fusion
○ May show progression to higher grade neoplasm with MICROSCOPIC
increased metastatic risk fibrosarcomatous DFSP
Histologic Features
CLINICAL ISSUES • Dermal-based, ill-defined proliferation
○ Diffuse infiltration of dermis and subcutis
Epidemiology – Infiltration along fibrous connective tissue septa and
• Incidence into subcutaneous fat (honeycomb pattern)
○ Overall rare (< 1% of all sarcomas) – Deeply growing or recurrent tumors may superficially
– However, most common dermal sarcoma infiltrate underlying fascia and skeletal muscle
• Age – Tumor cells encase, but do not destroy, cutaneous
○ Most common in young to middle-aged adults adnexal structures
– May also occur in children (including congenitally) or – Rare cases grow in linear, plaque-like fashion with less
elderly infiltration (atrophic DFSP or plaque-like DFSP)
• Sex ○ Overlying skin is uninvolved
○ Slight male predominance – Uninvolved subepithelial layer of dermis (grenz zone)
may or may not be present
Site
○ Rare cases are confined to subcutaneous tissue with no
• Most common in trunk (chest, back, shoulder, abdominal dermal involvement
wall) and proximal extremities • Uniform spindled cells characteristically arranged in
• Also head/neck and distal extremities storiform or whorled growth pattern
• Rare in genital areas ○ Plump or elongated wavy nuclei
Presentation – Minimal to mild nuclear atypia
• Persistent, slow-growing, protuberant, nodular or – Mitoses usually sparse (or < 5 mitoses per 10 HFP)
multinodular cutaneous mass • Collagenous stroma containing small blood vessels
○ Can show rapid growth within setting of ○ Rare cases show prominent vasculature
fibrosarcomatous transformation ○ Myointimal proliferation may be seen in some vessels
○ Rapid growth also seen in pregnancy – When prominent and occlusive, appear as small
• Early lesions may appear flat and plaque-like nodules or "myoid balls"
• Variable myxoid stromal change
Treatment ○ Rarely may be extensive (myxoid DFSP)
• Complete surgical excision with widely negative margins – More nodular growth with accentuation of stromal
○ 2- to 3-cm margins recommended vasculature
○ Mohs surgery can significantly reduce local recurrence – Prominent storiform growth often lost
with less tissue loss – Can mimic other low-grade myxoid neoplasms
• Radiotherapy may be used for margin-positive, (especially neural)
unresectable disease • May contain scattered pigmented melanocytic cells
• Treatment with imatinib and other tyrosine kinase ○ Described as pigmented DFSP or Bednar tumor
inhibitors in advanced, fibrosarcomatous, and metastatic • Rare findings: Granular cytoplasmic change, bundled or
cases braided growth pattern
Prognosis • May show areas of giant cell fibroblastoma (GCFB)
morphology
• Local recurrences common (up to 50% of cases) if not
○ Pure DFSP may recur as pure GCFB and vice versa
completely excised
○ Can recur multiple times Fibrosarcomatous Transformation
• Metastases extremely rare (< 0.5%) • Represents morphologic form of progression to higher
• Tumors with fibrosarcomatous progression grade tumor
○ Similar recurrence risk as conventional DFSP ○ Often intermediate grade; rarely high grade
○ Distant metastases in 10-15% • More frequently occurs de novo; rarely in local recurrence
○ May arise in any form or variant of DFSP
MACROSCOPIC • Abrupt or gradual transformation from areas of
General Features conventional DFSP morphology to zones showing more
cellular and fascicular architecture
• Indurated dermal plaque with nodularities

175
 Dermatofibrosarcoma Protuberans
Fibroblastic/Myofibroblastic Lesions

○ Herringbone pattern common Dermatomyofibroma

○ Increased cytologic atypia and mitotic activity (> 5 per 10 • Superficial, plaque-like dermal neoplasms
HPF) • Elongated spindled cells with myofibroblastic features
○ Often nodular, expansile growth rather than infiltrative ○ Cells oriented parallel to surface; no prominent storiform
○ May show myxoid change or contain pigmented growth
dendritic cells • Increased number of small elastic fibers
○ Necrosis may be present • CD34(+), usually focal
• Rare high-grade pleomorphic morphology
Solitary Fibrous Tumor
ANCILLARY TESTS • Predominantly arise in subcutaneous and deep soft tissues
Immunohistochemistry • Generally well circumscribed and lacks infiltrative border
with surrounding tissue
• Diffuse CD34(+)
• Ectatic "staghorn" vasculature common
○ Often lost or decreased in areas of fibrosarcomatous
• CD34(+); STAT6(+)
transformation
• Negative for S100 protein, keratin, SMA, desmin Spindle Cell (Desmoplastic) Melanoma
○ Myoid bundles are SMA(+) • Often in actinically damaged skin in elderly patients
Molecular Genetics • Often associated with lentigo maligna
• Homogeneous expression of S100 protein
• Characteristic t(17;22)(q22;q13) leading to COL1A1-PDGFB
fusion product
SELECTED REFERENCES
○ Identical rearrangement seen in GCFB
1. Dadone-Montaudié B et al: Alternative PDGFD rearrangements in
• Subset of PDGFB-fusion negative tumors contain PDGFD dermatofibrosarcomas protuberans without PDGFB fusions. Mod Pathol.
rearrangements ePub, 2018
○ COL6A3-PDGFD and EMILIN2-PDGFD fusions reported 2. Dickson BC et al: Dermatofibrosarcoma protuberans with a novel COL6A3-
PDGFD fusion gene and apparent predilection for breast. Genes
Chromosomes Cancer. 57(9):437-45, 2018
DIFFERENTIAL DIAGNOSIS 3. Shah KK et al: Dermatofibrosarcoma protuberans of distal extremities and
acral sites: a clinicopathologic analysis of 27 cases. Am J Surg Pathol.
Dermatofibroma (Fibrous Histiocytoma) 42(3):413-9, 2018
• Particularly cellular and aneurysmal variants 4. Llombart B et al: Subcutaneous dermatofibrosarcoma protuberans, a rare
subtype with predilection for the head: a retrospective series of 18 cases. J
• Often polymorphous cellular infiltrate Am Acad Dermatol. 77(3):503-11.e1, 2017
• Lacks diffuse honeycomb-like fat infiltration 5. Zhang Z et al: Application of COL1A1-PDGFB fusion gene detection by
• Lacks diffuse CD34 expression (peripheral positivity in some fluorescence in situ hybridization in biopsy tissue of dermatofibrosarcoma
protuberans. J Dermatol. 44(7):798-802, 2017
cellular variants)
6. Cesinaro AM et al: An unusual presentation of dermatofibrosarcoma
• Lacks COL1A1-PDGFB fusion protuberans with pleomorphic sarcomatous transformation: potential pitfall
and diagnostic strategy. J Cutan Pathol. 43(7):589-93, 2016
Perineurioma 7. Thway K et al: Dermatofibrosarcoma protuberans: pathology, genetics, and
• Elongated tumor cells with thin, elongated cytoplasmic potential therapeutic strategies. Ann Diagn Pathol. 25:64-71, 2016
8. Santos-Briz A et al: Braided pattern in a dermatofibrosarcoma protuberans: a
processes potential mimicker of neural neoplasms. Am J Dermatopathol. 36(11):920-4,
• Lacks highly infiltrative growth of DFSP 2014
• EMA(+), claudin-1 (+), GLUT-1(+) 9. Serra-Guillén C et al: Mohs micrographic surgery in dermatofibrosarcoma
protuberans allows tumour clearance with smaller margins and greater
• CD34(+) in many cases (focal to extensive) preservation of healthy tissue compared with conventional surgery: a study
• Lacks COL1A1-PDGFB fusion of 74 primary cases. Br J Dermatol. ePub, 2014
10. Llombart B et al: Dermatofibrosarcoma protuberans: a comprehensive
Deep Benign Fibrous Histiocytoma review and update on diagnosis and management. Semin Diagn Pathol.
30(1):13-28, 2013
• Chronic inflammatory component 11. Llombart B et al: Dermatofibrosarcoma protuberans: a clinicopathological,
• Ectatic "staghorn" vasculature common immunohistochemical, genetic (COL1A1-PDGFB), and therapeutic study of
• Variable nuclear pleomorphism low-grade versus high-grade (fibrosarcomatous) tumors. J Am Acad
Dermatol. 65(3):564-75, 2011
• Lacks COL1A1-PDGFB fusion 12. Llombart B et al: Dermatofibrosarcoma protuberans: clinical, pathological,
and genetic (COL1A1-PDGFB ) study with therapeutic implications.
Diffuse Neurofibroma Histopathology. 54(7):860-72, 2009
• Lacks prominent storiform pattern 13. Bague S et al: Dermatofibrosarcoma protuberans presenting as a
subcutaneous mass: a clinicopathological study of 15 cases with exclusive or
• Presence of Meissner-like corpuscles is common near-exclusive subcutaneous involvement. Am J Dermatopathol. 30(4):327-
• S100 protein (+) 32, 2008
• Patchy to focal CD34(+) 14. Reimann JD et al: Myxoid dermatofibrosarcoma protuberans: a rare variant
analyzed in a series of 23 cases. Am J Surg Pathol. 31(9):1371-7, 2007
• Lacks COL1A1-PDGFB fusion 15. Terrier-Lacombe MJ et al: Dermatofibrosarcoma protuberans, giant cell
fibroblastoma, and hybrid lesions in children: clinicopathologic comparative
Plaque-Like CD34(+) Dermal Fibroma analysis of 28 cases with molecular data--a study from the French Federation
• Benign, superficial, plaque-like proliferation with medallion- of Cancer Centers Sarcoma Group. Am J Surg Pathol. 27(1):27-39, 2003
like clinical appearance
• Tumor contains dilated venules and spares adnexal
structures
• Lacks COL1A1-PDGFB fusion
176
 Dermatofibrosarcoma Protuberans
Uniform Cytologic Features
Interstitial Collagen
Subcutaneous Septal Growth
Fibroblastic/Myofibroblastic Lesions
Cellular Storiform Pattern
(Left) All cases of DFSP are
composed of uniform spindle
cells with minimal to no
nuclear atypia. Nuclei can
appear wavy and suggest
neural origin. Mitotic activity
varies from sparse to no more
than 5 figures per 10 HPF.
(Right) Although many cases
of DFSP show more than a
single architectural pattern,
some cases display only a
repetitive, tight storiform
growth pattern throughout
the lesion, as depicted.
Interstitial Collagen
(Left) The amount of
interstitial collagen varies
widely in DFSP. Some cases
appear to have very little, and
in others, like the case shown
here, the collagen is more
prominent. Note the
underlying storiform
architecture. (Right) More
heavily collagenized areas ſt
may occasionally appear to
interdigitate with more typical
cellular areas ﬊ in DFSP.
Honeycomb Fat Infiltration
(Left) Tumor cells in DFSP
characteristically infiltrate
along subcutaneous
fibroconnective septa, as
shown, and then out into the
adipose tissue. Infiltration of
adipose tissue is a nearly
constant feature of this tumor.
(Right) The tumor cells in DFSP
not only grow around lobules
of adipose tissue but also
through them, usually with
entrapment of single
adipocytes. This overall
appearance has been likened
to a honeycomb pattern.
177
 Dermatofibrosarcoma Protuberans
Fibroblastic/Myofibroblastic Lesions

Fat Infiltration Pseudolipoblastic Entrapped Fat

(Left) Fat infiltration may be
impressively extensive in some
cases of DFSP and may lead to
confusion with diffuse-type
neurofibroma, particularly on
small biopsy. (Right) In some
cases of DFSP, lobules of
entrapped fat may contain
many small atrophic
adipocytes, closely simulating
lipoblastic differentiation.
Coupled with myxoid stroma,
this finding may lead to
confusion with myxoid
liposarcoma.

Skeletal Muscle Infiltration Entrapment of Normal Structures

(Left) Although a honeycomb
pattern of fat infiltration is
characteristic of DFSP, it is
important to note that a
similar pattern of skeletal
muscle infiltration ﬊ may be
seen in deeply extending or
recurrent tumors. (Right) As a
testimony to its highly
infiltrative nature, the tumor
cells of DFSP are also
commonly identified growing
around and entrapping normal
structures, such as nerve twigs
﬊ and cutaneous adnexal
structures (e.g., eccrine ducts)
(not shown).

Grenz Zone Infiltration of Dermal Collagen

(Left) Most cases of DFSP
show a thin layer of
uninvolved dermis ﬈ (grenz
zone) beneath the epidermis.
In some cases, however, the
tumor may appear to directly
contact the surface. (Right)
Infiltration of dermal collagen
is not uncommon in DFSP and
may lead to misdiagnosis as
dermatofibroma (fibrous
histiocytoma). More typical
features of DFSP are usually
present.

178
 Dermatofibrosarcoma Protuberans
Less Prominent Storiform Growth
Rare Bundled or Braided Growth
Myoid Nodules
Fibroblastic/Myofibroblastic Lesions
Rare Nuclear Palisading
(Left) Not uncommonly,
storiform growth is less
prominent in some areas of
DFSP, and tumor cells may
show a curly or lamellar
growth. This finding is
particularly common in the
superficial (dermal) portion of
the tumor. (Right) Nuclei
appear to focally palisade ﬊
in this image of a collagenized
DFSP. Nuclear palisading,
however, is not a typical
feature of DFSP and should
lead to consideration of other
entities first.
Rare Prominent Stromal Hyalinization
(Left) A rare morphologic
pattern in DFSP is that of
intersecting or interwoven
small bundles, cords, and
nodules of tumor cells. This
pattern may impart a neural
appearance. (Right) In rare
cases of DFSP, stromal
collagenization or
hyalinization is prominent and
may leave little clue to the
diagnosis; however, areas of
more conventional
morphology are usually
present.
CD34 Expression
(Left) Small, localized myoid
nodules ﬊ are an unusual
feature seen in some cases of
DFSP. These structures likely
represent a nonneoplastic
myointimal proliferation
within stromal vessels. (Right)
CD34 expression is
characteristically strong and
diffuse in most cases of DFSP,
making it a sensitive and
useful marker for supporting
the diagnosis. It lacks
specificity, however, and can
be expressed in a variety of
spindled mesenchymal
neoplasms, including
neurofibroma and
perineurioma.
179
 Dermatofibrosarcoma Protuberans
Fibroblastic/Myofibroblastic Lesions

Myxoid Stroma Myxoid Dermatofibrosarcoma Protuberans

(Left) Myxoid stromal change
may be seen in DFSP.
Although not uncommon as a
focal finding, rare cases are
predominantly or entirely
myxoid. (Right) Although the
characteristic storiform
pattern of DFSP may be
retained in myxoid variants, it
is more often than not less
well developed or lost
completely. Stromal vessels
often become more prominent
and may lead to confusion
with other tumors, such as
myxofibrosarcoma.

Myxoid Dermatofibrosarcoma Protuberans Reticulated Morphology

(Left) This example of myxoid
DFSP shows complete loss of
storiform growth and
prominent stromal blood
vessels. Many nuclei also
appear thin and wavy. A
variety of other myxoid
mesenchymal neoplasms must
be considered with this
morphologic appearance.
(Right) Myxoid DFSP may show
an interconnecting,
reticulated or sieve-like
morphology, similar to the
microcystic/reticular variant of
schwannoma. Note that
pseudocystic or
pseudovascular spaces ﬉ may
also be present.

Pigmented Dermatofibrosarcoma Plaque-Like or Atrophic

Protuberans (Bednar Tumor) Dermatofibrosarcoma Protuberans
(Left) Occasional cases of
otherwise conventional DFSP
may contain scattered
dendritic cells containing
melanin pigment. A stellate
appearance ﬊ to these cells is
not uncommon. This variant is
also known as a Bednar tumor.
Rarely, these cells may also be
seen in fibrosarcomatous
transformation in DFSP.
(Right) Rare cases of DFSP
show a plaque-like growth
with less conspicuous
infiltration of subcutaneous
adipose tissue. These
neoplasms are easily
misdiagnosed as benign
mesenchymal neoplasms.

180
 Dermatofibrosarcoma Protuberans
Giant Cell Fibroblastoma Morphology
Recurrent Myxoid Dermatofibrosarcoma
Protuberans With Areas of Giant Cell
Fibroblastoma
Fibrosarcomatous Dermatofibrosarcoma
Protuberans
Fibroblastic/Myofibroblastic Lesions
Giant Cell Fibroblastoma
(Left) Foci of giant cell
fibroblastoma (right) may
occur in otherwise
conventional DFSP (far left).
Of note, DFSP may recur in
some patients as pure giant
cell fibroblastoma and vice
versa. (Right) Giant cell
fibroblastoma
characteristically contains
hyperchromatic,
multinucleated tumor cells
within a hyalinized to myxoid
stroma. The cells often line
stromal clefts ﬈, imparting a
pseudovascular appearance.
Fibrosarcomatous Dermatofibrosarcoma
Protuberans
(Left) This case of recurrent
DFSP not only showed diffuse
myxoid stromal changes but
also foci resembling giant cell
fibroblastoma. Note the vague
pseudovascular spaces lined
by tumor cells ﬈. (Right)
Fibrosarcomatous
dermatofibrosarcoma
protuberans (FS-DFSP) is most
easily recognized by a
prominent cellular, fascicular
growth pattern rather than a
tight storiform pattern. This
finding represents transition
from a low-grade to a higher
grade (usually intermediate)
neoplasm.
Herringbone Architecture
(Left) Fascicular growth is well
developed in FS-DFSP and is
usually easily distinguished
from conventional low-grade
DFSP. Fibrosarcomatous
transformation may be seen
de novo (most common) or in
recurrences. (Right) A well-
developed herringbone
architecture is a common
finding in FS-DFSP and may
lead to consideration of other
entities, such as synovial
sarcoma, malignant peripheral
nerve sheath tumor (MPNST),
and adult-type fibrosarcoma.
181
 Dermatofibrosarcoma Protuberans
Fibroblastic/Myofibroblastic Lesions

Expansile Growth Neural-Like Morphology

(Left) In contrast to
conventional DFSP, FS-DFSP
often shows a leading edge
that is more expansile and
"pushing" than frankly
infiltrative. However, more
typical infiltrative growth can
also be seen. (Right) As in all
forms of DFSP, tumor cell
nuclei in FS-DFSP can appear
thin and wavy. Combined with
a fascicular growth pattern,
this finding may lead to
confusion with MPNST.

Uniform Cytologic Features Increased Mitotic Rate

(Left) Similar to low-grade
DFSP, the tumor cells in FS-
DFSP are relatively uniform;
however, nuclei show greater
atypia. Very rare cases show
an undifferentiated
pleomorphic sarcoma-like
morphology. (Right) Compared
to low-grade DFSP, the mitotic
rate in FS-DFSP is usually
higher than 5 figures per 10
HPF. Note the 3 mitoses ﬊ in
this image.

Stromal Collagenization in
Fibrosarcomatous Dermatofibrosarcoma
Round Cell Morphology Protuberans
(Left) Given its prominent
fascicular growth, some areas
of FS-DFSP may appear to
show a round cell morphology
when fascicles are viewed in
cross section. (Right) As in
conventional DFSP, FS-DFSP
may also show increased
stromal collagenization. Note
the otherwise prominent
fascicular growth.

182
 Dermatofibrosarcoma Protuberans
Stromal Collagenization in
Fibrosarcomatous Dermatofibrosarcoma
Protuberans
Myxoid Change in Fibrosarcomatous
Dermatofibrosarcoma Protuberans
CD34 Expression Decreased or Lost
Fibroblastic/Myofibroblastic Lesions
Myoid Nodules in Fibrosarcomatous
Dermatofibrosarcoma Protuberans
(Left) Increased stromal
collagen in conjunction with
prominent fascicular growth in
FS-DFSP may lead to
confusion with
leiomyosarcoma or low-grade
myofibroblastic sarcoma.
(Right) Myoid nodules may be
seen in both conventional,
low-grade DFSP and FS-DFSP;
however, they are more
common in the latter setting,
as depicted.
Rare Compartmentalized Pattern
(Left) Myxoid stromal change
may be seen in FS-DFSP. In
contrast to the myxoid variant
of conventional DFSP, myxoid
FS-DFSP usually retains its
characteristic fascicular
growth. (Right) This unusual
case of FS-DFSP contained foci
showing an interwoven,
bundled or braided growth
pattern similar to what has
been reported in low-grade
DFSP. Most of the tumor,
however, showed more typical
features of FS-DFSP.
COL1A1-PDGFB Fusion by FISH
(Left) In contrast to low-grade
DFSP and its variants, FS-DFSP
characteristically shows lost or
diminished expression of
CD34. This loss can often be
demonstrated nicely in
transition areas with low-
grade areas (upper left). Rare
cases of FS-DFSP retain strong
expression of this antigen.
(Right) FISH analysis of DFSP
shows the characteristic 17;22
translocation with fusion of
the COL1A1 and PDGFB
genes. The red and green
signals colocalize, resulting in
a yellow signal ﬇.
183
 Solitary Fibrous Tumor

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY • Fibrous stroma often with abundant collagen

• Fibroblastic mesenchymal neoplasm often featuring
prominent branching staghorn vascular pattern
○ Includes tumors once classified as soft tissue
hemangiopericytoma and giant cell angiofibroma
CLINICAL ISSUES
• Usually adults (range: 20-70 years)
• Can arise virtually anywhere (somatic or visceral)
○ Subcutaneous or deep soft tissue
• Treatment: Complete surgical resection
• Most are benign (85-90%)
• Combination of patient age, tumor size, mitotic activity, and
necrosis is predictive of metastatic risk (Demicco et al)
MICROSCOPIC
• Classic variably cellular patternless pattern
• Uniform, spindled to ovoid fibroblastic cells
• Characteristic prominent staghorn vascular pattern
• Stromal myxoid change in some cases and may be diffuse
• Mitotic activity low (usually < 3 figures per 10 HPF)
• Malignant and dedifferentiated forms occur
• Variants: Lipomatous ("fat forming")
ANCILLARY TESTS
• Strong, diffuse CD34(+) and nuclear STAT6(+)
• Usually keratin, S100, desmin, CD117, CD31 (-)
• Molecular: Characteristic NAB2-STAT6 fusion
TOP DIFFERENTIAL DIAGNOSES
• Deep benign fibrous histiocytoma
• Spindle cell lipoma
• Cellular angiofibroma
• Dermatofibrosarcoma protuberans
• Angiofibroma of soft tissue
• Synovial sarcoma (monophasic)

Solitary Fibrous Tumor Bland Fibroblastic Cells

(Left) Low-power view of a
solitary fibrous tumor (SFT)
shows areas of varying
cellularity and a prominent
vascularized stroma that
classically features ectatic and
irregularly shaped vessels ﬈.
These vessels are often
described as staghorn, given
their antler-like shapes.
(Right) The lesional cells of
SFT are spindled to ovoid,
contain bland, relatively
uniform nuclei, and are often
arranged in a patternless
pattern. A collagenous stroma
﬈ is characteristic, but its
prominence varies by regional
cellularity.

CD34 Expression STAT6 Expression

(Left) CD34 expression is
present in the vast majority of
cases of SFT and is typically
strong and diffuse, although
there are often small foci of
decreased or absent
expression ﬉. Rare cases are
negative for this antigen.
(Right) Diffuse nuclear
expression of STAT6 is
characteristic of SFT and is
seen is the vast majority of
cases. With the exception of
rare cases of dedifferentiated
liposarcoma, most entities on
the differential diagnosis of
SFT are negative.

184
 Solitary Fibrous Tumor
TERMINOLOGY
Abbreviations
• Solitary fibrous tumor (SFT)
Synonyms
• Hemangiopericytoma
• Giant cell angiofibroma (giant cell-rich variant of SFT)
• Localized fibrous mesothelioma (obsolete)
Definitions
• Fibroblastic mesenchymal neoplasm often featuring
prominent branching staghorn vascular pattern
○ Includes tumors once classified as soft tissue
hemangiopericytoma
CLINICAL ISSUES
Epidemiology
• Age
○ Usually adults (range: 20-70 years)
○ Occasionally in children and adolescents
• Sex
○ M=F
– Slight male predominance in lipomatous SFT
– Strong female predominance in superficial SFT
Site
• Pleura, thoracic cavity
• Extrathoracic sites
○ Extremities
○ Head and neck, including orbit and intracranial sites
○ Abdominal cavity, pelvis, retroperitoneum
○ Visceral organs
• However, may occur at almost any site
Presentation
• Slow-growing, often painless mass
• May arise in subcutaneous or deep soft tissue
○ Rare tumors are dermal/cutaneous
• Larger tumors may be associated with paraneoplastic
hypoglycemia due to production of IGF2
Treatment
• Complete surgical resection with negative margins
• Combination of radiation therapy and chemotherapy may
be utilized in malignant SFT
Prognosis
• Most are benign (85-90%)
• Minority behave aggressively
○ Recurrences and distant metastases
• Updated risk stratification model (Demicco et al)
○ Based on patient age, tumor size, mitotic activity, and
necrosis
○ Scoring
– Age: 0 if < 55 years; 1 if ≥ 50 years
– Tumor size: 0 if < 5 cm; 1 if 5 to < 10 cm; 2 if 10 to < 15
cm; 3 if ≥ 15 cm
– Mitotic activity: 0 if < 1 mitosis/10 HPF; 1 if 1-3
mitoses/10 HPF; 2 if ≥ 4 mitoses/10 HPF
– Necrosis: 0 if < 10%, 1 if ≥ 10%
Fibroblastic/Myofibroblastic Lesions
○ Total score
– Low risk: 0-3
– Intermediate risk: 4-5
– High risk: 6-7
○ Metastatic risk (5 years): 10% (intermediate-risk group)
and 73% (high-risk group)
– No metastasis seen in low-risk group (in 2017 study)
• Activating mutations in telomerase reverse transcriptase
gene (TERT) associated with adverse outcome
○ Strongly associated with older patient age, large tumor
size, and higher risk classifications
MACROSCOPIC
General Features
• Lobulated, circumscribed mass
○ Histologically malignant tumors may be locally infiltrative
• Firm, gray-white or brown cut surface
• Occasional cystic degeneration or hemorrhage
Size
• Range: 1-20 cm (most 5-10 cm)
MICROSCOPIC
Histologic Features
• Classic patternless pattern showing field-to-field variations
in cellularity and general absence of defined architectural
organization
○ Spindled to ovoid fibroblastic cells with scanty cytoplasm
and small, uniform, vesicular nuclei
– Isolated degenerative nuclear atypia occasionally
present
– Mitotic activity low (usually < 3 figures per 10 HPF)
– Rare rounded or epithelioid cytomorphology
○ Some tumors are diffusely cellular
– Cellular SFT once classified as classic
hemangiopericytoma
○ Cells often appear randomly arranged (patternless
pattern)
– Tumors can show areas of more defined storiform,
trabecular, or loose fascicular growth
○ Characteristic prominent vascular pattern
– Branching or staghorn-shaped vessels
– Perivascular hyalinization common
○ Varying component of fibrous stroma (often abundant)
– Frequent dense, keloid-like hyalinization
– Densely hyalinized stroma may show cracking artifact
– Distinctive collagen fibers may appear thick, irregular,
or nodular
○ Stromal myxoid change in some cases and may be
diffuse
○ Mast cells common
○ Occasional multinucleated stromal giant cells
– May be abundant and line pseudovascular spaces
□ Originally described as distinct entity: Giant cell
angiofibroma
• Atypical or potentially malignant features in SFT
○ Hypercellularity, nuclear pleomorphism, infiltrative
margins, necrosis
○ > 4 mitoses per 10 HPF
– One of better indicators of prognosis
185
 Solitary Fibrous Tumor
Fibroblastic/Myofibroblastic Lesions
• Dedifferentiated SFT
○ Abrupt transition from conventional low-grade SFT to
areas of high-grade sarcoma
– High-grade areas may contain heterologous elements
Morphologic Variant
• Lipomatous ("fat-forming") SFT
○ Conventional or cellular SFT admixed with variable
amount of mature fat
○ Synonym: Lipomatous hemangiopericytoma
○ Rare histologically malignant forms
– May contain lipoblasts or areas resembling well-
differentiated liposarcoma
ANCILLARY TESTS
Immunohistochemistry
• Strong CD34(+), often diffuse (but can be patchy)
○ Rare, benign-appearing tumors (-)
○ May also be decreased or lost in
malignant/dedifferentiated SFT
• Strong, diffuse nuclear STAT6(+)
• Diffuse TLE1(+) in rare subset (pitfall)
• Retained nuclear Rb protein expression
• Focal EMA(+) or SMA(+) in up to 40%
• Nuclear β-catenin (+) in minor subset
• Generally keratin, S100 protein, desmin, CD117, DOG1,
CD31 (-)
Molecular Genetics
• Recurrent intrachromosomal rearrangement (12q)
resulting in NAB2-STAT6 fusion
○ Detectable by RT-PCR (difficult by FISH)
DIFFERENTIAL DIAGNOSIS
Deep Benign Fibrous Histiocytoma
• Well-developed storiform growth pattern common
• Uniform cellularity
• Foamy macrophages &/or giant cells in 50% of cases
• Variable CD34; STAT6(-)
Spindle Cell Lipoma
• Can show morphologic overlap with lipomatous SFT
• Most common in back, neck, shoulder
• Staghorn vasculature rare
• Loss of nuclear Rb protein expression
• STAT6(-)
Cellular Angiofibroma
• Can show morphologic overlap with SFT
• Most common in vulvovaginal/inguinal regions
• Vessels often smaller than in SFT and show
hyalinization/fibrosis
• Loss of nuclear Rb protein expression
• STAT6(-)
Dermatofibrosarcoma Protuberans
• Dermal component
• Infiltrative growth and well-developed storiform pattern
• Staghorn vascular pattern absent
• STAT6(-)
• Characteristic t(17;22) with COL1A1-PDGFB fusion
186
Angiofibroma of Soft Tissue
• Can show marked morphologic overlap with SFT
• Prominent thin- to thick-walled stromal vasculature
• CD34 and STAT6 (-)
• t(5;8) with AHRR-NCOA2 gene fusion
Synovial Sarcoma (Monophasic)
• Usually hypercellular spindle cell neoplasm with variable
fascicular growth
• Prominent staghorn vascular pattern uncommon
• Focal cytokeratin (+) &/or EMA(+) expression
• Diffuse TLE1 (+) characteristic (but also rarely seen in SFT)
• STAT6 and CD34 (-)
• Characteristic t(X;18) with SS18 (SYT) rearrangement
Myopericytoma
• Conspicuous perivascular growth or arrangement
• SMA(+); CD34 and STAT6 (-)
Gastrointestinal Stromal Tumor
• Arises from wall of GI tract, mesentery, or omentum
• Staghorn vasculature may be present
• CD117(+) and DOG1(+) in most cases; also CD34(+)
• Most show KIT or PDGFRA oncogenic mutations
Dedifferentiated Liposarcoma
• High-grade pleomorphic morphology in many cases
• Rare cases with SFT-like morphology
○ May also show STAT6(+)
• MDM2(+) and CDK4(+) by IHC
• MDM2 amplification
SELECTED REFERENCES
1. Feasel P et al: Superficial solitary fibrous tumor: a series of 26 cases. Am J
Surg Pathol. 42(6):778-785, 2018
2. Lin Y et al: Telomerase promoter mutations and copy number alterations in
solitary fibrous tumours. J Clin Pathol. 71(9):832-839, 2018
3. Olson NJ et al: Dedifferentiated solitary fibrous tumor: a concise review.
Arch Pathol Lab Med. 142(6):761-766, 2018
4. Demicco EG et al: Risk assessment in solitary fibrous tumors: validation and
refinement of a risk stratification model. Mod Pathol. 30(10):1433-1442,
2017
5. Kouba E et al: Solitary fibrous tumour of the genitourinary tract: a
clinicopathological study of 11 cases and their association with the NAB2-
STAT6 fusion gene. J Clin Pathol. 70(6):508-514, 2017
6. Smith SC et al: Solitary fibrous tumors of the head and neck: a multi-
institutional clinicopathologic study. Am J Surg Pathol. 41(12):1642-56, 2017
7. Yang EJ et al: Solitary fibrous tumour of the female genital tract: a
clinicopathological analysis of 25 cases. Histopathology. 72(5):749-759, 2017
8. Bahrami A et al: TERT promoter mutations and prognosis in solitary fibrous
tumor. Mod Pathol. 29(12):1511-1522, 2016
9. Doyle LA et al: Nuclear expression of STAT6 distinguishes solitary fibrous
tumor from histologic mimics. Mod Pathol. 27(3):390-5, 2014
10. Koelsche C et al: Nuclear relocation of STAT6 reliably predicts NAB2-STAT6
fusion for the diagnosis of solitary fibrous tumour. Histopathology.
65(5):613-22, 2014
11. Demicco EG et al: Solitary fibrous tumor: a clinicopathological study of 110
cases and proposed risk assessment model. Mod Pathol. 25(9):1298-306,
2012
12. Lee JC et al: Malignant fat-forming solitary fibrous tumor (so-called
"lipomatous hemangiopericytoma"): clinicopathologic analysis of 14 cases.
Am J Surg Pathol. 35(8):1177-85, 2011
13. Mosquera JM et al: Expanding the spectrum of malignant progression in
solitary fibrous tumors: a study of 8 cases with a discrete anaplastic
component--is this dedifferentiated SFT? Am J Surg Pathol. 33(9):1314-21,
2009
14. Guillou L et al: Lipomatous hemangiopericytoma: a fat-containing variant of
solitary fibrous tumor? Clinicopathologic, immunohistochemical, and
ultrastructural analysis of a series in favor of a unifying concept. Hum Pathol.
31(9):1108-15, 2000
 Solitary Fibrous Tumor
Variable Cellularity
Bland Cytologic Features
Cystic Hyalinized Vessels
Fibroblastic/Myofibroblastic Lesions
Stromal Collagen
(Left) Variations in cellularity
are common in SFT, as seen in
this H&E showing areas of
both high ﬊ and low cell
density ﬉. Note also the
absence of any defined
cytoarchitectural pattern.
(Right) Stromal collagen is
generally more prominent in
less cellular regions of SFT, as
depicted. Note the artifactual
clefts or "cracks" ﬊ present in
the more densely collagenized
foci.
Vascular Hyalinization
(Left) The nuclei of SFT are
small, vesicular, and relatively
uniform. Nucleoli, if present,
are small and inconspicuous.
Mitotic activity is low and
usually does not exceed 3
mitoses per 10 HPF. (Right)
Ectatic staghorn vessels are
characteristic of SFT but are
not specific for the diagnosis.
Perivascular hyalinization or
fibrosis may also be seen and
in some cases can be striking,
as in this H&E.
Focal Marked Vascularity
(Left) This unusual case of SFT
shows areas containing large,
cystically dilated blood
vessels. Hypervascular
examples, such as this, may be
embolized prior to surgery.
Note the focus ﬈ of more
typical SFT. (Right) This
otherwise conventional case
of SFT contains several
discrete, centrally located foci
featuring a more complex
anastomosing vasculature ﬉,
as depicted. Note the more
characteristic larger staghorn
vessels ﬊.
187
 Solitary Fibrous Tumor
Fibroblastic/Myofibroblastic Lesions

Lipomatous ("Fat-Forming") Solitary Hyalinized Lipomatous Solitary Fibrous

Fibrous Tumor Tumor
(Left) SFT may contain varying
amounts of mature adipose
tissue, as depicted, and has
been referred to as the
lipomatous or "fat-forming"
variant of SFT. Cases
containing abundant fat may
be confused with a true
lipomatous neoplasm. (Right)
Some cases of SFT may
feature both diffuse hyalinized
stroma and abundant mature
adipose tissue. In conjunction
with CD34 expression,
misdiagnosis as spindle cell
lipoma, cellular angiofibroma,
or myofibroblastoma is
possible.

Myxoid Solitary Fibrous Tumor Myxoid Solitary Fibrous Tumor

(Left) Myxoid stromal change
is not uncommon in SFT but is
often focal when present.
Rare tumors are
predominantly myxoid and can
be challenging to distinguish
from other low-grade myxoid
neoplasms. A prominent
staghorn vasculature ﬊ can
be a helpful clue. (Right) H&E
shows marked hypocellularity
within a myxoid area of SFT.
Note the dilated vessels.

Myxoid Lipomatous Solitary Fibrous Tumor Myxoid Solitary Fibrous Tumor Vasculature
(Left) This case of myxoid SFT
contains diffuse mature
adipose tissue, resembling
myxoid liposarcoma; however,
DDIT3 FISH is negative, and
STAT6 immunohistochemistry
is diffusely positive. (Right)
Myxoid areas of SFT may also
contain the characteristic
prominent vasculature seen in
more conventional, nonmyxoid
areas.

188
 Solitary Fibrous Tumor
Prominent Stromal Collagen
Hypocellular, Hyalinized Solitary Fibrous
Hyalinized Solitary Fibrous Tumor
Striking Collagen Production
Fibroblastic/Myofibroblastic Lesions
Keloidal Collagen Fibers
(Left) This case of SFT shows
prominent thickened collagen
fibers arranged haphazardly.
Dilated vascular channels are
not evident in this particular
field but were more
conspicuous elsewhere in the
tumor. (Right) Thick, glassy
collagen bundles similar to
those seen in keloids can be
present in SFT. Note the
prominent "cracking" artifact
(clear slits and spaces)
between collagen bundles.
Tumor
(Left) H&E shows a
hyalinized/sclerotic region of
SFT in which the cells are
arranged randomly rather
than in linear cords.
Artifactual clefting ﬈ or
"cracking" is also conspicuous.
(Right) H&E shows a
longstanding case of SFT
featuring prominent stromal
sclerosing and marked
hypocellularity. Note the
various gaping vessels.
Architectural Patterns
(Left) This example of SFT
features large, irregular
bundles of eosinophilic,
keloidal-like collagen,
imparting a striking low-power
appearance. (Right) Although
tumor cells are classically
arranged in a relatively
random or haphazard fashion
in most cases of SFT, it is not
uncommon to find areas
showing more defined
architectures, including
storiform arrays, short
bundles, or loose fascicles.
189
 Solitary Fibrous Tumor
Fibroblastic/Myofibroblastic Lesions

Mast Cells Cystic Change

(Left) Mast cells ﬈ are a
common, but nonspecific
finding in SFT. They are often
more prominent in
hypocellular regions with
loose edematous or myxoid
stroma. (Right) Focal cystic
change can be present in some
cases of SFT, as depicted, and
may be quite prominent in rare
cases. Associated hemorrhage
may or may not be present.

Cellular Solitary Fibrous Tumor Cellular Solitary Fibrous Tumor

(Left) Most cases of SFT
contain areas of varying
cellularity; however, some
tumors show predominantly
increased cellularity and can
resemble synovial sarcoma or
malignant peripheral nerve
sheath tumor. (Right) Cellular
examples of SFT with a more
ovoid or rounded
cytomorphology and
prominent vasculature, as
depicted, represent tumors
that were formerly classified
as classic
hemangiopericytoma.

Multinucleated Stromal Giant Cells Giant Cell Angiofibroma Morphology

(Left) The lesional cells of SFT
are relatively uniform and
usually show no more than
mild pleomorphism. Some
cases, however, contain cells
featuring multiple enlarged
nuclei ﬈. (Right) In some
cases of SFT, multinucleated
stromal giant cells ﬊ are
more abundant and can be
seen lining pseudovascular
spaces ﬈. Tumors with this
morphology were formerly
classified as giant cell
angiofibroma but are now
recognized as a form of SFT.
Areas of more conventional
morphology are almost always
present.

190
 Solitary Fibrous Tumor
Osteoclast-Like Giant Cells
Malignant Solitary Fibrous Tumor:
Elevated Mitotic Rate
Malignant Solitary Fibrous Tumor:
Pleomorphism
Fibroblastic/Myofibroblastic Lesions
Malignant Solitary Fibrous Tumor
(Left) Osteoclast-like giant
cells ﬈ are a rare finding in
SFT and are distinct from the
multinucleated stromal giant
cells that line pseudovascular
spaces in tumors with a giant
cell angiofibroma morphology.
(Right) Histologically
malignant forms of SFT do
occur but are uncommon. They
are often characterized by a
variable combination of
hypercellularity (shown),
nuclear pleomorphism,
elevated mitotic activity,
invasive growth, and necrosis.
Malignant Solitary Fibrous Tumor:
Fascicular Growth
(Left) Mitotic activity ﬈
appears to be the best
prognostic indicator of
behavior in SFT, and the rate
in malignant tumors often
exceeds 4 mitoses per 10 HPF.
As a point of practice, the
mitotic rate should be
assessed on all cases of
cellular SFT, even in cases
without nuclear
pleomorphism. (Right)
Malignant SFT can show a
more prominently fascicular
growth pattern, as depicted,
resembling other spindle cell
sarcomas. A small focus of
tumor necrosis ﬊ is also
evident in this H&E.
Malignant Solitary Fibrous Tumor: Loss of
CD34
(Left) In some cases,
malignant SFT may feature
prominent nuclear
pleomorphism and atypia ﬈.
Note that the overall
background architecture and
vasculature somewhat
resembles conventional SFT.
(Right) CD34 expression is
highly variable in malignant
SFT and may be patchy,
decreased, or absent.
Demonstration of nuclear
STAT6 expression can be very
helpful in CD34(-) cases.
191
 Low-Grade Myofibroblastic Sarcoma

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY MICROSCOPIC
• Atypical, infiltrative spindle cell neoplasm with • Often diffusely infiltrative growth
morphologic, immunohistochemical, &/or ultrastructural • Fascicles or storiform arrays of spindled cells
evidence of myofibroblastic differentiation ○ Pale eosinophilic cytoplasm and indistinct borders
• Synonym: Myofibrosarcoma ○ Elongated, fusiform, vesicular nuclei with variable
CLINICAL ISSUES nucleoli
– Mild to moderate atypia present at least focally
• Occurs predominantly in adult patients
• Prominent stromal collagen
• Frequently occurs in head and neck region
• Mitotic rate often low (< 5 mitoses per 10 HPF)
○ Also extremities, trunk, groin, abdomen/pelvis, other
sites ANCILLARY TESTS
• Treatment: Complete surgical excision • Variable SMA(+) &/or desmin (+)
• Local recurrence is common • H-caldesmon, CD34, keratin, EMA, S100, myogenin (-)
• Metastases are rare
TOP DIFFERENTIAL DIAGNOSES
MACROSCOPIC • Desmoid fibromatosis
• Well-circumscribed or ill-defined firm mass • Leiomyosarcoma
• Variable size range, often < 5 cm • Spindle cell rhabdomyosarcoma

Low-Grade Myofibroblastic Sarcoma Low-Grade Myofibroblastic Sarcoma

(Left) Gross photograph shows
a low-grade myofibroblastic
sarcoma (LGMS) arising in the
testis. The cut surface of this
tumor usually appears tan-
white-gray and fibrous on cut
section. (Right) LGMS (a.k.a.
myofibrosarcoma) is
characterized in most cases by
diffuse infiltration of
preexisting structures and
normal tissue, as seen in this
H&E involving skeletal muscle.

Infiltrative Growth Infiltrative Growth

(Left) Cases of LGMS that arise
in subcutaneous tissue often
show extensive infiltration of
adipose tissue by fascicles of
tumor cells ﬊, as shown in
this H&E. (Right) Infiltration of
skeletal muscle fibers in LGMS
often shows a checkerboard
pattern with tumor cell
growth around individual
fibers. Also note the scattered
hyperchromatic nuclei ﬊,
another characteristic feature
of LGMS.

192
 Low-Grade Myofibroblastic Sarcoma

Fibroblastic/Myofibroblastic Lesions
○ Often cellular or hypercellular; rarely hypocellular
TERMINOLOGY
○ Spindled cells show pale eosinophilic cytoplasm and
Abbreviations indistinct borders
• Low-grade myofibroblastic sarcoma (LGMS) ○ Elongated, fusiform, vesicular nuclei with variable
nucleoli
Synonyms – May show nuclear indentations
• Myofibrosarcoma – Mild to moderate atypia present at least focally
Definitions □ Enlargement, hyperchromasia
• Atypical, infiltrative spindle cell neoplasm with – Rare cases contain cells with marked nuclear
morphologic, immunohistochemical, &/or ultrastructural pleomorphism
evidence of myofibroblastic differentiation • Prominent stromal collagen
○ May show hyalinization or keloidal collagen
CLINICAL ISSUES • Stroma may contain increased number of thin-walled
capillaries
Epidemiology • Mitotic rate is often low (< 5 mitoses per 10 HPF)
• Incidence • Tumor necrosis uncommon
○ Rare • May progress to higher grade morphology
– May be more common due to lack of well-defined
diagnostic criteria ANCILLARY TESTS
• Age
Immunohistochemistry
○ Occurs predominantly in adult patients
○ Children are rarely affected • Variable SMA(+) &/or desmin (+)
• Sex ○ Diffuse desmin (+) may be seen in subset
○ Slight male predominance • H-caldesmon, CD34, keratin, EMA, S100 protein, myogenin
(-)
Site • Nuclear β-catenin (+) in subset
• Occurs frequently in head and neck region
○ Particularly tongue and oral cavity DIFFERENTIAL DIAGNOSIS
• Also extremities, trunk, groin, abdomen/pelvis, other sites Desmoid Fibromatosis
• May arise in subcutaneous or deep soft tissues
• Shows infiltrative growth but lacks diffuse growth through
○ Very rare dermal origin
and around preexisting structures
Presentation • Lacks cytologic atypia
• Slow-growing, painless mass • Desmin usually (-)

Treatment Leiomyosarcoma
• Complete surgical excision • Cells with brightly eosinophilic cytoplasm and distinct cell
borders
Prognosis • Elongated, blunted, cigar-shaped nuclei
• Local recurrence is common • Usually diffuse cytoplasmic SMA(+), h-caldesmon (+)
○ May recur repeatedly
Spindle Cell Rhabdomyosarcoma
• Metastases are rare
○ Often after prolonged time interval • Clinical and morphologic overlap with LGMS
• Contains scattered rhabdomyoblasts
MACROSCOPIC • Desmin (+); focal myogenin (+)
General Features Inflammatory Myofibroblastic Tumor
• Well-circumscribed or ill-defined firm mass • Prominent inflammatory infiltrate (lymphocytes, plasma
• Pale gray-white, fibrous cut surface cells)
• Myxoid stroma common
Size • ALK(+) in 50% of cases
• Variable, often < 5 cm
○ Some cases may grow to > 10 cm SELECTED REFERENCES
1. Taweevisit M et al: Distinctive features of low-grade myofibroblastic
MICROSCOPIC sarcoma on aspiration cytology: a case report. Cytopathology. 73(4): 634-44,
2018
Histologic Features 2. Cai C et al: In myofibroblastic sarcomas of the head and neck, mitotic activity
• Often highly infiltrative growth and necrosis define grade: a case study and literature review. Virchows Arch.
463(6):827-36, 2013
○ Tumor cells may grow diffusely between individual 3. Fisher C: Myofibrosarcoma. Virchows Arch. 445(3):215-23, 2004
preexisting cells and structures 4. Montgomery E et al: Myofibrosarcoma: a clinicopathologic study. Am J Surg
– Checkerboard pattern of infiltration within skeletal Pathol. 25(2):219-28, 2001
muscle 5. Mentzel T et al: Low-grade myofibroblastic sarcoma: analysis of 18 cases in
the spectrum of myofibroblastic tumors. Am J Surg Pathol. 22(10):1228-38,
• Fascicles or storiform arrays of spindled cells 1998

193
 Low-Grade Myofibroblastic Sarcoma
Fibroblastic/Myofibroblastic Lesions

Nuclear Atypia Cytologic Features

(Left) LGMS is composed of
fascicles and storiform arrays
of spindled myofibroblastic
cells with ill-defined, pale
eosinophilic cytoplasm.
Scattered hyperchromatic
nuclei are frequently identified
﬊. (Right) The nuclei of LGMS
are cytologically
myofibroblastic with vesicular
chromatin and a small
eosinophilic nucleolus. They
may appear elongated and
tapering or plump with
irregular/notched contours.

Stromal Collagen Stromal Collagen

(Left) Stromal collagen is a
consistent feature of LGMS
and is often abundant. (Right)
In some cases of LGMS, the
stromal collagen is more
conspicuously bundled and
thicker and may even appear
keloidal. This morphologic
appearance may be retained in
the rare event of metastasis.

Fibromatosis-Like Morphology Fascicular Growth

(Left) Some areas of LGMS
may show a streaming,
fascicular growth similar to
fibromatosis. Importantly,
nuclear
atypia/hyperchromasia is a
feature of LGMS and not
fibromatosis, and the former
typically shows a greater
degree of soft tissue
infiltration. (Right) A
fascicular growth pattern is
common in LGMS and may
show focal herringbone
architecture, as depicted. Note
the abundant stromal
collagen.

194
 Low-Grade Myofibroblastic Sarcoma
Rare Hypercellular Areas
Hypocellular Areas
Higher Grade Morphology
Fibroblastic/Myofibroblastic Lesions
Fasciitis-Like Areas
(Left) Hypercellular areas may
be found in LGMS but are
generally very rare. Other
entities, such as synovial
sarcoma, adult-type
fibrosarcoma, and
leiomyosarcoma, must be
carefully excluded. (Right)
Myxoid and loosely arranged
architecture may be seen
focally in LGMS and may raise
the possibility of nodular
fasciitis or inflammatory
myofibroblastic tumor.
Infiltrative growth, nuclear
atypia, and lack of a
prominent chronic
inflammatory cell component
favor LGMS.
Stromal Hyalinization
(Left) Areas showing marked
stromal hyalinization are not
uncommon in LGMS; however,
tumors with diffuse
hyalinization are rare. Note
the scattered hyperchromatic
nuclei ﬈ in this H&E. (Right)
This example of LGMS is
hypocellular and shows
abundant stromal
hyalinization. Scattered
mitotic figures are also
present ﬈.
Rare Metastases
(Left) Rare cases of LGMS may
show areas of transition to a
higher grade sarcoma;
however, this is more likely to
be seen in recurrences.
Primary tumors with high-
grade features are probably
best classified as
undifferentiated pleomorphic
sarcoma. (Right) H&E shows a
lung metastasis in a 45-year-
old woman with LGMS of the
hip diagnosed 3-4 years prior.
The tumor is cytologically low
grade and shows abundant
collagen production, similar to
the original. Note the
entrapped alveolar spaces ﬊.
195
 Inflammatory Myofibroblastic Tumor

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY MICROSCOPIC
• Myofibroblastic spindle cell neoplasm of predominantly • Spindled or stellate myofibroblastic cells
children and young adults that classically features mixed • Main histologic patterns: Myxoid, fascicular, sclerosing
chronic inflammatory infiltrate • Inflammatory cell infiltrate common
CLINICAL ISSUES ANCILLARY TESTS
• Most common in children and young adults • SMA(+), variable desmin (+)
• Abdominopelvic region (mesentery, omentum, • Cytoplasmic ALK(+) in 50-60%
retroperitoneum) common • Molecular: Rearrangement of 2p23 (ALK) in ~ 50% of cases
○ Also lung, bladder, female genital tract, CNS, others ○ ALK-RANBP2 rearrangement identified in EIMS variant
• Treatment: Complete surgical resection ○ Other gene fusions reported in subset of ALK-negative
• Prognosis variable but generally good inflammatory myofibroblastic tumor (IMT) (e.g., ROS1)
○ Up to 35% may recur and < 5% metastasize
TOP DIFFERENTIAL DIAGNOSES
○ Usually intraabdominal or retroperitoneal tumors
○ Distinctive intraabdominal morphologic variant, • Nodular fasciitis
epithelioid inflammatory myofibroblastic sarcoma • Desmoid fibromatosis
(EIMS), shows aggressive course • Leiomyosarcoma
• IgG4-related sclerosing disease

Inflammatory Myofibroblastic Tumor Myxoid Stroma

(Left) Inflammatory
myofibroblastic tumor (IMT) is
a myofibroblastic neoplasm of
intermediate biologic
potential that most frequently
occurs in children and young
adults. A variably cellular
myxoid morphology is
common in these tumors.
(Right) The cells of IMT are
typically spindled or stellate
and show eosinophilic to
amphophilic cytoplasm.
Extravasated erythrocytes
may be seen. Heavily myxoid
tumors may resemble nodular
fasciitis or a reactive process.

Cytologic Features ALK Expression

(Left) Cytologically, the
lesional cells of IMT show
vesicular nucleoli with 1 or 2
conspicuous nucleoli. In some
cases, the nucleoli may be
larger and more prominent.
The mitotic rate varies but is
often low. (Right) Cytoplasmic
ALK expression is identified in
~ 50% of cases of IMT and may
be patchy or extensive. This
expression roughly correlates
with the presence of an ALK
gene arrangement.

196
 Inflammatory Myofibroblastic Tumor

Fibroblastic/Myofibroblastic Lesions
• Tumor size, mitotic rate, cellularity, nuclear atypia, and
TERMINOLOGY necrosis do not appear to correlate well with outcome in
Abbreviations conventional IMT
• Inflammatory myofibroblastic tumor (IMT)
MACROSCOPIC
Synonyms
General Features
• Inflammatory myofibroblastic sarcoma
• Inflammatory fibrosarcoma • Often multilobulated
• Inflammatory pseudotumor • Solid tan-white-pink firm cut surface
• Plasma cell granuloma Size
Definitions • 1-20 cm (most < 10 cm)
• Myofibroblastic spindle cell neoplasm of predominantly
children and young adults that classically features mixed MICROSCOPIC
chronic inflammatory infiltrate Histologic Features
• Expansile or infiltrative peripheral border
CLINICAL ISSUES • Myofibroblastic cells
Epidemiology ○ Usually spindled, ovoid, or stellate
• Incidence – Rarely epithelioid
○ Rare ○ Vesicular nuclei with 1 or 2 conspicuous nucleoli
• Age ○ Occasional cells have enlarged nuclei with macronucleoli
○ Wide range (most common in children and young adults) or "smudgy" chromatin
• Sex • 3 main histologic patterns
○ Slight female predominance ○ Spindle or stellate cells within prominent loose myxoid
stroma
Site ○ Compact spindle cells in fascicles or storiform arrays
• Abdominopelvic region (mesentery, omentum, ○ Hypocellular, sclerotic matrix
retroperitoneum) most common • Inflammatory cells common but vary in number
• Many other sites including head/neck, lung, bladder, female ○ Lymphocytes and plasma cells predominate
genital tract, CNS ○ Variable numbers of neutrophils and eosinophils
○ Peripheral soft tissue sites are rare ○ Histiocytes
Presentation • Mitotic rate varies (often low)
• Site specific • Necrosis is rare
○ Lung • Occasional calcification and ossification
– Chest pain, dyspnea Morphologic Variants
○ Mesentery, omentum, uterus, gastrointestinal tract • EIMS
– Obstruction (often large tumors) ○ Predominantly composed of rounded to epithelioid cells
– May have constitutional symptoms (e.g., fever, weight with prominent nucleoli
loss) ○ Often shows prominent myxoid stroma rich in
– May show laboratory evidence of anemia, inflammatory cells, particularly neutrophils or
hypergammaglobulinemia, or elevated ESR lymphocytes
○ Soft tissue ○ Strong desmin (+) and ALK(+) in nuclear membrane
– Painless mass staining pattern
○ Bladder
– Hematuria ANCILLARY TESTS
Treatment Immunohistochemistry
• Complete surgical resection • SMA(+), variable desmin (+)
○ Reexcision of recurrences • Cytoplasmic ALK(+) in 50-60% of cases
• Potential for targeted therapy with specific tyrosine kinase ○ Positive expression roughly correlates with presence of
inhibitors provides rationale for routine molecular analysis ALK gene rearrangement
of IMT ○ ALK expression is more common in younger patients
○ ROS1(+) in subset of ALK(-) tumors (if ROS1
Prognosis
rearrangement is present)
• Variable but generally good • Subset shows focal keratin (+)
• Up to 35% may recur and < 5% metastasize • Negative for S100 protein, myogenin, CD117, and EMA
○ Usually intraabdominal or retroperitoneal tumors
– Distinctive intraabdominal variant, epithelioid Molecular Genetics
inflammatory myofibroblastic sarcoma (EIMS), shows • Rearrangement of 2p23 (ALK) in ~ 50% of cases
aggressive course ○ Variety of partner genes including ATIC, TPM3, TPM4,
CLTC, RANBP2, EML4, IGFBP5, THBS1
197
 Inflammatory Myofibroblastic Tumor
Fibroblastic/Myofibroblastic Lesions

– ALK-RANBP2 rearrangement identified in most Inflammatory Fibroid Polyp

reported cases of EIMS • Bland spindle cells in loose edematous or myxoid stroma
• Subset of ALK-negative tumors harbor fusions involving with eosinophils and lymphocytes
ROS1, RET, PDGFRB, or ETV6 and NTRK3 • Usually in submucosa of gastric antrum or duodenum;
often polypoid
DIFFERENTIAL DIAGNOSIS • CD34(+)
Nodular Fasciitis • Negative for ALK by IHC
• Most common in extremity • PDGFRA mutations
• Usually subcutaneous and < 3 cm in size Anaplastic Large Cell Lymphoma
• Negative for ALK by IHC
• May show morphologic overlap with EIMS
• MYH9-USP6 fusion
• Seldom spindled
Desmoid Fibromatosis • Expresses lymphoid markers
• Usually in small bowel mesentery • CD30(+), ALK(+), similar to EIMS
• Fascicles of spindle cells with interspersed collagen and
usually negligible inflammation SELECTED REFERENCES
• Small-caliber vessels often with perivascular edema 1. Mohammad N et al: ALK is a specific diagnostic marker for inflammatory
• SMA(+) myofibroblastic tumor of the uterus. Am J Surg Pathol. 42(10):1353-9, 2018
2. Bennett JA et al: Inflammatory myofibroblastic tumor of the uterus: a
• Negative for ALK by IHC clinicopathological, immunohistochemical, and molecular analysis of 13
• Nuclear β-catenin (+) in majority cases highlighting their broad morphologic spectrum. Mod Pathol.
30(10):1489-503, 2017
Leiomyosarcoma 3. Haimes JD et al: Uterine inflammatory myofibroblastic tumors frequently
harbor ALK fusions with IGFBP5 and THBS1. Am J Surg Pathol. 41(6):773-80,
• May have prominent inflammation or myxoid stroma 2017
○ Myxoid leiomyosarcoma usually lacks lymphoplasmacytic 4. Inamura K et al: A novel fusion of HNRNPA1-ALK in inflammatory
infiltrate myofibroblastic tumor of urinary bladder. Hum Pathol. 69:96-100, 2017
5. Lahlou G et al: Sinonasal inflammatory myofibroblastic tumor with anaplastic
• Deep soft tissues of older adults lymphoma kinase 1 rearrangement: case study and literature review. Head
• Foci of classic leiomyosarcoma morphology may be present Neck Pathol. 11(2):131-8, 2017
• Generally diffuse SMA(+); variable desmin (+) 6. Pickett JL et al: Inflammatory myofibroblastic tumors of the female genital
tract are under-recognized: a low threshold for ALK immunohistochemistry
• Negative for ALK by IHC is required. Am J Surg Pathol. 41(10):1433-42, 2017
7. Antonescu CR et al: Molecular characterization of inflammatory
IgG4-Related Sclerosing Disease myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare
• May closely resemble sclerosing pattern of IMT novel RET rearrangement. Am J Surg Pathol. 39(7):957-67, 2015
8. Hornick JL et al: Expression of ROS1 predicts ROS1 gene rearrangement in
• Obstructive phlebitis common inflammatory myofibroblastic tumors. Mod Pathol. 28(5):732-9, 2015
• Negative for ALK by IHC 9. Lovly CM et al: Inflammatory myofibroblastic tumors harbor multiple
• Ratio of IgG4(+) to IgG(+) plasma cells much higher than IMT potentially actionable kinase fusions. Cancer Discov. 4(8):889-95, 2014
10. Li J et al: Inflammatory myofibroblastic tumor with RANBP2 and ALK gene
Well-Differentiated Liposarcoma rearrangement: a report of two cases and literature review. Diagn Pathol.
8:147, 2013
• May show prominent chronic inflammatory component 11. Mariño-Enríquez A et al: Epithelioid inflammatory myofibroblastic sarcoma:
• More common in older adults an aggressive intra-abdominal variant of inflammatory myofibroblastic
• Adipocytic differentiation often clearly present elsewhere tumor with nuclear membrane or perinuclear ALK. Am J Surg Pathol.
35(1):135-44, 2011
Dedifferentiated Liposarcoma 12. Yamamoto H et al: Inflammatory myofibroblastic tumor versus IgG4-related
sclerosing disease and inflammatory pseudotumor: a comparative
• Most common in older adults clinicopathologic study. Am J Surg Pathol. 33(9):1330-40, 2009
• Nonlipogenic component may rarely resemble IMT 13. Gleason BC et al: Inflammatory myofibroblastic tumours: where are we now?
J Clin Pathol. 61(4):428-37, 2008
• Often occurs in retroperitoneum of older adults 14. Coffin CM et al: Inflammatory myofibroblastic tumor: comparison of
• Most contain component of conventional well- clinicopathologic, histologic, and immunohistochemical features including
differentiated liposarcoma ALK expression in atypical and aggressive cases. Am J Surg Pathol. 31(4):509-
20, 2007
• Negative for ALK by IHC 15. Patel AS et al: RANBP2 and CLTC are involved in ALK rearrangements in
inflammatory myofibroblastic tumors. Cancer Genet Cytogenet. 176(2):107-
Gastrointestinal Stromal Tumor 14, 2007
• May occur in abdomen/pelvis but outside tubular GI tract 16. Cole B et al: Inflammatory myofibroblastic tumor with thrombocytosis and a
unique chromosomal translocation with ALK rearrangement. Arch Pathol
• Monomorphic spindled &/or epithelioid cells Lab Med. 130(7):1042-5, 2006
• May have stromal lymphocytes; plasma cells or eosinophils 17. Montgomery EA et al: Inflammatory myofibroblastic tumors of the urinary
are rare tract: a clinicopathologic study of 46 cases, including a malignant example
inflammatory fibrosarcoma and a subset associated with high-grade
• CD34(+) urothelial carcinoma. Am J Surg Pathol. 30(12):1502-12, 2006
• CD117(+) 18. Coffin CM et al: Inflammatory myofibroblastic tumor, inflammatory
• DOG1(+) fibrosarcoma, and related lesions: an historical review with differential
diagnostic considerations. Semin Diagn Pathol. 15(2):102-10, 1998
• Negative for ALK by IHC 19. Coffin CM et al: Extrapulmonary inflammatory myofibroblastic tumor
• KIT or PDGFRA mutations (inflammatory pseudotumor). A clinicopathologic and immunohistochemical
study of 84 cases. Am J Surg Pathol. 19(8):859-72, 1995

198
 Inflammatory Myofibroblastic Tumor
Inflammatory Infiltrate
Fascicular Architecture
Hemorrhage
Fibroblastic/Myofibroblastic Lesions
Plasma Cells
(Left) A characteristic feature
of IMT is the presence of a
stromal inflammatory
infiltrate. Lymphocytes and
plasma cells ﬉ are most
common, but eosinophils ﬊
and neutrophils may also be
seen. (Right) A stromal
inflammatory infiltrate is not
specific for IMT and may be
seen in a variety of other
tumors; however, a prominent
component of plasma cells is
often considered more typical
of IMT, as depicted. In some
cases, the plasma cells may
even form small aggregates.
Fascicular Architecture
(Left) In the more cellular
areas of a myxoid IMT, the
tumor cells often show a
vague, subtle, or well-formed
fascicular growth pattern.
(Right) In some cellular
examples of IMT, fascicular
growth is more pronounced
and may closely resemble a
smooth muscle neoplasm,
particularly leiomyosarcoma.
These tumors can also be a
challenge
immunohistochemically,
although strong cytoplasmic
ALK expression would support
IMT.
Cellular Fascicular Growth
(Left) Intratumoral
hemorrhage may be seen in
IMT, particularly myxoid
tumors. When extensive, a
vascular neoplasm may be
considered. (Right) Another
major morphologic pattern in
IMT is solid, moderately
cellular fascicular growth with
prominent inflammatory cells.
Scattered lymphoid
aggregates may be present
﬉, occasionally with reactive
germinal centers.
199
 Inflammatory Myofibroblastic Tumor
Fibroblastic/Myofibroblastic Lesions

Cytologic Features Macronucleoli

(Left) The lesional cells of IMT
show vesicular nucleoli with 1
or few conspicuous nucleoli. A
conspicuous stromal
inflammatory infiltrate is
present. (Right) Some tumor
cells in IMT contain enlarged
nuclei with prominent
basophilic or eosinophilic
macronucleoli resembling
Reed-Sternberg cells ﬉ or
viral infection ﬊. Although
atypical, in isolation these
cells do not appear to predict
behavior.

"Smudgy" Chromatin Occasional Herringbone Growth

(Left) Scattered tumor cells
with hyperchromatic and
"smudgy" chromatin ﬈ are
not uncommon in more
cellular examples of IMT. In
some cases, they may be more
numerous. (Right) A focal
herringbone fascicular growth
pattern may be seen in cellular
cases of IMT. This finding may
lead to misclassification as a
frank sarcoma.

Vague Storiform Growth Hyalinized Stroma

(Left) A vague loose or tight
storiform growth pattern may
also be seen in IMT. This
example also shows an
increase in stromal collagen.
(Right) Another major
morphologic pattern in IMT is
that of a prominent hyalinized
or collagenous stroma with
low cellularity. This pattern is
often admixed with more
cellular and morphologically
typical areas ﬉.

200
 Inflammatory Myofibroblastic Tumor
Stromal Sclerosis
Prominent Inflammation
Peripheral Changes
Fibroblastic/Myofibroblastic Lesions
Stromal Sclerosis
(Left) In sclerotic areas of IMT,
the lesional cells often form
small clusters ﬈ within a
prominent eosinophilic
collagenized stroma. The
characteristic inflammatory
infiltrate is common in these
zones. (Right) In this sclerotic
focus of IMT, only stromal
collagen and chronic
inflammatory cells are
conspicuous, and lesional cells
are difficult to identify. This
pattern may closely mimic
IgG4-related sclerosing
disease.
Rare Giant Cells
(Left) In some cases of IMT,
the stromal mixed
inflammatory infiltrate is quite
prominent, as depicted, and
the neoplastic nature of the
lesion may be overlooked.
(Right) Osteoclast-like giant
cells ﬈ are a rare finding in
IMT and may be seen in
association with focal
calcification or metaplastic
bone formation, which are
also rare findings.
Epithelioid Morphology
(Left) The periphery of some
expansile, intraabdominal
IMTs may show ulceration,
granulation tissue formation,
or dilated congested blood
vessels ﬈, simulating a
reactive process. (Right) An
epithelioid morphology is
occasionally seen in
conventional IMT. When this
morphology is diffuse,
however, and the tumor arises
in the abdominal cavity, the
aggressive variant epithelioid
inflammatory myofibroblastic
sarcoma (EIMS) should be
carefully excluded through
molecular analysis.
201
 Myxoinflammatory Fibroblastic Sarcoma

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY • Inflammatory component shows variable mixture of

• Distinctive locally aggressive and rarely metastasizing
mesenchymal neoplasm of fibroblastic/myofibroblastic
origin that shows predilection for distal (acral) extremities
CLINICAL ISSUES
• Slow-growing infiltrative mass in subcutaneous tissue of
adults
• Predilection for distal (acral) extremities, particularly dorsal
aspects of fingers and hand
• Treatment: Wide local excision with negative margins
• Local recurrence rate 30-50%
• Metastasis very rare
• Higher grade tumors have worse prognosis
MICROSCOPIC
• Poorly marginated, often multinodular tumor
• Variable mixture of hyalinized and myxoid zones merging
with variably prominent inflammatory component
lymphocytes, plasma cells, neutrophils, and eosinophils
• Scattered enlarged epithelioid tumor cells with smudgy
heterochromatin or enlarged/macronucleoli
• Pseudolipoblasts common in myxoid zones
• Low mitotic rate
ANCILLARY TESTS
• Nonspecific, variable expression of CD34, CD68, D2-40,
CD117, EMA reported
• BRAF abnormalities identified in subset
• TGFBR3 and MGEA5 rearrangements rare in pure MIFS
TOP DIFFERENTIAL DIAGNOSES
• Myxofibrosarcoma
• Diffuse-type tenosynovial giant cell tumor
• Extranodal Hodgkin disease
• Hemosiderotic fibrolipomatous tumor
• Proliferative fasciitis

Multinodular Growth Stromal Variation

(Left) At low magnification,
myxoinflammatory
fibroblastic sarcoma (MIFS)
classically shows a
multinodular growth pattern.
This nodularity may be
prominent and well
delineated, as in this example,
or subtle and more
compartmentalized. (Right)
MIFS typically shows a
variable admixture of 3
morphologic zones: Myxoid,
hyalinized, and inflammatory.
The exact composition is
highly variable, and some
cases may show
predominantly 1 type of zone.

Conspicuous Inflammation Viral Inclusion-Like Nucleoli

(Left) A relatively consistent
finding in MIFS is the presence
of a conspicuous inflammatory
infiltrate. This inflammation
may be in the form of dense
sheets of lymphocytes and
plasma cells or appear as a
scattered stromal infiltrate.
(Right) The tumor cells in MIFS
range from plump spindle cells
to histiocytoid or epithelioid
cells with enlarged basophilic
or eosinophilic macronucleoli
﬈. The latter are often
reminiscent of virally infected
nuclei. Intranuclear
pseudoinclusions ﬊ are also
common.

202
 Myxoinflammatory Fibroblastic Sarcoma
TERMINOLOGY
Abbreviations
• Myxoinflammatory fibroblastic sarcoma (MIFS)
Synonyms
• Acral myxoinflammatory fibroblastic sarcoma
• Atypical myxoinflammatory fibroblastic tumor
• Inflammatory myxohyaline tumor of distal extremities with
virocyte or Reed-Sternberg-like cells
Definitions
• Distinctive locally aggressive and rarely metastasizing
mesenchymal neoplasm of fibroblastic/myofibroblastic
origin that shows predilection for distal (acral) extremities
• Recent evidence suggests that MIFS may not be related to
hemosiderotic fibrolipomatous tumor (HFLT) or
pleomorphic hyalinizing angiectatic tumor (PHAT)
CLINICAL ISSUES
Epidemiology
• Age
○ Adults (25-50 years most common)
Site
• Marked predilection for distal (acral) extremities,
particularly dorsal aspects
○ Fingers and hand most common
○ Also wrist, forearm, toes, feet, ankles, lower leg
• Rare extraacral cases but increasingly reported
○ Higher grade tumors tend to arise in proximal locations
Presentation
• Slow-growing, painless, ill-defined mass
○ Usually subcutaneous
– May involve dermis or invade underlying skeletal
muscle
• May be mistaken clinically for ganglion cyst or lipoma
Treatment
• Wide local excision with negative margins
○ Amputation may be considered in distal lesions
• Indefinite clinical follow-up recommended
• Radiation therapy following excision may have role in
reducing local recurrence
Prognosis
• Local recurrences common (30-50%)
○ Risk associated with adequacy of surgical excision
• Very low, but definite risk of metastasis
○ Most reported cases of metastatic MIFS in literature
showed local recurrence before metastasis
• Tumors with high-grade or dedifferentiated morphology
have worse prognosis
○ Metastasis in 50% of cases in one series (18 cases),
including 7 deaths
MACROSCOPIC
General Features
• Usually multinodular, infiltrative, poorly circumscribed
Fibroblastic/Myofibroblastic Lesions
Size
• 1-10 cm, usually 3-4 cm
MICROSCOPIC
Histologic Features
• Poorly marginated, multinodular
• Combination of myxoid and hyalinized zones merging with
variably prominent inflammatory infiltrate
○ Exact composition varies from case to case
○ Zones may be separated by cleft-like spaces in more
nodular tumors
• Inflammatory component shows variable mixture of
lymphocytes, plasma cells, neutrophils, and eosinophils
○ Lymphoplasmacytic infiltrates can be dense and may
show reactive germinal center formation
– Can be prominent and extensive and mimic
inflammatory pseudotumor, lymphoma, or reactive
condition
○ Neutrophils may be prominent in myxoid areas
• Plump epithelioid to spindled cells with moderate to
marked nuclear atypia
○ Epithelioid cells have eosinophilic cytoplasm and
enlarged nucleoli
– Basophilic or eosinophilic macronucleoli may resemble
intranuclear viral inclusions
– Some nuclei contain "smudgy" heterochromatin or
show bizarre atypia
– Occasional cells contain inflammatory cells in
cytoplasm (emperipolesis)
○ Smaller epithelioid cells may appear ganglion-like and
form clusters or larger aggregates
• Myxoid zones often contain unusual highly vacuolated cells
that resemble lipoblasts (pseudolipoblasts)
• Generally low mitotic rate (usually ≤ 5 per 50 HPF)
• Multinucleated giant cells (including Touton forms) may be
seen
• Unusual features
○ Branching or thick-walled arcuate curvilinear vessels
○ Cellular zones displaying solid, whorled, fascicular, or
storiform patterns
○ Absence of large epithelioid cells with macronucleoli
• High-grade morphologic features
○ Variable combination of increased cellularity, marked
nuclear atypia, high mitotic activity (> 10 per HPF),
atypical mitoses, and necrosis
○ Dedifferentiation: Areas of conventional MIFS
juxtaposed to undifferentiated pleomorphic sarcoma
• Rare tumors may contain areas resembling HFLT
○ Bland, spindled fibroblastic cells admixed with abundant
adipose tissue with hemosiderin pigment
○ Recent evidence suggests that these tumors may
actually represent HFLT with sarcomatous progression
ANCILLARY TESTS
Immunohistochemistry
• Nonspecific immunophenotype
○ Variable expression of CD34, CD68, D2-40, CD117, EMA
○ Rare cases show focal keratin expression
• Nuclear INI1 expression retained/intact
203
 Myxoinflammatory Fibroblastic Sarcoma
Fibroblastic/Myofibroblastic Lesions
• Negative for desmin, clusterin
• Negative for CD15, CD30, CD45 in cells with inclusion-like
macronucleoli
Molecular Genetics
• BRAF gene abnormalities recently described in subset of
cases
○ TOM1L2-BRAF rearrangements in 5 cases; 1 case with
BRAF amplification
○ Not yet reported in HFLT, PHAT, or so-called hybrid
HFLT/MIFS
• Rearrangements of TGFBR3 (1p22) and MGEA5 (10q24) are
rare in pure MIFS
○ These rearrangements mostly reported in cases of pure
HFLT, hybrid HFLT/MIFS, and hybrid HFLT/PHAT
– Recent data suggests that MIFS with TGFBR3 or
MGEA5 rearrangements actually represents HFLT with
sarcomatous progression
DIFFERENTIAL DIAGNOSIS
Myxofibrosarcoma
• Usually in superficial soft tissues of proximal extremities of
older adults
• Often lobulated rather than infiltrative
• Myxoid stroma abundant in low- to intermediate-grade
lesions
○ Curvilinear vascular network variably prominent
• No hyalinized zones
• Inflammatory cells comprise minor component
• Higher grade tumors show solid sheets of overtly malignant
cells, often with numerous mitoses, including atypical forms
Diffuse-Type Tenosynovial Giant Cell Tumor
• a.k.a. pigmented villonodular synovitis
• Often localized to large joints, such as knee and hip
• Proliferation of uniform rounded histiocytoid cells in sheets
and aggregates
• Background of hemosiderin, foamy histiocytes, and
lymphoplasmacytic cells
• Myxoid stromal changes, pseudolipoblasts, and enlarged
atypical cells with bizarre atypia not typical features of
conventional diffuse-type tenosynovial giant cell tumor
• Often contains population of scattered desmin (+),
dendritic-like cells
Extranodal Hodgkin Disease
• Patients usually have history of nodal disease
• Myxoid areas very unusual
• Inflammatory cells are mostly lymphoid
○ Neutrophils not common; eosinophils may be present
• Reed-Sternberg cells label with CD15 and CD30 and are
lymphoid rather than fibroblastic
Hemosiderotic Fibrolipomatous Tumor
• Classically involves ankle and feet
• Mildly atypical spindle cells and hemosiderin in background
of adipose tissue
• May show areas resembling MIFS
• Strongly CD34(+)
• t(1;10)(p22;q24) (TGFBR3; MGEA5)
204
Proliferative Fasciitis
• Small, often rapidly growing lesion on extremities of young
adults
• Bland spindled to stellate myofibroblastic cells in loose
myxoid to hyalinized stroma
• Contains variably prominent population of small ganglion
cell-like myofibroblasts with prominent nucleoli
○ No bizarre nuclear atypia
• Mitotic figures are common; no atypical forms
• No pseudolipoblasts or prominent inflammatory
component
• Variant occurring in childhood is highly cellular and may
show necrosis and acute inflammation
Inflammatory Myofibroblastic Tumor
• Most commonly affects children and young adults
• Occurrence in extremity uncommon
• Variable loose myxoid to hyalinized stroma
• Intermingled chronic inflammatory infiltrate common,
particularly plasma cells
• SMA(+), ALK(+) in most cases
• ALK gene rearrangements often detectable
Superficial CD34(+) Fibroblastic Tumor
• Rare, but increasingly reported
• Shows many overlapping histologic features with MIFS
• Generally more cellular than MIFS and lacks prominent
myxoid and hyalinized zones
• Lacks t(1;10) and rearrangements of TGFBR3 and MGEA5
• CD34(+); variable keratin (+)
SELECTED REFERENCES
1. Boland JM et al: Hemosiderotic fibrolipomatous tumor, pleomorphic
hyalinizing angiectatic tumor, and myxoinflammatory fibroblastic sarcoma:
related or not? Adv Anat Pathol. 24(5):268-77, 2017
2. Kao YC et al: Recurrent BRAF gene rearrangements in myxoinflammatory
fibroblastic sarcomas, but not hemosiderotic fibrolipomatous tumors. Am J
Surg Pathol. 41(11):1456-65, 2017
3. Lucas DR: Myxoinflammatory fibroblastic sarcoma: review and update. Arch
Pathol Lab Med. 141(11):1503-7, 2017
4. Gaetke-Udager K et al: Myxoinflammatory fibroblastic sarcoma: spectrum of
disease and imaging presentation. Skeletal Radiol. 45(3):347-56, 2016
5. Zreik RT 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. 53:14-24, 2016
6. Michal M et al: High-grade myxoinflammatory fibroblastic sarcoma: a report
of 23 cases. Ann Diagn Pathol. 19(3):157-63, 2015
7. Ieremia E et al: Myxoinflammatory fibroblastic sarcoma: morphologic and
genetic updates. Arch Pathol Lab Med. 138(10):1406-11, 2014
8. Laskin WB et al: Myxoinflammatory fibroblastic sarcoma: a clinicopathologic
analysis of 104 cases, with emphasis on predictors of outcome. Am J Surg
Pathol. 38(1):1-12, 2014
9. Weiss VL et al: Myxoinflammatory fibroblastic sarcoma in children and
adolescents: clinicopathologic aspects of a rare neoplasm. Pediatr Dev
Pathol. 16(6):425-31, 2013
10. Jurcić V et al: Myxoinflammatory fibroblastic sarcoma: a tumor not restricted
to acral sites. Ann Diagn Pathol. 6(5):272-80, 2002
11. Lambert I et al: Acral myxoinflammatory fibroblastic sarcoma with unique
clonal chromosomal changes. Virchows Arch. 438(5):509-12, 2001
12. Meis-Kindblom JM et al: Acral myxoinflammatory fibroblastic sarcoma: a
low-grade tumor of the hands and feet. Am J Surg Pathol. 22(8):911-24,
1998
13. Montgomery EA et al: Inflammatory myxohyaline tumor of distal extremities
with virocyte or Reed-Sternberg-like cells: a distinctive lesion with features
simulating inflammatory conditions, Hodgkin's disease, and various
sarcomas. Mod Pathol. 11(4):384-91, 1998
 Myxoinflammatory Fibroblastic Sarcoma
Mixed Inflammatory Infiltrate
Small Ganglion-Like Cells
Smudgy Heterochromatin
Fibroblastic/Myofibroblastic Lesions
Large Ganglion-Like Cells
(Left) The stromal
inflammatory infiltrate is
often composed of a mixture
of cell types, including
lymphocytes, plasma cells,
eosinophils, and neutrophils.
The exact composition varies,
and some cases show a
predominantly neutrophilic
infiltrate. Note also the
presence of macronucleoli ﬊.
(Right) Enlarged epithelioid
tumor cells ﬈ with abundant
eosinophilic cytoplasm and
eccentric nuclei may resemble
ganglion cells, particularly
when they form small
aggregates or cluster in some
tumors.
Sheets of Plump Tumor Cells
(Left) Some of the tumor cells
﬈ in MIFS may resemble the
ganglion cell-like
myofibroblasts seen in
proliferative fasciitis/myositis.
(Right) In some cases of MIFS,
sheets of plump spindled and
epithelioid cells with
conspicuous nucleoli, as
depicted, may closely
resemble cellular areas of a
tenosynovial giant cell tumor.
A more collagenized stroma
may also be seen in these
cases.
Low Mitotic Rate
(Left) Nuclear atypia in the
form of irregular nuclear
contours with smudgy
heterochromatin is a common
finding in MIFS. These cells ﬈
are similar in appearance to
the atypical stromal cells of
well-differentiated
liposarcoma. (Right) Mitotic
activity ﬈ in MIFS is often low
(usually < 5 per 50 HPF) and
may even be seemingly
nonexistent. Rare atypical
cases show a higher mitotic
rate, and very rare cases can
show atypical mitoses.
205
 Myxoinflammatory Fibroblastic Sarcoma
Fibroblastic/Myofibroblastic Lesions

Myxoid Zones Pseudolipoblasts

(Left) Myxoid areas are very
common in MIFS and range
from small foci to large zones.
The tumor cells within these
areas are often spindled and
show mild to moderate
nuclear atypia. These zones
may also be quite paucicellular
and resemble myxoma. (Right)
Bizarre, enlarged tumor cells
with extensive cytoplasmic
vacuolization ﬈ are common
in myxoid zones of MIFS and
may be misconstrued as true
lipoblasts. As a caveat, similar
cells may also be seen in some
cases of myxofibrosarcoma.

Emperipolesis Hyalinized Zones

(Left) Scattered large
ganglion-like tumor cells may
show emperipolesis of
inflammatory cells,
particularly neutrophils ﬈. In
some cases, the cytoplasm
may be packed with cells.
(Right) Hyalinized zones in
MIFS are often hypo- to
modestly cellular and may
show prominent sclerosis. The
diagnosis may be challenging
in rare cases that are
predominantly sclerotic. Note
the interface with a myxoid
focus ﬈. In some cases, cleft-
like spaces may separate these
zones.

Inflammatory Zone Germinal Center Formation

(Left) The inflammatory zones
in MIFS may be discrete and
dense. In rare cases, this
inflammation is so extensive
that the neoplastic cells may
be obscured, potentially
leading to misdiagnosis as a
reactive or infectious process.
(Right) Occasionally, zones of
dense lymphoplasmacytic
inflammation will show
reactive germinal center
formation ſt. When located
at the periphery of a tumor,
this finding may mimic a
lymph node metastasis.

206
 Myxoinflammatory Fibroblastic Sarcoma
Reed-Sternberg-Like Cells
Arcuate Vasculature
Hemosiderotic Fibrolipomatous Tumor-
Focal Necrosis
Fibroblastic/Myofibroblastic Lesions
Multinucleated Giant Cells
(Left) Some atypical tumor
cells in MIFS appear
binucleated and are
reminiscent of Reed-Sternberg
cells ﬈. Within the setting of
a predominantly inflammatory
background, this finding may
lead to confusion with
Hodgkin lymphoma. (Right)
Multinucleated giant cells are
not infrequent in MIFS and
may show a Touton-like
morphology (similar to
solitary/juvenile
xanthogranuloma) or
osteoclastic morphology ﬊.
These cells may also show
emperipolesis or engulfment
of other cells.
Rare Architectural Organization
(Left) A rare and unusual
finding in MIFS is the presence
of an arcuate or curvilinear
vascular pattern ﬊. This
vascularity is similar to what is
often seen in
myxofibrosarcoma and low-
grade fibromyxoid sarcoma
and may potentially lead to
misdiagnosis if other clinical
and histologic features are not
taken into account. (Right)
Very rare cases of MIFS may
show focal architectures such
as storiform, whorling, or
fascicular growth patterns.
Other more typical features of
MIFS are often present
elsewhere.
Like Areas
(Left) Focal necrosis is rarely
encountered in MIFS and can
be fibrinoid ﬊ or coagulative.
(Right) Unusual tumors may
show areas containing
features of both MIFS and
hemosiderotic fibrolipomatous
tumor (HFLT), as depicted, and
these tumors have been
described as hybrid
MIFS/HFLT. Recent studies
have proposed that these
tumors are actually HFLT with
sarcomatous progression
rather than a hybrid or variant
of MIFS.
207
 Myxoinflammatory Fibroblastic Sarcoma
Fibroblastic/Myofibroblastic Lesions

Superficial/Cutaneous Myxoinflammatory
Fibroblastic Sarcoma Cleft-Like Spaces
(Left) This MIFS is superficial
and shows a
myxoinflammatory expansion
of the subcutaneous fat. Such
neoplasms can also be
associated with tendons and
have an infiltrative
appearance. A prominent
lymphoid infiltrate is present
throughout the neoplasm.
(Right) This case of MIFS
contained discrete areas of
seemingly detached myxoid
nodules separated from more
cellular, inflammatory zones
by cleft-like spaces.

Infiltration of Dermal and Subcutaneous

Infiltration of Fat Structures
(Left) MIFS most commonly
arises superficially and
demonstrates an infiltrative
border with the surrounding
tissue (in this case, mature
fat). (Right) Given its strong
tendency for infiltrative
growth, MIFS can also show
involvement/entrapment of
normal structures such as
vessels and nerves. A pacinian
corpuscle ﬉ is shown in this
image.

Prominent Chronic Inflammation CD34 Expression

(Left) This case of MIFS shows
a massive chronic
inflammatory infiltrate,
raising concerns for Hodgkin
lymphoma. Other, more
conventional areas with
typical features were
identified in additional
sections. (Right) Variable
CD34 expression is not
uncommon in MIFS and can be
quite prominent in some cases,
as depicted here.

208
 Myxoinflammatory Fibroblastic Sarcoma

Fibroblastic/Myofibroblastic Lesions
Eosinophils Cellular Zones
(Left) Neutrophils are a
relatively common finding in
MIFS, but eosinophils ﬉ can
also be conspicuous in some
cases. (Right) Some cases of
MIFS feature areas with
increased cellularity and
comparatively less myxoid,
hyalinized, and inflammatory
morphology. Despite the
cellularity, mitotic activity is
generally low, and
characteristic virocyte-like
macronucleoli can often be
identified without trouble.

Prominent Sclerotic and Inflammatory

Zones Sclerotic Matrix
(Left) The appearance of
sclerotic and inflammatory
zones in MIFS may lead to the
mistaken impression of a
nonneoplastic process. (Right)
Sclerosing zones in MIFS can
be markedly paucicellular,
leading to confusion with a
reactive process. This pitfall
can cause particular problems
on a small biopsy.

Hypocellular Myxoid Zones High-Grade Morphology

(Left) This case of MIFS
contained large myxoid zones
with relatively small tumor
cells and scattered
inflammation. This pattern can
mimic a low-grade
myxofibrosarcoma; however,
the 2 tumors often present
differently clinically. (Right)
Rare cases of MIFS contain
high-grade features, including
a mixture of marked atypia,
cellularity, mitotic activity,
&/or necrosis.
Dedifferentiation
(conventional MIFS adjacent
to undifferentiated
pleomorphic sarcoma) has also
been reported.

209
 Superficial CD34(+) Fibroblastic Tumor

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY
• Distinctive low-grade fibroblastic neoplasm arising in
superficial soft tissues and featuring fascicular growth,
prominent nuclear pleomorphism, and consistent CD34
expression
CLINICAL ISSUES
• Wide age range (median: 38 years)
• Solitary, slow-growing, painless mass or nodule arising in
superficial soft tissues
• Lower extremity most common site
• Treatment: Complete surgical excision
• Generally indolent clinical course
○ No local recurrence or tumor-related deaths reported
○ Regional nodal metastases in 1 published case
MACROSCOPIC
• Mean size: 4.1 cm
• Well-circumscribed, firm mass
MICROSCOPIC
• Spindled to epithelioid cells arranged in fascicles or
storiform arrays
○ Prominent eosinophilic cytoplasm, may be glassy
○ Characteristically striking nuclear pleomorphism
○ Prominent macronucleoli, also nuclear pseudoinclusions
• Mitotic figures rare to infrequent; no necrosis
ANCILLARY TESTS
• Strong, diffuse CD34(+)
• Patchy, focal cytokeratin (+) in majority of cases
• Retained nuclear INI1 expression
• Negative for TGFBR3, MGEA5, PDGFB, and ALK gene
rearrangements
TOP DIFFERENTIAL DIAGNOSES
• Myxoinflammatory fibroblastic sarcoma
• Pleomorphic dermal sarcoma
• Epithelioid sarcoma

Superficial CD34(+) Fibroblastic Tumor Prominent Nuclear Atypia

(Left) Superficial CD34(+)
fibroblastic tumor (SCD34FT)
is a rare but distinctive
mesenchymal neoplasm that
arises in superficial soft tissue
sites and is composed of
variably pleomorphic spindle
cells. It often shows a well-
circumscribed peripheral
border, as depicted. (Right) A
characteristic feature of the
tumor is striking nuclear
atypia, often in the form of
hyperchromasia,
pleomorphism, and
multinucleation. Bizarre
atypia is also common, which
can raise concerns for
malignancy.

Macronucleoli and Pseudoinclusions Strong CD34 Expression

(Left) Prominent basophilic or
eosinophilic macronuclei ﬈
can be seen in some of the
larger cells. Intranuclear
pseudoinclusions ﬊ are also
common. Similar findings are
seen in myxoinflammatory
fibroblastic sarcoma, a
neoplasm that does not
appear to be related. (Right)
All reported cases of SCD34FT
have strong CD34 expression,
usually in the majority of the
tumor cells.

210
 Superficial CD34(+) Fibroblastic Tumor
TERMINOLOGY
Abbreviations
• Superficial CD34(+) fibroblastic tumor (SCD34FT)
Definitions
• Distinctive low-grade fibroblastic neoplasm arising in
superficial soft tissues and featuring fascicular growth,
prominent nuclear pleomorphism, and consistent CD34
expression
CLINICAL ISSUES
Epidemiology
• Incidence
○ Very rare (~ 35 cases reported in literature)
• Age
○ Wide range (median: 38 years)
○ No tumors reported < 18 years
Site
• Lower extremity most common
○ Thigh, buttock, lower leg, foot
• Also shoulder, upper arm, groin, others
Presentation
• Solitary, slow-growing, painless mass or nodule
○ Often present for > 1 year
• Arises in superficial soft tissues
○ Absent to minimal involvement of underlying muscle
Treatment
• Complete surgical excision
Prognosis
• Generally indolent clinical course
○ No local recurrence or tumor-related deaths reported
thus far
○ Regional nodal metastases in 1 published case, occurring
7 years following incomplete excision
MACROSCOPIC
General Features
• Well-circumscribed, firm mass
• Tan/gray/yellow, fleshy cut surface
Size
• Mean: 4.1 cm (range: 1.5-10.0 cm)
MICROSCOPIC
Histologic Features
• Well demarcated but may show limited extension into
adjacent adipose tissue
• Spindled to epithelioid cells arranged in fascicles or
storiform arrays
○ Prominent eosinophilic cytoplasm, may be granular,
fibrillar, or glassy
– Large epithelioid or polygonal cells may appear
ganglion-like
○ Characteristically striking nuclear atypia
– Hyperchromatic, pleomorphic nuclei, often bizarre
– Prominent macronucleoli common
Fibroblastic/Myofibroblastic Lesions
– Also nuclear pseudoinclusions
• Mild to moderate inflammatory cell infiltrate, particularly
lymphocytes and mast cells
○ Occasional xanthoma cells
• Mitotic figures rare to infrequent
• Necrosis absent
ANCILLARY TESTS
Immunohistochemistry
• Strong, diffuse CD34(+)
• Patchy, focal cytokeratin (+) in majority of cases
• EMA, S100 protein, SMA, desmin, CD31, ERG, STAT6, HMB-
45, Melan-A, ALK, and FLI-1 (-)
• Retained nuclear INI1 expression
In Situ Hybridization
• Negative for TGFBR3, MGEA5, PDGFB, and ALK gene
rearrangements
DIFFERENTIAL DIAGNOSIS
Myxoinflammatory Fibroblastic Sarcoma
• Generally multinodular and poorly delineated
• Predilection for distal extremities
• Myxoid stroma common, also hyalinized and inflammatory
zones
Pleomorphic Dermal Sarcoma
• Mitotic figures and necrosis are common
• CD34, keratin (-)
• Aggressive growth (can invade fascia, muscle)
Epithelioid Sarcoma
• Nodules of atypical epithelioid cells, ± central necrosis
• Spindle cell morphology in subset
• Diffuse cytokeratin (+); patchy CD34(+) in 50%
• Loss of nuclear INI1
Atypical Fibroxanthoma
• Dermal lesion, usually small
• Mitotic activity common, including atypical mitoses
• CD34, keratin (-)
Inflammatory Myofibroblastic Tumor
• Predilection for lung and abdominal cavity; rare in
extremities
• SMA(+); subset are focally keratin (+)
• ALK expression in 50% of cases
• CD34(-)
SELECTED REFERENCES
1. Lao IW et al: Superficial CD34-positive fibroblastic tumour: a
clinicopathological and immunohistochemical study of an additional series.
Histopathology. 70(3):394-401, 2017
2. Sood N et al: Superficial CD34-positive fibroblastic tumor: a new entity; case
report and review of literature. Indian J Pathol Microbiol. 60(3):377-380,
2017
3. Yamaga K et al: Detailed analysis of a superficial CD34-positive fibroblastic
tumor: a case report and review of the literature. Oncol Lett. 14(3):3395-
3400, 2017
4. Wada N et al: Superficial CD34-positive fibroblastic tumor: a new case from
Japan. J Dermatol. 43(8):934-6, 2016
5. Carter JM et al: Superficial CD34-positive fibroblastic tumor: report of 18
cases of a distinctive low-grade mesenchymal neoplasm of intermediate
(borderline) malignancy. Mod Pathol. 27(2):294-302, 2014
211
 Superficial CD34(+) Fibroblastic Tumor
Fibroblastic/Myofibroblastic Lesions

Limited Extension Into Adipose Tissue Cytoplasmic Eosinophilia

(Left) Although all cases of
SCD34FT are grossly well
circumscribed, microscopic
evidence of limited infiltration
into adjacent adipose tissue is
not uncommon. (Right) Similar
to smooth muscle neoplasms,
the tumor cells that comprise
SCD34FT characteristically
show prominent cytoplasmic
eosinophilia. Morphologic
architectures include fascicles,
vague bundles, and storiform
arrays.

Epithelioid or Polygonal Cells Glassy, Fibrillar, or Granular Cytoplasm

(Left) Larger epithelioid or
polygonal cells are a common
finding in SCD34FT, similar to
many cases of
myxoinflammatory
fibroblastic sarcoma. (Right)
Tumor cell cytoplasm, though
often eosinophilic, can also
appear glassy, fibrillary, or
granular in texture. A focal
clear cell appearance is also
possible. Similar findings can
be seen in PEComa.

Chronic Inflammatory Cells Xanthoma Cells

(Left) An intratumoral
infiltrate of chronic
inflammatory cells is seen in
most cases of SCD34FT.
Lymphocytes are most
common, but mast cells and
histiocytes can also be
present. (Right) Foamy
histiocytes (xanthoma cells)
﬈ can be present focally in
SCD34FT. Hemosiderin
pigment may also be seen but
is generally rare.

212
 Superficial CD34(+) Fibroblastic Tumor
Focal Areas Lacking Atypia
Glassy Epithelioid Cells
Collagen Fiber Entrapment
Fibroblastic/Myofibroblastic Lesions
Rare Mitotic Figures
(Left) Some regions lack the
characteristic prominent
nuclear atypia that
characterizes SCD34FT,
however, they do not tend to
predominate. (Right) Mitotic
figures ﬉ are rare to absent
in SCD34FT. This finding
supports the notion that most
of the nuclear atypia seen in
this tumor is degenerative in
nature.
Nuclear Hyperchromasia
(Left) This image shows
epithelioid to polygonal tumor
cells with smooth and glassy
eosinophilic cytoplasm ﬈, a
common finding in SCD34FT.
(Right) Nuclear
hyperchromasia,
pleomorphism, and
multinucleation can give some
tumor cells a smudgy
appearance ﬈, similar to cells
seen in well-differentiated
liposarcoma,
myxoinflammatory
fibroblastic sarcoma, and
inflammatory myofibroblastic
tumor.
Focal to Patchy Keratin Expression
(Left) Entrapment of dermal
collagen fibers ﬈ can be seen
in the superficial aspects of
SCD34FT, which may lead to
diagnostic confusion with
atypical fibrous histiocytoma
(dermatofibroma). (Right)
Keratin expression can be seen
in up to 2/3 of cases of
SCD34FT, however, this
finding is characteristically
focal or patchy.
213
 Adult-Type Fibrosarcoma

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY
• Sarcoma composed of uniform spindle cells resembling
fibroblasts
• Vast majority of tumors classified as fibrosarcoma in older
literature now reclassified as other entities
• Currently, vanishingly rare entity; diagnosis of exclusion
• High-grade fibroblastic sarcomas with nuclear
pleomorphism are currently classified as undifferentiated
pleomorphic sarcoma rather than fibrosarcoma
MICROSCOPIC
• Uniform, hyperchromatic spindle cells in herringbone
fascicles
• Lacks characteristic features of other defined entities
ANCILLARY TESTS
• Negative for keratins, EMA, S100 protein, desmin, most
others
• Lacks molecular signatures of other defined sarcomas

CLINICAL ISSUES TOP DIFFERENTIAL DIAGNOSES

• Most arise in deep soft tissues of extremities in adults • Undifferentiated pleomorphic sarcoma
• Treatment: Wide surgical resection • Synovial sarcoma
• Limited prognostic data using modern, strict diagnostic • Malignant peripheral nerve sheath tumor
criteria • Fibrosarcomatous dermatofibrosarcoma protuberans
• 50% overall mortality • Desmoid fibromatosis
• Cellular dermatofibroma
• Low-grade myofibroblastic sarcoma
• Leiomyosarcoma

Adult-Type Fibrosarcoma Fascicular Herringbone Pattern

(Left) The rare, adult-type
fibrosarcoma should be
diagnosed only after all
morphologically similar
entities have been rigorously
excluded. All strictly defined
cases demonstrate prominent
fascicular growth by spindled
tumor cells lacking significant
nuclear pleomorphism.
(Courtesy K. Fritchie, MD.)
(Right) Relatively uniform
spindle cells are arranged in
prominent fascicles that
intersect at acute angles,
giving rise to the characteristic
(but nonspecific) herringbone
pattern. (Courtesy K. Fritchie,
MD.)

Mitoses Intervening Collagen Fibers

(Left) Mitotic figures ﬈ are
usually present in adult-type
fibrosarcoma; however, the
overall mitotic rate is variable.
Importantly, the
hyperchromatic tumor cells
show no more than mild to
moderate nuclear
pleomorphism. (Courtesy K.
Fritchie, MD.) (Right) Fine,
wavy, pink collagen fibers ﬈
separate the hyperchromatic
spindle cells from one another
in adult-type fibrosarcoma.
The amount of intervening
collagen is variable, but it is
usually less than that seen in
desmoid fibromatosis.
(Courtesy K. Fritchie, MD.)

214
 Adult-Type Fibrosarcoma
TERMINOLOGY
Definitions
• Sarcoma composed of uniform spindle cells resembling
fibroblasts
○ Vast majority of tumors classified as fibrosarcoma in
older literature now reclassified as other entities
○ Currently, vanishingly rare entity; diagnosis of exclusion
○ Diagnosis should only be made with extreme caution
• Lacks features of other distinct defined fibrosarcoma
subtypes (e.g., myxofibrosarcoma, infantile fibrosarcoma,
sclerosing epithelioid fibrosarcoma, etc.)
• High-grade fibroblastic sarcomas with nuclear
pleomorphism are currently classified as undifferentiated
pleomorphic sarcoma (UPS) rather than fibrosarcoma
CLINICAL ISSUES
Epidemiology
• Incidence
○ Very rare (if strictly defined)
• Age
○ Median age: 50 years
Presentation
• Usually deep mass of lower extremity but may occur
anywhere
○ Rarely arise in subcutis; most apparent fibrosarcoma in
skin or subcutis actually represent fibrosarcomatous
transformation of dermatofibrosarcoma protuberans
Treatment
• Wide surgical resection
Prognosis
• Only 2 modern studies using strict diagnostic criteria
○ Most older series represent wide variety of sarcoma
types (by current criteria); thus, unreliable data
• 50% mortality (low-grade tumors have better prognosis)
MACROSCOPIC
Size
• Median size: 6.5 cm (range: 2-17 cm)
MICROSCOPIC
Histologic Features
• Elongated, hyperchromatic, relatively uniform
fusiform/spindle cells with little cytoplasm
○ Only mild-moderate pleomorphism allowed
○ If severe pleomorphism, classify as UPS, not
fibrosarcoma
○ Variable mitotic rate, but mitoses present in most cases
• Fascicles, usually arranged in characteristic (but nonspecific)
herringbone pattern
• Parallel collagen fibers between cells (variable)
• Hypocellular or myxoid areas may mimic fibromatosis
○ These are usually focal; other areas show more cellular
zones typical of fibrosarcoma
• Lacks features of distinct, defined fibrosarcoma subtypes
○ Low-grade fibromyxoid sarcoma, sclerosing epithelioid
fibrosarcoma, myxofibrosarcoma, infantile fibrosarcoma
Fibroblastic/Myofibroblastic Lesions
ANCILLARY TESTS
Immunohistochemistry
• May express variable smooth muscle actin (SMA) (similar to
other fibroblastic neoplasms)
• Most other markers negative: Keratins, EMA, S100 protein,
desmin, CD34, etc.
Genetic Testing
• No known characteristic molecular abnormality
• Lacks molecular signatures that define other sarcomas
DIFFERENTIAL DIAGNOSIS
Undifferentiated Pleomorphic Sarcoma
• Sheets of markedly pleomorphic cells
• Severe nuclear atypia
Synovial Sarcoma
• Commonly has herringbone fascicular pattern
• Biphasic form also has glandular epithelial structures
• Monotonous spindle/ovoid nuclei; no pleomorphism
• Cytokeratin (+), EMA(+), diffuse nuclear TLE1(+)
• Characteristic t(X;18), SS18-SSX1/2/4 gene fusion
Malignant Peripheral Nerve Sheath Tumor
• Commonly has herringbone fascicular pattern
• Perivascular cuffing by large atypical tumor cells
• Evidence of neural origin (clinical, cytologic, or IHC)
• Arises in: Nerve, neurofibroma, or patient with NF1
• Focal/patchy S100 or SOX10 (+) (50% are negative)
• Loss of nuclear H3K27me3 expression in majority
Fibrosarcomatous Dermatofibrosarcoma
Protuberans
• Histologically identical to fibrosarcoma but arising from
dermatofibrosarcoma protuberans
• CD34 expression may be lost in fibrosarcomatous zones
• Characteristic t(17;22), COL1A1-PDGFB gene fusion
Desmoid Fibromatosis
• Less cellular; broad sweeping fascicles, not herringbone
Cellular Dermatofibroma
• Majority in dermis/subcutis (unlike fibrosarcoma)
• Can have intersecting hypercellular fascicles with mitoses
but also conventional dermatofibroma areas at periphery
Low-Grade Myofibroblastic Sarcoma
• Cells tend to have more cytoplasm than fibrosarcoma
• Multifocal SMA(+), sometimes focal desmin (+)
Leiomyosarcoma
• Abundant eosinophilic cytoplasm; diffuse SMA and desmin
(+)
• Herringbone pattern uncommon
SELECTED REFERENCES
1. Bahrami A et al: Adult-type fibrosarcoma: a reevaluation of 163 putative
cases diagnosed at a single institution over a 48-year period. Am J Surg
Pathol. 34(10):1504-13, 2010
2. Hansen T et al: Low-grade fibrosarcoma--report on 39 not otherwise
specified cases and comparison with defined low-grade fibrosarcoma types.
Histopathology. 49(2):152-60, 2006
215
 Myxofibrosarcoma

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY
• Malignant fibroblastic neoplasm with cellular
pleomorphism; variably prominent myxoid stroma; and
prominent elongated, thin-walled stromal blood vessels
• Synonym: Myxoid malignant fibrous histiocytoma
CLINICAL ISSUES
• Most common sarcoma of elderly patients
• Most common in patients 50-70 years of age
• Most common in limbs and limb girdles
○ More often superficial than deep
○ Extremely rare in retroperitoneum and abdominal cavity
• Treatment: Complete surgical excision with negative
margins
• Local, often repeated recurrences in up to 50-60% of cases,
unrelated to histologic grade
• Metastatic potential and mortality rate are associated with
histologic grade
MACROSCOPIC
• Often multinodular (particularly superficial tumors)
MICROSCOPIC
• Often multinodular growth with incomplete fibrous septa
• Myxoid stroma and characteristic elongated, curvilinear,
thin-walled blood vessels
• Pseudolipoblasts may be seen
• Spectrum of cellularity, atypia, and proliferative activity
reflected by 3 histologic grades (low, intermediate, high)
• Morphologic variant: Epithelioid myxofibrosarcoma (MFS)
TOP DIFFERENTIAL DIAGNOSES
• Low-grade fibromyxoid sarcoma
• Cellular myxoma
• Undifferentiated pleomorphic sarcoma
• Dedifferentiated liposarcoma
• Pleomorphic liposarcoma

Myxofibrosarcoma Myxofibrosarcoma
(Left) Unlike many sarcomas,
myxofibrosarcoma (MFS) more
often arises superficially in the
subcutaneous tissue or dermis
than in deep soft tissues
locations, as shown in this
photograph. Grossly, MFS is
usually multinodular ſt and
demonstrates a variably
gelatinous cut surface. (Right)
Deep-seated (subfascial or
intramuscular) cases of MFS
may show the characteristic
multinodular growth (shown)
or more of a solitary nodular
mass. Note the glistening,
gelatinous cut surface.

Superficial Tissues of Extremities Multinodular With Fibrous Septa

(Left) MFS most commonly
arises in the extremities of
older/elderly adults. It is more
likely to arise in the
subcutaneous tissue, as
depicted, than in skeletal
muscle. (Right) A multinodular
growth pattern with thin,
variably incomplete fibrous
septa is a feature of many
cases of MFS. Note the
infiltrated skeletal muscle ﬊
in this deep-seated example.

216
 Myxofibrosarcoma
TERMINOLOGY
Abbreviations
• Myxofibrosarcoma (MFS)
Synonyms
• Myxoid malignant fibrous histiocytoma
Definitions
• Malignant fibroblastic neoplasm characterized by cellular
pleomorphism; variably prominent myxoid stroma; and
prominent elongated, thin-walled stromal blood vessels
CLINICAL ISSUES
Epidemiology
• Incidence
○ Relatively common
– Most common sarcoma of elderly patients
• Age
○ Wide range but most common in patients 50-70 years
○ Exceptionally rare in patients < 20 years
• Sex
○ Slight male predominance
Site
• Most common in limbs and limb girdles
○ Lower extremity > upper extremity
○ Majority (65%) arise in superficial tissues
(dermis/subcutaneous) vs. subfascial/intramuscular
• Also, rarely on trunk, head/neck region, and hands/feet
• Extremely rare in retroperitoneum and abdominal cavity
Presentation
• Slow-growing, painless mass
Treatment
• Complete surgical excision with negative margins
• Radiotherapy may decrease risk of local recurrence in some
cases
• Chemotherapy has not been proven to be effective
Prognosis
• Local, often repeated recurrences in up to 50-60% of cases,
unrelated to histologic grade
• Metastatic potential and mortality rate are associated with
histologic grade
○ Low grade
– Metastases very rare
– May show tumor progression in subsequent
recurrences and may acquire metastatic potential
○ Intermediate and high grade
– Metastases in 20-35% of cases
○ Metastases to lungs, viscera, retroperitoneum, bone,
regional lymph nodes
• Overall 5-year survival is 60-70%
○ Tumor size, histologic grade, and margin status are
statistically significant predictors of survival
• Epithelioid variant of MFS appears to be more clinically
aggressive
○ Local recurrence in 70% and metastases in 50%, even
with relatively short follow-up period
Fibroblastic/Myofibroblastic Lesions
MACROSCOPIC
General Features
• Often multinodular (particularly superficial tumors)
• Variably firm to gelatinous cut surfaces
Size
• Wide size range: 3 cm to > 10 cm
MICROSCOPIC
Histologic Features
• Often multinodular growth with incomplete fibrous septa
• Usually peripherally infiltrative
• Myxoid stroma is consistent but variable feature
• Conspicuous, elongated, curvilinear, thin-walled blood
vessels are characteristic
○ Variation in number of these vessels from case to case
• Vacuolated fibroblastic cells containing mucin
(pseudolipoblasts) are not uncommon
○ More common in lower grade tumors but may be seen in
areas of high-grade examples
• Inflammatory cells may be present
• Spectrum of cellularity, cytologic atypia, and proliferative
activity reflected by 3 histologic grades
○ Low-grade MFS
– Hypocellular, prominently myxoid
– Scattered, noncohesive, spindled to stellate cells with
ill-defined eosinophilic cytoplasm and enlarged,
hyperchromatic nuclei
– Curvilinear vasculature often prominent
– Mitoses infrequent
– No tumor necrosis
○ Intermediate-grade MFS
– More cellular and pleomorphic than low-grade tumors
□ Lacks solid/sheet-like areas of high-grade tumors
– Mitoses more common than in low-grade tumors but
are not numerous
– Curvilinear vasculature often prominent
– No tumor necrosis
○ High-grade MFS
– Partly or predominantly composed of solid sheets and
cellular fascicles of tumor cells
□ Often marked nuclear and cytologic pleomorphism
□ Bizarre, multinucleated tumor giant cells common
□ Mitotic figures, often atypical, and coagulative
necrosis are common
– At least focally, areas of lower grade MFS can be
identified
Morphologic Variants
• Epithelioid MFS
○ Contains aggregates &/or cellular sheets of atypical
epithelioid cells
– Abundant eosinophilic cytoplasm
– Round, vesicular nuclei with prominent nucleoli
□ Severe nuclear pleomorphism and atypia not
uncommon
□ Frequent mitoses, often atypical
○ Other features or areas of conventional MFS present
217
 Myxofibrosarcoma
Fibroblastic/Myofibroblastic Lesions
ANCILLARY TESTS
Immunohistochemistry
• May show focal expression of SMA, MSA, CD34
○ Diffuse expression of CD34 more common in superficial
tumors
• Desmin, keratins, S100 protein, CD163 (-)
Molecular Genetics
• Nondistinctive complex karyotypic abnormalities
○ Increasingly complex aberrations often seen in recurrent
lesions
DIFFERENTIAL DIAGNOSIS
Low-Grade Fibromyxoid Sarcoma
• Usually affects younger age group than that of MFS
• More common in deep soft tissue sites than superficial
• Hypocellular fibrous zones alternating with more cellular
myxoid areas
○ Whorling and swirling growth pattern of tumor cells
○ Arcades of blood vessels in myxoid areas are similar to
those of MFS
○ Most cases lack significant nuclear atypia and
pleomorphism
• FUS rearrangements (most commonly FUS-CREB3L2)
Cellular Myxoma (Superficial, Intramuscular, or
Juxtaarticular)
• Absence of nuclear atypia and pleomorphism
• Lacks characteristic vasculature of MFS
• Activating mutations of GNAS gene in intramuscular
myxoma
Neurofibroma
• Absence of significant nuclear pleomorphism in most cases
○ Atypical (degenerative) neurofibromas show
disproportionately low mitotic rate for level of nuclear
atypia
• Lacks characteristic vasculature of MFS
• Consistent S100 protein (+)
Myxoid Liposarcoma
• Usually affects younger age group than that of MFS
• More common in deep soft tissue sites than superficial
• Contains univacuolated and multivacuolated lipoblasts
• Delicate plexiform capillary vascular pattern
• No prominent cytologic atypia
• DDIT3 rearrangements
Undifferentiated Pleomorphic Sarcoma
• Can be indistinguishable from cellular, solid, high-grade
areas of MFS
• Lacks myxoid areas with curvilinear vasculature and other
features of lower grade MFS
• Usually arises in deep soft tissue of extremities
Pleomorphic Liposarcoma
• Commonly contains areas that are essentially
morphologically indistinguishable from MFS
• True lipoblastic differentiation (particularly pleomorphic
lipoblasts) present
218
Dedifferentiated Liposarcoma
• Very common in retroperitoneum in contrast to MFS
• May contain areas that are essentially morphologically
indistinguishable from MFS
• Component of well-differentiated liposarcoma is often
present, at least focally
• MDM2(+), CDK4(+) by IHC
• MDM2 amplification by FISH
Myxoinflammatory Fibroblastic Sarcoma
• Most frequently arises in subcutaneous tissues of distal
extremities (hands, wrists, feet, and ankles)
○ Can rarely arise more proximally
• Spindled; polygonal; and bizarre, ganglion-like tumor cells
with huge, inclusion-like nucleoli
• Characteristic prominent mixed inflammatory infiltrate in
most cases
Malignant Peripheral Nerve Sheath Tumor
• Fascicular arrangement of spindle-shaped tumor cells
common
• Often perivascular whorling or accentuation of tumor cells
○ Generally lacks characteristic vasculature of MFS
• Focal expression of S100 protein in 50% of cases
• May show evidence of origin from neurofibroma or nerve
trunk
• Loss of h3k27me3 by IHC
Metastatic Carcinoma/Melanoma
• Can be difficult to distinguish morphologically from
epithelioid MFS
• History of primary tumor may be present
• IHC helpful
○ Keratin (+) for carcinoma; S100 protein (+) for melanoma
SELECTED REFERENCES
1. Ma S et al: MET-overexpressing myxofibrosarcoma frequently exhibit
polysomy of chromosome 7 but not MET amplification, especially in high-
grade cases: clinical and pathological review of 30 myxofibrosarcoma cases.
Diagn Pathol. 13(1):56, 2018
2. Heitzer E et al: Expanded molecular profiling of myxofibrosarcoma reveals
potentially actionable targets. Mod Pathol. 30(12):1698-1709, 2017
3. Scoccianti G et al: Soft tissue myxofibrosarcoma: a clinico-pathological
analysis of a series of 75 patients with emphasis on the epithelioid variant. J
Surg Oncol. 114(1):50-5, 2016
4. Look Hong NJ et al: Prognostic factors and outcomes of patients with
myxofibrosarcoma. Ann Surg Oncol. 20(1):80-6, 2013
5. Riouallon G et al: Superficial myxofibrosarcoma: assessment of recurrence
risk according to the surgical margin following resection. A series of 21
patients. Orthop Traumatol Surg Res. 99(4):473-7, 2013
6. Smith SC et al: CD34-positive superficial myxofibrosarcoma: a potential
diagnostic pitfall. J Cutan Pathol. 40(7):639-45, 2013
7. Olson MT et al: Myxofibrosarcoma: cytomorphologic findings and
differential diagnosis on fine needle aspiration. Acta Cytol. 56(1):15-24, 2012
8. Sanfilippo R et al: Myxofibrosarcoma: prognostic factors and survival in a
series of patients treated at a single institution. Ann Surg Oncol. 18(3):720-5,
2011
9. Nascimento AF et al: Epithelioid variant of myxofibrosarcoma: expanding the
clinicomorphologic spectrum of myxofibrosarcoma in a series of 17 cases.
Am J Surg Pathol. 31(1):99-105, 2007
10. Willems SM et al: Local recurrence of myxofibrosarcoma is associated with
increase in tumour grade and cytogenetic aberrations, suggesting a
multistep tumour progression model. Mod Pathol. 19(3):407-16, 2006
11. Mansoor A et al: Myxofibrosarcoma presenting in the skin:
clinicopathological features and differential diagnosis with cutaneous
myxoid neoplasms. Am J Dermatopathol. 25(4):281-6, 2003
12. Mentzel T et al: Myxofibrosarcoma. Clinicopathologic analysis of 75 cases
with emphasis on the low-grade variant. Am J Surg Pathol. 20(4):391-405,
1996
 Myxofibrosarcoma
Characteristic Stromal Vasculature
Perivascular Condensation
Nuclear Pleomorphism and Atypia
Fibroblastic/Myofibroblastic Lesions
Elongated, Thin-Walled Vessels
(Left) A distinctive and
characteristic feature of MFS
is the presence of elongated,
thin-walled stromal blood
vessels in short arcs and linear
arrays; however, in some
cases, the vessels may not be
prominent. Of note, this
vascular pattern may be seen
in other tumors, including low-
grade fibromyxoid sarcoma.
(Right) The characteristic
blood vessels ﬈ in MFS are
often referred to as
curvilinear, given their
frequent linear and short
arcing appearance. Branching
﬊ is also a common finding.
Nuclear Pleomorphism and Atypia
(Left) An increase in tumor cell
density around vessels is not
uncommonly noted in MFS, as
depicted. Chronic
inflammatory cells may also
congregate around these
stromal vessels. (Right) The
consistent presence of nuclear
pleomorphism and atypia is
one of the more important
features of MFS. In low-grade
examples, it may be one of the
few clues that help distinguish
MFS from morphologically
similar myxoid neoplasms.
Mitoses are also often
conspicuous but vary with
histologic grade.
Multinucleated Tumor Cells
(Left) Nuclear pleomorphism
may be extreme in some cases
of MFS, as shown. Such high-
grade areas can be
morphologically
indistinguishable from
undifferentiated pleomorphic
sarcoma. (Right)
Multinucleated tumor giant
cells are commonly identified
in MFS and often adopt a
floret-like appearance ﬈
similar to what is seen in
pleomorphic lipoma and well-
differentiated liposarcoma.
These cells often show densely
eosinophilic cytoplasm and
may even suggest myogenic
differentiation.
219
 Myxofibrosarcoma
Fibroblastic/Myofibroblastic Lesions

Multinucleated Tumor Cells Pseudolipoblasts

(Left) The multinucleated
tumor cells of MFS may also
show a peripheral ring or
wreath-like orientation of
nuclei. The high-grade MFS
depicted in this H&E shows
numerous multinucleated cells
within cellular nodules. (Right)
Vacuolated fibroblastic tumor
cells ﬊ distended with acid
mucin are a common finding in
MFS, particularly low- and
intermediate-grade cases.
These cells may erroneously
suggest lipoblastic
differentiation and are often
described as pseudolipoblasts.

Pseudolipoblasts Variable CD34 Expression

(Left) The pseudolipoblasts of
MFS contain cytoplasmic
mucin instead of lipid and are
not truly lipogenic.
Histochemical stains can
clarify the issue, but they are
usually not necessary. (Right)
Variable expression of CD34
may be seen in MFS,
particularly superficial and
cutaneous forms. Diffuse
expression can lead to
confusion with entities, such
as pleomorphic lipoma and
dermatofibrosarcoma
protuberans.

Low-Grade Myxofibrosarcoma Low-Grade Myxofibrosarcoma

(Left) The overall cellularity
and level of atypia and mitotic
activity vary depending on the
histologic grade of MFS. Low-
grade tumors are highly
myxoid and of low cellularity
and show scattered atypical
hyperchromatic tumor cells
with a low proliferation rate.
Necrosis is absent. (Right)
Some areas in low-grade MFS
can be strikingly hypocellular
and myxoid, and cytologic
atypia can be focal. Other
more conventional and
atypical areas are often
present; however, on small
biopsy, these relatively banal
zones can be treacherous.

220
 Myxofibrosarcoma
Intermediate-Grade Myxofibrosarcoma
Regional Variation in Histologic Grade
Epithelioid Variant
Fibroblastic/Myofibroblastic Lesions
High-Grade Myxofibrosarcoma
(Left) Intermediate-grade MFS
shows increased cellularity,
nuclear pleomorphism, and
mitotic activity compared to
low-grade tumors; however,
these features do not reach
the severe degree seen in high-
grade tumors. (Right) High-
grade MFS contains cellular
sheets and fascicles of highly
pleomorphic tumor cells,
essentially morphologically
identical to other high-grade
pleomorphic sarcomas.
Mitoses, including atypical
forms, and coagulative
necrosis are also very
common.
Epithelioid Variant
(Left) In any given case of MFS,
the histologic grade may vary
from one field to the next, as
evidenced at low
magnification by the variation
in cellularity and degree of
myxoid stroma. Note the
differences between high-
grade ﬇ and lower grade ﬉
areas. (Right) The rare
epithelioid variant of MFS
contains areas of variably
sized, rounded cells with
abundant eosinophilic
cytoplasm and vesicular nuclei
with prominent nucleoli. Other
areas showing features of
conventional MFS are often
present elsewhere.
Epithelioid Variant
(Left) The tumor cells in
epithelioid MFS may be
present singly or form
architectures, including nests,
aggregates, sheets, or linear
cords. Increased perivascular
tumor cell density ﬊ can also
be seen. (Right) In some areas
of epithelioid MFS, the tumor
cells form diffuse sheets and
may closely resemble a poorly
differentiated carcinoma or
melanoma. IHC is very helpful
in making the distinction.
221
 Low-Grade Fibromyxoid Sarcoma

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY
• Deceptively bland, malignant fibroblastic neoplasm
composed of spindle cells in variable collagenous to myxoid
matrix and characterized in most cases by FUS-CREB3L2 or
FUS-CREB3L1 fusion
• Synonym: Evans tumor
CLINICAL ISSUES
• Uncommon but incidence likely underestimated
• Most common in young adults
○ ~ 20% occur in patients < 18 years old
• Most common in proximal extremities and trunk
• Slow-growing, painless mass, often of long clinical duration
• Vast majority arise in deep soft tissue
• Treatment: Wide surgical excision
• Generally indolent clinical course
○ However, higher rates of recurrence and metastatic
disease with longer clinical follow-up
• Indefinite, long-term follow-up is mandatory
MICROSCOPIC
• Classically shows combination of hypocellular
fibrocollagenous and cellular myxoid zones
• Cytologically bland spindle cells with indistinct cytoplasm
• Short fascicular and whorling growth patterns characteristic
• Vasculature often prominent in myxoid zones
• Mitotic figures generally rare to absent
• Sclerosing epithelioid fibrosarcoma-like areas in some cases
• Morphologic variant with paucicellular collagen nodules
ANCILLARY TESTS
• Strong, diffuse MUC4(+) with cytoplasmic expression
• Molecular: t(7;16) with FUS-CREB3L2 (75% of cases)
TOP DIFFERENTIAL DIAGNOSES
• Desmoid fibromatosis
• Perineurioma
• Intramuscular myxoma
• Myxofibrosarcoma

Low-Grade Fibromyxoid Sarcoma Fibrous Zones

(Left) Low-grade fibromyxoid
sarcoma (LGFMS) is a
malignant fibroblastic
neoplasm that most
commonly arises in the deep
soft tissue of young adults.
The classic low-power
appearance is that of cellular
myxoid zones ﬉ admixed with
hypocellular fibrocollagenous
zones ﬈. (Right) The fibrous
zones of LGFMS are often
hypocellular and feature
regular, cytologically banal
spindle cells. Mitoses are rare.
This deceptively bland
appearance is a common
reason for misdiagnosis as a
benign neoplasm.

Myxoid Zones MUC4 Expression

(Left) The myxoid zones or
nodules of LGFMS are
generally more cellular than
the fibrous zones and
frequently show a variable
prominent vascular network
composed of arcades of thin-
walled vessels ﬉. This
vascularity may sometimes
resemble that of
myxofibrosarcoma. (Right)
MUC4 is a highly sensitive and
specific marker of LGFMS and
is not seen in its morphologic
mimics. Of note, MUC4
expression is also common in
sclerosing epithelioid
fibrosarcoma (SEF), a
genetically related entity.

222
 Low-Grade Fibromyxoid Sarcoma
TERMINOLOGY
Abbreviations
• Low-grade fibromyxoid sarcoma (LGFMS)
Synonyms
• Evans tumor
• Fibrosarcoma, fibromyxoid type
• Hyalinizing spindle cell tumor with giant rosettes
(morphologic variant)
Definitions
• Deceptively bland, malignant fibroblastic neoplasm
composed of spindle cells in variable collagenous to myxoid
matrix and characterized in most cases by FUS-CREB3L2 or
FUS-CREB3L1
○ Appear to be genetically related to subset of sclerosing
epithelioid fibrosarcoma (SEF)
CLINICAL ISSUES
Epidemiology
• Incidence
○ Once considered rare
– Incidence likely underestimated and underreported in
literature due to misclassification as other tumors
• Age
○ Young adults (typically in 4th decade) but wide age
distribution
– Significant proportion (~ 20%) occurs in patients < 18
years old
Site
• Most common in proximal extremities and trunk
• Rarely other locations, including viscera
Presentation
• Slow-growing, painless mass
○ Often of prolonged duration (> 1 year)
• Vast majority arise in deep soft tissue
• Rare tumors arise in subcutis or dermis
○ Superficial tumors more common in children
Treatment
• Wide surgical excision with negative margins
• Indefinite, long-term follow-up is mandatory to monitor for
recurrences and late metastases
Prognosis
• Generally indolent clinical course
○ Low rates of local recurrence and metastatic disease in
1st few years after initial surgery
• Higher rates of recurrence and metastatic disease with
longer clinical follow-up
○ Metastatic disease may occur many years after primary
surgery (up to 45 years reported)
– Most commonly to lung, pleura, and chest wall
○ In one recent study with long-term follow-up, death
from disease occurred in 42% of patients with median
interval to tumor-related death of 15 years
• Superficial tumors (subcutis or dermis) appear to have
better overall outcome
Fibroblastic/Myofibroblastic Lesions
○ Lower risk of local recurrence and as of yet, no reported
cases of metastatic disease
• Generally, no correlation between histologic features or
translocation status
○ Exception: "Dedifferentiated" LGFMS with
undifferentiated round cells shows aggressive clinical
course
• Exact behavior of LGFMS with areas resembling SEF (so-
called hybrid LGFMS/SEF) is difficult to predict but appears
to behave more like conventional LGFMS than pure SEF
MACROSCOPIC
General Features
• Well-defined mass
• White, fibrous cut surface, often with glistening areas
• Sometimes cystic foci but necrosis rare
Size
• Median: 5 cm (range: 1 cm to > 20 cm)
MICROSCOPIC
Histologic Features
• Well circumscribed but often shows microscopic infiltration
of peripheral soft tissues
• Cytologically bland spindle cells with indistinct cytoplasm
○ Usually at most mild nuclear enlargement &/or
hyperchromasia
○ Mitotic figures generally rare to absent
• Classically shows combination of fibrous and myxoid zones
○ Exact composition of given tumor is highly variable
– Occasional cases are almost entirely fibrous or myxoid
○ Transitional interface may be gradual or abrupt
(cannonball-like myxoid nodules)
○ Fibrous zones
– Usually hypocellular with abundant fine, fibrillary or
feathery stromal collagen
– Short fascicular and whorling growth patterns
characteristic
– Scattered paucicellular collagen rosettes may be seen
in subset of cases
○ Myxoid zones
– More cellular than fibrous zones
– Vasculature often prominent
□ Arcades of small blood vessels with variable
perivascular sclerosis
□ Increased perivascular cellularity may be seen
• Necrosis rare (may be focal)
• Rare findings: Cystic degeneration, osseous metaplasia,
staghorn blood vessels
• Minority of cases feature foci of increased cellularity,
nuclear pleomorphism, mitoses, or epithelioid morphology
○ These findings are more common in recurrent and
metastatic tumors
• Areas morphologically similar to or indistinguishable from
SEF can be seen
○ Sheets, nests, and cords of small epithelioid cells with
clear to eosinophilic cytoplasm within prominent
sclerotic matrix
• Rare undifferentiated round cell component reported in
recurrences ("dedifferentiated" LGFMS)
223
 Low-Grade Fibromyxoid Sarcoma
Fibroblastic/Myofibroblastic Lesions
Morphologic Variants
• Hyalinizing spindle cell tumor with giant rosettes
○ Prominent paucicellular hyalinized nodules bordered by
more rounded tumor cells
○ Background morphology similar to conventional LGFMS
○ No genetic, immunohistochemical, or behavioral
differences in this variant
○ This term is no longer recommended
ANCILLARY TESTS
Immunohistochemistry
• Strong, diffuse MUC4(+) with cytoplasmic expression
• May show focal expression of EMA, CD34, SMA, p63,
claudin-1
• Variable DOG1(+) reported in 5/10 cases in one series
• Desmin, S100 protein, keratin, p40, CD117 (-)
• Nuclear β-catenin expression absent
Molecular Genetics
• Characteristic chromosomal translocations
○ t(7;16)(q33;p11) is most common (75% of cases)
– Results in FUS-CREB3L2 fusion
○ t(11;16)(p11;p11)
– Results in FUS-CREB3L1 fusion
○ Very rare tumors reported with EWSR1-CREB3L1 fusion
DIFFERENTIAL DIAGNOSIS
Desmoid Fibromatosis
• Infiltrative growth
• Characteristic sweeping fascicular pattern
• Nuclear β-catenin (+)
• MUC4(-)
• Lacks genetic features of LGFMS
Perineurioma
• Can show significant morphologic overlap with LGFMS
• Perivascular whorls and storiform arrays
• Myxoid areas lack prominent vasculature
• EMA(+), claudin-1 (+); variable CD34(+)
• MUC4(-)
• Lacks genetic features of LGFMS
Intramuscular Myxoma
• Paucicellular myxoid areas predominate
• Lacks prominent vasculature
• MUC4(-)
• Lacks genetic features of LGFMS
Myxofibrosarcoma
• Most common in superficial soft tissues of elderly patients
• Abundant myxoid stroma in lower grade tumors
• Prominent nuclear atypia and pleomorphism
• Can feature similar vasculature to LGFMS
• MUC4(-)
• Lacks genetic features of LGFMS
Sclerosing Epithelioid Fibrosarcoma
• Nests and cords of small epithelioid cells within prominent
sclerotic matrix
• MUC4(+) in most cases
224
• May show pure SEF morphology or contain minor areas of
conventional LGFMS
○ Clear point of distinction between classification as SEF vs.
"hybrid LGFMS/SEF" is unclear
– However, EWSR1 and CREB3L1 rearrangements
appear to predominate in pure SEF
□ In contrast to predominately FUS and
CREB3L2 rearrangements in pure LGFMS and
hybrid LGFMS/SEF
Myxoid Liposarcoma
• General absence of fibrous zones
• More delicate plexiform or arborizing capillary vasculature
• Often contains lipoblasts
• MUC4(-)
• Distinctive t(12;16) with FUS-DDIT3 fusion in most cases
Hybrid Nerve Sheath Tumor
• Often resembles perineurioma
• Variable fibromyxoid matrix
• Contains Schwann cells and perineurial cells
○ S100 protein (+), EMA(+), claudin-1 (+)
• MUC4(-)
• Lacks genetic features of LGFMS
SELECTED REFERENCES
1. Swanson AA et al: Low-grade fibromyxoid sarcoma arising within the median
nerve. Neuropathology. 38(3):309-14, 2018
2. Ud Din N et al: Abdominopelvic and retroperitoneal low-grade fibromyxoid
sarcoma: a clinicopathologic study of 13 cases. Am J Clin Pathol. 149(2):128-
34, 2018
3. Mohamed M et al: Low-grade fibromyxoid sarcoma: clinical, morphologic
and genetic features. Ann Diagn Pathol. 28:60-7, 2017
4. Cowan ML et al: Low-grade fibromyxoid sarcoma of the head and neck: a
clinicopathologic series and review of the literature. Head Neck Pathol.
10(2):161-6, 2016
5. Prieto-Granada C 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. 54(1):28-38, 2015
6. Thway K et al: Pediatric low-grade fibromyxoid sarcoma mimicking ossifying
fibromyxoid tumor: adding to the diagnostic spectrum of soft tissue tumors
with a bony shell. Hum Pathol. 46(3):461-6, 2015
7. Thway K et al: DOG1 expression in low-grade fibromyxoid sarcoma: a study
of 11 cases, with molecular characterization. Int J Surg Pathol. 23(6):454-60,
2015
8. Lau PP et al: EWSR1-CREB3L1 gene fusion: a novel alternative molecular
aberration of low-grade fibromyxoid sarcoma. Am J Surg Pathol. 37(5):734-
8, 2013
9. Maretty-Nielsen K et al: Low-grade fibromyxoid sarcoma: incidence,
treatment strategy of metastases, and clinical significance of the FUS gene.
Sarcoma. 2013:256280, 2013
10. Doyle LA et al: MUC4 is a highly sensitive and specific marker for low-grade
fibromyxoid sarcoma. Am J Surg Pathol. 35(5):733-41, 2011
11. Evans HL: Low-grade fibromyxoid sarcoma: a clinicopathologic study of 33
cases with long-term follow-up. Am J Surg Pathol. 35(10):1450-62, 2011
12. Rekhi B et al: 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. 15(5):303-11, 2011
13. Guillou L 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. 31(9):1387-402, 2007
14. Billings SD et al: 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. 29(2):204-10, 2005
15. Folpe AL et al: Low-grade 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. 24(10):1353-60, 2000
 Low-Grade Fibromyxoid Sarcoma
Irregular Zonal Interface
Gradual Zonal Interface
Zonal Variations in Cellularity
Fibroblastic/Myofibroblastic Lesions
Abrupt Zonal Interface
(Left) In most cases of LGFMS,
the fibrous ﬉ and myxoid ﬈
zones are well delineated from
one another, although the
border/interface is often
somewhat irregular, as
depicted in this H&E. (Right)
Occasionally, myxoid zones
are very well demarcated in
LGFMS and truly show an
abrupt interface with the
fibrous areas, as seen in this
H&E.
"Tigroid" Zonal Interface
(Left) Myxoid areas showing a
more gradual transition to and
from fibrous zones are also
relatively common in LGFMS,
as depicted in this H&E. (Right)
Rare cases of LGFMS can show
an unusual pattern of fibrous
and myxoid zones alternating
in rows. This striped
morphology has been referred
to as tigroid.
Hypocellular Myxoid Zones
(Left) The myxoid zones ﬈ of
LGFMS are generally more
cellular than the adjacent
fibrous zones. This is in
contrast to many other soft
tissue tumors, wherein a
myxoid matrix is often
associated with a decrease in
cellularity. (Right)
Occasionally, a myxoid region
in LGFMS is very hypocellular,
as depicted. In conjunction
with the bland spindled cells,
these areas can resemble a
benign tumor, such as myxoma
or myxoid neurofibroma.
225
 Low-Grade Fibromyxoid Sarcoma
Fibroblastic/Myofibroblastic Lesions

Prominent Vasculature Prominent Vasculature

(Left) A characteristic finding
in many of the myxoid zones
of LGFMS is an accentuated
stromal vasculature composed
of arcades of branching, thin-
walled blood vessels ﬈. A
mild degree of perivascular
sclerosis is also a frequent
finding in some cases. (Right)
An increase in cell density
around blood vessels may be
seen in LGFMS, as shown in
this H&E. Note that the tumor
cells show no more than mild
atypia, unlike
myxofibrosarcoma.

Prominent Vasculature Prominent Vasculature

(Left) The characteristic
vasculature of LGFMS may be
quite prominent and plexiform
in some tumors, as depicted in
this H&E. Although somewhat
resembling the ramifying
vascular pattern of myxoid
liposarcoma, the fascicles and
whorls of tumor cells are not
features of that diagnosis.
(Right) H&E shows increased
cellularity in a highly vascular
myxoid region of a case of
LGFMS.

Perivascular Sclerosis Perivascular Sclerosis

(Left) A variable degree of
perivascular hyalinization or
sclerosis is not uncommon in
LGFMS. This finding often
imparts an eosinophilic
accentuation ﬉ to the
individual blood vessels.
(Right) Higher power H&E of
LGFMS shows prominent
perivascular sclerosis, as
evidenced by eosinophilic
collagen surrounding variably
distinct vascular channels ﬈.

226
 Low-Grade Fibromyxoid Sarcoma
Cyst-Like Changes
Feathery Stromal Collagen
Storiform Growth
Fibroblastic/Myofibroblastic Lesions
Cystic Degeneration
(Left) Some myxoid foci in
LGFMS can demonstrate a
loose mucoid quality with cyst-
like degeneration, similar to
the stromal "holes" or "tears"
seen in nodular fasciitis.
(Right) Larger, degenerative
cystic spaces ﬈ may be seen
in some longstanding cases of
LGFMS.
Haphazard Growth
(Left) The stromal collagen
fibers of LGFMS often show a
fine, fibrillary or feathery
quality, as depicted in this
H&E. Note the generally bland
nuclei. (Right) A variety of
architectural patterns may be
seen in LGFMS, including
fascicular, whorling, storiform,
and random, haphazard
growth. The latter pattern is
featured in this case.
Hypocellular Fibrous Zone
(Left) H&E shows a loose
storiform architectural
pattern in a case of LGFMS.
(Right) LGFMS shows
hypocellular fibrous areas
with haphazard cellular
growth mimicking a nerve
sheath tumor, such as
neurofibroma. IHC is often
helpful in this setting. Note
the fine, fibrillary or feathery
stromal collagen.
227
 Low-Grade Fibromyxoid Sarcoma
Fibroblastic/Myofibroblastic Lesions

Discrete Collagen Fibers Increased Cellularity

(Left) Collagen fibers may
form more discrete bundles in
LGFMS, as depicted in this
H&E. This morphology can
lead to serious consideration
of neurofibroma. Note the
scattered wavy nuclei ﬈
further complicating the issue.
(Right) Areas of increased
cellularity are seen in a minor
subset of cases of LGFMS,
occurring both de novo and in
recurrent/metastatic tumor
(the latter being much more
common).

Cellular but Minimal Atypia Fascicular Growth

(Left) Despite the finding of
increased cellularity in this
case of LGFMS, the tumor cells
are regular and still relatively
cytologically bland. (Right)
Fascicular growth may be seen
in LGFMS, particularly in
cellular areas, as depicted in
this H&E. Focal herringbone
architecture can also be seen,
similar to other types of
fibrosarcoma.

Fascicular Growth Perivascular Cellularity

(Left) The combination of
fascicular growth and uniform,
cytologically bland spindled
cells in LGFMS can easily lead
to consideration of
fibromatosis, particularly on
biopsy. (Right) Increased
perivascular cellularity is not
uncommon in myxoid zones of
LGFMS; however, it can also
be seen in fibrous areas, as
shown in this H&E. Note the
vessels ﬈.

228
 Low-Grade Fibromyxoid Sarcoma
Perivascular Cellularity
Stromal Hyalinization
Metaplastic Bone Formation
Fibroblastic/Myofibroblastic Lesions
Focal Vague Palisaded Growth
(Left) In some cases of LGFMS,
the increased perivascular
cellularity is accentuated by a
more epithelioid
cytomorphology ﬈ in the
tumor cells. Occasionally, the
vessels are inconspicuous, and
the structures resemble loose
epithelial nests. (Right) Focal
vague palisading of tumor
cells or nuclei is a rare finding
in LGFMS, as depicted in this
H&E.
Stromal Hyalinization
(Left) Prominent hyalinization
of a large fibrous area (upper
left) is seen in this H&E of
LGFMS. Note the more cellular
myxoid region (lower right).
(Right) Stromal hyalinization
can be marked in LGFMS and
may make for a challenging
case if more conventional
morphologic areas are not
present. These areas can also
closely resemble SEF.
Rare Staghorn Blood Vessels
(Left) Metaplastic bone
formation ﬊ is an uncommon
but well-documented finding
in LGFMS. (Right) Larger
ectatic or staghorn blood
vessels are an uncommon
finding in LGFMS. In rare
cases, these vessels are quite
prominent, as depicted in this
H&E, and may lead to
consideration of solitary
fibrous tumor.
229
 Low-Grade Fibromyxoid Sarcoma
Fibroblastic/Myofibroblastic Lesions

Collagenous Rosettes Epithelioid Perinodular Cells

(Left) Up to 30% of cases of
LGFMS feature unusual
nodular structures composed
of paucicellular collagen
rimmed by plump tumor cells.
These collagenous rosettes
may range from focal and
isolated to numerous and
confluent. (Right) The tumor
cells rimming the collagenous
rosettes of LGFMS generally
show a plumper and more
epithelioid cytomorphology
﬊.

Early Collagenous Rosettes Perivascular Collagenous Rosettes

(Left) In some cases of LGFMS
with collagenous rosettes, the
structures are only seen
focally and can appear less
distinctive than usual. (Right)
The collagenous rosettes of
LGFMS may be seen to
encompass a central vessel ﬈
and likely originate as nodules
of perivascular
hyalinization/sclerosis. Note
the peripheral epithelioid
fibroblastic tumor cells st.

Hyalinizing Spindle Cell Tumor With Giant Hyalinizing Spindle Cell Tumor With Giant
Rosettes Rosettes
(Left) Cases of LGFMS showing
prominent collagenous
rosettes, as depicted in this
H&E, were previously classified
as hyalinizing spindle cell
tumor with giant rosettes
(HSCTGR) before it become
widely accepted as a
morphologic variant of
LGFMS. (Right) H&E shows a
predominantly
fibrocollagenous and
hyalinized example of LGFMS
(formerly HSCTGR). Note the
numerous collagenous
rosettes ﬉.

230
 Low-Grade Fibromyxoid Sarcoma
Infrequent Nuclear Atypia
Sclerosing Epithelioid Fibrosarcoma-Like
Areas
Sclerosing Epithelioid Fibrosarcoma-Like
Areas
Fibroblastic/Myofibroblastic Lesions
Epithelioid Cytomorphology
(Left) Nuclear atypia in the
form of pleomorphism ﬈ or
multinucleation is an
uncommon finding in LGFMS
and is more likely to be
present in recurrent or
metastatic tumors. (Right)
Rare cases of LGFMS feature
foci of plumper epithelioid
cells ﬉. Although not shown
in this H&E, very rare cases of
recurrent LGFMS may show
"dedifferentiated" areas
containing an anaplastic
round cell component.
Sclerosing Epithelioid Fibrosarcoma-Like
Areas
(Left) Some cases of LGFMS
may feature areas ﬈ that are
morphologically similar to or
indistinguishable from SEF.
Tumors featuring
predominantly SEF
morphology are probably
better classified and followed
as SEF, given its propensity for
more aggressive behavior.
(Right) Foci resembling SEF are
characterized by small
epithelioid tumor cells forming
cords and nests within a
prominent hyalinized or
sclerotic matrix.
Sclerosing Epithelioid Fibrosarcoma-Like
Areas
(Left) A corded growth pattern
is a common finding in SEF and
may also be seen in SEF-like
areas of LGFMS, as depicted.
(Right) Clear cytoplasm is a
common finding in tumor cells
in SEF and SEF-like areas of
LGFMS, as depicted. These
areas may be completely
indistinguishable from true
"pure" SEF in a limited biopsy.
Molecular analysis may assist
in favoring diagnosis over the
other.
231
 Sclerosing Epithelioid Fibrosarcoma

KEY FACTS
Fibroblastic/Myofibroblastic Lesions

TERMINOLOGY ○ Clear to eosinophilic cytoplasm

• Aggressive but deceptively bland sarcoma characterized by ○ Bland, ovoid, sometimes angulated, nuclei
epithelioid tumor cells with prominent sclerotic matrix • Mitotic rate low and necrosis uncommon
○ Subset appears to be genetically related to low-grade • Minor areas of conventional fibrosarcoma or LGFMS may be
fibromyxoid sarcoma (LGFMS) present

CLINICAL ISSUES ANCILLARY TESTS

• Most common in middle-aged to older adults • MUC4(+) in majority
• Most common in limbs, limb girdles, trunk, neck • SATB2, keratin, S100 protein, SMA, desmin (-)
• Rarely in abdomen/pelvis, retroperitoneum, viscera, bone • Molecular: Most cases show EWSR1-CREB3L1 fusion
• Solitary, deeply seated (intramuscular) mass TOP DIFFERENTIAL DIAGNOSES
• Treatment: Wide surgical excision with negative margins
• Metastatic carcinoma
• Generally aggressive tumor with overall poor prognosis
• LGFMS
○ Local recurrence in > 50% and metastasis in up to 80%
• Sclerosing rhabdomyosarcoma
MICROSCOPIC • Extraskeletal osteosarcoma
• Densely hyalinized, sclerotic matrix characteristic
• Nests, cords, and chains of small to medium-sized
epithelioid cells

Sclerosing Epithelioid Fibrosarcoma Prominent Hyalinized Matrix

(Left) Sclerosing epithelioid
fibrosarcoma (SEF) is a
clinically aggressive sarcoma
that most commonly arises in
the deep soft tissue of the
extremities. The characteristic
eosinophilic collagenous
matrix ﬈ is often evident at
low power. (Right) A densely
hyalinized or sclerotic matrix is
a characteristic feature of SEF
and may be strikingly
abundant in areas. Lesional
cells are small to medium
sized and contain pale
eosinophilic cytoplasm;
however, a clear cell
appearance ﬉ is an extremely
common finding in this tumor.

Cytologic Features MUC4 Expression

(Left) The cells of SEF usually
contain relatively bland,
uniform, oval or angulated ﬉
nuclei. Subtle nuclear grooves
﬈ or folds may also be seen.
(Right) MUC4 expression is
seen in the majority of cases of
SEF; however, it is also
expressed in almost all cases
of low-grade fibromyxoid
sarcoma, which can show
histologic and genetic overlap
with SEF. MUC4 has also been
reported in a minor subset of
ossifying fibromyxoid tumor.

232
 Sclerosing Epithelioid Fibrosarcoma

Fibroblastic/Myofibroblastic Lesions
TERMINOLOGY MICROSCOPIC
Abbreviations Histologic Features
• Sclerosing epithelioid fibrosarcoma (SEF) • Well-demarcated tumor but often microscopically
infiltrative at periphery
Definitions
• Prominent densely hyalinized, sclerotic matrix characteristic
• Aggressive but deceptively bland sarcoma characterized by ○ Some areas may be largely paucicellular
epithelioid tumor cells with prominent sclerotic matrix
○ Thin strands of collagen can resemble osteoid
○ Subset appears to be genetically related to low-grade
○ Occasional myxoid foci
fibromyxoid sarcoma (LGFMS)
○ Calcification or metaplastic bone/cartilage may be seen
○ Rare cases are cellular without abundant
CLINICAL ISSUES
hyalinization/sclerosis
Epidemiology • Nests, cords, and chains of small to medium-sized
• Age epithelioid cells
○ Most common in middle-aged to older adults ○ Clear to eosinophilic cytoplasm
– Wide range reported ○ Bland, ovoid, sometimes angulated, nuclei
• Sex – Rare foci with prominent nuclear pleomorphism
○ M=F ○ Nests can appear to lose cohesion, imparting
pseudoalveolar/pseudoacinar appearance
Site ○ Generally low mitotic index
• Limbs and limb girdles most common • Necrosis uncommon
○ Lower > upper extremity • Focal staghorn vasculature pattern in some cases
• Also trunk, neck • Other patterns of fibrosarcoma can coexist
• May rarely arise in abdomen/pelvis, retroperitoneum, ○ Spindle cell fascicular areas, resembling conventional
viscera, bone fibrosarcoma
Presentation ○ Small areas resembling LGFMS (± collagenous rosettes)
• Solitary, deeply seated (intramuscular) mass
ANCILLARY TESTS
○ May erode underlying bone
• Often painless but may be painful Immunohistochemistry
• Metastatic disease may exist at time of presentation • MUC4(+) in majority
Treatment • Focal EMA(+) in some cases
• SATB2, keratin, S100, SMA, desmin, CD34 (-)
• Wide surgical excision with negative margins
○ Can require amputation especially when bone involved Molecular Genetics
• Chemotherapy or radiation therapy may be attempted to • EWSR1-CREB3L1 fusion in most cases of pure SEF
control recurrence and metastasis ○ CREB3L2 and CREB3L3 also reported
Prognosis • Rare cases with FUS-CREB3L2 fusion
○ In contrast to cases of pure LGFMS and "hybrid
• Generally aggressive tumor with overall poor prognosis
LGFMS/SEF" in which FUS-CREB3L2 fusion clearly
○ Local recurrence in > 50%
predominates
○ Metastasis in up to 80%
– Most common to lung, pleura, bone, CNS DIFFERENTIAL DIAGNOSIS
– Metastases may occur many years after primary
surgery Metastatic Carcinoma
○ 5-year survival is 43-75% • Clinical evidence of primary tumor
• Cord-like growth in some breast carcinomas
MACROSCOPIC • Densely sclerotic matrix generally uncommon
General Features • Strong keratin (+), EMA(+)
• Circumscribed, nodular mass Low-Grade Fibromyxoid Sarcoma
• Often involves underlying periosteum • Classic admixture of hypocellular fibrous zones and cellular
• Firm, gray-white cut surface myxoid zones
○ Can show calcification or ossification • May contain areas resembling SEF either in primary tumor
(so-called hybrid LGFMS/SEF) or in recurrences
Size
• LGFMS and "hybrid LGFMS/SEF" contain substantial
• Usually 5-10 cm in maximal dimension component of tumor with LGFMS-type morphology
○ Occasional tumors > 20 cm • Majority of cases characterized by t(7;16)(q33;p11)
resulting in FUS-CREB3L2 fusion
○ Includes pure LGFMS, "hybrid LGFMS/SEF," and LGFMS
that recurs with areas resembling SEF

233
 Sclerosing Epithelioid Fibrosarcoma
Fibroblastic/Myofibroblastic Lesions

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234
 Sclerosing Epithelioid Fibrosarcoma
Circumscribed but Infiltrative
Nests and Aggregates
Polygonal Cells
Fibroblastic/Myofibroblastic Lesions
Corded Growth Pattern
(Left) The peripheral border of
SEF is often well delineated,
but microscopic evidence of
infiltrative growth ﬈ can
often be identified.
Peritumoral foci of vascular
invasion can also be seen (not
shown). (Right) A linear corded
growth pattern is a common
feature of SEF, as depicted.
Out of context, this
architecture could easily be
misconstrued as infiltrating
carcinoma, particularly lobular
carcinoma of the breast.
Pseudoalveolar Appearance
(Left) Nests, clusters, and
aggregates of tumor cells are
a common finding in SEF. Note
that although clear cells are
frequently seen in most cases,
in some areas they may not be
well visualized. (Right) Nests
of tumor cells in SEF can
appear dyscohesive and may
resemble alveolar or acinar
structures, as shown in this
H&E. Note also the prominent
angulated nuclei.
Deceptively Bland Appearance
(Left) In some cases of SEF, the
tumor cells are more
polygonal and may more
closely resemble carcinoma,
particularly with nested
growth. Note the dense
collagenous matrix. (Right) It
is not uncommon for some
areas of SEF to appear
extremely bland, as depicted,
which may easily lead to
misdiagnosis as a benign
neoplasm, particularly on
limited biopsy.
235
 Sclerosing Epithelioid Fibrosarcoma
Fibroblastic/Myofibroblastic Lesions

Prominent Stromal Collagen Spindled, Fibrosarcoma-Like Areas

(Left) The prominence of the
fibrocollagenous matrix in SEF
often varies from tumor to
tumor and sometimes from
field to field. Some cases may
contain paucicellular areas
with abundant matrix and
striking cracking artifact, as
shown here. (Right) Small
areas demonstrating a
spindled, fascicular
appearance resembling low-
grade fibrosarcoma are noted
in some cases of SEF.

Cellular Areas Cellular Areas

(Left) This H&E shows an area
of increased cellularity in SEF.
Note that the collagenous
matrix and clear cells are less
prominent in this area. (Right)
This H&E shows an area of SEF
with markedly compressed
cords and nests, resembling
sheet-like growth; however,
the intervening collagenous
matrix ﬉ can still be
identified. Note also the
relatively uniform, oval to
angular nuclei.

Cytologic Pitfalls Focal Increased Pleomorphism

(Left) Small tumor cells ﬈
with eccentric nuclei and
eosinophilic cytoplasm may
sometimes mimic plasma cells
or even osteoblasts in SEF.
(Right) Foci of increased
nuclear pleomorphism and
atypia may be seen in SEF but
are generally uncommon.
Necrosis is also uncommon in
SEF but can be seen in larger
tumors.

236
 Sclerosing Epithelioid Fibrosarcoma
Metaplastic Bone or Cartilage
Focal Myxoid Change
Low-Grade Fibromyxoid Sarcoma
Fibroblastic/Myofibroblastic Lesions
Focal Ectatic Staghorn Vasculature
(Left) Foci ﬈ of metaplastic
bone &/or cartilage can be
seen in SEF. Bone formation
may be extensive in some
tumors and raise
considerations of an
extraskeletal osteosarcoma.
(Right) Dilated staghorn-
shaped blood vessels ﬉ may
be a focal finding in SEF, as
depicted. This finding is very
nonspecific and is seen in a
wide variety of both benign
and malignant soft tissue
neoplasms.
Myxoid Change
(Left) Focal myxoid stromal
change may be seen in SEF but
is uncommon. Note the area
﬈ of more conventional
morphology featuring clear
cells and a prominent
hyalinized matrix. (Right) This
case of a large SEF of the
thigh predominantly features
the characteristic sclerosing
matrix but also shows several
small myxoid foci, as depicted.
Note the small epithelioid
tumor cells that appear to line
the cystic or cleft-like myxoid
spaces.
Lung Metastases
(Left) Some cases of SEF
contain minor areas with
morphologic features of
LGFMS ﬊. In light of current
published reports, molecular
analysis in these cases is more
likely to show FUS/CREB3L2
than EWSR1/CREB3L1
rearrangements. (Right)
Pulmonary metastases of SEF
often feature nodular
hyalinized deposits ﬈ of
hypocellular or acellular
tumor filling alveolar spaces
within the lesion. Note the
normal lung tissue at the
bottom left of the H&E.
237
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 SECTION 5

Pediatric Fibroblastic/Myofibroblastic
Tumors

Benign
Fibrous Hamartoma of Infancy 240
Calcifying Aponeurotic Fibroma 244
Calcifying Fibrous Tumor 248
Inclusion Body Fibromatosis 250
Hyaline Fibromatosis Syndrome 252
Fibromatosis Colli 254
Gardner Fibroma 256

Intermediate (Locally Aggressive)

Lipofibromatosis 258
Giant Cell Fibroblastoma 260

Intermediate (Rarely Metastasizing)

Infantile Fibrosarcoma 264
 Fibrous Hamartoma of Infancy

KEY FACTS
Pediatric Fibroblastic/Myofibroblastic Tumors

TERMINOLOGY MICROSCOPIC
• Benign superficial fibrous tumor with characteristic • Classic organoid growth pattern
organoid pattern of 3 distinct components: Fibrous tissue, ○ 3 distinct components in widely varying amounts
fat, primitive mesenchymal cells – Fascicles and sheets of fibroblasts/myofibroblasts
CLINICAL ISSUES – Nests of immature mesenchymal cells in loose myxoid
stroma
• Infants and children up to 2 years
– Mature adipose tissue
○ Up to 25% congenital
○ Also hypocellular areas with prominent stromal collagen
○ Male predilection
• Most common in deep dermis or subcutis of trunk, ANCILLARY TESTS
including axilla, upper back, and groin/perineum • SMA(+) in fibroblastic component
• Slow-growing or rapidly enlarging, painless mass • CD34(+) in myxoid and collagenous/pseudovascular areas
• Treatment: Complete local excision
TOP DIFFERENTIAL DIAGNOSES
• Benign
• Up to 15% recur locally • Lipofibromatosis
• Fibromatosis
MACROSCOPIC • Giant cell fibroblastoma
• Soft, poorly defined mass  • Lipofibromatosis-like neural tumor
• Usually < 5 cm • Lipoblastoma

Fibrous Hamartoma of Infancy Fibroblastic Component

(Left) Fibrous hamartoma of
infancy (FHI) is a benign
fibrous tumor that typically
occurs in the 1st year of life
and has a predilection for
males. The usual case shows
an irregular conglomeration of
3 main components: Immature
mesenchymal zones ﬈,
fascicles of fibroblasts ﬊, and
mature adipose tissue ﬉.
(Right) The fibroblastic portion
of FHI is composed of irregular
bands, fascicles, and sheets of
bland spindled cells in a
collagenous background. Note
the small immature myxoid
focus ﬈.

Immature Myxoid Mesenchymal

Component Collagenous Zones
(Left) The immature
mesenchymal component of
FHI is composed of bland
spindled to ovoid cells within a
basophilic myxoid matrix.
These foci ﬈ are often small
and scattered haphazardly,
but rarely they may be large,
confluent, or dominant.
(Right) Approximately 1/2 of
cases of FHI contain a highly
collagenized zone with
scattered blood vessels. These
areas are often centrally
located within the tumor and
may somewhat resemble a
neurofibroma.

240
 Fibrous Hamartoma of Infancy

Pediatric Fibroblastic/Myofibroblastic Tumors

• Hypocellular areas with prominent stromal collagen also
TERMINOLOGY common
Abbreviations ○ Can resemble vascular growth pattern
• Fibrous hamartoma of infancy (FHI) (pseudoangiomatous) or neurofibroma
○ Often centrally located (may be maturation
Definitions phenomenon)
• Benign superficial fibrous tumor with characteristic • Mitotic figures rare to absent
organoid pattern of 3 distinct components: Fibrous tissue, • Exceptional cases reported with sarcomatous features
fat, primitive mesenchymal cells ○ Undifferentiated spindled or round cell morphology
○ Hypercellularity with mitoses
CLINICAL ISSUES
Epidemiology ANCILLARY TESTS
• Age Immunohistochemistry
○ Infants and children up to 2 years • SMA(+) in fibroblastic component
– Up to 25% congenital ○ Desmin rare
○ Very rarely in older children • CD34(+), CD31(-) in myxoid and
• Sex collagenous/pseudovascular areas
○ Male predominance • S100 protein (+) in mature adipose tissue only
Site • Absence of nuclear β-catenin expression
• Deep dermis or subcutis Molecular Genetics
• Most common in trunk, including axilla, upper back, and • EGFR exon 20 insertion/duplication mutations
groin/perineum • No PDGFB, PLAG1, or NTRK1 rearrangements
○ Also extremities and many other reported sites
• Usually solitary DIFFERENTIAL DIAGNOSIS
Presentation Lipofibromatosis
• Slow-growing or rapidly enlarging painless mass • Predilection for distal extremities
• May have overlying skin changes (e.g., altered • Fascicles of fibroblasts infiltrating adipose tissue
pigmentation, hypertrichosis) • Absence of immature myxoid mesenchymal component
• No known syndromic or familial associations and organoid growth pattern
○ Isolated reports of FHI occurring in setting of tuberous
sclerosis or Williams syndrome Fibromatosis
• Adipose tissue not typically integral component
Treatment • Lacks organoid growth pattern and immature myxoid
• Complete local excision mesenchymal component
Prognosis • Nuclear β-catenin (+) in majority
• Benign Giant Cell Fibroblastoma
○ Has not been shown to spontaneously regress • Irregular slit-like or ectatic pseudovascular spaces lined by
• Up to 15% recur locally multinucleated cells
○ Likely related to incomplete excision • Lacks organoid growth pattern
•  t(17;22) with PDGFB-COL1A1 fusion
MACROSCOPIC
Lipofibromatosis-Like Neural Tumor
General Features • Rare; recently described
• Soft, poorly defined mass  • Affects older children and young adults
• Cut surface shows mixture of tan-white tissue and fat • Coexpression of CD34 and S100 protein
Size • NTRK1 gene rearrangements
• Usually < 5 cm Lipoblastoma
• Prominent lobulated architecture
MICROSCOPIC • Immature adipocytes (lipoblasts) in myxoid stroma
Histologic Features • Lacks organoid growth pattern
• Classic organoid growth pattern
○ 3 distinct components in widely variable proportions SELECTED REFERENCES
– Intersecting bands and sheets of mature 1. Al-Ibraheemi A et al: Fibrous hamartoma of infancy: a clinicopathologic study
of 145 cases, including 2 with sarcomatous features. Mod Pathol. 30(4):474-
fibroblasts/myofibroblasts 85, 2017
– Nests of immature ovoid to spindled mesenchymal 2. Park JY et al: EGFR exon 20 insertion/duplication mutations characterize
cells in loose basophilic, myxoid stroma fibrous hamartoma of infancy. Am J Surg Pathol. 40(12):1713-8, 2016
□ May contain subtle chronic inflammatory infiltrate 3. Saab ST et al: Fibrous hamartoma of infancy: a clinicopathologic analysis of
60 cases. Am J Surg Pathol. 38(3):394-401, 2014
– Mature adipose tissue
241
 Fibrous Hamartoma of Infancy
Pediatric Fibroblastic/Myofibroblastic Tumors

Fat-Fibrous Pattern Fat-Predominant Pattern

(Left) This image shows an
area of FHI that is composed
of irregular, ramifying bands
and fascicles of fibroblasts,
admixed with mature adipose
tissue, resembling
lipofibromatosis. Immature
mesenchymal foci were
identified elsewhere. (Right)
Fat is a predominant
component in some cases of
FHI. The fibroblastic
component appears as thin
ramifying fascicles infiltrating
fat resembling
lipofibromatosis; however,
small immature mesenchymal
foci are present ﬈.

Fat-Predominant Pattern Fibroblastic Component

(Left) In FHI with a fat-
predominant morphology,
identification of immature
mesenchymal foci is
diagnostic. In challenging
cases, they may be small and
widely scattered and thereby
easily overlooked. (Right) The
fibroblastic component of FHI
is identified by sheets and
fascicles of uniform spindled
cells set in a collagenous
background. Nuclear atypia is
not present.

Fibroblastic Component Immature Mesenchymal Component

(Left) The fibroblastic
component may bear a
striking resemblance to
conventional fibromatosis,
with long streaming fascicles
of bland spindled cells in a
collagenous background
punctuated by blood vessels.
(Right) The immature
mesenchymal component of
FHI is typically quite myxoid,
but the cellularity varies. A
subtle chronic inflammatory
infiltrate may be seen in these
foci. Note also the adipose ﬈
and fibrous ﬊ components.

242
 Fibrous Hamartoma of Infancy
Immature Mesenchymal Component
Cellular Immature Mesenchymal
Component
Hyalinized Zones
Pediatric Fibroblastic/Myofibroblastic Tumors
Immature Mesenchymal Component
(Left) This image shows
immature myxoid foci within a
prominent background of
mature fibrous tissue. At
times, these foci may appear
to be organized around small
veins or capillaries ﬈. (Right)
This image of FHI shows a
typical immature
mesenchymal focus ﬈ but
with a progressive decrease in
myxoid matrix ﬊ and
apparent increase in cellularity
﬉.
Collagenous Zones
(Left) Some immature foci may
have comparatively little
myxoid matrix and therefore
appear more cellular than
usual. Mitoses are absent.
(Right) Vascular collagenized
areas may be seen in a
significant number of cases of
FHI. Importantly, if a stromal
separation artifact is present
(shown), these zones may lead
to misdiagnosis as a vascular
lesion or giant cell
fibroblastoma.
Collagenous/Hyalinized Zones
(Left) In some cases of FHI,
marked stromal
hyalinization/sclerosis imparts
a pseudovascular appearance
similar to pseudoangiomatous
stromal hyperplasia of the
breast. (Right) Rare examples
of FHI contain a large,
centralized component of
collagenous or hyalinized
tissue. Foci of more
conventional triphasic
morphology are often seen at
the periphery.
243
 Calcifying Aponeurotic Fibroma

KEY FACTS
Pediatric Fibroblastic/Myofibroblastic Tumors

TERMINOLOGY ○ Older lesions tend to be more well circumscribed and

• Distinctive, infiltrative fibroblastic lesion containing calcified calcified
&/or chondroid foci and typically arising in hands or feet of • Usually < 3 cm in size
children MICROSCOPIC
CLINICAL ISSUES • Nodular growth with infiltration of surrounding tissue
• Most common: 5-15 years • Spindled to ovoid fibroblasts without nuclear atypia in
• 2:1 male predominance collagenous stroma
• Fingers or palm of hand most common site • Variable number of calcified or cartilaginous foci
○ Also plantar foot, ankle, toes ○ Epithelioid cells may be arranged around these foci
• Painless, slow-growing mass ○ Associated osteoclast-like giant cells may be present
○ Arise in subcutaneous tissue or attached to • Mitoses uncommon
aponeurosis/fascia • Exact proportion of components generally varies with age
• Treatment: Complete but conservative excision for primary TOP DIFFERENTIAL DIAGNOSES
lesion and recurrences
• Lipofibromatosis
○ ~ 40-50% recur locally
• Monophasic synovial sarcoma
MACROSCOPIC • Palmar and plantar fibromatosis
• Ill-defined, firm or rubbery, sometimes gritty cut surface • Soft tissue chondroma

Calcifying Aponeurotic Fibroma Calcified Foci

(Left) Calcifying aponeurotic
fibroma (CAF) is a rare
fibroblastic lesion that most
commonly occurs in the hands
or feet of children. At low
magnification, a classic
example shows irregular
calcified foci within a variably
cellular proliferation of
spindled fibroblasts. (Right)
Calcifications in CAF are finely
granular or coarse and chunky.
The surrounding fibroblasts
also typically adopt a more
plump, epithelioid morphology
﬈ and may radiate outward
from the calcification.

Osteoclast-Like Giant Cells Spindle Cell Component

(Left) Osteoclast-like giant
cells ﬈ are not uncommon in
CAF and are most commonly
identified in direct association
with the calcified or
cartilaginous foci. (Right) The
fibromatosis-like spindled
component of CAF varies in
cellularity from area to area,
but stromal collagen is
generally prominent.
Importantly, the fibroblastic
cells are cytologically bland,
and mitotic figures are
generally scarce.

244
 Calcifying Aponeurotic Fibroma

Pediatric Fibroblastic/Myofibroblastic Tumors

○ Associated osteoclast-like giant cells may be present
TERMINOLOGY
○ Ossification rare
Synonyms • Mitoses uncommon
• Juvenile aponeurotic fibroma • Overall appearance generally varies with age
• Calcifying fibroma ○ Infants and young children often have predominant
fibroblastic morphology with little to no calcification
Definitions
○ Older lesions are generally more well circumscribed and
• Distinctive, infiltrative fibroblastic lesion containing calcified contain more calcified/cartilaginous foci
&/or chondroid foci and typically arising in hands or feet of
children DIFFERENTIAL DIAGNOSIS
CLINICAL ISSUES Lipofibromatosis
• Usually involves proximal extremities or head and neck
Epidemiology
• Fascicles of elongated fibroblasts, often diffusely infiltrative
• Incidence • Calcification and osteoclast-like giant cells rare
○ Rare
• Age Monophasic Synovial Sarcoma
○ Most arise in children (most common: 5-15 years) • Large tumors, usually arising in deep soft tissue of
– May occur in adults (often recurrence) extremities
• Sex • Often highly cellular
○ 2:1 male predominance • Can be calcified, but calcified areas usually lack chondroid
rim
Site • Focal expression of keratins or EMA in most cases
• Fingers or palm of hand most common • SS18 (SYT) gene rearrangements
○ Subcutaneous tissue or attached to aponeurosis/fascia
• Also plantar foot, ankle, toes Palmar and Plantar Fibromatosis
• Very rarely other sites • Uni- or multinodular, centered on fascia
• "Sweeping" cellular fascicles of fibroblasts with dense
Presentation collagen
• Painless, slow-growing mass ○ May show brisk mitotic activity
• May be present for years • Compressed or dilated stromal vessels common
Treatment • Usually lack calcification and cartilage formation
• Complete, but conservative excision Soft Tissue Chondroma
○ Reexcision of recurrences • Sharply circumscribed nodular mass, most common in hand
Prognosis • Usually affects older adults
• Chondroid differentiation is well developed
• Benign
• Lack of prominent spindle cell fibromatosis-like component
○ Exceptionally rare case reports of malignant
degeneration (controversial)
• ~ 40-50% recur locally
SELECTED REFERENCES
1. Lee SM et al: Intraarticular calcifying aponeurotic fibroma of the wrist:
mimicking gout or calcium pyrophosphate dihydrate deposition disease.
MACROSCOPIC Skeletal Radiol. 47(5):729-34, 2018
General Features 2. Corominas L et al: Calcifying aponeurotic fibroma in children: our experience
and a literature review. J Pediatr Orthop B. 26(6):560-4, 2017
• Ill-defined, firm or rubbery, sometimes gritty cut surface 3. Shim SW et al: MRI features of calcifying aponeurotic fibroma in the upper
○ Older lesions tend to be more well circumscribed and arm: a case report and review of the literature. Skeletal Radiol. 45(8):1139-
43, 2016
calcified 4. Kim OH et al: Calcifying aponeurotic fibroma: case report with radiographic
and MR features. Korean J Radiol. 15(1):134-9, 2014
Size
5. Giuffre JL et al: Recurrent calcifying aponeurotic fibroma of the thumb: case
• Usually < 3 cm report. J Hand Surg Am. 36(1):110-5, 2011
6. Thakur JS et al: Calcifying (juvenile) aponeurotic fibroma of the scalp. Ear
Nose Throat J. 90(10):E14-6, 2011
MICROSCOPIC 7. Kramer JM et al: Calcifying aponeurotic fibroma with bone islands exhibiting
Histologic Features hematopoiesis: a case report and review of the literature. Oral Surg Oral
Med Oral Pathol Oral Radiol Endod. 109(6):878-82, 2010
• Nodular growth with infiltration of surrounding tissue 8. Fetsch JF et al: Calcifying aponeurotic fibroma: a clinicopathologic study of
• Spindled to ovoid fibroblasts without nuclear atypia in 22 cases arising in uncommon sites. Hum Pathol. 29(12):1504-10, 1998
9. Allen PW et al: Juvenile aponeurotic fibroma. Cancer. 26(4):857-67, 1970
collagenous stroma
10. Keasbey LE: Juvenile aponeurotic fibroma (calcifying fibroma); a distinctive
○ May be cellular with less stromal collagen tumor arising in the palms and soles of young children. Cancer. 6(2):338-46,
• Variable number of calcified and cartilaginous foci 1953
○ Calcifications range from fine granules to large, chunky
masses
○ Epithelioid chondrocyte-like cells may be arranged
around these foci
245
 Calcifying Aponeurotic Fibroma
Pediatric Fibroblastic/Myofibroblastic Tumors

Infiltrative Growth Infiltrative Growth

(Left) Most cases of CAF are
histologically infiltrative into
surrounding tissues,
particularly those that occur in
younger patients. Note the
characteristic calcified foci ﬈.
(Right) In more infiltrative
areas, CAF may show rays of
fibroblastic fascicles extending
into subcutaneous adipose
tissue, closely resembling
lipofibromatosis. The clinical
presentation and presence of
calcified foci are helpful in
avoiding misdiagnosis.

Noncalcified Foci Cartilaginous Foci

(Left) The formation of true
calcified or cartilaginous foci
in CAF may be preceded by
small aggregates of
epithelioid fibroblastic or
chondrocyte-like cells. This
finding may be one of the only
clues that distinguishes CAF
from lipofibromatosis. (Right)
Cartilage formation, as
evidenced by the presence of
chondrocytes within lacunae
﬈, is common in CAF and may
or may not be associated with
calcification. Absence of
calcification is more typical of
early lesions in younger
children.

Extensive Calcification Immature Cartilaginous Nodules

(Left) Calcification may be
extensive in some cases of
CAF, particularly in
established lesions and those
that occur in older individuals.
This feature may be readily
apparent on gross
examination and cut section.
(Right) Some cases of CAF may
show multiple hypocellular or
myxoedematous nodules ﬈
with little or no evidence of
cartilage formation ﬊.

246
 Calcifying Aponeurotic Fibroma
Osteoclast-Like Giant Cells
Fibroblastic Component
DDx: Lipofibromatosis
Pediatric Fibroblastic/Myofibroblastic Tumors
Fibroblastic Component
(Left) Osteoclast-like giant
cells, when present in CAF, are
usually associated with the
calcified or cartilaginous foci;
however, rarely they may be
isolated. (Right) The spindled
fibroblastic component of CAF
often shows varying degrees
of cellularity, even within the
same case. Some areas may be
alarmingly cellular, but
importantly, there is no
nuclear atypia, and mitoses
are rare.
Rare Ossification
(Left) Cellular fibroblastic
regions in CAF may raise
concerns for a possible
sarcoma, such as synovial
sarcoma or fibrosarcoma;
however, the clinical
presentation is generally
different for these entities,
and areas of more
conventional morphology are
often easily identified
elsewhere. (Right) True bone
formation ﬈ is a rare event in
CAF. Hematopoiesis in these
areas has also been reported.
DDx: Soft Tissue Chondroma
(Left) Calcifying aponeurotic
fibroma may closely resemble
lipofibromatosis (shown),
particularly in early lesions
lacking calcification and
cartilage formation; however,
CAF is generally less
infiltrative and rarely arises
outside the hands and feet.
(Right) In contrast to CAF, soft
tissue chondroma occurs in
older adults and usually shows
very well-developed lobules of
hyaline cartilage with or
without myxoid change and
calcification.
247
 Calcifying Fibrous Tumor

KEY FACTS
Pediatric Fibroblastic/Myofibroblastic Tumors

TERMINOLOGY MICROSCOPIC
• Synonyms: Calcifying fibrous pseudotumor; childhood • Hypocellular, fibrous lesion with bland spindled cells
fibrous tumor with psammoma bodies embedded in dense, hyalinized, collagenous stroma
• No atypia or mitotic activity
CLINICAL ISSUES
• Scattered psammomatous &/or dystrophic calcifications
• Wide age range (12-83 years)
• Variable lymphoplasmacytic infiltrate with lymphoid
○ Soft tissue lesions more common < 20 years of age aggregates
○ Visceral lesions more common in adults
• Most common in subcutaneous and deep soft tissue of ANCILLARY TESTS
extremities, trunk, and head and neck • CD34(+), factor XIIIA(+)
• Often asymptomatic; visceral lesions may produce site- • S100 protein, ALK1, keratin, CD117, DOG1, and STAT6 (-)
dependent symptoms
TOP DIFFERENTIAL DIAGNOSES
• Treatment: Complete local excision
• Benign; excellent prognosis • Inflammatory myofibroblastic tumor
• Rare local recurrence • Fibromatosis
• Synovial sarcoma
MACROSCOPIC • Gastrointestinal stromal tumor
• Well circumscribed and unencapsulated • Solitary fibrous tumor
• Firm, gray to white, gritty cut surfaces

Calcifying Fibrous Tumor Calcifications

(Left) A calcifying fibrous
tumor (CFT) is a hypocellular
lesion composed of hyalinized
fibrous tissue with scattered
calcifications ﬈. Chronic
inflammation with lymphoid
aggregates is commonly seen
﬊. (Right) Although the
presence of calcifications is
the salient feature of CFT,
they can be of variable size
and prominence, ranging from
scarce to extensive. The
calcifications can be of the
psammomatous type ﬈ or
dystrophic type ﬊. The
stroma is characteristically
composed of hyalinized,
collagenous tissue.

Bland Fibroblasts Lymphoplasmacytic Infiltrate

(Left) The fibroblastic
component of CFT is
characterized by the presence
of bland spindled cells ﬈ with
ovoid/round nuclei, minimal
cytologic atypia, and no
mitotic activity. These cells are
typically embedded in
collagenous stroma ﬊. (Right)
A variably prominent
population of chronic
inflammatory cells, including
plasma cells ﬈ and
lymphocytes ﬉ (± lymphoid
aggregates), is commonly seen
in the background of CFT.
Note the fibroblast nucleus
﬊.

248
 Calcifying Fibrous Tumor
TERMINOLOGY
Abbreviations
• Calcifying fibrous tumor (CFT)
Synonyms
• Calcifying fibrous pseudotumor
• Childhood fibrous tumor with psammoma bodies
Definitions
• Rare benign fibroblastic lesion characterized by dense
collagenization, psammomatous &/or dystrophic
calcification, and variable lymphoplasmacytic infiltrate
ETIOLOGY/PATHOGENESIS
Neoplastic
• Favored to represent neoplastic rather than reactive
process
• In past, postulated to represent sclerosing end-stage
inflammatory myofibroblastic tumor (IMT)
○ Absence of ALK expression and chromosome 2
abnormalities in CFT, in contrast to IMT, suggests these
are distinct entities
• Most are sporadic (rare reported occurrence of familial
peritoneal multifocal lesion)
• Deleterious, heterozygotic de novo mutations in ZNF717,
CDC27, and FRG1 genes have been identified in pleural-
based lesions
CLINICAL ISSUES
Presentation
• Wide age range
○ Soft tissue lesions more common in first 2 decades of life
○ Visceral lesions more common in adults (4th and 5th
decades)
• No sex predilection
• Wide anatomical distribution
○ Most commonly occur in subcutaneous and deep soft
tissues (extremities, trunk, head and neck, axilla,
mediastinum, mesentery)
○ Pleural, peritoneal, and visceral lesions most commonly
involving gastrointestinal tract
• Asymptomatic, painless soft tissue mass often discovered
as incidental finding
○ Visceral lesions may produce site-dependent symptoms
• Most lesions are solitary with reported cases of
multifocality (especially in pleura and peritoneum)
• Rare associations: Hyaline-type Castleman disease, IMT, and
sclerosing angiomatoid nodular transformation of spleen
Treatment
• Complete local excision
Prognosis
• Benign; excellent prognosis
• Rare cases of nondestructive short- and long-term local
recurrences ± complete local excision
• No reported malignant transformation
Pediatric Fibroblastic/Myofibroblastic Tumors
MACROSCOPIC
General Features
• Well circumscribed and unencapsulated
• Firm, gray to white, gritty cut surfaces
• Variable size (< 1 cm to > 10 cm in greatest dimension)
MICROSCOPIC
Histologic Features
• Well circumscribed and unencapsulated
• Hypocellular, fibrous lesion with bland spindled cells
embedded in dense, hyalinized, collagenous stroma
• Scattered psammomatous &/or dystrophic calcifications
• Variable lymphoplasmacytic infiltrate with lymphoid
aggregates
• No atypia or mitotic activity
ANCILLARY TESTS
Immunohistochemistry
• CD34(+), factor XIIIA(+)
• Rare cases with focal SMA(+) or desmin (+)
• S100 protein, ALK1, keratin, CD117, DOG1, and STAT6 (-)
• Absence of nuclear β-catenin staining
DIFFERENTIAL DIAGNOSIS
Inflammatory Myofibroblastic Tumor
• ALK1(+) in 40-60% of cases
• Chromosome 2p22-24 abnormalities often observed
Fibromatosis
• Cellular lesions with fascicular architecture
• Lacks prominent inflammation and calcifications
• Nuclear β-catenin (+), particularly in deep lesions
Synovial Sarcoma
• Highly cellular lesions that can be calcified
• Focal keratin (+) &/or EMA(+) in most cases
• Characteristic t(X;18) with SS18 (SYT) translocations
Gastrointestinal Stromal Tumor
• Cellular lesions with minimal inflammation
• Lack hyalinized collagen and calcifications
• CD117(+), DOG1(+)
Solitary Fibrous Tumor
• Calcification and lymphoplasmacytic infiltrate not typically
present
• CD34(+), STAT6(+)
• NAB2-STAT6 gene fusion
SELECTED REFERENCES
1. Mehrad M et al: Whole exome sequencing identifies unique mutations and
copy number losses in calcifying fibrous tumor of the pleura: report of three
cases and review of the literature. Hum Pathol. 78:36-43, 2018
2. Pezhouh MK et al: Clinicopathologic study of calcifying fibrous tumor of the
gastrointestinal tract: a case series. Hum Pathol. 62:199-205, 2017
3. Chorti A et al: Calcifying fibrous tumor: review of 157 patients reported in
international literature. Medicine (Baltimore). 95(20):e3690, 2016
4. Valladolid G et al: Calcifying fibrous tumor of the small intestine associated
with Castleman-like lymphadenopathy. J Gastrointest Surg. 18(6):1205-8,
2014
249
 Inclusion Body Fibromatosis

KEY FACTS
Pediatric Fibroblastic/Myofibroblastic Tumors

TERMINOLOGY MICROSCOPIC
• Synonym: Infantile digital fibromatosis • Overlying skin is often compressed/flattened with
• Benign fascicular myofibroblastic proliferation containing fewer/no rete ridges
eosinophilic intracytoplasmic inclusions that occur on digits ○ Entrapped dermal adnexal structures common
of young children • Fascicles, sheets, and whorls of uniform, bland, spindled
fibroblasts
CLINICAL ISSUES
• Paranuclear intracytoplasmic eosinophilic spherical
• Majority occur in 1st year of life (1/3 congenital) inclusions
• Most arise on dorsal or lateral aspects of fingers or toes ○ Highlighted by Masson trichrome stain
• Rapidly growing, nontender, dome-shaped swelling ○ Inclusions are less prominent in older lesions
• Treatment: Observation ± conservative surgical excision • No necrosis
• Benign
• High rate of local recurrence (> 50% of cases) TOP DIFFERENTIAL DIAGNOSES
• Superficial/desmoid fibromatoses
MACROSCOPIC
• Pilar leiomyoma
• Most < 2 cm • Perineurioma
• Usually covered by intact skin • Calcifying aponeurotic fibroma

Inclusion Body Fibromatosis Irregular Fascicular Architecture

(Left) Inclusion body
fibromatosis (a.k.a. infantile
digital fibromatosis) usually
arises in the fingers or toes of
infants and presents as a
rapidly growing, dome-shaped
mass with intact overlying
skin. Note the entrapped
adnexal structures ſt. (Right)
The lesional cells of inclusion
body fibromatosis are uniform
and spindled and form a
variety of patterns, including
irregular fascicles, sheets, and
whorls.

Paranuclear Inclusions Paranuclear Inclusions (Trichrome)

(Left) A characteristic finding
in inclusion body fibromatosis
is the presence of
intracytoplasmic eosinophilic
inclusions, often situated
alongside adjacent nuclei.
These inclusions ﬊ can be
identified on routine H&E
stain, as depicted. (Right) A
trichome stain nicely
highlights the characteristic
inclusions ﬊ of inclusion body
fibromatosis. The number of
inclusions varies from case to
case but are generally less
prominent in more mature
lesions.

250
 Inclusion Body Fibromatosis

Pediatric Fibroblastic/Myofibroblastic Tumors

• Fascicles, sheets, and whorls of uniform, bland, spindled
TERMINOLOGY fibroblasts
Synonyms • Stomal collagen usually abundant
• Infantile digital fibromatosis • Intracytoplasmic eosinophilic spherical inclusions
• Infantile digital fibroma ○ Often in perinuclear location
• Digital fibrous tumor of childhood ○ Highlighted by Masson trichrome stain
○ Inclusions are less prominent in older lesions
Definitions
• Rare mitoses
• Benign fascicular myofibroblastic proliferation containing • No necrosis
eosinophilic intracytoplasmic inclusions that occur on digits
of young children ANCILLARY TESTS
CLINICAL ISSUES Immunohistochemistry
Epidemiology • SMA(+), calponin (+)
• Most cases desmin (-), CD34(-), β-catenin (-)
• Incidence
• S100 protein (-)
○ Rare
• Age DIFFERENTIAL DIAGNOSIS
○ Majority occur in 1st year of life
– ~ 30% are congenital Superficial/Desmoid Fibromatoses
○ Rarely seen in older children and adults • Paranuclear cytoplasmic inclusions absent
• Superficial fibromatosis occurs in children but is rare in
Site infants
• Dorsal or lateral aspects of fingers or toes • Desmoid fibromatosis occurs in older children/adults and in
○ Thumb or big toe is only very rarely affected more proximal locations
• Very rare extradigital sites (i.e., arm, breast) have been ○ Nuclear β-catenin expression in ~ 70%
reported
• Most cases are superficial (dermal/subcutaneous), but rare Pilar Leiomyoma
cases may involve periosteum or underlying bone • Rare in infants
• Discrete nodules and bundles of eosinophilic spindled cells
Presentation
• Paranuclear cytoplasmic inclusions absent
• Rapidly growing, nontender, dome-shaped swelling • Diffuse cytoplasmic SMA(+), desmin (+)
○ Rarely multiple
Perineurioma
Treatment
• Rare in infants
• Complete but conservative surgical excision • Paranuclear cytoplasmic inclusions absent
○ Some authorities recommend observation after • EMA(+), Claudin-1 (+), SMA(-), desmin (-)
diagnosis, utilizing excision only for lesions that show
continuing growth or functional impairment, or for Calcifying Aponeurotic Fibroma
cosmetic purposes • Usually contains at least focal calcification or cartilage
• Intralesional injections of fluorouracil or corticosteroids formation
have been reported to induce regression in some cases • Paranuclear cytoplasmic inclusions absent
Prognosis Acral Fibromyxoma
• Benign • Occurs in adults
• High rate of local recurrence (> 50% of cases) • Varying myxoid and collagenous stroma
○ Spontaneous regression reported in some cases • Paranuclear cytoplasmic inclusions absent
• CD34(+), SMA(-), desmin (-)
MACROSCOPIC
Epithelioid Sarcoma
General Features
• Often shows ulceration clinically
• Firm, ill-defined growth with gray-white cut surface • Spindled morphology rare
• Usually covered by intact skin • Keratin (+); loss of nuclear INI1
Size
• Usually < 2 cm
SELECTED REFERENCES
1. Marks E et al: Infantile digital fibroma: a rare fibromatosis. Arch Pathol Lab
Med. 140(10):1153-6, 2016
MICROSCOPIC 2. Henderson H et al: Anti-calponin 1 antibodies highlight intracytoplasmic
Histologic Features inclusions of infantile digital fibromatosis. Histopathology. 64(5):752-5, 2014
3. Spingardi O et al: Infantile digital fibromatosis: our experience and long-term
• Overlying skin is often compressed/flattened with results. Chir Main. 30(1):62-5, 2011
fewer/no rete ridges 4. Laskin WB et al: Infantile digital fibroma/fibromatosis: a clinicopathologic
and immunohistochemical study of 69 tumors from 57 patients with long-
○ Dermal adnexal structures often present and entrapped term follow-up. Am J Surg Pathol. 33(1):1-13, 2009

251
 Hyaline Fibromatosis Syndrome

KEY FACTS
Pediatric Fibroblastic/Myofibroblastic Tumors

TERMINOLOGY • High rate of local recurrence after surgical excision

• Synonyms: Juvenile hyaline fibromatosis (JHF), infantile MICROSCOPIC
systemic hyalinosis (ISH), inherited systemic hyalinosis
• Bland, round to spindle cells embedded in homogeneous,
ETIOLOGY/PATHOGENESIS hyalinized stroma
• Mutations in ANTXR2 (CMG2) gene • PAS(+), diastase-resistant hyalinized stroma
• JHF and ISH represent allelic variations ○ May not be present in early lesions
• Pericellular clearing may impart chondroid-like appearance
CLINICAL ISSUES • No significant pleomorphism, atypia, or mitoses
• Autosomal recessive transmission
TOP DIFFERENTIAL DIAGNOSES
• Usually presents at < 5 years of age with development of
new lesions throughout life • Infantile myofibromatosis
• Cutaneous and soft tissue lesions of head, neck, gingiva, • Fibrodysplasia (myositis) ossificans progressiva
and perianal areas • Lipoid proteinosis
• Progressive joint contractures
• Mild phenotype presents later in childhood (JHF)
• Severe phenotype presents during infancy (ISH)
○ Visceral involvement, malnutrition, and protein-losing
enteropathy

Hyaline Fibromatosis Syndrome Variable Cellularity

(Left) Hyaline fibromatosis
syndrome (juvenile hyaline
fibromatosis) is characterized
by well-defined dermal and
subcutaneous hyalinization of
the stroma ﬇. Some lesions
have a tumor-free (grenz) zone
between the epidermis and
lesional tissue ſt. (Right) The
intratumoral cellularity in
hyaline fibromatosis may be
variable with some areas of
sparse cellularity ſt located
adjacent to areas of increased
cellularity. In more cellular
areas, the cells may form cords
that assume a vaguely parallel
arrangement ﬇.

Hyalinized Matrix Cytologic Features

(Left) The stroma is replaced
by uniform, glassy,
eosinophilic matrix imparting
a hyalinized appearance ﬇.
This hyalinized material is
strongly positive with PAS and
diastase resistant. The
embedded fibroblasts are
small, uniform, and arranged
in short curved cords ſt.
(Right) The fibroblasts are
variable in shape and may be
spindled ﬉ or round. The
round cells often times exhibit
pericellular clearing and
resemble chondrocytes ﬊.
Note the absence of cytologic
atypia and mitotic activity.

252
 Hyaline Fibromatosis Syndrome
TERMINOLOGY
Synonyms
• Juvenile hyaline fibromatosis (JHF)
• Infantile systemic hyalinosis (ISH)
• Inherited systemic hyalinosis
Definitions
• Rare autosomal recessive disorder characterized by hyaline
deposition in skin, soft tissue, bones, and viscera
ETIOLOGY/PATHOGENESIS
Genetic Disorder
• Due to deleterious mutations in ANTXR2 (CMG2) gene on
chromosome 4q21
○ Results in abnormal biosynthesis of glycosaminoglycans
and collagen and disruption of basement membrane
formation
• JHF and ISH represent allelic variations
• Autosomal recessive transmission
CLINICAL ISSUES
Epidemiology
• Incidence
○ Very rare
○ Increased incidence in consanguineous populations
• Age
○ Usually presents at < 5 years with development of new
lesions throughout life
Presentation
• Continuous phenotypic spectrum with variable levels of
severity
• Skin and soft tissue manifestations
○ Multiple plaques and papulonodular skin lesions on scalp,
face, neck, thorax, and perianal areas
○ Large superficial and deep soft tissue masses
• Extracutaneous manifestations
○ Gingival hyperplasia (most common)
○ Progressive joint contractures with severe limitation of
joint mobility
○ Osteolytic bone lesions and generalized osteoporosis
○ Variable visceral involvement (bowel, spleen, thyroid,
adrenal glands, heart, lung, and liver)
• Clinical variants
○ JHF characterized by milder clinical phenotype
– Presents later in childhood
– Skin, soft tissue, gingiva, and joint involvement
○ ISH characterized by severe clinical phenotype
– Very early onset at birth or within first 6 months of life
– Visceral involvement in addition to skin, soft tissue,
and joint abnormalities
– Chronic diarrhea and malnutrition due to protein-
losing enteropathy
Treatment
• Surgical excision of skin, soft tissue, and gingival lesions for
functional improvement or cosmetic purposes
• Intralesional steroid injections
Pediatric Fibroblastic/Myofibroblastic Tumors
Prognosis
• High rate of local recurrence after surgical excision
• Severe phenotype carries poor prognosis with death by 2
years of age
○ Death due to complications of protein-losing
enteropathy, infection, or multiorgan failure
• Mild phenotype carries better prognosis with survival into
adulthood
MACROSCOPIC
General Features
• Larger cutaneous lesions form soft tissue masses
• Poorly circumscribed with uniform, waxy, white cut
surfaces
MICROSCOPIC
Histologic Features
• Poorly circumscribed proliferation of bland, round to
spindled fibroblasts embedded in homogeneous,
eosinophilic hyalinized stroma
• Pericellular clearing may impart chondroid-like appearance
• PAS(+), diastase-resistant hyalinized stroma
○ Degree of hyalinization increases with age of lesions and
may not be present in early lesions
• No significant pleomorphism, atypia, or mitoses
• Displaces normal dermal components
DIFFERENTIAL DIAGNOSIS
Infantile Myofibromatosis
• Multiple lesions appearing in infancy
• May involve skin, soft tissue, bone, and viscera
• Biphasic pattern with central hemangiopericytoma-like
zones and peripheral myoid nodules
Fibrodysplasia (Myositis) Ossificans Progressiva
• Rare and autosomal dominant
• Soft tissue ossification at multiple sites and skeletal
abnormalities of digits and cervical spine
• Trauma (accidental or surgical) results in painful soft tissue
lesions
• Mitotically active myofibroblasts and variable ossification
depending on age of lesions
Lipoid Proteinosis
• Dermal pericapillary PAS(+), diastase-resistant hyaline
deposits and prominent basement membrane thickening
○ Basement membrane thickening not seen in hyaline
fibromatosis
• Due to mutations in ECM1 gene (1q21)
SELECTED REFERENCES
1. Bürgi J et al: CMG2/ANTXR2 regulates extracellular collagen VI which
accumulates in hyaline fibromatosis syndrome. Nat Commun. 8:15861, 2017
2. Haidar Z et al: Diagnosis implications of the whole genome sequencing in a
large Lebanese family with hyaline fibromatosis syndrome. BMC Genet.
18(1):3, 2017
3. Kalgaonkar PS et al: Juvenile hyaline fibromatosis- a rare autosomal
recessive disease. J Clin Diagn Res. 11(7):SD04-SD06, 2017
4. Rahvar M et al: Systemic hyalinosis with heterozygous CMG2 mutations: a
case report and review of literature. Am J Dermatopathol. 38(5):e60-3, 2016
253
 Fibromatosis Colli

KEY FACTS
Pediatric Fibroblastic/Myofibroblastic Tumors

TERMINOLOGY • Most cases are self-limited with spontaneous regression by

• Sterno(cleido) mastoid (pseudo)tumor of infancy 4-8 months of age

ETIOLOGY/PATHOGENESIS MICROSCOPIC
• Associated with birth trauma, forceps delivery, breech • Fibroblastic infiltrate between skeletal muscle fibers
presentation, difficult labor, and primiparous birth producing fine, checkerboard-like pattern
• Muscle fibers swell followed by progressive degeneration
CLINICAL ISSUES and atrophy
• Most common cause of neck mass in perinatal period • No significant nuclear hyperchromasia, pleomorphism, or
• Occurs in neonates and infants (presents within first 8 mitotic activity
weeks of life)
ANCILLARY TESTS
• Painless, firm mass in middle to lower 1/3 of
sternocleidomastoid muscle • Lesional cells are nuclear β-catenin (-)
○ Most commonly unilateral, right-sided mass TOP DIFFERENTIAL DIAGNOSES
– Rare reported bilateral cases • Nodular fasciitis
• 14-30% of cases are associated with congenital muscular • Fibromatosis
torticollis (CMT) • Focal myositis
• Primarily conservative management with physiotherapy
and stretching exercises

Fibromatosis Colli Degenerative Muscle

(Left) Fibromatosis colli is
characterized by
intramuscular interstitial
fibrosis. The proliferating
fibroblasts infiltrate between
and surround individual
muscle fibers, imparting a fine,
checkerboard-like pattern.
(Right) The infiltrating
fibroblasts dissect muscle fiber
groups to surround individual
myocytes. With time, the
myocytes show degenerative
and atrophic changes,
including myocyte swelling
and reduction in the size of
myofibers ﬈.

Early Stage Late Stage

(Left) Early-stage fibromatosis
colli lesions show increased
interstitial cellularity with
bland fibroblasts ﬊ and scant
inflammation. The myofibers
show architectural disarray
and progressive atrophic
changes, including
hypereosinophilia ﬉ and
reduction in size ﬈. Fatty
replacement of atrophied
muscle is not a feature of this
condition. (Right) In later
stage lesions, the degree of
cellularity decreases as muscle
fibers become replaced by
confluent areas of fibrosis ﬊.
The surrounding muscle fibers
are atrophic ſt.

254
 Fibromatosis Colli

Pediatric Fibroblastic/Myofibroblastic Tumors

TERMINOLOGY IMAGING
Synonyms Ultrasonographic Findings
• Sterno(cleido) mastoid (pseudo)tumor of infancy • Initial modality of choice (sensitivity ~ 100%)
• Focal or diffuse fusiform enlargement within SCM
Definitions
• Lesion displays synchronous mobility with SCM
• Benign fibrous proliferation involving sternocleidomastoid
muscle (SCM) in infants MACROSCOPIC
ETIOLOGY/PATHOGENESIS General Features
Developmental Anomaly • Firm, white, infiltrative lesion involving body of muscle
• Does not extend into adjacent soft tissue
• May be related to venous ischemia of muscle secondary to
• Average size: 2-3 cm in diameter
intrauterine malposition or birth trauma
Environmental Exposure MICROSCOPIC
• Associated with birth trauma, forceps delivery, breech Histologic Features
presentation, difficult labor, and primiparous birth
• Fibroblastic infiltrate between skeletal muscle fibers
producing fine, checkerboard-like pattern
CLINICAL ISSUES
• Increased cellularity during early proliferative phase
Epidemiology • Increased fibrosis in later stages
• Incidence • Muscle fibers swell followed by progressive degeneration
○ Rare, 0.4% of live births and atrophy
○ Most common cause of neck mass in perinatal period • No significant nuclear hyperchromasia, pleomorphism, or
• Age mitotic activity
○ Neonates and infants (presents within first 8 weeks of
life) ANCILLARY TESTS
• Sex Immunohistochemistry
○ Slight male predominance (M:F = 1.3-2.3:1.0) • Infiltrating fibroblasts are SMA(+) in early stages
Site • Lesional cells are nuclear β-catenin (-)
• Intramuscular location within SCM
○ Most commonly involves middle and lower 1/3 of muscle DIFFERENTIAL DIAGNOSIS
• Most commonly unilateral with rare reported bilateral cases Nodular Fasciitis
○ Predominantly right sided (75% of cases) • Does not infiltrate between muscle bundles
Presentation • Myxoid and storiform patterns are common
• Admixed extravasated red blood cells, lymphocytes, and
• Painless, firm mass in body of SCM
plasma cells are commonly seen
○ Rare reported cases of trapezius muscle involvement
○ Initial growth phase over 1st several weeks, then Fibromatosis
stabilizes in size • Solitary or multiple masses
• 14-30% of cases are associated with congenital muscular • Not confined to single muscle group as in fibromatosis colli
torticollis (CMT) • May entrap muscle fibers at periphery but does not replace
○ Prolonged torticollis may result in craniofacial muscle
asymmetry • Deep lesions exhibit nuclear β-catenin immunoreactivity
• Associated with developmental dysplasia of hip in 2.4-
10.0% of cases Focal Myositis
• Can occur at any age
Treatment
• Gastrocnemius and vastus lateralis muscles are most
• Primarily conservative management with physiotherapy common sites
and stretching exercises • Intramuscular mass with interstitial mixed inflammatory
• Surgical management reserved for patients with infiltrate and dense fibrosis
persistence of disease after 1 year of age or those with • Degenerative and regenerative myopathic changes
craniofacial abnormalities
Prognosis SELECTED REFERENCES
• Most cases are self-limited with spontaneous regression by 1. Sargar KM et al: Pediatric fibroblastic and myofibroblastic tumors: a pictorial
4-8 months of age review. Radiographics. 36(4):1195-214, 2016
2. Adamoli P et al: Rapid spontaneous resolution of fibromatosis colli in a 3-
• If conservative therapy is initiated early, 80-90% of cases week-old girl. Case Rep Otolaryngol. 2014:264940, 2014
resolve permanently 3. Coffin CM et al: Fibroblastic and myofibroblastic tumors in children and
adolescents. Pediatr Dev Pathol. 15(1 Suppl):127-80, 2012

255
 Gardner Fibroma

KEY FACTS
Pediatric Fibroblastic/Myofibroblastic Tumors

TERMINOLOGY • Range 1 cm to > 10 cm (mean: 3-4 cm)

• Uncommon fibrocollagenous lesion classically arising in MICROSCOPIC
paraspinal or back region of child
• Sheets of dense collagen bundles with intervening
• Majority linked to familial adenomatous polyposis cleft/cracking artifact
(FAP)/Gardner syndrome
• Sparse intermixed population of small bland fibroblastic
CLINICAL ISSUES spindle cells
• Majority (80%) arise in 1st decade of life • Variable amounts of entrapped fat, vessels, and nerves,
• Slight male predominance especially at periphery
• Back and paraspinal most common sites (60%) ANCILLARY TESTS
○ Also head/neck, extremities, abdomen/chest • Nuclear β-catenin (+) in majority
• Painless subcutaneous mass, occasionally multiple
• Treatment: Simple surgical excision TOP DIFFERENTIAL DIAGNOSES
• Benign but may recur after incomplete excision • Nuchal-type fibroma
• Majority (70%) associated with FAP/Gardner syndrome • Nuchal fibrocartilaginous pseudotumor
○ Nearly 20% of patients also have desmoid fibromatosis • Fibrolipoma
• Elastofibroma
MACROSCOPIC
• Desmoid fibromatosis
• Poorly circumscribed subcutaneous mass

Subcutaneous Mass Entrapped Fat

(Left) Gardner fibroma arises
as a hypocellular densely
collagenous mass in the
subcutis. This case was from
the scalp of a 5-year-old
patient. (Right) Islands of
adipocytes are often
entrapped within the dense
collagen of Gardner fibroma.

Hypocellular Sheets of Dense Collagen Artifactual Clefting

(Left) Gardner fibroma is
composed of sheets of dense
collagen with sparsely
scattered, bland, spindled
fibroblasts. (Right) Scattered,
small, spindled fibroblastic
cells ﬈ are present among
the dense collagen bundles
and are often only identifiable
by their thin, bland nuclei.
Cracking artifact ﬊ is clearly
seen in this H&E. (Courtesy M.
Edgar, MD.)

256
 Gardner Fibroma
TERMINOLOGY
Synonyms
• Gardner-associated fibroma; desmoid precursor lesion
Definitions
• Uncommon fibrocollagenous lesion classically arising in
paraspinal or back region of child
○ Majority linked to familial adenomatous polyposis
(FAP)/Gardner syndrome
• Distinct entity from nuchal-type fibroma (despite very
similar histologic features)
• Uncertain whether benign neoplasm or malformation
CLINICAL ISSUES
Epidemiology
• Age
○ Majority (80%) arise in 1st decade (mean age: 5 years)
– Remainder in teens or young adults
• Sex
○ Slight male predominance
Site
• Back and paraspinal most common sites (60%)
• Also head/neck, extremities, abdomen/chest
Presentation
• Painless subcutaneous mass
• Usually solitary; multiple lesions in 15% of patients
○ Multiple lesions more likely in FAP
• Large/unresectable lesions more likely in FAP
Treatment
• Simple surgical excision
• Celecoxib has been used for large/unresectable cases
Prognosis
• Benign but may recur after incomplete excision
• May transform into desmoid fibromatosis
• 24% of desmoid fibromatosis have adjacent areas of
Gardner fibroma (may be subtle)
• 70% are associated with FAP/Gardner syndrome
○ Nearly 20% of patients also have desmoid fibromatosis
○ Gardner fibroma may be sentinel event of FAP
MACROSCOPIC
General Features
• Poorly circumscribed subcutaneous mass
• Rubbery white to yellow cut surface
Size
• Range 1 cm to > 10 cm (mean: 3-4 cm)
MICROSCOPIC
Histologic Features
• Identical for sporadic vs. FAP-associated cases
• Sheets of dense collagen bundles with intervening
cleft/cracking artifact
• Sparse intermixed small bland fibroblasts
Pediatric Fibroblastic/Myofibroblastic Tumors
• Variable amounts of entrapped fat, vessels, and nerves,
especially at periphery
• Scattered mast cells may be present
ANCILLARY TESTS
Immunohistochemistry
• Immunostains usually not required for diagnosis
• Majority (+) for β-catenin (nuclear), CD34, cyclin-D1, myc
• Subset are β-catenin (-), particularly sporadic non-FAP cases
DIFFERENTIAL DIAGNOSIS
Nuchal-Type Fibroma
• Histologically very similar to Gardner fibroma
• Arises in young to middle-aged adults (not children)
• Lacks nuclear β-catenin (+)
• Uncommonly associated with FAP/Gardner syndrome
• Some have proliferation of small nerve bundles, unlike
Gardner fibroma
Nuchal Fibrocartilaginous Pseudotumor
• Arises in specific site: Posterior neck at junction of nuchal
ligament and deep cervical fascia
• Contains prominent cartilaginous tissue
Elastofibroma
• Arises beneath inferior tip of scapula; often bilateral
• Dense collagen admixed with mature adipose tissue
• Hallmark finding: Degenerated serrated elastic fibers with
"petaloid globules" or "caterpillar bodies"
Desmoid Fibromatosis
• Usually large deep mass
• Long, broad, sweeping fascicles of bland fibroblastic cells
○ Much more cellular and fascicular than Gardner fibroma
• Infiltration and entrapment of skeletal muscle fibers
Fibrolipoma
• Circumscribed mass of mature adipose tissue with
intervening fibrocollagenous septa
• Much more fat/less collagen than Gardner fibroma
Desmoplastic Fibroblastoma (Collagenous Fibroma)
• Dense sheets of collagen but usually more homogeneous
• Multinodular and well circumscribed; not infiltrative
• Has large stellate fibroblasts not seen in Gardner fibroma
DIAGNOSTIC CHECKLIST
Clinically Relevant Pathologic Features
• Raise possibility of FAP/Gardner syndrome; recommend
consultation with genetic counselor for further work-up
SELECTED REFERENCES
1. Dahl NA et al: Gardner fibroma: clinical and histopathologic implications of
germline APC mutation association. J Pediatr Hematol Oncol. 38(5):e154-7,
2016
2. Cates JM et al: Desmoid-type fibromatosis-associated Gardner fibromas:
prevalence and impact on local recurrence. Cancer Lett. 353(2):176-81, 2014
3. Coffin CM et al: Gardner fibroma: a clinicopathologic and
immunohistochemical analysis of 45 patients with 57 fibromas. Am J Surg
Pathol. 31(3):410-6, 2007
4. Wehrli BM 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. 25(5):645-51, 2001
257
 Lipofibromatosis

KEY FACTS
Pediatric Fibroblastic/Myofibroblastic Tumors

TERMINOLOGY • Most 1-3 cm

• Infiltrating, fibrofatty soft tissue tumor of childhood with MICROSCOPIC
predilection for distal extremities
• Lobules of mature adipose tissue traversed by fascicles of
• Synonym: Infantile/juvenile fibromatosis, nondesmoid type bland, spindled fibroblasts
(obsolete)
• Infiltrative growth pattern
CLINICAL ISSUES • No nuclear pleomorphism
• Presents from birth to childhood • Low to absent mitotic activity
○ Majority present prior to 3 years of age TOP DIFFERENTIAL DIAGNOSES
○ Male predominance
• Fibrous hamartoma of infancy
• Most commonly involves distal extremities (hands and feet)
• Lipomatosis of nerve
• Painless, slow-growing, subcutaneous or deep soft tissue
• Lipoblastoma
mass
• Fibroblastic connective tissue nevus
• Treatment: Complete surgical resection
• Lipofibromatosis-like neural tumor
• Benign with high rate of local recurrence
• No reported cases of metastasis
MACROSCOPIC
• Poorly demarcated with tan to yellow, firm cut surfaces

Lipofibromatosis Adipocytes and Fibroblasts

(Left) Lipofibromatosis is a
benign lesion characterized by
alternating lobules of mature
adipocytes ﬈ and fascicles of
variably cellular but bland
fibrous tissue ﬊. (Right) This
lesion is composed of 2 cell
types: Mature adipose tissue
and fibroblasts. The
fibroblasts are spindled in
shape with ovoid nuclei, no
cytologic atypia, and minimal
mitotic activity ﬈. Although
the majority of adipocytes are
mature, occasional
univacuolated lipoblast-like
cells ﬊ are encountered at
the interface of adipose and
fibrous tissue.

Variable Proportions Infiltrative Growth Pattern

(Left) The adipocytic and
fibrous components of
lipofibromatosis vary widely in
proportion from tumor to
tumor. Typically, the
adipocytic component is
abundant and comprises at
least 50% of the lesion. (Right)
Lipofibromatosis displays a
tendency for infiltrative
growth and can entrap muscle
﬊, nerves, and adnexal
structures. As such, there is a
high rate of local recurrence
after excision.

258
 Lipofibromatosis

Pediatric Fibroblastic/Myofibroblastic Tumors

• Vacuolated (lipoblast-like) cells at areas of interface
TERMINOLOGY between adipose and fibrous tissue
Synonyms • Scattered pigmented cells (containing melanin) reported in
• Infantile/juvenile fibromatosis, nondesmoid type (former rare cases
designation)
ANCILLARY TESTS
Definitions
• Infiltrating, fibrofatty soft tissue tumor of childhood with
Immunohistochemistry
predilection for distal extremities • Variable focal SMA(+), CD34(+), CD99(+)
• Nuclear β-catenin expression absent
ETIOLOGY/PATHOGENESIS • Fibroblasts/myofibroblasts (-) for S100, desmin, and ALK1
Genetics
DIFFERENTIAL DIAGNOSIS
• Single reported case of balanced 3-way t(4;9;6)
translocation Fibrous Hamartoma of Infancy
• Fibroblastic component demonstrates high expression of • More commonly occurs in axillary fold, proximal
connective tissue growth factor (CCN2), which is encoded extremities, and groin (rare in hands and feet)
by gene located on chromosome 6q23.1 • Classic organoid growth pattern with 3 distinct
components in varying amounts
CLINICAL ISSUES ○ Mature adipose tissue
Epidemiology ○ Fascicles and sheets of fibroblasts/myofibroblasts
○ Primitive mesenchymal cells in myxoid stroma
• Presents from birth to childhood
○ Median age of presentation: 1 year Lipomatosis of Nerve
○ Majority of cases present prior to 3 years of age • Typically affects median nerve and digital branches (80%)
• Tendency for male predominance (M:F = 2.7:1.0) • Associated with macrodactyly in 30% of cases
Site • Infiltration of perineurium and epineurium by adipose
tissue
• Most commonly involves distal extremities (hands and feet)
• Less common sites: Head, neck, orbit, jaw, back, chest wall, Lipoblastoma
abdominal wall • Admixture of mature and immature adipocytes
Presentation ○ Adipocytes mature over time and become separated by
prominent fibrous septa
• Slow-growing, subcutaneous or deep soft tissue mass • Lipoblasts prominent in early lesions
Treatment • Prominent plexiform vasculature within fat lobules
• Complete surgical resection • Variable amounts of myxoid stroma
• PLAG1 (8q11-13) gene rearrangements
Prognosis
• Benign
Fibroblastic Connective Tissue Nevus
• High rate of local recurrence due to infiltrative growth • Isolated plaque-like or nodular lesion on trunk, head and
pattern neck, and extremities of children
• Factors associated with recurrence • Interlacing fascicles of spindled fibroblasts/myofibroblasts
○ Congenital presentation, male sex, high mitotic activity, within reticular dermis and subcutis
and incomplete excision • Entrapped adnexal structures and adipocytes
Lipofibromatosis-Like Neural Tumor
MACROSCOPIC
• Fascicles of spindle cells infiltrating adipocytes in subcutis
General Features • May display mild cytologic atypia
• Tan to yellow, firm cut surfaces • S100(+), CD34(+) and NTRK1(+)
• Poorly demarcated with ill-defined margins • NTRK1 gene rearrangements
Size SELECTED REFERENCES
• Most 1-3 cm (rarely > 5 cm)
1. Lao QY et al: [Lipofibromatosis: a clinicopathological analysis of eight cases.]
Zhonghua Bing Li Xue Za Zhi. 47(3):186-191, 2018
MICROSCOPIC 2. Pennacchia I et al: Fibroblastic connective tissue nevus: clinicopathological
and immunohistochemical study of 14 cases. J Cutan Pathol. 44(10):827-
Histologic Features 834, 2017
• Lobules of mature adipose tissue traversed by fascicles of 3. Agaram NP et al: Recurrent NTRK1 gene fusions define a novel subset of
locally aggressive lipofibromatosis-like neural tumors. Am J Surg Pathol.
bland, spindled fibroblasts 40(10):1407-16, 2016
○ No nuclear pleomorphism 4. Boos MD et al: Lipofibromatosis: an institutional and literature review of an
○ Low to absent mitotic activity uncommon entity. Pediatr Dermatol. 31(3):298-304, 2014

• Infiltrative growth pattern with entrapped muscle, nerves,

and adnexal structures

259
 Giant Cell Fibroblastoma

KEY FACTS
Pediatric Fibroblastic/Myofibroblastic Tumors

TERMINOLOGY MICROSCOPIC
• Locally aggressive fibroblastic neoplasm, predominantly of • Infiltrative growth
childhood and adolescence, that classically features • Hypocellular proliferation of bland spindled cells within
multinucleated giant cells lining pseudovascular spaces myxoid to collagenous stroma
○ Histologically and genetically related to • Multinucleated giant cells in stroma and lining irregular
dermatofibrosarcoma protuberans (DFSP) pseudovascular spaces
CLINICAL ISSUES • Mitoses rare; necrosis absent
• Minority of cases contain areas of conventional DFSP
• Most arise in children (median: 6 years)
• 2:1 male predominance ANCILLARY TESTS
• Most common in superficial soft tissues of trunk • CD34(+) in spindled and multinucleated giant cells
• Superficial, often protuberant mass • Molecular: Characteristic t(17;22) with COL1A1-
○ May arise in site of previous DFSP excision PDGFB fusion
• Treatment: Wide surgical excision with margins
TOP DIFFERENTIAL DIAGNOSES
• Local recurrence in up to 50%
• DFSP
• No documented reports of metastasis in histologically pure
giant cell fibroblastoma • Angiosarcoma
• Dermatofibroma (fibrous histiocytoma)
• Myxofibrosarcoma

Giant Cell Fibroblastoma Giant Cell Fibroblastoma

(Left) Giant cell fibroblastoma
(GCFB) is a benign but locally
aggressive fibroblastic
neoplasm that most
frequently arises on the trunk,
usually in children. As shown
on this H&E, GCFB ﬈ is a
superficial lesion and arises in
the dermis &/or subcutis.
(Right) The classic histologic
appearance of GCFB shows
irregular, pseudovascular
("angiectoid") spaces lined by
multinucleated giant cells
within a variable collagenous
to myxoid stroma. An initial
impression of a vascular
neoplasm like angiosarcoma is
not uncommon.

Mono- and Multinucleated Stromal Cells Irregular Pseudovascular Spaces

(Left) Two types of stromal
fibroblastic cells can be
identified in GCFB:
Mononuclear cells ﬈ with
bland, wavy nuclei and
multinucleated giant cells ﬊
with nuclei in a floret-like or
centrally clustered
arrangement. Mitotic activity
is low to absent. (Right)
Although not seen in every
case, many examples of GCFB
contain characteristic irregular
pseudovascular spaces lined
by mono- and multinucleated
stromal cells. These spaces,
when present, may be dilated
and prominent, as depicted, or
slit-like and prominent.

260
 Giant Cell Fibroblastoma

Pediatric Fibroblastic/Myofibroblastic Tumors

• Variable number of multinucleated giant cells in stroma
TERMINOLOGY
○ These cells also characteristically line irregular, cleft-like
Abbreviations pseudovascular spaces
• Giant cell fibroblastoma (GCFB) • Mitoses rare; necrosis absent
• Intralesional hemorrhage may be present
Definitions
• Perivascular chronic inflammatory infiltrate not uncommon
• Locally aggressive fibroblastic neoplasm, predominantly of • Minority of cases contain areas of conventional DFSP
childhood and adolescence, that classically features (hybrid DFSP/GCFB)
multinucleated giant cells lining pseudovascular spaces ○ May be present in primary tumor or in recurrence
○ Histologically and genetically related to ○ Rare pigmented cells, myoid nodules, or
dermatofibrosarcoma protuberans (DFSP) fibrosarcomatous change
CLINICAL ISSUES ANCILLARY TESTS
Epidemiology Immunohistochemistry
• Incidence • CD34(+) in spindled and multinucleated giant cells
○ Rare • S100 protein, SMA, desmin, keratin (-)
• Age
○ Most arise in children (median: 6 years) Molecular Genetics
○ 75% occur before 20 years • Characteristic t(17;22) leading to COL1A1-PDGFB fusion
○ Occasionally may occur in adults protein
• Sex
○ 2:1 male predominance DIFFERENTIAL DIAGNOSIS
Site Dermatofibrosarcoma Protuberans
• Arises in dermis &/or subcutaneous tissue • Pure DFSP lacks multinucleated giant cells
• Most common on trunk • Well-developed storiform architecture in most cases
• Infrequent on extremities, head/neck region • DFSP can contain areas of GCFB

Presentation Angiosarcoma
• Superficial, often protuberant mass • Very rare in pediatric age group
○ May be polypoid • Prominent nuclear atypia and mitoses
• Slow growing, often painless • CD31(+), CD34(+)
• May arise in site of previous DFSP excision Dermatofibroma (Fibrous Histiocytoma)
Treatment • May contain multinucleated giant cells
• Wide surgical excision with margins • Lacks irregular pseudovascular spaces lined by
multinucleated cells
Prognosis • Generally CD34(-)
• Local recurrence in up to 50% • Lacks COL1A1-PDGFB fusion
○ Often related to marginal or incomplete excision
Pleomorphic Lipoma
• No documented reports of metastasis in histologically pure
GCFB • Well circumscribed, noninfiltrative
○ Hybrid GCFB/DFSP tumors behave more like DFSP • Contains characteristic floret-like multinucleated cells
• Adipose tissue component often abundant
MACROSCOPIC • Lacks COL1A1-PDGFB fusion
General Features Myxofibrosarcoma
• Poorly defined, superficial lesion • Most common in older/elderly adults
• Tan-gray to yellow mucoid cut surface • Usually prominent nuclear atypia and mitotic activity
• Occasionally shows CD34(+)
Size
• Mean: 3.5 cm SELECTED REFERENCES
1. Shah KK et al: Dermatofibrosarcoma protuberans of distal extremities and
MICROSCOPIC acral sites: a clinicopathologic analysis of 27 cases. Am J Surg Pathol.
42(3):413-419, 2018
Histologic Features 2. Macarenco RS et al: Genomic gains of COL1A1-PDFGB occur in the histologic
• Infiltrative growth evolution of giant cell fibroblastoma into dermatofibrosarcoma
protuberans. Genes Chromosomes Cancer. 47(3):260-5, 2008
○ Adnexal structures entrapped but not destroyed
3. Jha P et al: Giant cell fibroblastoma: an update and addition of 86 new cases
○ Often shows honeycomb pattern of fat infiltration from the Armed Forces Institute of Pathology, in honor of Dr. Franz M.
• Hypocellular proliferation of small spindled cell with bland, Enzinger. Ann Diagn Pathol. 11(2):81-8, 2007
wavy nuclei within myxoid to collagenous stroma 4. Terrier-Lacombe MJ et al: Dermatofibrosarcoma protuberans, giant cell
fibroblastoma, and hybrid lesions in children: clinicopathologic comparative
○ Areas of increased cellularity can be seen analysis of 28 cases with molecular data--a study from the French Federation
of Cancer Centers Sarcoma Group. Am J Surg Pathol. 27(1):27-39, 2003

261
 Giant Cell Fibroblastoma
Pediatric Fibroblastic/Myofibroblastic Tumors

Cells Lining Pseudovascular Spaces Prominent Pseudovascular Spaces

(Left) The pseudovascular
spaces of GCFB may appear to
be lined by either the
mononuclear or
multinucleated cells.
Importantly, these cells are
stromal rather than
endothelial. (Right) The
pseudovascular spaces can be
prominent and sinusoidal in
some cases of GCFB.

Inconspicuous Pseudovascular Spaces Adnexal Sparing

(Left) When present, the
pseudovascular spaces of
GCFB may be small, slit-like,
and less prominent, as shown
on this H&E. (Right) GCFB is a
highly infiltrative tumor and
can display extension into
both dermal connective tissues
and subcutaneous fat.
Cutaneous adnexal structures
﬊, if present, are often
entrapped but spared.

"Honeycomb" Fat Infiltration Mimicry of Lipomatous Neoplasm

(Left) Similar to the related
dermatofibrosarcoma
protuberans (DFSP), GCFB
often shows a honeycomb
pattern of infiltrative growth
into subcutaneous adipose
tissue. (Right) When
multinucleated giant cells are
prominent in GCFB, the
honeycomb pattern of fat
infiltration can lead to the
mistaken impression of a
pleomorphic lipoma or well-
differentiated liposarcoma.

262
 Giant Cell Fibroblastoma
Parallel Cellular Orientation
Prominent Collagenous Stroma
Intralesional Hemorrhage
Pediatric Fibroblastic/Myofibroblastic Tumors
Increased Cellularity
(Left) The lesional cells of
GCFB may show a more
orderly but loose parallel
arrangement, as depicted. A
storiform growth pattern is
absent, unless a component of
DFSP is present. (Right) Most
cases of GCFB are largely
hypocellular; however, some
areas can show increased
cellularity, as seen on this
H&E. This field lacks
multinucleated cells. Also note
the presence of a perivascular
lymphoid infiltrate ﬊, a
relatively common finding.
Prominent Myxoid Stroma
(Left) Prominent collagenous
stroma is a common finding in
GCFB and may impart an
overall hyalinized or sclerotic
appearance to the lesion. Note
the multinucleated cells ﬈
evident even at low power.
(Right) Myxoid stroma is
common in GCFB but varies in
extent. The combination of a
prominent myxoid stroma and
multinucleated floret-like cells
may lead to confusion with
myxofibrosarcoma. The latter
tumor, however, occurs in a
much older age group than
GCFB.
Areas of Conventional
Dermatofibrosarcoma Protuberans
(Left) Intralesional
hemorrhage can be seen in a
significant number of cases
and, in conjunction with the
irregular stromal clefts and
spaces, can lead to
misdiagnosis as angiosarcoma.
(Right) Areas of DFSP
morphology (bottom right)
may be seen in some cases of
GCFB (hybrid DFSP/GCFB).
This component may be
identified by a significant
increase in cell density and an
absence of multinucleated
cells and pseudovascular
spaces. Evidence of storiform
growth is also supportive.
263
 Infantile Fibrosarcoma

KEY FACTS
Pediatric Fibroblastic/Myofibroblastic Tumors

TERMINOLOGY ○ May show primitive round cell morphology in some cases

• Synonym: Congenital fibrosarcoma ○ Mitoses common and may be brisk
• Infiltrative, rarely metastasizing fibroblastic sarcoma of • Scattered foci of hemorrhage and necrosis common
infancy associated with ETV6-NTRK3 gene fusion • Other findings: Myxoid foci, hemangiopericytoma-like
vasculature
CLINICAL ISSUES
ANCILLARY TESTS
• Most arise in 1st year of life (often congenital)
• Superficial and deep soft tissues of distal extremities (most • May show SMA(+) or CD34(+) but often focally
common site) • Pan-TRK cytoplasmic positivity
○ Also trunk and head/neck; rarely visceral sites • Desmin, myogenin, keratin, S100 protein (-)
• Solitary, rapidly enlarging, often large mass • Molecular: Characteristic t(12;15)(p13;q25) producing ETV6-
• Treatment: Complete surgical excision ± chemotherapy NTRK3 gene fusion
• Overall favorable prognosis TOP DIFFERENTIAL DIAGNOSES
○ Recurrence rate varies (5-50%); metastases are rare • Lipofibromatosis
MICROSCOPIC • Infantile myofibroma
• Infiltrative growth • Fibrosarcomatous dermatofibrosarcoma protuberans
• Sheets and intersecting or sweeping fascicles of • Spindle cell rhabdomyosarcoma
monomorphic spindled to ovoid cells • Synovial sarcoma

Infantile Fibrosarcoma Infantile Fibrosarcoma

(Left) Infantile fibrosarcoma
(IFS) is a low- to intermediate-
grade sarcoma that
predominantly affects infants
and is often present at birth.
Grossly, IFS often forms a
large, lobulated mass with a
tan, fleshy cut surface and
areas of hemorrhage and
necrosis. (Right) Most cases of
IFS are densely cellular and
resemble adult-type
fibrosarcoma; however, the
degree of cellularity varies
with the stromal collagen
content. Significant nuclear
pleomorphism is not a feature.

Infiltration and Entrapment Uniform Cytology

(Left) IFS is generally an
infiltrative neoplasm and
grows through adipose tissue
and around muscle bundles,
nerves, and cutaneous adnexal
structures ﬊. Some highly fat-
infiltrative tumors may
resemble lipofibromatosis.
(Right) Nuclei in IFS are
atypical but relatively uniform
and not pleomorphic. Nucleoli
may or may not be
identifiable. Mitotic activity is
often conspicuous.

264
 Infantile Fibrosarcoma

Pediatric Fibroblastic/Myofibroblastic Tumors

○ Mitoses common and may be brisk
TERMINOLOGY
• Scattered foci of hemorrhage and necrosis common
Abbreviations • Variable stromal collagen formation
• Infantile fibrosarcoma (IFS) • Other findings
○ Chronic inflammatory infiltrate, myxoid foci,
Synonyms
hemangiopericytoma-like vasculature, dystrophic
• Congenital fibrosarcoma calcification, extramedullary hematopoiesis
Definitions ○ May contain areas reminiscent of myofibroma
• Infiltrative, rarely metastasizing fibroblastic sarcoma of • Postchemotherapy changes include diffuse fibrosis and
infancy associated with ETV6-NTRK3 gene fusion hypocellular scar-like appearance

CLINICAL ISSUES ANCILLARY TESTS

Epidemiology Immunohistochemistry
• Age • Variable, often focal SMA(+), CD34(+)
○ Most arise in 1st year of life • Desmin, myogenin, keratin, S100 protein (-)
– Over 1/2 are congenital • Pan-TRK(+)
□ May be detected and diagnosed antenatally ○ Cytoplasmic expression sensitive but not specific for
NTRK3 fusion
Site
Molecular Genetics
• Superficial and deep soft tissues of distal extremities (most
common) • Characteristic t(12;15)(p13;q25) with ETV6-NTRK3 fusion
• Also trunk and head/neck; rarely visceral sites ○ Also seen in cellular mesoblastic nephroma of kidney
• Rare EML4-NTRK3 fusion also reported
Presentation
• Solitary, rapidly enlarging, often large mass DIFFERENTIAL DIAGNOSIS
• Overlying skin may be erythematous &/or ulcerated Lipofibromatosis
Treatment • Less cellular than IFS; lower mitotic rate; no necrosis
• Complete surgical excision with negative margins • Pan-TRK(-)
• Preoperative chemotherapy also effective • Lacks ETV6-NTRK3 fusion
Prognosis Myofibroma/Myofibromatosis
• Overall indolent clinical course with favorable prognosis • Biphasic growth pattern in most cases
○ Recurrence rate up to 50%; metastasis are rare • Consistently SMA(+), often diffuse
○ Mortality usually < 5% • Lacks ETV6-NTRK3 fusion
– Often related to local invasion of vital structures Synovial Sarcoma
• Spontaneous regression has been reported
• More common in teenagers and young adults
• Keratin (+), EMA(+), TLE-1(+)
MACROSCOPIC
• Characteristic t(X;18)(p11;q11) involving SS18 (SYT)
General Features
Spindle Cell Rhabdomyosarcoma
• Poorly circumscribed, lobulated, tan-gray, firm or fleshy
• Arise predominantly in paratesticular location in kids
Size • Desmin (+), myogenin (+)
• Often large (reports up to 30 cm) • Rearrangements of NCOA2 or VGLL2 in infantile cases
Fibrosarcomatous DFSP
MICROSCOPIC
• Usually affects older patients but may be congenital
Histologic Features • Diffuse CD34(+)
• Irregular peripheral border • Characteristic COL1A1-PDGFB gene fusion
○ May show pseudocapsule formation
• Infiltrative growth
Lipofibromatosis-Like Neural Tumor
○ Entraps adipose tissue, muscle, nerves, cutaneous • Spindled cells with variable cytologic atypia
adnexal structures • Diffuse S100 protein (+); pan-TRK cytoplasmic positivity
• Sheets and intersecting or sweeping fascicles of • NTRK1 gene rearrangements
monomorphic spindled to ovoid cells
○ May show herringbone architecture SELECTED REFERENCES
○ Occasional vague storiform growth 1. Church AJ et al: Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma
• Immature spindled or ovoid cells and congenital mesoblastic nephroma suggest a revised testing strategy.
Mod Pathol. 31(3):463-473, 2018
○ Tapered, relatively uniform nuclei with variable nucleoli 2. Hung YP et al: Evaluation of pan-TRK immunohistochemistry in infantile
– Lacks significant nuclear pleomorphism  fibrosarcoma, lipofibromatosis-like neural tumour and histological mimics.
Histopathology. 73(4):634-644, 2018
○ May show primitive round cell morphology in some cases
265
 Infantile Fibrosarcoma
Pediatric Fibroblastic/Myofibroblastic Tumors

Mitoses Common Fascicular Growth

(Left) Although the rate is
variable, mitotic figures ﬈ are
usually easily identified in IFS.
In some cases, mitoses are
numerous. (Right) Fascicular
growth is a common feature
of IFS and may be prominent.
A herringbone architectural
pattern may be seen focally in
some cases. Others show more
sheet-like growth or, rarely, a
focal, vague storiform
architecture.

Fascicular Growth Thin-Walled Vasculature

(Left) When viewed in cross
section, fascicles of spindled
tumor cells often appear more
rounded. Some tumors may
show alternating spindled ﬈
and round cell areas ﬊.
(Right) Small, thin-walled
vascular channels are a
common finding in IFS but in
some cases appear markedly
dilated and irregular,
imparting a staghorn
appearance, similar to what is
seen in a solitary fibrous
tumor, among other
neoplasms.

Hemangiopericytoma-Like Vasculature Perivascular Edema

(Left) A focally prominent
ramifying
hemangiopericytoma-like
pattern composed of extensive
irregular and ectatic vascular
channels is depicted in this
example of IFS. Most other
fields demonstrated more
conventional solid growth.
(Right) Although not present
in all tumors, some cases of
IFS show perivascular edema
or myxoid change, as depicted.

266
 Infantile Fibrosarcoma

Pediatric Fibroblastic/Myofibroblastic Tumors

Necrosis Chronic Inflammatory Infiltrate
(Left) Foci of tumor necrosis
﬊ and hemorrhage are
common in IFS and are often
also identifiable at the time of
gross examination. Occasional
cases show widespread, zonal
necrosis. (Right) A chronic
inflammatory infiltrate,
usually composed of
lymphocytes, is a relatively
common finding in IFS but
varies in degree from brisk to
very subtle.

Immature Round Cell Morphology Cutaneous Extension

(Left) In some cases of IFS,
tumor cells adopt a cellular
immature round cell
morphology. Spindled areas
are often present elsewhere
but may be inconspicuous.
(Right) Larger examples of IFS
may show involvement of the
overlying skin, and ulceration
is not uncommon. Entrapment
of adipose tissue and adnexal
structures is typical, given the
infiltrative nature of the
tumor.

Myxoid Change Cellular Mesoblastic Nephroma of Kidney

(Left) Myxoid change ﬊ may
be seen focally in IFS. Note the
more conventional spindled
morphology (lower left).
(Right) IFS is characterized by
a distinctive chromosomal
translocation,
t(12;15)(p13;q25), resulting in
ETV6-NTRK3 gene fusion. An
identical translocation is
present in cellular mesoblastic
nephroma (shown), a renal
neoplasm that shows
histologic similarity to IFS.

267
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 SECTION 6

Fibrohistiocytic, Histiocytic, and

Dendritic Cell Tumors

Benign
Dermatofibroma and Fibrous Histiocytoma 270
Deep Benign Fibrous Histiocytoma 276
Localized-Type Tenosynovial Giant Cell Tumor 278
Diffuse-Type Tenosynovial Giant Cell Tumor 284
Cellular Neurothekeoma 290
Xanthomas 294
Solitary (Juvenile) Xanthogranuloma 298
Reticulohistiocytoma 300
Deep Granuloma Annulare 304
Rheumatoid Nodule 306
Langerhans Cell Histiocytosis 308
Extranodal Rosai-Dorfman Disease 310
Crystal-Storing Histiocytosis 314

Intermediate (Rarely Metastasizing)

Plexiform Fibrohistiocytic Tumor 316
Giant Cell Tumor of Soft Tissue 320

Malignant
Histiocytic Sarcoma 324
Follicular Dendritic Cell Sarcoma 326
Interdigitating Dendritic Cell Sarcoma 328
 Dermatofibroma and Fibrous Histiocytoma

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY MICROSCOPIC
• Benign, limited proliferation of histiocytic and fibroblastic • Dermal-based proliferation of typically bland, spindled to
cells in dermis histiocytoid-appearing cells
• Terms dermatofibroma (DF) and fibrous histiocytoma (FH) ○ Early lesions typically show more histiocytes and
are interchangeable lymphocytes
• Characteristic collagen trapping at periphery
ETIOLOGY/PATHOGENESIS
• Overlying epithelial basilar induction with
• Evidence supports both neoplastic and reactive hyperpigmentation
pathogenesis
• Numerous morphologic variants
CLINICAL ISSUES ANCILLARY TESTS
• Affects all ages but most common in young adults
• FXIIIA(+), CD163(+), CD68(+), CD34(-)
• Typically occur on distal extremities but may present at any
cutaneous site TOP DIFFERENTIAL DIAGNOSES
• Firm, isolated, flesh-colored, subcutaneous papule or • Dermatofibrosarcoma protuberans
nodule • Atypical fibroxanthoma
• Excellent prognosis in vast majority of cases • Basal cell carcinoma
○ Metastasis and death in very rare cases of cellular and • Angiosarcoma
atypical DF

Dermal Spindle Cell Proliferation With

Dermatofibroma Epidermal Hyperplasia
(Left) This photograph shows
the typical appearance of
dermatofibroma (DF),
occurring here on the lower
leg of an adult patient, which
is a common presentation of
this tumor. Note the light
reddish/brown appearance of
the lesion. (Right) Classic DF
shows a dermal-based
proliferation of small, bland,
spindled to histiocytic-
appearing cells associated
with a grenz zone. Note the
overlying epidermal
hyperplasia with basilar
pigmentation st.

Hemosiderotic Dermatofibroma With

Collagen Entrapment Sclerosis
(Left) Higher power
examination of a classic DF
shows a proliferation of bland,
spindled to histiocytoid cells
entrapping numerous
hyalinized balls of collagen
﬊. (Right) This is an example
of a hemosiderotic (or
sclerosing hemangioma)
variant of DF with prominent
stromal sclerosis and
hemosiderin within many of
the histiocytic cells ﬉.

270
 Dermatofibroma and Fibrous Histiocytoma

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
– Usually large and deep, cellular lesions
TERMINOLOGY
Abbreviations MACROSCOPIC
• Dermatofibroma (DF) General Features
• Fibrous histiocytoma (FH)
• Firm, circumscribed, but nonencapsulated, dermal-based
Synonyms tumor
• Cutaneous FH • White to yellow cut surface
• Sclerosing hemangioma • Can have cystic changes and hemorrhage

Definitions
• Common, benign, localized proliferation of fibroblastic and
histiocytic cells in dermis
• DF and FH are interchangeable terms
ETIOLOGY/PATHOGENESIS
Unknown
• Evidence supports both reactive and neoplastic
pathogenesis
○ Histiocytic population may be clonal;
fibroblast/myofibroblastic population may be polyclonal
(reactive)
• Tumor may be preceded by local trauma, including insect
bite, in some cases
○ However, no inciting event identified in majority of cases
CLINICAL ISSUES
Epidemiology
• Incidence
○ Common tumors in most populations
• Age
○ All but most common in 4th and 5th decades
• Sex
○ Occur in male and female patients equally
Site
• Typically occur on distal extremities but may present at any
cutaneous site
Presentation
• Firm, isolated, flesh-colored, subcutaneous papule or
nodule
○ New DFs are typically pink (vascular); older DFs are
brown (overlying epidermal hyperplasia with basilar
pigmentation)
• Multiple DFs may occur in immunosuppressed populations
• Dimpling sign when in vivo DF is pinched by fingers
Treatment
• Complete excision is curative in most cases
• Reexcision &/or clinical follow-up of cellular, atypical, and
aneurysmal variants may be prudent
Prognosis
• Excellent in vast majority of cases
○ Local recurrence potentially significant (up to 30%) with
cellular variant
○ Very rare reports of metastasis and death from
otherwise benign-appearing DF/FH
– Most are cellular, aneurysmal, or atypical morphologic
variants
MICROSCOPIC
Histologic Features
• Tumors are grossly circumscribed but microscopically have
irregular, often jagged borders
• Dermal-based proliferation of typically bland, spindled to
histiocytoid-appearing cells
○ Either spindled (fibroblastic) or histiocytoid cells may
predominate
○ Early lesions typically show more histiocytes and
lymphocytes
○ Established lesions show greater cellularity and spindled
cells
○ Older lesions show more fibrosis
○ Spindled cells show elongated eosinophilic cytoplasmic
processes
○ Histiocytic-type cells are larger, epithelioid-shaped, and
have abundant, pale, vacuolated cytoplasm
○ Cytologic atypia and pleomorphism are usually minimal
but can be present
• Collagen trapping at periphery
○ Spheres of intensely eosinophilic collagen (so-called
collagen balls) separated by bands of pale fibrohistiocytic
cells
• Grenz zone
○ Tumor often spares band of superficial papillary dermis
• Folliculosebaceous induction and basilar epidermal
hyperplasia overlying DF
○ Can mimic basal cell carcinoma (BCC) if basilar induction
is marked, especially in superficial shave biopsy
• Overlying epidermal hyperplasia with basilar
hyperpigmentation is common, occasional melanocytic
hyperplasia
○ So-called dirty feet or dirty sock sign
• Adjacent adnexal hyperplasia
Morphologic Variants
• Aneurysmal
○ Also described as hemosiderotic/sclerosing hemangioma
variant of DF/FH
○ Pseudovascular spaces, hemosiderin, reactive spindled
and epithelioid cells
– May mimic vascular tumor, including Kaposi sarcoma
and angiosarcoma
○ Aneurysmal DF can show mild cytologic atypia but lacks
high-grade atypia, infiltrative features, and increased or
atypical mitotic figures
• Cellular
○ Uncommon, often large, deeply penetrating tumors
– May show overlapping features with atypical DF
– Occasional mitoses and multinucleated cells are seen
– Up to 12% of cases may show focal central necrosis

271
Fibrohistiocytic, Histiocytic, and Dendritic Cell Dermatofibroma and Fibrous Histiocytoma
Tumors
○ Most likely subtype to recur (up to 30% in some studies)
• Epithelioid
○ Also described as epithelioid cell histiocytoma and may
represent distinct tumor
○ Nodular to sheet-like, well-circumscribed proliferation of
plump cells in papillary dermis
– Often has associated epidermal collarette
• Atypical
○ Also described as pseudosarcomatous DF or DF with
monster cells
○ Shows population of atypical cells with nuclear
hyperchromasia and prominent nucleoli, often with
abundant cytoplasm
– Mitotic figures are sparse, usually not atypical in
appearance
• Lipidized
○ Often large tumors, typically present in ankle region
○ Numerous large, foamy cells are present with few
hemosiderin-containing cells
○ Stromal hyalinization is typically present, which may be
wiry or keloidal in appearance
• Many other rare variants described, including granular cell,
clear cell, histiocytic/xanthomatous, osteoclastic, myxoid,
keloidal/scar-like, palisading, deep penetrating [may mimic
dermatofibrosarcoma protuberans (DFSP)], and lichenoid
ANCILLARY TESTS
Immunohistochemistry
• FXIIIA, CD10, CD163, HMGA1/HMGA2, MMP-11 (+)
○ CD68(+) but may be weak; typically highlights histiocytic-
appearing cells
○ Focal SMA(+); may indicate myofibroblastic
differentiation
• Recent reports of ALK1 expression in epithelioid FH
• CD34 typically (-) but may show focal staining, especially at
periphery of lesion (but should lack strong and diffuse
staining typical of DFSP)
• S100, MART-1/Melan-A, HMB-45, CD31, cytokeratins,
desmin, nestin (-)
DIFFERENTIAL DIAGNOSIS
Dermatofibrosarcoma Protuberans
• Shows deep, cellular, monotonous proliferation of spindled
cells
• Typically extends deeply along septa of subcutaneous fat
with honeycomb-like fat entrapment
• CD34(+), nestin (+), CD163(-), HMGA1/HMGA2(-), FXIIIA(±)
Basal Cell Carcinoma
• In superficial biopsies, BCC may be difficult to distinguish
from benign follicular induction overlying DF
○ CK20 highlights Merkel cells in basal layer overlying DF;
these cells are typically absent in BCC
Angiosarcoma
• May be considered in differential diagnosis with aneurysmal
DF
• Infiltrative, dissecting growth pattern with endothelial
atypia in most cases
• CD31, CD34 (+)
272
Kaposi Sarcoma
• Nodular/tumor stage Kaposi sarcoma shows atypical
cellular spindle cell proliferation
• Slit-like vascular spaces and extravasated red blood cells are
often present
○ CD31, HHV8 (+)
Atypical Fibroxanthoma
• Dermal nodule composed of highly atypical spindled and
pleomorphic epithelioid cells
• Typically occurs in heavily sun-damaged skin (especially
head and neck area) of elderly patients
○ Both atypical fibroxanthoma (AFX) and DF are positive
for nonspecific markers, including CD68, CD10, and
vimentin
○ FXIIIA may show greater positivity in DF
DIAGNOSTIC CHECKLIST
Clinically Relevant Pathologic Features
• Cellularity and atypia
• Tumor size (more aggressive cases typically large and deep)
Pathologic Interpretation Pearls
• "Collagen balls" classically seen
• Basilar epidermal induction with hyperpigmentation
• Occasional adnexal and melanocytic hyperplasia
SELECTED REFERENCES
1. Acar EM et al: Hemosiderotic dermatofibroma mimicking melanoma in a 12-
year-old boy: a case report. Clin Case Rep. 6(6):1006-9, 2018
2. Felty CC et al: Epithelioid fibrous histiocytoma: a concise review. Am J
Dermatopathol. ePub, 2018
3. Jedrych JJ et al: Aneurysmal fibrous histiocytomas with recurrent
rearrangement of the PRKCD gene and LAMTOR1-PRKCD fusions. J Cutan
Pathol. 45(12):966-8, 2018
4. Liu S et al: Giant aneurysmal benign fibrous histiocytoma (dermatofibroma).
J Cutan Pathol. 45(10):774-6, 2018
5. Beatrous SV et al: Associated conditions in patients with multiple
dermatofibromas: case reports and literature review. Dermatol Online J.
23(9), 2017
6. Romano RC et al: Fibrohistiocytic tumors. Clin Lab Med. 37(3):603-31, 2017
7. Jedrych J et al: Epithelioid cell histiocytoma of the skin with clonal ALK gene
rearrangement resulting in VCL-ALK and SQSTM1-ALK gene fusions. Br J
Dermatol. 172(5):1427-9, 2014
8. Doyle LA et al: Metastasizing "benign" cutaneous fibrous histiocytoma: a
clinicopathologic analysis of 16 cases. Am J Surg Pathol. 37(4):484-95, 2013
9. Fernandez-Flores A et al: Mitosis in dermatofibroma: a worrisome
histopathologic sign that does not necessarily equal recurrence. J Cutan
Pathol. 35(9):839-42, 2008
10. Gleason BC et al: Deep "benign" fibrous histiocytoma: clinicopathologic
analysis of 69 cases of a rare tumor indicating occasional metastatic
potential. Am J Surg Pathol. 32(3):354-62, 2008
11. Mori T et al: Expression of nestin in dermatofibrosarcoma protuberans in
comparison to dermatofibroma. J Dermatol. 35(7):419-25, 2008
12. Sachdev R et al: Expression of CD163 in dermatofibroma, cellular fibrous
histiocytoma, and dermatofibrosarcoma protuberans: comparison with
CD68, CD34, and Factor XIIIa. J Cutan Pathol. 33(5):353-60, 2006
13. Mahmoodi M et al: Anti-cytokeratin 20 staining of Merkel cells helps
differentiate basaloid proliferations overlying dermatofibromas from basal
cell carcinoma. J Cutan Pathol. 32(7):491-5, 2005
14. Hui P et al: Clonal analysis of cutaneous fibrous histiocytoma
(dermatofibroma). J Cutan Pathol. 29(7):385-9, 2002
15. Kaddu S et al: Atypical fibrous histiocytoma of the skin: clinicopathologic
analysis of 59 cases with evidence of infrequent metastasis. Am J Surg
Pathol. 26(1):35-46, 2002
16. Chen TC et al: Dermatofibroma is a clonal proliferative disease. J Cutan
Pathol. 27(1):36-9, 2000
17. Altman DA et al: Differential expression of factor XIIIa and CD34 in
cutaneous mesenchymal tumors. J Cutan Pathol. 20(2):154-8, 1993
 Dermatofibroma and Fibrous Histiocytoma
Hemosiderotic and Cellular
Dermatofibroma
Aneurysmal Variant Hemosiderin-Laden Macrophages
Histiocytic Variant
Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Hemosiderotic and Cellular
Dermatofibroma
(Left) This is an example of a
hemosiderotic and cellular DF
with a prominent grenz zone
﬇ separating the lesion from
the overlying epidermis. Note
the marked epidermal
acanthosis and basilar
pigmentation ﬉ also present.
(Right) Intermediate
magnification of the dermal
tumor in the same patient
shows a cellular proliferation
of spindled and histiocytic cells
associated with a sclerotic
stroma.
(Left) An example of an
aneurysmal fibrous
histiocytoma shows large,
irregular, blood-filled spaces
and prominent hemosiderin
deposition ﬈. (Right) Higher
magnification of an
aneurysmal fibrous
histiocytoma shows numerous
hemosiderin-laden
multinucleated macrophages
﬉.
Histiocytic Variant
(Left) High-power examination
of histiocytic DF shows a
proliferation of large,
epithelioid-shaped cells with
abundant, pale to vacuolated
cytoplasm and bland-
appearing nuclei. (Right)
Histiocyte-predominant DF
shows a proliferation of large,
epithelioid-appearing cells
with abundant,
pale/vacuolated cytoplasm
and scattered, small,
entrapped collagen bundles
﬊.
273
Fibrohistiocytic, Histiocytic, and Dendritic Cell Dermatofibroma and Fibrous Histiocytoma
Tumors

Incidental Osteoma Cutis in Scar-Like Dermatofibroma With Keloidal

Dermatofibroma Collagen
(Left) Scanning magnification
shows an otherwise typical-
appearing DF with overlying
epidermal hyperplasia and a
small associated osteoma
cutis ﬈. (Right) Higher power
view of scar-like DF shows
dense and glassy-appearing
bundles of keloidal collagen
﬊.

Epithelioid Cell Histiocytoma Epithelioid Cell Histiocytoma

(Left) Low-power view of an
epithelioid cell histiocytoma
(DF variant) shows a relatively
cellular proliferation of
histiocytic-appearing cells.
These tumors often have an
associated epidermal
collarette, a feature not seen
in conventional DFs. (Right)
High-power view of an
epithelioid cell histiocytoma
shows a relatively cellular
proliferation of small, bland,
histiocytic-appearing cells. The
stroma is vascular and fibrotic
but does not show prominent
collagen entrapment.

Cellular Variant Cellular Variant With Atypia

(Left) Low-power view of a
cellular DF shows a dense
proliferation of spindled and
histiocytic-appearing cells
with nuclear hyperchromasia.
(Right) Higher power view of a
cellular DF with focal atypia
(or so-called DF with monster
cells) shows scattered, bizarre-
appearing cells with enlarged,
irregular, hyperchromatic-
staining nuclei ﬊.

274
 Dermatofibroma and Fibrous Histiocytoma
FXIIIA Expression
CD163 Expression
Differential Diagnosis:
Dermatofibrosarcoma Protuberans Dermatofibrosarcoma Protuberans
Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
FXIIIA Expression
(Left) Strongly positive FXIIIA
staining of many of the
spindled and dendritic-
appearing tumor cells ﬉ is
seen in some cases of DF.
(Right) Weakly positive FXIIIA
stain in a biopsy shows
weak/patchy staining of the
tumoral spindled cells and
stronger staining of scattered
dermal dendritic cells ﬉.
CD34 Staining
(Left) CD163 IHC shows strong
and diffuse staining in a
cellular and histiocytic-type
DF. CD163 is a more sensitive
marker and usually shows
stronger staining than FXIIIA.
(Right) CD34 strongly
highlights vessels ﬈ and
shows weak background
staining of some of the
peripheral dermis ﬊ but is
negative within the tumoral
cells.
Higher Magnification of
(Left) Low magnification of a
dermatofibrosarcoma
protuberans (DFSP) shows a
deep dermal and
subcutaneous cellular spindle
cell tumor with honeycombing
fat entrapment ﬈. The
epidermis is separated from
the tumor by a thin grenz zone
st. (Right) Higher power
examination of DFSP shows a
cellular, deep dermal and
subcutaneous spindle cell
tumor with storiforming and
honeycombing fat invasion.
275
 Deep Benign Fibrous Histiocytoma

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY
• Distinctive variant of cutaneous fibrous histiocytoma
(dermatofibroma) that occurs in subcutaneous tissue
CLINICAL ISSUES
• Wide age range (median: 40 years)
• Subcutaneous tissue of extremities most common site
○ Also head and neck, trunk
○ Rarely retroperitoneum, mediastinum, pelvis
• Slow-growing, often painless mass
• Treatment: Complete surgical excision
• Local recurrences common (~ 20%)
• Rare metastases and rarer tumor-associated deaths
reported
MACROSCOPIC
• Size usually 2-3 cm (subcutaneous lesions)
○ Visceral lesions can be very large (up to 25 cm reported)
MICROSCOPIC
• Well circumscribed ± thin fibrous pseudocapsule
• Storiform &/or short fascicular growth patterns
• Plump, ovoid to spindle cells with indistinct cytoplasm
• Secondary chronic inflammatory component often present
• Large, branching "staghorn" vessels common
• Variable stromal hyalinization or myxoid change
• Mitotic activity varies (median: 3 per 10 HPF)
ANCILLARY TESTS
• CD34(+) in almost 1/2 of cases
• Desmin (-), EMA(-), STAT6(-)
TOP DIFFERENTIAL DIAGNOSES
• Dermatofibrosarcoma protuberans
• Solitary fibrous tumor
• Perineurioma
• Tenosynovial giant cell tumor, localized type

Deep Benign Fibrous Histiocytoma Chronic Inflammatory Component

(Left) Deep benign fibrous
histiocytoma (BFH) is a distinct
variant of cutaneous fibrous
histiocytoma
(dermatofibroma) that occurs
in the subcutaneous tissue.
Essentially, all cases are well
circumscribed and many show
a fibrous pseudocapsule ﬈.
(Right) The lesional cells of
deep BFH are generally
cytologically bland and similar
to those seen in conventional
cutaneous cases. Stromal
chronic inflammatory cells,
including lymphocytes and
foamy histocytes ﬈, are
common.

Hemangiopericytoma-Like Vasculature Stromal Changes

(Left) A common finding in
deep BFH, in contrast to
cutaneous forms, is the
presence of large, dilated, and
branching "staghorn"
hemangiopericytoma-like
vasculature, which may be
focal or numerous. When
these vessels are prominent, a
solitary fibrous tumor must be
considered. (Right) Although
most cases of deep BFH show
a uniform, cellular storiform or
short fascicular morphology,
areas showing stromal
hyalinization (shown) or
myxoid changes are
occasionally seen.

276
 Deep Benign Fibrous Histiocytoma

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
• Variable stromal hyalinization or myxoid change
TERMINOLOGY
• Variable hemorrhage and stromal hemosiderin (aneurysmal
Synonyms change)
• Deep penetrating dermatofibroma • Rare scattered pleomorphic cells with prominent nuclear
atypia
Definitions • Mitotic activity varies (median: 3 per 10 HPF)
• Distinctive, well-circumscribed variant of cutaneous fibrous
histiocytoma (dermatofibroma) occurring in subcutaneous ANCILLARY TESTS
tissue
Immunohistochemistry
CLINICAL ISSUES • CD34(+) in almost 1/2 of cases
• Variable SMA(+)
Epidemiology
• Desmin (-), EMA(-), STAT6(-)
• Incidence
○ Rare DIFFERENTIAL DIAGNOSIS
• Age
○ Wide range (median: 40 years) Dermatofibrosarcoma Protuberans
• Sex • Superficial, usually localized to dermis
○ Slight male predominance • Highly infiltrative growth pattern with entrapped skin
appendages and "honeycomb" fat infiltration
Site • Uniform spindle cells in diffuse storiform growth pattern
• Subcutaneous tissue of extremities most common • Negligible chronic inflammatory component, no giant cells
• Head and neck, trunk • Consistently CD34(+)
• Also rarely retroperitoneum, mediastinum, pelvis • t(17;22)(q22;q23) with COL1A1-PDGFB fusion
Presentation Solitary Fibrous Tumor
• Slow-growing, often painless mass • Classic patternless pattern with regional variations in
Treatment cellularity
• Prominent hemangiopericytoma-like vascular pattern
• Complete surgical excision
• Stromal collagen and hyalinization varies
Prognosis • Minimal stromal chronic inflammation
• Local recurrences common (~ 20%) • Consistently CD34(+)
• Rare metastases and rarer tumor-associated deaths • Nuclear STAT6(+)
reported Perineurioma
○ Currently no reliable features for predicting aggressive
behavior • Often show storiform or whorled growth
– Local recurrence and presence of necrosis may • Lack "staghorn" vessels and chronic inflammatory
increase risk (limited data) component
• EMA(+), claudin-1 (+)
MACROSCOPIC Tenosynovial Giant Cell Tumor, Localized Type
General Features • Most common on fingers/toes
• Well marginated and often encapsulated • Composed of histiocytoid cells with variable hemosiderin,
• Yellow-tan, firm cut surface giant cells, and stromal sclerosis
• Lacks "staghorn" vessels
Size • CD34(-)
• Usually 2-3 cm (subcutaneous lesions)
• Visceral lesions can be very large (up to 25 cm reported) SELECTED REFERENCES
1. Puopolo A et al: Deep benign fibrous histiocytoma of the anterior
MICROSCOPIC mediastinum mimicking malignancy. Lung. 195(4):503-506, 2017
2. Kim SI et al: Deep penetrating fibrous histiocytoma: a case report and
Histologic Features implications for surgical management. Am J Dermatopathol. 38(4):e49-51,
• Well circumscribed ± thin fibrous pseudocapsule 2016
3. Chung J et al: Deep penetrating benign fibrous histiocytoma of the foot
○ May focally extend into dermis, where conventional associated with throbbing pain. Ann Dermatol. 23(Suppl 2):S239-42, 2011
peripheral collagen trapping is present 4. Gleason BC et al: Deep "benign" fibrous histiocytoma: clinicopathologic
• Storiform &/or short fascicular growth patterns analysis of 69 cases of a rare tumor indicating occasional metastatic
potential. Am J Surg Pathol. 32(3):354-62, 2008
• Plump, ovoid to spindle cells with indistinct cytoplasm 5. Fletcher CD: Benign fibrous histiocytoma of subcutaneous and deep soft
○ Bland nuclei, vesicular chromatin, delicate nucleoli tissue: a clinicopathologic analysis of 21 cases. Am J Surg Pathol. 14(9):801-9,
• Secondary chronic inflammatory component often present 1990

○ Lymphocytes, plasma cells, foamy histocytes, osteoclast-

like giant cells
• Large, branching hemangiopericytoma-like "staghorn"
vessels common
277
 Localized-Type Tenosynovial Giant Cell Tumor

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY • Benign but recurs locally (10-20%)

• Localized-type tenosynovial giant cell tumor (L-TGCT) • Intraarticular tumors called localized PVNS
• Giant cell tumor of tendon sheath, nodular tenosynovitis, MACROSCOPIC
localized pigmented villonodular synovitis (PVNS)
• Average size: 1.1 cm (range: 0.5-6.0 cm)
• Benign soft tissue tumor of synovial origin
• Arises from tendon sheath, intraarticular site, bursa MICROSCOPIC
• Polymorphous population of epithelioid cells,
ETIOLOGY/PATHOGENESIS
macrophages, and osteoclast-like giant cells
• Balanced translocation involving 1p13 (CSF1 gene) • Well demarcated
○ CSF1 overexpression by neoplastic stromal cells • Multinodular with fibrous septa
○ Autocrine activation of neoplastic cells via CSF1R • Stromal fibrosis
○ Recruitment and activation of macrophages and giant • Mitotic rate 1-20 per 10 HPF (average: 5 per 10 HPF)
cells via CSF1R
TOP DIFFERENTIAL DIAGNOSES
CLINICAL ISSUES
• Diffuse-type TGCT (PVNS)
• 2nd most common tumor of hand
• Giant cell tumor of soft tissue
• Any age; peak: 3rd-4th decades
• Fibroma of tendon sheath
• Digits (85%)
• Dermatofibroma
• Around large joints (10%)

Localized-Type Tenosynovial Giant Cell

Tumor Clinical Presentation
(Left) Localized-type
tenosynovial giant cell tumor
(L-TGCT) is composed of a
polymorphous cell population,
including large epithelioid
cells with abundant
eosinophilic cytoplasm and
eccentric vesicular nuclei ﬉;
mononuclear stromal cells
with smaller, round or
reniform nuclei ﬈; and
osteoclast-like giant cells ﬊.
Note the hemosiderin deposits
﬈. (Right) L-TGCT typically
presents as a painless, slowly
growing mass that arises from
a tendon sheath, most often
on the volar aspect of a finger,
such as this thumb mass ſt.

Gross Appearance Lobular Architecture

(Left) Grossly, L-TGCT is well
demarcated, yellow to red-
brown, and typically has a
lobular configuration with
surface clefting, as depicted.
Average size is 1.1 cm, ranging
from 0.5-6.0 cm. (Right) L-
TGCT has a multinodular
architecture, as illustrated by
this low-power micrograph.
Note the long, thick fibrous
septa ﬈ that divide the tumor
into nodules ﬉.

278
 Localized-Type Tenosynovial Giant Cell Tumor

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
• Within bursae
TERMINOLOGY
• Intraarticular L-TGCT
Abbreviations ○ Also called localized PVNS
• Localized-type tenosynovial giant cell tumor (L-TGCT) ○ Knee most common site
○ Complete excision usually curative
Synonyms
• Giant cell tumor of tendon sheath Presentation
• Nodular tenosynovitis • Painless mass
• Localized pigmented villonodular synovitis (PVNS) • Slowly growing
○ Intraarticular forms • Uncommon findings
○ Triggering
Definitions
○ Carpal and ulnar tunnel syndromes
• Benign soft tissue neoplasm of synovial origin ○ Multifocal cases
○ Polymorphous cell population
– Large epithelioid cells Treatment
– Macrophages • Complete local excision
– Osteoclast-like giant cells
Prognosis
○ Well circumscribed, noninvasive
• Benign but recurs locally (10-20%)
ETIOLOGY/PATHOGENESIS • Risk factors for recurrence
○ Degenerative joint disease
Histogenesis ○ Distal phalanx
• Neoplastic growth ○ Interphalangeal joint of thumb
○ Balanced translocation involving 1p13 (CSF1 gene) in ○ Osseous erosion
many tumors
– COL6A3-CSF1 fusion transcripts often present IMAGING
– CSF1 overexpression by neoplastic stromal cells
Radiographic Findings
– Autocrine activation of neoplastic cells via CSF1R
– Recruitment and activation of intratumoral • Soft tissue mass
macrophages and osteoclasts via CSF1R • Cortical bony erosion (10%)
• Synoviocytic differentiation ○ Rarely invades bone to mimic primary bone tumor
○ Clusterin (+) MR Findings
• Lobulated mass with low T1 and T2 signal
CLINICAL ISSUES
Epidemiology MACROSCOPIC
• Incidence General Features
○ 40 patients/1 million • Well circumscribed
– 2nd most common tumor of hand • Partially encapsulated
□ Ganglion cyst most common • Multinodular configuration
• Age ○ Surface clefting
○ Wide spectrum ○ Sometimes grooved along tendon interface
– Peak: 3rd-4th decades • Variegated cut surface: Tan, red-brown, yellow
• Sex
○ F > M: 2:1 Size
• Average: 1.1 cm (range: 0.5-6.0 cm)
Site
○ Large joint tumors often larger than digital tumors
• Digits (85%) (average: 2.0 cm)
○ Especially fingers (75%)
○ Tendon sheath MICROSCOPIC
– Usually volar
Histologic Features
– Often adjacent to interphalangeal joint
• Around large joints (10%) • Well demarcated
○ Ankle • Multinodular with fibrous septa
○ Knee • Stromal fibrosis
○ Wrist ○ Can be extensive
○ Elbow ○ Can mimic osteoid
• Unusual sites • Hemosiderin deposits
○ Scapular region • Dyscohesive areas render pseudoglandular appearance
○ Brachial plexus • Cleft-like spaces lined by synoviocytes
○ Spine • Distal tumors can invade dermis

279
Fibrohistiocytic, Histiocytic, and Dendritic Cell Localized-Type Tenosynovial Giant Cell Tumor
Tumors
Cytologic Features
• Polymorphous cell population
○ Large epithelioid cells
– Abundant, eccentric, eosinophilic cytoplasm
□ Often contain hemosiderin pigment
– Vesicular, round nuclei with prominent nucleoli
○ Histiocytes with pale cytoplasm and round or reniform
nuclei
○ Osteoclast-like multinucleated giant cells
– Can be sparse in some tumors
○ Xanthoma cells
○ Hemosiderin-laden macrophages
• Mitotic rate 1-20 per 10 HPF (average: 5 per 10 HPF)
ANCILLARY TESTS
Immunohistochemistry
• Epithelioid cells are clusterin (+)
• Histiocytes are CD68(+)
• Osteoclast-like giant cells are CD68(+), CD45(+), TRAP(+)
• Desmin (+) cells in 50% of tumors
○ Usually patchy
DIFFERENTIAL DIAGNOSIS
Diffuse-Type Tenosynovial Giant Cell Tumor (PVNS)
• Microscopically similar to L-TGCT
• Diffuse intraarticular tumors form villonodular masses
• Large joints; knee most common site
• Diffuse extraarticular tumors invade adjacent tissues
Giant Cell Tumor of Soft Tissue
• More uniform, less polymorphous mononuclear stromal
cell population
• Osteoclast-like giant cell component prominent
• Less stromal fibrosis
• Often encased by shell of bone
Giant Cell Tumor of Bone
• Identical histology to giant cell tumor of soft tissue
• Primary osseous tumor but can invade soft tissue
• Immunohistochemically (+) for G34W-mutated site of
histone H3.3
○ L-TGCT(-)
Fibroma of Tendon Sheath
• Lacks hemosiderin and multinucleated giant cells
• Peripheral, thin-walled vessels &/or clefts
• Usually occurs in fingers
• L-TGCT may show diffuse fibrosis mimicking fibroma of
tendon sheath (FTS)
Dermatofibroma
• Rare in digits
• Lacks osteoclast-like giant cells
• L-TGCT can sometimes invade dermis
Plexiform Fibrohistiocytic Tumor
• Often has osteoclast-like giant cells
• Plexiform architecture but can be nodular
• Involves dermis and subcutis
• Rare in acral extremities
280
• Usually children and young adults
SELECTED REFERENCES
1. Ehrenstein V et al: Tenosynovial giant cell tumor: incidence, prevalence,
patient characteristics, and recurrence. a registry-based cohort study in
Denmark. J Rheumatol. 44(10):1476-83, 2017
2. Mastboom MJL et al: Higher incidence rates than previously known in
tenosynovial giant cell tumors. Acta Orthop. 88(6):688-94, 2017
3. Beytemür O et al: Localized giant cell tenosynovial tumor seen in the knee
joint. Case Rep Orthop. 2014:840243, 2014
4. Ding Y et al: Tenosynovial giant cell tumors lacking giant cells: report of
diagnostic pitfalls. Ann Clin Lab Sci. 44(2):222-7, 2014
5. Palmerini E et al: Tenosynovial giant cell tumour/pigmented villonodular
synovitis: outcome of 294 patients before the era of kinase inhibitors. Eur J
Cancer. 51(2):210-7, 2014
6. Panagopoulos I et al: Novel CSF1-S100A10 fusion gene and CSF1 transcript
identified by RNA sequencing in tenosynovial giant cell tumors. Int J Oncol.
44(5):1425-32, 2014
7. Ye JM et al: Tenosynovial giant cell tumour of brachial plexus. J Clin
Neurosci. 21(6):1070-2, 2014
8. Yoshimoto T et al: Hepatoid tenosynovial giant cell tumor - a rare
morphologic variant case report. Pathol Res Pract. 210(10):694-7, 2014
9. Atik E et al: Tenosynovial giant cell tumor in an unusual localization. Acta
Orthop Traumatol Turc. 47(2):139-41, 2013
10. Di Grazia S et al: Giant cell tumor of tendon sheath: study of 64 cases and
review of literature. G Chir. 34(5-6):149-52, 2013
11. Fukuda A et al: Tenosynovial giant cell tumor arising on the scapular region.
Case Rep Dermatol. 5(3):267-71, 2013
12. Lanzinger WD et al: Giant cell tumor of the tendon sheath. J Hand Surg Am.
38(1):154-7; quiz 157, 2013
13. van der Heijden L et al: A multidisciplinary approach to giant cell tumors of
tendon sheath and synovium--a critical appraisal of literature and treatment
proposal. J Surg Oncol. 107(4):433-45, 2013
14. Ho CY et al: Giant cell tumor of tendon sheath: cytomorphologic and
radiologic findings in 41 patients. Diagn Cytopathol. 40 Suppl 2:E94-8, 2012
15. Lucas DR: Tenosynovial giant cell tumor: case report and review. Arch Pathol
Lab Med. 136(8):901-6, 2012
16. Okutan O et al: Tenosynovial giant cell tumor in the cervico-thoracic junction.
Turk Neurosurg. 22(6):769-71, 2012
17. Kim HS et al: Localized tenosynovial giant cell tumor in both knee joints.
Skeletal Radiol. 39(9):923-6, 2010
18. Boland JM 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. 33(8):1225-9, 2009
19. Darwish FM et al: Giant cell tumour of tendon sheath: experience with 52
cases. Singapore Med J. 49(11):879-82, 2008
20. Möller E et al: Molecular identification of COL6A3-CSF1 fusion transcripts in
tenosynovial giant cell tumors. Genes Chromosomes Cancer. 47(1):21-5,
2008
21. Murphey MD et al: Pigmented villonodular synovitis: radiologic-pathologic
correlation. Radiographics. 28(5):1493-518, 2008
22. Cupp JS 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. 31(6):970-6, 2007
23. Dines JS et al: Long-term follow-up of surgically treated localized pigmented
villonodular synovitis of the knee. Arthroscopy. 23(9):930-7, 2007
24. Jafarian F et al: Plexiform fibrohistiocytic tumor in three children. Pediatr
Dermatol. 23(1):7-12, 2006
25. West RB et al: A landscape effect in tenosynovial giant-cell tumor from
activation of CSF1 expression by a translocation in a minority of tumor cells.
Proc Natl Acad Sci U S A. 103(3):690-5, 2006
26. Nilsson M et al: Molecular cytogenetic mapping of recurrent chromosomal
breakpoints in tenosynovial giant cell tumors. Virchows Arch. 441(5):475-80,
2002
27. Reilly KE et al: Recurrent giant cell tumors of the tendon sheath. J Hand Surg
Am. 24(6):1298-302, 1999
28. Enzinger FM et al: Plexiform fibrohistiocytic tumor presenting in children
and young adults. An analysis of 65 cases. Am J Surg Pathol. 12(11):818-26,
1988
29. Ushijima 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 common digit group. Cancer. 57(4):875-84, 1986
30. Chung EB et al: Fibroma of tendon sheath. Cancer. 44(5):1945-54, 1979
 Localized-Type Tenosynovial Giant Cell Tumor
Gross Cut Surface
Medium-Power View Polymorphous Cellular Population
Xanthoma Cells
Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Radiographic Appearance
(Left) L-TGCT is well
circumscribed, encapsulated,
and multinodular. Fibrous
septa ﬈ divide it into nodules.
The cut surface is variegated
with gold, tan, red-brown, and
yellow areas. Bright yellow
areas ﬊ represent xanthoma
cells. (Right) Radiographically,
L-TGCT appears as a soft
tissue density most often on
the volar side of a finger ﬈.
Approximately 10% erode the
bony cortex as shown. Rare
tumors invade medullary
bone, mimicking a primary
bone tumor ﬉, such as this
2nd toe tumor.
(Left) L-TGCT has a mixture of
mononuclear stromal cells,
multinucleated giant cells ﬈,
and macrophages, including
xanthoma cells ﬉. Stromal
fibrosis ﬇ and hemosiderin
deposits ſt are very common.
(Right) This high-power view
depicts large epithelioid cells
with eccentric nuclei ﬈,
(believed to be the neoplastic
element), macrophages with
smaller round to reniform
nuclei ﬉, and osteoclast-like
giant cells ﬊.
Hemosiderin Deposition
(Left) Sheets and clusters of
xanthoma cells are very
common in L-TGCT. Xanthoma
cells (foamy macrophages)
have copious, finely
vacuolated cytoplasm and
small, central nuclei as
depicted ﬈. Hemosiderin-
laden macrophages ﬉ are
also common. (Right) Some
tumors have very extensive
hemosiderin deposition, as
depicted ﬈.
281
Fibrohistiocytic, Histiocytic, and Dendritic Cell Localized-Type Tenosynovial Giant Cell Tumor
Tumors

Osteoid-Like Fibrosis Stromal Fibrosis

(Left) Stromal fibrosis is
usually present in L-TGCT but
highly variable in its extent. In
some tumors, fibrosis consists
of lace-like, hyalinized
collagen that resembles
osteoid ﬈. (Right)
Occasionally, fibrosis can be
very extensive, affecting large
areas of a tumor. This low-
power micrograph shows
diffuse stromal fibrosis that
entraps both mononuclear
stromal cells and
multinucleated giant cells ﬈.

Localized-Type Tenosynovial Giant Cell

Pseudoglandular Pattern Tumor Without Giant Cells
(Left) Areas of cellular
dyscohesion are not
uncommon in L-TGCT. In some
tumors, it can be so
pronounced as to form cystic
spaces ﬈, creating a
pseudoglandular pattern.
(Right) Occasionally, L-TGCT
can have very few giant cells
as in this example, which
consists of a uniform
population of mononuclear
stromal cells with round
nuclei.

Epithelioid Cells Clusterin Immunostain

(Left) Some L-TGCTs contain
sheets of large epithelioid cells
with abundant eosinophilic
cytoplasm and eccentric
vesicular nuclei. Note the
intracytoplasmic hemosiderin
deposits ﬈. (Right) The large
epithelioid cells are positive
for clusterin ﬈, indicating
synoviocytic differentiation.
By contrast, infiltrating
macrophages and giant cells
﬉ are negative.

282
 Localized-Type Tenosynovial Giant Cell Tumor
Brisk Mitotic Activity
Skin Involvement
Intraarticular Localized-Type Tenosynovial
Giant Cell Tumor (Localized PVNS)
Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Giant Cells
(Left) Mitotic activity ranges
from 1-20 mitoses per 10 HPF
(average 5 per 10 HPF). Brisk
mitotic activity, therefore, is
not uncommon in these
lesions, as evidenced by 2
mitotic figures in this single
high-power field ﬈. (Right)
Although osteoclast-like
multinucleated giant cells are
most common, occasionally, L-
TGCT can have Touton-like
(left) or Langhans-type (right)
giant cells.
Skin Involvement
(Left) In a distal acral location,
L-TGCT can adhere to and
invade the overlying skin, as
depicted ſt by this tumor of
the middle finger. (Right) In
this example of L-TGCT, the
tumor invades the dermis,
mimicking a dermatofibroma.
Unlike L-TGCT, however,
dermatofibroma does not
contain osteoclast-like giant
cells ﬈.
Intraarticular Localized-Type Tenosynovial
Giant Cell Tumor (Localized PVNS)
(Left) Localized intraarticular
TGCT [or localized pigmented
villonodular synovitis (PVNS)]
forms a well-demarcated
tumor within the joint space.
The knee is the most common
site, as depicted in this MR ﬈.
(Right) Grossly, intraarticular
tumors are well circumscribed
and form pedunculated or
sessile polypoid masses
attached to the synovial
surface by a stalk ſt (inverted
here). Unlike diffuse-type
TGCT, localized intraarticular
tumors rarely recur following
complete excision and have an
excellent prognosis.
283
 Diffuse-Type Tenosynovial Giant Cell Tumor

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY MACROSCOPIC
• Diffuse-type tenosynovial giant cell tumor (D-TGCT) • Most of synovial surface affected
• Synonym: Pigmented villonodular synovitis (PVNS) • Villous, nodular, or villonodular
• Generally benign, locally aggressive neoplastic proliferation • Large, usually > 5 cm
of synovial origin
MICROSCOPIC
○ Intra- or extraarticular
• Thin, delicate villi and broad papillary structures
ETIOLOGY/PATHOGENESIS • Solid cellular areas with multinodular architecture
• Balanced translocation involving 1p13 (CSF1) • Heterogeneous cell population
CLINICAL ISSUES ○ Large epithelioid cells
○ Osteoclastic giant cells
• Average age: 35 years; range: 1st-7th decades
○ Macrophages/xanthoma cells
• Knee (75-80%)
• Hemosiderin, fibrosis
• High recurrence rate (15-55%)
TOP DIFFERENTIAL DIAGNOSES
IMAGING
• Localized tenosynovial giant cell tumor
• Low signal on T1 and T2, enhancement with contrast
• Hemarthrosis
• MR signal voids secondary to hemosiderin
• Chondroblastoma of craniofacial bones
• Giant cell tumor of soft tissue

Diffuse-Type Tenosynovial Giant Cell

Tumor Villonodular Architecture
(Left) D-TGCT typically has a
mix of large eosinophilic cells
with eccentric vesicular nuclei
﬈, smaller stromal cells and
macrophages with oval to
reniform nuclei ﬉, and
osteoclast-like giant cells ﬊.
Note the presence of stromal
hemorrhage and hemosiderin
deposits ſt. (Right) D-TGCT
has a villonodular architecture
composed of elongated villi
﬈, solid cellular areas ﬇
containing a heterogeneous
population of mononuclear
stromal cells and
multinucleated giant cells, and
hemosiderin deposits ﬉.

Gross Appearance MR of Knee Tumor

(Left) D-TGCT (or pigmented
villonodular synovitis) usually
presents as a large,
intraarticular mass. 75-80%
occur in the knee. It diffusely
covers most of the synovial
surface, has a villonodular
appearance, and is red-brown.
(Right) Sagittal T1 MR of the
knee depicts an advanced,
locally destructive D-TGCT
forming a large mass involving
both anterior and posterior
synovium ﬈, which erodes
into the distal femur and
proximal tibia ﬊. On MR, D-
TGCT shows low signal on T1
and T2 and enhances with
contrast.

284
 Diffuse-Type Tenosynovial Giant Cell Tumor

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
○ Tyrosine kinase inhibitors (e.g., CSFR1 inhibitor or
TERMINOLOGY imatinib) for relapsing or uncontrolled tumors
Abbreviations • Radiation
• Diffuse-type tenosynovial giant cell tumor (D-TGCT) ○ May improve local control
Synonyms Prognosis
• Pigmented villonodular synovitis (PVNS) • Locally aggressive
• Diffuse-type giant cell tumor ○ High recurrence rate (15-55%)
• Giant cell tumor of tendon sheath, diffuse type ○ Multiple relapses common
○ Very rare tumors progress to malignancy
Definitions
– Often radiation associated
• Generally benign but locally aggressive neoplastic ○ Very rare histologically benign tumors metastasize
proliferation of synovial origin
○ Intraarticular tumors within large joints IMAGING
○ Extraarticular invasive tumors of tendon sheath, bursa,
or soft tissue origin General Features
• Ill-defined periarticular soft tissue mass
ETIOLOGY/PATHOGENESIS • Bone erosions
Neoplastic Proliferation • Subchondral cysts

• Balanced translocation involving 1p13 (CSF1) in most MR Findings

tumors • Low signal on T1 and T2
○ Most often fused with 2q35 (COL6A3), promoter • Enhancement with contrast
○ Overexpression of CSF1 by neoplastic cells • MR signal voids secondary to hemosiderin ("blooming")
○ Autocrine activation via CSFR1
○ Paracrine inflammatory cell recruitment and activation MACROSCOPIC
via CSFR1
General Features
• Trisomy 5 or 7 in some tumors
• Diffusely covers most of synovial surface
CLINICAL ISSUES • Villous, nodular, or villonodular
○ Heterogeneous synovial projections
Epidemiology – Thin villi, thick papillae, nodules
• Incidence • Firm to sponge-like
○ Rare, annual incidence 4-8 patients/1 million • Variegated cut surface
• Age ○ Red-brown, tan, yellow
○ Wide range (1st-7th decades) • Poorly demarcated from adjacent soft tissue
– Average: 35 years • Extraarticular tumors form multinodular masses
• Sex
○ Women slightly outnumber men
Size
• Large, usually > 5 cm
Site
• Intraarticular MICROSCOPIC
○ Knee (75-80%)
Histologic Features
○ Hip (15%)
○ Ankle, elbow, shoulder, temporal mandibular joint, spine • Elongated villi
• Extraarticular ○ Vary from thin, delicate villi to broad papillary structures
○ Knee region most common ○ Lined by 1 to few layers of synoviocytes
○ Foot, wrist, inguina, elbow region, digits • Solid cellular areas
○ Multinodular architecture
Presentation ○ Fibrous septa surround nodules
• Painful mass ○ Stromal fibrosis
• Long duration of symptoms (years) – Varies from minimal to extensive
• Hemorrhagic joint effusion – Irregular, hyalinized collagen mimics osteoid
• Decreased range of motion ○ Hemosiderin deposits usually abundant
Treatment Cytologic Features
• Surgical approaches • Heterogeneous cell population
○ Wide local excision ○ Large epithelioid cells
○ Total synovectomy – Abundant eosinophilic cytoplasm
○ Prosthetic joint replacement □ Often contain hemosiderin pigment
○ Amputation in advanced cases – Vesicular, round to oval, eccentric nuclei with
• Drugs prominent nucleoli

285
Fibrohistiocytic, Histiocytic, and Dendritic Cell Diffuse-Type Tenosynovial Giant Cell Tumor
Tumors
○ Macrophages with smaller, oval or reniform nuclei
– Xanthoma cells
– Hemosiderin-laden macrophages
○ Osteoclast-like giant cells
– Usually abundant
○ Synoviocytes line villi and cleft-like spaces
• Frequent mitotic figures
• Homogenous mononuclear cell population in some tumors
○ Large areas may be devoid of giant cells
Diffuse-Type Tenosynovial Giant Cell Tumor of
Temporal Mandibular Joint
• Distinctive microscopic features
• Sheets of large epithelioid cells
• Chondroid metaplasia
• Can invade temporal bone
• May be mistaken for chondroblastoma of craniofacial
bones
ANCILLARY TESTS
Immunohistochemistry
• Large epithelioid cells clusterin (+)
○ Indicates synovial differentiation
• Often desmin (+)
○ Usually patchy but sometimes diffuse
• Macrophages CD163(+)
• Osteoclastic giant cell CD68(+), CD45(+), TRAP(+)
• G34W mutated site of histone H3.3 (-)
○ Giant cell tumor of bone (+)
DIFFERENTIAL DIAGNOSIS
Localized Tenosynovial Giant Cell Tumor
• Well circumscribed and encapsulated
• Lacks villi
• Otherwise identical microscopic features
• Localized to digits (85%)
• Intraarticular tumors (usually knee)
○ Localized PVNS
Hemarthrosis
• Villiform synovial hyperplasia with hemosiderosis
• Lacks solid cellular areas
• History of repetitive hemarthrosis
○ Trauma or hemophilia
Malignant Tenosynovial Giant Cell Tumor
• Malignant cytoarchitectural features
○ Pleomorphic spindle cells
○ Epithelioid cells with prominent nucleoli
○ High mitotic rate and necrosis
○ Often with past history of radiation therapy
Chondroblastoma
• D-TGCT of temporal mandibular joint can invade temporal
bone mimicking primary bone tumor
○ Large epithelioid cells
○ Zones of chondroid matrix
○ Dystrophic chicken-wire calcification
○ Closely resembles chondroblastoma of craniofacial
bones
286
– Many reported cases of chondroblastoma in temporal
bone probably represent D-TGCT with chondroid
metaplasia
Giant Cell Tumor of Soft Tissue
• Identical histology to giant cell tumor of bone
○ Uniform mononuclear stromal cells
○ Numerous evenly distributed giant cells
○ Metaplastic bone may be present
• Less heterogeneous cell population
• Less stromal fibrosis
SELECTED REFERENCES
1. Ehrenstein V et al: Tenosynovial giant cell tumor: incidence, prevalence,
patient characteristics, and recurrence. a registry-based cohort study in
Denmark. J Rheumatol. 44(10):1476-83, 2017
2. Lüke J et al: H3F3A mutation in giant cell tumour of the bone is detected by
immunohistochemistry using a monoclonal antibody against the G34W
mutated site of the histone H3.3 variant. Histopathology. 71(1):125-33, 2017
3. Mastboom MJL et al: Higher incidence rates than previously known in
tenosynovial giant cell tumors. Acta Orthop. 88(6):688-94, 2017
4. Staals EL et al: Diffuse-type tenosynovial giant cell tumour: current
treatment concepts and future perspectives. Eur J Cancer. 63:34-40, 2016
5. Righi A et al: Metastasizing tenosynovial giant cell tumour, diffuse
type/pigmented villonodular synovitis. Clin Sarcoma Res. 5:15, 2015
6. Asano N et al: Multiple metastases from histologically benign intraarticular
diffuse-type tenosynovial giant cell tumor: a case report. Hum Pathol.
45(11):2355-8, 2014
7. Ding Y et al: Tenosynovial giant cell tumors lacking giant cells: report of
diagnostic pitfalls. Ann Clin Lab Sci. 44(2):222-7, 2014
8. Pina S et al: Recurrent temporal bone tenosynovial giant cell tumor with
chondroid metaplasia: the use of imaging to assess recurrence. Neuroradiol
J. 27(1):97-101, 2014
9. Wang K et al: Primary diffuse-type tenosynovial giant cell tumor of the spine:
a report of 3 cases and systemic review of the literature. Turk Neurosurg.
24(5):804-13, 2014
10. Yoshimoto T et al: Hepatoid tenosynovial giant cell tumor - a rare
morphologic variant case report. Pathol Res Pract. 210(10):694-7, 2014
11. Fisher M et al: Chondroid tenosynovial giant cell tumor of the temporal
bone. Otol Neurotol. 34(6):e49-50, 2013
12. Lucas DR: Tenosynovial giant cell tumor: case report and review. Arch Pathol
Lab Med. 136(8):901-6, 2012
13. van der Heijden L et al: The management of diffuse-type giant cell tumour
(pigmented villonodular synovitis) and giant cell tumour of tendon sheath
(nodular tenosynovitis). J Bone Joint Surg Br. 94(7):882-8, 2012
14. Hoch BL et al: Chondroid tenosynovial giant cell tumor: a clinicopathological
and immunohistochemical analysis of 5 new cases. Int J Surg Pathol.
19(2):180-7, 2011
15. Yoon HJ et al: Malignant pigmented villonodular synovitis of the
temporomandibular joint with lung metastasis: a case report and review of
the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 111(5):e30-
6, 2011
16. Boland JM 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. 33(8):1225-9, 2009
17. Blay JY et al: Complete response to imatinib in relapsing pigmented
villonodular synovitis/tenosynovial giant cell tumor (PVNS/TGCT). Ann Oncol.
19(4):821-2, 2008
18. Oda Y et al: Pigmented villonodular synovitis with chondroid metaplasia,
resembling chondroblastoma of the bone: a report of three cases. Mod
Pathol. 20(5):545-51, 2007
19. West RB et al: A landscape effect in tenosynovial giant-cell tumor from
activation of CSF1 expression by a translocation in a minority of tumor cells.
Proc Natl Acad Sci U S A. 103(3):690-5, 2006
20. Nilsson M et al: Molecular cytogenetic mapping of recurrent chromosomal
breakpoints in tenosynovial giant cell tumors. Virchows Arch. 441(5):475-80,
2002
21. Bertoni F et al: Malignant giant cell tumor of the tendon sheaths and joints
(malignant pigmented villonodular synovitis). Am J Surg Pathol 21(2):153-63,
1997
22. Fletcher JA et al: Trisomy 5 and trisomy 7 are nonrandom aberrations in
pigmented villonodular synovitis: confirmation of trisomy 7 in uncultured
cells. Genes Chromosomes Cancer. 4(3):264-6, 1992
23. Bertoni F et al: Chondroblastoma of the skull and facial bones. Am J Clin
Pathol. 88(1):1-9, 1987
 Diffuse-Type Tenosynovial Giant Cell Tumor

Villous Architecture
Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Nodular Architecture
(Left) Intraarticular D-TGCT
(pigmented villonodular
synovitis) forms long villous
processes that extend into the
joint space. They vary from
thin and delicate ﬈ to broad
﬉ and are lined by plump
synoviocytes ﬊. Hemosiderin
is often abundant in the villi
﬈. (Right) In the solid areas,
D-TGCT has a multinodular
architecture composed of
cellular areas ﬊ separated by
fibrous septa ﬉. Giant cells
ſt and zones of stromal
fibrosis ﬇ are also seen.

Slit-Like Clefts Gross Appearance

(Left) Slit-like, clefted areas
lined by synoviocytes are
common in D-TGCT. This
micrograph depicts linear clear
spaces ﬈ rimmed by plump
synoviocytes with abundant
eosinophilic cytoplasm and
rounded nuclei ﬉. (Right) D-
TGCT broadly involves the
synovial membrane and has a
very distinctive gross
appearance consisting of
villiform papillary fronds that
extend into the joint cavity. It
is usually red-brown,
secondary to congestion and
hemosiderosis.

Gross Appearance Erosion of Bone and Cartilage

(Left) This close-up
photograph depicts long,
delicate villi ﬈ emanating
from a broad papillary stalk
﬊ resembling a sea anemone.
The yellow coloration ﬉ is
due to sheets of xanthoma
cells. (Right) Intraoperative
postsynovectomy photographs
from 2 patients with D-TGCT
of the knee illustrate multiple
surface bone erosions ſt and
penetration of the articular
cartilage ﬈.

287
Fibrohistiocytic, Histiocytic, and Dendritic Cell Diffuse-Type Tenosynovial Giant Cell Tumor
Tumors

Epithelioid Cells and Macrophages Dyscohesive Pattern

(Left) This micrograph depicts
a mix of large epithelioid cells
(many with hemosiderin-laden
cytoplasm) ﬈ and smaller
mononuclear inflammatory
cells ﬉. Inflammatory cells
are recruited into the milieu by
CSF1, a potent inflammatory
cytokine, produced by the
neoplastic cells. (Right) In
areas, the cells become
dyscohesive and form irregular
cystic spaces ﬈, creating a
pseudoalveolar pattern, a
common finding in D-TGCT.

Diffuse-Type Tenosynovial Giant Cell

Tumor Without Giant Cells Osteoid-Like Fibrosis
(Left) Large zones containing
uniform, mononuclear cells
with few or no giant cells may
be present. This H&E depicts a
monotonous population of
histiocytoid stromal cells with
uniform, round to oval nuclei
and abundant eosinophilic
cytoplasm. (Right) Stromal
fibrosis and hyalinization are
common in D-TGCT. Hyalinized
collagen can form irregular
branching structures that
mimic an osteoid ſt.
Numerous osteoclast-like
giant cells are present ﬈,
further adding to this mimicry.

Xanthoma Cells and Hemosiderin Pigment Clusterin

(Left) Clusters of xanthoma
cells (foamy macrophages) ﬈
are common. They have
abundant, vacuolated, lipid-
filled cytoplasm, which
imparts a yellow color to the
gross tissue. Hemosiderin
deposits secondary to remote
hemorrhage are common and
can be abundant as illustrated
﬈. (Right) The large
epithelioid cells in D-TGCT are
positive for clusterin ﬈,
indicative of synovial
differentiation. By contrast,
the osteoclast-like giant cells
﬉ and macrophages are
negative.

288
 Diffuse-Type Tenosynovial Giant Cell Tumor
Extraarticular Diffuse-Type Tenosynovial
Giant Cell Tumor
Temporal Mandibular Joint Tumor
Chondroid Metaplasia
Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Invasive Growth in Extraarticular Tumor
(Left) Extraarticular D-TGCT
presents as an invasive soft
tissue tumor arising from a
tendon sheath, bursa, or soft
tissue. This T1-weighted MR
depicts a low-signal mass that
diffusely infiltrates between
metatarsals to involve both
deep and superficial
compartments of the foot ﬈.
(Right) Unlike localized-type
TCGT, which is usually encased
by a pseudocapsule, D-TGCT
invades adjacent tissues as
illustrated by infiltration and
entrapment of adipose tissue.
Epithelioid Cells in Temporal Mandibular
Joint Tumor
(Left) D-TGCT can arise in the
temporal mandibular joint
(TMJ) as depicted in this TI MR
of recurrent tumor ﬈. In this
location, it may invade into
the temporal bone to mimic a
primary bone tumor. (Right)
TMJ tumors have distinctive
histologic features
characterized by sheets of
large epithelioid cells with
abundant eosinophilic
cytoplasm, eccentric nuclei,
and hemosiderin pigmentation
﬈. Note the single osteoclast-
like giant cell ﬉.
Malignant Tenosynovial Giant Cell Tumor
(Left) Chondroid metaplasia is
uncommon in D-TGCT but is
more likely in TMJ tumors. It is
characterized by geographic
areas of pale blue hyaline
matrix ﬈. Areas of dystrophic
calcification can impart a
chicken-wire pattern ﬉
mimicking a chondroblastoma.
(Right) Malignant
transformation of TCGT is a
rare event that usually follows
multiple recurrences. Many
cases had prior radiotherapy.
Most are high-grade
undifferentiated sarcomas,
often having sheets of
malignant epithelioid cells
with prominent nucleoli ﬈.
289
 Cellular Neurothekeoma

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY
• Rare dermal tumor of uncertain histogenesis composed of
epithelioid cells in multiple nests divided by fibrous septa
• Unrelated to dermal nerve sheath myxoma (conventional
neurothekeoma)
CLINICAL ISSUES
• Children and young adults (mean age: 25 years)
• Head/neck and upper extremity (mostly on face and
shoulder)
• Benign (even if atypical histologic features)
MICROSCOPIC
• Epithelioid to spindled cells with abundant pale eosinophilic
cytoplasm arranged in nests divided by dense fibrous septa
• Myxoid change common (30%)
• Multinucleated giant cells (osteoclastic or Touton)
• Nuclear atypia/pleomorphism in 25%
• Mitotic activity common (mean: 3/10 HPF; range: 0-22)
○ Subset have brisk mitotic activity (> 5/10 HPF in 20%; >
10/10 HPF in 5%)
○ Atypical mitotic figures may be seen
ANCILLARY TESTS
• Negative for S100 protein and SOX10
○ Most important IHC; essentially excludes melanocytic
• Often positive for variety of nonspecific markers, including
CD63 (NKI/C3), NSE, PGP9.5
○ No specific positive IHC marker
TOP DIFFERENTIAL DIAGNOSES
• Spitz nevus or spitzoid melanoma
• Dermal nerve sheath myxoma (conventional
neurothekeoma)
• Plexiform fibrohistiocytic tumor
• Epithelioid fibrous histiocytoma
• Benign cutaneous biphasic (or plexiform) hybrid tumor of
perineurioma and cellular neurothekeoma

Cellular Neurothekeoma Nests and Aggregates of Tumor Cells

(Left) Cellular neurothekeoma
is a benign tumor of uncertain
histogenesis that typically
presents as a multilobular
tumor ﬈ centered in the
dermis. (Right) Cellular
neurothekeoma is generally
characterized by multiple
nests or aggregates of
histiocytoid tumor cells
divided by intervening fibrous
bands.

Bland Histiocytoid Cells Atypia and Mitotic Activity

(Left) Nests are composed of
histiocytoid cells with
abundant pale cytoplasm and
uniform round nuclei. (Right)
Nuclear atypia ﬉ or
pleomorphism is seen in 25%
of cellular neurothekeoma and
does not indicate aggressive
behavior. Mitotic activity ﬈ is
common and may be brisk.

290
 Cellular Neurothekeoma
TERMINOLOGY
Definitions
• Rare dermal tumor of uncertain histogenesis composed of
epithelioid cells in multiple nests divided by fibrous septa
• Unrelated to dermal nerve sheath myxoma (conventional
neurothekeoma)
CLINICAL ISSUES
Site
• Head/neck and upper extremity (mostly on face and
shoulder)
Presentation
• Children & young adults (mean: 25 years; most < 40 years)
• Painless solitary skin nodule, often present > 1 year
○ Rarely agminated (cluster of multiple lesions in 1 site)
○ Rarely may occur in oral cavity
Treatment
• Simple but complete excision
Prognosis
• Benign (even if atypical histologic features)
• Small subset recur, especially if incompletely excised
MACROSCOPIC
General Features
• Rounded or dome-shaped skin lesion, usually < 2 cm
MICROSCOPIC
Histologic Features
• Micronodular or lobulated dermal tumor
○ No epidermal involvement
○ Usually has infiltrative borders
○ 50% also involve subcutis
• Epithelioid to spindled cells with abundant pale eosinophilic
cytoplasm, arranged in nests divided by dense fibrous septa
• May have plexiform, desmoplastic, or focally sheet-like
growth patterns
• Myxoid change common (30%)
○ Spindling more prominent in myxoid areas; may
resemble pattern of dermal nerve sheath myxoma
(conventional neurothekeoma)
• Multinucleated giant cells (osteoclastic or Touton) in some
• Nuclear atypia/pleomorphism in 25%
○ Atypical multinucleated tumor giant cells may be seen
• Mitotic activity common (mean: 3 mitoses/10 HPF; range: 0-
22 mitoses)
○ Subset have brisk mitotic activity (> 5/10 HPF in 20%; >
10/10 HPF in 5%)
○ Atypical mitotic figures may be seen
• Lymphovascular or perineural invasion rarely
• Necrosis rarely
ANCILLARY TESTS
Immunohistochemistry
• Negative for S100 protein and SOX10
○ Most important IHC; essentially excludes melanocytic
Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
• Positive for variety of relatively nonspecific markers
○ CD63 (NKI/C3), NSE, MITF, PGP9.5 (most cases)
○ SMA, p63 (~ 1/2 of cases)
○ Lack of specificity limits utility of these stains
• No specific positive IHC marker
• Also negative: MART-1, HMB-45, desmin, keratin
DIFFERENTIAL DIAGNOSIS
Spitz Nevus or Spitzoid Melanoma
• Small skin nodule, sometimes nonpigmented, on face or
extremity of young patients
• Nests of epithelioid to spindled cells with abundant
eosinophilic cytoplasm
• Often have intraepidermal component
• Cellular neurothekeoma should always be in differential of
intradermal atypical spitzoid lesion, especially on face of
child or young adult
○ Atypical spitzoid lesions often treated with wider
excision ± sentinel lymph node biopsy; sometimes
behave aggressively
• S100 protein, SOX10, MART-1, and HMB-45 (+) in Spitzoid
lesions; negative in cellular neurothekeoma
Dermal Nerve Sheath Myxoma (Conventional
Neurothekeoma)
• Skin nodule of middle-aged adults
• Usually on distal extremities (especially fingers)
• Circumscribed, multilobulated dermal tumor
• Hypocellular myxoid nodules with strands of spindle cells
• Nodules divided by fibrous septa
• S100 protein and SOX10 (+) (100%)
Plexiform Fibrohistiocytic Tumor
• Skin nodule on extremities of children and young adults
• Plexiform pattern of multiple small nodules infiltrating
deep dermis and subcutis
• Nodules composed of round histiocytoid cells ±
multinucleated giant cells
○ Similar to nested pattern of cellular neurothekeoma
• Usually has fascicles of spindled fibroblasts
• Usually lacks dense collagen septa
Epithelioid Fibrous Histiocytoma
• Often polypoid nodule with epidermal collarette
• Epithelioid histiocytoid cells arranged in sheets (not nests)
• ALK-1(+) in majority
Benign Cutaneous Biphasic (or Plexiform) Hybrid
Tumor of Perineurioma and Cellular Neurothekeoma
• Usually perioral
• Biphasic (often plexiform) admixture of cellular
neurothekeoma and perineurioma components
• Perineurioma component has whorls of bland spindle cells
• Often EMA(+), claudin-1 (+), GLUT1(+)
SELECTED REFERENCES
1. Fried I et al: SOX-10 and MiTF expression in cellular and 'mixed'
neurothekeoma. J Cutan Pathol. 41(8):640-5, 2014
2. Stratton J et al: Cellular neurothekeoma: analysis of 37 cases emphasizing
atypical histologic features. Mod Pathol. 27(5):701-10, 2014
3. Hornick JL et al: Cellular neurothekeoma: detailed characterization in a series
of 133 cases. Am J Surg Pathol. 31(3):329-40, 2007
291
Fibrohistiocytic, Histiocytic, and Dendritic Cell Cellular Neurothekeoma
Tumors

Dome-Shaped Nodule Nested Growth

(Left) Nests of tumor cells fill
the dermis, forming a dome-
shaped nodule in this low-
power H&E of cellular
neurothekeoma. (Right) Nests
of histiocytoid cells are
separated by thin fibrous
septa. The cells have uniform
nuclei, a moderate amount of
cytoplasm, and indistinct cell
margins in this case.

Myxoid Change Mimicking Nerve Sheath Myxoma

(Left) Myxoid change is
present in 30% of cellular
neurothekeoma and may be
prominent, as seen here.
(Right) Areas of myxoid
change in cellular
neurothekeoma may be
arranged into myxoid nodules
with intervening fibrous septa,
an appearance very similar to
that of dermal nerve sheath
myxoma (conventional
neurothekeoma), an unrelated
entity.

Myxoid and Nonmyxoid Zones Multinucleated Tumor Giant Cells

(Left) Nests of typical
nonmyxoid cellular
neurothekeoma ﬈ transition
to myxoid spindled zones
resembling nerve sheath
myxoma ﬊ in the depicted
case. (Right) Atypical
multinucleated tumor giant
cells ﬈ may be present in
cellular neurothekeoma. This
is a benign finding not
indicative of aggressive
behavior. Classic Touton or
osteoclastic giant cells may
also be seen.

292
 Cellular Neurothekeoma

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Mitotic Activity Nests of Atypical Cells
(Left) Nuclei are oval/round
and usually have fine, powdery
or pale chromatin. Mitotic
activity ﬈ is common in
cellular neurothekeoma and
may be brisk (≥ 10 figures/10
HPF). (Right) This H&E shows a
case of cellular
neurothekeoma with typical
nests of tumor cells but with
the additional feature of
cellular atypia.

Pleomorphism Subcutaneous Involvement

(Left) Nuclear pleomorphism is
a relatively common finding in
cellular neurothekeoma; it not
does not indicate malignancy
or aggressive behavior. (Right)
Subcutaneous involvement ﬈
is present in 50% of cases of
cellular neurothekeoma. Note
the focal, small, discrete nests
﬉ of tumor cells in the
overlying dermis.

Sheet-Like Growth Spindle Cell Areas

(Left) Areas of cellular sheet-
like growth without nesting
may be seen in occasional
cases of cellular
neurothekeoma, as depicted.
More conventional nested or
nodular areas are typically
seen elsewhere. (Right) Sheets
or fascicles of more spindled
tumor cells are occasionally
encountered in cellular
neurothekeoma.

293
 Xanthomas

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY • Treatment: Medical therapy or conservative excision

• Reactive, mass-forming collection of lipidized macrophages,
usually resulting from altered serum lipid levels
• Several forms
○ Xanthelasma, eruptive, tuberous, tendinous, plane,
plexiform
ETIOLOGY/PATHOGENESIS
• Associated with hereditary lipoproteinemias and
occasionally secondary lipoproteinemias
• May also occur in normolipemic patients
○ Particularly plexiform xanthoma
CLINICAL ISSUES
• Wide age range (children or adults)
• Usually occur in skin and subcutaneous tissue
• Occasionally arise in deep soft tissues (tendon, synovium,
bone)
• Classified based on clinical features and gross appearance
• Excellent prognosis
MICROSCOPIC
• Specific classification requires clinicopathologic correlation
• Sheets and aggregates of foamy macrophages
• Variable secondary changes, including inflammation, giant
cells, fibrosis, and cholesterol cleft formation
• Plexiform xanthoma features multinodular or plexiform
growth pattern
TOP DIFFERENTIAL DIAGNOSES
• Localized-type tenosynovial giant cell tumor (giant cell
tumor of tendon sheath)
• Solitary (juvenile) xanthogranuloma
• Lipidized-type dermatofibroma (fibrous histiocytoma)
• Verruciform xanthoma
• Plexiform fibrohistiocytic tumor

Xanthelasma Eruptive Xanthoma

(Left) Xanthelasmas (and
plane xanthomas) consist of a
sheet-like infiltrate of foamy
macrophages involving the
dermis and surrounding
adnexal structures. Small
areas of chronic inflammation
﬉ may be present, but fibrosis
and cholesterol clefts are not
typical. (Right) Eruptive
xanthoma is characterized by
sheets of macrophages within
the dermis. Extravascular lipid
deposits with a blue-gray,
amorphous appearance are
often seen ﬉ between dermal
collagen bundles. A sparse
perivascular inflammatory
infiltrate ﬈ can also be seen.

Early Eruptive Xanthoma Older Eruptive Xanthoma

(Left) In contrast to other
forms of xanthoma, the cells in
eruptive xanthoma are
nonfoamy in early lesions.
Note the rare foamy
macrophages ﬈ and
extravascular lipid ﬉. (Right)
Older eruptive xanthomas
accumulate more foamy
macrophages ﬈ and consist
of a mixture of foamy and
nonfoamy cells. Again, note
areas of lace-like, blue-gray
extravascular lipid between
the dermal collagen bundles
﬉.

294
 Xanthomas

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
□ Particularly extensor surfaces of elbow and knee
TERMINOLOGY regions
Synonyms – Usually in males
• Plexiform xanthomatous tumor (for plexiform xanthoma) – Patients usually normolipemic
○ Cerebrotendinous xanthomatosis
Definitions
– Rare autosomal recessive disease; sterol 27-
• Reactive, mass-forming collection of lipidized macrophages, hydroxylase gene (CYP27A1) mutation
usually resulting from altered serum lipid levels – Enzyme involved in bile acid synthesis; defect results
○ Several forms in accumulation of cholestanol, which is deposited
– Xanthelasma systemically
– Eruptive xanthoma – Bilateral Achilles tendon xanthomas and cataracts;
– Tuberous xanthoma CNS symptoms include ataxia, dementia, dysarthria,
– Tendinous xanthoma psychiatric disturbances, and seizures
– Planar xanthoma
Treatment
– Plexiform xanthoma
• May regress with medical therapy for hyperlipidemia or
ETIOLOGY/PATHOGENESIS underlying cause if secondary
• Conservative excision can be employed for large or
Hereditary or Nonhereditary symptomatic lesions
• Associated with hereditary lipoproteinemias and
Prognosis
occasionally secondary lipoproteinemias (e.g., diabetes,
hypothyroidism, primary biliary cirrhosis) • Excellent prognosis
• May also occur in normolipemic patients • Surgically treated lesions may recur
○ Particularly plexiform xanthoma
MACROSCOPIC
CLINICAL ISSUES General Features
Epidemiology • Diffuse or circumscribed
• Age ○ Plexiform xanthoma may appear grossly multinodular
○ Wide age range (children or adults) • Variegated yellow, tan, and white appearance

Presentation Size
• Usually occur in skin and subcutaneous tissue • Generally few mm to several cm depending on type
• Occasionally arise in deep soft tissues (tendon, synovium, • Tendinous xanthomas can be quite large (up to 20 cm)
bone)
• Classified based on clinical features MICROSCOPIC
○ Xanthelasma Histologic Features
– Soft, yellow plaques • Specific classification requires clinicopathologic correlation
– Predilection for eyelids and periorbital skin; often • Xanthelasma and planar xanthoma
bilateral ○ Sheets of foamy macrophages
○ Eruptive xanthoma • Eruptive xanthomas
– Sudden onset of small, yellow papules with ○ Sheets of mostly nonfoamy macrophages with some
erythematous halo foamy macrophages
– Predilection for gluteal region, thigh, and shoulders ○ Later lesions contain more foamy macrophages
○ Tuberous xanthoma • Tuberous and tendinous xanthoma
– Firm, yellow, subcutaneous nodules and plaques ○ Nodules of foamy macrophages
– Predilection for elbow, knee, gluteal region, and ○ Chronic inflammation, fibrosis, and cholesterol clefts
fingers with giant cells common
○ Tendinous xanthoma • Plexiform xanthoma
– Soft tissue mass associated with tendons, ligaments, ○ Multinodular or plexiform growth of nodules of foamy
&/or fascia; predilection for hands, feet, and Achilles histiocytes separated by fibrous or sclerotic stroma
tendon
○ Giant cells
– May impair joint function but often asymptomatic
○ Variable chronic inflammation, fibrosis, and cholesterol
○ Planar xanthoma clefts
– Variably sized yellow macules; predilection for palmar
creases ANCILLARY TESTS
– In normolipemic patients, consider underlying
reticuloendothelial malignancy Immunohistochemistry
○ Plexiform xanthoma • CD68(+), CD163(+)
– Dermal-based cutaneous nodule(s) occurring most • S100 protein (-)
often on extremities

295
Fibrohistiocytic, Histiocytic, and Dendritic Cell Xanthomas
Tumors

Clinical Forms of Xanthoma

Feature Xanthelasma Eruptive Tuberous Tendinous Plane Plexiform
Lipoprotein association None or IIa, III I, III, V, secondary IIa, III, secondary IIa, secondary None, III, Usually none
secondary
Characteristic location Eyelids Buttock Elbow, knee, Hand, foot, ankle Palm creases Elbow, knee,
buttock, finger (Achilles) foot/hand
Foamy macrophages Present Present (absent in Present Present Present Present
early lesions)
Characteristic Foamy Foamy and Foamy Foamy Foamy Plexiform nodules of
histopathology macrophages nonfoamy macrophages, macrophages, macrophages foamy macrophages;
macrophages cholesterol clefts, cholesterol clefts, giant cells
giant cells, giant cells,
inflammation, inflammation,
fibrosis fibrosis

Hyperlipoproteinemia (Fredrickson) Classification

Feature I IIa IIb III IV V
Elevated lipoprotein Chylomicrons LDL LDL, VLDL Chylomicrons, VLDL Chylomicrons, VLDL
VLDL remnants
Molecular defect Lipoprotein lipase, LDL receptor, Unknown ApoE Unknown Unknown
apoC-II apoB-100

• Cellular nodules of spindled Schwann cells

DIFFERENTIAL DIAGNOSIS
• Nuclear palisading common
Localize-Type Tenosynovial Giant Cell Tumor • Foamy histiocytes may be present but are not usually
• Synonym: Giant cell tumor of tendon sheath prominent
• Vast majority arise in digits • S100(+)
• Usually solitary; resembles tendinous xanthoma but
contains multinucleated giant cells and hemosiderin SELECTED REFERENCES
• Contains nonfoamy epithelioid, mononuclear stromal cells 1. Sasamura A et al: A case of late-onset cerebrotendinous xanthomatosis with
• Osteoclast-like giant cells and hemosiderin common a novel mutation in the cyp27a1 gene. Intern Med. 57(11):1611-1616, 2018
2. Ghosh SK et al: Tuberous xanthoma as a presenting feature of familial
Solitary (Juvenile) Xanthogranuloma homozygous hypercholesterolemia with aortic regurgitation. J Pediatr.
166(1):198, 2015
• Usually young children 3. Blankenship DW et al: Verruciform xanthoma of the upper-extremity in the
• Touton giant cells often present absence of chronic skin disease or syndrome: a case report and review of the
literature. J Cutan Pathol. 40(8):745-52, 2013
• Mixed inflammation, including eosinophils and neutrophils
4. Shahrabi Farahani S et al: Oral verruciform xanthoma associated with chronic
Lipidized-Type Dermatofibroma (Fibrous graft-versus-host disease: a report of five cases and a review of the
literature. Head Neck Pathol. 5(2):193-8, 2011
Histiocytoma) 5. Reichwaldt I et al: Differential diagnosis of tendon tumors: xanthomas
• Usually lower leg (ankle predominant) caused by hyperlipidemia in children. J Pediatr Surg. 45(10):e9-12, 2010
6. Oosterveer DM et al: 5-Lipoxygenase activating protein (ALOX5AP) gene
• Demonstrates dermal collagen entrapment variants associate with the presence of xanthomas in familial
hypercholesterolemia. Atherosclerosis. 206(1):223-7, 2009
Verruciform Xanthoma 7. Chuang AY et al: Xanthoma of the prostate: a mimicker of high-grade
• Most are intraoral or anogenital prostate adenocarcinoma. Am J Surg Pathol. 31(8):1225-30, 2007
• Verrucous epithelium with parakeratin plugs and stromal 8. Tsouli SG et al: Pathogenesis, detection and treatment of Achilles tendon
xanthomas. Eur J Clin Invest. 35(4):236-44, 2005
foam cells 9. Moghadasian MH: Cerebrotendinous xanthomatosis: clinical course,
genotypes and metabolic backgrounds. Clin Invest Med. 27(1):42-50, 2004
Plexiform Fibrohistiocytic Tumor 10. Michal M et al: Plexiform xanthomatous tumor: a report of 20 cases in 12
• DDx for plexiform xanthoma patients. Am J Surg Pathol. 26(10):1302-11, 2002
• Most common in children and adolescents 11. Michal M: Plexiform xanthomatous tumor. A report of three cases. Am J
Dermatopathol. 16(5):532-6, 1994
• Biphasic appearance 12. Beham A et al: Plexiform xanthoma: an unusual variant. Histopathology.
○ Fibromatosis-like fascicles of spindle cells 19(6):565-7, 1991
○ Nodules of epithelioid or histiocytoid cells ± 13. Cruz PD Jr et al: Dermal, subcutaneous, and tendon xanthomas: diagnostic
markers for specific lipoprotein disorders. J Am Acad Dermatol. 19(1 Pt
multinucleated giant 1):95-111, 1988
• Xanthomatous change rare and usually limited in extent 14. Parker F: Xanthomas and hyperlipidemias. J Am Acad Dermatol. 13(1):1-30,
1985
Plexiform Schwannoma
• DDx for plexiform xanthoma

296

Tuberous Xanthoma
Cholesterol Clefts and Giant Cells
Tendinous Xanthoma
Xanthomas
Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tuberous Xanthoma
(Left) Tuberous xanthoma is
shown involving the knee.
Tuberous xanthomas appear
as firm, yellow-red,
subcutaneous nodules and
occur at pressure areas, such
as the buttock and extensor
surfaces of the knee and
elbow. Smaller nodules often
coalesce to form larger
nodules or plaques. (Right)
Tuberous xanthomas consists
of a nodular infiltrate of
foamy macrophages involving
the dermis and may be
uninodular or multinodular, as
in this example.
Fibrosis, Necrosis, and Cholesterol Clefts
(Left) Unlike the other forms
of xanthoma, tuberous (and
tendinous) xanthomas usually
have secondary changes,
including collections of
extracellular cholesterol with
cholesterol cleft formation ﬉
and associated giant cells ﬈.
(Right) Other secondary
changes in tuberous (and
tendinous) xanthomas include
varying degrees of fibrosis st
and foci of necrosis ﬊
containing amorphous
eosinophilic debris with
cholesterol clefts and a
surrounding rim of foamy
macrophages ﬈.
Plexiform Xanthoma
(Left) Tendinous xanthomas
are histologically identical to
tuberous xanthomas except
that they involve deeper
structures, such as tendons ﬊
and ligaments. (Right) A
multinodular proliferation
with a plexiform architecture
filling the dermis is typical of
plexiform xanthoma. The deep
nodules ﬈ tend to be more
well developed than the
superficial ones.
297
 Solitary (Juvenile) Xanthogranuloma

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY MICROSCOPIC
• Stable or regressing histiocytic lesion that usually occurs in • Mononuclear and spindle cells
childhood • Multinucleated cells ± Touton features
○ Form of non-Langerhans histiocytosis • Inflammatory cell background, often with many eosinophils
CLINICAL ISSUES • Variable lipid and foamy histiocytes
• Negligible nuclear atypia
• Majority occur in children < 3 years of age
• Minimal mitotic activity
• Solitary cutaneous lesion in majority of cases
○ Head and neck > trunk > extremities ANCILLARY TESTS
• Visceral examples almost exclusively in infants and children • CD68(+), CD163(+)
• Treatment: Excision • CD1a(-), S100(-)
○ Chemotherapy administered to rare patients with
TOP DIFFERENTIAL DIAGNOSES
systemic disease
• Prognosis usually excellent • Xanthoma
○ Most lesions regress or stabilize (including large visceral • Fibrous histiocytoma/dermatofibroma
ones) • Langerhans cell histiocytosis
• Rare deaths associated with multiorgan disease • Rosai-Dorfman disease
• Reticulohistiocytoma

Solitary (Juvenile) Xanthogranuloma Mononuclear Cells

(Left) This is the typical
appearance of a juvenile
xanthogranuloma (JXG) at low
magnification. The lesion is
composed of a nodular,
cellular histiocytic
proliferation in the dermis
with no intervening grenz
zone between the tumor and
the epidermis. (Right) This
cellular example of JXG shows
an inflammatory background
composed mostly of
mononuclear histiocytic and
lymphoid cells.

Touton Giant Cells Eosinophils and Foamy Histiocytes

(Left) Many Touton giant cells
﬉ with a ring of peripheral
nuclei can be seen in this JXG.
The background cells are
spindled to ovoid with
eosinophilic cytoplasm, which
shows only minimal lipid in
this case. (Right) High
magnification shows
eosinophils ﬉ and foamy
histiocytes ﬊, which are
commonly encountered in
JXG.

298
 Solitary (Juvenile) Xanthogranuloma

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
• CD1a(-), S100(-)
TERMINOLOGY
Abbreviations DIFFERENTIAL DIAGNOSIS
• Juvenile xanthogranuloma (JXG) Xanthoma
Definitions • Proliferation of numerous foamy histiocytes
• Stable or regressing histiocytic lesion that usually occurs in • No Touton-type giant cells
childhood • Minimal background inflammation
○ Form of non-Langerhans histiocytosis • Can be associated with hyperlipidemia
○ Usually lesions of adults
CLINICAL ISSUES Fibrous Histiocytoma/Dermatofibroma
Epidemiology • Usually in adults
• Incidence • Prominent storiform pattern
○ Rare • Peripheral collagen trapping usually prominent
• Age • Overlying epidermal hyperplasia usually seen
○ Majority under 3 years • Intralesional hemorrhage, hemosiderin
– Visceral examples almost exclusively in infants and
Langerhans Cell Histiocytosis
children
○ 13-30% in older children and adults • Usually presents with skeletal disease but also in skin
• Sex • Atypical reniform-appearing histiocytic cells
○ Slight male predominance • Background of many eosinophils usually seen
• S100(+), CD1a(+), langerin (+)
Presentation
Rosai-Dorfman Disease
• Solitary cutaneous lesion in majority of cases
○ Head and neck > trunk > extremities • a.k.a. sinus histiocytosis with massive lymphadenopathy
• Up to 10% of patients with multiple cutaneous lesions • Usually involves lymph nodes but may present in skin and
• Up to 5% of patients with visceral systemic disease soft tissues
• Large histiocytes with abundant foamy cytoplasm
Treatment • Emperipolesis of inflammatory cells (including lymphocytes,
• Excision plasma cells, and neutrophils) is key diagnostic feature
• Chemotherapy administered to rare patients with systemic • Histiocytes are S100(+), CD1a(-)
disease
Reticulohistiocytoma
Prognosis • Lesions of adults
• Usually excellent • Brown-yellow papules at any site
○ Most lesions regress or stabilize (including large visceral • Nodules of densely eosinophilic or 2-toned histiocytes,
ones) some multinucleated
○ Rare deaths associated with multiorgan disease • Nuclear atypia may be present but not clinically significant
• CD68(+), S100(-), CD1a(-)
MICROSCOPIC
Histologic Features SELECTED REFERENCES
• Proliferation of numerous mononuclear and 1. Ladha MA et al: Giant juvenile xanthogranuloma: case report, literature
review, and algorithm for classification. J Cutan Med Surg.
multinucleated cells 1203475418777734, 2018
○ Multinucleated cells may show Touton-type features 2. López-Robles J et al: Juvenile xanthogranuloma with angiomatous
(ring of peripheral nuclei) appearance and a peculiar immunophenotype. Pediatr Dermatol. 35(1):e55-
e56, 2018
• Spindle cells 3. Meyer M et al: Systemic juvenile xanthogranuloma: a case report and brief
○ Variable finely vacuolated cytoplasm review. Clin Exp Dermatol. 43(5):642-4, 2018
○ Often lightly eosinophilic 4. Paxton CN et al: Genetic evaluation of juvenile xanthogranuloma: genomic
abnormalities are uncommon in solitary lesions, advanced cases may show
• Variable lipid and foamy histiocytes more complexity. Mod Pathol. 30(9):1234-40, 2017
○ Minimal lipid in early lesions 5. Song M et al: Structural correlations between dermoscopic and
• Inflammatory cell background histopathological features of juvenile xanthogranuloma. J Eur Acad
Dermatol Venereol. 25(3):259-63, 2011
○ Acute and chronic inflammatory cells 6. Kaur MR et al: Disseminated clustered juvenile xanthogranuloma: an unusual
– Eosinophils and lymphocytes are consistently present morphological variant of a common condition. Clin Exp Dermatol. 33(5):575-
7, 2008
– Neutrophils uncommon
7. Janssen D et al: Juvenile xanthogranuloma in childhood and adolescence: a
• Negligible nuclear atypia clinicopathologic study of 129 patients from the kiel pediatric tumor
• Minimal mitotic activity registry. Am J Surg Pathol. 29(1):21-8, 2005
8. Zelger B et al: Juvenile and adult xanthogranuloma. A histological and
immunohistochemical comparison. Am J Surg Pathol. 18(2):126-35, 1994
ANCILLARY TESTS
Immunohistochemistry
• CD68(+), CD163(+)
299
 Reticulohistiocytoma

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY • Occasional Touton-type giant cells containing lipid may be

• Proliferation of histiocytes with abundant dense, glassy- present
appearing eosinophilic cytoplasm • Early lesions characterized by more mononuclear cells with
• Solitary cutaneous reticulohistiocytoma (SCR) lymphocytes
• Cytologic atypia is usually minimal, and mitoses are few and
CLINICAL ISSUES nonatypical
• Usually occurs in adults > 40 years old
ANCILLARY TESTS
• Most commonly in head and neck region, including mucosal
sites, but may present at any cutaneous site • CD68 (KP1)(+), CD163(+), and lysozyme (+)
• Usually single lesion, but several may be present in some • Variable expression of FXIIIA, CD64, and α-1-antitrypsin
cases • S100(-); rarely focal (+)
• Often appear red-brown or yellow-brown TOP DIFFERENTIAL DIAGNOSES
• May be preceded by trauma in some cases • Multicentric and generalized cutaneous
MICROSCOPIC reticulohistiocytosis
• Dermal-based nodular proliferation of large mononuclear • Solitary (juvenile) xanthogranuloma
and multinucleated histiocytes • Langerhans cell histiocytosis
• Cells show characteristic abundant glassy/hyalinized- • Rosai-Dorfman disease
appearing eosinophilic cytoplasm

Reticulohistiocytoma Prominent Nucleoli

(Left) At low magnification,
reticulohistiocytoma shows a
dense, nodular but symmetric
and well-circumscribed
collection of large histiocytic-
appearing cells in the dermis.
(Right) The tumor cells of
reticulohistiocytoma show
abundant dense, eosinophilic,
glassy-appearing cytoplasm
and vesicular nuclei ﬈ with
prominent nucleoli.

Mixed Inflammatory Infiltrate Numerous Eosinophils

(Left) Higher power
examination shows sheets of
eosinophilic cells associated
with an inflammatory
infiltrate containing
lymphocytes, neutrophils ﬈,
and eosinophils. (Right)
Another case at high-power
examination shows large
eosinophilic cells associated
with an inflammatory
infiltrate with numerous
eosinophils ﬈.

300
 Reticulohistiocytoma

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
TERMINOLOGY Size
• Lesions typically range in size from 0.5-2.0 cm
Synonyms
• Solitary cutaneous reticulohistiocytoma (SCR) MICROSCOPIC
• Reticulohistiocytic granuloma
Histologic Features
• Giant cell reticulohistiocytoma
• Dermal-based nodular proliferation of large mononuclear
Definitions and multinucleated histiocytes
• Proliferation of histiocytes with abundant dense, glassy- ○ Cells show characteristic abundant glassy/hyalinized-
appearing, eosinophilic to 2-toned cytoplasm appearing eosinophilic to amphophilic-staining (2-toned)
cytoplasm
ETIOLOGY/PATHOGENESIS ○ Some cells may show finely granular cytoplasm
Environmental Exposure ○ Occasional Touton-type giant cells (similar to those in
juvenile xanthogranuloma) containing lipid may be
• May be related to stimuli, such as insect bites, infection, present but are not prominent
trauma, or ruptured folliculitis or cyst
○ Cytologic atypia is usually minimal, and mitoses are few
and nonatypical
CLINICAL ISSUES ○ No infiltrative features are present
Epidemiology • Overlying epidermis may show atrophy/thinning
• Incidence ○ Often grenz zone separating infiltrate from epidermis
○ Rare • Early lesions characterized by background inflammatory
• Age infiltrate with many small mononuclear cells and
○ Usually occurs in adults > 40 years lymphocytes
– However, some cases have been reported in • Later lesions show greater numbers of large mononuclear
adolescents and multinucleated cells with background infiltrate,
• Sex including neutrophils and eosinophils
○ M=F • Phagocytosis of inflammatory cells and collagen may be
present
Site • Occasional bizarre-appearing cells may be present but do
• Usually head and neck region, including mucosal sites not indicate malignancy
○ However, may present at any cutaneous site • Rare cases may show deep subcutaneous, and even lymph
node, involvement
Presentation
• Skin papule or nodule ANCILLARY TESTS
○ Usually single lesion, but several may be present in some
cases
Histochemistry
• Firm, rapidly growing lesion • PAS-D digestion and Sudan black
• Usually appear as red-brown or yellow-brown ○ Reactivity: Positive
• May be preceded by trauma in some cases ○ Staining pattern: Cytoplasmic; highlights granules
• Lack of systemic symptoms, including fever, weight loss, or Immunohistochemistry
weakness (which may be seen in multicentric
• CD68(+), CD4(+), CD163(+), and lysozyme (+)
reticulohistiocytosis)
• Variable expression of FXIIIA, CD64, and α-1-antitrypsin
Treatment • S100(-); rarely focal (+)
• Complete conservative excision is curative • Cells negative for CD1a, CD3, CD20, CD34, actin, desmin,
○ Usually not required unless lesion is very large or fails to HMB-45, Melan-A
resolve Electron Microscopy
Prognosis • Large cells showing abundant granular cytoplasm
• Excellent containing numerous mitochondria, phagolysosomes,
• Lesions often involute spontaneously dense bodies, and myelin figures
• No definite relationship with more aggressive multicentric ○ Also contain so-called pleomorphic cytoplasmic
reticulohistiocytosis inclusions
○ However, multiple skin lesions should suggest possibility – Highly complex structures consisting mainly of unit
of generalized cutaneous reticulohistiocytosis membranes, which may surround vesicles
• Birbeck granules are absent
MACROSCOPIC
DIFFERENTIAL DIAGNOSIS
General Features
• Dermal-based, nodular, well-circumscribed but
Multicentric and Generalized Cutaneous
unencapsulated lesion Reticulohistiocytosis
• These entities show different clinical features

301
Fibrohistiocytic, Histiocytic, and Dendritic Cell Reticulohistiocytoma
Tumors
○ Multicentric cutaneous reticulohistiocytosis (MCR)
presents with multiple lesions involving skin, mucosal
sites, joints, and occasionally internal organs
– MCR may show aggressive course with destructive
arthropathy and constitutional symptoms
○ Generalized cutaneous reticulohistiocytosis (GCR) is
characterized by eruption of multiple small cutaneous
lesions
– Some cases may progress to MCR
• Histologically, there is considerable overlap with solitary
reticulohistiocytoma, but some differences have been
described
○ Solitary lesions may be better circumscribed and show
more multinucleated giants cells
○ Neutrophils and xanthomatized cells have been reported
to be more common in solitary reticulohistiocytoma
○ FXIIIA expression may be lower in systemic cases
Juvenile Xanthogranuloma
• Typically occurs in children, but some cases occur in adults
(adult-type xanthogranuloma)
• Multiple papules are common, and dozens of lesions have
been reported in some cases
• Histologically, typically shows more foamy histiocytes and
Touton-type giant cells with peripheral wreath-like
arrangement of nuclei
○ Cells lack dense glassy eosinophilic cytoplasm of
reticulohistiocytoma
• Cells positive by immunohistochemistry for CD68 and
CD163, but negative for S100 and CD1a
Langerhans Cell Histiocytosis
• Langerhans cell histiocytosis includes Letterer-Siwe, Hand-
Schüller-Christian, eosinophilic granuloma, and congenital
self-healing reticulohistiocytosis variants
• Predominantly occur in children
○ Also 2nd peak in elderly adults (usually eosinophilic
granuloma variant)
• Typically characterized by multiple skin lesions and systemic
involvement (especially bone)
• Histologic examination shows proliferation of mononuclear
cells in dermis and occasionally in epidermis
○ Cells show large folded or reniform vesicular nuclei and
abundant eosinophilic cytoplasm
○ Cells lack dense eosinophilic or 2-toned cytoplasm of
reticulohistiocytoma
○ Background infiltrate often contains numerous
eosinophils and variable numbers of lymphocytes
• CD1a, langerin, and S100 are positive in vast majority of
cases (all are negative in reticulohistiocytoma)
Rosai-Dorfman Disease
• Also known as sinus histiocytosis with massive
lymphadenopathy (SHML)
• Often shows concomitant lymphadenopathy and
constitutional symptoms
• Lesions may be solitary or multiple
• Histologic examination shows proliferation of large, pale-
staining histiocytes with emperipolesis of lymphocytes,
plasma cells, and erythrocytes
○ Cells lack dense, glassy, 2-toned cytoplasm of
reticulohistiocytoma
302
• S100(+) (negative in reticulohistiocytoma), CD1a(-)
DIAGNOSTIC CHECKLIST
Pathologic Interpretation Pearls
• Nodular proliferation of large mononuclear and
multinucleated histiocytes
○ Cells show characteristic abundant glassy/hyalinized-
appearing eosinophilic cytoplasm
○ Occasional Touton-type giant cells containing lipid may
be present but are not prominent (as in juvenile
xanthogranuloma)
• Cells are typically positive for CD68, CD163, and lysozyme
• Cells are negative for S100, CD1a, CD3, CD20, and CD34
SELECTED REFERENCES
1. Shen WC et al: Co-existence of Langerhans cell histiocytosis and
reticulohistiocytosis with initial presentation of skull lesions: a case report. J
Cutan Pathol. 46(1):62-6, 2019
2. Aasano T et al: The utility of FDG-PET/CT imaging in the evaluation of
multicentric reticulohistiocytosis: a case report. Medicine (Baltimore).
97(33):e11449, 2018
3. Delorenze LM et al: Dermoscopy of solitary cutaneous reticulohistiocytoma.
G Ital Dermatol Venereol. 153(4):579-80, 2018
4. Gru AA et al: Cutaneous hematolymphoid and histiocytic proliferations in
children. Pediatr Dev Pathol. 21(2):208-51, 2018
5. Güleç AT: Solitary reticulohistiocytoma with arborizing vessels: a new
mimicker of basal cell carcinoma. J Am Acad Dermatol. 74(1):e5-6, 2016
6. Cohen PR et al: Adult-onset reticulohistiocytoma presenting as a solitary
asymptomatic red knee nodule: report and review of clinical presentations
and immunohistochemistry staining features of reticulohistiocytosis.
Dermatol Online J. 20(3), 2014
7. Kandiah DA: Multicentric reticulohistiocytosis. Mayo Clin Proc. 89(8):e73,
2014
8. Saba R et al: Multicentric reticulohistiocytosis presenting with papulonodular
skin lesions and arthritis mutilans. Case Rep Rheumatol. 2013:201563, 2013
9. Caputo R et al: Unusual variants of non-Langerhans cell histiocytoses. J Am
Acad Dermatol. 57(6):1031-45, 2007
10. Chen CH et al: Multicentric reticulohistiocytosis presenting with destructive
polyarthritis, laryngopharyngeal dysfunction, and a huge
reticulohistiocytoma. J Clin Rheumatol. 12(5):252-4, 2006
11. Miettinen M et al: Reticulohistiocytoma (solitary epithelioid histiocytoma): a
clinicopathologic and immunohistochemical study of 44 cases. Am J Surg
Pathol. 30(4):521-8, 2006
12. Wang KH et al: Cutaneous Rosai-Dorfman disease: clinicopathological
profiles, spectrum and evolution of 21 lesions in six patients. Br J Dermatol.
154(2):277-86, 2006
13. Nguyen TT et al: Expression of CD163 (hemoglobin scavenger receptor) in
normal tissues, lymphomas, carcinomas, and sarcomas is largely restricted to
the monocyte/macrophage lineage. Am J Surg Pathol. 29(5):617-24, 2005
14. Bakri SJ et al: Recurrent solitary reticulohistiocytoma of the eyelid. Ophthal
Plast Reconstr Surg. 19(2):162-4, 2003
15. Busam KJ et al: Immunohistochemical distinction of epithelioid histiocytic
proliferations from epithelioid melanocytic nevi. Am J Dermatopathol.
22(3):237-41, 2000
16. Burgdorf WH et al: The non-Langerhans' cell histiocytoses in childhood.
Cutis. 58(3):201-7, 1996
17. Suwabe H et al: Reticulohistiocytoma involving the skin, subcutaneous tissue
and a regional lymph node. Pathol Int. 46(7):531-7, 1996
18. Hunt SJ et al: Solitary reticulohistiocytoma in pregnancy:
immunohistochemical and ultrastructural study of a case with unusual
immunophenotype. J Cutan Pathol. 22(2):177-81, 1995
19. Zelger B et al: Reticulohistiocytoma and multicentric reticulohistiocytosis.
Histopathologic and immunophenotypic distinct entities. Am J
Dermatopathol. 16(6):577-84, 1994
20. Caputo R et al: Solitary reticulohistiocytosis (reticulohistiocytoma) of the skin
in children: report of two cases. Arch Dermatol. 128(5):698-9, 1992
21. Davies BT et al: The so-called reticulohistiocytoma of the skin; a comparison
of two distinct types. Br J Dermatol. 67(6):205-11, 1955
 Reticulohistiocytoma

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Reticulohistiocytoma High Magnification
(Left) The edge of this nodular
reticulohistiocytoma shows a
well-circumscribed collection
of large histiocytic-appearing
cells in the dermis, associated
with many lymphocytes and
eosinophils. (Right) High
magnification of the same
tumor shows large histiocytic
cells with abundant dense
eosinophilic to amphophilic (2-
toned) cytoplasm and large,
vesicular-appearing nuclei ﬉.

CD163 Expression S100 Immunohistochemical Stain

(Left) CD163
immunohistochemical stain is
strongly and diffusely positive
in reticulohistiocytoma,
highlighting the tumor cell
cytoplasm and membranes.
(Right) S100 protein is
essentially negative in
reticulohistiocytoma with only
very weak cytoplasmic, and no
nuclear, staining. A few
background dendritic cells are
strongly positive ﬉.

Differential Diagnosis: Multicentric Differential Diagnosis: Multicentric

Reticulohistiocytosis Reticulohistiocytosis
(Left) Multicentric
reticulohistiocytosis (MCR)
shows a nodular proliferation
of enlarged histiocytic cells in
the dermis. The findings are
very similar to those in solitary
reticulohistiocytoma, and
clinical history/description are
essential in differentiating
between these conditions.
(Right) Higher magnification
of MCR shows a proliferation
of numerous enlarged,
histiocytic-appearing cells ﬉
associated with a background
of mixed inflammatory
infiltrate containing scattered
eosinophils ﬈.

303
 Deep Granuloma Annulare

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY MICROSCOPIC
• Synonyms: Subcutaneous granuloma annulare (GA), • Multiple nodular subcutaneous granulomas with
pseudorheumatoid nodule necrobiosis and blue mucin, surrounded by palisading
histiocytes at periphery
CLINICAL ISSUES
• Typical GA in overlying dermis (25%)
• Children and young adults (mean age: 4 years old) • Often with surrounding inflammation and fibrosis
• 2:1 female predominance
• Painless subcutaneous nodules ANCILLARY TESTS
• Lower legs (especially tibial), forearms/hands, face, scalp, • Alcian blue (pH 2.5) and colloidal iron highlight mucin
buttocks • CD68(+), CD163(+)
• Some also have cutaneous papules of conventional GA • Keratin (-), EMA(-)
• No association with rheumatoid arthritis • Retained nuclear INI1
• Benign
TOP DIFFERENTIAL DIAGNOSES
• No consistently effective treatment; variable response to
steroids • Rheumatoid nodule
• Lesions often regress within several years but recurrence • Epithelioid sarcoma
seen in 20% or more • Infectious granulomas
• Necrobiosis lipoidica diabeticorum

Deep Granuloma Annulare Central Necrobiosis

(Left) Deep granuloma
annulare is composed of
palisaded granulomas
centered in the deep dermis or
subcutis. Central zones of
necrobiosis are evident even
from low magnification ﬈.
(Right) Bland, spindled and
epithelioid histiocytes ﬉ are
radially arranged (palisading)
around a central zone of
degenerated collagen bundles
(necrobiosis) ﬊.

Blue Granulomas Mimicking Rheumatoid Nodule

(Left) Blue acid
mucopolysaccharides (mucin)
are often deposited within the
palisading granulomas ﬇.
This is a useful feature in
distinguishing deep granuloma
annulare (blue granulomas)
from rheumatoid nodule (red
granulomas). (Right) Some
deep granuloma annulare
have abundant red fibrin but
minimal blue mucin, as
depicted, and can look
essentially identical to
rheumatoid nodule. Clinical
history is critical; this case is
from a 6-year-old boy without
rheumatoid arthritis.

304
 Deep Granuloma Annulare

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
TERMINOLOGY ANCILLARY TESTS
Abbreviations Histochemistry
• Granuloma annulare (GA) • Alcian blue (pH 2.5) and colloidal iron highlight mucin
• PAS, GMS, Fite stains negative for organisms
Synonyms
• Subcutaneous GA, pseudorheumatoid nodule, palisading Immunohistochemistry
subcutaneous granuloma • CD68(+), CD163(+), and other histiocytic markers
Definitions • Keratin (-), EMA(-)
• Retention of nuclear SMARCB1/INI1 expression
• Nodules due to deep dermal and subcutaneous necrobiotic
granulomas in children
DIFFERENTIAL DIAGNOSIS
CLINICAL ISSUES Rheumatoid Nodule
Epidemiology • Subcutaneous nodules in adults with rheumatoid arthritis
• Usually red granuloma due to abundant fibrin
• Children and young adults (mean age: 4 years old)
• Most lack blue mucin seen in GA (most useful feature)
• 2:1 female predominance
• Some deep GA can look identical; clinical info essential
Site
Epithelioid Sarcoma
• Lower legs (especially tibial), forearms/hands, face, scalp,
buttocks • Rare aggressive sarcoma with over 50% mortality
○ Misdiagnosis as deep GA or rheumatoid nodule
Presentation disastrous pitfall
• Painless subcutaneous nodules • Often subcutaneous nodule on distal extremity of young
○ Often involve periosteum adults
○ May be juxtaarticular • Tumor nodule with central zonal necrosis mimics
• Some also have cutaneous papules of conventional GA necrobiotic granuloma at low power
• No association with rheumatoid arthritis ○ Peripheral rim of epithelioid tumor cells
– Large atypical nuclei with vesicular chromatin
Treatment – Abundant dense eosinophilic cytoplasm
• No consistently effective treatment ○ Central zone of coagulative tumor cell necrosis
• Topical or systemic corticosteroids used most often with – Resembles fibrin but contains necrotic tumor cells
variable success • Keratin (+), EMA(+); loss of nuclear SMARCB1/INI1
Prognosis Infectious Granulomas
• Benign • Fungal or mycobacterial organisms identified by culture or
• Lesions often regress within several years, but recurrence PAS, GMS, or Fite stains
seen in 20% or more • Clinical features suspicious for infection
• Usually abundant neutrophils
MICROSCOPIC • Usually lack mucin or fibrin deposition
Histologic Features Necrobiosis Lipoidica Diabeticorum
• Multiple nodular subcutaneous granulomas
• Atrophic yellowish plaques on lower legs of adults
○ Center of granuloma
• Often associated with diabetes
– Necrobiosis (basophilic collagen degeneration)
• Dermal-based, rather than subcutaneous, process
– "Blue granuloma" due to mucin deposition (acid
• Multiple layers of fibrin, necrobiosis, fibrosis, and
mucopolysaccharide)
inflammation fill dermis
□ Usually abundant but sometimes scant or absent
○ Layered cake or parfait appearance
– Sometimes red fibrin (like rheumatoid nodule)
○ Abundant plasma cells usually
– Sometimes karyorrhectic nuclear debris
• Lacks nodular subcutaneous granulomas
○ Periphery of granuloma
– Rim of palisading spindled or epithelioid histiocytes SELECTED REFERENCES
– No atypia, but mitoses may be seen
1. Fathi K et al: Subcutaneous granuloma annulare of the penis associated with
– Often with surrounding fibrosis and inflammation a urethral anomaly: case report and review of the literature. Pediatr
(lymphocytes, eosinophils, multinucleated giant cells) Dermatol. 31(4):e100-3, 2014
– Tight sarcoid-like granulomas may be seen 2. Lynch JM et al: Collagenolytic (necrobiotic) granulomas: part 1--the "blue"
granulomas. J Cutan Pathol. 31(5):353-61, 2004
• Typical GA in overlying dermis (25%) 3. Grogg KL et al: Subcutaneous granuloma annulare in childhood:
○ Palisading histiocytes around necrobiotic dermal clinicopathologic features in 34 cases. Pediatrics. 107(3):E42, 2001
collagen and mucin 4. McDermott MB et al: Deep granuloma annulare (pseudorheumatoid
nodule) in children: clinicopathologic study of 35 cases. Pediatr Dev Pathol.
○ Interstitial histiocytes between individual dermal 1(4):300-8, 1998
collagen fibers 5. Felner EI et al: Subcutaneous granuloma annulare: a review of 47 cases.
Pediatrics. 100(6):965-7, 1997

305
 Rheumatoid Nodule

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY • Central necrobiosis (collagen degeneration) with abundant

• Nodules due to subcutaneous necrobiotic granulomas in
adults with rheumatoid arthritis (RA)
CLINICAL ISSUES
• Asymptomatic smooth, firm, subcutaneous nodules
• Solitary or numerous lesions
• Size: From mm up to 5 cm
• Occur in 20-30% of adults with RA
• Elbow, extensor forearms, hands, feet, scalp, back,
buttocks, and many other sites, including lung and heart
• Nodules may indicate severe RA (high titer of rheumatoid
factor, severe erosive arthritis, &/or vasculitis)
red fibrin (red granuloma); usually lack blue mucin
• Surrounded at periphery by palisading spindled and
epithelioid histiocytes
• No atypia, but mitoses may be seen
• Often with surrounding inflammation, granulation tissue,
fibrosis
• Mixed infiltrate with plasma cells, lymphocytes
ANCILLARY TESTS
• Alcian blue (pH 2.5) and colloidal iron negative for mucin
• PAS, GMS, Fite stains (-) for organisms
• Keratin, EMA (-); retention of nuclear INI1

MICROSCOPIC TOP DIFFERENTIAL DIAGNOSES

• Multiple nodular subcutaneous granulomas • Deep granuloma annulare
• May extend into overlying dermis and occasionally even • Epithelioid sarcoma
perforate epidermis • Infectious granulomas
• Necrobiosis lipoidica diabeticorum

Rheumatoid Nodule Red Granulomas

(Left) Rheumatoid nodules are
palisading granulomas
centered in the subcutis but
often with involvement of the
overlying dermis. The
distinctive red granuloma
appearance is due to
abundant central fibrin
deposition. (Right) Histiocytes
form a distinct palisading rim
﬈ around the central zone st
of necrobiosis and bright red
fibrin.

Lymphoplasmacytic Infiltrate Neutrophils and Nuclear Dust

(Left) Fibrosis and mixed
inflammation are commonly
seen adjacent to rheumatoid
nodules st. Lymphocytic
aggregates ﬈ and prominent
plasma cells are often present.
(Right) Bland histiocytes ﬉
with indistinct cytoplasm
surround the necrobiotic
center of the granuloma.
Scattered neutrophils ſt &/or
nuclear dust are sometimes
seen.

306
 Rheumatoid Nodule
TERMINOLOGY
Definitions
• Nodules due to subcutaneous necrobiotic granulomas in
adults with rheumatoid arthritis (RA)
CLINICAL ISSUES
Site
• Elbow, extensor forearms, hands, feet, scalp, back,
buttocks, and many other sites, including lung and heart
○ Often arise near joints, pressure points, sites of trauma
○ Often involve fascia or periosteum
Presentation
• Asymptomatic smooth, firm, subcutaneous nodules
○ Solitary or numerous lesions
○ Size: From millimeters up to 5 cm
○ Occur in 20-30% of adults with RA
○ May occur in other connective tissue or immune diseases
(systemic lupus erythematosus, ankylosing spondylitis,
scleroderma)
Treatment
• No standard treatment; recommendations vary
• Most nodules asymptomatic and do not require treatment
• Treatment of RA with methotrexate, infliximab, or letrozole
may lead to multiple small skin nodules (cutaneous
nodulosis)
○ Treatment with etanercept may rarely lead to extensive
pulmonary nodules (pulmonary nodulosis)
Prognosis
• Nodules may indicate severe RA (high titer of rheumatoid
factor, severe erosive arthritis, &/or vasculitis)
MICROSCOPIC
Histologic Features
• Multiple nodular subcutaneous granulomas
○ May extend into overlying dermis and occasionally even
perforate epidermis
• Central necrobiosis (collagen degeneration) with abundant
red fibrin (red granuloma); usually lack blue mucin
○ Sometimes karyorrhectic nuclear debris
○ May have clefts or cystic degeneration
• Surrounded at periphery by palisading spindled and
epithelioid histiocytes
○ No atypia, but mitoses may be seen
• Often with surrounding inflammation, granulation tissue,
fibrosis
○ Mixed infiltrate with plasma cells, lymphocytes
• Leukocytoclastic vasculitis sometimes present
ANCILLARY TESTS
Histochemistry
• Alcian blue (pH 2.5) and colloidal iron stains (-) for mucin
(usually)
• PAS, GMS, Fite stains (-) for organisms
Immunohistochemistry
• CD68(+), CD163(+), and other histiocytic markers
Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
• Keratin, EMA (-)
• Retained nuclear SMARCB1/INI1 expression
DIFFERENTIAL DIAGNOSIS
Deep Granuloma Annulare
• Painless subcutaneous nodules in children and young adults
• Blue granulomas featuring abundant mucin (most useful
feature)
• Some have red fibrin, look identical to rheumatoid nodule
○ Clinical info essential; no association with RA
Epithelioid Sarcoma
• Rare aggressive sarcoma with over 50% mortality
○ Misdiagnosis as deep granuloma annulare or rheumatoid
nodule disastrous pitfall
• Often subcutaneous nodule on distal extremity of young
adults
• Tumor nodule with central zonal necrosis mimics
necrobiotic granuloma at low power
○ Peripheral rim of epithelioid tumor cells
– Large, atypical nuclei with vesicular chromatin
– Abundant, dense eosinophilic cytoplasm
○ Central zone of coagulative tumor cell necrosis
– Red-like fibrin, but individual necrotic tumor cells seen
• Keratin (+), EMA(+)
• Loss of nuclear SMARCB1/INI1 expression
Infectious Granulomas
• Fungal or mycobacterial organisms identified by culture or
by PAS, GMS, or Fite stains
• Clinical features suspicious for infection
• Usually abundant neutrophils
• Usually lack mucin or fibrin deposition
Necrobiosis Lipoidica Diabeticorum
• Atrophic, yellowish plaques on lower legs of adults
• Often associated with diabetes
• Dermal-based rather than subcutaneous process
• Multiple layers of fibrin, necrobiosis, fibrosis, and
inflammation fill dermis
○ Layered cake or parfait appearance
○ Abundant plasma cells usually
• Lacks nodular subcutaneous granulomas
SELECTED REFERENCES
1. Prasad NK et al: A new pattern of lipomatosis of nerve: case report. J
Neurosurg. 126(3):933-937, 2017
2. Munns JJ et al: Rheumatoid nodules. J Hand Surg Am. 39(4):765-7; quiz 767,
2014
3. Chao J et al: Accelerated cutaneous nodulosis associated with aromatase
inhibitor therapy in a patient with rheumatoid arthritis. J Rheumatol.
36(5):1087-8, 2009
4. van Ede A et al: Etanercept-related extensive pulmonary nodulosis in a
patient with rheumatoid arthritis. J Rheumatol. 34(7):1590-2, 2007
5. Lynch JM et al: Collagenolytic (necrobiotic) granulomas: part II--the 'red'
granulomas. J Cutan Pathol. 31(6):409-18, 2004
6. Mackley CL et al: Accelerated cutaneous nodulosis during infliximab therapy
in a patient with rheumatoid arthritis. J Clin Rheumatol. 10(6):336-8, 2004
7. Veys EM et al: Rheumatoid nodules: differential diagnosis and
immunohistological findings. Ann Rheum Dis. 52(9):625-6, 1993
8. Smith ML et al: Rheumatoid papules: lesions showing features of vasculitis
and palisading granuloma. J Am Acad Dermatol. 20(2 Pt 2):348-52, 1989
9. Patterson JW: Rheumatoid nodule and subcutaneous granuloma annulare.
A comparative histologic study. Am J Dermatopathol. 10(1):1-8, 1988
307
 Langerhans Cell Histiocytosis

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY ○ High mortality for disseminated disease

• Clonal neoplastic proliferation of modified dendritic cells
(Langerhans cells)
• Synonyms: Histiocytosis X, eosinophilic granuloma, Hand-
Schüller-Christian disease, Letterer-Siwe disease
CLINICAL ISSUES
• Common
• Usually children and young adults
○ 3.5:1.0 male predominance
• Occurs in solitary, multifocal unisystem and disseminated
multisystem forms
○ Bony sites most common in solitary and multifocal forms
– Soft tissue extension common
○ Skin, bone, liver, lung, spleen, and bone marrow in
disseminated form
• Treatment: Surgical excision
○ Chemotherapy for disseminated disease
• Excellent prognosis for solitary lesions
MICROSCOPIC
• Sheets or nests of uniform, ovoid, or epithelioid cells
○ Irregular nuclei with grooves, folds, or indentations
• Prominent eosinophilic infiltrate
• Osteoclast-like multinucleated giant cells are common
ANCILLARY TESTS
• CD1a(+), S100 protein (+), langerin/CD207 (+)
• CD163(-), CD21(-), CD68 (variable)
• EM: Presence of characteristic Birbeck granules (tennis
racket-shaped)
• Molecular: BRAF V600E mutations common
TOP DIFFERENTIAL DIAGNOSES
• Langerhans cell sarcoma
• Histiocytic sarcoma
• Extranodal Rosai-Dorfman disease
• Granulomatous inflammation

Langerhans Cell Histiocytosis Prominent Eosinophils

(Left) Langerhans cell
histiocytosis (LCH) is
characterized by sheets ſt
and aggregates of palely
eosinophilic ovoid Langerhans
cells in a background of mixed
chronic inflammatory cells,
particularly eosinophils ﬇.
(Right) Eosinophils are very
common in LCH and are often
quite prominent. Eosinophilic
microabscesses may even be
formed, and in occasional
cases, Charcot-Leyden crystals
may be present.

Nuclear Grooves and Folds Osteoclast-Like Giant Cells

(Left) Nuclear grooves ſt,
folds ﬇, or indentations st
are characteristic cytologic
findings in cases of LCH.
Atypia is minimal. Note the
numerous eosinophils. (Right)
Osteoclast-like multinucleated
giant cells are often seen in
LCH and may be sparsely
distributed or found in
clusters. A background
eosinophilic infiltrate can also
be seen in this H&E.

308
 Langerhans Cell Histiocytosis

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
○ Vesicular chromatin ± small nucleoli
TERMINOLOGY
– Minimal nuclear atypia
Abbreviations • Prominent eosinophilic infiltrate
• Langerhans cell histiocytosis (LCH) ○ May form eosinophilic microabscesses
○ Other inflammatory cells may be variably present
Synonyms
(lymphocytes, neutrophils, foamy histiocytes,
• Histiocytosis X neutrophils)
• Eosinophilic granuloma • Variable mitotic rate; no atypical forms
○ Isolated lesions • Osteoclast-like multinucleated giant cells are common
• Hand-Schüller-Christian disease
○ Multifocal bony lesions ± proptosis, diabetes insipidus ANCILLARY TESTS
• Letterer-Siwe disease
Immunohistochemistry
○ Disseminated multiorgan involvement
• CD1a(+), S100 protein (+), langerin/CD207 (+)
Definitions • Cyclin-D1 (+)
• Clonal neoplastic proliferation of modified dendritic cells • CD163(-), CD21(-), CD68 (variable)
(Langerhans cells)
Electron Microscopy
CLINICAL ISSUES • Presence of characteristic Birbeck granules (tennis racket-
shaped)
Epidemiology
• Incidence Molecular Genetics
○ Common • BRAF V600E mutations common
• Age ○ Also, MAP2K1 mutations reported in BRAF (-) tumors
○ Children and young adults
– Disseminated multisystem disease usually in infants DIFFERENTIAL DIAGNOSIS
• Sex Langerhans Cell Sarcoma
○ 3.5:1.0 male predominance • Extremely rare
Site ○ Most reported cases occur in adults
• Solitary and multifocal forms • Overtly malignant cytology
○ Bony sites most common (may extend into soft tissue) • Nuclear grooves and eosinophilic infiltrate may be present
– Skull, mandible, femur, ribs, vertebra, others • Similar immunophenotype to LCH
○ In solitary form, also lymph nodes, skin Histiocytic Sarcoma
• Disseminated form (multiorgan involvement) • Diffuse sheets of enlarged epithelioid histiocytes, often
○ Skin, bone, liver, lung, spleen, and bone marrow with prominent nucleoli
Presentation • Marked atypia/pleomorphism present, at least focally
• Solitary and multifocal forms • CD163(+), CD1a(-), langerin (-)
○ Usually lytic bone lesion(s) with cortical disruption Extranodal Rosai-Dorfman Disease
• Disseminated form • Large sheets of polygonal to spindled histiocytes with pale
○ Fever, cytopenia, hepatosplenomegaly, skin lesions cytoplasm
Treatment • Emperipolesis is often present
• Plasma cells common; eosinophils rare
• Surgical excision
• Osteoclast-like giant cells rare
• Disseminated disease may be treated with chemotherapy
• S100 protein (+), CD163(+), CD1a(-), langerin (-)
Prognosis
Granulomatous Inflammation
• Excellent for solitary lesions
• Well-formed aggregates of syncytial histiocytes
• High mortality rate in infants with multisystem disease who
• CD163(+), CD1a(-), S100(-)
do not respond to chemotherapy

MACROSCOPIC SELECTED REFERENCES

1. Xerri L et al: CDKN2A/B Deletion and double-hit mutations of the MAPK
Size pathway underlie the aggressive behavior of Langerhans cell tumors. Am J
Surg Pathol. 42(2):150-159, 2018
• Variable
2. Shanmugam V et al: Cyclin D1 is expressed in neoplastic cells of Langerhans
cell histiocytosis but not reactive Langerhans cell proliferations. Am J Surg
MICROSCOPIC Pathol. 41(10):1390-1396, 2017
3. Morimoto A et al: Recent advances in Langerhans cell histiocytosis. Pediatr
Histologic Features Int. ePub, 2014
• Sheets or nests of uniform, ovoid, or epithelioid cells 4. Roden AC et al: BRAF V600E expression in Langerhans cell histiocytosis:
clinical and immunohistochemical study on 25 pulmonary and 54
○ Pale eosinophilic cytoplasm extrapulmonary cases. Am J Surg Pathol. 38(4):548-51, 2014
○ Irregular nuclei with grooves, folds, or indentations

309
 Extranodal Rosai-Dorfman Disease

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY
• Nonneoplastic, chronic inflammatory process of uncertain
etiology characterized by distinctive histiocytic proliferation
that presents with lymphadenopathy &/or extranodal
disease
CLINICAL ISSUES
• Wide range (4th-5th decades most common)
• Multiple sites often involved simultaneously
• Skin and subcutaneous tissue of extremities, trunk,
head/neck most common sites
○ Also nasal cavity, paranasal sinuses, eye/orbit, bone
• Treatment: Local excision for isolated lesions
• Benign; overall excellent prognosis for extranodal cases
MACROSCOPIC
• May be multiple
• Usually 2-5 cm
MICROSCOPIC
• Clusters, sheets, and syncytia of large histocytes
○ Can be spindled and form storiform architectures
○ May contain intracytoplasmic inflammatory cells
(emperipolesis)
○ Minimal to mild cytologic atypia
• Plasma cell aggregates (polyclonal) and reactive
lymphocytes common and characteristic
• Variable stromal collagen deposition and fibrosis
ANCILLARY TESTS
• S100 protein (+) in large histiocytes
• CD1a(-)
TOP DIFFERENTIAL DIAGNOSES
• Histiocytic sarcoma
• Langerhans cell histiocytosis
• Miscellaneous histiocytic proliferations
• Undifferentiated pleomorphic sarcoma

Extranodal Rosai-Dorfman Disease Subcutaneous Adipose Tissue

(Left) Rosai-Dorfman disease
(RDD) most commonly
presents as nodal disease ±
involvement of various
extranodal sites. Isolated soft
tissue involvement is even
rarer. At low magnification,
RDD is composed of a mixture
of pink to clear histiocytic
areas and darker
lymphoplasmacytic
aggregates. (Right) Although
well marginated grossly, most
cases of extranodal RDD show
at least focal intratumoral
subcutaneous adipose tissue,
giving it the appearance of a
locally infiltrative process.

Pale Eosinophilic Histiocytes Emperipolesis

(Left) The lesional histocytes
of RDD are polygonal to
spindled and typically
demonstrate pale eosinophilic
cytoplasm. Cell borders are
often inconspicuous. A
reactive lymphoid ﬈ and
plasmacytic infiltrate is
commonly present and may be
prominent. (Right) The
presence of inflammatory cells
(particularly lymphocytes)
within the cytoplasm of the
histiocytes (emperipolesis ﬈)
is characteristic of RDD;
however, it is seen much less
frequently in extranodal
tumors.

310
 Extranodal Rosai-Dorfman Disease

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
TERMINOLOGY Treatment
• Conservative surgical excision for isolated lesions
Abbreviations
• Rosai-Dorfman disease (RDD) Prognosis
• Benign
Synonyms • Overall excellent prognosis for pure extranodal RDD
• Soft tissue RDD ○ No deaths or metastases yet reported
• Sinus histiocytosis with massive lymphadenopathy (SHML) • Isolated skin lesions may spontaneously resolve
○ Not applied to extranodal disease • Rare reports of aggressive clinical course in nodal disease,
Definitions often with widespread dissemination, involvement of
kidneys or lower respiratory tract, &/or associated with
• Nonneoplastic, chronic inflammatory process of uncertain
immunologic abnormalities
etiology characterized by distinctive histiocytic proliferation
that presents with lymphadenopathy &/or extranodal
disease
MACROSCOPIC
General Features
ETIOLOGY/PATHOGENESIS • Well circumscribed, often multinodular
Under Investigation • Tan-yellow, firm
• Etiology still uncertain • May be multiple

Infectious Agents Size

• Various infections associated with cases of RDD/SHML, but • Usually 2-5 cm
none as yet proven to be etiologic infectious agent
○ Simian virus 40 (SV40, polyomavirus) in several MICROSCOPIC
extranodal cases Histologic Features
○ Also parvovirus, Epstein-Barr virus, HHV-6 in nodal cases • Extranodal RDD
○ Admixed subcutaneous fat often present
CLINICAL ISSUES ○ Clusters, sheets, and syncytia of large histocytes
Epidemiology – Cytoplasm ranges from clear and foamy to variably
• Incidence eosinophilic
○ Rare – May contain intracytoplasmic inflammatory cells
○ Most patients with extranodal involvement also have (emperipolesis)
nodal disease □ Generally much less conspicuous than in nodal RDD
– Extranodal involvement is seen in ~ 10% of cases – Histiocytes may be spindled and form storiform
□ Rarely sole manifestation of disease architectures
• Age – Minimal to mild cytologic atypia
○ Wide range (4th-5th decades most common) – Rare to no mitotic figures
– Patients with extranodal disease are often older than ○ Plasma cell aggregates (polyclonal) common and
those without characteristic
• Sex ○ Reactive B-cell aggregates and T-cell infiltrates common
○ May be more common in females ○ Neutrophils may be seen ± microabscess formation
○ Variable stromal collagen deposition and fibrosis
Site ○ Rare findings: Focal Touton giant cells, focal necrosis,
• Multiple sites often involved simultaneously scattered eosinophils
• Extranodal • Nodal RDD (SHML)
○ Skin and subcutaneous tissue ○ Expanded sinuses contain histiocytic cells with abundant
– Extremities, trunk, head/neck most common cytoplasm, sometimes multinucleated
○ Also nasal cavity, paranasal sinuses, eye/orbit, bone, ○ Emperipolesis often striking feature
salivary gland, central nervous system, many others
• Nodal ANCILLARY TESTS
○ Cervical lymph nodes involved in 90% of cases Immunohistochemistry
Presentation • S100 protein (+) in large histiocytes
• Varies with site of involvement ○ Often helps highlight emperipolesis
○ Painful or painless papules, nodules, or masses in • CD68(+), CD163(+)
skin/soft tissue • CD1a(-)
○ Painless lymphadenopathy with concomitant nodal • Plasma cells are polyclonal
disease (most frequent presenting symptom overall) Electron Microscopy
– Hepatosplenomegaly uncommon
• Lacks Birbeck granules

311
Fibrohistiocytic, Histiocytic, and Dendritic Cell Extranodal Rosai-Dorfman Disease
Tumors

• Often cutaneous; rarely subcutaneous or intramuscular

DIFFERENTIAL DIAGNOSIS
• Histiocytic cells with variable population of Touton giant
Histiocytic Sarcoma cells
• Marked cytologic atypia • Variable stromal eosinophilic infiltrate
• Conspicuous mitotic activity • S100 protein (-)
• S100 protein (-)
• Aggressive clinical course SELECTED REFERENCES
1. Meindl A et al: Extranodal Rosai-Dorfman disease with mucosal involvement
Langerhans Cell Histiocytosis of the stomach in a background of autoimmune atrophic Gastritis. Int J Surg
• Clusters and sheets of pale, pink epithelioid cells with Pathol. 26(7):671-675, 2018
nuclear grooves 2. Heidarian A et al: Extranodal Rosai-Dorfman disease arising in the heart:
clinical course and review of literature. Cardiovasc Pathol. 31:1-4, 2017
• Usually associated with significant eosinophilic infiltrate, 3. Mantilla JG et al: Extranodal Rosai-Dorfman disease: clinicopathologic series
including abscesses of 10 patients with radiologic correlation and review of the literature. Am J
• CD1a(+), S100 protein (+) Clin Pathol. 145(2):211-21, 2016
4. Komaragiri M et al: Extranodal Rosai-Dorfman disease: a rare soft tissue
Miscellaneous Histiocytic Proliferations neoplasm masquerading as a sarcoma. World J Surg Oncol. 11:63, 2013
5. Liu L et al: Relationship between Rosai-Dorfman disease and IgG4-related
• Secondary to infection disease: study of 32 cases. Am J Clin Pathol. 140(3):395-402, 2013
○ Usually contains well-formed granulomas, at least focally, 6. Al-Daraji W et al: Soft tissue Rosai-Dorfman disease: 29 new lesions in 18
often with necrosis patients, with detection of polyomavirus antigen in 3 abdominal cases. Ann
Diagn Pathol. 14(5):309-16, 2010
○ Lacks emperipolesis 7. Gaitonde S: Multifocal, extranodal sinus histiocytosis with massive
○ Organisms can be detected by culture/special stains lymphadenopathy: an overview. Arch Pathol Lab Med. 131(7):1117-21, 2007
○ S100 protein (-)  8. Mehraein Y et al: Parvovirus B19 detected in Rosai-Dorfman disease in nodal
and extranodal manifestations. J Clin Pathol. 59(12):1320-6, 2006
• Malakoplakia 9. Wang KH et al: Cutaneous Rosai-Dorfman disease: clinicopathological
○ Usually identified in bladder or GI tract profiles, spectrum and evolution of 21 lesions in six patients. Br J Dermatol.
154(2):277-86, 2006
○ Sheets of small or medium-sized eosinophilic histiocytes,
10. Maric I et al: Histologic features of sinus histiocytosis with massive
some of which contain targetoid Michaelis-Guttman lymphadenopathy in patients with autoimmune lymphoproliferative
bodies syndrome. Am J Surg Pathol. 29(7):903-11, 2005
○ S100 protein (-) 11. Hindermann W et al: [Extranodal Rosai Dorfman disease (sinus histiocytosis
with massive lymphadenopathy). Report of 5 cases.] Pathologe. 25(3):222-8,
Myxoinflammatory Fibroblastic Sarcoma 2004
12. Rodriguez-Galindo C et al: Extranodal Rosai-Dorfman disease in children. J
• Often contains prominent stromal inflammatory Pediatr Hematol Oncol. 26(1):19-24, 2004
component 13. Anders RA et al: Rosai-Dorfman disease presenting in the gastrointestinal
• Typically contains population of large histiocyte-like cells, tract. Arch Pathol Lab Med. 127(2):E74-5, 2003
14. Sneller MC et al: Autoimmune lymphoproliferative syndrome. Curr Opin
which may contain inflammatory cells Rheumatol. 15(4):417-21, 2003
• Bizarre nuclear atypia, including smudgy heterochromatin 15. Andriko JA et al: Rosai-Dorfman disease isolated to the central nervous
and prominent macronucleoli system: a report of 11 cases. Mod Pathol. 14(3):172-8, 2001
16. Lauwers GY et al: The digestive system manifestations of Rosai-Dorfman
Undifferentiated Pleomorphic Sarcoma disease (sinus histiocytosis with massive lymphadenopathy): review of 11
cases. Hum Pathol. 31(3):380-5, 2000
• Often contains subtle admixed histiocytic population
17. Green I et al: Breast involvement by extranodal Rosai-Dorfman disease:
• Usually significant and bizarre nuclear pleomorphism report of seven cases. Am J Surg Pathol. 21(6):664-8, 1997
• Mitoses, including atypical forms, and coagulative necrosis 18. Levine PH et al: Detection of human herpesvirus 6 in tissues involved by
sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease).
common J Infect Dis. 166(2):291-5, 1992
• S100 protein (-) 19. Montgomery EA et al: Rosai-Dorfman disease of soft tissue. Am J Surg
Pathol. 16(2):122-9, 1992
Sarcoidosis 20. Eisen RN et al: Immunophenotypic characterization of sinus histiocytosis
• Well-formed, confluent, nonnecrotizing granulomas with massive lymphadenopathy (Rosai-Dorfman disease). Semin Diagn
Pathol. 7(1):74-82, 1990
associated with fibrosis
21. Foucar E et al: Sinus histiocytosis with massive lymphadenopathy (Rosai-
• Pulmonary involvement common Dorfman disease): review of the entity. Semin Diagn Pathol. 7(1):19-73, 1990
• Lacks emperipolesis 22. Foucar E et al: Sinus histiocytosis with massive lymphadenopathy. An analysis
of 14 deaths occurring in a patient registry. Cancer. 54(9):1834-40, 1984
• S100 protein (-)
23. Walker PD et al: The osseous manifestations of sinus histiocytosis with
Follicular Dendritic Cell Sarcoma massive lymphadenopathy. Am J Clin Pathol. 75(2):131-9, 1981
24. Rosai J et al: Sinus histiocytosis with massive lymphadenopathy. A newly
• May involve lymph nodes, nodal tissue, or extranodal sites recognized benign clinicopathological entity. Arch Pathol. 87(1):63-70, 1969
• Oval to spindle cells with eosinophilic cytoplasm forming
syncytial sheets or storiform/whorling arrays
• Tumor cells intimately admixed with small lymphocytes,
with prominent perivascular cuffing
• CD21(+), CD25(+), D2-40 (podoplanin) (+)
• May express focal S100 protein
Juvenile Xanthogranuloma
• Most common in pediatric age groups
• Head/neck most common site
312
 Extranodal Rosai-Dorfman Disease
Occasional Distinct Cell Borders
Spindled Storiform Growth
Stromal Collagen
Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Foamy Cytoplasm
(Left) In some foci, the lesional
histiocytes of extranodal RDD
have more prominent
eosinophilic cytoplasm and
more distinct cell borders,
imparting somewhat of a
pseudoalveolar appearance.
(Right) Some of the lesional
histiocytes of extranodal RDD
may show foamy, somewhat
clear cytoplasm. This finding is
often particularly prominent in
RDD of bone.
Subtle Histiocytic Morphology
(Left) Storiform or whorled
growth by spindled histiocytes
is a common morphologic
pattern in extranodal RDD and
may lead to confusion with a
fibrohistiocytic neoplasm.
(Right) In some cases of
extranodal RDD, the
histiocytes are small and
subtle in foci and may be
mistaken for fibroconnective
tissue. Note that the pale
eosinophilic cytoplasm ﬈ is
still evident.
S100 Protein Expression
(Left) Stromal collagen
deposition or sclerosis is a
common finding in extranodal
RDD but is usually not
extensive. Sclerotic foci, such
as the one shown, may be
mistaken for nonspecific
chronic inflammation,
particularly on small samples.
(Right) S100 protein
expression by the lesional
histiocytes is characteristic of
RDD. Note that
intracytoplasmic lymphocytes
(emperipolesis ſt) may be
more easily demonstrated
using this immunostain.
313
 Crystal-Storing Histiocytosis

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY • May have signs of underlying lymphoproliferative disorder,

• Nonneoplastic histiocytic proliferation containing crystalline such as lymphadenopathy or hepatosplenomegaly
material, usually associated with underlying • Treatment and prognosis relate to underlying disease
lymphoproliferative or plasmacytic disorder MICROSCOPIC
ETIOLOGY/PATHOGENESIS • Sheets of polygonal, epithelioid, or spindled histiocytes
• Lymphoproliferative or plasma cell disorder most common ○ Eosinophilic cytoplasm containing elongated crystals
○ Lymphoplasmacytic lymphoma, MALT lymphoma, ○ Occasionally, cells are multinucleated
extranodal marginal zone lymphoma, others • Associated lymphoproliferative or plasmacytic neoplasm
○ MGUS, myeloma, plasmacytoma often present
• Rarely associated with chronic inflammatory conditions or ANCILLARY TESTS
clofazimine use
• CD68(+), S100 protein (-), desmin (-), myogenin (-)
• Crystals most commonly derived from immunoglobulins
TOP DIFFERENTIAL DIAGNOSES
CLINICAL ISSUES
• Rhabdomyoma
• Middle-aged to older adults
• Granular cell histiocytosis
• May be localized/solitary or generalized/systemic
• Granular cell tumor
• Wide variety of sites, including soft tissue and visceral
• Malakoplakia
organs
• Mycobacterial pseudotumor

Crystal-Storing Histiocytosis Crystalline Structures

(Left) Crystal-storing
histiocytosis (CSH) is a
nonneoplastic proliferation of
spindled or epithelioid,
eosinophilic histiocytes that is
most commonly associated
with a lymphoplasmacytic
neoplasm. This case involved
the lung, evidenced by
entrapped normal structures
﬈. (Right) The lesional
histiocytes of CSH
demonstrate eosinophilic
cytoplasm and contain
variably prominent clusters of
elongated crystalline material
﬈. These crystals are most
commonly composed of
immunoglobulin.

Polygonal Histiocytes Spindled Histiocytes

(Left) The rod-shaped
intracytoplasmic crystals ﬈
are numerous and easily
identified by light microscopy
in this case of pulmonary CSH.
(Right) Although spindled
histiocytes are a common
finding in CSH, in some cases
they may predominate and
exist within a loosely
collagenous stroma with a
mild chronic inflammatory
infiltrate.

314
 Crystal-Storing Histiocytosis

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
TERMINOLOGY Prognosis
• Relates to underlying disease
Abbreviations
• Crystal-storing histiocytosis (CSH) MACROSCOPIC
Definitions General Features
• Nonneoplastic histiocytic proliferation containing crystalline • Usually ill-defined, tan-yellow mass
material, usually associated with underlying
lymphoproliferative or plasmacytic disorder Size
• Often small (most < 3 cm)
ETIOLOGY/PATHOGENESIS
MICROSCOPIC
Paraneoplastic Phenomenon
• By far most common etiology overall Histologic Features
• Lymphoproliferative or plasma cell disorder • Sheets of polygonal, epithelioid, or spindled histiocytes
○ Lymphoplasmacytic lymphoma ○ Eosinophilic cytoplasm containing variably prominent
○ Chronic lymphocytic leukemia clusters of elongated crystals
○ Extranodal marginal zone lymphoma – Cells may be markedly distended
○ MALT lymphoma ○ Occasionally cells are multinucleated
○ Plasma cell dyscrasias • Fibrosis and chronic inflammatory cells may be present
– Monoclonal gammopathy of undetermined • Associated lymphoproliferative or plasmacytic neoplasm
significance (MGUS) often present
– Myeloma ○ May be overshadowed by histiocytic component
– Plasmacytoma
• Systemic mastocytosis ANCILLARY TESTS
Inflammatory Disease Immunohistochemistry
• CD68(+)
• Eosinophilic colitis
• S100 protein (-), desmin (-), myogenin (-), CD1a(-)
• Rheumatoid arthritis, Crohn disease
Iatrogenic DIFFERENTIAL DIAGNOSIS
• Treatment of lepromatous leprosy with clofazimine Rhabdomyoma
Pathogenesis • Granular eosinophilic cytoplasm
• Crystals are formed from • Desmin (+), myogenin (+)
○ Immunoglobulins (most common) Granular Cell Histiocytosis
○ Eosinophil cytoplasmic granules (Charcot-Leyden)
• Site of previous surgery
– Eosinophilic colitis or systemic mastocytosis
• Granular cytoplasm without crystals
○ Clofazimine
• Crystals are phagocytosed by histiocytes Granular Cell Tumor
• Histiocytes aggregate to form ill-defined mass • Granular cytoplasm without crystals
○ Infiltrate adjacent tissues • Diffuse S100 protein (+)
Malakoplakia
CLINICAL ISSUES
• Epithelioid, eosinophilic histiocytes without
Epidemiology intracytoplasmic crystals
• Incidence • Michaelis-Gutmann bodies characteristic
○ Very rare
Mycobacterial Pseudotumor
• Age
○ Middle-aged to older adults • Immunocompromised patients
• Abundant acid-fast bacilli
Site
• Wide variety of locations, including soft tissue SELECTED REFERENCES
• Also visceral organs 1. Kokuho N et al: Localized pulmonary crystal-storing histiocytosis
• May be localized/solitary or generalized/systemic complicating pulmonary mucosa-associated lymphoid tissue lymphoma
presenting with multiple mass lesions. Hum Pathol. 65:180-186, 2017
Presentation 2. Kanagal-Shamanna R et al: Crystal-storing histiocytosis: a clinicopathological
study of 13 cases. Histopathology. 68(4):482-91, 2016
• Painless mass or swelling (in soft tissue)
3. Rossi G et al: Localized pleuropulmonary crystal-storing histiocytosis: 5 cases
• May have signs of underlying lymphoproliferative disorder, of a rare histiocytic disorder with variable clinicoradiologic features. Am J
such as lymphadenopathy or hepatosplenomegaly Surg Pathol. 37(6):906-12, 2013
4. Dogan S et al: Crystal-storing histiocytosis: report of a case, review of the
○ Rare cases precede development of or are unassociated literature (80 cases) and a proposed classification. Head Neck Pathol.
with lymphoplasmacytic disorder 6(1):111-20, 2012
• Visceral lesions be incidentally detected by imaging

315
 Plexiform Fibrohistiocytic Tumor

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY
• Rarely metastasizing dermal-subcutaneous mesenchymal
neoplasm composed of variable mixture of fibroblasts and
histiocyte-like cells
CLINICAL ISSUES
• Children and young adults
• Most common in upper extremity
○ Most arise at dermal-subcutaneous interface
• Also lower extremity, trunk, head and neck
• Painless, slow-growing mass or plaque
• Treatment: Wide surgical excision with negative margins
• Local recurrence in up to 40%
• Low metastatic potential (6%)
MACROSCOPIC
• Multinodular, poorly delineated, tan-white
• Usually < 3 cm (range 0.3-8.5 cm)
MICROSCOPIC
• Poorly circumscribed with infiltrative growth pattern
• Morphologically subdivided into 3 types (fibroblastic,
histiocytic, mixed)
• Fascicles of spindled fibroblastic cells
• Nodules or aggregates of epithelioid histiocytoid cells
○ Osteoclast-like giant cells common
• Multinodular and plexiform growth
• Low mitotic rate; usually no cellular pleomorphism
ANCILLARY TESTS
• Spindle cells: SMA(+); histiocytes CD68(+) and CD163(+)
• Negative for S100 protein, CD34, desmin, keratin, MITF
TOP DIFFERENTIAL DIAGNOSES
• Cellular neurothekeoma
• Giant cell tumor of soft tissue
• Fibromatosis
• Low-grade myofibroblastic sarcoma

Plexiform Fibrohistiocytic Tumor Infiltrative Growth

(Left) Plexiform
fibrohistiocytic tumor (PFHT)
is an unusual, infiltrative
mesenchymal neoplasm ﬈
that typically arises near the
dermal-subcutaneous junction,
as depicted. Tumors are
characterized by fascicles or
sheets of spindled fibroblasts
&/or nests of histiocytoid cells
in a nodular and plexiform
growth pattern. (Right) Most
cases of PFHT are infiltrative
and characteristically show
extensions or projections of
tumor into the subcutaneous
adipose tissue.

Mixed-Type Plexiform Fibrohistiocytic

Tumor Histiocytoid Nests
(Left) The mixed subtype of
PFHT shows a complex
mixture of nests ﬈ of
histiocytoid cells with short
fascicles of bland spindled
cells ﬊. (Right) The
characteristic nests and
aggregates of PFHT, when
present, contain plump to
epithelioid mononuclear
histiocytoid cells.
Multinucleated giant cells ﬉
may or may not be present.

316
 Plexiform Fibrohistiocytic Tumor
TERMINOLOGY
Abbreviations
• Plexiform fibrohistiocytic tumor (PFHT)
Definitions
• Rarely metastasizing dermal-subcutaneous mesenchymal
neoplasm composed of variable mixture of fibroblasts and
histiocyte-like cells
CLINICAL ISSUES
Epidemiology
• Incidence
○ Rare
• Age
○ Most common in children and young adults
– Overall wide range: 1-77 years
Site
• Upper extremity (particularly forearm and hand)
• Also lower extremity, trunk, head and neck
• Most arise at dermal-subcutaneous interface
○ May also be purely dermal or subcutaneous
– Subcutaneous tumors may involve skeletal muscle
Presentation
• Painless, slow-growing mass or plaque
Treatment
• Wide surgical excision or reexcision with negative margins
• Examination of regional lymph nodes may be warranted
• Indefinite clinical follow-up recommended
Prognosis
• Local recurrence in up to 40%
• Low metastatic potential (6%)
○ Regional lymph nodes
○ Systemic metastases very rare (lung)
MACROSCOPIC
General Features
• Multinodular, poorly delineated, tan-white
Size
• Usually < 3 cm (range 0.3-8.5 cm)
MICROSCOPIC
Histologic Features
• Most are located near dermal-subcutaneous interface
• Poorly circumscribed with infiltrative growth pattern
○ Adnexa often spared
• Morphologically subdivided into 3 types
○ Fibroblastic
– Predominantly spindled fibroblastic cells
– Plexiform to infiltrative fascicular growth
□ Ray-like extensions into subcutis
– Chronic inflammatory infiltrate common
○ Histiocytic
– Epithelioid histiocytoid cells
– Cannonball-like, multinodular growth
Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
□ Nodules may show hemorrhage
– Osteoclast-like giant cells common
○ Mixed type
– Histiocytoid nodules separated by fascicles
• Cellular and nuclear pleomorphism is usually absent
• Stromal can show dense hyalinization or myxoid change
○ Rare metaplastic bone formation
• Usually low mitotic rate (very rare atypical mitoses)
• Necrosis absent
• Rare focal lymphovascular invasion
ANCILLARY TESTS
Immunohistochemistry
• Spindle cells are SMA(+), at least focally
• Histiocytes are CD68(+) and CD163(+)
• Negative for S100 protein, CD34, desmin, keratin
• Negative for MITF (may be focally positive)
DIFFERENTIAL DIAGNOSIS
Cellular Neurothekeoma
• Can show significant morphologic overlap with PFHT
○ Entities may be closely related
• 1/3 of cases arise in head/neck
• MITF(+), usually diffuse
Giant Cell Tumor of Soft Tissue
• Prominent nodularity with abundant osteoclast-like giant
cells
• Lacks infiltrative spindle cell component
• Peripheral shell of woven bone in 50%
Fibromatosis
• Lacks nodules of histiocytoid and osteoclast-like giant cells
• Characteristic elongated stromal vasculature
• Nuclear β-catenin (+)
Low-Grade Myofibroblastic Sarcoma
• Most common in head/neck and extremities
• Usually arise in deep subcutaneous tissue or skeletal muscle
• Highly infiltrative, often with checkerboard pattern
• At least focal nuclear enlargement, hyperchromasia
SELECTED REFERENCES
1. Liu CY et al: Myxoid plexiform fibrohistiocytic tumor masquerading as
ganglion cyst: a case report and literature review. Case Rep Pathol.
2017:5370894, 2017
2. Fox MD et al: Expression of MiTF may be helpful in differentiating cellular
neurothekeoma from plexiform fibrohistiocytic tumor (histiocytoid
predominant) in a partial biopsy specimen. Am J Dermatopathol. 34(2):157-
60, 2012
3. Luzar B et al: Cutaneous fibrohistiocytic tumours - an update.
Histopathology. 56(1):148-65, 2010
4. Jaffer S et al: Neurothekeoma and plexiform fibrohistiocytic tumor: mere
histologic resemblance or histogenetic relationship? Am J Surg Pathol.
33(6):905-13, 2009
5. Moosavi C et al: 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. 11(5):313-9, 2007
6. Remstein ED et al: Plexiform fibrohistiocytic tumor: clinicopathologic
analysis of 22 cases. Am J Surg Pathol. 23(6):662-70, 1999
7. Fisher C: Atypical plexiform fibrohistiocytic tumour. Histopathology.
30(3):271-3, 1997
8. Enzinger FM et al: Plexiform fibrohistiocytic tumor presenting in children
and young adults. An analysis of 65 cases. Am J Surg Pathol. 12(11):818-26,
1988
317
Fibrohistiocytic, Histiocytic, and Dendritic Cell Plexiform Fibrohistiocytic Tumor
Tumors

Multinucleated Giant Cells Histiocytoid Nodules

(Left) Osteoclast-like
multinucleated giant cells ﬉
are often seen within
histiocytoid nodules in PFHT;
however, they are absent in a
subset of cases. Note also that
the cells at the periphery of
the nests may be spindled ﬈
and appear to encircle the
plumper epithelioid cells ﬊.
(Right) The histiocytoid
nodules of PFHT may lack
multinucleated giant cells, as
depicted. In the histiocytic
subtype, this absence of giant
cells may lead to an overall
impression of cellular
neurothekeoma, an entity that
may be related to PFHT.

Intranodular Hemorrhage Fibroblastic Component

(Left) Hemorrhage may be
seen within PFHT and, when
present, is often localized to
histiocytoid nodules and nests,
particularly if osteoclast-like
multinucleated giant cells are
present. This appearance can
lead to consideration of a soft
tissue giant cell tumor. (Right)
The fibroblastic component of
PFHT is characterized by
fascicles and sheets ﬈ of
spindled cells within a variably
collagenous stroma.
Histiocytoid nodules ﬊ ±
giant cells are also seen in
mixed subtypes.

Fibroblastic Component Fibroblastic Component

(Left) The spindled fibroblastic
cells of PFHT are generally
cytologically banal and are
associated with a variable
amount of stromal collagen. In
some cases, the stroma can be
densely hyalinized or even
focally myxoid. (Right) This
case of PFHT shows areas of
fibroblastic morphology with
densely hyalinized stroma.

318
 Plexiform Fibrohistiocytic Tumor

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Fibroblastic-Type Plexiform
Cytologic Features Fibrohistiocytic Tumor
(Left) The lesional cells of
PFHT usually lack significant
cytologic atypia, and mitotic
activity is often low. Rare
tumors, however, can show
nuclear pleomorphism &/or
rare atypical mitoses. (Right)
The fibroblastic subtype of
PFHT is composed
predominantly, or entirely, of
short fascicles and sheets of
bland spindle cells with few to
no histiocytic nests. Together
with the infiltrative growth
pattern, this subtype
morphologically resembles
fibromatosis.

Histiocytic-Type Plexiform Fibrohistiocytic

Tumor Infiltrative Growth
(Left) The histiocytic subtype
of PFHT is composed of
infiltrating clusters and nests
of plump histiocytoid cells ±
giant cells. The surrounding
connective tissue may appear
reactive and contain
inflammatory cells &/or
hemosiderin pigment. (Right)
Infiltrative growth is
characteristic of PFHT, and the
fibroblastic component, if
present, often projects out
into surrounding tissues as
finger-like or ray-like
extensions ﬈. Isolated
nodules ﬊ of histiocytoid cells
and giant cells may also be
seen within fat.

Increased Cellularity Increased Cellularity

(Left) Rare cases of PFHT show
an increase in cellularity in the
spindled fibroblastic
component ﬉ that may be
easily mistaken for frank
sarcoma. Note the compressed
histiocytic nodules ﬊, some of
which contain osteoclast-like
giant cells and hemorrhage.
(Right) Image of a cellular
example of PFHT shows a
mixture of fibroblastic
elements (left) and
histiocytoid nodules (right).

319
 Giant Cell Tumor of Soft Tissue

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY
• Benign soft tissue neoplasm composed of mononuclear
stromal cells, osteoclastic giant cells, and metaplastic bone
• Microscopically identical to giant cell tumor of bone
• Genetically distinct from giant cell tumor of bone
○ Lacks H3F3A mutation
CLINICAL ISSUES
• Average age: ~ 40 years; wide range: 1-86 years
• Superficial (subcutaneous) in 2/3
• Arm, thigh, and calf most common sites
• Local recurrence ~ 10%
• No established reports of metastasis
MACROSCOPIC
• Average size: 3.5 cm
○ Range: 0.7-10.0 cm
MICROSCOPIC
• Multinodular with fibrous septa
• Peripheral rim of metaplastic ossification
○ Can extend into center of tumor
• Hemorrhage and cystic hemorrhage
• Aneurysmal bone cyst-like changes
• Mononuclear stromal cells
○ Oval to spindle-shaped nuclei
○ No significant cytological atypia
• Osteoclastic giant cells
○ Evenly distributed throughout tumor
• Mitotic rate 2-5/10 HPF; rare tumors with > 30/10 HPF
• Xanthoma cells in some
TOP DIFFERENTIAL DIAGNOSES
• Tenosynovial giant cell tumor
• Undifferentiated pleomorphic sarcoma (with giant cells)
• Extraskeletal recurrence of giant cell tumor of bone

Giant Cell Tumor of Soft Tissue Soft Tissue Mass of Shoulder

(Left) Microscopically, giant
cell tumor of soft tissue
(GCTST) is identical to giant
cell tumor of bone composed
of mononuclear stromal cells
and multinuclear osteoclastic
giant cells ﬈ that are evenly
distributed throughout the
tumor. (Right)
Radiographically, GCTST
presents as a soft tissue mass
﬈. Although most occur in the
subcutis, 1/3 involve the deep
soft tissue, such as this tumor
that saucerizes the clavicle ﬊.
GCTST can be associated with
Paget disease of bone, as in
this 64-year-old man.

Ossification Cytological Features

(Left) Metaplastic ossification
is present in ~ 1/2 of GCTST. It
typically forms a peripheral
rind of woven bone ﬈.
However, ossification can also
be found in the center of the
mass. (Right) GCTST is
composed of uniform
mononuclear stromal cells
with round to oval nuclei and
ill-defined cytoplasmic borders
﬈. Osteoclastic giant cells ﬊
are abundant and evenly
distributed throughout the
tumor. Although mitoses are
readily identified in most
tumors, none are atypical.

320
 Giant Cell Tumor of Soft Tissue

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
TERMINOLOGY MICROSCOPIC
Abbreviations Histologic Features
• Giant cell tumor of soft tissue (GCTST) • Multinodular with fibrous septa
• Peripheral rim of metaplastic ossification
Synonyms
○ Can extend into center of tumor
• Soft tissue giant cell tumor of low malignant potential
• Storiform pattern in some
Definitions • Hemorrhage and cystic hemorrhage
• Benign soft tissue neoplasm composed of mononuclear ○ Aneurysmal bone cyst-like changes
stromal cells, osteoclastic giant cells, and metaplastic bone ○ Hemosiderin deposition
○ Microscopically identical to giant cell tumor of bone • Variable stromal fibrosis
○ Genetically distinct from giant cell tumor of bone • Vascular invasion in 1/3
– Lacks H3F3A mutation Cytologic Features
• Mononuclear stromal cells
CLINICAL ISSUES
○ Oval to spindle-shaped nuclei
Epidemiology ○ Ill-defined cytoplasm and cytoplasmic boundaries
• Incidence ○ No significant cytologic atypia
○ Rare; exact incidence unknown ○ Mitoses readily identified
• Age – Rate = 2-5/10 HPF; rare tumors with > 30/10 HPF
○ Average: ~ 40 years (wide range: 1-86 years) – No atypical mitotic figures
• Sex • Osteoclastic giant cells
○ F=M ○ Evenly distributed throughout tumor
Site • Xanthoma cell (foamy macrophages) in some

• Arm, thigh, and calf most common sites ANCILLARY TESTS

○ Others: Hand, shoulder, foot, buttock, groin, hip, head
and neck, abdominal wall, chest wall, flank, back, Immunohistochemistry
ischiorectal fossa, presacrum, peripancreas, • Mononuclear cells p63(+)
mediastinum, intracranium, retroperitoneum, breast
• Superficial (subcutaneous) in 2/3, deep (subfascial) in 1/3 DIFFERENTIAL DIAGNOSIS
Presentation Tenosynovial Giant Cell Tumor
• Painless mass • Synovial-based or intraarticular tumor
• Can be associated with Paget disease of bone • More heterogeneous population of cells
• Epithelioid cells with eccentric, vesicular nuclei
Treatment
• Complete surgical excision Undifferentiated Pleomorphic Sarcoma (With Giant
Cells)
Prognosis
• High-grade sarcoma with numerous osteoclastic giant cells
• Very good; benign • Pleomorphic stromal cells, atypical mitotic figures, necrosis
• Local recurrence ~ 10%
• No established reports of metastasis Extraskeletal Recurrence of Giant Cell Tumor of
Bone
IMAGING • Grossly and microscopically indistinguishable from GCTST
Radiographic Findings
SELECTED REFERENCES
• Soft tissue mass
• Peripheral mineralization in some 1. Lee JC et al: Giant cell tumor of soft tissue is genetically distinct from its
bone counterpart. Mod Pathol. 30(5):728-33, 2017
• Deep-seated tumors can saucerize underlying bone 2. Mishra SS et al: Intracranial giant cell tumor of soft tissue: mimicking a
glioma. Neurol India. 61(2):192-3, 2013
MACROSCOPIC 3. Lau YS et al: Phenotypic and molecular studies of giant-cell tumors of bone
and soft tissue. Hum Pathol. 36(9):945-54, 2005
General Features 4. O'Connell JX et al: Giant cell tumors of soft tissue: a clinicopathologic study
of 18 benign and malignant tumors. Am J Surg Pathol. 24(3):386-95, 2000
• Most tumors well circumscribed 5. Oliveira AM et al: Primary giant cell tumor of soft tissues: a study of 22 cases.
• Multinodular Am J Surg Pathol. 24(2):248-56, 2000
• Red-brown 6. Galed-Placed I et al: Giant-cell tumor in soft parts in a patient with osseous
Paget's disease: diagnosis by fine-needle aspiration. Diagn Cytopathol.
• Peripheral rim of ossification in 1/2 19(5):352-4, 1998
• Hemorrhagic cystic spaces
Size
• Average: 3.5 cm (range: 0.7-10.0 cm)

321
Fibrohistiocytic, Histiocytic, and Dendritic Cell Giant Cell Tumor of Soft Tissue
Tumors

Giant Cell Tumor of Soft Tissue Circumscribed Border

(Left) In the absence of clinical
and radiographic correlation,
GCTST is indistinguishable
from giant cell tumor of bone,
consisting of sheets of
mononuclear stromal cells
with oval to spindle-shaped
nuclei admixed with uniformly
distributed osteoclastic giant
cells ﬈. (Right) Most often,
GCTST presents as a well-
circumscribed mass. This low-
power micrograph illustrates
sharp demarcation between
tumor ﬊ and surrounding
fibroadipose tissue by a thick
fibrous pseudocapsule ﬈.

Nodular Architecture Large Osteoclastic Giant Cells

(Left) Most tumors have a
multinodular architecture
defined by fibrous septa ﬈
that divide it into cellular
nodules ﬊. Numerous
osteoclastic giant cells ﬉ are
easily identified even at low
power. (Right) Similar to giant
cell tumor of bone, the
osteoclastic giant cells in
GCTST can be very large and
harbor very many nuclei, as
indicated by this huge giant
cell with > 50 nuclei ﬈.

Storiform Pattern Aneurysmal Bone Cyst-Like Change

(Left) Like giant cell tumor of
bone, GCTST can have a
storiform architecture, as
depicted by short curvilinear
fascicles of plump spindle cells
that intersect to form a
pinwheel pattern. (Right)
Stromal hemorrhage is
common, often presenting as
blood-filled cystic spaces or
aneurysmal bone cyst-like
change. This micrograph
depicts aneurysmal bone cyst-
like change in a giant cell
tumor characterized by blood
pools ſt separated by an
edematous fibromyxoid
trabecula ﬊ containing giant
cells ﬈.

322
 Giant Cell Tumor of Soft Tissue
Giant Cell Tumor of Soft Tissue of Finger
Hemosiderin Deposits
Xanthoma Cells
Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
MR
(Left) Although most common
in the arm, thigh, and calf,
GCTST has a wide anatomic
distribution, including the
fingers, as depicted in this
radiograph, which shows an
extraskeletal soft tissue mass
﬈ in the index finger of a 21-
year-old man. Differential
diagnosis would include
tenosynovial giant cell tumor.
(Right) This MR from the same
patient reveals a well-
circumscribed mass adjacent
﬈ to, but not directly
involving, the bony phalanx
﬊.
Fibrosis
(Left) Stromal hemorrhage is
common in GCTST with
subsequent hemosiderin
deposition. This micrograph
illustrates hemosiderin
pigment within macrophages
﬈ as well as within
osteoclastic giant cells ﬊.
(Right) Stromal fibrosis is
common in GCTST and is
highly variable in its extent. It
can sometimes form large
sheets of hyalinized
collagenous matrix, as
depicted ﬈.
Vascular Invasion
(Left) Areas containing sheets
of xanthoma cells (foamy
macrophages) can be seen in
GCTST. These cells contain
abundant phagocytized lipid
material, which imparts a
microvacuolar cytoplasm ﬈.
Here, they are admixed with
osteoclastic giant cells ﬊.
(Right) Vascular invasion ﬈
can be seen in ~ 1/3 of GCTST.
As in giant cell tumor of bone,
vascular invasion does not
have prognostic value nor
does it indicate an increased
risk of metastasis.
323
 Histiocytic Sarcoma

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY • Diffuse sheets of medium to large epithelioid cells with

• Malignant neoplasm showing morphologic and eosinophilic or foamy cytoplasm and irregular, vesicular
immunophenotypic evidence of histiocytic differentiation nuclei with prominent nucleoli
• Mitoses and necrosis common
CLINICAL ISSUES • Admixed inflammatory infiltrate common and may be
• Wide age range (median: 50 years) abundant
• Superficial or deep soft tissues of the extremities
ANCILLARY TESTS
• Also skin, gastrointestinal tract, other sites
• CD45, CD68, and CD163 (+)
• Treatment: Complete surgical resection with postoperative
chemotherapy or radiotherapy • S100 protein (+), usually focal
• Aggressive clinical course with overall poor prognosis • Negative for keratin, CD20, HMB45, CD21, CD30
○ Small, localized tumors that are completely removed TOP DIFFERENTIAL DIAGNOSES
may have better clinical outcome • Non-Hodgkin lymphoma
MACROSCOPIC • Metastatic carcinoma/melanoma
• Most 5-10 cm • Dedifferentiated liposarcoma
• Extranodal Rosai-Dorfman disease
MICROSCOPIC • Gastrointestinal stromal tumor
• Infiltrative periphery

Histiocytic Sarcoma Foamy Cytoplasm

(Left) Histiocytic sarcoma (HS)
is an aggressive malignant
neoplasm that is classically
composed of sheets of
epithelioid histiocytic cells
with pale eosinophilic
cytoplasm and vesicular nuclei
with prominent nucleoli.
Mitoses and necrosis are
common. (Right) Some tumor
cells in HS show foamy
cytoplasm and may be
confused for nonneoplastic
histiocytes; however, the
prominent nucleoli ﬊ and
mitoses ﬉ support HS. Note
also the background
neutrophilic inflammatory
infiltrate.

Binucleated and Multinucleated Cells Histiocytic Immunophenotype

(Left) Binucleated ﬊ and
multinucleated tumor cells are
a relatively common finding in
HS. The case depicted in this
image also shows cellular and
nuclear pleomorphism. Note
also the dyscohesive nature of
the cells; however, in some
cases, the cells are densely
packed. (Right) Histiocytic
sarcoma shows
immunoexpression of antigens
typically seen in mature
histiocytes, such as CD68
(shown) and lysozyme. CD163
is also expressed in HS and is a
better, more specific marker
of histiocytic origin.

324
 Histiocytic Sarcoma

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
• Necrosis common
TERMINOLOGY
• Admixed inflammatory infiltrate common and may be
Abbreviations abundant
• Histiocytic sarcoma (HS) ○ Usually neutrophils or lymphocytes
• Spindled morphology may be present in some cases
Definitions
• Malignant neoplasm showing morphologic and ANCILLARY TESTS
immunophenotypic evidence of histiocytic differentiation
Immunohistochemistry
CLINICAL ISSUES • CD45, CD68, and CD163 (+)
• CD4, CD31, and lysozyme (+)
Epidemiology
• S100 protein (+), often focal
• Incidence • Negative for keratin, CD20, CD1a, CD21, CD30, HMB45,
○ Very rare ALK, myeloperoxidase
• Age
○ Wide range (median: 50 years) DIFFERENTIAL DIAGNOSIS
Site Non-Hodgkin Lymphoma
• Superficial or deep soft tissues of extremities • Usually diffuse large B-cell lymphoma or anaplastic large
○ May arise in skin cell lymphoma
• Gastrointestinal tract • Utilization of immunohistochemistry and flow cytometry
• Lymph nodes, spleen, central nervous system, and others often necessary for distinction from HS
Presentation Metastatic Carcinoma/Melanoma
• Often solitary, painless mass • Usually easily excluded through use of
• Site-specific symptoms immunohistochemistry
○ Skin: Rash • History of previous diagnosis may be available
○ GI tract: Abdominal pain, obstruction Dedifferentiated Liposarcoma
• May have weight loss and other systemic symptoms
• Often contain areas of well-differentiated liposarcoma
• Prior history of lymphoma (e.g., follicular, mantle cell) may
• May show prominent admixed inflammatory component
exist
• MDM2 amplification by fluorescence in situ hybridization
Treatment (FISH) analysis
• Complete surgical resection with postoperative • MDM2 or CDK4 overexpression by immunohistochemistry
chemotherapy or radiotherapy
Extranodal Rosai-Dorfman Disease
Prognosis • Histiocytes lack prominent nucleoli and nuclear atypia
• Overall poor prognosis • No mitoses or necrosis
• Most show aggressive clinical course
Gastrointestinal Stromal Tumor
○ Metastases common (usually to lymph nodes, lung,
bone) • Most show spindled morphology; less commonly
epithelioid
• Small, localized tumors that are completely removed may
have better clinical outcome • Prominent nucleoli not usually a feature
• CD117 and DOG1(+)
MACROSCOPIC
SELECTED REFERENCES
General Features
1. Magro CM et al: Primary cutaneous histiocytic sarcoma: a report of five cases
• Tan-yellow, soft, fleshy cut surface with primary cutaneous involvement and review of the literature. Ann Diagn
• Hemorrhage and necrosis common Pathol. 32:56-62, 2018
2. Hung YP et al: Histiocytic sarcoma: new insights into FNA cytomorphology
Size and molecular characteristics. Cancer Cytopathol. 125(8):604-614, 2017
3. Takahashi E et al: Histiocytic sarcoma : an updated literature review based on
• Most 5-10 cm the 2008 WHO classification. J Clin Exp Hematop. 53(1):1-8, 2013
4. Sundersingh S et al: Multifocal histiocytic sarcoma of the gastrointestinal
MICROSCOPIC tract. Indian J Pathol Microbiol. 55(2):233-5, 2012
5. Vos JA et al: Histiocytic sarcoma: a study of five cases including the histiocyte
Histologic Features marker CD163. Mod Pathol. 18(5):693-704, 2005
6. Hornick JL et al: Extranodal histiocytic sarcoma: clinicopathologic analysis of
• Infiltrative periphery 14 cases of a rare epithelioid malignancy. Am J Surg Pathol. 28(9):1133-44,
• Diffuse sheets of medium to large epithelioid cells 2004
○ Abundant pale eosinophilic or foamy cytoplasm 7. Lau SK et al: CD163: a specific marker of macrophages in paraffin-embedded
tissue samples. Am J Clin Pathol. 122(5):794-801, 2004
○ Irregular, vesicular nuclei with prominent nucleoli 8. Mikami M et al: Monocyte/macrophage-specific marker CD163+ histiocytic
– Binucleation and multinucleation are common sarcoma: case report with clinical, morphologic, immunohistochemical, and
– Mitoses frequent molecular genetic studies. Int J Hematol. 80(4):365-9, 2004

○ Cellular pleomorphism may be seen

325
 Follicular Dendritic Cell Sarcoma

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY ○ Indistinct cell borders, eosinophilic cytoplasm

• Neoplastic proliferation of cells showing morphologic and
immunophenotypic features of follicular dendritic cells
CLINICAL ISSUES
• Young and middle-aged adults
• Female predominance in inflammatory pseudotumor-like
variant
• Majority involve lymph nodes, particularly cervical
• > 1/3 arise in extranodal sites (GI tract, soft tissue, etc.)
• Treatment: Complete surgical excision ± chemotherapy or
radiotherapy
• Generally protracted clinical course
○ Up to 50% recur locally
○ Up to 25% metastasize, often late
MICROSCOPIC
• Spindled to ovoid cells in sheets, fascicles, or storiform
whorls
○ Nuclei with finely dispersed, speckled chromatin and
nucleolus
• Lymphocytic infiltrate common
• Some cases show significant cytologic atypia and
pleomorphism
• Morphologic variant: Inflammatory pseudotumor-like
ANCILLARY TESTS
• CD21(+), CD23(+), CD35(+)
• Clusterin (+), fascin (+), vimentin (+)
• EMA (variable), S100 (variable), CD68 (variable)
• CD45(-), CD34(-), keratin (-), desmin (-), CD1a(-), HMB-45(-)
TOP DIFFERENTIAL DIAGNOSES
• Interdigitating dendritic cell sarcoma
• Metastatic sarcomatoid carcinoma
• Inflammatory myofibroblastic tumor

Follicular Dendritic Cell Sarcoma Whorling Architecture

(Left) Follicular dendritic cell
sarcoma (FDCS) may be
impossible to distinguish from
interdigitating dendritic cell
sarcoma histologically and
often requires
immunohistochemistry. In this
slide, sheets of ovoid tumor
cells are associated with
admixed lymphocytes and
capillary blood vessels. (Right)
Architecturally, FDCS typically
shows a storiform or whorling
growth pattern, at least
focally. Other patterns include
fascicular, nests, and sheet-
like growth.

Cytologic Features CD23 Expression

(Left) The neoplastic dendritic
cells of FDCS have distinctive
oval nuclei with speckled
chromatin, small nucleoli, and
prominent nuclear membrane
﬈. Indistinct cell margins give
a syncytial appearance to the
tumor. (Right) The lesional
cells of FDCS express markers
of follicular dendritic cell
origin, including CD21, CD23
(shown), and CD35, although
expression of each varies from
case to case. Keratins and
S100 protein are generally
negative.

326
 Follicular Dendritic Cell Sarcoma

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
TERMINOLOGY MICROSCOPIC
Abbreviations Histologic Features
• Follicular dendritic cell sarcoma (FDCS) • Spindled to ovoid cells in sheets, fascicles, or storiform
whorls
Synonyms
○ Indistinct cell borders, eosinophilic cytoplasm
• Follicular dendritic reticulum cell sarcoma ○ Nuclei distinctive
Definitions – Ovoid or elongated
• Neoplastic proliferation of cells showing morphologic and – Finely dispersed, speckled chromatin with nucleolus
immunophenotypic features of follicular dendritic cells – Pseudoinclusions common
– Multinucleated cells often seen
ETIOLOGY/PATHOGENESIS • Lymphocytic infiltrate common
• Mitotic rate usually < 10 per 10 HPF
Varied Etiologies
• Some cases show significant cytologic atypia and
• Most cases arise de novo pleomorphism
• 10-15% arise in hyaline-vascular-type Castleman disease ○ More likely to contain atypical mitoses and coagulative
○ Antecedent dendritic cell hyperplasia and dysplasia necrosis
• Inflammatory pseudotumor-like variant associated with • Rare features: Myxoid stroma, clear cells, oncocytic cells,
EBV epithelioid cells, cystic spaces, osteoclast-like giant cells

CLINICAL ISSUES Morphologic Variants

• Inflammatory pseudotumor-like variant
Epidemiology
○ Spindled to ovoid cells associated with prominent
• Age lymphoplasmacytic infiltrate
○ Young and middle-aged adults ○ Necrosis and hemorrhage common
• Sex ○ Fibrinoid vascular changes
○ M=F
– Female predominance in inflammatory pseudotumor- ANCILLARY TESTS
like variant
Immunohistochemistry
Site • CD21(+), CD23(+), CD35(+)
• Majority involve lymph nodes • Clusterin (+), fascin (+), vimentin (+)
○ Cervical node involved most commonly • EMA (variable), S100 (variable), CD68 (variable)
• Inflammatory pseudotumor-like variant • EBER(+) in inflammatory pseudotumor-like variant
○ Liver or spleen characteristic • CD45(-), CD34(-), keratin (-), desmin (-), CD1a(-), HMB-45(-)
• > 1/3 arise in extranodal sites
○ GI tract, tonsil, mediastinum, skin, soft tissue, others DIFFERENTIAL DIAGNOSIS
Presentation Interdigitating Dendritic Cell Sarcoma
• Slow-growing, painless mass • May be histologically indistinguishable from FDCS
• Systemic symptoms (e.g., fever) uncommon • Immunohistochemistry helpful
○ Exception: Inflammatory pseudotumor-like variant ○ S100(+), CD21(-), CD23(-), CD35(-), clusterin (-)
• Rare patients have paraneoplastic pemphigus or
Metastatic Sarcomatoid Carcinoma
myasthenia gravis
• Clinical history of primary tumor elsewhere
Treatment • Keratin (+)
• Complete surgical excision ± chemotherapy or radiotherapy
Inflammatory Myofibroblastic Tumor
Prognosis • Can mimic inflammatory pseudotumor-like FDCS
• Generally protracted clinical course • SMA (+); ALK-1(+) in up to 50% of cases
○ Up to 50% recur locally • CD21(-) and EBER(-)
○ Up to 25% metastasize
– Often later in disease course SELECTED REFERENCES
○ Up to 20% of patients die of disease, often after long 1. Wu A et al: Follicular dendritic cell sarcoma. Arch Pathol Lab Med.
period of time 140(2):186-90, 2016
• High-grade cytologic features, necrosis, size > 6 cm, or 2. Pang J et al: Follicular dendritic cell sarcoma of the head and neck: case
report, literature review, and pooled analysis of 97 cases. Head Neck. ePub,
intraabdominal location often indicate greater potential for 2015
aggressive behavior 3. Choe JY et al: Inflammatory pseudotumor-like follicular dendritic cell
sarcoma of the spleen: a report of six cases with increased IgG4-positive
plasma cells. Pathol Int. 63(5):245-51, 2013
MACROSCOPIC
4. Soriano AO et al: Follicular dendritic cell sarcoma: a report of 14 cases and a
Size review of the literature. Am J Hematol. 82(8):725-8, 2007

• Mean: 5 cm
327
 Interdigitating Dendritic Cell Sarcoma

KEY FACTS
Fibrohistiocytic, Histiocytic, and Dendritic Cell
Tumors

TERMINOLOGY ○ Paracortical localization of tumor cells is common

• Neoplastic proliferation of cells with immunophenotype
similar to normal interdigitating dendritic cells
CLINICAL ISSUES
• Very rare
• Most patients are adults (median: 6th-7th decades)
• Usually arises in single lymph node
○ Less commonly arises in extranodal sites
• Slow-growing, asymptomatic mass
○ Systemic symptoms (e.g., fever) occur in subset
• Treatment: Surgical resection ± radiation for localized
disease
• Prognosis is variable and largely unpredictable
○ 40-50% of patients develop disseminated disease
MICROSCOPIC
• Partial or complete replacement of lymph node
architecture
• Spindled-to-ovoid, eosinophilic cells forming sheets,
fascicles, whorls
○ Vesicular nuclei with small or prominent nucleoli
• Nuclei uniform to pleomorphic
• Mitotic rate usually < 5 per 10 HPF
• Infiltrate of small lymphocytes common
ANCILLARY TESTS
• S100(+), SOX10(+)
• Variable CD45(+), CD163(+), and CD68(+)
• CD21(-), CD23(-), CD35(-), CD1a(-), clusterin (-), EMA(-),
keratin (-), melanocytic markers (-)
TOP DIFFERENTIAL DIAGNOSES
• Follicular dendritic cell sarcoma
• Metastatic melanoma
• Histiocytic sarcoma

Interdigitating Dendritic Cell Sarcoma Cytologic Features

(Left) Interdigitating dendritic
cell sarcoma (IDCS) usually
arises in lymph nodes and
typically shows a paracortical
distribution with sparing of
lymphoid follicles ﬈. (Right)
Cytologically, the cells of IDCS
are spindled to ovoid with
eosinophilic cytoplasm and
indistinct borders. Nuclei are
often vesicular and contain
small-to-prominent nucleoli. A
chronic inflammatory
infiltrate, particularly
lymphocytes, is common.

Cytologic Features Nuclear Pleomorphism

(Left) This example of IDCS is
more cellular but still shows
typical cytologic features.
Mitoses are usually low.
Immunohistochemistry is often
very helpful in establishing the
diagnosis. (Right) Some cases
of IDCS may show marked
nuclear atypia and
pleomorphism as well as
increased mitoses ﬈. These
findings have not been
confirmed to portend a more
adverse prognosis.

328
 Interdigitating Dendritic Cell Sarcoma

Tumors
Fibrohistiocytic, Histiocytic, and Dendritic Cell
○ Abundant eosinophilic cytoplasm; indistinct cell borders
TERMINOLOGY
○ Occasional epithelioid morphology
Abbreviations • Nuclei may be relatively uniform or occasionally
• Interdigitating dendritic cell sarcoma (IDCS) pleomorphic
○ Mitotic rate is variable, but usually < 5 per 10 HPF
Synonyms
○ Occasional multinucleated cells
• Interdigitating dendritic cell tumor • Scattered infiltrate of small lymphocytes common
• Interdigitating dendritic reticulum cell sarcoma ○ Less commonly plasma cells, eosinophils
Definitions
• Neoplastic proliferation of cells with immunophenotype ANCILLARY TESTS
similar to normal interdigitating dendritic cells Immunohistochemistry
• S100(+), SOX10(+), fascin (+)
CLINICAL ISSUES • Variable CD45(+), CD163(+), and CD68(+)
Epidemiology • CD21(-), CD23(-), CD35(-), CD1a(-), clusterin (-), EMA(-),
• Incidence keratin (-), melanocytic markers (-)
○ Very rare
• Age DIFFERENTIAL DIAGNOSIS
○ Most patients are adults; median: 6th-7th decades Follicular Dendritic Cell Sarcoma
Site • May be histologically indistinguishable from IDCS
• Whorled or storiform architecture prominent
• Usually arises in single lymph node
• Nuclear pseudoinclusions
○ Usually cervical, axillary, or inguinal lymph node groups
• Immunohistochemistry helpful
• Extranodal sites can be involved
○ CD21(+), CD23(+), CD35(+), clusterin (+), D2-40(+)
○ Skin and soft tissue most common
○ S100(-), but may be focally (+)
○ Liver, spleen, other viscera
Metastatic Melanoma
Presentation
• Can closely simulate IDCS both histologically and
• Slow-growing, asymptomatic mass
immunohistochemically
• Systemic symptoms (e.g., fever) occur in subset
○ Prior history of melanoma may be crucial for diagnosis
• Rare hepatosplenomegaly, generalized lymphadenopathy
• More often cytologically atypical than IDCS
• May rarely arise in patients with history of low-grade B-cell
• CD45(-)
lymphoma or T-cell lymphoma
• HMB-45, melan-A, and tyrosinase variably positive but may
Treatment be negative
• Surgical resection ± radiation for localized disease Histiocytic Sarcoma
• No current established chemotherapy regimen due to rarity
• Epithelioid morphology is dominant, often with prominent
of disease
nucleoli
Prognosis • Strongly CD163(+), CD68(+)
• Variable, largely unpredictable clinical course • S100 (variable)
○ 40-50% of patients develop disseminated disease with Langerhans Cell Sarcoma
poor outcome
• Nuclear grooves may be present
MACROSCOPIC • Eosinophilic infiltrate
• S100(+), CD1a(+), langerin (+)
General Features
• Lobulated mass with firm or fleshy cut surface SELECTED REFERENCES
Size 1. Ninkovic S et al: Interdigitating dendritic cell sarcoma: diagnostic pitfalls,
treatment challenges and role of transdifferentation in pathogenesis.
• Usually < 10 cm Pathology. 49(6):643-646, 2017
2. Nguyen CM et al: Primary cutaneous interdigitating dendritic cell sarcoma: a
case report and review of the literature. Am J Dermatopathol. 38(8):628-31,
MICROSCOPIC 2016
Histologic Features 3. Stowman AM et al: Spindle cell melanoma and interdigitating dendritic cell
sarcoma: do they represent the same process? Am J Surg Pathol. 40(9):1270-
• Partial or complete replacement of lymph node 9, 2016
architecture 4. Ohtake H et al: Interdigitating dendritic cell sarcoma and follicular dendritic
cell sarcoma: histopathological findings for differential diagnosis. J Clin Exp
○ Paracortical localization of tumor cells is common Hematop. 53(3):179-84, 2013
– Spares lymphoid follicles 5. Perkins SM et al: Interdigitating and follicular dendritic cell sarcomas: a SEER
○ Sinusoidal pattern of involvement can be prominent analysis. Am J Clin Oncol. 36(4):395-8, 2013
6. Orii T et al: Differential immunophenotypic analysis of dendritic cell tumours.
• Spindled-to-ovoid cells forming sheets, fascicles, whorls J Clin Pathol. 63(6):497-503, 2010
○ Vesicular nuclei with small or prominent nucleoli 7. Gaertner EM et al: Interdigitating dendritic cell sarcoma. A report of four
– Nuclear membrane indentations may be seen cases and review of the literature. Am J Clin Pathol. 115(4):589-97, 2001

329
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 SECTION 7

Smooth Muscle Tumors

Benign
Smooth Muscle Hamartoma 332
Superficial Leiomyoma 334
Deep Leiomyoma 338

Intermediate
Epstein-Barr Virus-Associated Smooth Muscle Tumor 342

Malignant
Leiomyosarcoma 344
 Smooth Muscle Hamartoma

KEY FACTS
Smooth Muscle Tumors

TERMINOLOGY
• Synonym: Congenital smooth muscle hamartoma
• Rare, benign smooth muscle proliferation presenting in
infants
• Horizontal band-like dermal proliferation of haphazard
smooth muscle bundles
• Probably on spectrum with Becker nevus
• Probably unrelated to acquired smooth muscle hamartoma
of scrotum (reactive smooth muscle hyperplasia) despite
similar histologic features
CLINICAL ISSUES
• Lumbosacral area and proximal extremities
• Macule or slightly indurated plaque
• Often hyperpigmented
• Usually with increased &/or coarse hair (> 80%)
• Pseudo-Darier sign: Rubbing lesion produces temporary
induration or piloerection
MICROSCOPIC
• Horizontal band-like proliferation of smooth muscle in
dermis
• Haphazardly arranged bundles of benign smooth muscle
• Each bundle has similar appearance to arrector pili
• Lacks pleomorphism, mitoses, necrosis
• Often overlying epidermal hyperplasia with basal
hyperpigmentation
• If lentiginous junctional melanocytes also present = Becker
nevus
TOP DIFFERENTIAL DIAGNOSES
• Cutaneous leiomyoma (pilar leiomyoma)
• Cutaneous leiomyosarcoma (atypical intradermal smooth
muscle neoplasm)
• Acquired smooth muscle "hamartoma" of scrotum
• Combined blue nevus/smooth muscle hamartoma
• Normal skin from special sites (nipple, vulva, or scrotum)

Horizontal Band-Like Proliferation Haphazard Bundles

(Left) Smooth muscle
hamartoma is composed of
haphazardly arranged smooth
muscle bundles that form a
horizontal band-like
proliferation ﬈ in the dermis
and superficial subcutis.
(Right) Smooth muscle bundles
﬈ are arranged haphazardly
in the dermis in smooth muscle
hamartoma. This lesion lacks
the areas of solid growth more
typical of cutaneous (pilar)
leiomyoma.

Resemblance to Arrector Pili Muscles Minimal Atypia and Mitotic Activity

(Left) The smooth muscle
bundles in smooth muscle
hamartoma are very similar to
normal arrector pili. There
may be a thin clefting artifact
between the bundles and the
surrounding dermal collagen
﬈. (Right) The spindled nuclei
are bland, and mitoses are
usually not seen. There is
abundant eosinophilic
fibrillary cytoplasm typical of
normal smooth muscle.

332
 Smooth Muscle Hamartoma
TERMINOLOGY
Synonyms
• Congenital smooth muscle hamartoma
Definitions
• Rare, benign smooth muscle proliferation presenting in
infants
• Horizontal band of haphazard smooth muscle bundles in
dermis
• Probably at one end of spectrum that includes Becker
nevus
• Probably unrelated to acquired smooth muscle hamartoma
of scrotum (reactive smooth muscle hyperplasia) despite
similar histologic features
CLINICAL ISSUES
Site
• Lumbosacral area and proximal extremities
• Occasionally scrotum (debatable)
○ Some reported scrotal cases are actually reactive smooth
muscle hyperplasia rather than true hamartomas
Presentation
• Macule or slightly indurated plaque
○ Present since birth/infancy
○ Often hyperpigmented
○ Usually with increased &/or coarse hair (> 80%)
○ Sometimes with perifollicular papules but lacking
prominent hair
○ Rarely linear with perifollicular papules
○ Usually < 10 cm (sometimes much larger)
• Pseudo-Darier sign
○ Rubbing lesion produces temporary induration or
piloerection
• Rarely generalized (subset of "Michelin tire baby" cases)
• Rarely multiple
• Rarely familial
• Rarely admixed with port-wine stain (nevus flammeus)
Treatment
• Simple excision
Prognosis
• Excellent (completely benign)
MICROSCOPIC
Histologic Features
• Horizontal band-like proliferation of smooth muscle in
dermis and superficial subcutis
• Haphazardly arranged bundles of benign smooth muscle
○ Bundles are similar to arrector pili
○ May be cleft artifact between bundle and surrounding
dermis
○ Bland spindled nuclei
○ Abundant stringy eosinophilic cytoplasm
○ Lacks pleomorphism, mitoses, necrosis
• Often overlying epidermal hyperplasia with basal
hyperpigmentation
○ If lentiginous junctional melanocytes also present =
Becker nevus
Smooth Muscle Tumors
ANCILLARY TESTS
Immunohistochemistry
• Desmin, actins, other smooth muscle markers (+)
• Abundant CD34(+) dendritic cells may be seen in dermis
DIFFERENTIAL DIAGNOSIS
Cutaneous Leiomyoma (Pilar Leiomyoma)
• Young adults rather than infants
• Papules/nodules, sometimes multiple, sometimes
coalescing into plaques
• More abundant muscle bundles forming solid nodule with
irregular borders (not horizontal band)
Cutaneous Leiomyosarcoma (Atypical Intradermal
Smooth Muscle Neoplasm)
• Dermal nodule of atypical smooth muscle cells in
intersecting fascicles
• Marked nuclear atypia and increased mitoses
• More abundant muscle bundles forming solid nodule with
irregular borders (not horizontal band)
Acquired Smooth Muscle "Hamartoma" of Scrotum
• Similar histologic appearance; adults
• Reactive hyperplasia of scrotal smooth muscle (not true
hamartoma)
○ Often secondary to chronic lymphedema
Combined Blue Nevus/Smooth Muscle Hamartoma
• Haphazard benign smooth muscle bundles in dermis
• Admixed benign pigmented spindled melanocytes and
melanophages (blue nevus)
• Sometimes with nests of benign epithelioid melanocytes
(as in common nevi)
Normal Skin From Special Sites
• Abundant smooth muscle bundles normally present in
nipple, vulva, and scrotum
SELECTED REFERENCES
1. Jain S et al: Multiple acquired smooth muscle hamartomas with thick-walled
blood vessels on scalp. J Cutan Pathol. 45(8):629-32, 2018
2. Fernandez-Flores A et al: Combined cutaneous smooth muscle hamartoma
and nevus flammeus. J Cutan Pathol. 41(7):612-6, 2014
3. Tzu J et al: Combined blue nevus-smooth muscle hamartoma: a series of 12
cases. J Cutan Pathol. 40(10):879-83, 2013
4. Holland KE et al: Generalized congenital smooth muscle hamartoma
presenting with hypertrichosis, excess skin folds, and follicular dimpling.
Pediatr Dermatol. 25(2):236-9, 2008
5. Kharfi M et al: Michelin tire syndrome: a report of two siblings. Pediatr
Dermatol. 22(3):245-9, 2005
6. van Kooten EO et al: Acquired smooth-muscle hamartoma of the scrotum: a
histological simulator? J Cutan Pathol. 31(5):388-92, 2004
7. Gualandri L et al: Multiple familial smooth muscle hamartomas. Pediatr
Dermatol. 18(1):17-20, 2001
8. Jang HS et al: Linear congenital smooth muscle hamartoma with follicular
spotted appearance. Br J Dermatol. 142(1):138-42, 2000
9. Koizumi H et al: CD34-positive dendritic cells are an intrinsic part of smooth
muscle hamartoma. Br J Dermatol. 140(1):172-4, 1999
10. Gagné EJ et al: Congenital smooth muscle hamartoma of the skin. Pediatr
Dermatol. 10(2):142-5, 1993
11. Zvulunov A et al: Congenital smooth muscle hamartoma. Prevalence, clinical
findings, and follow-up in 15 patients. Am J Dis Child. 144(7):782-4, 1990
12. Johnson MD et al: Congenital smooth muscle hamartoma. A report of six
cases and a review of the literature. Arch Dermatol. 125(6):820-2, 1989
333
 Superficial Leiomyoma

KEY FACTS
Smooth Muscle Tumors

TERMINOLOGY
• Benign dermal smooth muscle neoplasm
○ Pilar type (piloleiomyoma) arises from arrector pili
○ Genital type arises from specialized genital smooth
muscle
ETIOLOGY/PATHOGENESIS
• Hereditary leiomyomatosis and renal cell cancer syndrome
(HLRCC)
○ Multiple leiomyomas of skin and uterus
○ Subsets develop renal cell carcinoma (RCC)
○ Mutations in fumarate hydratase (FH) gene (autosomal
dominant)
CLINICAL ISSUES
• Pilar leiomyoma: Multiple painful pink/brown
papules/nodules, most < 2 cm
• Genital leiomyoma: Solitary painless nodule on scrotum,
penis, vulva, or nipple of adults
MICROSCOPIC
• Pilar leiomyoma
○ Ill-defined dermal nodule composed of haphazardly
arranged smooth muscle bundles/fascicles
○ Bland, blunt-ended, spindled nuclei
○ Abundant fibrillary eosinophilic cytoplasm
○ Focal atypia and occasional mitoses (up to 1/10 HPF)
acceptable
○ Fascicles often dissect between dermal collagen
• Genital leiomyoma
○ Usually more circumscribed, cellular, and histologically
heterogeneous (e.g., myxoid change, hyalinization,
epithelioid cells) than pilar leiomyoma
TOP DIFFERENTIAL DIAGNOSES
• Superficial leiomyosarcoma
• Congenital smooth muscle hamartoma
• Angioleiomyoma
• Dermatomyofibroma

Cutaneous Leiomyomas and HLRCC Pilar Leiomyoma

(Left) Clinical photo shows
cutaneous leiomyomas in a
patient with hereditary
leiomyomatosis and renal cell
cancer (HLRCC). Numerous
red/brown papules coalescing
into plaques are present on
the chest, lower neck,
shoulder, and upper arm.
(Right) The pilar type of
superficial leiomyoma is an ill-
defined dermal nodule
composed of multiple
eosinophilic smooth muscle
bundles.

Resemblance to Arrector Pili Muscles Smooth Muscle Cytology

(Left) The individual
eosinophilic smooth muscle
bundles ﬈ of pilar leiomyoma
resemble normal arrector pili
muscles. (Right) The smooth
muscle fascicles/bundles of
pilar leiomyoma consist of
elongated spindled cells with
abundant fibrillary
eosinophilic cytoplasm. Nuclei
are oval with blunt ends
(cigar-shaped) and show little
cytologic atypia or mitotic
activity. Note the
characteristic pattern of
fascicles dissecting between
dermal collagen bundles ﬉.

334
 Superficial Leiomyoma
TERMINOLOGY
Synonyms
• Cutaneous leiomyoma, leiomyoma cutis
Definitions
• Benign dermal smooth muscle neoplasm
○ Pilar type (piloleiomyoma) arises from arrector pili
○ Genital type arises from specialized genital smooth
muscle
ETIOLOGY/PATHOGENESIS
Hereditary Leiomyomatosis and Renal Cell Cancer
Syndrome (HLRCC)
• Synonyms: Multiple cutaneous and uterine leiomyomatosis
syndrome, Reed syndrome
• Multiple leiomyomas of skin and uterus, risk of renal cell
carcinoma (RCC)
• Familial autosomal dominant germline loss of function
mutations in fumarate hydratase (FH) gene
○ Most with multiple cutaneous leiomyomas have FH
mutation
○ Most women with FH mutation have uterine leiomyomas
• Features of uterine leiomyomas in HLRCC
○ Multiple; 1-8 cm; presenting at young age
○ Increased cellularity and nuclear atypia
○ Unique prominent eosinophilic inclusion-like nucleoli
surrounded by clear halo
– Similar distinct nucleoli seen in RCC occurring in
HLRCC
– These nucleoli not present in cutaneous leiomyomas
of HLRCC
• Subset of HLRCC patients develop RCC
○ Often more aggressive; usually papillary, tubulopapillary,
or collecting duct types
○ Distinct large eosinophilic nucleoli with clear halo
CLINICAL ISSUES
Presentation
• Pilar leiomyoma
○ Most arise in adolescents or young adults
○ Multiple painful pink/brown papules/nodules, most < 2
cm
– Rare cases are solitary and painless
○ Papules may coalesce into nodules/plaques
○ Extensor surfaces of extremities, trunk, head, and neck
– Often 2 or more body sites affected
• Genital leiomyoma
○ Solitary painless nodule on scrotum, penis, vulva, or
nipple of adults
Treatment
• Depends on number of lesions and symptomatology
• Excision for localized or symptomatic lesions
• Conservative management for extensive lesions
• Imaging of kidneys and uterus if multiple skin lesions
• Cryotherapy and laser ablation: Mixed results
Prognosis
• Benign; does not undergo malignant transformation
Smooth Muscle Tumors
• Excised lesions may recur (or new lesions may develop)
MICROSCOPIC
Histologic Features
• Pilar leiomyoma
○ Ill-defined dermal nodule composed of haphazardly
arranged smooth muscle bundles/fascicles
○ Bland, blunt-ended, spindled nuclei
○ Abundant fibrillary eosinophilic cytoplasm
○ Focal atypia and occasional mitoses (up to 1 figure per 10
HPF) acceptable
– Numerous mitoses, diffuse/marked atypia, high
cellularity, &/or necrosis: Leiomyosarcoma
○ Fascicles often dissect between dermal collagen
○ Rare cases are circumscribed
• Genital leiomyoma
○ Usually more circumscribed, cellular, and histologically
heterogeneous (e.g., myxoid change, hyalinization,
epithelioid cells) than pilar leiomyoma
• "Symplastic" pilar and genital leiomyoma (very rare, use
caution): Scattered pleomorphism but no mitoses
ANCILLARY TESTS
Immunohistochemistry
• Strong, diffuse desmin (+) (best), SMA(+), MSA(+)
• Leiomyoma in HLRCC often (-) fumarate hydratase by IHC
(not 100% sensitive or specific)
DIFFERENTIAL DIAGNOSIS
Superficial Leiomyosarcoma
• Usually solitary; marked atypia, hypercellularity, mitoses
Congenital Smooth Muscle Hamartoma
• Usually solitary lumbosacral plaque in child, often with
increased hair and pigmentation
• Horizontal band-like dermal proliferation of haphazard
smooth muscle bundles
Angioleiomyoma
• Solitary painful subcutaneous nodule, usually in lower
extremity of middle-aged women
• Sharply circumscribed; smooth muscle intimately admixed
with thick-walled vessels; usually lacks discrete bundles;
dermal involvement rare
Dermatomyofibroma
• Solitary plaque on shoulder/trunk of young adult
• Fascicles of spindled (myo)fibroblasts arranged parallel to
epidermis; lacks smooth muscle bundles
• Despite name, often lack desmin and actin staining
SELECTED REFERENCES
1. Jones C et al: Incidence of mature adipocytic component within cutaneous
smooth muscle neoplasms. J Cutan Pathol. 43(10):866-71, 2016
2. Llamas-Velasco M et al: Fumarate hydratase immunohistochemical staining
may help to identify patients with multiple cutaneous and uterine
leiomyomatosis (MCUL) and hereditary leiomyomatosis and renal cell cancer
(HLRCC) syndrome. J Cutan Pathol. 41(11):859-65, 2014
3. Matoso A et al: Symplastic leiomyomas of the scrotum: a comparative study
to usual leiomyomas and leiomyosarcomas. Am J Surg Pathol. 38(10):1410-
7, 2014
335
 Superficial Leiomyoma
Smooth Muscle Tumors

Multiple Pilar Leiomyomas Ill-Defined Dermal Nodule

(Left) Superficial leiomyomas
(pilar type) are usually under 2
cm and appear as multiple
pink or brown papules or
nodules. Clinically, they tend
to elicit pain and are often
distributed in a dermatomal
fashion. (Right) Low-power
H&E shows a superficial (pilar
type) leiomyoma involving the
majority of the dermis. The
lesion is unencapsulated and
vaguely circumscribed but
does have an irregular border
﬈ with displacement of
dermal appendages ﬊.

Collagen Bundles Grenz Zone

(Left) At higher power,
superficial leiomyomas consist
of short fascicles or bundles of
smooth muscle ﬈
haphazardly arranged within
the dermis and tend to dissect
between dermal collagen
bundles ﬉. (Right) Many
superficial leiomyomas have a
grenz zone ﬊ and epidermal
hyperplasia with elongated
rete pegs adjacent to normal
epidermis ﬈.

Incipient Pilar Leiomyoma Rare Sharp Circumscription

(Left) Surgical specimens often
reveal incipient pilar
leiomyomas ﬉ adjacent to
the primary tumor. The
primary tumor in this example
does show areas of
circumscription ﬊, but other
areas have the more typical
infiltrative pattern ﬈. (Right)
Rare examples of superficial
leiomyoma are well
circumscribed, such as this
solitary lesion, which shows
only focal areas with an
irregular border ﬉. Solitary
lesions, such as the example
shown, often present without
pain symptoms.

336
 Superficial Leiomyoma
Solitary, Circumscribed Leiomyoma
DDx: Angioleiomyoma
DDx: Superficial Leiomyosarcoma
Smooth Muscle Tumors
Solitary Leiomyoma
(Left) Similar to typical
superficial leiomyomas,
solitary and circumscribed
cutaneous leiomyomas can
arise from the pilar smooth
muscle. This solitary and
circumscribed tumor was
located adjacent to a
sebaceous gland ﬊ and pilar
smooth muscle bundle ﬈,
indicating likely origin from
this pilosebaceous unit. (Right)
Compared to typical pilar
leiomyomas, solitary
superficial leiomyomas are
more often solid and less often
characterized by small smooth
muscle fascicles intersecting
between dermal collagen.
Vessels in Angioleiomyoma
(Left) In contrast to superficial
leiomyoma, angioleiomyoma is
usually circumscribed and
contains numerous variably
sized vascular channels that
stand out at low power ﬉. In
addition, it is usually solitary
and located in the lower
extremity. (Right) Sheets of
smooth muscle cells with
abundant fibrillary
eosinophilic cytoplasm
intimately associated with
thick-walled, often slit-like
vascular channels characterize
angioleiomyoma at higher
power.
Atypia and Mitoses in Leiomyosarcoma
(Left) Superficial (or
cutaneous) leiomyosarcoma
also consists of fascicles of
cells with abundant fibrillary
eosinophilic cytoplasm with
blunt-ended, oval nuclei.
However, this tumor is more
cellular and demonstrates less
dissection of dermal collagen.
It is also usually larger than
superficial leiomyoma. (Right)
At higher power, superficial
leiomyosarcoma usually
features moderate to marked
nuclear atypia with a higher
nuclear:cytoplasmic ratio than
leiomyoma. Mitotic figures ﬈
are also generally more
frequent.
337
 Deep Leiomyoma

KEY FACTS
Smooth Muscle Tumors

TERMINOLOGY • Other findings: Myxoid change, fibrosis, cystic changes, rare

• Benign smooth muscle neoplasm arising in deep soft tissue epithelioid or clear cell morphology
of extremities (somatic), retroperitoneum, or • No significant nuclear pleomorphism, mitotic activity, or
abdominopelvic cavity necrosis
○ Low mitotic rates allowed in retroperitoneal/pelvic
CLINICAL ISSUES tumors in women
• 4th-6th decades of life most common
ANCILLARY TESTS
• Strong female predominance for retroperitoneal/pelvic
tumors • Diffuse SMA(+), MSA(+), desmin (+)
• Treatment: Simple surgical excision • ER, PR, and WT1 often expressed in retroperitoneal and
• Benign tumor if correctly diagnosed abdominopelvic tumors in women; rare in deep somatic
tumors
○ Recurrence rare (more likely in retroperitoneum/pelvis)
MACROSCOPIC TOP DIFFERENTIAL DIAGNOSES
• Leiomyosarcoma
• Well circumscribed with gray/white, firm cut surface
• Gastrointestinal stromal tumor
• 3-20 cm (wide size range)
• Cellular schwannoma
MICROSCOPIC • PEComa
• Short fascicles or aggregates of uniform spindle cells with
abundant eosinophilic cytoplasm and blunt-ended nuclei

Deep Leiomyoma Smooth Muscle Bundles

(Left) Deep leiomyoma is a
well-circumscribed (but
nonencapsulated) benign
smooth muscle tumor of deep
somatic soft tissue and the
retroperitoneum/abdominopel
vis. Myxoid stromal changes
﬊ and fibrosis may be seen in
some cases, similar to
gynecologic leiomyomas.
(Right) Similar to those that
occur in other sites,
leiomyoma of deep soft tissue
commonly shows variably
sized bundles of well-
differentiated smooth muscle
cells.

Smooth Muscle Cytology Myogenic Marker Expression

(Left) Deep leiomyoma shows
classic cytologic features of
smooth muscle differentiation,
including abundant
eosinophilic cytoplasm and
uniform nuclei with blunt ends
(cigar-shaped). Varying
degrees of fascicular growth is
also typical. (Right) Most cases
of deep leiomyoma show
diffuse cytoplasmic
immunoreactivity for smooth
muscle actin, muscle specific
actin, and desmin (shown). A
subset of tumors may show
focal keratin expression as
well.

338
 Deep Leiomyoma

Smooth Muscle Tumors

○ < 1 per 50 HPF in deep soft tissues of extremities
TERMINOLOGY (somatic)
Definitions – Between 1 and 5 per 50 HPF in this location should be
• Benign smooth muscle neoplasm arising in deep soft tissue classified as SMTUMP
of extremities (somatic), retroperitoneum, or ○ < 5 per 50 HPF in retroperitoneum/abdominopelvic
abdominopelvic cavity cavity in women
○ Gynecologic smooth muscle neoplasms are different and – Between 5 and 10 per 50 HPF in this location should
have well-established criteria for predicting behavior be classified as SMTUMP
○ < 1 per 50 HPF in retroperitoneum/abdominopelvic
CLINICAL ISSUES cavity in men
– Between 1 and 5 per 50 HPF in this location should be
Epidemiology
classified as SMTUMP
• Incidence • Necrosis is absent
○ Rare overall • Calcification common in deep somatic tumors
○ More common in retroperitoneum/pelvis than deep soft • Other findings: Myxoid change, fibrosis, mature adipose
tissue (somatic) tissue, clear cell change, osteoclast-like giant cells
• Age
○ 4th-6th decades most common ANCILLARY TESTS
• Sex
○ M = F  for deep soft tissue (somatic) tumors
Immunohistochemistry
○ Female predominance for retroperitoneal/pelvic tumors • Diffuse SMA(+), MSA(+), desmin (+), h-caldesmon (+)
• Subset express patchy keratin/EMA
Site • ER, PR, and WT1 often expressed in
• Most in retroperitoneum or abdominopelvic cavity retroperitoneal/abdominopelvic tumors in women
• Deep subcutis or intramuscularly in extremities (somatic)
Presentation DIFFERENTIAL DIAGNOSIS
• Slow-growing painless mass Leiomyosarcoma
• Necrosis &/or nuclear pleomorphism ± mitotic activity
Treatment
• If no nuclear pleomorphism or necrosis
• Simple surgical excision ○ Presence of > 5 mitoses per 50 HPF in deep soft tissue
Prognosis (somatic) tumors
• Benign tumor if correctly diagnosed ○ > 10 mitoses per 50 HPF in
retroperitoneal/abdominopelvic tumors in females
○ Tumors with certain levels of mitotic activity may recur
and are better classified as smooth muscle tumors of ○ > 5 mitoses per 50 HPF in
uncertain malignant potential (SMTUMP) retroperitoneal/abdominopelvic tumors in males
• Possibility of metastasis from uterine or abdominopelvic Gastrointestinal Stromal Tumor
leiomyosarcoma should always be excluded clinically • Most cases arise from muscular wall of gastrointestinal
tract
MACROSCOPIC • CD117(+), DOG1(+)
General Features • SMA, desmin expression occur but are uncommon
• Well circumscribed with gray/white, firm cut surface Cellular Schwannoma
• Calcification not uncommon
• Diffuse S100 protein (+)
Size • SMA(-) and desmin (-)
• 3-20 cm (wide range) PEComa
• Spindled to ovoid and epithelioid cells with clear or finely
MICROSCOPIC granular eosinophilic cytoplasm
Histologic Features • SMA(+), HMB-45(+), MART-1(+)
• Short fascicles or aggregates of uniform spindle cells ○ May show desmin (+)
○ Abundant eosinophilic cytoplasm
○ Blunt-ended nuclei (cigar-shaped) SELECTED REFERENCES
• No significant nuclear pleomorphism 1. Panagopoulos I et al: Genetic heterogeneity in leiomyomas of deep soft
○ Focal degenerative atypia may be present (symplastic tissue. Oncotarget. 8(30):48769-48781, 2017
2. Miettinen M: Smooth muscle tumors of soft tissue and non-uterine viscera:
change) biology and prognosis. Mod Pathol. 27 Suppl 1:S17-29, 2014
○ More than minimal true nuclear pleomorphism ± mitoses 3. Miettinen M et al: Evaluation of biological potential of smooth muscle
should be classified as leiomyosarcoma tumours. Histopathology. 48(1):97-105, 2006
• Mitotic rate should be absent or low, depending on site and 4. Hornick JL et al: Criteria for malignancy in nonvisceral smooth muscle
tumors. Ann Diagn Pathol. 7(1):60-6, 2003
sex of patient 5. Paal E et al: Retroperitoneal leiomyomas: a clinicopathologic and
immunohistochemical study of 56 cases with a comparison to
retroperitoneal leiomyosarcomas. Am J Surg Pathol. 25(11):1355-63, 2001

339
 Deep Leiomyoma
Smooth Muscle Tumors

Calcification Calcification
(Left) Calcification ﬈ is
generally a common finding in
deep leiomyoma and varies
from small and
psammomatous to large and
chunky. Clear cell change may
occasionally be associated
with the calcification. (Right)
Small concentric or
psammomatous calcifications
﬈ may be seen in some cases
of deep leiomyoma,
particularly in cases with other
degenerative features.

Stromal Edema Myxoid Stromal Change

(Left) Scattered, separated,
eosinophilic smooth muscle
cells ﬈ are evident at lower
magnification in this H&E from
a deep leiomyoma with areas
of prominent stromal edema.
(Right) Focal myxoid stromal
change is common in deep
leiomyoma and may
occasionally be prominent.
Rare cases are entirely myxoid.

Stromal Hyalinization Nuclear Palisading

(Left) Stromal hyalinization
and hypocellularity is another
common finding in leiomyoma
and may be focal or diffuse.
This finding is typical of
longstanding tumors and may
also be associated with
stromal calcification. (Right)
Nuclear palisading is an
uncommon but well-described
finding in deep leiomyoma. It
is often a focal finding when
present, but rare cases have
been described with diffuse
palisading.

340
 Deep Leiomyoma
Macrotrabecular Architecture
Microtrabecular Architecture
Epithelioid Morphology
Smooth Muscle Tumors
Microtrabecular Architecture
(Left) Macrotrabecular growth
in deep leiomyoma is
characterized by thick,
elongated bundles of smooth
muscle cells within a loose
myxoid or edematous stroma.
(Right) Microtrabecular
growth in deep leiomyoma is
characterized by thin bundles
or cords of smooth muscle
cells within a loose myxoid or
edematous stroma.
Organization around blood
vessels ﬈ is often apparent.
Epithelioid Morphology
(Left) Deep leiomyoma with a
microtrabecular growth
pattern may also show areas
with a variably complex
reticular appearance. (Right)
Epithelioid cytomorphology is
an uncommon finding in deep
leiomyoma and is often focal.
Clear cell change ﬈ may also
be seen but is likewise usually
focal and, in some cases,
associated with calcification.
Mature Adipose Tissue
(Left) H&E of a retroperitoneal
deep leiomyoma shows a
mixture of conventional
spindled smooth muscle cells
﬈ and epithelioid smooth
muscle cells ﬇ with more
prominent eosinophilic
cytoplasm. (Right) Mature
adipose tissue is occasionally
encountered in deep
leiomyoma and is often focal.
When prominent,
classification as an
extrauterine lipoleiomyoma or
myolipoma may be warranted.
341
 Epstein-Barr Virus-Associated Smooth Muscle Tumor

KEY FACTS
Smooth Muscle Tumors

TERMINOLOGY • Most patients survive with persistent disease (80%)

• Well-differentiated smooth muscle tumor associated with • HIV-related disease and intracranial tumors have worse
Epstein-Barr virus, often multifocal, occurring in overall survival
immunocompromised patients • Prognosis determined by immune condition of patient, not
by histology
CLINICAL ISSUES
MACROSCOPIC
• Adults and children (median age: 30 years)
• Pain and organ dysfunction • Median: 3-4 cm (range: 0.7-21.0 cm)
• Late complication of transplantation/immunosuppression MICROSCOPIC
• Arises in visceral organs, skin, and soft tissue • Well circumscribed
○ HIV related (50%): CNS most common • Fascicles of well-differentiated smooth muscle cells
○ Post transplant (45%): Liver most common • Primitive rounded cells in 50%
○ Congenital immunodeficiency related (5%): Lung/larynx • Tumor infiltrating T cells
most common
• Mitotic rate = 1-3 mitotic figures per 10 HPF
• Multifocal in > 50% of cases
• Only rare tumors with malignant (sarcoma-like) features
• Surgical excision is 1st-line therapy
• Reduction of immunosuppressive agents TOP DIFFERENTIAL DIAGNOSES
• Efficacy of chemotherapy, antiviral therapy, radiotherapy • Leiomyoma
unproven • Leiomyosarcoma

EBV-Associated Smooth Muscle Tumor Low-Power Appearance

(Left) Epstein-Barr virus-
associated smooth muscle
tumor (EBV-SMT) typically
presents as a visceral tumor in
an immunocompromised host
as exemplified by this lung
tumor in a postrenal
transplant patient. The tumors
are well circumscribed and
often multifocal. (Right) Most
EBV-SMTs are comprised by
sheets or fascicles of well-
differentiated smooth muscle
cells with uniform nuclei, low
mitotic activity, and no
necrosis. Only rare sarcoma-
like tumors occur, which have
not been found to have
prognostic significance.

Fascicles of Smooth Muscle Cells EBER In Situ Hybridization

(Left) The cells of EBV-SMT are
usually arranged in fascicles
﬊ and have low-grade
cytologic atypia as illustrated.
Tumor-infiltrating T cells ﬉
are common. Primitive round
cells (not shown) are present
in 50% of cases. (Right) The
diagnosis of EBV-SMT is
confirmed by detection of
Epstein-Barr-encoded RNA
(EBER) by in situ hybridization,
as depicted by diffuse, dark
blue nuclear stippling ﬈.

342
 Epstein-Barr Virus-Associated Smooth Muscle Tumor

Smooth Muscle Tumors

TERMINOLOGY MACROSCOPIC
Abbreviations General Features
• Epstein-Barr virus-associated smooth muscle tumor (EBV- • Circumscribed, solid or cystic
SMT)
Size
Definitions • Median: 3-4 cm (range: 0.7-21.0 cm)
• Well-differentiated SMT associated with EBV, often
multifocal, occurring in immunocompromised patients MICROSCOPIC
Histologic Features
ETIOLOGY/PATHOGENESIS
• Well circumscribed
Infectious Agents • Fascicles of well-differentiated smooth muscle cells
• EBV (EBV-1 and EBV-2) • Primitive rounded cells in 50%
• Small tumor seedlings often found next to main tumor
CLINICAL ISSUES • Tumor infiltrating T cells
Epidemiology • Mitotic rate = 1-3 mitotic figures per 10 HPF
• Age ○ Higher in HIV-related disease
○ Adults and children (median: 30 years; range: 1-66 years) • Only rare tumors with malignant (sarcoma-like) features
• Sex ○ More common in HIV-related disease
○ F > M (55-67%)
ANCILLARY TESTS
Site
Immunohistochemistry
• Visceral organs, skin, soft tissue
• Smooth muscle actin (+) in all cases
• Varies by clinical subtype
• Desmin (+) in 50%
○ HIV related (50%)
• CD21(+) also common
– CNS most common, followed by GI, liver, skin, lungs
○ Post transplant (45%) In Situ Hybridization
– Liver most common, followed by lungs/larynx, • EBV-encoded RNA (EBER)
GI/spleen, CNS
○ Congenital immunodeficiency related (5%) DIFFERENTIAL DIAGNOSIS
– Lungs/larynx most common, followed by CNS, liver,
Leiomyoma
adrenal, spleen
• Histologically indistinguishable from EBV-SMT in most cases
Presentation ○ Lacks primitive round cells
• Pain and organ dysfunction • Rare in visceral organs outside uterus
• Late complication of transplantation/immunosuppression • EBER(-)
(median: 48 months)
• Multifocal in > 50% of cases Leiomyosarcoma
○ Distinct clones • Most EBV-SMT are histologically bland
– Indicates multiple infections, not metastases • Rare sarcoma-like tumors, usually in HIV-related disease
• EBER(-)
Treatment
• Surgical excision is 1st-line therapy Angioleiomyoma
○ Most effective in unifocal disease • Prominent muscular vascular stroma
• Reduction of immunosuppressive agents • Soft tissues in extremities
○ Risk of transplant organ rejection • Rare in visceral organs
• Antiviral agents recommended for HIV patients Myopericytoma
• Efficacy of chemotherapy, antiviral therapy, radiotherapy
• Smaller cells, prominent pericytomatous vascular stroma
unproven
• Soft tissues in extremities
Prognosis • Rare in visceral organs
• Most patients survive with persistent disease (80%)
○ Most patients who die succumb to infections SELECTED REFERENCES
○ Only rare patients die of disease 1. Hussein K et al: Clinico-pathological characteristics of different types of
• HIV-related disease and intracranial tumors have worse immunodeficiency-associated smooth muscle tumours. Eur J Cancer.
50(14):2417-24, 2014
overall survival 2. Issarachaikul R et al: Epstein-Barr virus-associated smooth muscle tumors in
• Prognosis determined by immune condition of patient, not AIDS patients: a largest case (series). Intern Med. 53(20):2391-6, 2014
by histology 3. Deyrup AT et al: Epstein-Barr virus-associated smooth muscle tumors are
distinctive mesenchymal tumors reflecting multiple infection events: a
clinicopathologic and molecular analysis of 29 tumors from 19 patients. Am
J Surg Pathol. 30(1):75-82, 2006

343
 Leiomyosarcoma

KEY FACTS
Smooth Muscle Tumors

TERMINOLOGY
• Malignant neoplasm composed of cells exhibiting true
smooth muscle differentiation
CLINICAL ISSUES
• Most common in middle-aged to older adults
• Female predilection in retroperitoneum/pelvis
• Retroperitoneum most common site
○ Also inferior vena cava, extremities, head/neck
• Vena caval tumors may cause Budd-Chiari syndrome
• Treatment: Complete surgical resection
• Overall poor prognosis
○ Local recurrence and metastasis common
○ Retroperitoneal tumors have worst prognosis
• Lung is most common site of metastasis
○ Can also metastasize to skin, lymph nodes, bone, and
other soft tissue sites
MICROSCOPIC
• Well-defined, cellular, intersecting fascicles or bundles of
spindle cells
• Eosinophilic cytoplasm with elongated, blunt-ended nuclei
○ Nuclear pleomorphism and hyperchromasia common
○ Mitotic rate varies but is often high
• Variants: Myxoid, pleomorphic
ANCILLARY TESTS
• SMA(+), usually diffuse and cytoplasmic
• Variable desmin and caldesmon expression
TOP DIFFERENTIAL DIAGNOSES
• Leiomyoma
• PEComa
• Desmoid fibromatosis
• Malignant peripheral nerve sheath tumor
• Undifferentiated pleomorphic sarcoma

Leiomyosarcoma Large Vessel Association

(Left) Leiomyosarcoma (LMS)
of soft tissue is a malignant
smooth muscle neoplasm that
most commonly arises in the
retroperitoneum or is
associated with a large vessel
(shown), particularly the
inferior vena cava. It arises
less frequently in the
extremities and head/neck
region. Uterine LMS has
separate defined diagnostic
criteria and is not addressed in
this text. (Right) LMS ﬊ is
often associated with (and
arises from) the muscular wall
of larger blood vessels (note
the vein ﬈ in this image).

Fascicles and Bundles Cytologic Features

(Left) The classic morphology
of LMS is that of cellular
fascicles and bundles of
prominently eosinophilic
spindle cells. Not infrequently,
fascicles appear to be
arranged perpendicularly to
each other, both longways ﬉
and en face ﬊, as depicted.
(Right) As is the case with
benign true smooth muscle
tumors, tumor cell nuclei in
LMS are generally elongated
with blunted ends (cigar
shaped). Note the
characteristic eosinophilic
fibrillary cytoplasm.

344
 Leiomyosarcoma

Smooth Muscle Tumors

– Lesions restricted to dermis/cutis can recur but almost
TERMINOLOGY never metastasize
Abbreviations □ Some observers have advocated classification as
• Leiomyosarcoma (LMS) atypical intradermal smooth muscle neoplasm
• Lung is most common site of metastasis
Definitions ○ Can also spread to skin, bone, lymph nodes, and other
• Malignant neoplasm composed of cells exhibiting true soft tissue sites
smooth muscle differentiation • Adverse prognostic factors: Larger size, high histologic
• Primary uterine/gynecologic and gastrointestinal LMS not grade, bone/vascular involvement
considered in this chapter
MACROSCOPIC
CLINICAL ISSUES
General Features
Epidemiology • Firm to fleshy, tan-gray cut surface
• Age • Hemorrhage &/or necrosis common
○ Most common in middle-aged to older adults
– Rarely arise in children Size
• Sex • Wide range (often large)
○ No gender preference overall ○ Retroperitoneal tumors are frequently > 10 cm
– Retroperitoneal and pelvic tumors show clear female ○ Superficial tumors of somatic soft tissue often < 5 cm
predilection
MICROSCOPIC
Site
• Retroperitoneum (including pelvis) most common
Histologic Features
• Large blood vessels (particularly inferior vena cava) • Peripheral border may be sharply circumscribed and
• Extremities (particularly lower limb) and head/neck region "pushing" or irregular and infiltrative
• Visceral organs • Well-defined, cellular, intersecting fascicles or bundles of
spindle cells
Presentation ○ Usually prominent, brightly eosinophilic cytoplasm
• Solitary, often large mass ○ Elongated blunt-ended (cigar-shaped) nuclei
○ Extremity lesions often smaller compared to other sites – Nuclear pleomorphism and hyperchromasia common
• Retroperitoneal lesions can be associated with abdominal but variable in extent
pain – Mitotic rate variable, but often high
○ Vena cava examples often symptomatic □ Atypical forms frequently seen
– Upper portion: Budd-Chiari syndrome (hepatomegaly, • Coagulative necrosis common but variable in extent
jaundice, ascites) • Stromal myxoid change or fibrosis/hyalinization
– Mid portion: Renal obstruction and dysfunction • Many cases are histologically high grade with prominent
– Lower portion: Lower extremity edema atypia, mitoses, and necrosis
• In extremities, may arise in subcutaneous fat or muscle ○ Low-grade tumors have minimal to no atypia, low mitotic
○ Often relatively asymptomatic indices, and no necrosis
• Large, ectatic staghorn vasculature occasionally present
Treatment
• Some cases feature prominent inflammatory cell infiltrate
• Complete surgical resection ○ May be extensive and obscuring
• Radiation &/or chemotherapy • Osteoclast-like multinucleated giant cells in some cases
Prognosis • Focal palisaded architecture rare
• Overall poor prognosis Morphologic Variants
○ Outcome depends on site and stage • Epithelioid LMS
– Retroperitoneum ○ Sheets and nests of small cells with minimal cytoplasm or
□ Very poor prognosis large eosinophilic cells with macronucleoli
□ Difficult to resect completely ○ Myxoid &/or hyalinized stroma can be seen
□ ~ 80% of patients die of disease, typically with • Myxoid LMS
metastases ○ Extensively myxoid stroma
– Inferior vena cava ○ Tends to be of low histologic grade
□ 5- and 10-year survival: 50% and 30%, respectively ○ Areas of conventional LMS usually present at least focally
– Extremities and head/neck • Pleomorphic LMS
□ Somewhat better prognosis, likely due to increased ○ Contains large, sheet-like areas of markedly pleomorphic
chance of complete resection tumor cells, similar to undifferentiated pleomorphic
□ Up to 30-50% of tumors metastasize sarcoma
□ Subcutaneous tumors have been associated with ○ Prominent cytoplasmic eosinophilia
improved survival over deep (subfascial) tumors in ○ Identification of more conventional areas of LMS often
some studies necessary for diagnosis

345
 Leiomyosarcoma
Smooth Muscle Tumors
ANCILLARY TESTS
Immunohistochemistry
• SMA(+), usually diffuse and cytoplasmic
• Variable desmin and caldesmon expression
○ Higher grade tumors more likely to be negative for these
markers
• Focal keratin (+) or EMA(+) in some tumors
• Generally CD117, ALK1, S100 protein, CD34, HMB-45,
MART-1, p63 (-)
DIFFERENTIAL DIAGNOSIS
Leiomyoma
• Well circumscribed
○ Superficial (pilar) leiomyoma is not well circumscribed
but is small and superficial
• Variable cellularity, often low
• Generally lack significant nuclear atypia
○ However, rare cases with symplastic (degenerative)
atypia
• Degenerative changes (e.g., calcification, fibrosis) common
• Mitoses rare to absent
○ Deep leiomyomas of retroperitoneum/abdominopelvic
cavity in females may show up to 5 mitoses per 50 HFP
• Strong diffuse SMA(+), desmin (+), and caldesmon (+)
Malignant Peripheral Nerve Sheath Tumor
• May demonstrate clinical or histologic origin from nerve
• Can arise in association with benign nerve sheath tumor
(usually neurofibroma) or within context of NF1
• Alternating regions of varying cellularity
• Increased perivascular tumor cell density
• S100(+) &/or SOX10(+) in 50% of cases (often focal)
• Loss of nuclear H3K27me3
• SMA and desmin (-)
○ Desmin and myogenin expression seen in
rhabdomyoblastic elements, if present (malignant Triton
tumor)
PEComa
• May show morphologic overlap with LMS
○ Can arise in similar locations (including uterus and
bladder)
• Sheets and fascicles of spindled to epithelioid cells with
clear to eosinophilic "stringy" cytoplasm
• May show focal association with walls of larger blood
vessels
• Characteristic myomelanocytic immunophenotype
○ Variable expression of SMA, desmin, HMB-45, MART-
1/Melan-A, MITF
– Exact expression pattern varies case by case
• Minor subset shows nuclear TFE3(+)
Desmoid Fibromatosis
• Long fascicles of slender spindle cells without atypia
• Prominent collagenous stroma
• Nuclear β-catenin (+) in majority
Gastrointestinal Stromal Tumor
• Significant nuclear pleomorphism uncommon in spindled
tumors
346
• CD117(+), CD34(+), DOG1(+)
• Minor subset expresses SMA
• Desmin (-)
• KIT or PDGFRA mutations
Inflammatory Myofibroblastic Tumor
• Most common in children and young adults
• Some tumors show prominent fascicular growth
• Admixed chronic inflammatory component common
(particularly plasma cells)
• Variable SMA(+) and desmin (+)
• ALK1(+) by IHC
• 2p23 rearrangements involving ALK gene
Synovial Sarcoma (Monophasic)
• Cytologically monomorphic (lacks significant nuclear
pleomorphism)
• Strong, diffuse nuclear TLE1(+)
• Negative for SMA, desmin, and caldesmon
• t(X;18) with SS18 (SYT) gene fusions
Sarcomatoid Squamous Cell Carcinoma
• May be associated with in situ dysplastic component
• May contain foci showing more conventional epithelial
architectures (e.g., nests)
• p63(+), p40(+)
Cellular Fibrous Histiocytoma (Dermatofibroma)
• Can show morphologic overlap with superficial LMS
• Primarily dermal based but often shows extension into
subcutaneous fat
• May feature overlying epidermal alterations, such as basal
cell hyperplasia
• Focal SMA(+), if any; no diffuse expression
• Negative for both desmin and caldesmon
Undifferentiated Pleomorphic Sarcoma
• Can be indistinguishable from pleomorphic LMS
• Lacks areas of conventional LMS
• SMA expression usually limited to focal positivity, at most
• Negative for both desmin and caldesmon
SELECTED REFERENCES
1. Arbajian E et al: Inflammatory leiomyosarcoma is a distinct tumor
characterized by near-haploidization, few somatic mutations, and a primitive
myogenic gene expression signature. Mod Pathol. 31(1):93-100, 2018
2. Schneider N et al: The adequacy of core biopsy in the assessment of smooth
muscle neoplasms of soft tissues: implications for treatment and prognosis.
Am J Surg Pathol. 41(7):923-31, 2017
3. Gupta S et al: Renal leiomyoma and leiomyosarcoma: a study of 57 cases. Am
J Surg Pathol. 40(11):1557-63, 2016
4. Liau JY et al: Leiomyosarcoma with alternative lengthening of telomeres is
associated with aggressive histologic features, loss of ATRX expression, and
poor clinical outcome. Am J Surg Pathol. 39(2):236-44, 2015
5. Baltz RG et al: Cutaneous scalp metastases from retroperitoneal
leiomyosarcoma: a case report. J Cutan Pathol. 41(8):680-5, 2014
6. Miettinen M: Smooth muscle tumors of soft tissue and non-uterine viscera:
biology and prognosis. Mod Pathol. 27 Suppl 1:S17-29, 2014
7. Bathan AJ et al: Diagnosis, prognosis, and management of leiomyosarcoma:
recognition of anatomic variants. Curr Opin Oncol. 25(4):384-9, 2013
8. Oda Y et al: Pleomorphic leiomyosarcoma: clinicopathologic and
immunohistochemical study with special emphasis on its distinction from
ordinary leiomyosarcoma and malignant fibrous histiocytoma. Am J Surg
Pathol. 25(8):1030-8, 2001
9. Rubin BP et al: Myxoid leiomyosarcoma of soft tissue, an underrecognized
variant. Am J Surg Pathol. 24(7):927-36, 2000
 Leiomyosarcoma
Intersecting Fascicles
Paranuclear Vacuoles
Circumscribed Border
Smooth Muscle Tumors
Mitotic Activity
(Left) Intersecting fascicles
and bundles are a common
architectural arrangement in
LMS, as shown in this image.
This morphology is not well
developed in all tumors,
however. Note the presence of
scattered pleomorphic and
hyperchromatic nuclei ﬈, a
frequent, but not invariable,
finding in LMS. (Right) The
mitotic rate in LMS varies from
tumor to tumor, but figures ﬉
are generally easy to find in
most cases and include both
normal and abnormal forms.
Coagulative Necrosis
(Left) Some tumoral smooth
muscle cells in LMS feature a
perinuclear vacuole ﬉ that
may or may not indent the
adjacent nucleus. A similar
finding is seen in
gastrointestinal stromal
tumor. (Right) Coagulative
tumor necrosis ﬈ is common
in LMS and is more frequently
seen in tumors that are larger
&/or of higher histologic
grade. Stromal fibrosis and
hyalinization may also be
present ± necrosis.
Infiltrative Growth
(Left) Not infrequently, LMS
shows a well-circumscribed,
expansile, or "pushing" border
﬈ with the surrounding soft
tissue, as depicted. An
irregular, infiltrative periphery
can be seen in other tumors,
however. (Right) Despite the
apparent circumscription seen
in many cases of LMS,
microscopic evidence of
infiltrative growth, including
entrapped adipocytes ﬉ or
muscle fibers, is often present.
347
 Leiomyosarcoma
Smooth Muscle Tumors

Cutaneous Leiomyosarcoma Stromal Collagen

(Left) Based on the dermal
confinement and lack of
involvement of the
subcutaneous adipose tissue, a
favorable prognosis would be
anticipated for this cutaneous
example of LMS. In fact, some
observers have suggested
diagnosing such superficial
lesions as atypical intradermal
smooth muscle neoplasm
given that they may recur but
essentially never metastasize.
(Right) Discrete bundles of
collagen ﬈ may be
conspicuous in LMS,
particularly superficial
(dermal/subcutaneous)
tumors.

Stromal Changes Myxoid Leiomyosarcoma

(Left) Foci of stromal myxoid
change or hyalinization may
be seen in LMS. Some tumors
may even have large,
paucicellular, sclerotic zones.
At times, the collagen ﬈ may
resemble osteoid deposits and
raise considerations of
extraskeletal osteosarcoma.
(Right) Myxoid stromal change
is not uncommon in LMS but is
often patchy or focal.
Occasional tumors are
predominantly myxoid. Of
note, cytologic atypia and
mitotic activity are often
milder/lower in this variant
compared to conventional
LMS.

Inflammatory Leiomyosarcoma Pleomorphic Leiomyosarcoma

(Left) A mixed chronic
inflammatory infiltrate may
be seen in LMS. In rare cases,
this infiltrate is prominent
(inflammatory LMS) and may
obscure other typical diagnosis
features of LMS. (Right) Areas
of severe cytologic atypia and
pleomorphism, as depicted,
may be seen in otherwise
typical LMS. In occasional
cases, the majority or entirety
of the neoplasm is
pleomorphic and resembles
undifferentiated pleomorphic
sarcoma (UPS). Cytoplasmic
eosinophilia is often more
prominent in pleomorphic LMS
than UPS, however.

348
 Leiomyosarcoma
Epithelioid Leiomyosarcoma
Highly Cellular Leiomyosarcoma
SMA Expression
Smooth Muscle Tumors
Epithelioid Leiomyosarcoma
(Left) Epithelioid change in
LMS, if present, is often focal,
but it can be prominent in rare
tumors. This variant is
composed of sheets and cords
of either small blue tumor
cells (shown) or larger pink
cells with prominent nucleoli.
Malignant cytologic features
and mitotic activity are
consistent findings. (Right)
This epithelioid LMS is
composed of large rounded
cells with abundant
eosinophilic cytoplasm and
prominent nucleoli. A mitotic
figure ﬈ is also present.
Focal Nuclear Palisading
(Left) Occasional cases of LMS
show marked cellularity with
comparatively less abundant
eosinophilic cytoplasm, as
depicted. These cases may be
confused for other spindle cell
sarcomas, including malignant
peripheral nerve sheath tumor
or synovial sarcoma, the latter
particularly when nuclear
pleomorphism ﬉ is focal or
absent. (Right) As is the case
with leiomyoma, LMS may
show foci of palisading nuclei
﬈. This feature is more
common (and generally more
prominent) in neural tumors.
Desmin Expression
(Left) Diffuse cytoplasmic
expression of smooth muscle
actin (SMA) is a characteristic
finding in most cases of LMS;
however, patchy expression
may also be seen. Loss of
expression may be seen in
markedly pleomorphic areas.
Note that the pattern of SMA
expression differs from
myofibroblastic tumors in
which it is often finer and
more wispy. (Right) Desmin
expression is usually strong in
LMS but is often patchy or
focal in extent and may be
absent in higher grade tumors.
349
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 SECTION 8

Pericytic (Perivascular) Tumors

Benign
Glomus Tumors (and Variants) 352
Myopericytoma 358
Myofibroma and Myofibromatosis 362
Angioleiomyoma 366
 Glomus Tumors (and Variants)

KEY FACTS
Pericytic (Perivascular) Tumors

TERMINOLOGY MICROSCOPIC
• Perivascular mesenchymal neoplasm composed of cells • Typically solid nests of round cells closely associated with
closely resembling modified smooth muscle cells of normal variably sized blood vessels
glomus body ○ Characteristic centralized, rounded, uniform nuclei
○ Considered to fall on morphologic spectrum with • Hyalinized to myxoid stroma
myopericytoma, myofibroma, and angioleiomyoma • No mitotic activity or necrosis
CLINICAL ISSUES • Variants: Glomangioma, glomangiomyoma,
glomangiomatosis, symplastic GT
• Most common in young adults (20-40 years)
• Malignant forms exist but are very rare
• Female predilection in subungual tumors
• Most common in distal extremities (particularly nail bed) ANCILLARY TESTS
• Typically small, red-blue nodule, often solitary and painful • SMA(+), caldesmon (+)
• Most arise in skin or subcutis • Desmin, S100 protein, keratin, synaptophysin (-)
• Treatment: Complete surgical excision
TOP DIFFERENTIAL DIAGNOSES
• Excellent prognosis in conventional glomus tumor (GT)
• Malignant GT is clinically aggressive • Myopericytoma
• Benign adnexal tumors
MACROSCOPIC • Dermal melanocytic nevus
• Most are < 1 cm in size • Paraganglioma

Glomus Tumor Circumscription

(Left) Glomus tumor (GT) is a
rare, benign tumor that may
arise almost anywhere but
shows a predilection for the
distal extremities, particularly
under the nail bed
(subungual). It is histologically
characterized by sheets and
nests of uniform, round to
epithelioid cells arranged
around a conspicuous
vasculature ﬈. (Right) Most
cases of solid GT are well
circumscribed and may or may
not feature a variably
thickened, fibrous
pseudocapsule ﬈.

Monotonous Nuclei SMA Expression

(Left) The distinctive nuclei in
GT are strikingly monomorphic
and feature a sharply defined,
round, nuclear contour. They
are often described as being
punched-out. Cytoplasmic
borders vary in prominence
and may be easy or difficult to
visualize, depending upon the
individual tumor. Mitotic
figures are absent. (Right)
Strong, diffuse cytoplasmic
expression of SMA is
characteristic of GT.
Caldesmon is also typically
positive. Desmin is negative.

352
 Glomus Tumors (and Variants)

Pericytic (Perivascular) Tumors

○ Includes symplastic forms, glomangiomatosis, and other
TERMINOLOGY variants
Abbreviations • Malignant GT is clinically aggressive
• Glomus tumor (GT) ○ Metastases and death of patients in up to 40% of cases
• Large, visceral GT have potential for aggressive behavior
Definitions regardless of histology
• Perivascular mesenchymal neoplasm composed of cells
closely resembling modified smooth muscle cells of normal MACROSCOPIC
glomus body
○ Considered to fall on morphologic spectrum with General Features
myopericytoma, myofibroma, and angioleiomyoma • Red-blue nodular lesions
• Several morphologic variants exist, including glomangioma Size
(glomuvenous malformation), glomangiomyoma,
glomangiomatosis, and symplastic GT • Most are < 1 cm
○ Deeper lesions may be larger
ETIOLOGY/PATHOGENESIS
MICROSCOPIC
Small Subset Are Inherited
Histologic Features
• Often feature multiple lesions
• Multiple familial GT • Well circumscribed ± fibrous pseudocapsule
○ Inactivation of GLMN gene ○ Small nests of glomus cells associated with small vessels
may be identified around periphery of main tumor
• Neurofibromatosis type 1 (NF1)
• Typically solid nests of cells within highly vascularized
○ Biallelic inactivation of NF1 gene
stroma
○ Vessels range from small to large and ectatic
CLINICAL ISSUES
("staghorn")
Epidemiology ○ Tumor cells arranged around vessels, often as cuffs
• Incidence ○ Diffuse, nodular, sheet-like appearance in highly cellular
○ Rare tumors
– Malignant GT extremely rare • Characteristic small, round, uniform tumor cells with pale,
• Age eosinophilic to amphophilic cytoplasm
○ Most common in young adults (20-40 years) ○ Each cell contains single centralized small, round,
– Overall wide range uniform nucleus
– Glomangioma variant more common in childhood – Sometimes described as punched-out
• Sex – Absence of nuclear atypia and significant mitotic
○ Female predilection in subungual tumors activity
○ Occasionally cases feature oncocytic or epithelioid
Site cytomorphology
• Overall wide distribution ○ Each cell surrounded by basal lamina
• Most common in distal extremities • Hyalinized to myxoid stroma
○ Particularly subungual location • No necrosis
• Rarely in other anatomic locations, including visceral organs • Rare intravascular growth
(particularly GI tract), bone, mediastinum
Morphologic Variants
Presentation • Glomangioma (glomuvenous malformation)
• Typically small, red-blue nodule, often solitary ○ 20% of cases
○ Multiple in up to 10% of cases ○ Less well circumscribed
– Multifocality also seen within setting of NF1 ○ Large, gaping veins surrounded by clusters of glomus
• Most arise in skin or subcutis cells
○ Rarely in deep soft tissues and viscera – Resembles vascular spaces of cavernous hemangioma
• Usually painful – Secondary thrombosis may occur
○ Long history of pain • Symplastic GT
○ Pain with exposure to cold &/or tactile stimulation ○ Prominent degenerative atypia in form of marked
nuclear hyperchromasia and pleomorphism
Treatment
– Lacks mitotic activity and necrosis
• Complete surgical excision – Lacks other atypical features (e.g., large size, deep
• Clinical follow-up for malignant GT and GT of uncertain location)
malignant potential ○ Otherwise typical features of GT
Prognosis • Glomangiomyoma
• Excellent in conventional GT ○ Typical GT or glomangioma with additional component
○ < 10% recur locally of spindled cells resembling smooth muscle
○ Rare

353
 Glomus Tumors (and Variants)
Pericytic (Perivascular) Tumors

• Glomangiomatosis • Synaptophysin (+), chromogranin (+)

○ Diffuse, infiltrative growth pattern resembling
angiomatosis
○ Nests of glomus cells around vessels
○ Very rare
Malignant Glomus Tumor (Glomangiosarcoma)
• Preexisting conventional GT may or may not be present
• Criteria for malignancy
○ Tumors showing marked nuclear atypia and any degree
of mitotic activity or
○ Tumor showing atypical mitotic figures
• 2 main morphologies
○ Spindled cells in bundles or fascicles, often resembling
leiomyosarcoma or fibrosarcoma
○ Sheets of small round cells with high-grade nuclei
○ Mitoses frequent
• S100 protein(+) in sustentacular cells
• SMA (-)
Dermal Melanocytic Nevus
• Nests of melanocytic cells, ± pigmentation
• Intranuclear pseudoinclusions common
• Cells lack close association with blood vessels
• Expression of melanocytic markers (e.g., S100, Melan-A)
• SMA, caldesmon (-)
Angioleiomyoma
• Predominantly composed of bundles of mature,
eosinophilic smooth muscle cells
• Lacks prominent uniform round cell component of GT
• SMA(+), desmin (+)
• Often painful

Glomus Tumor of Uncertain Malignant Potential Carcinoid Tumor

• Reserved for tumors that do not fulfill above criteria for • Visceral organs
malignancy but that show at least 1 atypical feature other • Can show close architectural overlap with GT
than nuclear pleomorphism • Speckled or salt and pepper chromatin pattern
• Also includes deeply situated tumors that are > 2 cm • SMA(-)
• Keratin (+), synaptophysin (+), chromogranin (+)
ANCILLARY TESTS
Immunohistochemistry
SELECTED REFERENCES
1. Luzar B et al: Cutaneous malignant glomus tumours: applicability of
• SMA(+), caldesmon (+) currently established malignancy criteria for tumours occurring in the skin.
• Variable CD34(+) Pathology. ePub, 2018
• Abundant pericellular type IV collagen (+) 2. Bozdogan N et al: Transducing-like enhancer of split 1: a potential
immunohistochemical marker for glomus tumor. Am J Dermatopathol.
• Desmin, S100 protein, keratin, synaptophysin (-) 39(7):524-527, 2017
• Recent report suggests frequent TLE-1 positivity in benign 3. Karamzadeh Dashti N et al: BRAF V600E mutations occur in a subset of
GT glomus tumors, and are associated with malignant histologic characteristics.
Am J Surg Pathol. 41(11):1532-1541, 2017
Molecular Genetics 4. Kumar R et al: Glomangiomatosis of the sciatic nerve: a case report and
review of the literature. Skeletal Radiol. 46(6):807-815, 2017
• NOTCH gene rearrangements (NOTCH1, NOTCH2, or 5. Damavandy AA et al: Malignant glomus tumor arising in a long standing
NOTCH3) reported in recent series of benign and malignant precursor lesion. Am J Dermatopathol. 38(5):384-7, 2016
GTs 6. Weissferdt A et al: Intrathoracic glomus tumors and glomangiosarcomas: a
clinicopathological and immunohistochemical study of 14 cases with
○ 1 case of NOTCH3-MIR143 fusion reported emphasis on anatomic distribution. Virchows Arch. 469(5):541-546, 2016
• BRAF (V600E) and KRAS (G12A) mutations reported in some 7. Mravic M et al: Clinical and histopathological diagnosis of glomus tumor: an
cases of sporadic GT institutional experience of 138 cases. Int J Surg Pathol. 23(3):181-8, 2015
8. Kumar MG et al: Glomus tumors in individuals with neurofibromatosis type 1.
○ BRAF (V600E) may be associated with increased risk of J Am Acad Dermatol. 71(1):44-8, 2014
aggressive behavior 9. Mosquera JM et al: Novel MIR143-NOTCH fusions in benign and malignant
glomus tumors. Genes Chromosomes Cancer. 52(11):1075-87, 2013
DIFFERENTIAL DIAGNOSIS 10. Chakrapani A et al: BRAF and KRAS mutations in sporadic glomus tumors.
Am J Dermatopathol. 34(5):533-5, 2012
Myopericytoma 11. Sheehan JP et al: Gamma Knife surgery for the management of glomus
tumors: a multicenter study. J Neurosurg. 117(2):246-54, 2012
• Exists on morphologic spectrum with GT
12. Semaan MT et al: Current assessment and management of glomus tumors.
• Pure forms lack uniform, round cell component of GT Curr Opin Otolaryngol Head Neck Surg. 16(5):420-6, 2008
• Characteristic perivascular, concentric growth of ovoid to 13. Brouillard P et al: Four common glomulin mutations cause two thirds of
glomuvenous malformations ("familial glomangiomas"): evidence for a
spindled tumor cells founder effect. J Med Genet. 42(2):e13, 2005
Benign Adnexal Tumors 14. Mentzel T et al: CD34-positive glomus tumor: clinicopathologic and
immunohistochemical analysis of six cases with myxoid stromal changes. J
• e.g., nodular hidradenoma, spiradenoma Cutan Pathol. 29(7):421-5, 2002
• Epithelial, ductal/glandular, or sebaceous differentiation 15. Folpe AL et al: Atypical and malignant glomus tumors: analysis of 52 cases,
with a proposal for the reclassification of glomus tumors. Am J Surg Pathol.
should be identifiable 25(1):1-12, 2001
• Keratin (+) 16. Hiruta N et al: Malignant glomus tumor: a case report and review of the
• SMA(-) literature. Am J Surg Pathol. 21(9):1096-103, 1997
17. Van Geertruyden J et al: Glomus tumours of the hand. A retrospective study
Paraganglioma of 51 cases. J Hand Surg [Br]. 21(2):257-60, 1996
18. Gould EW et al: Locally infiltrative glomus tumors and glomangiosarcomas. A
• Deceptively termed glomus tympanicum in ear and glomus clinical, ultrastructural, and immunohistochemical study. Cancer. 65(2):310-8,
jugulare in neck 1990
• Prominent nested zellballen growth pattern common 19. Slater DN et al: Oncocytic glomus tumour: a new variant. Histopathology.
11(5):523-31, 1987

354
 Glomus Tumors (and Variants)
Variable Stromal Hyalinization
Sheet-Like Growth
Pericellular Type IV Collagen
Pericytic (Perivascular) Tumors
Peritumoral Glomus Proliferations
(Left) The stroma in GT varies
from hyalinized to myxoid.
Some zones of prominent
hyalinization or sclerosis can
feature tumor cells arranged
singly or in small aggregate or
cords (right). (Right) In some
cases of GT, small vessels at
the periphery of the tumor
may contain a subtle or
conspicuous glomus cell
proliferation ﬈. This finding
can be diagnostically helpful in
distinguishing a solid GT from
an adnexal tumor.
Conspicuous Vasculature
(Left) Some GTs may feature a
strikingly solid growth pattern
with a less prominent
vasculature, as depicted here.
These tumors can closely
mimic a cutaneous adnexal
neoplasm. (Right) The stromal
vasculature ﬉ can be very
prominent in some cases of GT
and may also adopt irregular
or staghorn shapes. This
morphology can lead to
consideration of a cellular
solitary fibrous tumor.
Oncocytic Change
(Left) Although not widely
utilized in general practice, a
collagen IV (or laminin)
immunostain can nicely
highlight the pericellular
basement membrane material
characteristic of GT. (Right)
Oncocytic change is an
occasional finding in GT and is
characterized by tumor cells
with abundant granular
cytoplasm, as depicted here.
This particular tumor also
features a myxoid stroma.
355
 Glomus Tumors (and Variants)
Pericytic (Perivascular) Tumors

Glomangioma Prominent Dilated Vessels

(Left) Glomangioma is a
variant of GT that features
larger, dilated vascular spaces
﬉ lined by the characteristic
tumor cells. Compared to
conventional GT,
glomangioma is often less well
circumscribed and is more
common in children and in
familial cases. (Right) The
large, dilated spaces of
glomangioma are always lined
by arrays of neoplastic glomus
cells ﬈; however, this lining
can vary widely in thickness
from field to field.

Cavernous Vascular Pattern Symplastic Glomangioma

(Left) As shown in this H&E,
vascular spaces in
glomangioma may be
markedly expanded and
closely resemble those of
cavernous hemangioma.
However, the glomus cell
lining is distinctive. Also note
that large thrombi or
phleboliths ﬊ may be present
in some cases. (Right) Rare
cases of GT (or any of its other
variants) may contain
scattered pleomorphic nuclei
﬉, suggesting malignancy.
Mitoses and other atypical
features are absent, however.
These changes are likely
degenerative in nature.

Glomangiomyoma Glomangiomatosis
(Left) Glomangiomyoma is a
variant of GT that features a
smooth muscle component ﬉
in addition to areas of
otherwise conventional-
appearing GT or
glomangioma. Note the small
areas of rounded glomus cells
﬈. (Right) Glomangiomatosis
is a rare, benign, diffuse
variant of GT that resembles
the pattern seen in
angiomatosis; however, small
vessels in glomangiomatosis
feature glomus cell
proliferations ﬈.

356
 Glomus Tumors (and Variants)
Interface Between Benign and Malignant
Glomus Tumor
Malignant Round Cell Morphology
Nuclear Pleomorphism
Pericytic (Perivascular) Tumors
Malignant Spindle Cell Morphology
(Left) Malignant GT ﬉ is rare.
A preexisting component of
conventional benign-
appearing GT ﬊ may or may
not be present. In the latter
situation,
immunohistochemistry is often
needed to support the
diagnosis. (Right) The spindled
morphology of malignant GT
often resembles other spindle
cell sarcomas, such as
leiomyosarcoma or
fibrosarcoma. Short fascicles
and whorls are common.
Mitoses are usually numerous.
Nuclear Atypia and Mitoses
(Left) The round cell
morphology of malignant GT
mimics somewhat
conventional GT in
architecture; however, the
nuclei often show a high
degree of atypia, and mitoses
﬉ are easily identified. (Right)
Malignant GT with a round cell
pattern shows increased
nuclear atypia, including
prominent nucleoli in some
cases. Note the mitoses ſt.
Multinodularity and Vascular Invasion
(Left) Some cases of malignant
GT feature marked nuclear
pleomorphism &/or
hyperchromasia. Distinction
from symplastic GT is possible
through identification of other
atypical features, including
multiple mitoses ﬉. (Right)
Malignant GT can show a
more prominent multinodular
growth pattern compared to
conventional GT. Vascular
invasion ﬊ may also be seen.
357
 Myopericytoma

KEY FACTS
Pericytic (Perivascular) Tumors

TERMINOLOGY MICROSCOPIC
• Benign perivascular myoid neoplasm with prominent • Characteristic multilayered concentric growth of myoid
vascularity tumor cells around thin-walled blood vessels
○ Forms morphologic spectrum with angioleiomyoma, • Mitoses are rare
myofibroma, and glomus tumor • Some hybrid cases have focal features of glomus tumor,
angioleiomyoma, or myofibroma
CLINICAL ISSUES
• Wide age range (most common in middle-aged adults) ANCILLARY TESTS
• Most common in dermal or subcutaneous tissue of distal • SMA(+), h-caldesmon (+)
extremities • Negative for desmin, CD31, CD34, S100 protein, keratin
• Usually solitary and slow growing; rarely multiple • PDGFRB alterations identified in both myopericytoma,
• Treatment: Simple surgical excision myopericytomatosis, and myofibroma
• Excellent prognosis: Local recurrence rare
TOP DIFFERENTIAL DIAGNOSES
○ Very rare malignant forms are clinically aggressive
• Myofibroma
MACROSCOPIC • Angioleiomyoma
• Usually < 2 cm • Solitary fibrous tumor
• Glomus tumor

Myopericytoma Well Circumscribed

(Left) Grossly, myopericytoma
is characterized by a nodular,
well-circumscribed neoplasm
with numerous vessels ﬇ and
a tan-white cut surface.
(Right) Myopericytoma is a
benign perivascular neoplasm
that is generally small, well
circumscribed, and
unencapsulated; however,
some tumors may show a
compressed pseudocapsule
﬈.

Concentric Perivascular Growth Smooth Muscle Actin Expression

(Left) A characteristic feature
of myopericytoma is
multilayered, concentric
perivascular growth by the
lesional cells, as depicted. The
prominence of this finding
varies from case to case, but is
often easy to spot. Note that
the nuclei are relatively
uniform, and mitoses are rare.
(Right) Homogeneous
expression of SMA (red
chromogen shown) is
characteristic of
myopericytoma (and related
pericytic neoplasms) and
highlights the striking
perivascular growth ﬊ of
neoplastic cells.

358
 Myopericytoma

Pericytic (Perivascular) Tumors

○ Nearby blood vessels peripheral to tumor may show
TERMINOLOGY similar concentric growth of myoid cells
Definitions • Cellularity varies widely
• Benign perivascular myoid neoplasm with prominent • Degenerative changes in longstanding tumors
vascularity ○ Scattered atypical nuclei, myxoid stroma, hyalinization,
○ Forms morphologic spectrum with angioleiomyoma, hemorrhage, infarction, metaplastic bone formation
myofibroma, and glomus tumor • Some hybrid cases have focal features of glomus tumor,
• Myopericytomatosis angioleiomyoma, or myofibroma
○ Diffuse involvement of dermis and subcutaneous tissue • May show intramural or intravascular growth
by microscopic myopericytomatous nodules • Myopericytomatosis
○ Diffuse involvement of dermis and subcutaneous tissue
CLINICAL ISSUES by microscopic myopericytomatous nodules
Epidemiology • Very rare malignant forms
○ Prominent nuclear atypia and numerous mitoses
• Age
○ Evidence of perivascular growth usually present
○ Wide age range (most common in middle-aged adults)
• Sex ANCILLARY TESTS
○ Male predominance
Immunohistochemistry
Site
• SMA(+), h-caldesmon (+)
• Most common in dermal or subcutaneous tissue • Negative for desmin, CD31, CD34, S100, keratin, STAT6
○ Rarely in deep soft tissues
• Distal extremities are most frequently involved In Situ Hybridization
○ Less commonly proximal extremities, neck, trunk • PDGFRB alterations identified in both myopericytoma,
myopericytomatosis, and myofibroma
Presentation ○ Includes mutations and low-level amplification
• Usually solitary, slow-growing mass
○ Rarely multiple DIFFERENTIAL DIAGNOSIS
Treatment Myofibroma
• Simple surgical excision • Can show morphologic overlap with myopericytoma
Prognosis • More common in pediatric age group than myopericytoma
• Shows conspicuous areas of myoid nodule formation
• Benign
• Local recurrence rare Angioleiomyoma
○ Additional, new tumors may arise in same region • Can show morphologic overlap with myopericytoma
• Very rare malignant myopericytomas are often clinically • Predominance of plump, eosinophilic spindle cells in
aggressive bundles and fascicles
○ Cytologic features of smooth muscle
MACROSCOPIC • Desmin (+), SMA(+)
General Features Glomus Tumor
• Well-circumscribed, nodular/lobular mass • Usually sheets of rounded, strikingly monomorphic cells
• Tan-white firm cut surface with evidence of vascularity arranged around ectatic vasculature
Size Solitary Fibrous Tumor
• Usually < 2 cm • No concentric, multilayered, perivascular growth
○ Deeply situated lesions can be larger • Diffuse CD34(+), STAT6(+); negative for SMA and desmin

MICROSCOPIC SELECTED REFERENCES

Histologic Features
• Generally well circumscribed, unencapsulated
• Uniform, plump spindled and ovoid cells
○ Eosinophilic cytoplasm and elongated, bland nuclei
○ Mitoses are rare
• Characteristic multilayered concentric growth of myoid
tumor cells around thin-walled blood vessels
○ Vessels often numerous and variable in size
○ Some vessels are large, dilated, and irregular ("staghorn")
– Extensive hemangiopericytoma-like vasculature may
be seen in some cases
1. Hung YP et al: Myopericytomatosis: clinicopathologic analysis of 11 cases
with molecular identification of recurrent PDGFRB alterations in
myopericytomatosis and myopericytoma. Am J Surg Pathol. 41(8):1034-44,
2017
2. Dray MS 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. 59(1):67-73, 2006
3. Mentzel T et al: Myopericytoma of skin and soft tissues: clinicopathologic
and immunohistochemical study of 54 cases. Am J Surg Pathol. 30(1):104-
13, 2006
4. McMenamin ME et al: Malignant myopericytoma: expanding the spectrum
of tumours with myopericytic differentiation. Histopathology. 41(5):450-60,
2002

359
 Myopericytoma
Pericytic (Perivascular) Tumors

Perivascular Myxoid Change Solid Growth

(Left) In some cases of
myopericytoma, the
immediate region around the
blood vessels is myxoid and
less cellular than the
surrounding areas. Note that a
concentric, perivascular
growth is readily identified.
(Right) In other areas of
myopericytoma, concentric
vascular growth is not as
overtly conspicuous, and
tumor cells appear to form
haphazard sheets of variable
cellularity.

Ectatic Vascular Channels Hemangiopericytoma-Like Growth

(Left) Ectatic, "staghorn"
vascular channels ﬊ are a
common finding in
myopericytoma and may be
prominent. This appearance
can suggest solitary fibrous
tumor (SFT); however, the
concentric, perivascular tumor
cell arrangement of
myopericytoma is not a typical
feature of SFT. (Right) A
prominent, visually striking
hemangiopericytoma-like
vascular pattern may be seen
in some cases of
myopericytoma, as depicted.
The lesional cells express SMA
and are negative for CD34.

Angioleiomyoma-Like Areas Focal Myoid Bundles

(Left) Some cases of
myopericytoma contain areas
that are cytomorphologically
similar to the smooth muscle
cells of angioleiomyoma,
which is considered to be
another perivascular neoplasm
related to myopericytoma.
(Right) Myopericytoma may
contain myoid nodules ﬊
similar to what is seen in
myofibroma. There is
significant histologic overlap
between these 2 entities;
however, classification as
myofibroma is more
appropriate in the setting of a
significant myoid component.

360
 Myopericytoma
Degenerative Changes
Intravascular Growth
Malignant Myopericytoma Malignant Myopericytoma
Pericytic (Perivascular) Tumors
Degenerative Changes
(Left) Degenerative changes
are not uncommon in
myopericytoma and include
hemorrhage, cystic change ﬊,
fibrosis, and stromal
hyalinization. These changes
may be so extensive that the
underlying diagnosis is
obscured. (Right) Other
degenerative changes that
occur in myopericytoma
include stromal myxoid
change, chronic inflammation,
and scattered hyperchromatic
nuclei with "smudgy"
chromatin ﬈.
Peritumoral Vessels
(Left) Intravascular and
intramural growth is an
occasional finding in
myopericytoma. Note the
muscular wall ﬈ of the
involved blood vessel at the
periphery. (Right) An
interesting finding noted in
some cases of myopericytoma
is the presence of a subtle,
concentric proliferation of
pericytic cells around the
blood vessels ﬈ located
peripherally in the vicinity of
the main tumor.
(Left) Malignant forms of
myopericytoma are extremely
rare and are usually
characterized by significant
nuclear atypia, pleomorphism,
and mitotic activity. Of note, a
perivascular arrangement of
the tumor cells is usually
maintained, at least focally.
(Right) This case of a
malignant myopericytoma
showed extensive nuclear
pleomorphism and numerous
mitoses, including atypical
forms ﬈.
361
 Myofibroma and Myofibromatosis

KEY FACTS
Pericytic (Perivascular) Tumors

TERMINOLOGY MICROSCOPIC
• Benign pericytic neoplasm classically composed of lobules • Most lesions are small and well marginated
of myoid cells separated by cellular, vascularized zones • Classic biphasic pattern
○ Solitary form (myofibroma); multicentric form ○ Myoid nodules separated by cellular zones of ovoid cells
(myofibromatosis) with hemangiopericytoma-like NTRK3 (biphasic pattern)
CLINICAL ISSUES – Variable amounts of each component (vascular zones
more prominent in children and less so in adults)
• Wide age range (most common in infants and children)
• Hypercellular variant often shows long fascicles and
• Solitary form most common in dermis and subcutis of head resembles fibrosarcoma
and neck, trunk, and extremities
• Multicentric form occurs in dermis, subcutis, muscle, bones, ANCILLARY TESTS
and visceral organs • SMA(+); desmin and S100 protein (-)
• Treatment: Simple conservative excision
TOP DIFFERENTIAL DIAGNOSES
○ Both nonvisceral solitary and multicentric forms often
spontaneously regress • Leiomyoma
• All forms are benign • Fibromatosis
○ Excellent prognosis without visceral organ involvement • Nodular fasciitis
○ Extensive visceral organ involvement may be fatal • Infantile fibrosarcoma

Myofibroma Myoid Nodules

(Left) The classic case of
myofibroma shows a biphasic
morphology consisting of
vague nodules ſt of myoid
cells admixed with more
cellular zones demonstrating a
pericytomatous
(hemangiopericytoma-like)
vasculature ﬊. (Right) The
myoid cells are thin to plump,
elongated spindle cells with
eosinophilic cytoplasm, often
within myxoid matrix. These
cells may be loosely arranged
or may form short fascicles or
whorls. Note that the myoid
nodules may project or extend
into thin-walled vascular
channels ﬈.

Cytologic Features Cellular Vascular Zones

(Left) Cytologically, the cells
of myofibroma are bland and
relatively uniform. Significant
nuclear pleomorphism is not a
feature of this tumor. The
mitotic index is generally low
and without atypical figures.
(Right) The centralized or
internodular vascular zones
are composed of smaller,
ovoid tumor cells between
irregularly shaped, small to
large vessels, many of which
have a staghorn appearance.
The overall appearance is
often described as
hemangiopericytoma-like.

362
 Myofibroma and Myofibromatosis

Pericytic (Perivascular) Tumors

• Classic biphasic pattern
TERMINOLOGY
○ Myoid nodules separated by cellular zones of ovoid cells
Synonyms with pericytomatous (hemangiopericytoma-like) vascular
• Infantile myofibroma/myofibromatosis pattern
○ Variable amounts of each component (vascular zones
Definitions more prominent in children and less so in adults)
• Benign, biphasic neoplasm classically composed of lobules • Myoid nodules
of myoid cells separated by cellular, vascularized zones ○ More common at periphery of tumor
○ Solitary form (myofibroma) ○ Bland spindle cells with pale eosinophilic cytoplasm and
○ Multicentric form (myofibromatosis) elongated nuclei arranged in short fascicles or whorls
• Currently considered to be pericytic neoplasm related to ○ Myxoid change or hyalinization
myopericytoma ○ Absence of nuclear pleomorphism
• Cellular hemangiopericytoma-like vascular zones
CLINICAL ISSUES ○ Round to ovoid cells without nuclear pleomorphism
Epidemiology ○ Prominent small, irregular vascular spaces
• Incidence ○ May contain area of coagulative necrosis or hemorrhage
○ Solitary form more common than multicentric form • Hypercellular variant
• Age ○ Overall higher cellularity with long fascicle formation
○ Wide range (most common in infants and children) ○ Hemangiopericytoma-like vascular component often
• Sex minimal or absent
○ 2:1 male predominance • Mitotic rate is generally low

Site ANCILLARY TESTS

• Solitary Immunohistochemistry
○ Dermis and subcutaneous tissue
• Smooth muscle actin (+)
○ Most common in head and neck region
• Desmin, caldesmon, CD34, S100 protein, keratins, STAT6 (-)
○ Also lower and upper extremities and trunk
○ Occasional intraosseous examples Genetic Testing
• Multicentric form • PDGFRB gene alterations
○ Dermis, subcutaneous tissue, muscle, bones
○ Also visceral sites (gastrointestinal tract, lung, heart, DIFFERENTIAL DIAGNOSIS
others)
Leiomyoma
Presentation • Perpendicularly oriented fascicles of pink spindled cells
• Small, painless growth • Lacks hemangiopericytoma-like zones
○ Superficial nodules may appear purple, clinically
simulating hemangioma
Fibromatosis
○ Larger tumors may ulcerate overlying epidermis • Highly infiltrative growth pattern
• Prominent stromal collagen
Treatment • Nuclear β-catenin expression in 70%
• Both nonvisceral solitary and multicentric forms often
spontaneously regress Nodular Fasciitis
• Simple conservative excision • Rare in infants
• Often very myxoid; lacks hemangiopericytoma-like areas
Prognosis
• All forms are benign Infantile Fibrosarcoma
• Excellent prognosis in solitary and multicentric forms • Often large mass in extremity of newborns/infants
without visceral organ involvement • t(12;15)(p13;q25) with ETV6-NTRK3 fusion
○ Solitary form recurrence rate ~ 10%
• Extensive visceral organ involvement may be fatal in infants SELECTED REFERENCES
and young children 1. Agaimy A et al: Recurrent somatic PDGFRB mutations in sporadic
infantile/solitary adult myofibromas but not in angioleiomyomas and
myopericytomas. Am J Surg Pathol. 41(2):195-203, 2017
MACROSCOPIC 2. Arts FA et al: PDGFRB gain-of-function mutations in sporadic infantile
Size myofibromatosis. Hum Mol Genet. 26(10):1801-1810, 2017
3. Linos K et al: Myofibromas with atypical features: expanding the
• Usually small (1-5 cm) morphologic spectrum of a benign entity. Am J Surg Pathol. 38(12):1649-54,
2014
MICROSCOPIC 4. Oudijk L et al: Solitary, multifocal and generalized myofibromas:
clinicopathological and immunohistochemical features of 114 cases.
Histologic Features Histopathology. 60(6B):E1-11, 2012
5. Granter SR et al: Myofibromatosis in adults, glomangiopericytoma, and
• Most lesions are well marginated myopericytoma: a spectrum of tumors showing perivascular myoid
○ Can be locally infiltrative and with intravascular growth differentiation. Am J Surg Pathol. 22(5):513-25, 1998

363
 Myofibroma and Myofibromatosis
Pericytic (Perivascular) Tumors

Cellular Vascular Zones Myoid Morphology

(Left) In the vascular zones of
myofibroma, the tumor cells
are smaller and more
primitive-appearing, and the
overall cellularity is higher
than the myoid areas. In
occasional tumors, where the
vessels are not as prominent,
this cellularity may be
alarming and lead to
consideration of a sarcoma.
(Right) In some areas, the
appearance of plump
eosinophilic cells forming
bundles and short fascicles
closely resembles smooth
muscle tissue, particularly if
the fascicles are cut in cross
section.

Myoid Zones Stromal Hyalinization

(Left) In some cases, the myoid
zones are paucicellular and
contain a chronic
inflammatory infiltrate,
resembling a reactive
myofibroblastic process.
Identification of a low-power
nodular growth pattern or
presence of a pericytomatous
vascular component is helpful.
(Right) Stromal collagen and
hyalinization are seen in some
cases of myofibroma and may
be present in either zone.

Stromal Hyalinization Smooth Muscle Actin

(Left) Myoid zones may show
extensive stromal
hyalinization. When these
areas are larger, it may be
difficult to recognize the
lesion as a myofibroma,
particularly if a more cellular
pericytomatous component is
inconspicuous or absent.
(Right) The lesional cells of
myofibroma commonly
express smooth muscle actin
and are almost always
negative for desmin, in
contrast to benign smooth
muscle tumors.

364
 Myofibroma and Myofibromatosis
Multinucleated Giant Cells
Prominent Vascularity
Increased Cellularity
Pericytic (Perivascular) Tumors
Necrosis
(Left) Multinucleated giant
cells ﬈ are rarely seen in
myofibroma but are more
likely to be seen in
intraosseous cases. When
present in soft tissue lesions, a
diagnosis of nodular fasciitis
may be considered. (Right)
Coagulative necrosis ﬈ may
be seen in some cases of
myofibroma and is usually
localized to the cellular
vascular component,
particularly when prominent
and centrally located.
Hemorrhage and calcification
may also be seen. Note the
peripheral myoid area ﬇.
Vascular Intimal Involvement
(Left) Myofibroma is currently
thought to be related to other
pericytic tumors, such as
myopericytoma, glomus
tumor, and angioleiomyoma,
and may show overlapping
features with 1 or more of
these entities. Tumors with a
conspicuous myoid component
﬈ are probably best classified
as myofibroma. (Right) Intimal
involvement of peripheral
blood vessels is not uncommon
in myofibroma and appears to
have no significant prognostic
importance. This finding is also
commonly seen in
myopericytoma.
Hypercellularity
(Left) Rare cases of
myofibroma show a relatively
significant increase in
cellularity and may mimic a
sarcoma. Most of these cases,
however, show myoid nodule
﬈ formation, at least focally.
Despite the cellularity,
significant nuclear atypia is
not seen. (Right) Prominent
fascicular growth may be seen
in hypercellular regions of
myofibroma. In these cases, a
variety of spindle cell
sarcomas, such as infantile
fibrosarcoma and spindle cell
rhabdomyosarcoma, must be
diligently excluded first.
365
 Angioleiomyoma

KEY FACTS
Pericytic (Perivascular) Tumors

TERMINOLOGY • 3 types described: Solid (most common), venous, and

• Benign, well-circumscribed neoplasm composed of mature
smooth muscle cells arranged around prominent blood
vessels
• Synonyms: Vascular leiomyoma, angiomyoma
CLINICAL ISSUES
• Wide range (40-70 years most common)
• Upper and lower extremities (most common in lower leg)
• Usually small, solitary, subcutaneous nodule
○ More than 50% are painful
• Treatment: Simple, conservative excision
• Excellent prognosis; very rarely recurs
MACROSCOPIC
• Usually < 2 cm
MICROSCOPIC
• Sharp circumscription
cavernous
• Well-differentiated smooth muscle component
• Prominent component of medium- to large-sized blood
vessels with dilated or compressed lumina
○ Smooth muscle cells can show concentric, perivascular
accentuation in some cases
• No significant nuclear atypia or mitotic activity
• Mature adipose tissue, stromal hyalinization, myxoid
changes, or calcification may be present
ANCILLARY TESTS
• Strong, diffuse SMA(+) and h-caldesmon (+)
• Desmin (+) but varies in extent
TOP DIFFERENTIAL DIAGNOSES
• Myopericytoma
• Hemangioma
• PEComa

Angioleiomyoma Perivascular Growth

(Left) Angioleiomyoma is a
small, sharply circumscribed
smooth muscle neoplasm
containing a prominent
component of stromal blood
vessels. These vessels vary in
size and may be compressed
(solid variant, shown) or
markedly dilated/ectatic
(venous and cavernous
variants). (Right) Perivascular
arrangement ﬈ of the
lesional smooth muscle cells is
a common finding in
angioleiomyoma and creates
morphologic overlap with
myopericytoma. This finding,
however, may be focal or
absent in some cases.

Mature Smooth Muscle Cells Cavernous Morphology

(Left) The well-differentiated
smooth muscle cells of
angioleiomyoma show classic
cytologic features, including
prominent eosinophilic
cytoplasm and elongated,
blunt, cigar-shaped nuclei.
They are also typically
arranged in bundles and
fascicles, as seen in other
smooth muscle neoplasms.
(Right) The cavernous type of
angioleiomyoma has thin-
walled, dilated vascular
channels ﬈ arranged in small
clusters within a stroma
composed of smooth muscle
fibers ﬊ that form branching
fascicles.

366
 Angioleiomyoma

Pericytic (Perivascular) Tumors

– Mature smooth muscle arranged around dilated,
TERMINOLOGY thick-walled vascular channels
Synonyms □ Smooth muscle cells often show concentric,
• Vascular leiomyoma perivascular accentuation
• Angiomyoma ○ Cavernous type (least common)
– Resembles cavernous hemangioma
Definitions – Intervascular septa contain smooth muscle cells
• Benign, well-circumscribed neoplasm composed of mature • Occasional cases show some morphologic overlap with
smooth muscle cells arranged around prominent blood myopericytoma
vessels • No significant nuclear atypia or mitotic activity
○ Now classified as tumor of pericytic (perivascular) origin ○ Focal (likely degenerative) atypia may be present in older
(2013 WHO Classification) lesions
○ Considered to exist on morphologic spectrum with • Mature adipose tissue, stromal hyalinization, or myxoid
myopericytoma changes may be present
• Calcification is more common in older lesions
CLINICAL ISSUES • Small nerve twigs are occasionally identifiable within or at
Epidemiology periphery of lesion
• Age
○ Wide range (40-70 years most common) ANCILLARY TESTS
• Sex Immunohistochemistry
○ Male predominance in upper extremity • Strong, diffuse SMA(+) and h-caldesmon (+)
○ Female predominance in lower extremity • Desmin (+) but varies in extent
Site • Negative for HMB-45
• Upper and lower extremities (most common in lower leg)
• Head and neck (particularly oral cavity, lip, palate)
DIFFERENTIAL DIAGNOSIS
• Rare on trunk Myopericytoma
Presentation • May show morphologic overlap with angioleiomyoma
• Prominent perivascular growth
• Usually small, solitary, subcutaneous nodule
• Lesional cells lack mature smooth muscle cytomorphology
• Often slow growing
• SMA(+), desmin (-)
• More than 50% are painful
○ May be exacerbated by pregnancy, menses, or change in Hemangioma
temperature • Vascular (capillary or cavernous) channels are numerous
Treatment • Lacks prominent intervascular smooth muscle cell
proliferation
• Simple, conservative excision
PEComa (a.k.a. Perivascular Epithelioid Cell Tumor)
Prognosis
• Tumor cell cytoplasm varies from eosinophilic to clear
• Excellent
• Variably sclerotic stroma
• Recurrences very rare
• May contain fat (angiomyolipoma)
• Most coexpress SMA and melanocytic markers (HMB-45,
MACROSCOPIC
MART-1, etc.)
General Features
• Small, well circumscribed SELECTED REFERENCES
• White, rubbery cut surface 1. Rawal SY et al: Angioleiomyoma (vascular leiomyoma) of the oral cavity.
○ Calcified examples may be gritty Head Neck Pathol. 12(1):123-126, 2018
2. Marco VS et al: Acral angioleiomyoma with tumoral calcinosis: a complication
Size of the insertional Achilles tendinopathy. J Cutan Pathol. ePub, 2017
3. Agaimy A et al: Angioleiomyoma of the sinonasal tract: analysis of 16 cases
• Usually < 2 cm and review of the literature. Head Neck Pathol. 9(4):463-73, 2015
4. Liu Y et al: Angioleiomyomas in the head and neck: a retrospective clinical
MICROSCOPIC and immunohistochemical analysis. Oncol Lett. 8(1):241-247, 2014
5. Houdek MT et al: Angioleiomyoma of the upper extremity. J Hand Surg Am.
Histologic Features 38(8):1579-83, 2013
6. Matsuyama A et al: Angioleiomyoma: a clinicopathologic and
• Sharp circumscription immunohistochemical reappraisal with special reference to the correlation
• 3 morphologic forms described with myopericytoma. Hum Pathol. 38(4):645-51, 2007
○ Solid type (most common) 7. Fox SB et al: Angioleiomyomas: an immunohistological study.
Histopathology. 16(5):495-6, 1990
– Bundles and fascicles of spindled, well-differentiated
8. Hachisuga T et al: Angioleiomyoma. A clinicopathologic reappraisal of 562
smooth muscle cells cases. Cancer. 54(1):126-30, 1984
– Intervening compressed, slit-like vessels
○ Venous type

367
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 SECTION 9

Tumors of Skeletal Muscle

Benign
Focal Myositis 370
Adult Rhabdomyoma 372
Fetal Rhabdomyoma 374
Genital Rhabdomyoma 376
Cardiac Rhabdomyoma 378

Malignant
Embryonal Rhabdomyosarcoma 380
Alveolar Rhabdomyosarcoma 386
Spindle Cell Rhabdomyosarcoma 392
Sclerosing Rhabdomyosarcoma 396
Pleomorphic Rhabdomyosarcoma 400
Epithelioid Rhabdomyosarcoma 404
 Focal Myositis

KEY FACTS
Tumors of Skeletal Muscle

TERMINOLOGY MICROSCOPIC
• Benign self-limiting, intramuscular inflammatory • Skeletal muscle with marked variation in size of individual
pseudotumor myocytes
• Dense fibrosis common (endomysial more prominent than
CLINICAL ISSUES
perimysial)
• Wide range (median: 36 years) • Chronic inflammatory infiltrate, particularly lymphocytes
• Single muscle involvement is typical • Regenerative myocytes with basophilic cytoplasm and large
• Limbs most common site, especially lower extremities vesicular nuclei with nucleoli
• Rapidly appearing and growing mass • Focal denervation changes
○ Generally asymptomatic • Variable fatty replacement of muscle
○ Weakness is rare, and joint involvement is not present • No atypia, calcification, or ossification
• Treatment usually not required
○ Many cases spontaneously regress TOP DIFFERENTIAL DIAGNOSES
• Excellent prognosis • True inflammatory myopathies
• Proliferative myositis
MACROSCOPIC
• Lymphoma
• Between 1-20 cm in size (median: 3 cm) • Myositis ossificans
• Inflammatory myofibroblastic tumor

Focal Myositis Focal Myositis

(Left) Focal myositis is a
benign, nonneoplastic
inflammatory pseudotumor
that classically arises as a
rapidly growing, solitary mass
affecting 1 muscle.
Histologically, it is
characterized in most cases by
skeletal muscle with variable
inflammation, fibrosis, and
myopathic/neurogenic
changes. (Right) Variation in
size of myocytes is a common
finding in focal myositis, and it
is not unusual to see
hypertrophic fibers
immediately adjacent to small-
or normal-sized ones.

Inflammatory Component Endomysial Fibrosis

(Left) Chronic inflammatory
cells are seen in the vast
majority of cases of focal
myositis, with lymphocytes
generally dominating the
distribution. Plasma cells,
histiocytes, and eosinophils ſt
may also be seen. (Right)
Fibrosis is a common finding in
focal myositis and tends to
predominate in the
endomysium, separating
individual myofibers.

370
 Focal Myositis

Tumors of Skeletal Muscle

○ Mainly lymphocytes
TERMINOLOGY
○ Plasma cells, histiocytes, and eosinophils are less
Definitions common
• Benign self-limiting, intramuscular inflammatory • Focal denervation changes
pseudotumor ○ Axonal swelling, demyelination, endoneurial fibrosis
• Variable fatty replacement of muscle
ETIOLOGY/PATHOGENESIS • No atypia, calcification, or ossification
Idiopathic
DIFFERENTIAL DIAGNOSIS
• Exact cause(s) uncertain
• Some cases may be related to previous trauma True Inflammatory Myopathies
• Infectious etiologies and relationship to transient • Polymyositis, dermatomyositis, inclusion body myositis
autoimmune disease have been suggested • Typical presentation: Progressive weakness on both sides
of body
CLINICAL ISSUES ○ Proximal muscles often affected 1st
Epidemiology • Only rare reported cases of solitary mass-like involvement
• Histologic overlap with focal myositis is common
• Incidence
○ Uncommon Proliferative Myositis
• Age • Checkerboard pattern, less muscle fiber damage
○ Wide range (median: 36 years) • Ganglion cell-like myofibroblasts characteristic
Site ○ Not feature of focal myositis
• Single muscle involvement Lymphoma
• Limbs most common, especially lower extremities • Sheet-like growth of atypical lymphocytes
○ Particularly gastrocnemius and vastus lateralis • B- or T-cell clonality present
• Also head/neck, trunk, other
Myositis Ossificans
Presentation • Shows central fasciitis-like morphology and evidence of
• Rapidly appearing and growing mass woven bone formation with maturation
• Generally asymptomatic • No intratumoral damaged muscle fibers
○ Most are painless
Inflammatory Myofibroblastic Tumor
• Weakness is rare, and joint involvement is not present
• Spindled myofibroblasts with prominent stromal
Treatment inflammatory infiltrate, particularly plasma cells
• None required • Lacks myopathic and neurogenic changes
○ Surgery is generally not indicated • ALK(+) in 50% of cases
Prognosis Rhabdomyoma
• Excellent • Involvement of extremities rare
• Most cases regress over time • Sheets of large polygonal eosinophilic cells with nucleoli
○ Rare cases recur • Fibrosis and chronic inflammation are not typical features

MACROSCOPIC SELECTED REFERENCES

General Features
• Ovoid, unencapsulated, firm mass
• No involvement of tendons, fascia, or subcutaneous fat
Size
• Between 1-20 cm (median: 3 cm)
MICROSCOPIC
Histologic Features
• Skeletal muscle with marked variation in size of individual
myocytes
• Fibrosis common (endomysial more prominent than
perimysial)
○ Dense fibrosis in older lesions
• Regenerative myocytes with basophilic cytoplasm and large
vesicular nuclei with nucleoli
• Patchy necrosis of single myofibers may be seen
• Chronic inflammatory infiltrate common
1. Gallay L et al: Focal myositis: new insights on diagnosis and pathology.
Neurology. ePub, 2018
2. Auerbach A et al: Focal myositis: a clinicopathologic study of 115 cases of an
intramuscular mass-like reactive process. Am J Surg Pathol. 33(7):1016-24,
2009
3. Georgalas C et al: Inflammatory focal myositis of the sternomastoid muscle:
is there an absolute indication for biopsy? A case report and review of the
literature. Eur Arch Otorhinolaryngol. 263(2):149-51, 2006
4. Smith AG et al: Clinical and pathologic features of focal myositis. Muscle
Nerve. 23(10):1569-75, 2000
5. Moskovic E et al: Benign mimics of soft tissue sarcomas. Clin Radiol.
46(4):248-52, 1992
6. Moskovic E et al: Focal myositis, a benign inflammatory pseudotumour: CT
appearances. Br J Radiol. 64(762):489-93, 1991
7. Vercelli-Retta J et al: Focal myositis and its differential diagnosis. A case
report and review of the literature. Ann Pathol. 8(1):54-6, 1988
8. Heffner RR Jr et al: Denervating changes in focal myositis, a benign
inflammatory pseudotumor. Arch Pathol Lab Med. 104(5):261-4, 1980
9. Heffner RR Jr et al: Focal myositis. Cancer. 40(1):301-6, 1977
371
 Adult Rhabdomyoma

KEY FACTS
Tumors of Skeletal Muscle

TERMINOLOGY ○ Scattered "spider cells" may be seen

• Extracardiac lobular neoplasm composed of polygonal, • Cytoplasmic cross striations &/or rod-like crystalline
differentiated skeletal muscle cells structures may be identified
• Mitotic figures and necrosis are not seen
CLINICAL ISSUES
ANCILLARY TESTS
• Usually adults (mean age: 50 years)
• Predilection for men (4:1) • Strongly PAS(+) but diastase resistant
• Predominantly head and neck region • Positive for diffuse desmin, myogenin, and MYOD1
• Solitary, painless, slow-growing mass • Negative for keratin, CD68, CD163, TFE3, synaptophysin,
• Treatment: Surgical excision and chromogranin
• Benign but local recurrence in up to 40% TOP DIFFERENTIAL DIAGNOSES
MACROSCOPIC • Cardiac rhabdomyoma
• Well-circumscribed, lobulated red/brown/gray mass • Granular cell tumor
• 1-10 cm (median: 3 cm) • Alveolar soft part sarcoma
• Hibernoma
MICROSCOPIC • Crystal-storing histiocytosis
• Sheets and large nests of large, polygonal tumor cells with • Paraganglioma
granular eosinophilic or vacuolated cytoplasm

Adult Rhabdomyoma Fine Capillary Network

(Left) Adult rhabdomyoma is a
benign tumor of differentiated
skeletal muscle cells that
typically occurs in the head
and neck region of adults. It is
composed of sheets and
lobules of eosinophilic and
clear, vacuolated cells. (Right)
Adult rhabdomyoma also
contains a fine capillary
network ﬈, which may impart
an overall nested appearance
reminiscent of alveolar soft
part sarcoma or a high-grade
clear cell renal cell carcinoma.

Eosinophilic Polygonal Cells Cross Striations and Inclusions

(Left) In most cases of adult
rhabdomyoma, the
predominant tumor cell is
large and polygonal and
contains prominent
eosinophilic cytoplasm. Tumor
cells may also contain
cytoplasmic vacuolizations
and appear completely clear
or demonstrate a retracted
"spider cell" morphology ﬈.
(Right) Cytoplasmic cross
striations ﬈ or rod-like
inclusions may be seen in
scattered tumor cells in adult
rhabdomyoma. Tumor cells
also commonly show
prominent nucleoli.

372
 Adult Rhabdomyoma

Tumors of Skeletal Muscle

• Mitotic figures and necrosis are not seen
TERMINOLOGY
• Fine stromal capillary vascular network
Definitions
• Extracardiac lobular neoplasm composed of polygonal, ANCILLARY TESTS
differentiated skeletal muscle cells Histochemistry
• Strong PAS staining that is diastase sensitive (due to
CLINICAL ISSUES
prominent intracytoplasmic glycogen)
Epidemiology
Immunohistochemistry
• Incidence
• Positive for diffuse desmin, myogenin, and MYOD1
○ Rare but most common type of extracardiac
rhabdomyoma • S100 protein and SMA may be focally (+) but not diffuse
• Age • Negative for keratin, CD68, CD163, pax-8, TFE3,
synaptophysin, and chromogranin
○ Usually adults (mean age: 50 years)
– Rare cases reported in children
DIFFERENTIAL DIAGNOSIS
• Sex
○ Predilection for men (4:1) Cardiac Rhabdomyoma
Site • Usually occurs in association with tuberous sclerosis
• Most tumor cells are vacuolated, and spider cells are
• Predominantly head and neck region common
○ Particularly in region of pharynx, larynx, base of tongue,
and floor of mouth Granular Cell Tumor
• Rare cases reported all over body • Lacks cytoplasmic vacuolizations
Presentation • Diffuse PAS(+) but diastase resistant (phagolysosomes)
• Diffuse S100 protein (+)
• Solitary, painless, slow-growing mass
○ Minority of cases (20%) are multifocal, usually in neck Alveolar Soft Part Sarcoma
• Hoarseness or symptoms related to airway obstruction may • Large tumors, usually with prominent nested architecture
be present • Nuclear TFE3(+), desmin (-), myogenin (-)
Treatment • Presence of t(X;17) unbalanced translocation
• Surgical excision Hibernoma
Prognosis • Eosinophilic cells containing numerous tiny intracytoplasmic
lipid vacuoles
• Benign
• Often show obvious component of adipocytic
• Local recurrence in up to 40% differentiation
○ May recur multiple times or many years after initial • Desmin (-), myogenin (-)
excision
• Spontaneous regression has not been reported Crystal-Storing Histiocytosis
• Lesional cells are histiocytes, not myocytes
MACROSCOPIC • Accompanying lymphoplasmacytic infiltrate is typically
General Features clonal/neoplastic
• CD68(+), CD163(+), desmin (-), myogenin (-)
• Well-circumscribed, lobulated mass
○ May be pedunculated Paraganglioma
• Red/brown/gray coloration • Prominent nested or organoid growth
Size • Synaptophysin (+), desmin (-), myogenin (-)
• 1-10 cm (median: 3 cm)
SELECTED REFERENCES
MICROSCOPIC 1. Dermawan JK et al: Cytologic findings of an adult rhabdomyoma in the
parapharyngeal space: a report of a case and review of the literature. Diagn
Histologic Features Cytopathol. 46(5):419-24, 2018
2. Altissimi G et al: Adult-type rhabdomyoma of the larynx: clinicopathologic
• Sheets and large nests of large, polygonal tumor cells study of an uncommon tumor in a rare location. Case Rep Otolaryngol.
○ Most cells have finely granular eosinophilic cytoplasm 2017:7186768, 2017
3. Zhang GZ et al: Intraoral multifocal and multinodular adult rhabdomyoma:
○ Subset of cells have cytoplasmic vacuolizations and report of a case. J Oral Maxillofac Surg. 70(10):2480-5, 2012
appear optically clear 4. Hansen T et al: Rhabdomyoma of the head and neck: morphology and
– Cells with retracted cytoplasm ("spider cells") may be differential diagnosis. Virchows Arch. 447(5):849-54, 2005
seen 5. Willis J et al: Extracardiac rhabdomyomas. Semin Diagn Pathol. 11(1):15-25,
1994
• 1 or 2 central or peripherally located nuclei, often with 6. Kapadia SB et al: Adult rhabdomyoma of the head and neck: a
prominent nucleoli clinicopathologic and immunophenotypic study. Hum Pathol. 24(6):608-17,
• Cytoplasmic cross striations &/or rod-like inclusions may be 1993
identified

373
 Fetal Rhabdomyoma

KEY FACTS
Tumors of Skeletal Muscle

TERMINOLOGY MICROSCOPIC
• Benign rhabdomyoblastic tumor demonstrating immature • Well circumscribed; infiltrative growth always absent
skeletal muscle differentiation • Classic (myxoid) type
ETIOLOGY/PATHOGENESIS ○ Loose bundles of eosinophilic spindled fetal myotubules
○ Prominent myxoid stroma
• Subset arise in association with nevoid basal cell carcinoma
• Intermediate (juvenile) type
syndrome (Gorlin syndrome)
○ Greater cellularity and mitotic activity than classic type
CLINICAL ISSUES ○ Greater degree of rhabdomyoblastic differentiation
• Very rare • Both types lack nuclear atypia, atypical mitoses, and
• Usually in children < 3 years of age necrosis
○ Male predilection ANCILLARY TESTS
• Head and neck region most common
• Desmin (+), myogenin (+)
• Treatment: Complete surgical excision
• Excellent prognosis TOP DIFFERENTIAL DIAGNOSES
MACROSCOPIC • Embryonal rhabdomyosarcoma
• Spindle cell rhabdomyosarcoma
• Well circumscribed
• Genital rhabdomyoma
• Median size: 3 cm (range: 1.0-12.5 cm)

Fetal Rhabdomyoma Absence of Nuclear Pleomorphism

(Left) Fetal rhabdomyoma is a
well-circumscribed tumor with
a predilection for arising in the
head and neck region of
infants and young children. It
is characterized by loose
bundles and fascicles of
spindled eosinophilic cells
within a prominent myxoid
stroma. (Right) Similar to
other forms of rhabdomyoma,
fetal rhabdomyoma lacks
significant nuclear atypia,
atypical mitoses, and necrosis.
These pertinent negative
findings help in the distinction
from rhabdomyosarcoma.

Fetal Rhabdomyoma (Intermediate Type) Cross Striations

(Left) The intermediate (or
juvenile) type of fetal
rhabdomyoma is more
uniformly cellular than the
classic type and can show
increased mitotic activity.
Cellular differentiation also
resembles late-stage
embryonic skeletal muscle.
Nuclei still lack pleomorphism
and there are no atypical
mitoses or necrosis. (Right)
Cytoplasmic cross-striations
﬊, characteristic of skeletal
muscle differentiation, are
apparent in some of the tumor
cells in fetal rhabdomyoma.

374
 Fetal Rhabdomyoma

Tumors of Skeletal Muscle

– Prominent myxoid stroma
TERMINOLOGY
– Elongated rhabdomyoblasts (strap cells) with cross
Definitions striations
• Benign rhabdomyoblastic tumor demonstrating immature – No significant nuclear atypia
skeletal muscle differentiation – Mitotic rate usually low
○ Intermediate (juvenile) type
ETIOLOGY/PATHOGENESIS – Greater cellularity and mitotic activity than classic type
Genetics – Myxoid stroma less prominent
– Greater degree of rhabdomyoblastic differentiation
• Subset arise in association with nevoid basal cell carcinoma
– May contain cells with smooth muscle differentiation
syndrome (Gorlin syndrome)
– No significant nuclear atypia
○ PTCH1 mutations
– Lacks atypical mitoses and necrosis
CLINICAL ISSUES
ANCILLARY TESTS
Epidemiology
Immunohistochemistry
• Incidence
• Desmin (+), myogenin (+)
○ Very rare
• May also express SMA and S100 protein
• Age
• Negative for keratin, CD68, and CD163
○ Usually in children < 3 years
– 1/2 arise within 1st year, including congenitally
DIFFERENTIAL DIAGNOSIS
– Overall wide range; rare in adults
• Sex Embryonal Rhabdomyosarcoma
○ Male predilection • Nuclear atypia
Site • Infiltrative growth; lacks circumscription
• Atypical mitoses &/or necrosis
• Head and neck region most common
• Cellular cambium layer in botryoid-type tumors
○ Particularly postauricular area
○ Oral cavity, oropharynx, nasal cavity Spindle Cell Rhabdomyosarcoma
• Occasionally elsewhere • Often displays cellular, prominently fascicular growth
Presentation • Nuclear atypia
• Head and neck common site in adults
• Vast majority arise in subcutaneous tissue
• Solitary, slow-growing mass Genital Rhabdomyoma
○ Multifocal/multicentric tumors in Gorlin syndrome • Stroma is loose and fibrous rather than prominently myxoid
• Oropharyngeal lesions may create obstructive breathing • Can show morphologic overlap with classic fetal
difficulties rhabdomyoma
Treatment • Arises in genital sites rather than head and neck
• Strong female predilection
• Complete surgical excision
Prognosis SELECTED REFERENCES
• Excellent prognosis 1. Thompson LD: Ear fetal rhabdomyoma. Ear Nose Throat J. 96(9):358, 2017
• Generally does not recur 2. Zheng L et al: Paratesticular fetal-type rhabdomyoma in a 12-year-old boy: a
case report and literature review. Urology. 82(5):1150-2, 2013
• No metastatic potential 3. Fletcher DM et al: WHO Classification of Tumours of Soft Tissue and Bone.
Lyon: IARC, 2013
MACROSCOPIC 4. Yang S et al: Mediastinal fetal rhabdomyoma in nevoid basal cell carcinoma
syndrome: a case report and review of the literature. Virchows Arch.
General Features 459(2):235-8, 2011
5. Walsh SN et al: Cutaneous fetal rhabdomyoma: a case report and historical
• Well circumscribed review of the literature. Am J Surg Pathol. 32(3):485-91, 2008
• Sessile or polypoid in mucosal sites 6. Hansen T et al: Rhabdomyoma of the head and neck: morphology and
differential diagnosis. Virchows Arch. 447(5):849-54, 2005
Size 7. Watson J et al: Nevoid basal cell carcinoma syndrome and fetal
• Median: 3 cm (range: 1.0-12.5 cm) rhabdomyoma: a case study. Ear Nose Throat J. 83(10):716-8, 2004
8. Crotty PL et al: Juvenile rhabdomyoma. An intermediate form of skeletal
muscle tumor in children. Arch Pathol Lab Med. 117(1):43-7, 1993
MICROSCOPIC 9. Kapadia SB et al: Fetal rhabdomyoma of the head and neck: a
clinicopathologic and immunophenotypic study of 24 cases. Hum Pathol.
Histologic Features 24(7):754-65, 1993
• Well circumscribed; infiltrative growth always absent 10. DiSanto S et al: Fetal rhabdomyoma and nevoid basal cell carcinoma
syndrome. Pediatr Pathol. 12(3):441-7, 1992
• 2 main forms
○ Classic (myxoid) type
– Loose bundles of eosinophilic spindled fetal
myotubules

375
 Genital Rhabdomyoma

KEY FACTS
Tumors of Skeletal Muscle

TERMINOLOGY MACROSCOPIC
• Benign neoplasm of rhabdomyoblastic origin arising in • Usually small (< 3 cm)
genital tract
MICROSCOPIC
• Synonym: Vaginal rhabdomyoma
• Hypocellular proliferation of differentiated
CLINICAL ISSUES rhabdomyoblasts within loose fibrous stroma
• Rare ○ Spindled (strap cells) or polygonal rhabdomyoblasts
• Usually adults • No cytologic atypia, mitoses, or necrosis
○ Occasionally children or adolescents • Morphologic variant: Sclerosing rhabdomyoma
• Strong female predilection
ANCILLARY TESTS
• Females: Vagina (most common), vulva, cervix
• Desmin (+), myogenin (+)
• Males: Paratesticular region, including spermatic cord and
tunica vaginalis • S100 protein (-), keratin (-)
• Treatment: Conservative surgical excision TOP DIFFERENTIAL DIAGNOSES
• Excellent prognosis • Embryonal rhabdomyosarcoma
○ Generally does not recur • Fetal rhabdomyoma
○ Does not metastasize • Fibroepithelial stromal polyp
• Spindle cell rhabdomyosarcoma

Genital Rhabdomyoma Hypocellular Proliferation

(Left) Genital rhabdomyoma is
the rarest form of
rhabdomyoma. It usually
arises in adult women
(particularly in the vagina) but
can also be seen in men and in
children. In women, lesions are
generally polypoid, as
depicted, with overlying
squamous epithelium ﬈. Note
the absence of a cambium
layer. (Right) Genital
rhabdomyoma features a
hypocellular proliferation of
mature rhabdomyoblastic
elements ﬈ within a loose
fibrous stroma. Small vessels
are often conspicuous ﬉.

Differentiated Rhabdomyoblasts DDx: Botryoid-Type ERMS

(Left) Rhabdomyoblastic
elements are well
differentiated in genital
rhabdomyoma and show an
elongated or polygonal
morphology. Cytoplasmic
cross striations are common
﬉. Mitotic figures are absent.
(Right) Botryoid-type ERMS
may mimic genital
rhabdomyoma, particularly
following treatment with
chemotherapy. Note however,
that botryoid-type ERMS is
generally more cellular and
often shows a cellular,
subepithelial cambium layer
﬉.

376
 Genital Rhabdomyoma

Tumors of Skeletal Muscle

TERMINOLOGY Morphologic Variants
• Sclerosing rhabdomyoma
Synonyms ○ Arises in paratesticular region of young men
• Vaginal rhabdomyoma ○ Features mature rhabdomyoblastic elements within
Definitions abundant dense collagenous stroma
○ No atypia, mitoses, or necrosis
• Benign neoplasm of rhabdomyoblastic origin arising in
genital tract
ANCILLARY TESTS
CLINICAL ISSUES Immunohistochemistry
Epidemiology • Desmin (+), myogenin (+)
• Incidence • S100 protein (-), keratin (-)
○ Rare
• Age
DIFFERENTIAL DIAGNOSIS
○ Usually adults Embryonal Rhabdomyosarcoma
– Occasionally children or adolescents • Often forms larger lesions
• Sex • Wide range of cellularity
○ Strong female predilection ○ Postchemotherapy embryonal rhabdomyosarcoma
(ERMS) can mimic genital rhabdomyoma
Site
– Hypocellular and with mature rhabdomyoblastic
• Females elements
○ Vagina (most common) • Cytologic atypia, mitoses, &/or necrosis
○ Vulva • Botryoid-type ERMS usually features cellular subepithelial
○ Cervix layer (cambium layer)
• Males
○ Paratesticular region, including spermatic cord and Fetal Rhabdomyoma
tunica vaginalis • Myxoid rather than fibrous stroma
• Predilection for head and neck region
Presentation
• Some cases can show morphologic overlap with genital
• Slow growing rhabdomyoma
• Painless
Fibroepithelial Stromal Polyp
Treatment
• Similar clinical presentation to genital rhabdomyoma
• Conservative surgical excision • Lacks rhabdomyoblasts
Prognosis Teratoma
• Excellent prognosis • Epithelial elements common
• Generally does not recur • May contain skeletal muscle or rhabdomyoblastic elements
• No metastatic potential • In males, often intratesticular rather than paratesticular

MACROSCOPIC Spindle Cell Rhabdomyosarcoma

• Paratesticular region is common site
General Features
• Generally far more cellular than genital rhabdomyoma
• Firm, well-circumscribed, lobulated mass
○ Fascicular growth common
• Often polypoid in females
• Atypia and mitoses common
○ Covered by mucosa
Size SELECTED REFERENCES
• Usually small (< 3 cm) 1. Schoolmeester JK et al: Genital rhabdomyoma of the lower female genital
tract: a study of 12 cases with molecular cytogenetic findings. Int J Gynecol
Pathol. 37(4): 349-55, 2018
MICROSCOPIC 2. Jo VY et al: Paratesticular rhabdomyoma: a morphologically distinct
sclerosing variant. Am J Surg Pathol. 37(11):1737-42, 2013
Histologic Features
3. Lu DY et al: Genital rhabdomyoma of the urethra in an infant girl. Hum
• Hypocellular proliferation of differentiated Pathol. 43(4):597-600, 2012
rhabdomyoblasts within loose fibrous stroma 4. Cooper CL et al: Paratesticular rhabdomyoma. Pathology. 39(3):367-9, 2007
5. Wehner MS et al: Epididymal rhabdomyoma: report of a case, including
○ Spindled (strap cells) or polygonal rhabdomyoblasts histologic and immunohistochemical findings. Arch Pathol Lab Med.
• In females, lesion shows overlying squamous epithelium 124(10):1518-9, 2000
• Small stromal vessels often prominent 6. Tanda F et al: Rhabdomyoma of the tunica vaginalis of the testis: a histologic,
immunohistochemical, and ultrastructural study. Mod Pathol. 10(6):608-11,
• No cytologic atypia 1997
• No mitoses 7. Iversen UM: Two cases of benign vaginal rhabdomyoma. Case reports.
• No necrosis APMIS. 104(7-8):575-8, 1996
8. Suarez Vilela D et al: Vaginal rhabdomyoma and adenosis. Histopathology.
16(4):393-4, 1990

377
 Cardiac Rhabdomyoma

KEY FACTS
Tumors of Skeletal Muscle

TERMINOLOGY MACROSCOPIC
• Benign cardiac neoplasm composed of fetal cardiac • Relatively well demarcated
myoblasts • Usually 0.1-3.0 cm
ETIOLOGY/PATHOGENESIS MICROSCOPIC
• Most arise within setting of tuberous sclerosis complex • Sheets of large polygonal cells with large, clear vacuoles
CLINICAL ISSUES • Some cells have eosinophilic cytoplasm that is retracted
away from cell membrane ("spider cells")
• Most common primary pediatric cardiac tumor
• Occurs primarily in infants and young children ANCILLARY TESTS
• Right and left ventricular walls are most common sites • Immunophenotype: Desmin (+), myogenin (+), MYOD1(+)
○ Multifocality is common • Mutations in TSC2 (tuberin) on chromosome 16 and TSC1
• May be asymptomatic or cause arrhythmia, ventricular (hamartin) on chromosome 9
outflow obstruction, tachycardia, Wolff-Parkinson-White
TOP DIFFERENTIAL DIAGNOSES
syndrome, sudden death
• Treatment: Usually nonsurgical and conservative • Adult-type rhabdomyoma
○ Many cases regress spontaneously over time • Cardiac fibroma

Cardiac Rhabdomyoma Prominent Clear Cell Morphology

(Left) Cardiac rhabdomyoma is
the most common primary
pediatric neoplasm of the
heart and is associated with
the tuberous sclerosis
syndrome in most cases.
Histologically, it can be readily
distinguished from normal
cardiac muscle ﬈ by the
prominent cytoplasmic
vacuolization/clearing ﬊.
(Right) Cardiac rhabdomyoma
is composed predominantly of
large polygonal cells
containing prominent
cytoplasmic vacuolizations,
imparting a clear cell
morphology.

Vacuolated Tumor Cells "Spider Cells"

(Left) Although most of the
tumor cells in cardiac
rhabdomyoma are heavily
vacuolated clear cells, some
cells are less vacuolated and
show eosinophilic cytoplasm
﬈. (Right) The combination of
eosinophilic cytoplasm and
intracytoplasmic
vacuolizations often gives the
appearance of centralized
cells with radially oriented
cytoplasmic extensions ﬈.
These cells are aptly described
as "spider cells."

378
 Cardiac Rhabdomyoma

Tumors of Skeletal Muscle

TERMINOLOGY MICROSCOPIC
Definitions Histologic Features
• Benign cardiac neoplasm composed of fetal cardiac • Sheets of large polygonal cells with large, clear vacuoles
myoblasts ○ Vacuoles result from glycogen accumulation
• Some cells have eosinophilic cytoplasm that is retracted
ETIOLOGY/PATHOGENESIS away from cell membrane
Genetics ○ Described as "spider cells"
• Cytoplasmic cross striations rare
• Most arise within setting of tuberous sclerosis (TS)
• Small nuclei with irregular contours; may show nucleoli
○ More than 1/2 of patients with TS have 1 or more cardiac
rhabdomyoma • Mitoses rare
• May also arise in association with congenital abnormalities, • Necrosis absent
such as ventricular or valvular malformations
ANCILLARY TESTS
CLINICAL ISSUES Immunohistochemistry
Epidemiology • Desmin (+), myogenin (+), MYOD1(+)
• Incidence • HMB-45(+) reported in some cases
○ Most common primary pediatric cardiac tumor Genetic Testing
• Age • Mutations in TSC2 (tuberin) on chromosome 16
○ Infants and young children • Mutations in TSC1 (hamartin) on chromosome 9
– Most common in 1st year of life
• Sex DIFFERENTIAL DIAGNOSIS
○ Slight male predilection
Adult-Type Rhabdomyoma
Site • Extracardiac in nearly all cases
• Right and left ventricular walls most common ○ Very rare intracardiac cases reported
○ Rarely intraventricular septum or atrial walls • Cellular sheets of polygonal eosinophilic cells
• Multifocality is common • "Spider cells" not usually prominent
Presentation Cardiac Fibroma
• May cause arrhythmia, ventricular outflow obstruction, • Composed of loose fascicles of spindled fibroblastic cells
tachycardia, Wolff-Parkinson-White syndrome, or sudden • SMA(+), desmin (-), myogenin (-)
death
• May be asymptomatic SELECTED REFERENCES
Treatment 1. Bejiqi R et al: Prenatally diagnosis and outcome of fetuses with cardiac
rhabdomyoma - single centre experience. Open Access Maced J Med Sci.
• Usually conservative 5(2):193-6, 2017
○ Medical therapy for arrhythmias 2. Chang JS et al: Regression of neonatal cardiac rhabdomyoma in two months
○ Surgical excision is often utilized in tumors causing through low-dose everolimus therapy: a report of three cases. Pediatr
Cardiol. 38(7):1478-84, 2017
outflow obstruction or those that are refractive to 3. Sciacca P et al: Rhabdomyomas and tuberous sclerosis complex: our
medical therapy experience in 33 cases. BMC Cardiovasc Disord. 14:66, 2014
○ Everolimus (mTOR inhibitor) may have role in facilitating 4. Chaurasia AK et al: Cardiac rhabdomyoma in familial tuberous sclerosis. J
Cardiovasc Thorac Res. 5(2):71-2, 2013
regression
5. Kutluk T et al: Cardiac rhabdomyomas in childhood: six cases from a single
Prognosis institution. Turk J Pediatr. 55(1):69-73, 2013
6. Benyounes N et al: Cardiac rhabdomyomas in tuberous sclerosis patients: a
• Benign case report and review of the literature. Arch Cardiovasc Dis. 105(8-9):442-5,
• Many cases regress spontaneously over time 2012
7. Demir HA et al: Everolimus: a challenging drug in the treatment of multifocal
inoperable cardiac rhabdomyoma. Pediatrics. 130(1):e243-7, 2012
IMAGING 8. Madueme P et al: Tuberous sclerosis and cardiac rhabdomyomas: a case
report and review of the literature. Congenit Heart Dis. 6(2):183-7, 2011
General Features
9. Tiberio D et al: Regression of a cardiac rhabdomyoma in a patient receiving
• Often multiple intramural lesions everolimus. Pediatrics. 127(5):e1335-7, 2011
• May be detected antenatally on ultrasound 10. Burke A, Virmani R. Pediatric heart tumors. Cardiovasc Pathol. 2008 Jul-
Aug;17(4):193-8.
11. Burke AP et al: Cardiac rhabdomyoma: a clinicopathologic study. Mod
MACROSCOPIC Pathol. 4(1):70-4, 1991

General Features
• Relatively well demarcated
• Pale pink-tan cut surface
Size
• Usually 0.1-3.0 cm
379
 Embryonal Rhabdomyosarcoma

KEY FACTS
Tumors of Skeletal Muscle

TERMINOLOGY MICROSCOPIC
• Malignant primitive mesenchymal neoplasm that shows • Patternless sheets of spindled, stellate, and ovoid cells
variable differentiation toward embryonic skeletal muscle ○ Widely variable cellularity
○ May originate in epithelial-lined viscera (botryoid type) • Myxoid stromal matrix is common
CLINICAL ISSUES • Rhabdomyoblastic differentiation often conspicuous but
variable
• Embryonal rhabdomyosarcoma (ERMS) is most common
• Variants: Botryoid, anaplastic
subtype (60-70%)
• Most occur in 1st decade of life ANCILLARY TESTS
• Most arise in head/neck region or genitourinary system • Diffuse desmin (+)
• Suddenly enlarging mass • Nuclear myogenin (+) and MYOD1(+)
○ Botryoid-type ERMS arises as polypoid growth in • Molecular: Absence of FOXO1 translocations
mucosal sites (e.g., vagina, bladder)
TOP DIFFERENTIAL DIAGNOSES
• Treatment: Multimodality therapy
• Main prognostic parameters are histologic type, disease • Rhabdomyoma
stage, age, and site • ARMS
○ ERMS has significantly better prognosis than alveolar • Malignant peripheral nerve sheath tumor with
rhabdomyosarcoma (ARMS) rhabdomyoblastic differentiation
• Neuroblastoma

Embryonal Rhabdomyosarcoma Variable Cellularity

(Left) Embryonal
rhabdomyosarcoma (ERMS)
often shows a somewhat
marbled appearance due to
regional variations in
cellularity; however, some
cases are more or less evenly
hypo- or hypercellular. Of
note, perivascular regions ﬈
are often more cellular than
the adjacent looser myxoid
zones ﬊. (Right) This higher
power image shows a loose,
more myxoid zone
transitioning into a denser,
less myxoid area. The cells
vary from spindled or stellate
to ovoid.

Rhabdomyoblastic Differentiation Myogenin Expression

(Left) Rhabdomyoblastic
differentiation is usually
evident in most cases of ERMS
and is heralded by
development of dense
eosinophilic cytoplasm in
tumor cells. Some cells show a
rounded epithelioid
morphology with an eccentric
nucleus ﬈. (Right) Myogenin
expression is usually seen in
ERMS; however, in contrast to
alveolar rhabdomyosarcoma
(ARMS), it is often sparse,
focal, or patchy. Only nuclear
expression should be counted,
as cytoplasmic expression is
nonspecific.

380
 Embryonal Rhabdomyosarcoma
TERMINOLOGY
Abbreviations
• Embryonal rhabdomyosarcoma (ERMS)
Definitions
• Malignant primitive mesenchymal neoplasm that shows
variable differentiation toward embryonic skeletal muscle
○ May originate in epithelial-lined viscera (botryoid type)
• Spindle cell rhabdomyosarcoma is now provisionally listed
as rhabdomyosarcomas (RMS) subtype, separate and
distinct from ERMS (2013 WHO Classification)
CLINICAL ISSUES
Epidemiology
• Incidence
○ RMS are most frequent soft tissue sarcomas in children
and young adults
– ERMS is most common subtype (60-70%)
• Age
○ Most occur in 1st decade of life
– Majority in children < 5 years
□ Occasional cases congenital
○ Less common in adolescence
– Rare in adults
Site
• Most arise in head/neck region or genitourinary system
○ Periorbital soft tissues, sinonasal tract, oral cavity,
auditory canal
○ Bladder, prostate, paratesticular soft tissue
• Less frequent sites
○ Biliary tract, retroperitoneum, abdomen/pelvis
• Rare involvement of trunk and extremities
Presentation
• Suddenly enlarging mass
○ Local symptoms pertaining to site of origin
○ Botryoid-type ERMS arises as polypoid growth in
mucosal sites (e.g., vagina, bladder)
• May be associated with variety of genetic syndromes
○ Neurofibromatosis type 1, Noonan syndrome, Costello
syndrome
○ Also Beckwith-Wiedemann syndrome, Li-Fraumeni
syndrome, Gorlin syndrome, others
○ Pleuropulmonary blastoma syndrome associated with
ERMS of uterine cervix
Treatment
• Multimodality therapy with chemotherapy in conjunction
with surgery &/or radiotherapy
Prognosis
• Main prognostic parameters are histologic type, disease
stage, age, and site
○ ERMS has significantly better prognosis than alveolar
rhabdomyosarcoma (ARMS)
– Likely related to absence of FOXO1 fusions
○ Botryoid-type ERMS associated with better prognosis
○ Anaplasia in ERMS associated with worse outcome
Tumors of Skeletal Muscle
○ Intergroup Rhabdomyosarcoma Study Group (IRSG)
surgicopathologic grouping is predictive of outcome
○ Children generally show better outcome than infants,
adolescents, and adults
○ Favorable sites are orbital, paratesticular, and bile duct
– Parameningeal and extremities unfavorable
MACROSCOPIC
General Features
• Poorly demarcated, friable mass
• Tan-white, fleshy or rubbery cut surface
• Hemorrhage or necrosis may be present
• Botryoid-type RMS
○ Exophytic, polypoid, grape like
○ Often gelatinous cut surface
MICROSCOPIC
Histologic Features
• Patternless sheets of spindled, stellate, and ovoid cells
○ Hyperchromatic nuclei
○ Cytoplasm ranges from scant and amphophilic to more
prominent and eosinophilic
• Myxoid stromal matrix is common
• Widely variable cellularity
○ Often show alternating hyper- and hypocellular zones
(marbled pattern)
– Cellularity is often higher around stromal blood
vessels
○ Hypercellular dense zones may resemble ARMS
• Rhabdomyoblastic differentiation often conspicuous, but
variable
○ Rounded or spindled cells with eccentric nuclei and
prominent eosinophilic cytoplasm
○ May show cytoplasmic cross striations &/or
multinucleation
○ Includes strap cells, tadpole cells, and spider cells
• Mitoses common
• Variable coagulative necrosis
• Multinucleated wreath cells absent
• Some composite (mixed-type) tumors show features of
both ERMS and ARMS
○ Previously classified automatically as ARMS
○ Current recommendation: Greater than 50% alveolar
elements needed to designate as ARMS
○ Determination of fusion status through molecular
analysis recommended in mixed-type cases
• Occasional tumors have histologic features of both ERMS
and spindle cell RMS
• Postchemotherapy changes
○ Residual cells often appear less primitive and more
differentiated
○ Prominent fibrosis, myxoid change, necrosis
Morphologic Variants
• Botryoid type
○ Arises at mucosal sites underneath epithelial surface
lining
○ Presence of cambium layer characteristic
– Tightly packed cellular layer of tumor cells closely
abutting epithelial surface
381
 Embryonal Rhabdomyosarcoma
Tumors of Skeletal Muscle

○ Otherwise loose myxoid stroma and variable cellularity • Occur mostly in adults
• Anaplastic • Can be associated with neurofibromatosis type 1
○ Singly scattered, clusters, or sheets of markedly atypical • Predominantly shows histologic features of malignant
cells peripheral nerve sheath tumor (MPNST)
– Enlarged, hyperchromatic, pleomorphic nuclei ○ Contains foci of rhabdomyoblastic cells with prominent
– Atypical mitotic figures common eosinophilic cytoplasm
○ Areas of more typical ERMS present – Desmin (+), myogenin (+) in rhabdomyoblastic cells
only
ANCILLARY TESTS Pleomorphic Rhabdomyosarcoma
Immunohistochemistry • Almost exclusively in adults
• Diffuse desmin (+) • Most common in extremities
○ Can highlight cytoplasmic cross striations • Diffuse, overtly malignant, pleomorphic, high-grade
• Nuclear myogenin (+) and MYOD1(+) cytomorphology
○ Cytoplasmic staining is nonspecific and should be Neuroblastoma
disregarded
• Intraabdominal sympathetic chain, adrenal gland
○ Expression often focal or patchy (unlike ARMS)
• Variable amount of neurofibrillary matrix
• Variable SMA(+)
• NB84(+), desmin (-), myogenin (-)
• May show focal aberrant keratin (+)
Molecular Genetics Pleuropulmonary Blastoma
• Occurs in peripheral lung, pleura, chest wall
• Absence of PAX3-FOXO1 and PAX7-FOXO1 fusions
• Small primitive blastemal cells with focal differentiation
• Complex karyotypes
toward other mesenchymal lineages, including skeletal
○ Often gains of chromosomes 2, 8, 12, and 13
muscle
• Loss of heterozygosity at 11p15.5 considered hallmark of
ERMS Infantile Fibrosarcoma
• Usually occurs in extremities in first 2 years of life
DIFFERENTIAL DIAGNOSIS • Intersecting fascicles of primitive ovoid and spindled tumor
Rhabdomyoma cells
• Desmin (-), myogenin (-)
• Head and neck predilection, especially fetal type
• Characteristic t(12;15) with NTRK3-ETV6 fusion
• Fetal-type rhabdomyoma
○ No significant nuclear atypia, necrosis, or infiltrative Ectomesenchymoma
margins • Usually in infants; very rare
○ Mitoses may be conspicuous but are not atypical • ERMS admixed with neuronal or neural component
• Adult-type rhabdomyoma ○ e.g., ganglion cells, ganglioneuroma, neuroblastoma,
○ Middle-aged adults, often men MPNST
○ Sheets of large polygonal, eosinophilic cells
• Genital-type rhabdomyoma SELECTED REFERENCES
○ Mostly middle-aged women; genital region 1. Rekhi B et al: Clinicopathologic features of 300 rhabdomyosarcomas with
○ Bland strap cells in loose fibrous stroma; no mitoses emphasis upon differential expression of skeletal muscle specific markers in
the various subtypes: single institutional experience. Ann Diagn Pathol.
Alveolar Rhabdomyosarcoma 36:50-60, 2018
2. McInturff M et al: Embryonal rhabdomyosarcoma of the oral cavity. Head
• Nests of tumor cells divided by fibrous septa Neck Pathol. 11(3):385-8, 2017
(pseudoalveolar pattern) 3. Rudzinski ER et al: The World Health Organization Classification of Skeletal
○ Solid areas may be nearly indistinguishable from dense Muscle Tumors in Pediatric Rhabdomyosarcoma: a report from the
Children's Oncology Group. Arch Pathol Lab Med. 139(10):1281-7, 2015
foci of ERMS
4. Rudzinski ER et al: Myogenin, AP2β, NOS-1, and HMGA2 are surrogate
• Most common in extremities and trunk in adolescents and markers of fusion status in rhabdomyosarcoma: a report from the soft tissue
young adults sarcoma committee of the children's oncology group. Am J Surg Pathol.
38(5):654-9, 2014
• Diffuse nuclear myogenin (+)
5. Li RF et al: Embryonal rhabdomyosarcoma (botryoid type) of the uterine
• Characteristic translocations between FOXO1 and PAX3 or corpus and cervix in adult women: report of a case series and review of the
PAX7 literature. Am J Surg Pathol. 37(3):344-55, 2013
6. Rudzinski ER et al: Dense pattern of embryonal rhabdomyosarcoma, a lesion
Spindle Cell Rhabdomyosarcoma easily confused with alveolar rhabdomyosarcoma: a report from the Soft
Tissue Sarcoma Committee of the Children's Oncology Group. Am J Clin
• Most common in paratesticular region of children or Pathol. 140(1):82-90, 2013
head/neck region of adults 7. Raney RB et al: Results of the Intergroup Rhabdomyosarcoma Study Group
• Predominantly fascicles of spindled cells; rhabdomyoblasts D9602 protocol, using vincristine and dactinomycin with or without
cyclophosphamide and radiation therapy, for newly diagnosed patients with
often sparse low-risk embryonal rhabdomyosarcoma: a report from the Soft Tissue
Sarcoma Committee of the Children's Oncology Group. J Clin Oncol.
Malignant Peripheral Nerve Sheath Tumor With 29(10):1312-8, 2011
Rhabdomyoblastic Differentiation 8. Davicioni E et al: Molecular classification of rhabdomyosarcoma--genotypic
and phenotypic determinants of diagnosis: a report from the Children's
• a.k.a. malignant triton tumor Oncology Group. Am J Pathol. 174(2):550-64, 2009

382
 Embryonal Rhabdomyosarcoma
Prominent Myxoid Stroma
Perivascular Accentuation
Increased Cellularity
Tumors of Skeletal Muscle
Bland Cytomorphology
(Left) Myxoid stroma is a
characteristic feature of ERMS
and is especially prominent in
less cellular cases. (Right) In
addition to the prominent
myxoid matrix, some cases of
ERMS may show paradoxically
bland cytologic features,
potentially leading to
confusion with a myxoma or
myxoid neurofibroma.
Focal Fascicular Morphology
(Left) Tumor cell condensation
around a stromal blood vessel
﬈ is a feature of some cases
of ERMS and contrasts nicely
with the less cellular adjacent
areas. (Right) Typical
examples of ERMS may show
focal areas of increased
cellularity with loose
fascicular growth ﬈. Tumors
with extensive fascicular
growth are best considered
spindle cell
rhabdomyosarcomas.
Hypercellularity
(Left) Cellularity varies widely
in ERMS from patient to
patient and even within the
same patient. This image
shows increased cellularity
within a still prominent
myxoid matrix. (Right) This
image shows a hypercellular
focus in ERMS with extensive
nuclear overlapping. Note the
lack of nuclear pleomorphism
despite the marked cellularity.
383
 Embryonal Rhabdomyosarcoma
Tumors of Skeletal Muscle

Ovoid Cellular Morphology Rhabdomyoblasts

(Left) The tumor cells may
show a more ovoid
cytomorphology with rounded
nuclei in some cases of ERMS.
This morphology may simulate
solid growth in ARMS if
myxoid stroma is limited.
(Right) Rhabdomyoblastic cells
are generally easier to identify
in ERMS compared to other
forms of rhabdomyosarcoma.
In addition to larger
epithelioid cells ﬊, some cells
are more elongated and
myofiber-shaped and may be
referred to as strap cells ﬈ or
tadpole cells. Cross striations
may also be evident.

Rhabdomyoblasts Focal Pseudoalveolar Growth

(Left) Occasional
rhabdomyoblastic cells in
ERMS show centralized
cytoplasmic retraction and
have been referred to as
spider cells. (Right) Focal
pseudoalveolar growth may
be present in otherwise
conventional ERMS and
currently no longer warrants
immediate classification as
ARMS. However, if suspicions
are high, molecular studies to
evaluate for FOXO1 fusions
are warranted.

Necrosis Focal Cystic Change

(Left) Coagulative necrosis is a
common finding in ERMS and
usually manifests as small
pockets of dead or dying cells;
however, extensive zones of
necrosis with perivascular
sparing may also be seen.
(Right) This unusual case of
otherwise conventional ERMS
showed foci of intratumoral
cystic change with
hemorrhage, somewhat
reminiscent of the pattern
seen in aneurysmal bone cyst.

384
 Embryonal Rhabdomyosarcoma

Tumors of Skeletal Muscle

Botryoid-Type Embryonal
Anaplasia Rhabdomyosarcoma
(Left) The presence of
scattered enlarged tumor cells
with hyperchromatic and
pleomorphic nuclei are seen in
some cases of ERMS and is
termed anaplasia ﬈. Some
variants show diffuse
anaplasia and contain atypical
mitotic figures. In either case,
the presence of anaplasia
portends a worsened
prognosis. (Right) Botryoid-
type ERMS presents as an
exophytic, polypoid growth
from underneath a mucosal
surface and, in some cases,
resembles a bunch of grapes
macroscopically.

Cambium Layer Reactive Appearance

(Left) A characteristic finding
in botryoid-type ERMS is the
presence of a superficial zone
﬈ of increased cellular
density underneath the
epithelial surface ﬊. This
zone is termed the cambium
layer. (Right) In some cases of
botryoid-type ERMS, the
neoplastic cells ﬊ deep to the
surface are small and
relatively innocuous appearing
and may be mistaken for
inflammatory cells or reactive
tissue. Hypocellularity further
complicates the issue.
However, note the cambium
layer ﬈.

Posttherapy Changes Posttherapy Maturation

(Left) Following
chemotherapy, ERMS often
shows prominent stromal
fibrosis with areas of myxoid
change. Of note, islands of
more mature/differentiated
rhabdomyoblasts ﬊ are not
uncommon. (Right) Occasional
cases of ERMS may show a
highly differentiated
appearance following
chemotherapy and may closely
resemble an adult-type
rhabdomyoma.

385
 Alveolar Rhabdomyosarcoma

KEY FACTS
Tumors of Skeletal Muscle

TERMINOLOGY ○ Nests show central loss of cellular cohesion

• Cellular, malignant neoplasm composed of primitive round
cells with evidence of skeletal muscle differentiation
CLINICAL ISSUES
• Most common between 10-25 years of age
• Most frequent in deep soft tissues of extremities
• Often high stage at presentation
• Treatment: Multimodality approach
• Fully malignant, high-grade sarcoma
○ Overall, worse prognosis than embryonal
rhabdomyosarcoma (ERMS)
○ Recent evidence suggests that prognosis may be related
to fusion status
• Rhabdomyoblasts may be seen
• Distinctive multinucleate tumor giant cells ("wreath cells")
in some cases
• Some tumors show both alveolar and embryonal features
• Morphologic variant: Solid type
ANCILLARY TESTS
• Usually diffuse desmin (+), myogenin (+), MyoD1(+)
• May show focal expression of keratin, CD99,
neuroendocrine markers
• Molecular: 2 characteristic recurrent chromosomal
translocations (80% of cases)
○ t(2;13)(PAX3-FOXO1) or t(1;13)(PAX7-FOXO1)

MICROSCOPIC TOP DIFFERENTIAL DIAGNOSES

• Generally, highly cellular • ERMS
• Nests and sheets of primitive rounded cells separated by • Sclerosing rhabdomyosarcoma (RMS)
variably prominent fibrous septa • Various small round blue cell tumors

Alveolar Rhabdomyosarcoma Pseudoalveolar Pattern

(Left) Alveolar
rhabdomyosarcoma (ARMS) is
a high-grade, malignant
neoplasm composed of nests
and sheets of primitive
rounded cells within a
fibrovascular stroma. At least
focal cellular dyscohesion ﬈
is usually evident at low
magnification. (Right) In
ARMS, a pseudoalveolar
pattern ﬈ is imparted by the
central loss of cellular
cohesion and viability within
the tumor nests.

Pseudoalveolar Pattern Cytologic Features

(Left) Despite the loss of
cellular cohesion in the center
of the nests, the peripheral
cells often remain attached to
the fibrous septa, an
appearance somewhat
resembling alveoli. This
pattern is similar to what is
seen in alveolar soft-part
sarcoma. (Right) The lesional
cells of ARMS are medium-
sized with relatively
monomorphic nuclei and
usually little eosinophilic
cytoplasm. Small, centralized
nucleoli may or may not be
present. Mitoses ﬈ are
common.

386
 Alveolar Rhabdomyosarcoma
TERMINOLOGY
Abbreviations
• Alveolar rhabdomyosarcoma (ARMS)
Definitions
• Cellular, malignant neoplasm composed of primitive,
monomorphic round cells with evidence of skeletal muscle
differentiation
CLINICAL ISSUES
Epidemiology
• Incidence
○ 2nd most common type of rhabdomyosarcoma (RMS)
[after embryonal rhabdomyosarcoma (ERMS)]
• Age
○ Predominantly adolescents and young adults (most
common 10-25 years)
– Less common than ERMS in children
– Rare in adults > 45 years
– Very rare cases are congenital
• Sex
○ M=F
• Ethnicity
○ No ethnic or geographical predilections
Site
• Most common in deep soft tissues of extremities
• Also head and neck, trunk, paraspinal, perineal,
retroperitoneum
Presentation
• Usually rapidly enlarging mass
○ Local symptoms pertaining to site of origin
– Proptosis or cranial nerve deficits (head and neck)
– Paresthesia or paresis (paraspinal areas of trunk)
– Constipation (perineal region)
○ Can present with widespread dissemination
– Lymphadenopathy or marrow infiltration
– Rarely may present without obvious primary
• Often high stage at presentation
Treatment
• Multimodality approach
○ Surgery, chemotherapy, &/or radiotherapy
– RMS is sensitive to both chemotherapy and radiation
therapy
Prognosis
• Fully malignant, high-grade sarcoma
○ Overall, worse prognosis than ERMS
○ Intergroup Rhabdomyosarcoma Study (IRS) stage
grouping is predictive of outcome
• Recent evidence suggests that prognosis may be related to
fusion status
○ ARMS with PAX3-FOXO1 or PAX7-FOXO1 fusion shows
worse outcome than ERMS and fusion; negative ARMS
– PAX3-FOXO1-fusion ARMS may have worse outcome
than PAX7-FOXO1-fusion ARMS
○ Fusion-negative ARMS shows similar outcome to ERMS
Tumors of Skeletal Muscle
MACROSCOPIC
General Features
• Tan-gray-white with fleshy cut surface
• Hemorrhage &/or necrosis may be present
MICROSCOPIC
Histologic Features
• Generally highly cellular
• Nests and sheets of primitive rounded cells separated by
variably prominent fibrous septa
○ Lesional cells are relatively monomorphic and medium
sized with minimal cytoplasm
– Hyperchromatic nuclei ± small nucleoli
– Mitotic figures often abundant
○ Sheets and nests characteristically show central loss of
cellular cohesion
– Forms alveolar-like (pseudoalveolar) spaces
– Central cells often poorly preserved and necrotic
□ Many appear freely floating
– Layer of cells cling to fibrous septa
○ Fibrous septa vary in thickness
– Fibrous stroma may appear abundant in some cases
• Rhabdomyoblasts may be seen (less frequent than ERMS)
○ Usually round or oval
– Elongated, strap cells less common
• Distinctive multinucleate tumor giant cells in some cases
○ Peripheral or wreath-like arrangement of nuclei
• Variable tumor necrosis
• Rare findings
○ Clear cell change
○ Scattered pleomorphic cells (anaplasia)
• Some composite tumors show features of both ARMS and
ERMS (mixed type)
○ Previously classified automatically as ARMS
○ Current recommendation: > 50% alveolar elements
needed to designate as ARMS
– Determination of fusion status through molecular
analysis recommended in mixed-type cases
Morphologic Variants
• Solid-type ARMS
○ Similar in appearance to conventional ARMS but lacks
pseudoalveolar pattern
○ Fibrous stroma/septa may or may not be conspicuous
○ Cytomorphology similar to conventional type
ANCILLARY TESTS
Immunohistochemistry
• Desmin (+) and MSA(+), usually diffuse
• Myogenin (+), MyoD1(+)
○ Only nuclear expression counts
○ Characteristically diffuse (in contrast to ERMS)
• May show focal/patchy keratin (+), particularly in sinonasal
ARMS
• Variable expression of neuroendocrine markers (CD56,
synaptophysin)
• Patchy, variable CD99(+)
387
 Alveolar Rhabdomyosarcoma
Tumors of Skeletal Muscle
Molecular Genetics
• 2 characteristic recurrent chromosomal translocations (80%
of cases)
○ t(2;13)(q35;q14)
– PAX3 on chromosome 2 and FOXO1 on chromosome
13
– Most common translocation
○ t(1;13)(p36;q14)
– PAX7 on chromosome 1 and FOXO1 on chromosome
13
• ~ 20% of cases of ARMS are fusion (-) by routine RT-PCR
○ Fusion (-) ARMS is genetically heterogeneous
– May have alternate fusions with other genes (NCOA1,
INO80D)
– Some may be truly fusion (-)
• Histologic appearances of ARMS do not predict presence or
type of gene fusion
○ However, solid growth or mixed embryonal/alveolar
patterns show higher incidence of fusion negativity
DIFFERENTIAL DIAGNOSIS
Embryonal Rhabdomyosarcoma
• More common in urogenital or head and neck sites
• Overall, affects younger age group than in ARMS
• More morphologically heterogeneous
• Spindle morphology and myxoid stroma common
• Rhabdomyoblastic differentiation usually more
pronounced
• Desmin and myogenin expression less diffuse than in ARMS
• Absence of FOXO1 translocations
Sclerosing Rhabdomyosarcoma
• Abundant hyalinizing matrix
• Absence of FOXO1 translocations
• Pronounced MyoD1(+); weaker expression of myogenin
• Desmin (+), often perinuclear dot like
Alveolar Soft Part Sarcoma
• Shows similar pseudoalveolar growth
• Large, rounded oncocytic cells rather than small blue cells
• Nuclear TFE3(+); nuclear myogenin (-)
• PAS(+), diastase-resistant cytoplasmic crystals
• Presence of t(X;17) translocation
• Absence of FOXO1 translocations
Lymphoma/Leukemia
• Often systemic involvement by disease ± lymphadenopathy
• Architecture dispersed and sheet like rather than nested
• Expression of hematolymphoid markers
• Desmin (-), myogenin (-)
• Absence of FOXO1 translocations
Ewing Sarcoma
• Can show morphologic overlap with ARMS
• Many cases CD99(+) with strong, membranous expression
• Desmin (-), myogenin (-), MyoD1(-)
• Usually CD56(-)
• Characteristic translocations involving EWSR1
Desmoplastic Small Round Cell Tumor
• Intraabdominal location common
388
• Prominent stromal fibroplasia
• Keratin (+), desmin (+), myogenin (-), MyoD1(-)
• Characteristic EWSR1-WT1 gene fusion
Neuroblastoma
• Younger age group affected
• Often in characteristic locations
○ Adrenal gland
○ Intraabdominal sympathetic chain
• Variable amount of neurofibrillary matrix
• Homer Wright rosettes in some cases
• NB84(+), desmin (-), myogenin (-)
• Absence of FOXO1 translocations
Extrarenal Rhabdoid Tumor
• Affects infants and very young children
• Larger cells with eccentric nuclei and hyaline cytoplasmic
inclusions
○ Some tumors are composed of smaller cells with scant
cytoplasm
• Keratin (+), desmin (-), myogenin (-)
• Loss of nuclear INI1 expression
• Absence of FOXO1 translocations
SELECTED REFERENCES
1. Rekhi B 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.
36:50-60, 2018
2. Thompson LDR 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. 12(2):181-92,
2018
3. Chen E et al: Head and neck rhabdomyosarcoma: clinical and pathologic
characterization of seven cases. Head Neck Pathol. 11(3):321-6, 2017
4. Charville GW et al: PAX7 expression in rhabdomyosarcoma, related soft
tissue tumors, and small round blue cell neoplasms. Am J Surg Pathol.
40(10):1305-15, 2016
5. Shern JF 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. 4(2):216-31, 2014
6. Parham DM et al: Classification of rhabdomyosarcoma and its molecular
basis. Adv Anat Pathol. 20(6):387-97, 2013
7. Skapek SX et al: PAX-FOXO1 fusion status drives unfavorable outcome for
children with rhabdomyosarcoma: a children's oncology group report.
Pediatr Blood Cancer. 60(9):1411-7, 2013
8. Liu J et al: FOXO1-FGFR1 fusion and amplification in a solid variant of
alveolar rhabdomyosarcoma. Mod Pathol. 24(10):1327-35, 2011
9. Williamson D et al: Fusion gene-negative alveolar rhabdomyosarcoma is
clinically and molecularly indistinguishable from embryonal
rhabdomyosarcoma. J Clin Oncol. 28(13):2151-8, 2010
10. Downs-Kelly E et al: The utility of FOXO1 fluorescence in situ hybridization
(FISH) in formalin-fixed paraffin-embedded specimens in the diagnosis of
alveolar rhabdomyosarcoma. Diagn Mol Pathol. 18(3):138-43, 2009
11. Sullivan LM et al: PAX immunoreactivity identifies alveolar
rhabdomyosarcoma. Am J Surg Pathol. 33(5):775-80, 2009
12. Yasuda T et al: Alveolar rhabdomyosarcoma of the head and neck region in
older adults: genetic characterization and a review of the literature. Hum
Pathol. 40(3):341-8, 2009
13. Bahrami A et al: Aberrant expression of epithelial and neuroendocrine
markers in alveolar rhabdomyosarcoma: a potentially serious diagnostic
pitfall. Mod Pathol. 21(7):795-806, 2008
14. Parham DM et al: Correlation between histology and PAX/FKHR fusion
status in alveolar rhabdomyosarcoma: a report from the Children's Oncology
Group. Am J Surg Pathol. 31(6):895-901, 2007
15. Sorensen PH et al: PAX3-FKHR and PAX7-FKHR gene fusions are prognostic
indicators in alveolar rhabdomyosarcoma: a report from the children's
oncology group. J Clin Oncol. 20(11):2672-9, 2002
16. Dias P et al: Strong immunostaining for myogenin in rhabdomyosarcoma is
significantly associated with tumors of the alveolar subclass. Am J Pathol.
156(2):399-408, 2000
 Alveolar Rhabdomyosarcoma

Tumors of Skeletal Muscle

Rhabdomyoblasts Rhabdomyoblasts
(Left) Rhabdomyoblasts ﬈ in
ARMS vary widely in number
from case to case and may be
identified singly or in clusters.
When present, they are usually
round or polygonal rather
than spindled or elongated.
(Right) Ovoid or rounded
rhabdomyoblasts ﬈ typically
show eccentric nuclei and
prominent cytoplasmic
eosinophilia. Spindled strap
cells and cytoplasmic cross-
striations are uncommon in
ARMS.

Multinucleated Tumor Giant Cells Clear Cell Change

(Left) A distinctive finding in
some cases of ARMS is the
presence of multinucleated
tumor giant cells ﬈. These
cells classically show a
peripheral or wreath-like
arrangement of nuclei and
abundant eosinophilic
cytoplasm. (Right) Clear cell
change is an uncommon but
well-documented finding in
ARMS. It is usually focal but
may be extensive. This
morphology may lead to
confusion with Ewing
sarcoma, and
immunohistochemistry is often
helpful.

Thick Fibrous Septa Thick Fibrous Septa

(Left) The fibrous septa of
ARMS vary in thickness and
may be quite striking in some
cases. Variably dilated
vascular channels ﬈ are
commonly present within the
septa. (Right) The combination
of thickened or sclerotic
fibrous septa and loss of
cellular cohesion may impart a
pseudopapillary appearance in
ARMS. The illusion of discrete
fibrovascular nodules ﬈ may
be seen in some foci.

389
 Alveolar Rhabdomyosarcoma
Tumors of Skeletal Muscle

Ramifying Fibrous Septa Diffuse Dyscohesion

(Left) This case of ARMS shows
extensive cellular drop out and
at low magnification appears
as ramifying and
interconnecting fibrous cords
or trabeculae. Note that a thin
layer of tumor cells remain
attached to the septa.
Scattered "wreath cells" ﬈
can also be seen. (Right) This
ARMS shows diffuse cellular
dyscohesion with thin
fibrovascular septa,
reminiscent of a germ cell
neoplasm.

Hemorrhage Unusual Corded Growth

(Left) Foci of intratumoral
hemorrhage may be seen in
ARMS and may appear mostly
within nests of tumor cells,
mimicking vascular channels
or vascularized carcinomas
such as renal cell carcinoma.
(Right) This case of otherwise
conventional ARMS contained
rare, peripherally located foci
demonstrating tumor cells
with a corded growth pattern.
This finding is not well
described in ARMS but mimics
carcinoma.

Solid Variant Solid Variant

(Left) The solid variant of
ARMS shows large nodules
and diffuse sheets of lesional
cells within minimal to no
fibrous septation and an
absence of pseudoalveolar
growth. To qualify for this
designation, this solid growth
should reflect the majority of
the tumor. This variant
appears to show a higher
incidence of fusion negativity
than conventional ARMS.
(Right) Solid ARMS may show
areas of nested growth with
thin fibrous septa; however, a
pseudoalveolar pattern is
absent.

390
 Alveolar Rhabdomyosarcoma

Tumors of Skeletal Muscle

Myoinvasion Procedure Artifact
(Left) ARMS most commonly
arises in deep soft tissues of
the extremities. In some cases,
infiltration of skeletal muscle
is prominent and resembles
the myoinvasive pattern of
lymphoma. (Right) Cauterized
or crushed tumor samples of
ARMS may be impossible to
distinguish histologically from
a variety of other small round
blue cell tumors, such as small
cell carcinoma, lymphoma,
Ewing sarcoma, desmoplastic
small round cell tumor, and
others.

Mixed Morphology Cutaneous Involvement

(Left) Some cases of ARMS
contain areas ﬈
morphologically compatible
with embryonal
rhabdomyosarcoma (ERMS).
These composite or mixed-
type tumors are more likely to
be fusion negative than pure
ARMS and may, therefore, be
more closely related to ERMS
than ARMS. (Right) ARMS may
grow and extend to involve
the skin and can be mistaken
for a variety of other lesions
including nevi and malignant
melanoma.
Immunohistochemistry is often
discriminatory in a small
biopsy.

Desmin Myogenin
(Left) Diffuse cytoplasmic
expression of desmin is
characteristic of ARMS. (Right)
Nuclear expression of
myogenin (shown) or MyoD1 is
a consistent finding in ARMS.
Of note, the expression is
often diffuse and prominent in
ARMS, whereas it is often
patchy or focal in ERMS.
Importantly, only nuclear
expression counts for these
markers, as cytoplasmic
staining is nonspecific and
should be ignored.

391
 Spindle Cell Rhabdomyosarcoma

KEY FACTS
Tumors of Skeletal Muscle

TERMINOLOGY
• Subtype of rhabdomyosarcoma (RMS) affecting both
children and adults that features prominent fascicular
spindle cell morphology
○ Currently considered to be very closely related to
sclerosing RMS and not embryonal RMS (2013 WHO
classification)
CLINICAL ISSUES
• Affects both children and adults
○ Strong male predilection
• Most common sites
○ Paratesticular region in children
○ Head and neck region in adults
• Differences in behavior and outcome depending upon age
group
○ Overall good prognosis in children (< 10 years)
○ Clinically aggressive in adults
MICROSCOPIC
• Cellular proliferation of relatively uniform spindle cells
○ Mitotic figures common
• Fascicular growth is usually prominent
• Variable number of rhabdomyoblasts
• Prominent collagenous stroma in some tumors
ANCILLARY TESTS
• Desmin (+), myogenin (+), MYOD1(+)
• SMA(+) and MSA(+) common
• Molecular: Recurrent MYOD1 mutations
○ VGLL2 and NCOA2 rearrangements in infancy
TOP DIFFERENTIAL DIAGNOSES
• Synovial sarcoma (monophasic)
• Malignant peripheral nerve sheath tumor
• Low-grade myofibroblastic sarcoma
• Infantile fibrosarcoma
• Leiomyosarcoma

Spindle Cell Rhabdomyosarcoma Rhabdomyoblasts

(Left) Spindle cell
rhabdomyosarcoma (SCRMS)
is a distinctive subtype of RMS
that affects both children and
adults. It appears to be both
morphologically and
genetically related to
sclerosing RMS. As shown on
this H&E, most cases of SCRMS
feature prominent fascicular
growth with moderate to high
cellularity. (Right)
Rhabdomyoblasts ﬈ are
often seen in SCRMS but vary
in number and distribution
from case to case. Both
polygonal and spindled (strap
cell) forms may be seen.

Herringbone Architecture Myogenin Expression

(Left) A herringbone
architectural pattern can be
encountered in SCRMS, as
depicted, and may lead to
morphologic overlap with a
variety of other mesenchymal
spindle cell neoplasms. (Right)
Strong myogenin expression is
typical of SCRMS; however, in
general, expression of this
antigen is patchy or focal
rather than diffuse and
widespread. Cytoplasmic
staining is nonspecific and
should be disregarded.

392
 Spindle Cell Rhabdomyosarcoma

Tumors of Skeletal Muscle

○ Scant, pale, eosinophilic or amphophilic cytoplasm
TERMINOLOGY
– Cross striations may be seen
Abbreviations ○ Mitotic figures common
• Spindle cell rhabdomyosarcoma (SCRMS) • Fascicular growth is usually prominent
○ Can show herringbone pattern
Definitions
○ Storiform growth in some tumors
• Subtype of rhabdomyosarcoma (RMS) affecting both • Variable number of rhabdomyoblasts
children and adults that features prominent fascicular
○ Spindled (strap cell) or polygonal
spindle cell morphology
○ Brightly eosinophilic cytoplasm and hyperchromatic
○ Currently considered to be very closely related to
nucleus
sclerosing RMS and not embryonal RMS (2013 WHO
○ May be sparse in adult tumors
classification)
• Less cellular tumors may show more prominent
CLINICAL ISSUES collagenous stroma
○ Collagen may be densely hyalinized
Epidemiology – Areas may be indistinguishable from sclerosing RMS
• Age • Necrosis may be present but is uncommon
○ Affects both children and adults
– Children (< 10 years) ANCILLARY TESTS
– Adults (median: 30 years) Immunohistochemistry
• Sex
• Desmin (+)
○ Strong male predilection
○ Characteristically strong, diffuse cytoplasmic expression
Site • Myogenin (+) and MYOD1(+)
• Children ○ Nuclear expression
○ Most frequently arise in paratesticular region ○ Variable in extent (may be focal)
• Adults • SMA(+) and MSA(+) common
○ Head and neck region (> 50% of cases) • Generally S100 protein, keratin, caldesmon, CD34, TLE1, β-
○ Occasionally other sites, including extremities, catenin (-)
retroperitoneum, trunk Molecular Genetics
Presentation • Lacks genetic features of embryonal and alveolar RMS
• Usually deeply situated, often painless mass • Recurrent MYOD1 mutations reported in SCRMS as well as
○ Local symptoms pertaining to site of origin sclerosing RMS
○ Supports relationship between these 2 entities
Prognosis
• VGLL2 and NCOA2 gene rearrangements reported in cases
• Significant differences in behavior and outcome depending of infantile/congenital SCRMS
upon age group
○ Overall good prognosis in children (< 10 years) DIFFERENTIAL DIAGNOSIS
– Usually low stage at presentation
Synovial Sarcoma (Monophasic)
– > 95% survival at 5 years
○ Clinically aggressive in adults • Cellular fascicular of monomorphic spindled cells
– Recurrence and metastasis in up to 50% • Stromal calcifications common
○ Metastases to lymph nodes, lungs, other sites • Rhabdomyoblasts absent
• Keratin (+), EMA(+), typically patchy/focal
MACROSCOPIC • Diffuse nuclear TLE1(+)
• Desmin, myogenin, MYOD1 (-)
General Features
• t(X;18) with fusions involving SS18 (SYT)
• Generally well circumscribed
• Firm, tan-white, fibrous cut surface Malignant Peripheral Nerve Sheath Tumor
• Hemorrhage &/or necrosis infrequent • May arise from large nerves, preexisting benign nerve
sheath tumors, or within setting of neurofibromatosis type
Size 1
• Wide range (mean: 6 cm) • Buckled, wavy, or bullet-shaped nuclei
○ Tumors > 30 cm reported • Increased perivascular cellularity common
• Necrosis common (can show perivascular preservation)
MICROSCOPIC • S100 protein (+) in 60% of cases, classically focal
Histologic Features • May contain rhabdomyoblasts (a.k.a. malignant triton
tumor)
• Cellular proliferation of relatively uniform spindle cells
○ Expression of desmin, myogenin, MYOD1 restricted to
○ Ovoid, elongated, or wavy and vesicular or
rhabdomyoblasts
hyperchromatic nuclei ± nucleoli
– Frank pleomorphism absent

393
 Spindle Cell Rhabdomyosarcoma
Tumors of Skeletal Muscle
Low-Grade Myofibroblastic Sarcoma
• Common in head and neck region of adults
• Prominent infiltrative growth
• Stromal collagen often abundant
• Rhabdomyoblasts absent
• Variable SMA(+), desmin (+)
• Myogenin (-), MYOD1(-)
Infantile Fibrosarcoma
• Can show morphologic overlap with SCRMS
• Rhabdomyoblasts absent
• Desmin, myogenin, MYOD1 (-)
• t(12;15) with ETV6-NTRK3 fusion
Embryonal Rhabdomyosarcoma
• Most common in head/neck and genitourinary tract
• Cambium layer in epithelial-lined mucosal sites
• Myxoid stroma common
• Lacks prominent fascicular architecture
• Similar expression of myogenic markers to SCRMS
Fetal Rhabdomyoma
• Predilection for head and neck
• Bland spindled cells without atypia
• Mitoses usually absent; no necrosis
Desmoid Fibromatosis
• Low to moderate cellularity with prominent stromal
collagen
• Nuclear atypia absent
• Distinctive thin-walled blood vessels, often with mild
perivascular edema
• Rhabdomyoblasts absent
• Nuclear β-catenin (+) in 70%
• Desmin, myogenin, MYOD1 (-)
Leiomyosarcoma
• Characteristic smooth muscle cytology
○ Prominent cytoplasmic eosinophilia
○ Elongated nuclei with blunted ends (cigar-shaped)
• Strong diffuse SMA(+) and caldesmon (+) in most cases
• Variable desmin (+)
• Myogenin (-), MYOD1(-)
Myofibroma
• Cellular variant can show prominent fascicular growth
• Rhabdomyoblasts absent
• SMA(+)
• Desmin, myogenin, MYOD1 (-)
Fibrosarcomatous Dermatofibrosarcoma
Protuberans
• Prominent fascicular growth in fibrosarcomatous areas
• Lower grade areas of conventional storiform
dermatofibrosarcoma protuberans often present
• Rhabdomyoblasts absent
• Variable CD34(+)
• Desmin, myogenin, MYOD1 (-)
• t(17;22) with COL1A1-PDGFRB fusion
Inflammatory Myofibroblastic Tumor
• Myxoid stroma common
394
• Prominent chronic inflammatory cell infiltrate
• Rhabdomyoblasts absent
• ALK gene rearrangements in ~ 50% of cases
○ ALK(+) by immunohistochemistry
• Myogenin (-), MYOD1(-)
Adult-Type Fibrosarcoma
• Diagnosis of exclusion
• Prominent fascicular growth and herringbone pattern
• Rhabdomyoblasts absent
• Desmin, myogenin, MYOD1 (-)
Sarcomatoid Carcinoma
• Overlying epithelium may show dysplastic or in situ changes
• History of carcinoma may be present
• Keratin (+), EMA(+)
• Desmin, myogenin, MYOD1 (-)
Spindle Cell Melanoma
• Junctional component may be present in epidermis
• Diffuse S100 protein (+)
• Variable expression of melanocytic markers
• Desmin, myogenin, MYOD1 (-)
Cellular Schwannoma
• Most common in retroperitoneum, posterior mediastinum,
pelvis
• Admixed lymphocytes and sheets of foamy histiocytes may
be seen
• Lacks rhabdomyoblasts
• Strong, diffuse S100 protein (+)
• Desmin, myogenin, MYOD1 (-)
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and histopathological examination of this rare variant with three new cases
from the oral cavity. Head Neck Pathol. 11(4):494-500, 2017
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rhabdomyosarcoma: identification of novel and recurrent VGLL2-related
fusions in infantile cases. Am J Surg Pathol. 40(2):224-35, 2016
3. Rekhi B et al: MYOD1 (L122R) mutations are associated with spindle cell and
sclerosing rhabdomyosarcomas with aggressive clinical outcomes. Mod
Pathol. 29(12):1532-1540, 2016
4. Agaram NP et al: Recurrent MYOD1 mutations in pediatric and adult
sclerosing and spindle cell rhabdomyosarcomas: evidence for a common
pathogenesis. Genes Chromosomes Cancer. 53(9):779-87, 2014
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cytogenetic analysis of 21 spindle cell/sclerosing rhabdomyosarcomas.
APMIS. 122(11):1144-52, 2014
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event in adult spindle cell rhabdomyosarcoma. J Pathol. 232(3):300-7, 2014
7. Yasui N et al: Clinicopathologic analysis of spindle cell/sclerosing
rhabdomyosarcoma. Pediatr Blood Cancer. 62(6):1011-6, 2014
8. Carroll SJ et al: Spindle cell rhabdomyosarcoma: a brief diagnostic review
and differential diagnosis. Arch Pathol Lab Med. 137(8):1155-8, 2013
9. Mosquera JM et al: Recurrent NCOA2 gene rearrangements in
congenital/infantile spindle cell rhabdomyosarcoma. Genes Chromosomes
Cancer. 52(6):538-50, 2013
10. Stock N et al: Adult-type rhabdomyosarcoma: analysis of 57 cases with
clinicopathologic description, identification of 3 morphologic patterns and
prognosis. Am J Surg Pathol. 33(12):1850-9, 2009
11. Mentzel T et al: Spindle cell rhabdomyosarcoma in adults: clinicopathological
and immunohistochemical analysis of seven new cases. Virchows Arch.
449(5):554-60, 2006
12. Parham DM et al: Rhabdomyosarcomas in adults and children: an update.
Arch Pathol Lab Med. 130(10):1454-65, 2006
13. Nascimento AF et al: Spindle cell rhabdomyosarcoma in adults. Am J Surg
Pathol. 29(8):1106-13, 2005
 Spindle Cell Rhabdomyosarcoma

Tumors of Skeletal Muscle

Cytologic Features Desmin Expression
(Left) Tumor cells in SCRMS
are generally relatively
uniform and may show ovoid,
elongated, or wavy forms;
however, nuclear atypia varies
widely from case to case.
Mitotic figures ﬊ are often
easily identified. (Right)
Strong, diffuse cytoplasmic
expression of desmin is
characteristic of SCRMS.
Weaker staining is seen within
the fascicles of normal
skeletal muscle ﬊ in this
stain.

Infiltrative Borders Variable Cellularity

(Left) SCRMS often shows an
infiltrative peripheral border,
as evidenced on this H&E by
entrapped subcutaneous
adipose tissue. Note the
scattered rhabdomyoblasts
﬈. H&E also shows a mixture
of fascicular and storiform
growth patterns. (Right) Many
cases of SCRMS are highly
cellular ﬉; however, areas of
lower cellularity ﬊ and
increased stromal collagen are
not uncommon.

Stromal Collagen Densely Hyalinized Foci

(Left) H&E shows an area of
SCRMS with a lower degree of
cellularity and more
prominent stromal collagen
than is usually seen. A
fascicular growth pattern is
still present, but no obvious
rhabdomyoblasts are seen in
this field. (Right) Some cases
of SCRMS contain minor foci
showing densely hyalinized
stromal collagen and a
pseudovascular morphology,
identical to what is seen in the
related entity, sclerosing RMS.

395
 Sclerosing Rhabdomyosarcoma

KEY FACTS
Tumors of Skeletal Muscle

TERMINOLOGY • Characteristic prominent hyaline collagenous stroma

• Synonym: Sclerosing pseudovascular rhabdomyosarcoma
(RMS)
• Distinctive subtype of RMS featuring prominent hyalinized
stroma and primitive-appearing tumor cells arranged
predominantly in cords and nests
○ Currently considered to be very closely related to spindle
cell RMS, not embryonal RMS (2013 WHO classification)
CLINICAL ISSUES
• Wide age range (median: 30 years)
• Most common in extremities
• Treatment: Wide surgical excision with negative margins
• Overall poor prognosis, particularly in adults
○ Recurrence and metastasis in up to 50%
MICROSCOPIC
• Primitive round, ovoid, or spindled tumor cells arranged
predominantly in cords or nests
○ Often imparts pseudovascular appearance
• Rhabdomyoblasts are generally uncommon
• Areas of fascicular growth may be seen
○ Indistinguishable from spindle cell RMS
ANCILLARY TESTS
• MYOD1(+), typically diffuse
• Variable desmin (+), myogenin (+)
○ Both/either may be very focally expressed
• Molecular: Recurrent MYOD1 mutations
• Lacks genetic features of embryonal and alveolar RMS
TOP DIFFERENTIAL DIAGNOSES
• Alveolar RMS
• Sclerosing epithelioid fibrosarcoma
• Metastatic carcinoma
• Angiosarcoma

Sclerosing Rhabdomyosarcoma Pseudovascular Appearance

(Left) Sclerosing
rhabdomyosarcoma (SRMS) is
an aggressive sarcoma that
may affect both children and
adults. It is morphologically
and genetically related to
spindle cell
rhabdomyosarcoma (RMS). At
low power, the
hyalinized/sclerotic
collagenous stroma is one of
the more characteristic
features of this tumor. (Right)
Densely hyalinized or sclerotic
stroma classically leads to
cellular dyscohesion ﬈ in
SRMS, which in turn can
resemble infiltrating vascular
channels of angiosarcoma.

Cords and Nests Myogenic Immunophenotype

(Left) Tumor cells in SRMS are
usually arranged in small nests
and cords within the
hyalinized collagenous stroma.
Some smaller nests may show
central dyscohesion, imparting
a microalveolar appearance
﬈. (Right) MYOD1 expression
(shown) is characteristically
strong and diffuse in SRMS. In
contrast, expression of
myogenin is much more
variable and can be very focal.
Of note, only nuclear
expression of MYOD1 (and
myogenin) should be
considered positive.

396
 Sclerosing Rhabdomyosarcoma

Tumors of Skeletal Muscle

TERMINOLOGY
Abbreviations
• Sclerosing rhabdomyosarcoma (SRMS)
Synonyms
• Sclerosing pseudovascular rhabdomyosarcoma (RMS)
Definitions
• Distinctive subtype of RMS featuring prominent hyalinized
stroma and primitive-appearing tumor cells arranged
predominantly in cords and nests
○ Currently considered to be very closely related to spindle
cell RMS and not embryonal RMS (2013 WHO
classification)
CLINICAL ISSUES
ANCILLARY TESTS
Immunohistochemistry
• Variable desmin (+), myogenin (+)
○ Expression of either/both may be very focal
○ Desmin may show perinuclear, dot-like expression
• MYOD1(+), typically diffuse
• SMA(+) in subset of cases
• Keratin, S100 protein, SATB2, CD31, CD34 (-)
Molecular Genetics
• Lacks genetic features of embryonal and alveolar RMS
• Recurrent MYOD1 mutations reported in SRMS as well as
spindle cell RMS
○ Supports relationship between these 2 entities
• Also PIK3CA mutations

Epidemiology DIFFERENTIAL DIAGNOSIS

• Age
Alveolar Rhabdomyosarcoma
○ Wide range (median: 30 years)
• Sex • Generally lacks densely hyalinized stroma of SRMS
○ Strong male predilection • Wreath-like multinucleated giant cells
• Lacks spindle cell component
Site • Myogenin (+) characteristically diffuse
• Most common in extremities • t(2;13) or t(1;13) rearrangement with FOXO1 fusion
• Also head/neck region
Sclerosing Epithelioid Fibrosarcoma
Presentation • Bland tumor cell nuclei
• Painless, often deep-seated mass • MUC4(+)
Treatment • Desmin, myogenin, MYOD1 (-)
• EWSR1 and CREB3L2 rearrangements
• Wide surgical excision with negative margins, if possible
○ May require amputation Angiosarcoma
• Chemotherapy &/or radiotherapy • More complex branching architecture
Prognosis • CD31, CD34, ERG (+)
• Desmin, myogenin, MYOD1 (-)
• Overall poor prognosis, particularly in adults
○ Recurrence and metastasis in up to 50% Metastatic Carcinoma
• Worse prognosis reported in presence of MYOD1 mutation • Keratin (+)
• Desmin, myogenin, MYOD1 (-)
MACROSCOPIC
Extraskeletal Osteosarcoma
General Features • Often features sheets of large pleomorphic cells
• White to tan, firm to fleshy, hemorrhagic areas • SATB2(+)
Size • Desmin, myogenin, MYOD1 (-)
• Wide range (median: 6 cm)
SELECTED REFERENCES
MICROSCOPIC 1. Smith MH et al: Rhabdomyosarcoma, spindle cell/sclerosing variant: a clinical
and histopathological examination of this rare variant with three new cases
Histologic Features from the oral cavity. Head Neck Pathol. 11(4):494-500, 2017
2. Rekhi B et al: MYOD1 (L122R) mutations are associated with spindle cell and
• Infiltrative borders sclerosing rhabdomyosarcomas with aggressive clinical outcomes. Mod
• Primitive round, ovoid, or spindled tumor cells arranged Pathol. 29(12):1532-1540, 2016
predominantly in cords or nests 3. Rekhi B et al: Histopathological, immunohistochemical and molecular
cytogenetic analysis of 21 spindle cell/sclerosing rhabdomyosarcomas.
○ Scant eosinophilic or clear cytoplasm APMIS. 122(11):1144-52, 2014
○ Mitoses frequent 4. Robinson JC et al: Sclerosing rhabdomyosarcoma: report of a case arising in
the head and neck of an adult and review of the literature. Head Neck
• Characteristic prominent hyaline collagenous stroma Pathol. 7(2):193-202, 2013
○ Can mimic osteoid 5. Wang J et al: Sclerosing rhabdomyosarcoma: a clinicopathologic and
○ Often imparts pseudovascular appearance immunohistochemical study of five cases. Am J Clin Pathol. 129(3):410-5,
2008
• Solid, cellular areas present in some tumors
6. Chiles MC et al: Sclerosing rhabdomyosarcomas in children and adolescents:
• Rhabdomyoblasts are generally uncommon a clinicopathologic review of 13 cases from the Intergroup
• Areas of fascicular growth may be seen Rhabdomyosarcoma Study Group and Children's Oncology Group. Pediatr
Dev Pathol. 8(1):141, 2005
○ Indistinguishable from spindle cell RMS
397
 Sclerosing Rhabdomyosarcoma
Tumors of Skeletal Muscle

Cytologic Features Rhabdomyoblasts

(Left) Tumors cells in SRMS are
cytologically variable and may
feature nuclear atypia that
ranges from mild to marked.
Mitotic figures ﬊, however,
are generally abundant.
(Right) Rhabdomyoblasts are
often sparse and difficult to
find in SRMS; however, in rare
cases, they are more readily
identified. As is often the case
in other forms of RMS, these
cells have abundant, deeply
eosinophilic cytoplasm and are
polygonal ﬈ or fusiform-
shaped ﬉.

Prominent Corded Morphology Cellular Corded Morphology

(Left) Corded or trabecular
growth is common in SRMS
and may be quite prominent in
some cases, as depicted. Note
the densely hyalinized stroma
between the cords. (Right)
H&E shows a case of SRMS in
which the cords of tumor cells
are more compressed,
subsequently creating a more
cellular overall appearance.
Note, however, that the
characteristic hyalinized
stroma can still be
appreciated, even at low
magnification.

Microalveolar Pattern Cellular, Solid Foci

(Left) A microalveolar pattern
is a common finding in SRMS
and may cause confusion with
alveolar RMS. It is
characterized by clusters and
nests of loosely cohesive
tumor cells ﬈ with central
spaces, reminiscent of small
pulmonary alveoli. These
spaces are smaller than what
is typically seen in alveolar
RMS, and wreath-like
multinucleated cells are
absent. (Right) Areas of more
densely cellular and sheet-like
growth may be seen in SRMS;
however, these areas are
generally not extensive.

398
 Sclerosing Rhabdomyosarcoma
Clear Cell Change
Diffusely Hyalinized Zones
Fascicular Growth
Tumors of Skeletal Muscle
Infiltrative Growth
(Left) Tumor cells with clear
cytoplasm can be seen in
SRMS. In conjunction with the
sclerotic stroma, this
appearance may easily lead to
confusion with sclerosing
epithelioid fibrosarcoma.
Immunohistochemistry may be
needed to make the
distinction. (Right) Most cases
of SRMS show an infiltrative
pattern of growth, and tumors
can contain areas of
entrapped adipose tissue ﬉,
nerves, muscle, or large
vessels ﬈. Involvement of the
latter may complicate or
preclude local resection.
Spindle Cell Morphology
(Left) Paucicellular hyalinized
zones may be present in SRMS
but are usually not a dominant
feature. (Right) Spindled
tumor cells (± fascicular
growth) are not uncommon in
SRMS and serve to establish a
morphologic link with the
related entity spindle cell
RMS. Note the densely
hyalinized stroma.
Desmin Expression
(Left) Prominent fascicular
growth by spindled tumor
cells, as depicted, is seen in
some cases of SRMS. These
areas may be morphologically
indistinguishable from spindle
cell RMS, which is related to
SRMS. (Right) Desmin
expression is highly variable in
SRMS and can range from
focal to extensive. Notably, in
some cases, it may show a
perinuclear, dot-like pattern of
expression.
399
 Pleomorphic Rhabdomyosarcoma

KEY FACTS
Tumors of Skeletal Muscle

TERMINOLOGY – Clusters of pleomorphic rhabdomyoblasts

• High-grade sarcoma of adulthood composed of varying
numbers of pleomorphic rhabdomyoblasts
CLINICAL ISSUES
• Almost exclusively in adults > 45 years
• Deep soft tissue of lower extremity, particularly thigh
• Aggressive disease with frequent early metastasis
MICROSCOPIC
• Variable numbers of pleomorphic rhabdomyoblasts: Large
polygonal cells with pleomorphic nuclei and abundant,
deeply eosinophilic cytoplasm
• Frequent mitoses with atypical mitotic forms
• Geographic tumor necrosis often present
• 3 main histologic patterns
○ Classic
– Diffuse sheets of pleomorphic rhabdomyoblasts
○ Round cell
– Background of medium-sized round cells with slight
pleomorphism
○ Spindle cell
– Pleomorphic spindle cells predominate
– Storiform or fascicular growth pattern
– Only scattered pleomorphic rhabdomyoblasts
ANCILLARY TESTS
• Strong desmin (+)
• Strong nuclear myogenin (+) and MYOD1(+)
• No consistent molecular abnormality
TOP DIFFERENTIAL DIAGNOSES
• Other pleomorphic sarcomas
• Alveolar or embryonal rhabdomyosarcoma
• Epithelioid rhabdomyosarcoma
• Undifferentiated or metastatic carcinoma
• Melanoma

Pleomorphic Rhabdomyosarcoma Pleomorphic Rhabdomyoblasts

(Left) Pleomorphic
rhabdomyosarcoma (RMS) is a
high-grade, adult-type
sarcoma composed of a
variable number of
pleomorphic rhabdomyoblasts.
Pleomorphic rhabdomyoblasts
are large polygonal cells with
markedly atypical nuclei and
abundant, deeply eosinophilic
cytoplasm. These cells are the
hallmark of pleomorphic RMS.
(Right) Pleomorphic
rhabdomyoblasts may display
a variety of appearances,
including large,
multinucleated polygonal cells
﬈ and elongated, strap-like
cells ſt.

Pleomorphic Rhabdomyoblasts Pleomorphic Rhabdomyoblasts

(Left) Pleomorphic
rhabdomyoblasts exhibit a
diverse array of shapes and
sizes. Some are tadpole- or
racquet-shaped ﬊. Rhabdoid
cells ﬊ with an eccentric
nucleus and a dense
eosinophilic globule in the
paranuclear cytoplasm are
uncommon in pleomorphic
RMS but may be seen. (Right)
These pleomorphic
rhabdomyoblasts display
unusual dense, eosinophilic
inclusions within their
abundant cytoplasm.

400
 Pleomorphic Rhabdomyosarcoma

Tumors of Skeletal Muscle

• Geographic tumor necrosis often present
TERMINOLOGY
• Only rarely display "rhabdoid" features (eccentric nucleus,
Definitions dense paranuclear eosinophilic globule)
• High-grade sarcoma of adulthood composed of varying
numbers of pleomorphic rhabdomyoblasts ANCILLARY TESTS
Immunohistochemistry
CLINICAL ISSUES
• Strong desmin (+) but may be focal
Epidemiology • Strong nuclear myogenin (+) and MYOD1(+)
• Age ○ Often more focal than in pediatric (embryonal and
○ Almost exclusively in adults > 45 years alveolar) RMS
– Median: 6th-7th decades • Other myogenic markers (e.g., actins) variably expressed
○ Vanishingly rare in childhood • May express keratin focally
• Sex
○ M>F DIFFERENTIAL DIAGNOSIS
Site Other Pleomorphic Sarcomas
• Deep soft tissue of lower extremity, particularly thigh • Pleomorphic leiomyosarcoma
• Less common sites ○ Lower grade areas with intersecting fascicles
○ Retroperitoneum ○ Myogenin (-) and MYOD1(-)
○ Abdominal wall or chest wall • Pleomorphic liposarcoma
○ Spermatic cord and testes ○ Must have pleomorphic lipoblasts
○ Upper extremity • Undifferentiated pleomorphic sarcoma
○ Visceral organs ○ Desmin (-), myogenin (-), and MYOD1(-)
○ Skin Alveolar or Embryonal Rhabdomyosarcoma
Presentation • Children and adolescents
• Rapidly growing mass • May have pleomorphic foci resembling pleomorphic RMS
○ Diffuse, marked pleomorphism absent
Prognosis • Areas of classic alveolar or embryonal RMS usually present
• Aggressive disease with frequent early metastasis • Characteristic translocation in alveolar RMS
• Mortality approaches 70% in some series
Epithelioid Rhabdomyosarcoma
MACROSCOPIC • Affects children and adults
• Large, monomorphic cells; lacks prominent nuclear and
General Features cytologic pleomorphism
• Usually large (> 10-cm), circumscribed mass in deep skeletal • Obvious evidence of rhabdomyoblastic differentiation (e.g.,
muscle rhabdomyoblasts, strap cells) usually absent
• Fleshy cut surface often with extensive necrosis
Anaplastic Large Cell Lymphoma
MICROSCOPIC • Expresses CD30, ALK1, some T-cell markers
Histologic Features Undifferentiated or Metastatic Carcinoma
• Variable numbers of pleomorphic rhabdomyoblasts: Large • Clinical scenario/history favoring carcinoma over sarcoma
polygonal cells with pleomorphic nuclei and abundant, • Often at least focally (+) for cytokeratin, EMA, or p63/p40
deeply eosinophilic cytoplasm
Melanoma
○ Rhabdomyoblasts may be tadpole- or racquet-shaped as
in embryonal rhabdomyosarcoma (RMS) but are usually • S100 and SOX10 (+)
larger and more irregular • Often HMB-45 and MART-1 (+), but some are (-)
– Cross striations are rare
• 3 main histologic patterns SELECTED REFERENCES
○ Classic 1. Nishijima Y et al: Pleomorphic rhabdomyosarcoma arising in the anterior
– Diffuse sheets of pleomorphic rhabdomyoblasts mediastinum: a case report with cytological features of imprint and liquid-
based cytology specimens. Diagn Cytopathol. 45(4):333-8, 2017
○ Round cell 2. Marburger TB et al: Primary cutaneous rhabdomyosarcoma: a
– Clusters of pleomorphic rhabdomyoblasts clinicopathologic review of 11 cases. J Cutan Pathol. 39(11):987-95, 2012
– Background of medium-sized round cells with slight 3. Li G et al: Cytogenetic and real-time quantitative reverse-transcriptase
polymerase chain reaction analyses in pleomorphic rhabdomyosarcoma.
pleomorphism Cancer Genet Cytogenet. 192(1):1-9, 2009
○ Spindle cell 4. Furlong MA et al: Pleomorphic rhabdomyosarcoma in adults: a
– Pleomorphic spindle cells predominate; arranged in clinicopathologic study of 38 cases with emphasis on morphologic variants
and recent skeletal muscle-specific markers. Mod Pathol. 14(6):595-603,
storiform or fascicular (less common) pattern 2001
– Only scattered pleomorphic rhabdomyoblasts 5. Furlong MA et al: Pleomorphic rhabdomyosarcoma in children: four cases in
the pediatric age group. Ann Diagn Pathol. 5(4):199-206, 2001
• Frequent mitoses with atypical mitotic forms

401
 Pleomorphic Rhabdomyosarcoma
Tumors of Skeletal Muscle

Circumscribed With Pseudocapsule Geographic Necrosis

(Left) Pleomorphic RMS is
often relatively circumscribed
with a smooth, pushing border
and dense fibrous
pseudocapsule ﬉ separating
the tumor ſt from adjacent
skeletal muscle ﬈. Focal
inflammation is also present
﬊. (Right) Geographic zones
of tumor necrosis ﬈ are
usually present in pleomorphic
RMS.

Classic Pattern Pleomorphism and Mitoses

(Left) Pleomorphic
rhabdomyoblasts are arranged
in diffuse sheets in the classic
pattern of pleomorphic RMS.
The degree of atypia can be
severe in some cases and
easily suggest a diagnosis of
undifferentiated pleomorphic
sarcoma at first. (Right) There
is marked nuclear atypia with
pleomorphism and prominent
nucleoli in pleomorphic RMS.
Mitotic figures ﬈ are usually
abundant.

Round Cell Pattern Round Cell Pattern

(Left) Large pleomorphic
rhabdomyoblasts are
distributed in a background of
smaller oval/round cells in the
round cell pattern of
pleomorphic RMS. (Right)
Large pleomorphic
rhabdomyoblasts ﬈ are
distributed in a background of
smaller round cells ﬈ in the
round cell pattern of
pleomorphic RMS. The smaller
cells have oval/round, slightly
pleomorphic nuclei and scant
amounts of deeply eosinophilic
cytoplasm.

402
 Pleomorphic Rhabdomyosarcoma
Spindle Cell Pattern
Storiform Areas
Desmin Expression
Tumors of Skeletal Muscle
Spindle Cell Pattern
(Left) Atypical spindle cells
predominate over pleomorphic
rhabdomyoblasts in the
spindle cell pattern of
pleomorphic RMS. The spindle
cells may be arranged in long,
intersecting fascicles, as
shown here. (Right) Some of
the spindle cells are elongated
pleomorphic rhabdomyoblasts
with abundant, deeply
eosinophilic cytoplasm ﬈.
Multinucleated Rhabdomyoblasts
(Left) Atypical spindle cells
predominate over pleomorphic
rhabdomyoblasts in the
spindle cell pattern of
pleomorphic RMS. The spindle
cells may be arranged in a
storiform pattern, as shown
here. (Right) Multinucleated
pleomorphic rhabdomyoblasts
may be seen in pleomorphic
RMS.
Myogenin Expression
(Left) The tumor cells of
pleomorphic RMS display
diffuse, strong cytoplasmic
expression of desmin. The
intervening normal skeletal
muscle fibers are also positive
﬈. (Right) Strong nuclear
expression of myogenin is
usually seen, but it may be
more focal than in the
pediatric forms of RMS.
403
 Epithelioid Rhabdomyosarcoma

KEY FACTS
Tumors of Skeletal Muscle

TERMINOLOGY MICROSCOPIC
• Distinctive rhabdomyosarcoma (RMS) variant characterized • Relatively uniform epithelioid cells with abundant
by uniform epithelioid cytomorphology eosinophilic cytoplasm
○ Large, vesicular nuclei often with prominent nucleoli
CLINICAL ISSUES
○ Intracytoplasmic rhabdoid inclusions may be seen
• Very rare
• Diffuse, sheet-like growth pattern
• Wide age reported (6-78 years)
• Mitotic figures abundant, including atypical forms
○ Often in older or elderly adults
• Necrosis common
• Male predilection
• Deep soft tissues of the extremities, head/neck, trunk ANCILLARY TESTS
○ Occasionally, superficial or cutaneous sites • Desmin (+), myogenin (+), MYOD1(+)
• Treatment: Combination of surgery and chemotherapy • Retention of nuclear INI1 expression
&/or radiation
TOP DIFFERENTIAL DIAGNOSES
• Favorable prognosis and outcome in children
• Aggressive clinical course in adults • Carcinoma or melanoma
○ Recurrence and metastases common • Myoepithelial carcinoma (malignant myoepithelioma)
○ Very poor 5-year survival rate • Epithelioid sarcoma
• Pleomorphic RMS
• Epithelioid angiosarcoma

Epithelioid Rhabdomyosarcoma Rhabdoid Morphology

(Left) Epithelioid
rhabdomyosarcoma (RMS) is a
distinctive subtype that
features sheets of epithelioid
tumor cells with abundant
eosinophilic cytoplasm and
often prominent nucleoli. Cells
and nuclei are relatively
uniform. (Right) Rhabdoid
cytomorphology may be seen
in epithelioid RMS, as
depicted; however, overt
features of rhabdomyoblastic
differentiation (e.g., strap
cells) are generally absent.
Note that occasional
multinucleated tumor cells ﬈
can also be seen.

Prominent Nucleoli Myogenic Marker Expression

(Left) Nuclei are relatively
uniform in size in epithelioid
RMS and often show 1 or more
prominent nucleoli ﬉.
Immunohistochemistry is
essentially required to prove
myogenic differentiation and
exclude carcinoma and
melanoma. (Right) Similar to
other forms of RMS,
epithelioid RMS expresses
desmin, myogenin (shown),
and MYOD1. In general,
myogenin positivity is less
diffuse than in alveolar RMS
but much more prominent
than in pleomorphic RMS.

404
 Epithelioid Rhabdomyosarcoma

Tumors of Skeletal Muscle

• Necrosis frequent
TERMINOLOGY
Definitions ANCILLARY TESTS
• Distinctive rhabdomyosarcoma (RMS) variant characterized Immunohistochemistry
by relatively uniform epithelioid cytomorphology
• Desmin (+), usually strong and diffuse
• Nuclear myogenin (+) and MYOD1(+)
CLINICAL ISSUES
○ Extent of expression varies
Epidemiology • Rare focal keratin (+)
• Incidence • Retention of nuclear INI1 expression
○ Very rare • Negative for S100 protein, CD31, CD34, HMB-45, Melan-A
• Age
Molecular Genetics
○ Wide age reported (6-78 years)
– Often in older or elderly adults • Lacks characteristic genetic features of other types of RMS
• Sex
○ Male predilection
DIFFERENTIAL DIAGNOSIS
Poorly Differentiated Carcinoma
Site
• Diffuse keratin (+)
• Deep soft tissues of extremities, head/neck, trunk
• Negative for desmin, myogenin, MYOD1
○ Less common in superficial tissues (subcutis or dermis)
Melanoma
Presentation
• Can show significant morphologic overlap with epithelioid
• Painful mass, usually of short clinical duration
RMS
• Metastases may be present at time of presentation
• Expression of S100 protein and melanocytic markers
Treatment • Negative for desmin, myogenin, MYOD1
• Limited data Myoepithelial Carcinoma (Malignant
• Most reported cases treated by combination of surgery and Myoepithelioma)
chemotherapy &/or radiation
• Can show significant morphologic overlap with epithelioid
• Reported childhood cases respond well to established
RMS
chemotherapy regimens for high-risk RMS
• Variable expression of keratin, S100 protein, calponin, SMA,
Prognosis desmin, others
• Favorable prognosis and outcome in children • Negative for myogenin, MYOD1
• Aggressive clinical course in adults Epithelioid Sarcoma
○ Recurrence and metastases common
• Diffuse keratin (+)
– Lymph nodes and lung
• CD34(+) in 50% of cases
○ Very poor 5-year survival rate
• Loss of nuclear INI1 expression
• Negative for desmin, myogenin, MYOD1
MACROSCOPIC
General Features Pleomorphic Rhabdomyosarcoma
• Characterized by pronounced nuclear and cytologic
• Poorly circumscribed, nodular mass
pleomorphism
• Fleshy cut surface
• May contain areas showing epithelioid cytomorphology
• Necrosis common
Extrarenal Rhabdoid Tumor
Size
• Affects infants and children
• Range: 3-15 cm
• Loss of nuclear INI1 expression
MICROSCOPIC • Keratin (+); negative for myogenic markers

Histologic Features SELECTED REFERENCES

• Infiltrative appearance
• Diffuse, sheet-like growth pattern
• Relatively uniformly sized epithelioid cells with abundant
eosinophilic cytoplasm
○ Intracytoplasmic "glassy" rhabdoid inclusions can be seen
• Large, vesicular nuclei often with prominent nucleoli
○ Minimal to mild cytologic pleomorphism only
○ Rare multinucleated tumor cells
• Overt features of rhabdomyoblastic differentiation (e.g.,
strap cells) absent
• Usually numerous mitotic figures, including atypical forms
1. Jokoji R et al: Epithelioid rhabdomyosarcoma; a case report with
immunohistochemical and molecular study. Diagn Pathol. 10:124, 2015
2. Feasel PC et al: Primary cutaneous epithelioid rhabdomyosarcoma: a rare,
recently described entity with review of the literature. J Cutan Pathol.
41(7):588-91, 2014
3. Zin A et al: Epithelioid rhabdomyosarcoma: a clinicopathologic and molecular
study. Am J Surg Pathol. 38(2):273-8, 2014
4. Marburger TB et al: Primary cutaneous rhabdomyosarcoma: a
clinicopathologic review of 11 cases. J Cutan Pathol. 39(11):987-95, 2012
5. Bowe SN et al: Primary intranodal epithelioid rhabdomyosarcoma. Am J Clin
Pathol. 136(4):587-92, 2011
6. Jo VY et al: Epithelioid rhabdomyosarcoma: clinicopathologic analysis of 16
cases of a morphologically distinct variant of rhabdomyosarcoma. Am J Surg
Pathol. 35(10):1523-30, 2011

405
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 SECTION 10

Vascular Tumors (Including Lymphatics)

Benign
Papillary Endothelial Hyperplasia 408
Bacillary Angiomatosis 410
Congenital Hemangioma 412
Infantile Hemangioma 416
Lobular Capillary Hemangioma 420
Epithelioid Hemangioma 422
Spindle Cell Hemangioma 426
Intramuscular Hemangioma 430
Hobnail Hemangioma 434
Acquired Tufted Angioma 436
Microvenular Hemangioma 438
Sinusoidal Hemangioma 440
Glomeruloid Hemangioma 442
Angiomatosis 444
Lymphangioma 446
Massive Localized Lymphedema 450
Atypical Vascular Lesion 452

Intermediate (Locally Aggressive)

Kaposiform Hemangioendothelioma 454

Intermediate (Rarely Metastasizing)

Papillary Intralymphatic Angioendothelioma 456
Retiform Hemangioendothelioma 458
Composite Hemangioendothelioma 460
Pseudomyogenic Hemangioendothelioma 462

Malignant
Epithelioid Hemangioendothelioma 466
Angiosarcoma 470
Kaposi Sarcoma 476
 Papillary Endothelial Hyperplasia

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY MACROSCOPIC
• Synonym: Masson tumor • Small, cystic lesions with red-purple discoloration
• Benign, reactive intravascular papillary endothelial ○ Usually < 2 cm
proliferation • Often surrounded by pseudocapsule
ETIOLOGY/PATHOGENESIS MICROSCOPIC
• Manifestation of organizing intravascular thrombus • Circumscribed lesion with pseudocapsule
• Papillary endothelial hyperplasia-like changes may be • Fibrin thrombi often present
present in preexisting hemangiomas or vascular • Papillary structures lined by endothelial cells
malformations • Significant nuclear pleomorphism is absent
CLINICAL ISSUES • Endothelial cells in single layer
• Wide site distribution; located in deep dermis or • Vessel rupture may lead to extension of papillary
subcutaneous tissue endothelial proliferation into adjacent soft tissue
○ Common sites includes head and neck, fingers, trunk TOP DIFFERENTIAL DIAGNOSES
• Clinically presents as painless mass • Angiosarcoma
• Excision is curative • Hemangiomas
• Excellent prognosis • Arteriovenous malformation
• Hematoma

Papillary Endothelial Hyperplasia Fibrin Thrombi and Fibrous Papillary Cores

(Left) Papillary endothelial
hyperplasia (PEH) is a well-
circumscribed, reactive lesion
in which papillary fronds ﬊
lined by a single layer of
endothelial cells proliferate
within a vascular lumen ﬉.
(Right) Fibrin thrombi ﬊ are
apparent in early stages and
with time are replaced by
papillary fronds with a fibrous
core ﬈ characteristic of PEH.

Prominent Papillary Fronds Intravascular Localization

(Left) PEH with prominent
papillary fronds can be
mistaken for the
anastomosing and dissecting
vascular spaces of low-grade
angiosarcoma. However, note
the endothelial lining ﬊ of
the blood vessel lumen. (Right)
Desmin immunohistochemical
stain highlights remnants of
smooth muscle in the blood
vessel wall ﬉, confirming the
intravascular location of PEH.

408
 Papillary Endothelial Hyperplasia

Vascular Tumors (Including Lymphatics)

• Rare examples of extravascular variant in soft tissue have
TERMINOLOGY been reported
Abbreviations ○ Represent reactive endothelial proliferation in
• Papillary endothelial hyperplasia (PEH) organizing hematoma

Synonyms Cytologic Features

• Masson tumor • Enlarged endothelial cells but lack significant cytologic
• Intravascular angiomatosis atypia or pleomorphism

Definitions DIFFERENTIAL DIAGNOSIS

• Benign intravascular papillary endothelial proliferation
Angiosarcoma
ETIOLOGY/PATHOGENESIS • Angiosarcoma is infiltrative process that involves
surrounding tissue, unlike PEH, which is intraluminal
Reactive Vascular Proliferation • Even PEH cases with soft tissue extension have bulk of
• Manifestation of organizing intravascular thrombus lesion confined to vascular lumen
• PEH-like changes may be present in preexisting • PEH lacks nuclear atypia, tumor cell necrosis, and mitotic
hemangiomas or vascular malformations activity present in angiosarcoma
Hemangiomas
CLINICAL ISSUES
• PEH-like changes may occur in hemangiomas complicated
Site by thrombosis
• Wide distribution
Arteriovenous Malformations
• Common sites include
○ Head and neck, fingers, trunk • PEH-like changes may occur in arteriovenous
malformations
Presentation • Important to recognize, since these may recur
• Painless mass
Hematoma
• Located in deep dermis or subcutaneous tissue
• Soft tissue hematomas may have foci of PEH
Treatment • May be mistaken for angiosarcoma
• Excision is curative
DIAGNOSTIC CHECKLIST
Prognosis
• Excellent Clinically Relevant Pathologic Features
• Cases with underlying hemangioma or vascular • Intravascular process
malformation may recur Pathologic Interpretation Pearls
MACROSCOPIC • Intravascular papillary proliferation lined by endothelial
cells without significant nuclear atypia
General Features
• Cystic mass with red-purple discoloration SELECTED REFERENCES
• Often surrounded by pseudocapsule 1. Díaz-Flores L et al: Sinusoidal hemangioma and intravascular papillary
endothelial hyperplasia: interrelated processes that share a histogenetic
Size piecemeal angiogenic mechanism. Acta Histochem. 120(3):255-62, 2018
• Mostly small in size (< 2 cm) 2. Vicensoto Moreira Milhan N et al: A mixed form of intravascular papillary
endothelial hyperplasia in an uncommon location: case and literature review.
Dermatol Online J. 24(2), 2018
MICROSCOPIC 3. Gupta A et al: Intravascular papillary endothelial hyperplasia presenting as a
cystic mass in the scalp with underlying bone involvement: A Rare Entity. Int
Histologic Features J Appl Basic Med Res. 7(4):269-71, 2017
• Circumscribed lesion with pseudocapsule 4. Liné A et al: Papillary endothelial hyperplasia (Masson's tumor) in children.
Ann Chir Plast Esthet. 62(3):232-7, 2017
○ Residual smooth muscle or elastic lamina of preexisting 5. Shah HC et al: Intravascular papillary endothelial hyperplasia (Masson's
vessel may be apparent tumor) of the scalp with intracranial extension. J Pediatr Neurosci. 9(3):260-
• Fibrin thrombi often seen 2, 2014
6. Handa U et al: Cytologic diagnosis of intravascular papillary endothelial
• Papillary structures lined by endothelial cells hyperplasia: a report of two cases and review of cytologic literature. Acta
○ Endothelial cells in single layer Cytol. 56(2):199-203, 2012
– May appear plump or hobnail in appearance 7. Inoue H et al: Intravascular papillary endothelial hyperplasia of the oral cavity.
J Oral Sci. 53(4):475-80, 2011
– Significant nuclear pleomorphism is absent 8. Branton PA et al: Papillary endothelial hyperplasia of the breast: the great
○ Papillae form anastomosing network impostor for angiosarcoma: a clinicopathologic review of 17 cases. Int J Surg
Pathol. 11(2):83-7, 2003
• Papillary cores may consist of fibrin or fibrous connective
9. Hashimoto H et al: Intravascular papillary endothelial hyperplasia. A
tissue clinicopathologic study of 91 cases. Am J Dermatopathol. 5(6):539-46, 1983
• Vessel rupture may lead to extension of papillary 10. Kuo T et al: Masson's "vegetant intravascular hemangioendothelioma:" a
endothelial proliferation into adjacent soft tissue lesion often mistaken for angiosarcoma: study of seventeen cases located in
the skin and soft tissues. Cancer. 38(3):1227-36, 1976

409
 Bacillary Angiomatosis

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY • May have overlying epidermal ulceration and collarette

• Bacillary angiomatosis (BA) (similar to pyogenic granuloma)
• Reactive vascular proliferation associated with • Vessels are arranged in loose lobular configuration
Bartonella bacterial infection • Deeper parts of lesion may show greater cellularity and
crowding of vessels
ETIOLOGY/PATHOGENESIS • Background stroma shows fibrosis, edema, and mixed
• Most patients are immunocompromised, especially inflammatory infiltrate
HIV/AIDS
TOP DIFFERENTIAL DIAGNOSES
• Also associated with organ transplantation, systemic
steroids, and leukemia • Pyogenic granuloma
○ Polypoid dermal-based lesion composed of lobular
CLINICAL ISSUES collection of capillary-type vessels
• May involve any cutaneous site; uncommonly involves ○ Overlying ulceration and peripheral epidermal collarette
mucosal sites, deep soft tissues are typically present, similar to BA
○ Internal organ involvement rare but may affect liver • Kaposi sarcoma
(peliosis hepatis) ○ Plaque-like or nodular dermal collection of slit-like
MICROSCOPIC vessels lined by atypical spindle cells
○ Inflammatory infiltrate is typically composed of
• Nodular to dome-shaped/polypoid dermal-based vascular
lymphocytes and plasma cells, not neutrophils
proliferation

Bacillary Angiomatosis Blood Vessels and Inflammation

(Left) Low-power examination
of bacillary angiomatosis (BA)
demonstrates a superficial
dermal proliferation of blood
vessels in a lobular
configuration ﬊ associated
with edema and inflammation.
(Right) Intermediate
magnification of BA shows a
proliferation of small blood
vessels arranged in a vaguely
lobular configuration with
prominent stromal edema,
mild fibrosis, and mixed
inflammatory infiltrate.

Acute Inflammation Warthin-Starry Stain

(Left) High magnification of
bacillary angiomatosis
demonstrates a proliferation
of small blood vessels with
swollen endothelial cells ﬊
surrounded by edema and
acute inflammation with
leukocytoclasia ﬇. (Right)
Warthin-Starry stain
demonstrates positive staining
of numerous clusters ﬈ and
single bacterial organisms.

410
 Bacillary Angiomatosis

Vascular Tumors (Including Lymphatics)

○ Deeper parts of lesion may show greater cellularity and
TERMINOLOGY crowding of vessels
Abbreviations ○ No significant cytologic atypia or atypical mitotic activity
• Bacillary angiomatosis (BA) • Background stroma shows fibrosis, edema, and mixed
inflammatory infiltrate
Synonyms ○ Infiltrate is rich in neutrophils with leukocytoclasia,
• Epithelioid angiomatosis macrophages, lymphocytes, and may show focal
Definitions collections of basophilic granular material (clumps of
bacteria)
• Reactive vascular proliferation associated with Bartonella
– Neutrophils are more plentiful in deeper lesions
bacterial infection
ANCILLARY TESTS
ETIOLOGY/PATHOGENESIS
Histochemistry
Infectious Agents
• Warthin-Starry
• Caused by infection with Bartonella (gram-negative
○ Reactivity: Positive
coccobacilli) species, usually B. henselae or B. quintana
○ Staining pattern: Granular (coccobacillary organisms)
○ Most patients have history of cat exposure (and may
have preceding scratch or bite) • Gomori methenamine silver
• Most patients are immunocompromised, especially due to ○ Reactivity: Positive
HIV/AIDS ○ Staining pattern: Granular (coccobacillary organisms)
○ Also has been associated with organ transplantation, PCR
systemic steroids, and leukemia • PCR for Bartonella species may be ordered if organisms are
not identified on histochemical stains
CLINICAL ISSUES
Epidemiology DIFFERENTIAL DIAGNOSIS
• Age Pyogenic Granuloma
○ May occur in both adults and children • Polypoid dermal-based lesion composed of lobular
Site collections of capillary-type vessels
• Can involve any cutaneous site; uncommonly may involve • Overlying ulceration and peripheral epidermal collarette
mucosal sites and deep soft tissues are typically present, similar to BA
○ Internal organ involvement rare but may affect liver • No organisms identified on H&E or special stains
(peliosis hepatis), spleen, lungs Kaposi Sarcoma
Presentation • Plaque-like or nodular collection of slit-like vessels lined by
• Skin nodules or, less likely, plaques atypical spindle cells
○ Typically present with multiple lesions, often pyogenic • Inflammatory infiltrate is typically composed mostly of
granuloma-like lymphocytes and plasma cells, not neutrophils
• No bacterial organisms identified
Treatment • HHV8(+) is diagnostic
• Drugs
○ Antibiotics typically lead to resolution of lesions DIAGNOSTIC CHECKLIST
Prognosis Pathologic Interpretation Pearls
• Typically good, but depends on patient's immune status • Proliferation of vessels associated with neutrophils and
and sites involved clumps of bacterial organisms

MACROSCOPIC SELECTED REFERENCES

General Features
• Reddish-brown, dermal-based nodular, hemorrhagic lesion
MICROSCOPIC
Histologic Features
• Typically nodular to dome-shaped/polypoid dermal-based
vascular proliferation
○ May have overlying epidermal ulceration and collarette
(similar to pyogenic granuloma)
• Vessels are arranged in loose lobular configuration
○ Endothelial cells show mild enlargement and oval to
epithelioid shape
1. Nikam BP et al: Bacillary angiomatosis in an immunocompetent individual.
Indian Dermatol Online J. 9(3):205-6, 2018
2. Eyer-Silva WA et al: An unusual case of bacillary angiomatosis in the oral
cavity of an AIDS patient who had no concomitant tegumentary lesions -
case report and review. Rev Inst Med Trop Sao Paulo. 59:e59, 2017
3. Diniz LM et al: Bacillary angiomatosis with bone invasion. An Bras Dermatol.
91(6):811-4, 2016
4. Moulin C et al: Cutaneous bacillary angiomatosis in renal transplant
recipients: report of three new cases and literature review. Transpl Infect
Dis. 14(4):403-9, 2012
5. Amsbaugh S et al: Bacillary angiomatosis associated with
pseudoepitheliomatous hyperplasia. Am J Dermatopathol. 28(1):32-5, 2006
6. LeBoit PE et al: Bacillary angiomatosis. The histopathology and differential
diagnosis of a pseudoneoplastic infection in patients with human
immunodeficiency virus disease. Am J Surg Pathol. 13(11):909-20, 1989

411
 Congenital Hemangioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY MICROSCOPIC
• 2 major clinicopathologic subtypes • Well-defined lobules of capillaries with central draining
○ Rapidly involuting congenital hemangioma (RICH) vessels and separated by fibrous tissue
○ Noninvoluting congenital hemangioma (NICH) • RICH
○ Focal hemosiderin and extramedullary hematopoiesis
CLINICAL ISSUES
○ Involutional changes: Increased interstitial fibrosis, cysts,
• Antenatal or congenital presentation of exophytic or and microthrombi
plaque-like soft tissue mass at birth • NICH
○ Fully developed at birth without accelerated postnatal ○ Focal hobnailed endothelial cells
growth
○ Interlobular stroma with prominent dysplastic vessels
• Most common sites of involvement: Head, neck, and
extremities in close proximity to joints ANCILLARY TESTS
• RICH: Spontaneous, rapid involution complete by 8-14 • GLUT1(-)
months of age
TOP DIFFERENTIAL DIAGNOSES
• NICH: Postnatal growth proportionate with child
○ Does not regress and persists indefinitely • Infantile hemangioma
• Excellent prognosis for uncomplicated lesions • Vascular malformation
• Tufted angioma
• Kaposiform hemangioendothelioma

Congenital Hemangioma Central Draining Vessel

(Left) Congenital
hemangiomas are
characterized by a dermal &/or
subcutaneous proliferation of
capillaries growing in lobules
﬊, which are separated by
dense fibrous tissue ﬈.
(Right) Within both subtypes
of congenital hemangioma
[rapidly involuting congenital
hemangioma (RICH) and
noninvoluting congenital
hemangioma (NICH)], the
cellular lobules contain
prominent centrally placed
draining vessels ﬊. The
endothelial cells and pericytes
are moderately plump with
bland cytologic features.

Interlobular Stromal Vessels GLUT1 Negative

(Left) The lobules within NICH
are typically larger than those
seen in RICH. In addition, the
interlobular stroma contains
an increased number of large,
irregular vessels ﬈. (Right) In
contrast to infantile
hemangiomas, the endothelial
cells in RICH and NICH are
negative for GLUT1 ﬈. This
immunophenotypic difference
is a useful marker for
differentiating between the 2
entities, which have
overlapping morphologic
features. Of note, erythrocytes
are positive for GLUT1,
allowing them to serve as an
internal control ﬊.

412
 Congenital Hemangioma
TERMINOLOGY
Synonyms
• Congenital nonprogressive hemangioma
• Rapidly involuting congenital hemangioma (RICH)
• Noninvoluting congenital hemangioma (NICH)
Definitions
• Benign congenital vascular neoplasm that is fully developed
at birth and does not display accelerated postnatal growth
ETIOLOGY/PATHOGENESIS
Developmental Anomaly
• Lesions arise and proliferate in utero
• Relationship to infantile hemangioma is heavily debated
and controversial
○ Presence of reported cases of congenital hemangioma
and infantile hemangioma arising in same patient may
suggest lesions are part of clinical spectrum
○ Differential protein and mRNA expression in congenital
vs. infantile hemangiomas may suggest these are distinct
entities
– Congenital hemangiomas demonstrate higher levels
of expression of FLT-1 (VEGFR-R1) and lower levels of
IGF-2 than infantile hemangiomas
Genetics
• Associated with somatic activating mutations in GNAQ and
GNA11
CLINICAL ISSUES
Epidemiology
• Incidence
○ Affects 0.3% of infants
○ RICH is more common than NICH
• Demographics
○ Newborns (presentation at birth)
○ No gender predilection
Site
• Most common sites of involvement are head, neck, and
extremities in close proximity to joints
• RICH may demonstrate hepatic involvement ± skin lesions
Presentation
• 2 major clinicopathologic subtypes: RICH and NICH
• Antenatal or congenital presentation at birth
○ May be detected as early as 12 weeks of gestation by
prenatal ultrasonography
• Usually solitary lesions
• Solitary, exophytic, or bossed plaque-like soft tissue mass
○ Violaceous overlying skin with telangiectasia and
peripheral draining veins
• Natural course varies by subtype
• Rare reports of RICH occurring in setting of PHACE
syndrome
○ PHACE syndrome: Posterior fossa abnormalities,
hemangiomas, arterial lesions, cardiac and eye
abnormalities, sternal clefting or supraumbilical raphe
• Potential complications
Vascular Tumors (Including Lymphatics)
○ Ulceration relatively frequent in large lesions during
involution
○ Transient thrombocytopenia and coagulopathy in large
RICH prior to regression
– Self-limited and minor, in contrast to Kasabach-Merritt
phenomenon (most commonly associated kaposiform
hemangioendothelioma)
– Usually resolves by 2 weeks of age without treatment
○ High-output cardiac failure secondary to arteriovenous
shunting in large RICH prior to regression
Natural History
• Both subtypes have reached or passed their proliferative
peak at birth
○ Proliferative phase occurs in utero
• RICH
○ Stable size at birth with subsequent spontaneous and
rapid involution early in postnatal period
○ Involution begins within few days to weeks after birth
○ Majority of lesions completely involute by 8-14 months
of age
○ Rare reports of rapid involution in utero with complete
regression prior to birth
○ Following involution, skin is anetodermic with dermal or
subcutaneous atrophy in area of lesion
• NICH
○ Stable size at birth with static course
– Rare reported cases of growth and expansion during
adolescence
○ Demonstrates postnatal growth proportionate with
somatic growth of child
○ Does not spontaneously regress and persists indefinitely
throughout adulthood
• Minor subset of RICH lesions demonstrate initial rapid but
incomplete involution resulting in persistent residual
vascular plaque that is indistinguishable from NICH
○ Raises possibility that NICH represents RICH in arrested
growth phase
Treatment
• RICH
○ Observation as 1st-line treatment
○ Surgical excision reserved for cases complicated by
persistent/repeated ulceration, severe hemorrhage, or
congestive heart failure secondary to arteriovenous
shunting
○ Cosmetic repair of residual skin changes after involution
• NICH
○ Pulsed dye laser therapy
○ Surgical excision ± preoperative embolization for large or
symptomatic lesions
Prognosis
• RICH
○ Excellent for uncomplicated lesions
○ Vast majority of lesions completely regress without
treatment
○ High mortality rate associated with rare complication of
high-output heart failure
• NICH
○ Favorable with no risk of recurrence following excision
○ Persists indefinitely without surgical intervention
413
 Congenital Hemangioma
Vascular Tumors (Including Lymphatics)
MACROSCOPIC
General Features
• Red to violaceous nodule or plaque
• Telangiectasia of overlying skin (more prominent in NICH)
• Peripheral white or bluish pallor producing halo effect
(more characteristic of RICH)
• May have central ulceration, fissure, or depression (more
characteristic of RICH)
• Typically solitary
Size
• Average diameter: 5-6 cm at birth
MICROSCOPIC
Histologic Features
• Early RICH and NICH lesions (prior to involution)
demonstrate similar morphologic features  • Randomly dispersed compact nodules of capillaries in
○ Usually best distinguished using clinical features
• RICH
○ Well-defined, variably sized lobules of capillaries within
dermis and subcutaneous tissue
○ Prominent, thin-walled centrilobular, draining vessels
○ Dense, interlobular fibrous tissue
○ Focal hemosiderin and extramedullary hematopoiesis
commonly seen
○ Mitoses may be present
– No atypical figures
○ No significant cytologic atypia
○ Involutional changes initially occur in center of lesion
– Decreased numbers of lobules with progressive
interstitial fibrosis, cystic spaces, and vascular thrombi
– No fibrofatty residuum after involution (in contrast to
infantile hemangioma)
• NICH
○ Well-defined, large lobules of capillaries within dermis
and subcutaneous tissue
○ Centrilobular draining vessels appear larger, stellate, and
more ectatic than in RICH
○ Focal hobnailed appearance of endothelial cells with
small, hyperchromatic nuclei bulging into lumen
○ Round, eosinophilic globules may be present in
cytoplasm of endothelial cells
○ Interlobular fibrovascular stroma with arteries, large
dysplastic veins, and lymphatic-like structures
– Prominence of large interlobular vessels may be
misleading and confused for vascular malformation
○ Rare mitoses
○ No significant cytologic atypia
ANCILLARY TESTS
Histochemistry
• Elastin stain highlights deficient or excessive elastic tissue in
walls of interlobular dysplastic vessels
Immunohistochemistry
• Endothelial cells express CD31, CD34, factor VIII-related
antigen, and WT-1
• Typically GLUT1(-), but rare focal reactivity has been
reported in RICH
414
DIFFERENTIAL DIAGNOSIS
Infantile Hemangioma
• Majority are not present at birth (presents within few
weeks after birth)
• Demonstrates accelerated postnatal growth
○ Growth rate of lesion exceeds that of child
• GLUT1(+)
Vascular Malformation
• Congenital lesions that grow proportionately with child and
persist without regression
• Not hypercellular and nonproliferative endothelial cells
• WT1(-)
Tufted Angioma
• Slow, indolent growth over months to years followed by
stabilization &/or regression
cannonball configuration
Kaposiform Hemangioendothelioma
• Infiltrating spindled endothelial cells forming slit-like
vascular spaces and glomeruloid-like nests
• Associated with Kasabach-Merritt phenomenon
• Periphery of lobules D2-40(+)
○ Lobular component of congenital hemangiomas typically
D2-40(-)
– Interlobular or perilesional lymphatic channels may be
immunoreactive
SELECTED REFERENCES
1. Lewis D et al: Rapidly involuting congenital haemangioma of the liver. BMJ
Case Rep. 2018
2. Ayturk UM et al: Somatic activating mutations in GNAQ and GNA11 are
associated with congenital hemangioma. Am J Hum Genet. 98(6):1271,
2016
3. Nasseri E et al: Partially involuting congenital hemangiomas: a report of 8
cases and review of the literature. J Am Acad Dermatol. 70(1):75-9, 2014
4. Patrick LM et al: Rapid involuting congenital hemangioma in the setting of
PHACE association. Pediatrics. 133(6):e1777-80, 2014
5. Bruder E et al: Vascular and perivascular lesions of skin and soft tissues in
children and adolescents. Pediatr Dev Pathol. 15(1 Suppl):26-61, 2012
6. Kanada KN et al: A prospective study of cutaneous findings in newborns in
the United States: correlation with race, ethnicity, and gestational status
using updated classification and nomenclature. J Pediatr. 161(2):240-5, 2012
7. Roebuck D et al: Rapidly involuting congenital haemangioma (RICH) of the
liver. Pediatr Radiol. 42(3):308-14, 2012
8. Fadell MF 2nd et al: Prenatal diagnosis and postnatal follow-up of rapidly
involuting congenital hemangioma (RICH). Pediatr Radiol. 41(8):1057-60,
2011
9. Niimi R et al: Epithelioid hemangioendothelioma after radiotherapy for
congenital hemangioma: a case report. Med Oncol. 27(1):130-3, 2010
10. Ozcan UA: Rapidly involuting congenital hemangioma: a case of complete
prenatal involution. J Clin Ultrasound. 38(2):85-8, 2010
11. Moukaddam H et al: MRI characteristics and classification of peripheral
vascular malformations and tumors. Skeletal Radiol. 38(6):535-47, 2009
12. Picard A et al: IGF-2 and FLT-1/VEGF-R1 mRNA levels reveal distinctions and
similarities between congenital and common infantile hemangioma. Pediatr
Res. 63(3):263-7, 2008
 Congenital Hemangioma
Dense Interlobular Fibrosis
Eosinophilic Globules
Prominent Interlobular Vessels
Vascular Tumors (Including Lymphatics)
Vascular Microthrombi
(Left) RICH is composed of
well-defined, variably sized
lobules of capillaries ﬊ that
are separated by dense fibrous
tissue ﬈. The interlobular
vascular component is
oftentimes less prominent
than that seen in NICH. (Right)
Although they can be seen in
both subtypes of congenital
hemangioma, the lobular
vessels within RICH more
frequently contain organizing
fibrin thrombi ﬈ with
evidence of recanalization ﬊.
Hobnailed Endothelium
(Left) Lobular endothelial cells
of NICH may contain foci of
intracytoplasmic eosinophilic
globules, which tend to cluster
﬈. (Right) The lobular
endothelial cells within NICH
are often small,
hyperchromatic, and bulge
into the vascular lumen,
imparting a hobnailed
appearance ﬈.
Dysplastic Vessels
(Left) The interlobular stroma
of NICH frequently contains
abundant large and irregularly
shaped venous, arterial, and
lymphatic-like structures ﬈.
These vessels can be a
dominant feature and may
lead to misdiagnosis as a
vascular malformation. (Right)
Many of the interlobular
vessels in NICH are distorted in
shape and composition. This
stellate-shaped, venous-like
structure has poorly developed
media with variable areas of
thickness and deficient
smooth muscle and elastic
tissue.
415
 Infantile Hemangioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY MICROSCOPIC
• Juvenile hemangioma • Proliferative phase
• Hemangioma of infancy ○ Tightly packed lobules of capillaries lined by plump
endothelial cells and pericytes
CLINICAL ISSUES
○ Early lesions densely cellular and mitotically active
• Most common vascular tumor of infancy (usually present • Involutional phase
within 1st few weeks of life)
○ Dilated capillaries with flattened endothelial cells
• Most common sites of involvement: Skin and soft tissue of
○ Progressive fibrosis and fatty replacement
face, head, and neck
• Multifocal disease associated with visceral involvement ANCILLARY TESTS
• Syndromic associations: PHACE and LUMBAR syndrome • Endothelial cells (+) for GLUT1, Lewis-Y antigen, and IGF-2
• Characteristic proliferative and involutional growth phases ○ GLUT1 is most reliable and specific marker
○ Proliferative phase: Occurs in 1st several months with
TOP DIFFERENTIAL DIAGNOSES
rapid enlargement
○ Involutional phase: Proceeding 1-12 years of life • Congenital hemangioma
• Excellent prognosis with complete spontaneous regression • Lobular capillary hemangioma (pyogenic granuloma)
occurring in 80-90% of cases • Tufted angioma
• Kaposiform hemangioendothelioma
• Vascular malformation

Infantile Hemangioma Proliferative Phase: Dense Cellularity

(Left) Infantile hemangioma is
characterized by a dermal &/or
subcutaneous proliferation of
tightly packed capillaries
growing in lobules ﬇, which
are separated by thin, fibrous
bands ﬈. (Right) The
proliferative phase
demonstrates increased
cellularity with dense, solid-
appearing areas containing
inconspicuous vascular lumina
﬈. These solid-appearing
areas are composed of plump
endothelial cells and pericytes.

Involution Phase: Dilated Vessels GLUT1 Positive

(Left) During the involution
phase of infantile
hemangioma, the capillaries
become more dilated, and the
endothelial cells are flattened.
(Right) Infantile hemangiomas
are immunoreactive with
GLUT1, which stains the
cytoplasm of the endothelial
cells in all phases of
development ﬈. As such, it is
the most reliable and specific
marker for this entity.
Erythrocytes are also
immunoreactive for GLUT1
and serve as an internal
control ﬊.

416
 Infantile Hemangioma
TERMINOLOGY
Synonyms
• Juvenile hemangioma
• Hemangioma of infancy
Definitions
• Benign vascular neoplasm of infancy with characteristic
proliferative and involutional phases
ETIOLOGY/PATHOGENESIS
Developmental Anomaly/Environmental Exposure
• Postulated to result from hypoxia-induced stimulation of
endothelial progenitor cells and angiogenic peptides or
clonal expansion of placental emboli
○ VEGF, β-adrenergic, and NOTCH signaling pathways have
been implicated
• Risk factors include prematurity, low birth weight, and
product of multiple gestations
Genetics/Inheritance
• Most cases are sporadic
• Rare reports of autosomal-dominant pattern of inheritance
with linkage to 5q31-33 (region containing FLT4 and FGFR4)
CLINICAL ISSUES
Epidemiology
• Incidence
○ Affects 4-5% of infants
○ Most common vascular tumor of infancy
• Demographics
○ Neonates and infants (present at birth or within 1st few
weeks of life)
○ Female predominance (M:F = 3-5:1)
○ Caucasians more commonly affected
Site
• Skin and soft tissue of face, head, and neck are most
common sites of involvement (60%)
• Other sites: Trunk, extremities, and viscera (central nervous
system, liver, lungs, eyes, and kidneys)
• Typically solitary lesion (85%) but can be variable in
distribution
○ Localized, segmental, or multifocal
○ Multifocal disease defined as > 5 lesions
– Associated with visceral involvement
Presentation
• Superficial lesions present at birth and are telangiectatic in
appearance early on
○ Appear as bright red plaques or nodules when fully
formed
• Deep lesions appear later (at 2-3 months of age) as
subcutaneous bluish swellings
• Segmental lesions may be associated with congenital
anomalies
○ PHACE syndrome presents in 20-31% of those with large
segmental facial lesions
– Posterior fossa abnormalities, hemangiomas, arterial
lesions, cardiac and eye abnormalities, sternal clefting,
or supraumbilical raphe
Vascular Tumors (Including Lymphatics)
○ LUMBAR syndrome presents in 10% of those with
perineal or reticular hemangiomas
– Lower body hemangiomas, urogenital anomalies,
myelopathy, bony abnormalities, anorectal
malformations or arterial anomalies, and renal
anomalies
Natural History
• Characteristic proliferative and involutional growth phases
• Proliferative growth phase occurs in 1st several months,
during which lesion rapidly enlarges in noncommensurate
manner
○ Proliferation after 1st year of life is uncommon
○ Deep lesions tend to have longer proliferative phase
than superficial ones
• Spontaneous involution occurs over proceeding 1-12 years
• Clinical variant: Infantile hemangioma with minimal or
arrested growth (IH-MAG)
○ Minor subset that fails to proliferate beyond precursor
telangiectatic stage
○ Usually located on lower body (associated with LUMBAR
syndrome)
Treatment
• Close observation of small lesions
• Pharmacotherapy: Systemic or topical corticosteroids, β-
blockers, imiquimod, or interferon-α
• Pulsed dye laser therapy
• Surgical excision usually reserved for involuted lesions with
residual skin abnormalities
Prognosis
• Excellent
• Complete regression in 80-90% without medical or surgical
intervention
• Rare case report of malignant transformation to
angiosarcoma
MACROSCOPIC
General Features
• Superficial lesions: Bright red, lobulated nodules or plaques
• Deep lesions: Bluish color with telangiectasia of overlying
skin
Size
• Variable in size (ranging from pinpoint lesions to > 20 cm)
MICROSCOPIC
Histologic Features
• Variable histologic appearance based on growth phase
• Proliferative phase
○ Tightly packed syncytial aggregates of small capillaries
lined by plump endothelial cells and pericytes
○ Lobules of capillaries separated by thin bands of fibrous
tissue
○ Replacement or displacement of normal dermal
structures
○ Early lesions are densely cellular with inconspicuous
vascular lumina and solid-appearing areas
○ Abundant typical mitotic figures may be present during
early proliferative phase
417
 Infantile Hemangioma
Vascular Tumors (Including Lymphatics)

○ No atypical mitotic figures or significant cytologic atypia • Periphery of lobules D2-40(+)

• Involutional phase ○ Lobular component of infantile hemangiomas typically
○ Dilated capillaries with flattened endothelial cells D2-40(-)
○ Progressive interstitial fibrosis and increasing amounts of – Perilesional lymphatic channels may be
adipose tissue immunoreactive
○ More pronounced lobular architecture Vascular Malformation
○ Increased number of mast cells and apoptotic bodies
• Congenital lesions that grow proportionately with child and
○ Thickening and hyalinization of vessel walls
persist without regression
• End stage
• Not hypercellular and nonproliferative endothelial cells
○ Fibrofatty replacement with sparse vessels
• GLUT1(-)
○ Residual larger feeder vessels and draining veins
• IH-MAG variant SELECTED REFERENCES
○ Proliferative component comprises < 25% of total
1. Adams DM et al: Infantile hemangiomas in the head and neck region.
surface area of lesion and Otolaryngol Clin North Am. 51(1):77-87, 2018
○ Patient is > 2 years of age 2. Valdivielso-Ramos M et al: Infantile hemangioma with minimal or arrested
growth as the skin manifestation of PHACE syndrome. Pediatr Dermatol.
35(5):622-627, 2018
ANCILLARY TESTS
3. Yin RR et al: Expression and correlation of MMP-9, VEGF, and p16 in infantile
Immunohistochemistry hemangioma. Eur Rev Med Pharmacol Sci. 22(15):4806-4811, 2018
4. Darrow DH et al: Diagnosis and management of infantile hemangioma:
• Endothelial cells express GLUT1, IGF-2, CD31, CD34, factor executive summary. Pediatrics. 136(4):786-91, 2015
VIII-related antigen, Lewis-Y antigen, and WT1 5. Bellaud G et al: PHACE syndrome, a series of six patients: clinical and
○ GLUT1 is most reliable and specific marker morphological manifestations, propranolol efficacy, and safety. Int J
Dermatol. 54(1):102-7, 2014
– Positive in all growth phases 6. Jeng MR et al: Malignant transformation of infantile hemangioma to
– Negative in most other vascular tumors angiosarcoma: response to chemotherapy with bevacizumab. Pediatr Blood
Cancer. 61(11):2115-7, 2014
• Pericytes are SMA(+)
7. Kwon SH et al: Effect of early long-pulse pulsed dye laser treatment in
• Loss of immunoreactivity for CD31, CD34, and factor VIII- infantile hemangiomas. Dermatol Surg. 40(4):405-11, 2014
related antigen in fully involuted lesions 8. Sethuraman G et al: Management of infantile hemangiomas: current trends.
J Cutan Aesthet Surg. 7(2):75-85, 2014
9. Chen TS et al: Infantile hemangiomas: an update on pathogenesis and
DIFFERENTIAL DIAGNOSIS therapy. Pediatrics. 131(1):99-108, 2013
Congenital Hemangioma 10. Greenberger S et al: Pathogenesis of infantile haemangioma. Br J Dermatol.
169(1):12-9, 2013
• In utero growth with fully developed lesions present at 11. Lee KC et al: Update on infantile hemangiomas. Semin Perinatol. 37(1):49-
birth 58, 2013
• Rapidly involuting type regresses faster than infantile 12. Malik MA et al: Effect of propranolol vs prednisolone vs propranolol with
prednisolone in the management of infantile hemangioma: a randomized
hemangiomas controlled study. J Pediatr Surg. 48(12):2453-9, 2013
• Noninvoluting type does not regress and grows 13. Reddy KK et al: Retrospective study of the treatment of infantile
commensurately with child hemangiomas using a combination of propranolol and pulsed dye laser.
Dermatol Surg. 39(6):923-33, 2013
• Hemosiderin and extramedullary hematopoiesis commonly 14. Bischoff J: Progenitor cells in infantile hemangioma. J Craniofac Surg. 20
present Suppl 1:695-7, 2009
• GLUT1(-) 15. Calicchio ML et al: Identification of signaling systems in proliferating and
involuting phase infantile hemangiomas by genome-wide transcriptional
Lobular Capillary Hemangioma (Pyogenic profiling. Am J Pathol. 174(5):1638-49, 2009
Granuloma) 16. Kilcline C et al: Infantile hemangiomas: how common are they? A systematic
review of the medical literature. Pediatr Dermatol. 25(2):168-73, 2008
• Usually older children and adolescents (mean age: 6 years in 17. Haggstrom AN et al: Prospective study of infantile hemangiomas: clinical
pediatric population) characteristics predicting complications and treatment. Pediatrics.
118(3):882-7, 2006
• Polypoid or sessile mass ± ulceration 18. Nguyen VA et al: Infantile hemangioma is a proliferation of LYVE-1-negative
• Lobule(s) of capillaries surrounded by epidermal/mucosal blood endothelial cells without lymphatic competence. Mod Pathol.
collarette 19(2):291-8, 2006
19. North PE et al: infancy and childhood: beyond capillary hemangioma.
• GLUT1(-) Cardiovasc Pathol. 2006 Nov-Dec;15(6):303-17. 15(6):303-17,
Tufted Angioma 20. Dadras SS et al: Infantile hemangiomas are arrested in an early
developmental vascular differentiation state. Mod Pathol. 17(9):1068-79,
• Slow, indolent growth over months to years followed by 2004
stabilization &/or regression 21. Pagliai KA et al: Pyogenic granuloma in children. Pediatr Dermatol. 21(1):10-
3, 2004
• Randomly dispersed compact nodules of capillaries in 22. Walter JW et al: Somatic mutation of vascular endothelial growth factor
cannonball configuration receptors in juvenile hemangioma. Genes Chromosomes Cancer. 33(3):295-
• GLUT1(-) 303, 2002
23. North PE et al: immunohistochemical marker for juvenile hemangiomas.
Kaposiform Hemangioendothelioma Hum Pathol. 2000 Jan;31(1):11-22. 31(1):11-22,

• Infiltrating spindled endothelial cells forming slit-like

vascular spaces and glomeruloid-like nests
• Associated with Kasabach-Merritt phenomenon
• GLUT1(-)

418
 Infantile Hemangioma

Vascular Tumors (Including Lymphatics)

Bland Endothelium Mitotic Activity
(Left) During the proliferative
phase, the endothelial cells
and pericytes are plump with
bland cytologic features ﬈.
(Right) Early proliferative
lesions may be mitotically
active with multiple mitotic
figures observed per HPF ﬈.
However, no atypical mitoses,
significant nuclear
pleomorphism, or frank atypia
are present.

Mixed Phases Interstitial Fibrosis

(Left) The periphery of
infantile hemangiomas
involute first with eventual
involution of the remainder of
the lesion. As such, within the
same specimen, features of
both the proliferative ﬈ and
involution phases ﬊ may be
evident. (Right) During
involution, the overall
cellularity of the lesion
decreases secondary to
progressively increasing
interstitial fibrosis ﬈.

Thick, Hyalinized Vessels Fibrofatty Replacement

(Left) Late in the involution
phase, the remaining vessels
often develop thickened
basement membranes with
subsequent hyalinization of
the vessel walls. (Right)
Toward the end stage of
involution, the vascular
component of infantile
hemangiomas are
progressively replaced by
fibrous and fatty tissue ﬈. A
few small lobules of capillaries
may persist.

419
 Lobular Capillary Hemangioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY MICROSCOPIC
• Clinically distinctive benign vascular lesion characterized by • Well circumscribed or demarcated
vague lobules of capillary channels arranged around larger • Overlying squamous mucosa is often ulcerated with acute
"feeder" vessels and chronic inflammation
• Synonym: Pyogenic granuloma • Vague lobules of capillary channels organized around larger
"feeder" vessels
CLINICAL ISSUES
• Edematous to fibromyxoid stroma
• Wide age range (common in children and young adults)
• Mitotic rate may be brisk
• Occurs in superficial skin and mucosal sites
• Intravascular variant exists
○ Head and neck most common (particularly lip, gingiva,
nasal cavity) ANCILLARY TESTS
• Small (< 2.5 cm), red-purple, rapidly growing exophytic • CD31(+), CD34(+), ERG(+) in endothelial cells
nodule • SMA(+) pericytic cell population
○ Overlying mucosal surface often atrophic or ulcerated • GLUT1 and D2-40 (-)
○ May occur during pregnancy (granuloma gravidarum)
TOP DIFFERENTIAL DIAGNOSES
• Treatment: Simple excision
• Benign • Bacillary angiomatosis
○ Local recurrence is rare • Angiofibroma of soft tissue
• Angiosarcoma

Lobular Capillary Hemangioma Central Ectatic Vessels

(Left) Lobular capillary
hemangioma, also commonly
referred to as pyogenic
granuloma, is a common
benign vascular lesion that has
a predilection for the head and
neck region of children and
young adults. Tumors are well
circumscribed or demarcated
and often show surface
mucosal atrophy or ulceration.
(Right) A characteristic finding
in lobular capillary
hemangioma is the presence
of capillary channels arranged
around larger, dilated "feeder"
vessels ﬉.

Bland Endothelial Cell Lining Compressed Capillary Lumina

(Left) The capillary channels
are lined by small, benign
endothelial cells ﬈ that may
show, at most, mild nuclear
atypia. Mitotic activity can be
brisk, particularly in cases
associated with ulceration.
(Right) Vascular lumina may
not be readily apparent in
some cases of lobular capillary
hemangioma due to
compression of the capillary
channels ﬈. This change
varies in extent and may be
diffuse in larger cases.

420
 Lobular Capillary Hemangioma

Vascular Tumors (Including Lymphatics)

○ Endothelial cells usually bland but may show mild nuclear
TERMINOLOGY atypia
Synonyms ○ Capillaries may be compressed and lack visible lumina
• Pyogenic granuloma (PG) • Edematous to fibromyxoid stroma
• Mitotic rate may be brisk
Definitions
• Intravascular variant
• Clinically distinctive benign vascular lesion characterized by ○ Usually occurs within small veins
vague lobules of capillary channels arranged around larger ○ Histologically similar to conventional types
"feeder" vessels
ANCILLARY TESTS
CLINICAL ISSUES
Immunohistochemistry
Epidemiology
• CD31(+), CD34(+), ERG(+), WT1(+) in endothelial cells
• Incidence
• SMA(+) pericytic cell population
○ Common
• GLUT1 and D2-40 (-)
• Age
○ Wide range (common in children and young adults) DIFFERENTIAL DIAGNOSIS
• Sex
○ Slight male predominance Bacillary Angiomatosis
• May appear histologically similar to lobular capillary
Site hemangioma but with more solid growth pattern
• Superficial skin and mucosal sites • Plump endothelial cells with focally clear cytoplasm
○ Rarely subcutaneous or intravascular • Characteristically contains stromal neutrophilic
• Head and neck most common (particularly lip, gingiva, nasal microabscesses and foci of amorphous eosinophilic
cavity) extracellular material (contains bacillary organisms)
• Also upper extremity (mainly subcutaneous and
intravascular variants) and other sites Angiofibroma of Soft Tissue
• Most occur in extremities (rare in head and neck)
Presentation • Usually larger lesions than PG
• Small, red-purple, rapidly growing exophytic nodule • t(5;8) (p15;q13) with AHRR and NCOA2 genes
○ Overlying mucosal surface often atrophic or ulcerated
• Most are solitary; rarely multifocal Angiosarcoma
• Minority of cases associated with trauma • Usually poorly circumscribed with infiltrative growth
• May occur during pregnancy (granuloma gravidarum) • Malignant cytologic features

Treatment Cavernous Hemangioma

• Simple excision • Usually large and can occur in wide variety of locations,
including viscera
Prognosis • Contain large, dilated, thin-walled vessels separated by thin
• Benign bands of fibroconnective tissue
○ Do not generally spontaneously regress • Thrombosis and calcification are common
– Exception is granuloma gravidarum, which often
regresses following parturition SELECTED REFERENCES
• Local recurrence is rare 1. Johnson EF et al: Vascular tumors in infants: case report and review of
clinical, histopathologic, and immunohistochemical characteristics of
MACROSCOPIC infantile hemangioma, pyogenic granuloma, noninvoluting congenital
hemangioma, tufted angioma, and kaposiform hemangioendothelioma. Am
General Features J Dermatopathol. 40(4):231-239, 2018
2. Wollina U et al: Pyogenic granuloma - a common benign vascular tumor with
• Soft red lesion, often with friable overlying mucosa variable clinical presentation: new findings and treatment options. Open
Access Maced J Med Sci. 5(4):423-426, 2017
Size 3. Handra-Luca A et al: CD99 expression in nasal lobular capillary
• Usually < 2.5 cm haemangioma. Histopathology. 65(4):583-5, 2014
4. Puxeddu R et al: Lobular capillary hemangioma of the nasal cavity: a
○ Nasal cavity lesions may be larger retrospective study on 40 patients. Am J Rhinol. 20(4):480-4, 2006
5. Truss L et al: Deletion (21)(q21.2q22.12) as a sole clonal cytogenetic
MICROSCOPIC abnormality in a lobular capillary hemangioma of the nasal cavity. Cancer
Genet Cytogenet. 170(1):69-70, 2006
Histologic Features 6. Epivatianos A et al: Pyogenic granuloma of the oral cavity: comparative study
of its clinicopathological and immunohistochemical features. Pathol Int.
• Well circumscribed or demarcated 55(7):391-7, 2005
• Overlying squamous mucosa is often ulcerated with acute 7. Toida M et al: Lobular capillary hemangioma of the oral mucosa:
and chronic inflammation clinicopathological study of 43 cases with a special reference to
immunohistochemical characterization of the vascular elements. Pathol Int.
○ May show peripheral epidermal collarette 53(1):1-7, 2003
• Vague lobules of capillary channels organized around larger 8. Patrice SJ et al: Pyogenic granuloma (lobular capillary hemangioma): a
"feeder" vessels clinicopathologic study of 178 cases. Pediatr Dermatol. 8(4):267-76, 1991

421
 Epithelioid Hemangioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY
• Synonym: Angiolymphoid hyperplasia with eosinophilia
• Definition: Benign, likely neoplastic vascular proliferation
featuring epithelioid endothelial cells and usually
associated with stromal eosinophils
CLINICAL ISSUES
• Wide age range (most common: 20-50 years)
• Head and neck most common region (particularly around
ear)
○ Also distal extremities (digits)
• Usually solitary subcutaneous or dermal nodule
○ May be multifocal
• Treatment: Complete surgical excision
• Benign; local recurrence in up to 30%
MACROSCOPIC
• Usually small size (0.5-2.0 cm)
MICROSCOPIC
• Lobular proliferation of capillaries, often surrounding
central vessel
○ Capillaries lined by plump, epithelioid endothelial cells
– May appear to project into lumen of dilated channels
(hobnail or tombstone appearance)
• Usually abundant stromal chronic inflammation, particularly
eosinophils
• No necrosis; mitotic figures uncommon
ANCILLARY TESTS
• CD31(+), CD34(+), nuclear ERG(+) in endothelial cells
• FOS or FOSB gene rearrangements in subset
TOP DIFFERENTIAL DIAGNOSES
• Kimura disease
• Epithelioid hemangioendothelioma
• Epithelioid angiosarcoma

Epithelioid Hemangioma Typical Features

(Left) Epithelioid hemangioma
(EH) is a benign vascular
tumor that occurs most
commonly in the head and
neck region. At low power, it
typically shows a vaguely
lobular growth pattern and
may be associated with a
small artery or vein ſt. (Right)
The lesional endothelial cells
﬈ of EH are usually plump
and epithelioid and have
eosinophilic or amphophilic
cytoplasm. An associated brisk
chronic inflammatory
infiltrate is typical.

Epithelioid Cytomorphology Eosinophils

(Left) The lesional cells of EH
are plump and
ovoid/epithelioid and show a
single nucleus with a central
nucleolus. Mitotic figures ﬈
are usually sparse and
inconspicuous. Erythrocytes
are common given the
vascular origin of the tumor.
(Right) A brisk eosinophilic
infiltrate is characteristic of
EH; however, the eosinophils
may be sparse in some cases
(particularly dermal lesions).
Mast cells and plasma cells
may also be identified.

422
 Epithelioid Hemangioma

Vascular Tumors (Including Lymphatics)

– Epithelioid endothelial cells not always prominent
TERMINOLOGY
□ Lesional vascular channels may be lined by more
Abbreviations typical flattened endothelial cells
• Epithelioid hemangioma (EH) ○ Increased cellularity/density may be seen centrally in
some cases
Synonyms – Rare spindled cellular morphology
• Angiolymphoid hyperplasia with eosinophilia ○ Necrosis very rare
• Histiocytoid hemangioma • Usually abundant stromal chronic inflammation (may
Definitions obscure vascular channels)
○ Brisk eosinophilic infiltrate characteristic of most lesions
• Benign, likely neoplastic vascular proliferation featuring
epithelioid endothelial cells and usually associated with ○ Mostly lymphocytes but also mast cells, plasma cells
stromal eosinophils – Lymphoid tissue may form reactive germinal centers,
particularly at periphery of lesion
CLINICAL ISSUES • Rare tumors arise intravascularly
• Atypical features can be seen in FOSB-rearranged cases
Epidemiology ○ Solid growth, increased cellularity, focal necrosis,
• Age decreased inflammation, nuclear pleomorphism
○ Wide range (most common: 20-50 years) • Dermal lesions
• Sex ○ Less well defined at low magnification
○ Slight female predominance ○ Endothelial cells may be less plump
Site ○ Centralized vessels usually not present
○ Inflammatory infiltrate may be sparse
• Head and neck most common region
○ Particularly around ear
ANCILLARY TESTS
• Also distal extremities (digits)
• Other sites include bone, penis, oral cavity, lymph node Immunohistochemistry
• CD31(+), CD34(+), nuclear ERG(+) in endothelial cells
Presentation
• May show focal keratin (+)
• Usually solitary subcutaneous or dermal nodule
○ May be multiple within same region Molecular Genetics
○ Rare lesions arise in deep soft tissue • FOS gene rearrangements reported in up to 30% of cases
• Slow growing; may be ulcerated • Also, FOSB, FOSL1, and FOSL2 rearrangements
Treatment
DIFFERENTIAL DIAGNOSIS
• Complete surgical excision
○ Reexcision of local recurrences Kimura Disease
• Endemic in Asian population
Prognosis • Associated with lymphadenopathy, peripheral eosinophilia,
• Benign elevated serum IgE
○ Local recurrence in up to 30% • Prominent eosinophils; lacks epithelioid endothelial cells
○ No distant metastasis reported
Epithelioid Hemangioendothelioma
MACROSCOPIC • Usually larger tumors
• Cords of tumor cells in myxohyaline matrix
Size
• Well-formed, dilated capillary channels and chronic
• Usually small (0.5-2.0 cm) inflammatory component are not features

MICROSCOPIC Epithelioid Angiosarcoma

Histologic Features
• Most are nodular and well demarcated
• Lobular proliferation of capillaries, often surrounding
central vessel
○ Capillaries lined by plump, epithelioid endothelial cells
– Abundant eosinophilic or amphophilic cytoplasm
□ Can show vacuolization, ± erythrocytes
– May appear to project into lumen of dilated channels
(hobnail or tombstone appearance)
– Single large nucleus with fine chromatin and central
nucleolus
□ Nuclear pleomorphism usually absent
□ Mitotic figures uncommon
• Frank nuclear atypia, prominent macronucleoli, and
conspicuous mitotic activity
• Lacks characteristic inflammatory component of EH
• More conventional, complex interanastomosing or
dissecting growth pattern may be present
SELECTED REFERENCES
1. Ortins-Pina A et al: FOSB immunoreactivity in endothelia of epithelioid
hemangioma (angiolymphoid hyperplasia with eosinophilia). J Cutan Pathol.
45(6):395-402, 2018
2. Huang SC et al: Frequent FOS gene rearrangements in epithelioid
hemangioma: a molecular study of 58 cases with morphologic reappraisal.
Am J Surg Pathol. 39(10):1313-21, 2015
3. Antonescu CR et al: ZFP36-FOSB fusion defines a subset of epithelioid
hemangioma with atypical features. Genes Chromosomes Cancer.
53(11):951-9, 2014

423
 Epithelioid Hemangioma
Vascular Tumors (Including Lymphatics)

Hobnail Nuclei Cytoplasmic Vacuolization

(Left) Dilated vascular
channels in EH may be lined by
cuboidal or epithelioid
endothelial cells, imparting a
hobnail or tombstone
appearance. This finding is a
helpful clue to the diagnosis,
but it is not present in every
case. (Right) Cytoplasmic
vacuolization ﬈ is a common
finding in EH and may be
focally prominent. The
additional presence of
erythrocytes ﬊ indicates early
vasoformation.

Myopericytic Layer Present Cellular Foci

(Left) Although the vessels
appear immature in EH, they
are well formed, and all cases
show an intact layer of
myopericytic/smooth muscle
cells. In some cases, the
endothelial cells are more
flattened than epithelioid.
(Right) Some cases of EH
contain cellular foci that
appear as relatively solid
aggregates of epithelioid cells.
These foci, when present, are
more likely to be seen
centrally within the lesion.

Rare Spindled Foci Large Vessel Involvement

(Left) A spindled tumor cell
morphology ﬊ is a rare
finding in EH and is usually
focal when present. This
morphology is much more
common in EH of bone. (Right)
Lobules of lesional tissue may
be associated with an artery
or vein in EH. These vessels
may appear damaged or show
evidence of rupture.

424
 Epithelioid Hemangioma
Vessel Involvement
Vascular Lumina Chronic Inflammatory Infiltrate
Eosinophils Reactive Germinal Centers
Vascular Tumors (Including Lymphatics)
Dilated Vascular Lumina
(Left) The epithelioid
endothelial-lined vascular
channels ﬈ may also be seen
within the muscular wall of
the involved vessel and may
even communicate with the
lumen in some cases. (Right)
This H&E shows an EH with
prominent dilated and
irregular vascular channels,
reminiscent of the "staghorn"
vessels of a solitary fibrous
tumor. Hobnailed nuclei ﬈
are somewhat apparent at this
magnification.
(Left) Well-defined vascular
lumina are not always
identified in EH, as shown in
this H&E, and vascular origin
may be difficult to discern in
these cases. (Right) A chronic
inflammatory infiltrate is
common in EH and may be
quite prominent, particularly
at the periphery of the lesion.
Most of the cells are
lymphocytes, but eosinophils
are also usually prominent.
(Left) The inflammatory
stromal infiltrate may appear
diffuse in some foci of EH and
obscure the characteristic
epithelioid endothelial cells.
Note the admixed brisk
infiltrate of eosinophils, a
finding that should always
raise the possibility of EH.
(Right) The lymphoid tissue in
EH may show a formation of
reactive germinal centers ﬈.
This feature may be very
prominent and is often seen at
the periphery of the lesion.
425
 Spindle Cell Hemangioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY • Clear endothelial vacuoles common, often grouped

• Benign vascular tumor featuring both cavernous and
cellular, predominantly spindled zones
• Synonym: Spindle cell hemangioendothelioma (obsolete)
CLINICAL ISSUES
• Young adults
• Distal extremities, often acral
• Subcutaneous mass
• Often multifocal
• May be associated with Maffucci syndrome (multiple
enchondromas + spindle cell hemangioma)
MICROSCOPIC
• 2 zones
○ Large, dilated cavernous spaces
○ Solid areas of bland spindled and epithelioid endothelial
cells with slit-like vascular spaces
resembling clusters of small adipocytes
• Often arises from vessel; may be intravascular
• Minimal atypia or mitotic activity
• Large calcified thrombi (phleboliths) may be present
ANCILLARY TESTS
• Expression of vascular markers (CD31, CD34, ERG)
• Often have IDH1 (or IDH2) mutation
TOP DIFFERENTIAL DIAGNOSES
• Kaposi sarcoma (tumor stage)
• Kaposiform hemangioendothelioma
• Epithelioid hemangioendothelioma
• Organizing thrombus/intravascular papillary endothelial
hyperplasia
• Cavernous hemangioma (venous malformation)

Spindle Cell Hemangioma Cavernous and Cellular Zones

(Left) Spindle cell
hemangioma (SCH) is
classically characterized by
cavernous vascular spaces ﬈
adjacent to more cellular
zones of spindle and
epithelioid endothelial cells
﬇. (Right) The cavernous
vascular channels ﬈ of SCH
are essentially identical to
those of cavernous
hemangioma. The cellular
zones ﬇ are composed of
sheets of plump, spindled, and
epithelioid endothelial cells
that may bear some
resemblance to Kaposi
sarcoma.

Vacuolated Endothelial Cells Kaposi-Like Cellular Zones

(Left) Some of the endothelial
cells display clear cytoplasmic
vacuoles ﬈ and are often
clustered together within the
cellular zones creating a
striking resemblance to
entrapped groups of
miniaturized adipocytes. This
is a characteristic feature of
SCH. (Right) Cellular zones of
plump spindled and epithelioid
endothelial cells lack atypia or
significant mitotic activity in
SCH. Compressed vascular
channels ﬈ may resemble the
slit-like vascular spaces of
Kaposi sarcoma. Note the
vacuolated endothelial cells
﬉.

426
 Spindle Cell Hemangioma

Vascular Tumors (Including Lymphatics)

• Usually in either HIV(+) patients or in elderly
TERMINOLOGY
• Cavernous vascular channels are uncommon
Abbreviations • Greater cytologic atypia and more mitoses than SCH
• Spindle cell hemangioma (SCH) • More prominent slit/sieve-like vascular channels with
abundant erythrocyte extravasation
Synonyms
• Plasma cells almost always present
• Spindle cell hemangioendothelioma (obsolete term) • HHV-8 (LANA1) (+) by immunohistochemistry
Definitions Kaposiform Hemangioendothelioma
• Benign vascular tumor featuring both cavernous and • Almost exclusively in children
cellular, predominantly spindled zones • Glomeruloid nodules of spindled endothelial cells
• Usually lacks cavernous areas
CLINICAL ISSUES
• Associated with Kasabach-Merritt phenomenon
Epidemiology
Epithelioid Hemangioendothelioma
• Age
• Cords of epithelioid endothelial cells; usually lacks well-
○ Young adults
formed vascular channels
Site • Endothelial vacuoles contain erythrocyte fragments
• Distal extremities, often acral ("blister" cells)
• Characteristic myxohyaline stroma
Presentation • Lacks cavernous spaces
• Subcutaneous mass
• Often multifocal
Organizing Thrombus/Intravascular Papillary
• May be associated with Maffucci syndrome (multiple Endothelial Hyperplasia
enchondromas + SCH), Klippel-Trenaunay syndrome, • Spindled areas have myxoid background and merge with
varicosities, and congenital lymphedema fibrin
• Spindled areas are within cavernous vascular spaces rather
Treatment than adjacent
• Simple surgical excision • Papillary architecture of endothelial cells overlying fibrin
Prognosis cores
• Lacks clusters of adipocyte-like vacuoles
• Regional "recurrence" most likely multifocal disease and
not true recurrence Cavernous Hemangioma (Venous Malformation)
• No metastatic potential • Lacks cellular spindled and epithelioid zone

MICROSCOPIC DIAGNOSTIC CHECKLIST

Histologic Features
• 2 distinct zones characteristic
○ Large, dilated cavernous spaces
– Large thrombi, often calcified (phleboliths), may be
present
○ Solid, cellular areas of bland, spindled, and epithelioid
endothelial cells with slit-like vascular spaces
– Clear endothelial vacuoles common, often grouped
resembling clusters of small adipocytes
• Often arises from vessel; may be intravascular
• Minimal atypia or mitotic activity
ANCILLARY TESTS
Immunohistochemistry
• CD34(+), CD31(+), ERG(+)
• HHV-8(-)
Genetic Testing
• IDH1 (or IDH2) mutation common in both sporadic and
Maffucci-associated SCH
○ These mutations are absent in other vascular lesions
DIFFERENTIAL DIAGNOSIS
Kaposi Sarcoma (Tumor Stage)
• Usually dermal based rather than subcutaneous
Pathologic Interpretation Pearls
• 2 zones
○ Cavernous spaces
○ Cellular spindled and epithelioid cells
• Clustered vacuoles resemble miniature fat cells; very
characteristic
SELECTED REFERENCES
1. Ten Broek RW et al: Mutational analysis using Sanger and next generation
sequencing in sporadic spindle cell hemangiomas: a study of 19 cases. Genes
Chromosomes Cancer. 56(12):855-60, 2017
2. Kurek KC et al: R132C IDH1 mutations are found in spindle cell
hemangiomas and not in other vascular tumors or malformations. Am J
Pathol. 182(5):1494-500, 2013
3. Perkins P et al: Spindle cell hemangioendothelioma. An analysis of 78 cases
with reassessment of its pathogenesis and biologic behavior. Am J Surg
Pathol. 20(10):1196-204, 1996
4. Fanburg JC et al: Multiple enchondromas associated with spindle-cell
hemangioendotheliomas. An overlooked variant of Maffucci's syndrome.
Am J Surg Pathol. 19(9):1029-38, 1995
5. Fletcher CD et al: Spindle cell haemangioendothelioma: a clinicopathological
and immunohistochemical study indicative of a non-neoplastic lesion.
Histopathology. 18(4):291-301, 1991
6. Weiss SW et al: Spindle cell hemangioendothelioma. A low-grade
angiosarcoma resembling a cavernous hemangioma and Kaposi's sarcoma.
Am J Surg Pathol. 10(8):521-30, 1986
427
 Spindle Cell Hemangioma
Vascular Tumors (Including Lymphatics)

Violaceous Dermal Papule Cavernous Spaces

(Left) SCH may present as a
dermal or subcutaneous mass,
usually on the distal
extremities. More superficial
lesions like this example may
have a violaceous appearance.
(Courtesy C. Montgomery,
MD.) (Right) The cavernous
vascular channels of SCH are
lined by bland endothelium.
They are essentially identical
to those seen in cavernous
hemangioma.

Calcified Thrombi (Phleboliths) Origin From Thick-Walled Vessel

(Left) Large fibrin thrombi
with secondary calcification
(phleboliths) are commonly
present within the cavernous
spaces ﬈ of SCH. (Right) SCH
often arises from a thick-
walled muscular vessel ﬊.
Intravascular tumor growth
﬉ may be seen; this is not an
indication of malignancy or
aggressive behavior.

Clear Cytoplasmic Vacuoles Vacuolated Endothelial Cells

(Left) In the cellular areas of
SCH, the spindled and
epithelioid endothelial cells
often display clear cytoplasmic
vacuoles ﬈. These should not
be confused with the
vacuolated "blister" cells of
epithelioid
hemangioendothelioma, which
are usually smaller and can
contain erythrocyte
fragments. (Right) Vacuolated
endothelial cells can
occasionally be quite
numerous and prominent in
SCH, as depicted in this H&E.

428
 Spindle Cell Hemangioma
Kaposi-Like Areas
Maffucci Syndrome
Maffucci Syndrome MR of Maffucci Syndrome
Vascular Tumors (Including Lymphatics)
Kaposi-Like Areas
(Left) The cellular zones of
SCH are composed of both
spindled ﬈ and epithelioid ﬊
endothelial cells. Blood-filled
compressed vascular channels
are seen ﬈, but unlike Kaposi
sarcoma, extravasation of
erythrocytes is usually
minimal. (Right) Even in the
absence of detectable
vasoformation, relatively solid
areas like this can resemble
the infiltrative spindled
morphology of Kaposi
sarcoma.
Maffucci Syndrome
(Left) This patient with
Maffucci syndrome has
multiple SCHs of the right foot
﬈. Radiographic studies also
revealed multiple
enchondromas in the foot, leg,
and pelvis. (Courtesy C.
Montgomery, MD.) (Right)
Plain radiograph of the foot in
a patient with Maffucci
syndrome shows multiple
expansile lytic bone lesions
consistent with enchondromas
in the phalanges ſt.
(Left) MR of a patient with
Maffucci syndrome displays
hyperintense bone lesions
consistent with enchondromas
﬈ in the calcaneus and distal
tibia. The hyperintense plantar
subcutaneous nodule is an
SCH ﬊. (Right) STIR MR of a
patient with Maffucci
syndrome suppresses the
subcutaneous fat signal,
allowing for better
visualization of multiple
subcutaneous SCHs of the
lateral plantar foot ﬊.
429
 Intramuscular Hemangioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY
• Benign vascular proliferation located within skeletal muscle
with varying amounts of mature adipose tissue
• Synonyms: Infiltrating (intramuscular) angiolipoma,
intramuscular angioma
ETIOLOGY/PATHOGENESIS
• Likely represents vascular malformation
CLINICAL ISSUES
• 85% diagnosed prior to 30 years of age
• Most commonly arises in skeletal muscle of thigh
○ Other common sites: Head and neck, upper extremities,
trunk
• Deep-seated, slow-growing mass
○ Frequently associated with pain
• Treatment: Complete surgical excision
• Significant recurrence rate (30-50%)
MACROSCOPIC
• Ill-defined mass within skeletal muscle
• Wide size range: 1-29 cm; mean size: 6.5 cm
MICROSCOPIC
• Vary greatly in histologic appearance
• Typically consist of mixture of thick-walled veins; arteries;
capillaries; and ectatic, thin-walled vascular spaces
○ Historically classified into capillary, cavernous, and mixed
types
• Associated with varying amounts of mature adipose tissue
• Vascular and adipose elements infiltrate among skeletal
muscle fibers
TOP DIFFERENTIAL DIAGNOSES
• Angiosarcoma
• Angiomatosis
• Angiolipoma

Intramuscular Hemangioma Intramuscular Hemangioma

(Left) Gross photograph of
intramuscular hemangioma
(IMH) demonstrates a solid,
tan mass involving skeletal
muscle st. The lesion has an
irregular border with the
muscle, and there are grossly
evident, large vascular
structures ﬇. (Right) The
typical case of IMH shows a
complex mixture of blood
vessels, including large, ectatic
vessels ﬈ and capillaries ﬉
and adipose tissue that
appears to infiltrate skeletal
muscle ﬇.

Skeletal Muscle Infiltration Mature Adipose Tissue

(Left) Infiltration of skeletal
muscle is a common feature of
IMH with capillary-sized
vessels arranged in between
skeletal muscle fibers. Note
the overall checkerboard
appearance, a common
occurrence. (Right) Mature
adipose tissue is a common
feature of IMH and may be
abundant in some cases. The
presence of fat accounts for
the previous designation as an
infiltrating or intramuscular
angiolipoma.

430
 Intramuscular Hemangioma

Vascular Tumors (Including Lymphatics)

TERMINOLOGY Size
• Wide range: 1-29 cm; mean: 6.5 cm
Abbreviations
• Intramuscular hemangioma (IMH) MICROSCOPIC
Synonyms Histologic Features
• Intramuscular angioma • Vary greatly in histologic appearance
• Infiltrating/intramuscular angiolipoma ○ Typically consist of mixture of thick-walled veins; arteries;
capillaries; and ectatic, thin-walled vascular spaces
Definitions
– Tumors may also have lymphatic component
• Benign vascular proliferation located within skeletal muscle
○ Associated with varying amounts of mature adipose
with varying amounts of mature adipose tissue
tissue
○ Vascular and adipose elements infiltrate among skeletal
ETIOLOGY/PATHOGENESIS muscle fibers
Developmental Anomaly – Pattern of infiltration may appear checkerboard-like
• Likely represents vascular malformation – Muscle atrophy and degenerative sarcolemmal
• No relation to trauma changes may be seen
• Historically classified into capillary, cavernous, and mixed
CLINICAL ISSUES types (latter most common)
○ Capillary type
Epidemiology
– More frequent in head and neck sites
• Incidence – Composed of numerous small (capillary-sized) vessels
○ Uncommon – Lumen formation typically apparent
• Age – Solid growth akin to juvenile hemangiomas may be
○ Most occur in young adults, but all ages affected seen
– 85% diagnosed prior to 30 years – Endothelial cells are plump and cytologically bland
Site with rare mitoses
○ Cavernous type
• Most frequent in skeletal muscle of lower extremities
– More common in trunk locations
○ Thigh is most common site
– Endothelial cells are attenuated and cytologically
• Other common sites: Head and neck, upper extremities,
bland
trunk
• Presurgical embolization may result in secondary changes
• Can also arise in cardiac muscle
and presence of embolization material
Presentation
• Deep-seated, slow-growing mass DIFFERENTIAL DIAGNOSIS
• Frequently associated with pain Angiosarcoma
○ Pain often occurs during exercise • Very uncommon in deep-seated locations
Treatment • Complex anastomosing vascular channels
• Complete surgical excision • Multilayered endothelial cells, often with pleomorphic and
hyperchromatic nuclei
Prognosis
Angiomatosis
• Benign; no risk of malignant transformation
• Significant recurrence rate (30-50%) • Histologically identical to IMH in many cases, so distinction
is clinical
○ Often secondary to incomplete excision
• Usually congenital
○ Histologic parameters (e.g., vessel type) not predictive of
recurrence risk • Involves large region of body and multiple tissues (e.g., skin,
muscle, and bone)
IMAGING Angiolipoma
Radiographic Findings • Small and well circumscribed; often multiple
• Intramuscular soft tissue mass • Arises in subcutaneous tissue
○ Fatty areas will appear low density on CT • Capillary channels contain fibrin thrombi
• Frequently show foci of calcification
○ Phleboliths or metaplastic ossification SELECTED REFERENCES
1. Patnaik S et al: Intramuscular arteriovenous hemangioma of thigh: a case
report and review of literature. J Orthop Case Rep. 6(5):20-23, 2016
MACROSCOPIC
2. Yilmaz S et al: Intramuscular capillary-type hemangioma: radiologic-
General Features pathologic correlation. Pediatr Radiol. 44(5):558-65, 2014
3. Beham A et al: Intramuscular angioma: a clinicopathological analysis of 74
• Ill-defined mass within skeletal muscle cases. Histopathology. 18(1):53-9, 1991
• Color varies depending on cellularity, vessel type, and 4. Cohen AJ et al: Intramuscular hemangioma. JAMA. 249(19):2680-2, 1983
amount of adipose tissue

431
 Intramuscular Hemangioma
Vascular Tumors (Including Lymphatics)

Intramuscular Hemangioma Dense Growth

(Left) Hematoxylin and eosin
of IMH demonstrates
scattered large blood vessels
﬈ mixed in with dense zones
﬇ of small capillary channels,
all proliferating around and in
between mature skeletal
muscle fibers. (Right)
Capillary- and mixed-types
IMH may show large zones of
dense capillary channels,
which at low magnification
can raise concerns for a
sarcoma. The impression of
infiltrated adipose tissue and
skeletal muscle may amplify
this concern if the pathologist
is not aware of this entity.

Benign Cytologic Features Abundant Mature Adipose Tissue

(Left) The endothelial cells in
all types of IMH are
cytologically bland and lack
nuclear pleomorphism and
malignant atypia. In some
cases, capillary lumina ﬊ are
inconspicuous, as in this
hematoxylin and eosin. (Right)
Some cases of IMH contain
abundant mature adipose
tissue and a comparatively
small vascular component,
potentially leading to
consideration of an
intramuscular lipoma or an
angiolipoma.

Degenerative Skeletal Muscle Fibers Degenerative Skeletal Muscle Fibers

(Left) Small, entrapped
myocytes ﬇ with
degenerative/reactive
sarcolemmal changes may be
seen in some cases of IMH.
(Right) High-power
examination shows the
features of a
degenerative/reactive
myocyte ﬉ in IMH, including
dense eosinophilic cytoplasm
and multiple, small
hyperchromatic nuclei in
clusters ("grapes") and
peripheral ring-like
arrangements. This finding can
also be seen in other
intramuscular tumors.

432
 Intramuscular Hemangioma
Cavernous Intramuscular Hemangioma
Lobulated Growth
Embolization Material
Vascular Tumors (Including Lymphatics)
Cavernous Intramuscular Hemangioma
(Left) Cavernous IMH is
characterized by ectatic, thin-
walled vascular spaces with
associated adipose tissue ﬊
and infiltrating within
degenerating skeletal muscle
﬉. (Right) Cavernous IMHs
are frequently associated with
an irregular proliferation of
smooth muscle bundles ﬊
and smaller, slit-like vascular
channels ﬉ at the periphery
of the larger, ectatic vessels
﬈.
Secondary Changes
(Left) Some IMHs have a
lobulated appearance,
imparting a resemblance to
lobular capillary hemangioma.
The lobules in this example are
composed of numerous small
capillaries with larger, feeder-
type vascular channels ﬉.
(Right) Secondary changes are
common in IMH. Note the
compressed and atrophic
skeletal muscle bundles ﬉ in
this cavernous IMH. Cavernous
examples frequently develop
thrombi ﬊ that may calcify
and become phleboliths.
Imaging Characteristics
(Left) Many cases of suspected
IMH are embolized prior to
resection and show
embolization material and
thrombus formation in vessels
﬊ with secondary
inflammation &/or necrosis.
(Right) Axial CT through the
midthigh shows phleboliths ﬈
within an IMH. The low-
density areas ﬇ represent fat
within the lesion.
433
 Hobnail Hemangioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY MICROSCOPIC
• Synonym: Targetoid hemosiderotic hemangioma • Vascular proliferation with wedge-shaped appearance
• Definition: Benign vascular proliferation, typically wedge- • Superficial vessels are dilated and thin walled
shaped, showing intravascular papillae and hobnail • Deeper vessels are progressively smaller
endothelial cells • Vessels are lined by small, bland-appearing endothelial cells
ETIOLOGY/PATHOGENESIS with hobnail appearance
• Focal papillary projections with fibrous cores may be
• Postulated to represent traumatized lymphangioma or
present
hemangioma
• Hemorrhage and hemosiderin deposition are typically
CLINICAL ISSUES prominent
• Typically presents on lower extremities; may also occur on • Inflammation is usually minimal
upper extremities, rarely in oral cavity TOP DIFFERENTIAL DIAGNOSES
• Young to middle-aged adults
• Progressive lymphangioma
• More common in male patients
• Kaposi sarcoma
• Often pigmented due to hemosiderin deposition
• Microvenular hemangioma
• May show halo (targetoid appearance) in minority of cases
• Retiform hemangioendothelioma
• Excellent prognosis

Hobnail Hemangioma Dilated Vascular Spaces

(Left) Low magnification of a
hobnail hemangioma shows
superficial dilated vascular
spaces ﬊ in the papillary
dermis with deeper small
blood vessels and stromal
hemosiderin deposits ﬈.
(Right) Higher magnification
of the superficial portion of
the tumor shows small
endothelial cells protruding
into the dilated vascular
spaces ﬊.

Hobnail Endothelial Cells Hemosiderin Deposition

(Left) High-power examination
demonstrates superficial
dilated vessels lined by small
endothelial cells protruding
into the lumina ﬈ and
showing nuclear
hyperchromasia. (Right)
Histologic examination of the
deeper aspect of the lesion
shows smaller blood vessels
﬊ and prominent hemosiderin
deposition in the stroma ﬈.

434
 Hobnail Hemangioma

Vascular Tumors (Including Lymphatics)

• Deeper vessels are progressively smaller and show narrow
TERMINOLOGY lumina
Abbreviations • Hemorrhage and hemosiderin deposition are typically
• Hobnail hemangioma (HH) prominent
• Inflammation is usually minimal
Synonyms
• Targetoid hemosiderotic hemangioma (clinical term) DIFFERENTIAL DIAGNOSIS
Definitions Progressive Lymphangioma
• Benign vascular proliferation, typically wedge-shaped, • Thin-walled, dilated, superficial vascular spaces with
showing intravascular papillae and hobnailed endothelial narrower deeper vessels
cells • Lacks hobnail endothelial cell morphology and hemosiderin
deposition of HH
ETIOLOGY/PATHOGENESIS
Kaposi Sarcoma
Unknown • Shows proliferation of slit-like spaces lined by atypical
• Trauma has been implicated in some cases spindle cells
○ Postulated to represent traumatized lymphangioma or • Typically lacks superficial, dilated vascular spaces and
hemangioma hobnail cells
• HHV8(+) by immunohistochemistry
CLINICAL ISSUES
Microvenular Hemangioma
Epidemiology
• Proliferation of small, round to slit-like, thin-walled vessels
• Age involving reticular dermis
○ Young to middle-aged adults • Lacks superficial, dilated vascular spaces, hobnail cells, and
• Sex hemosiderin deposition
○ M>F
Retiform Hemangioendothelioma
Site • Dermal and subcutaneous tumor characterized by
• Typically presents on lower extremities; also may occur on proliferation of arborizing vessels lined by hobnail
upper extremities, rarely in oral cavity endothelial cells
Presentation • Typically prominent lymphoid infiltrate, which is lacking in
HH
• Skin papule or nodule
• HH is usually more superficial, and deeper vessels are
○ Often pigmented due to hemosiderin deposition smaller and compact
○ May show halo (targetoid appearance) but only in
minority of cases DIAGNOSTIC CHECKLIST
Treatment Pathologic Interpretation Pearls
• Complete, conservative excision • Wedge-shaped vascular proliferation
Prognosis • Dilated, superficial vessels, deeper small/collapsed vessels
• Excellent with no tendency for local recurrence • Intravascular papillae and hobnail endothelial cells
• Prominent hemosiderin deposition
MACROSCOPIC
SELECTED REFERENCES
General Features
1. Biondo G et al: A pigmented papule acting like a playful ghost: dermoscopy
• Dermal-based, reddish-brown lesion with hemorrhage of three targetoid hemosiderotic hemangiomas. G Ital Dermatol Venereol.
153(5):685-91, 2018
Size 2. Porriño-Bustamante ML et al: Hobnail hemangioma with an unusual clinical
presentation. J Cutan Med Surg. 21(2):164-6, 2017
• Small, usually < 2 cm
3. Joyce JC et al: Superficial hemosiderotic lymphovascular malformation
(hobnail hemangioma): a report of six cases. Pediatr Dermatol. 31(3):281-5,
MICROSCOPIC 2014
4. Kim DS et al: Multiple hobnail hemangiomas. Int J Dermatol. 53(4):e240-2,
Histologic Features 2014
• Vascular proliferation with wedge-shaped appearance 5. Hejnold M et al: Hobnail hemangioma: a immunohistochemical study and
literature review. Pol J Pathol. 63(3):189-92, 2012
• Superficial vessels are dilated and thin walled 6. Trindade F et al: Hobnail hemangioma reclassified as superficial lymphatic
○ Some vessels may resemble lymphatics malformation: a study of 52 cases. J Am Acad Dermatol. 66(1):112-5, 2012
○ Focal papillary projections with fibrous cores may be 7. Fernandez-Flores A et al: Clinical changes in "true" hobnail hemangioma
during menstruation. Bratisl Lek Listy. 109(3):141-3, 2008
present
8. Franke FE et al: Hobnail hemangiomas (targetoid hemosiderotic
○ Vessels are lined by small, uniform, bland-appearing hemangiomas) are true lymphangiomas. J Cutan Pathol. 31(5):362-7, 2004
endothelial cells with hobnail appearance (nuclei project 9. Pabuccuoğlu U et al: Hobnail haemangioma occurring on the nasal dorsum.
into lumina) Br J Dermatol. 146(1):162-4, 2002
10. Santonja C et al: Hobnail hemangioma. Dermatology. 191(2):154-6, 1995
○ Mitoses usually not present

435
 Acquired Tufted Angioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY
• Acquired tufted angioma (ATA)
• Synonym: Angioblastoma (of Nakagawa)
• Definition: Multiple cannonball-like, cellular collections of
small vessels in dermis
ETIOLOGY/PATHOGENESIS
• Most cases sporadic; rare familial cases described
• Some cases associated with pregnancy or liver
transplantation
CLINICAL ISSUES
• Rare tumors
• Mostly occur in children and young adults
• Neck, shoulders, and upper trunk most common sites
• Slowly growing erythematous macules and plaques
• May be associated with Kasabach-Merritt syndrome
(consumptive coagulopathy)
MICROSCOPIC
• Scattered, lobular collections of small, capillary-type vessels
throughout dermis; may involve subcutis
• Cleft-like lumina often present around capillary tufts; may
impart glomerular appearance
• Cells are oval to spindle-shaped
• Mitoses may be present but cells lack significant cytologic
atypia or pleomorphism
• Hemosiderin deposition may be seen
• Inflammation typically not present
TOP DIFFERENTIAL DIAGNOSES
• Lobular capillary hemangioma
• Glomeruloid hemangioma
• Infantile (juvenile) hemangioma
• Kaposiform hemangioendothelioma
• Kaposi sarcoma

Acquired Tufted Angioma Lobules and Nests of Vessels

(Left) Acquired tufted
angioma (ATA) is a benign
vascular proliferation that
usually arises in the dermis. At
low magnification, ATA shows
a diffuse, lobular, dermal
proliferation of blood vessels.
(Right) Intermediate-
magnification view of ATA
shows a diffuse, dermal
proliferation of small, lobular
or nested clusters of blood
vessels. A cannonball-like
appearance, as depicted, is
typical.

Collapsed, Slit-Like Lumina Bland Cytologic Features

(Left) Higher magnification
shows a lobular cluster of
blood vessels lined by small,
oval to spindle-shaped cells.
Lumina are collapsed and slit-
like ﬊. (Right) High-power
view shows bland cytologic
features of the tufted
angioma endothelial cells.
Some of the cells show mild
nuclear hyperchromasia ﬇,
but no significant cytologic
atypia is identified.

436
 Acquired Tufted Angioma

Vascular Tumors (Including Lymphatics)

• Inflammation typically not present
TERMINOLOGY
• Subcutaneous tissue usually not involved
Abbreviations
• Acquired tufted angioma (ATA) DIFFERENTIAL DIAGNOSIS
Synonyms Lobular Capillary Hemangioma
• Tufted angioma, angioblastoma (of Nakagawa) • Shows exophytic appearance and epidermal collarette,
often ulcerated and acutely inflamed
Definitions • Proliferation of small, capillary-type blood vessels typically
• Multiple scattered, cannonball-like, cellular collections of arranged in a few larger, nodular collections rather than
small vessels in dermis multiple smaller, dispersed collections seen in ATA

ETIOLOGY/PATHOGENESIS Glomeruloid Hemangioma

• Usually associated with Castleman disease or POEMS
Unknown syndrome (polyneuropathy, organomegaly,
• Most cases sporadic; rare familial cases described endocrinopathy, M-protein, skin changes)
• Some cases associated with pregnancy or liver • Smaller, capillary-like collections inside vascular spaces with
transplantation clefts around them
• PAS(+) cytoplasmic globules (immunoglobulin aggregates)
CLINICAL ISSUES
Infantile (Juvenile) Hemangioma
Epidemiology • Cellular, dermal nodules composed of lobular collections of
• Incidence oval endothelial cells
○ Rare tumors • Vascular lumina often small and slit-like, become larger,
• Age later stage lesions
○ Children and young adults • GLUT1(+)
Site Kaposiform Hemangioendothelioma
• Neck, shoulders, and upper trunk most common • May exist on clinical and morphologic spectrum with ATA
Presentation ○ Similar or identical histologic features to ATA; very similar
demographics & clinical features between both entities
• Slow growing; erythematous macules and plaques
– However, kaposiform hemangioendothelioma often
Prognosis larger than ATA and may be deeply located
• Excellent; completely benign behavior Kaposi Sarcoma
• May be associated with Kasabach-Merritt syndrome • Proliferation of interlacing bundles of spindle cells forming
(consumptive coagulopathy) slit-like, vascular spaces
• Cytoplasmic hyalinized globules, plasma cells, and
MACROSCOPIC hemosiderin deposits typically present
General Features • HHV8(+) by immunohistochemistry
• Reddish brown, nonencapsulated, dermal lesion
DIAGNOSTIC CHECKLIST
Size
Pathologic Interpretation Pearls
• Typically small papules but may be large plaque
• Multiple scattered, cannonball-like, lobular collections of
MICROSCOPIC small-capillary-type vessels throughout dermis

Histologic Features SELECTED REFERENCES

• Multiple scattered, lobular collections of small, capillary-
type vessels throughout dermis
○ Typical cannonball-like appearance at low magnification
○ Collections are larger in middle and lower dermis
○ Cleft-like lumina often present around capillary tufts;
may impart glomerular appearance
○ Capillaries may be so closely packed that lumina may be
inconspicuous
○ Cells are oval to spindle-shaped
○ May show nuclear hyperchromasia but lack significant
cytologic atypia or pleomorphism
○ A few mitoses may be present
• Hemosiderin deposition may be seen
1. Marušić Z et al: Histopathology of spindle cell vascular tumors. Surg Pathol
Clin. 10(2):345-66, 2017
2. Croteau SE et al: The clinical spectrum of kaposiform
hemangioendothelioma and tufted angioma. Semin Cutan Med Surg.
35(3):147-52, 2016
3. Pesapane F et al: A case of acquired tufted angioma in adulthood. An Bras
Dermatol. 90(3 Suppl 1):16-8, 2015
4. Omori M et al: Acquired tufted angioma in pregnancy showing expression of
estrogen and progesterone receptors. Eur J Dermatol. 23(6):898-9, 2013
5. Arai E et al: Usefulness of D2-40 immunohistochemistry for differentiation
between kaposiform hemangioendothelioma and tufted angioma. J Cutan
Pathol. 33(7):492-7, 2006
6. Igarashi M et al: The relationship between angioblastoma (Nakagawa) and
tufted angioma: report of four cases with angioblastoma and a literature-
based comparison of the two conditions. J Dermatol. 27(8):537-42, 2000
7. Kleinegger CL et al: Acquired tufted angioma: a unique vascular lesion not
previously reported in the oral mucosa. Br J Dermatol. 142(4):794-9, 2000

437
 Microvenular Hemangioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY MICROSCOPIC
• Synonym: Microcapillary angioma • Poorly circumscribed dermal proliferation of small blood
• Definition: Slow-growing, benign vascular proliferation vessels that diffusely involve reticular dermis
composed of small, collapsed vessels ○ Branching vessels typically present
○ Most vessels show narrow or collapsed lumina
ETIOLOGY/PATHOGENESIS
• Endothelial cells may be slightly enlarged but lack
• Some cases reportedly related to pregnancy or significant cytologic atypia
contraceptives
• Tufted groups of vessels may be seen in deep dermis
CLINICAL ISSUES • Background of mild dermal sclerosis
• Young to middle-aged adults • Inflammation and hemosiderin deposition typically lacking
• Typically occurs on upper extremities, especially forearms TOP DIFFERENTIAL DIAGNOSES
• Slow-growing papule or nodule
• Kaposi sarcoma
○ Often present only several weeks to months at
• Stasis changes/stasis dermatitis
presentation
• Hobnail hemangioma (targetoid hemosiderotic
• Simple excision is curative but not necessary
hemangioma)
• Benign; excellent prognosis
• Early scar

Microvenular Hemangioma Branching and Narrow Lumina

(Left) Scanning magnification
shows a diffuse dermal
proliferation of small,
elongated blood vessels with
narrow to collapsed ﬈ lumina
and a background of dermal
sclerosis. (Right) Higher
magnification shows increased
numbers of small blood vessels
in the superficial dermis with
irregular branching ﬉ and
narrow lumina.

Sclerotic Stroma Bland Cytologic Features

(Left) Higher magnification of
microvenular hemangioma
shows a proliferation of small
blood vessels with thin walls
and small to collapsed lumina
﬊ associated with a sclerotic
stroma. (Right) High-power
examination of microvenular
hemangioma shows bland
cytologic features of the
endothelial cells with small,
hyperchromatic-staining
nuclei. No evidence of mitotic
activity or necrosis are
identified.

438
 Microvenular Hemangioma

Vascular Tumors (Including Lymphatics)

• Inflammation and hemosiderin deposition typically lacking
TERMINOLOGY
Abbreviations ANCILLARY TESTS
• Microvenular hemangioma (MVH) Immunohistochemistry
Synonyms • HHV8 and D2-40 (podoplanin) (-)
• Microcapillary angioma
DIFFERENTIAL DIAGNOSIS
Definitions
Kaposi Sarcoma
• Slow-growing, benign vascular proliferation composed of
small, collapsed vessels • Usually shows infiltrative, thin-walled vessels
• Irregular anastomosing spaces lined by atypical spindle cells
ETIOLOGY/PATHOGENESIS • Plasma cells and hyaline globules are seen (lacking in MVH)
• HHV-8(+) by immunohistochemistry
Unknown
• In most cases Targetoid Hemosiderotic Hemangioma (Hobnail
Hemangioma)
Hormonal Influence
• While deeper small vessels are similar to those in MVH,
• Some cases reportedly related to pregnancy or superficial vessels are larger and dilated
contraceptives • Hobnailed endothelial cells project into vascular lumina
• Hemosiderin deposition is typically very prominent
CLINICAL ISSUES
Stasis Changes/Stasis Dermatitis
Epidemiology
• Superficial proliferation of clustered small, thick-walled
• Age
blood vessels
○ Young to middle-aged adults
• Usually shows hemosiderin deposition throughout dermis
• Sex (lacking in MVH)
○ Occurs in both male and female patients about equally • Often shows more inflammation and overlying spongiosis
Site (stasis dermatitis)
• Typically occurs on upper extremities, especially forearms • Clinical presentation distinctive: Lower extremities of
elderly adults
Presentation
Early Scar
• Slow-growing papule or nodule
• Angiogenesis in early scars may mimic MVH
Natural History • Typically greater fibrosis, inflammation, extravasated red
• Often present for only several weeks to months at blood cells, and hemosiderin deposition in scars
presentation
DIAGNOSTIC CHECKLIST
Treatment
• Simple excision is curative but not necessary, as these are Pathologic Interpretation Pearls
benign lesions • Benign vascular proliferation composed of small, collapsed
vessels
Prognosis
• Branching vessels typically present
• Excellent • Endothelial cells may be enlarged but lack cytologic atypia
• Background of mild dermal sclerosis
MACROSCOPIC
Size SELECTED REFERENCES
• Small, typically < 1 cm 1. Giacaman A et al: Microvenular hemangioma: morphological study of 3
cases. Actas Dermosifiliogr. 109(4):381-4, 2018
2. Juan YC et al: A microvenular hemangioma with a rare expression of
MICROSCOPIC progesterone receptor immunocreativity and a review of the literature. J
Cutan Pathol. 45(11):847-50, 2018
Histologic Features 3. Mansur AT et al: An unusual lesion on the nose: microvenular hemangioma.
• Poorly circumscribed dermal proliferation of small blood Dermatol Pract Concept. 8(1):7-11, 2018
vessels that diffusely involve reticular dermis 4. Napekoski KM et al: Microvenular hemangioma: a clinicopathologic review of
13 cases. J Cutan Pathol. 41(11):816-22, 2014
○ Branching vessels typically present 5. Linos K et al: Microvenular hemangioma presenting with numerous bilateral
○ Most vessels show narrow or collapsed lumina macules, patches, and plaques: a case report and review of the literature.
– Several erythrocytes may be present with lumina Am J Dermatopathol. 35(1):98-101, 2013
6. Chang SE et al: Microvenular hemangioma in a boy with acute myelogenous
○ Endothelial cells may be slightly enlarged, but they show leukemia. Pediatr Dermatol. 20(3):266-7, 2003
bland nuclei without significant atypia or pleomorphism 7. Kim YC et al: Microvenular hemangioma. Dermatology. 206(2):161-4, 2003
○ Some cases may show large epithelioid cells resembling 8. Rikihisa W et al: Microvenular haemangioma in a patient with Wiskott-Aldrich
those seen in epithelioid (histiocytoid) hemangiomas syndrome. Br J Dermatol. 141(4):752-4, 1999
9. Hunt SJ et al: Acquired benign and "borderline" vascular lesions. Dermatol
• Tufted groups of vessels may be seen in deep dermis Clin. 10(1):97-115, 1992
• Background of mild dermal sclerosis 10. Hunt SJ et al: Microvenular hemangioma. J Cutan Pathol. 18(4):235-40, 1991

439
 Sinusoidal Hemangioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY MICROSCOPIC
• Acquired vascular lesion in adults with features similar to • Well-circumscribed vascular proliferation
venous malformation (cavernous hemangioma) • Vessels are thin-walled and closely packed with little
intervening stroma
ETIOLOGY/PATHOGENESIS
• Lining cells are small endothelial cells with nuclear
• May represent reactive vascular proliferation rather than hyperchromasia
true neoplastic process
• Pseudopapillary pattern may be seen (due to tangential
CLINICAL ISSUES sectioning)
• Typically occurs in adult female patients • Some cases may show smooth muscle in vessel walls
• Painless bluish or red nodule • Thrombosis may occur and be associated with Masson
• Often occurs on extremities, trunk, or breast tumor/change
• Complete excision is curative but not necessary given TOP DIFFERENTIAL DIAGNOSES
benign nature of lesions • Venous malformation (cavernous hemangioma)
• Excellent prognosis, no malignant potential • Cherry angioma
MACROSCOPIC • Arteriovenous hemangioma (malformation)
• Typically < 2 cm • Glomeruloid hemangioma

Sinusoidal Hemangioma Cytologic Features

(Left) Histologic section shows
the superficial portion of a
cutaneous sinusoidal
hemangioma with large,
dilated vascular spaces.
(Right) High-magnification
examination of sinusoidal
hemangioma demonstrates
the cytologic features of the
endothelial cells, which show
small, uniform nuclei with
hyperchromasia ﬈ and
inconspicuous nucleoli.

Thrombosis Masson Change

(Left) High magnification
shows sinusoidal vascular
spaces with thrombosis ﬈, a
finding often seen in
sinusoidal hemangioma.
(Right) Another example of a
sinusoidal hemangioma shows
hemorrhage, thrombosis ﬊,
and intravascular papillary
endothelial hyperplasia (a.k.a.
Masson tumor or change).

440
 Sinusoidal Hemangioma

Vascular Tumors (Including Lymphatics)

○ Lining cells are small endothelial cells with nuclear
TERMINOLOGY hyperchromasia
Abbreviations ○ Mitotic figures typically not seen
• Sinusoidal hemangioma (SH) ○ Calcifications may rarely be present
Synonyms Cytologic Features
• Cavernous hemangioma (variant of) • Nuclei are hyperchromatic but show regular borders and
uniform chromatin
Definitions
• Acquired vascular lesion in adults; features similar to DIFFERENTIAL DIAGNOSIS
cavernous hemangioma/venous malformation
Venous Malformation (Cavernous Hemangioma)
ETIOLOGY/PATHOGENESIS • Typically occurs in children
• Often larger and more poorly circumscribed than SH
Unknown
• No ramified pattern and less tightly packed vessels
• May represent reactive vascular proliferation rather than
true neoplastic process Cherry Angioma
• Very common small papular lesions occurring in adults
CLINICAL ISSUES • Superficial papillary dermal lesions, as opposed to SH
Epidemiology (which is typically deep dermal or subcutaneous)
• Incidence Arteriovenous Hemangioma (Malformation)
○ Rare • Typically occurs on lips, perioral skin, or nose of young
• Age adults
○ Typically occurs in adults • Proliferation of large, thick-walled blood vessels with
• Sex smooth muscle in their walls, which mostly represent veins
○ More common in female patients • Feeder vessel (ascending muscular artery) may be present
in some cases
Site
• Often occurs on extremities, trunk, or breast Glomeruloid Hemangioma
• Associated with Castleman syndrome and polyneuropathy,
Presentation organomegaly, endocrinopathy, monoclonal
• Subcutaneous or dermal mass paraproteinemia, and skin lesions (POEMS) syndrome
○ Solitary, painless, bluish (deep) or red (superficial) nodule • Typically presents as multiple eruptive lesions on trunk and
– Freely movable limbs
• Dilated vascular spaces filled by grape-like clusters of
Treatment
capillaries, reminiscent of renal glomeruli
• Complete excision is curative but not necessary given
benign nature of lesions DIAGNOSTIC CHECKLIST
Prognosis Pathologic Interpretation Pearls
• Excellent, no malignant potential • Closely packed lobular proliferation of vessels in deep
dermis or subcutis
MACROSCOPIC
Size SELECTED REFERENCES
• Typically < 2 cm 1. Díaz-Flores L et al: Sinusoidal hemangioma and intravascular papillary
endothelial hyperplasia: interrelated processes that share a histogenetic
piecemeal angiogenic mechanism. Acta Histochem. 120(3):255-62, 2018
MICROSCOPIC 2. Salemis NS: Sinusoidal hemangioma of the breast: diagnostic evaluation
management and literature review. Gland Surg. 6(1):105-9, 2017
Histologic Features 3. Konda P et al: Intramuscular sinusoidal haemangioma with secondary
• Proliferation of numerous thin-walled, anastomosing Masson's phenomenon. BMJ Case Rep. 2016, 2016
vessels 4. Halawar SS et al: Intramuscular sinusoidal hemangioma with Masson's lesion.
J Oral Maxillofac Pathol. 17(2):315-7, 2013
○ Well-circumscribed proliferation of vessels in sinusoidal 5. Ban M et al: Giant sinusoidal hemangioma revealing diffuse ancient change:
pattern hyalinization and organized thrombi. Int J Dermatol. 49(5):589-90, 2010
○ Vessels are thin walled and closely packed with little 6. Nakamura M et al: Calcifying sinusoidal haemangioma on the back. Br J
Dermatol. 141(2):377-8, 1999
intervening stroma
7. Ruck P et al: Diffuse sinusoidal hemangiomatosis of the spleen. A case report
– Occasional cases may show smooth muscle in vessel with enzyme-histochemical, immunohistochemical, and electron-
walls microscopic findings. Pathol Res Pract. 190(7):708-14; discussion 715-7, 1994
– Pseudopapillary pattern may be seen (due to 8. Calonje E et al: New entities in cutaneous soft tissue tumours. Pathologica.
85(1095):1-15, 1993
tangential sectioning) 9. Calonje E et al: Sinusoidal hemangioma. A distinctive benign vascular
– Thrombosis may occur and be associated with neoplasm within the group of cavernous hemangiomas. Am J Surg Pathol.
intravascular papillary endothelial hyperplasia (Masson 15(12):1130-5, 1991
tumor)

441
 Glomeruloid Hemangioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY MICROSCOPIC
• Benign proliferation of small vessels mimicking renal • Vessels show distinctive grape-like clusters mimicking renal
glomeruli glomeruli
• Synonym: Glomeruloid angioma • Endothelial cells are mildly enlarged, and many show
cytoplasmic eosinophilic globules
ETIOLOGY/PATHOGENESIS
○ Cytoplasmic globules represent secondary lysosomes
• Association with polyneuropathy, organomegaly, containing immunoglobulins
endocrinopathy, M-protein, skin changes (POEMS) or • Few mitoses; no necrosis or infiltrative features
multicentric Castleman syndrome in most cases
• Rare cases not associated with POEMS syndrome ANCILLARY TESTS
• PAS(+) cytoplasmic globules
CLINICAL ISSUES
• More common in Asian (especially Japanese) patients TOP DIFFERENTIAL DIAGNOSES
• More common in female patients • Acquired tufted hemangioma
• Typically presents as multiple red to purple eruptive • Lobular capillary hemangioma (pyogenic granuloma)
papules (POEMS syndrome) • Hobnail hemangioma (targetoid hemosiderotic
○ Single lesions may occur in patients without POEMS hemangioma)
• Excellent prognosis, no malignant potential • Kaposi sarcoma

Glomeruloid Hemangioma Glomeruloid Vascular Structures

(Left) Low-power H&E of
glomeruloid hemangioma
shows a superficial dermal
proliferation of small clusters
of vessels ﬊ with a
glomeruloid pattern. (Right)
The characteristic vasculature
of glomeruloid hemangioma
features a grape-like pattern
of clustered, small vessels
mimicking renal glomeruli, as
depicted here.

Cytologic Features and Eosinophilic

Glomeruloid Vascular Structures Globules
(Left) High-power H&E of
glomeruloid hemangioma
shows small, grape-like
clusters of vessels projecting
into vascular lumina (with
peripheral crescentic spaces
﬊). (Right) The vessels in
glomeruloid hemangioma
contain endothelial cells with
oval- to spindle-shaped nuclei.
Cytoplasmic eosinophilic
globules (containing
immunoglobulins) are present
focally ﬈. A few intraluminal
eosinophils are also seen ﬉ in
this image.

442
 Glomeruloid Hemangioma

Vascular Tumors (Including Lymphatics)

• Endothelial cells are mildly enlarged, and many show
TERMINOLOGY cytoplasmic eosinophilic globules
Abbreviations ○ Cytoplasmic globules represent secondary lysosomes
• Glomeruloid hemangioma (GH) containing immunoglobulins
• Endothelial cells may show nuclear hyperchromasia but do
Synonyms not show significant cytologic atypia
• Glomeruloid angioma • Few mitoses, no necrosis or infiltrative features
Definitions
ANCILLARY TESTS
• Benign proliferation of small vessels mimicking renal
glomeruli Histochemistry
• PAS(+) cytoplasmic globules
ETIOLOGY/PATHOGENESIS
Paraneoplastic Syndromes DIFFERENTIAL DIAGNOSIS
• Association with polyneuropathy, organomegaly, Acquired Tufted Hemangioma (Angioblastoma)
endocrinopathy, M-protein, skin changes (POEMS • Slowly spreading macules and plaques in young children
syndrome) or multicentric Castleman disease in almost all and adults
cases • Multiple dermal and subcutaneous vascular lobules
Unknown composed of spindled and polygonal-shaped cells
• Some cases may show overlapping features with GH
• Rare cases not associated with POEMS syndrome
Lobular Capillary Hemangioma (Pyogenic
CLINICAL ISSUES Granuloma)
Epidemiology • Often shows polypoid configuration with epidermal
• Incidence collarette
○ Rare • Lobular proliferation typically associated with ulceration,
edema, and acute inflammation
• Sex
○ More common in female patients Targetoid Hemosiderotic Hemangioma (Hobnail
• Ethnicity Hemangioma)
○ More common in Asian (especially Japanese) patients • Superficial dilated vessels and smaller, narrow, deeper
Site vessels lined by plump (hobnailed) cells
• Extravasated red blood cells and prominent stromal
• Trunk and extremities
hemosiderin deposition
Presentation
Kaposi Sarcoma
• Multiple red to purple eruptive papules (POEMS syndrome)
• Clinical history distinctive
○ Most patients also have diffuse skin hyperpigmentation
○ HIV positive with multiple lesions, or lower extremity
• Single lesions reported in patients without POEMS
lesion in elderly Mediterranean male
Treatment • Cords or fascicles of spindled cells with slit-like lumina
• Surgical excision is curative, but not necessary in most cases associated with hemosiderin deposition and plasma cells
• Treatment of underlying plasma cell disorder may lead to • HHV8(+)
regression of lesions ○ Not reported in GH

Prognosis DIAGNOSTIC CHECKLIST

• Excellent; no malignant potential
Pathologic Interpretation Pearls
MACROSCOPIC • Dermal proliferation of vessels showing distinctive
glomeruloid morphology
General Features
• Dermal-based, well-circumscribed, unencapsulated lesions SELECTED REFERENCES
Size 1. Shinozaki-Ushiku A et al: Glomeruloid hemangioma associated with TAFRO
syndrome. Hum Pathol. ePub, 2018
• Small; typically only a few millimeters 2. Gali VL et al: Cutaneous glomeruloid hemangioma: a report on two cases
and a review of literature. S D Med. 70(6):250-1, 2017
MICROSCOPIC 3. Lee JY et al: Glomeruloid hemangioma as a marker for the early diagnosis of
POEMS syndrome. Ann Dermatol. 29(2):249-51, 2017
Histologic Features 4. Jacobson-Dunlop E et al: Glomeruloid hemangiomas in the absence of
POEMS syndrome. J Cutan Pathol. 39(4):402-3, 2012
• Dermal-based proliferation of vascular spaces containing 5. Rongioletti F et al: Glomeruloid hemangioma. A cutaneous marker of
small capillary-type vessels POEMS syndrome. Am J Dermatopathol. 16(2):175-8, 1994
• Vessels show distinctive grape-like clusters projecting into 6. Chan JK et al: Glomeruloid hemangioma. A distinctive cutaneous lesion of
multicentric Castleman's disease associated with POEMS syndrome. Am J
lumina, mimicking renal glomeruli Surg Pathol. 14(11):1036-46, 1990

443
 Angiomatosis

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY MICROSCOPIC
• Definition: Diffuse, benign, vascular lesion of soft tissue • 2 common patterns
affecting large segments of body or multiple tissue planes ○ Haphazard arrangement of venous-, cavernous-, and
in contiguous fashion capillary-sized vessels
ETIOLOGY/PATHOGENESIS ○ Infiltrating nodules of capillary vessels
• May involve multiple tissue planes (vertical involvement)
• Likely represents congenital vascular malformation
○ Dermis, subcutis, muscle, and bone
CLINICAL ISSUES ○ May also involve only single tissue type
• Most present in early childhood • Lacks distinct lobular pattern
• Lower extremities (> 50%) • Osseous involvement can occur
• Treatment: Conservative but complete excision ANCILLARY TESTS
• Benign lesion with frequent recurrences and persistent
• GLUT1(-)
disease
TOP DIFFERENTIAL DIAGNOSES
MACROSCOPIC
• Glomangiomatosis
• Predominant fatty appearance
• Infantile hemangioma
• Wide size range (3-26 cm)
• Intramuscular hemangioma

Angiomatosis Capillary Vascular Pattern

(Left) This example of
angiomatosis shows a diffuse
vascular proliferation
involving the papillary and
reticular dermis ﬈ and
extending down into the
subcutaneous adipose tissue
﬉. In some cases, involvement
of muscle and bone may also
be seen. (Right) A large
cavernous vessel with an
irregular wall ﬈ is surrounded
by numerous small to medium-
sized capillaries ﬉.

Infiltrating Capillary Hemangioma Pattern Various Vessel Types

(Left) Numerous small and
dilated capillaries ﬈ are
shown infiltrating the fibrous
connective tissue and
extending down into the
adjacent adipose tissue.
(Right) Scattered vessels of
varying size and wall thickness
are seen within the fibrous
connective tissue and lobules
of mature adipose tissue,
consisting of muscular venous-
﬈, cavernous- ﬉, and
capillary-type vessels ﬊.

444
 Angiomatosis

Vascular Tumors (Including Lymphatics)

TERMINOLOGY Size
• 3-26 cm
Synonyms
• Diffuse hemangioma, vascular malformation, infiltrating Gross Features
angiolipoma • Variable coloration
• Most have predominantly fatty appearance
Definitions
• Diffuse, benign, vascular lesion of soft tissue affecting large MICROSCOPIC
segments of body or multiple tissue planes in contiguous
fashion Microscopic Features
• 2 common patterns
ETIOLOGY/PATHOGENESIS ○ Haphazard arrangement of venous-, cavernous-, and
capillary-sized vessels
Developmental Anomaly
– Most common and most characteristic pattern
• Benign congenital/developmental vascular malformation – Irregular and thick to attenuated walls with
○ Thought to arise in early intrauterine life during limb bud herniations and intimal redundancies
formation – Clusters of capillary vessels within or adjacent to vein
○ Disease associations: Von Hippel Lindau, Klippel- walls
Trénaunay-Weber, and Sturge-Weber syndromes – Large amounts of mature adipose tissue
○ Infiltrating nodules of capillary vessels
CLINICAL ISSUES
– Nodules infiltrate into soft tissue
Epidemiology – Large amounts of mature adipose tissue
• Age – Previously referred to as infiltrating angiolipoma
○ Most present in early childhood • May involve multiple tissue planes (vertical involvement)
○ 2/3 develop by 2nd decade of life ○ Dermis, subcutis, muscle, and bone
• Sex • May involve only single tissue type
○ Females affected slightly more than males ○ Multiple muscles
• Lacks distinct lobular pattern
Site
• Lower extremities (> 50%) ANCILLARY TESTS
• Chest wall, abdomen, and upper extremities
Immunohistochemistry
Presentation • CD31(+), CD34(+), GLUT1(-)
• Diffuse and persistent swelling; worsened by strenuous
exercise DIFFERENTIAL DIAGNOSIS
• Pain and discoloration
Glomangiomatosis
Treatment • Diffusely infiltrating
• Conservative but complete excision • Well-formed vessels of varying size surrounded by clusters
Prognosis of glomus cells
• Often accompanied by mature adipose tissue
• Benign lesion with frequent recurrences and persistent
disease Infantile Hemangioma
○ Majority will develop recurrences (60-90%) • Distinct lobular pattern
○ Multiple recurrences (40%) • Lacks extensive involvement
• Prognosis depends on size and location • GLUT1(+)
○ Death may occur due to complications of renal or brain
involvement
Intramuscular Hemangioma
○ Blindness • Homogeneous cellular groups of capillary-sized vessels
• Metastases or malignant transformation not reported • Usually lacks mixture of vessel sizes
• May require clinical correlation to make distinction
IMAGING
SELECTED REFERENCES
CT Findings
1. Khan S et al: Angiomatosis: a rare vascular proliferation of head and neck
• Ill-defined, nonhomogeneous mass region. J Cutan Aesthet Surg. 8(2):108-10, 2015
• Serpiginous densities within low-density areas 2. Rao VK et al: Angiomatosis of soft tissue. An analysis of the histologic
corresponding to tortuous vessels features and clinical outcome in 51 cases. Am J Surg Pathol. 16(8):764-71,
1992
3. Howat AJ et al: Angiomatosis: a vascular malformation of infancy and
MACROSCOPIC childhood. Report of 17 cases. Pathology. 19(4):377-82, 1987
4. Koblenzer PJ et al: Angiomatosis (hamartomatous hem-
General Features lymphangiomatosis). Report of a case with diffuse involvement. Pediatrics.
• Ill-defined mass 28:65-76, 1961

445
 Lymphangioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY • Excellent prognosis in most cases

• Benign proliferation of lymphatic vessels; may be
superficial, deep, or diffusely involve organ systems
○ Includes lymphangioma circumscriptum (LAC) (superficial
lymphangioma), lymphangiomatosis (systemic
angiomatosis), cystic lymphangioma, and deep
lymphangioma
ETIOLOGY/PATHOGENESIS
• Most cases considered developmental
malformations/hamartomas, not true neoplasms
• Associated with trisomies and other genetic syndromes,
including Turner (cystic hygroma), Noonan, and Maffucci
CLINICAL ISSUES
• More common in children (6% of benign childhood tumors);
present at birth or within first 2 years of life
• Typically presents as large, slow-growing, painless mass
(deep lymphangioma) or as multiple small, grouped,
superficial vesicular lesions (LAC)
• Recurrence rate is high if removal incomplete
MICROSCOPIC
• Variably sized anastomosing vascular spaces lined by small,
bland-appearing endothelial cells
○ Endothelial cells are small with uniform, bland-
appearing, oval to flattened, hyperchromatic nuclei
• Often contain abundant proteinaceous debris, scattered
lymphocytes, and erythrocytes
• Walls show stromal fibrosis (older lesions) and may contain
smooth muscle
TOP DIFFERENTIAL DIAGNOSES
• Hemangioma
• Progressive lymphangioma
• Secondary lymphangiectasia
• Atypical vascular proliferation
• Lymphangioma-like Kaposi sarcoma

Lymphangioma Gross Photograph of Lymphangioma

(Left) Clinical photograph
shows a large, deep cystic
lymphangioma on the lateral
neck of a child. In this location,
this lesion is also known as
cystic hygroma. (Right)
Macroscopic view of a
lymphangioma shows a
reddish/brown translucent
cystic mass. Small vessels are
noted within the lining, and
the cyst was filled with clear,
watery fluid.

Lymphangioma at Low Magnification Bland Endothelial Cell Lining

(Left) Histologic examination
of lymphangioma shows
multiple dilated, cystic,
endothelial-lined channels.
There are small collections of
lymphocytes ﬈ within the
lumina along with
proteinaceous lymphatic fluid
and erythrocytes. (Right) The
spaces of lymphangioma are
lined by a thin layer of
cytologically bland endothelial
cells ﬉. Note the granular,
eosinophilic proteinaceous
material (lymph ﬊) within the
lumina.

446
 Lymphangioma

Vascular Tumors (Including Lymphatics)

○ Intraabdominal lymphangiomas occur in mesentery,
TERMINOLOGY omentum, and retroperitoneum
Synonyms • LAC: Axillary folds, neck, and trunk are most common sites
• Lymphatic malformation • LAS: Can affect any organ system but often involves bones,
• Lymphangioma circumscriptum (superficial cutaneous soft tissues, and skin
lymphangioma) (LAC) Presentation
• Cystic lymphangioma (cystic hygroma)
• Cystic mass lesion; may be superficial or deep
• Deep lymphangioma (cavernous lymphangioma)
○ Typically presents as large, slow-growing, painless mass
• Lymphangiomatosis (generalized lymphangioma, systemic
(deep lymphangioma) or as multiple small, grouped,
angiomatosis) (LAS)
superficial vesicular lesions (LAC)
Definitions ○ LAS presents with numerous cystic lesions, both
• Benign proliferation of lymphatic vessels; may be superficial and deep
○ Superficial (LAC) • Soft and fluctuant swellings on palpation
○ Deep (cavernous lymphangioma) • Intraabdominal cases may present with abdominal
○ Diffusely involving most organ systems (LAS) distension, mass on palpation
○ May also develop abdominal obstruction, volvulus, and
ETIOLOGY/PATHOGENESIS infarction
• Generalized LAS: Depends on affected site
Developmental Anomaly ○ Bone: Pathologic fractures
• Most cases of lymphangioma considered developmental or ○ Lungs: Dyspnea, wheezing due to chylothorax, chylous
congenital malformations/hamartomas, not true ascites
neoplasms ○ Spleen: Splenomegaly, left upper quadrant pain
○ Maldevelopment of embryonic lymphangiogenesis most
likely etiology Treatment
– Leads to sequestered lymphatics that fail to • Surgical resection may be indicated in large, deep lesions,
communicate with normal lymphovascular system especially if symptomatic
○ LAS considered congenital in most cases ○ LAS not amenable to surgical excision
• Intralesional injection of sclerosing agents, including
Genetics bleomycin and OK-432
• Associated with genetic syndromes, including Turner
syndrome (cystic hygroma), Noonan syndrome, Maffucci Prognosis
syndrome, trisomies 13, 18, 21 • Excellent in most cases, although LAS may be fatal if
• Mutations in FLT4 (VEGFR-3), PROX1, FOXC2, and SOX18 involving mediastinum or internal organs, especially lungs
genes implicated • Recurrence rate high with incomplete removal
• No malignant transformation reported
Acquired
• Rare acquired cases occur in adults IMAGING
CLINICAL ISSUES Ultrasonographic Findings
• Unilocular or multilocular anechoic mass
Epidemiology
• Can be used in utero to detect cystic lymphangioma
• Incidence (associated with hydrops fetalis, Turner syndrome, and high
○ More common in children: Estimated 6% of benign death rate)
childhood tumors
• Age CT Findings
○ Often present at birth or within first 2 years of life (~ • Nonenhancing cystic lesions with homogeneous
90% of cases) attenuation
○ LAS usually presents within first 2 decades of life • Visceral and osseous lesions often show contrast
• Sex enhancement
○ Intraabdominal lymphangiomas have slight male • May displace surrounding organs
predominance
○ LAS has no sex predilection MACROSCOPIC
Site General Features
• Head and neck most common site for cystic • Multiple cystic spaces with clear to whitish fluid
lymphangiomas
○ Usually posterior triangle but can occur in anterior MICROSCOPIC
triangle Histologic Features
○ Also occur in axillae, abdomen, and internal organs • Variably sized anastomosing vascular spaces lined by
• Cavernous type more frequent in oral cavity, upper trunk, endothelial cells
limbs, and abdominal sites

447
 Lymphangioma
Vascular Tumors (Including Lymphatics)
○ Endothelial cells are small with uniform, bland-
appearing, oval to flattened, hyperchromatic nuclei
• Dilated lumina
○ Often contain abundant eosinophilic proteinaceous
debris, scattered lymphocytes, and erythrocytes
• Walls show stromal fibrosis (older lesions) and occasional
myxoid change
○ Often contain lymphoid infiltrates
– May show occasional reactive germinal centers
○ Mast cells are common
○ Hemosiderin deposition in stroma may be seen
• Large vessels may contain smooth muscle in their walls
• Cavernous lymphangioma has infiltrative margins and often
extends into surrounding tissues
ANCILLARY TESTS
Immunohistochemistry
• Endothelial lining cells show variable positivity with vascular
markers CD31, CD34, and FVIIIRAg
• Newer lymphatic markers, including D2-40 (podoplanin),
VEGFR-3, and LYVE-1, typically (+)
DIFFERENTIAL DIAGNOSIS
Hemangiomas
• Most cases show smaller vascular spaces with more red
blood cells, less proteinaceous material, and fewer
lymphocytes
• Often well-circumscribed, noninfiltrative borders
Progressive Lymphangioma
• Form of cutaneous lymphangioma with distinct clinical
findings
○ Typically presents on lower extremities of adults as slow-
growing patches or plaques
• Histologic findings very similar to other forms of
lymphangioma
○ Superficially dilated spaces that become progressively
smaller with deep extension
Secondary Lymphangiectasia
• May be due to local factors, such as obstruction (e.g., due to
tumor), scarring, or previous radiation therapy
• Identical histologic findings; can only be distinguished by
clinical history or other findings (if present)
Atypical Vascular Proliferation
• Radiation induced; most frequent in breast
• Clinically, presents as multiple small vesicles in radiation
field
• Irregularly dilated vascular spaces lined by atypical
endothelial cells
Lymphangioma-Like Kaposi Sarcoma
• Usually shows at least focal areas of more typical Kaposi
sarcoma
○ Infiltrative, slit-like spaces lined by hyperchromatic,
spindle-shaped cells
○ Stromal hemosiderin deposition and inflammatory
infiltrate containing plasma cells
• HHV8(+) is diagnostic
448
Angiosarcoma
• Highly atypical vascular proliferation showing irregular,
anastomosing vascular spaces
• Poorly circumscribed, infiltrative neoplasm
• Endothelial cells typically show epithelioid or spindle cell
features, prominent nuclear enlargement, and atypia with
enlarged nucleoli
○ Endothelial multilayering often present
○ Mitotic figures easily identified
DIAGNOSTIC CHECKLIST
Clinically Relevant Pathologic Features
• Margins
○ High recurrence rate with positive margins
Pathologic Interpretation Pearls
• Proliferation of superficial &/or deep dilated vascular
spaces lined by bland, oval or flattened endothelial cells
SELECTED REFERENCES
1. Akhavan S et al: Congenital lymphangioma circumscriptum of vulva
presenting as multiple giant mass lesions: a case report and literature
review. J Obstet Gynaecol Res. 44(5):978-982, 2018
2. Taylor D et al: A supernumerary nipple-like clinical presentation of
lymphangioma circumscriptum. Case Rep Dermatol Med. 2018:6925105,
2018
3. Patoulias D et al: Cystic lymphangioma of the chest wall in a 5-year-old male
patient: a rare and atypical localization-a case report and comprehensive
review of the literature. Case Rep Pediatr. 2017:2083204, 2017
4. Salman A et al: Acquired progressive lymphangioma: case report with partial
response to imiquimod 5% cream. Pediatr Dermatol. 34(6):e302-e304, 2017
5. Massa AF et al: Cutaneous Lymphangioma circumscriptum - dermoscopic
features. An Bras Dermatol. 90(2):262-4, 2015
6. Oiso N et al: Cutaneous lymphangioma circumscriptum with marked blood
presence: histopathologic evaluation of the endothelial cells. Eur J
Dermatol. 24(1):127-8, 2014
7. Flucke U et al: Radiation-induced vascular lesions of the skin: an overview.
Adv Anat Pathol. 20(6):407-15, 2013
8. Wang L et al: Benign lymphangioendothelioma: a clinical, histopathologic
and immunohistochemical analysis of four cases. J Cutan Pathol. 40(11):945-
9, 2013
9. Blei F: Lymphangiomatosis: clinical overview. Lymphat Res Biol. 9(4):185-90,
2011
10. Gupta SS et al: Cystic lymphangioma of the breast in an 8-year-old boy:
report of a case with a review of the literature. Surg Today. 41(9):1314-8,
2011
11. Ji RC et al: Multiple expressions of lymphatic markers and morphological
evolution of newly formed lymphatics in lymphangioma and lymph node
lymphangiogenesis. Microvasc Res. 80(2): 195-201, 2010
12. Chen EY et al: Similar histologic features and immunohistochemical staining
in microcystic and macrocystic lymphatic malformations. Lymphat Res Biol.
7(2):75-80, 2009
13. Gedikbasi A et al: Multidisciplinary approach in cystic hygroma: prenatal
diagnosis, outcome, and postnatal follow up. Pediatr Int. 51(5):670-7, 2009
14. Patel GA et al: Cutaneous lymphangioma circumscriptum: frog spawn on the
skin. Int J Dermatol. 48(12):1290-5, 2009
15. Patel GA et al: Zosteriform lymphangioma circumscriptum. Acta
Dermatovenerol Alp Panonica Adriat. 18(4):179-82, 2009
16. Richmond B et al: Adult presentation of giant retroperitoneal cystic
lymphangioma: case report. Int J Surg. 7(6):559-60, 2009
17. Edwards JR et al: Lymphatics and bone. Hum Pathol. 39(1):49-55, 2008
18. François M et al: Sox18 induces development of the lymphatic vasculature in
mice. Nature. 456(7222):643-7, 2008
19. Santo S et al: Prenatal ultrasonographic diagnosis of abdominal cystic
lymphangioma: a case report. J Matern Fetal Neonatal Med. 21(8):565-6,
2008
20. Norgall S et al: Elevated expression of VEGFR-3 in lymphatic endothelial cells
from lymphangiomas. BMC Cancer. 7:105, 2007
21. Wilting J et al: The transcription factor Prox1 is a marker for lymphatic
endothelial cells in normal and diseased human tissues. FASEB J.
16(10):1271-3, 2002

Dilated Lymphatic Spaces
Intraabdominal Lymphangioma
Superficial Lymphangioma With Papillary
Projections
Lymphangioma
Vascular Tumors (Including Lymphatics)
Lymphoid Aggregates in Lymphangioma
(Left) Deep lymphangioma
shows large vascular channels
filled with proteinaceous
material, a few lymphocytes
﬉, and scattered erythrocytes
﬊. (Right) Lymphocytes ﬊
may be seen not only within
the dilated spaces of
lymphangioma but also within
the septa, as depicted in this
H&E. In some cases, reactive
germinal centers may also be
present.
Superficial Lymphangioma
(Left) Lymphangiomas that
arise within the abdominal
cavity often contain mature
adipose tissue within the
septa. Note the numerous
cystically dilated lymphatic
spaces. Stromal myxoid
change ﬈ can also be
appreciated in this H&E.
(Right) Examination of a
superficial lymphangioma
shows the dilated vascular
spaces lined by small, bland
endothelial cells with uniform,
hyperchromatic-staining, oval
﬉ to flattened ﬈ nuclei.
Superficial Lymphangioma With Red Cells
(Left) Superficial
lymphangioma shows widely
dilated spaces in the
superficial dermis. The lumina
show several papillary
projections ﬊ with slightly
fibrinous cores lined by small,
hyperchromatic endothelial
cells. (Right) H&E of superficial
lymphangioma shows a large,
irregularly dilated space lined
by thin endothelial cells
containing scattered red blood
cells in the superficial dermis.
449
 Massive Localized Lymphedema

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY • May weep serous fluid

• Pseudoneoplastic process related to localized lymphatic MICROSCOPIC
obstruction
• Overlying skin is often thickened
CLINICAL ISSUES • Fibrous thickening of dermis with dilated lymphatics
• Seen in morbidly obese patients (> 300 lb) surrounded by lymphocytic infiltrate
• Medial thigh is most common site • Expanded subcutaneous septa between lobules of mature
○ Also lower abdominal wall, scrotum, proximal arm adipose tissue
• Usually middle aged (range: 30-60 years) ○ Prominent septal edema
• More common in women ○ Preserved lobular architecture of subcutaneous fat
• Benign • Reactive capillary vascular proliferation often seen at
interface of subcutaneous septa and lobules
• Recurrences are common
MACROSCOPIC TOP DIFFERENTIAL DIAGNOSES
• Atypical lipomatous tumor/well-differentiated liposarcoma
• Typically large specimens (> 20 cm)
• Myxoid liposarcoma
• Overlying skin has thickened, indurated peau d'orange
appearance • Myxofibrosarcoma (low grade)
• Cut surface shows pronounced connective tissue septa in
subcutaneous fat

Massive Localized Lymphedema Neovascularization

(Left) Massive localized
lymphedema (MLL) is a large
soft tissue pseudotumor that
occurs secondary to
obstruction of lymphatic
drainage in morbidly obese
patients. At low
magnification, MLL is
characterized by lobules of
adipose tissue separated by
expanded, edematous
interlobular connective tissue
septa ﬈. (Right) In many
cases of MLL, the fat lobules
characteristically show a
proliferation of reactive
capillary vessels ﬊ near the
interface with the interlobular
septa.

Bland, Reactive Fibroblasts Lymphoid Aggregates

(Left) The septal fibroblasts in
MLL are spindled to stellate
and generally appear mildly
atypical but reactive.
Occasional cells may be
enlarged and multinucleated
and may even resemble the
"floret cells" seen in well-
differentiated liposarcoma. In
general, however, there are no
atypical cells or lipoblasts
within the adipose tissue
lobules in MLL. (Right)
Lymphoid aggregates,
particularly around lymphatic
channels and blood vessels,
are common in MLL.

450
 Massive Localized Lymphedema

Vascular Tumors (Including Lymphatics)

TERMINOLOGY MICROSCOPIC
Synonyms Histologic Features
• Lymphatic pseudotumor • Overlying skin is often thickened
• Pseudosarcoma • Fibrous thickening of dermis with dilated lymphatic
surrounded by lymphocytic infiltrate
Definitions
• Expanded subcutaneous septa between lobules of mature
• Pseudoneoplastic process related to localized lymphatic adipose tissue
obstruction ○ Prominent septal edema
○ Increased mildly atypical fibroblasts
ETIOLOGY/PATHOGENESIS – May be multinucleated and with "floret cell"
Mechanical morphology
• Lymphatic obstruction by enlarged folds of fat ○ Preserved lobular architecture of subcutaneous fat
– Fat lacks lipoblasts and hyperchromatic atypical cells
Other – Pseudocyst formation in adipose tissue may be seen
• May also be seen secondary to lymphatic damage during • Mild perivascular lymphocytic infiltrate
surgery or trauma • Reactive capillary vascular proliferation often seen at
• Hypothyroidism may play role in some patients interface of subcutaneous septa and lobules
• Other findings may include calcification, metaplastic bone
CLINICAL ISSUES
Epidemiology DIFFERENTIAL DIAGNOSIS
• Age Atypical Lipomatous Tumor/Well-Differentiated
○ Usually middle aged (range: 30-60 years) Liposarcoma
• Sex • Lacks characteristic skin changes of lymphedema
○ More common in women • Thickened fibrous bands with atypical hyperchromatic
Site "smudge" cells
• Usually marked variation in size of adipocytes
• Medial thigh is most common
• Lipoblasts may be identified
○ May be bilateral
• MDM2 amplification
• Also lower abdominal wall, scrotum, proximal arm
Myxofibrosarcoma (Low Grade)
Presentation
• Hyperchromatic spindled cells
• Morbidly obese patients (> 300 lb)
• Variable nuclear pleomorphism and mitotic activity
• Large, painless mass
• Well-developed, arcing, "curvilinear" vasculature
• May be multiple
• Prominent myxoid stroma
Prognosis
Myxoid Liposarcoma
• Benign
• Hyperchromatic, small, monomorphic, spindled and ovoid
○ Recurrence or persistence common
cells
• Uni- and multivacuolated lipoblasts are common
IMAGING
• Delicate plexiform (chicken-wire) capillary vasculature
CT Findings • Abundant myxoid stroma with variable microcyst formation
• Soft tissue streaking due to expanded subcutaneous septa • t(12;16) translocation with FUS-DDIT3 fusion
• Cysts
• No discrete mass SELECTED REFERENCES
1. Kurt H et al: Massive localized lymphedema: a clinicopathologic study of 46
MACROSCOPIC patients with an enrichment for multiplicity. Mod Pathol. 29(1):75-82, 2016
2. Porrino J et al: Massive localized lymphedema of the thigh mimicking
General Features liposarcoma. Radiol Case Rep. 11(4):391-397, 2016
• Overlying skin has thickened, indurated peau d'orange 3. Chopra K et al: Massive localized lymphedema revisited: a quickly rising
complication of the obesity epidemic. Ann Plast Surg. 74(1):126-32, 2013
appearance 4. Lee S et al: Massive localized lymphedema of the male external genitalia: a
• Cut surface shows pronounced connective tissue septa in clinicopathologic study of 6 cases. Hum Pathol. 44(2):277-81, 2013
subcutaneous fat 5. Bogusz AM et al: Massive localized lymphedema with unusual presentations:
report of 2 cases and review of the literature. Int J Surg Pathol. 19(2):212-6,
• Edematous adipose tissue may weep serous fluid 2011
• May show small cysts of varying sizes containing serous 6. Bogusz AM et al: Massive localized lymphedema with unusual presentations:
fluid report of two cases and review of the literature. Int J Surg Pathol. 19(2):212-
6, 2008
Size 7. Wu D et al: Massive localized lymphedema: additional locations and
association with hypothyroidism. Hum Pathol. 31(9):1162-8, 2000
• Typically large specimens (> 20 cm)

451
 Atypical Vascular Lesion

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY
• Synonym: Atypical vascular proliferation
• Benign cutaneous vascular lesion presenting as small
papule or patch in radiated skin, comprised of thin-walled
lymphatic vessels, usually limited to dermis
ETIOLOGY/PATHOGENESIS
• Median latency 3 years post radiotherapy
CLINICAL ISSUES
• Wide age range; median in late 50s
• Skin of breast or chest wall most common following
radiotherapy for breast cancer
• Small, flesh-colored papule or erythematous patch
• Solitary or multiple
• Most lesions pursue benign course
• New lesions frequently appear
• Only rare reports of transformation to angiosarcoma
• Complete excision of all lesions recommended
MICROSCOPIC
• Dermal based, small, symmetrical, often wedge shaped
• Usually confined to superficial dermis
• Thin-walled lymphatic capillary vessels
• Dilated or jagged, anastomosing vascular structures
• Dissects preexisting dermal collagen
• Rarely extends into subcutis
• Lacks endothelial multilayering and significant atypia
• Mitoses rarely present
• No amplification of MYC
TOP DIFFERENTIAL DIAGNOSES
• Well-differentiated angiosarcoma
• Hobnail hemangioma
• Lymphangioma circumscriptum
• Progressive lymphangioma (benign
lymphangioendothelioma)

Atypical Vascular Lesion Clinical Appearance

(Left) An atypical vascular
lesion (AVL) typically appears
as a symmetrical, wedge-
shaped lesion ﬈ in the
superficial dermis. It is
composed of variably dilated
and narrow lymphatic
channels devoid of red blood
cells. AVL is usually confined
to the dermis; however, rare
lesions can infiltrate the
underlying subcutis. (Right) An
AVL typically presents as small
papules ﬈ and patches ﬉ in
radiated skin at a median time
of 3 years post radiotherapy.
Breast or chest wall are most
common sites. The lesions can
be solitary or multiple.

Dissecting Growth Pattern Cytologic Features

(Left) AVLs often have a
dissecting growth pattern
consisting of jagged,
anastomosing channels that
infiltrate dermal collagen; a
pattern that mimics well-
differentiated angiosarcoma.
Unlike angiosarcoma,
however, there is no
significant nuclear atypia, no
multilayering of cells, and
rarely any mitotic activity.
(Right) The lymphatic channels
of AVL, although irregular in
contour, are lined by a single
layer of endothelial cells ﬈
that lack significant nuclear
atypia.

452
 Atypical Vascular Lesion

Vascular Tumors (Including Lymphatics)

TERMINOLOGY DIFFERENTIAL DIAGNOSIS
Abbreviations Well-Differentiated Angiosarcoma
• Atypical vascular lesion (AVL) • Clinically presents as large, erythematous plaque (median: 7
cm)
Synonyms
• Anastomosing and infiltrating vascular structures
• Atypical vascular proliferation • Endothelial multilayering and nuclear atypia
Definitions • Mitotic figures often present
• Benign cutaneous vascular lesion presenting as small • Evidence of MYC amplification by FISH or
papule(s) or patch(es) in radiated skin, composed of thin- immunohistochemistry
walled lymphatic vessels, usually limited to dermis Hobnail Hemangioma
• Solitary papule or nodule
ETIOLOGY/PATHOGENESIS
• Biphasic pattern (dilated superficial vessels; narrow deep
Environmental Exposure vessels)
• Radiation (40-60 Gy) • Hobnail endothelial cells
• Median latency: 3 years post radiotherapy • Stromal fibrosis, hemosiderin deposits
Lymphangioma Circumscriptum
CLINICAL ISSUES
• Clinically, groups of small vesicles containing clear fluid
Epidemiology • Small and superficially located lesion
• Incidence • Large, ectatic lymphatic channels
○ Exact incidence unknown • Represents developmental malformation (infants, adults)
• Age • Similar lesion seen in radiated skin
○ Wide age range; median in late 50s
Progressive Lymphangioma (Benign
○ Usually 1 decade earlier than radiation-associated
Lymphangioendothelioma)
cutaneous angiosarcoma
• Presents clinically as large, slowly increasing, pink to red-
Site brown plaque
• Skin of breast or chest wall most common site, following • Infiltrating, dissecting lymphatic channels
radiotherapy for breast cancer • Lymphatics orientated horizontally in dermis
• Less frequent in radiation fields associated with • Similar lesion seen in radiated skin
gynecological and other malignancies
Presentation DIAGNOSTIC CHECKLIST
• Small, flesh-colored papule or erythematous patch Clinically Relevant Pathologic Features
• Solitary or multiple • Symptom time frame
Treatment • Gross appearance
• Complete excision of all lesions recommended SELECTED REFERENCES
Prognosis 1. Fernandez AP et al: FISH for MYC amplification and anti-MYC
immunohistochemistry: useful diagnostic tools in the assessment of
• Most lesions pursue benign course secondary angiosarcoma and atypical vascular proliferations. J Cutan Pathol.
• New lesions frequently appear 39(2):234-42, 2012
• Only rare reports of transformation to angiosarcoma 2. Manner J et al: MYC high level gene amplification is a distinctive feature of
angiosarcomas after irradiation or chronic lymphedema. Am J Pathol.
○ Usually following multiple recurrences 176(1):34-9, 2010
3. Lucas DR: Angiosarcoma, radiation-associated angiosarcoma, and atypical
MICROSCOPIC vascular lesion. Arch Pathol Lab Med. 133(11):1804-9, 2009
4. Patton KT et al: Atypical vascular lesions after surgery and radiation of the
Histologic Features breast: a clinicopathologic study of 32 cases analyzing histologic
heterogeneity and association with angiosarcoma. Am J Surg Pathol.
• Dermal based, small, symmetrical, often wedge shaped 32(6):943-50, 2008
• Usually confined to superficial dermis 5. Gengler C et al: Vascular proliferations of the skin after radiation therapy for
○ Rarely extends into subcutis breast cancer: clinicopathologic analysis of a series in favor of a benign
process: a study from the French Sarcoma Group. Cancer. 109(8):1584-98,
• Thin-walled lymphatic capillary vessels 2007
• Dilated or jagged, anastomosing vascular structures 6. Brenn T et al: Radiation-associated cutaneous atypical vascular lesions and
angiosarcoma: clinicopathologic analysis of 42 cases. Am J Surg Pathol.
• Dissects preexisting dermal collagen 29(8):983-96, 2005
• Single layer of slightly enlarged endothelial cells 7. Requena L et al: Benign vascular proliferations in irradiated skin. Am J Surg
• Lacks endothelial multilayering and significant cytologic Pathol. 26(3):328-37, 2002
atypia 8. Fineberg S et al: Cutaneous angiosarcoma and atypical vascular lesions of
the skin and breast after radiation therapy for breast carcinoma. Am J Clin
• Mitoses rarely present Pathol. 102(6):757-63, 1994

453
 Kaposiform Hemangioendothelioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

CLINICAL ISSUES MICROSCOPIC

• Usually occurs in infants and children • Lobular architecture
○ 50% in 1st year of life • Spindle cell areas resemble Kaposi sarcoma
○ Less common in teenagers • Capillary hemangioma-like areas
• Cutaneous lesions present as violaceous plaques • Glomeruloid structures
• Deep tumors often multinodular • Associated with peripheral lymphatic channels (or
• Associated with Kasabach-Merritt syndrome (especially lymphangioma) in some cases
retroperitoneal tumors) • Minimal atypia
○ Consumptive coagulopathy
ANCILLARY TESTS
○ Thrombocytopenia
• CD31(+), CD34(+), ERG(+), PROX1(+), D2-40 (podoplanin) (+)
• Treated with surgical excision
• GLUT1(-) and HHV8(-)
○ Adjuvant therapy in some cases
• Mortality ~ 10% TOP DIFFERENTIAL DIAGNOSES
○ Due to local effects of tumor or Kasabach-Merritt • Infantile hemangioma
syndrome • Kaposi sarcoma
• Rare regional lymph node metastasis • Acquired tufted angioma
• No distant metastasis • Spindle cell hemangioma

Kaposiform Hemangioendothelioma Spindle Cell Kaposiform Areas

(Left) Kaposiform
hemangioendothelioma (KHE)
is a rare vascular tumor that
usually presents during early
childhood. Deep-seated
tumors, such as this one,
present as nodular masses and
are more prone to develop
Kasabach-Merritt syndrome
than superficial tumors
(especially retroperitoneal
tumors). (Right) Solid spindle
cell areas account for the
major component of most
examples of KHE. These areas
resemble Kaposi sarcoma
consisting of long fascicles of
closely spaced spindle cells,
yet lack atypia.

Capillary Hemangioma-Like Areas Glomeruloid Structure

(Left) H&E depicts an interface
between spindle cell ﬈ and
hemangioma-like areas ﬉ in
KHE. The tumor shows an
overall lobular architecture, as
indicated by the fibrous
septum ﬊ traversing the
lesion. (Right) Glomeruloid
structures are a very
characteristic attribute of
KHE. They are composed of
tangles of endothelial cells
and pericytes arranged in
lobulated, whorling structures
that resemble renal glomeruli.
Entrapped thrombi may or
may not be evident.

454
 Kaposiform Hemangioendothelioma

Vascular Tumors (Including Lymphatics)

TERMINOLOGY DIFFERENTIAL DIAGNOSIS
Abbreviations Infantile Hemangioma
• Kaposiform hemangioendothelioma (KHE) • Early postnatal period
• Lobular capillary architecture
Definitions
• Lacks spindle cell areas
• Vascular neoplasm associated with development of
• GLUT1(+)
Kasabach-Merritt syndrome and demonstrates features
• Regresses spontaneously
reminiscent of both Kaposi sarcoma and capillary
hemangioma Kaposi Sarcoma
• Older or immunocompromised patients
CLINICAL ISSUES • Very rare in children, except in Africa
Epidemiology • Nodular phase composed of solid spindle cell areas
• Age • Lacks capillary hemangioma-like areas
○ Majority present in childhood to teen years • HHV8(+)
– 50% in 1st year of life Acquired Tufted Angioma
Site • Similar demographics as KHE
• Most common in extremities • Small, cutaneous lesion
○ Also retroperitoneum • Histologically almost indistinguishable from KHE
○ Nodular proliferation of closely packed capillaries in
Presentation dermis (cannonball pattern)
• Painful or painless mass • Kasabach-Merritt syndrome in some cases
○ Presents as superficial or deep mass
Spindle Cell Hemangioma
○ Cutaneous lesions present as violaceous plaques
○ Deep tumors often multinodular and desmoplastic • Occurs in adults in distal extremities
○ Associated with Kasabach-Merritt syndrome (especially • Often partially intravascular
retroperitoneal tumors) • Ectatic vessels and spindle cell areas
– Consumptive coagulopathy and thrombocytopenia • Vacuolated endothelial cells ("blister" cells)
– Majority of cases of Kasabach-Merritt syndrome • May have areas of thrombosis or phleboliths
associated with KHE
DIAGNOSTIC CHECKLIST
Treatment
Clinically Relevant Pathologic Features
• Wide surgical excision, best option when feasible
• Medical therapy (sirolimus, steroids, cytotoxic agents, α- • Age distribution
interferon) in some cases ○ Vast majority occur in children
• Symptom complex
Prognosis ○ Kasabach-Merritt syndrome
• Rare regional lymph node metastasis
• No distant metastasis
Pathologic Interpretation Pearls
• Mortality ~ 10%, related to local effects of tumor or • Vascular tumor in child, composed predominantly of
Kasabach-Merritt syndrome spindled endothelial cells: Consider KHE

MICROSCOPIC SELECTED REFERENCES

1. Schmid I et al: Kaposiform hemangioendothelioma in children: a benign
Histologic Features vascular tumor with multiple treatment options. World J Pediatr. 14(4):322-
• Lobular architecture 9, 2018
2. Miettinen M et al: ERG transcription factor as an immunohistochemical
• Spindle cell areas resemble Kaposi sarcoma marker for vascular endothelial tumors and prostatic carcinoma. Am J Surg
• Capillary hemangioma-like areas Pathol. 35(3):432-41, 2011
• Glomeruloid structures characteristic 3. Cheuk W et al: Immunostaining for human herpesvirus 8 latent nuclear
antigen-1 helps distinguish Kaposi sarcoma from its mimickers. Am J Clin
• Associated with peripheral lymphatic channels (or Pathol. 121(3):335-42, 2004
lymphangioma) in some cases 4. Lyons LL et al: Kaposiform hemangioendothelioma: a study of 33 cases
• Mitoses but minimal atypia emphasizing its pathologic, immunophenotypic, and biologic uniqueness
from juvenile hemangioma. Am J Surg Pathol. 28(5):559-68, 2004
5. Brasanac D et al: Retroperitoneal kaposiform hemangioendothelioma with
ANCILLARY TESTS tufted angioma-like features in an infant with Kasabach-Merritt syndrome.
Pathol Int. 53(9):627-31, 2003
Immunohistochemistry 6. Mentzel T et al: Kaposiform hemangioendothelioma in adults.
• CD31(+), CD34(+), ERG(+) Clinicopathologic and immunohistochemical analysis of three cases. Am J
Clin Pathol. 108(4):450-5, 1997
• Also PROX1(+) and D2-40 (podoplanin) (+) (especially in 7. Zukerberg LR et al: Kaposiform hemangioendothelioma of infancy and
peripheral lymphatic component) childhood. An aggressive neoplasm associated with Kasabach-Merritt
• GLUT1(-) and HHV8(-) syndrome and lymphangiomatosis. Am J Surg Pathol. 17(4):321-8, 1993

455
 Papillary Intralymphatic Angioendothelioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY MICROSCOPIC
• Also known as Dabska tumor • Dermal proliferation of vessels with papillary projections
• Low-grade malignant vascular tumor composed of lined by enlarged, cuboidal endothelial cells
hobnailed endothelial cells • Endothelial cells show prominent hobnail features with
plump, rounded profiles protruding into lumina
ETIOLOGY/PATHOGENESIS
○ Hobnail cells show high N:C ratio but lack significant
• May be associated with vascular or lymphatic atypia or mitotic activity
tumor/malformation • Typically associated with surrounding lymphoid infiltrate
CLINICAL ISSUES and sclerotic collagen
• Typically occur in children (minority in adults) • Vessels often extend into subcutaneous tissues
• Distal extremities most common, but may occur in other ANCILLARY TESTS
sites • CD31 and CD34 (+)
• High rate of local recurrence, rare metastasis
• Complete surgical excision recommended to prevent TOP DIFFERENTIAL DIAGNOSES
metastasis (rare) or recurrence • Retiform hemangioendothelioma
• Composite hemangioendothelioma
MACROSCOPIC
• Kaposi sarcoma
• Dermal-based infiltrative tumor with extension into
• Angiosarcoma
subcutis

Papillary Intralymphatic
Angioendothelioma Dilated Vascular Spaces
(Left) Scanning magnification
view of a papillary
intralymphatic
angioendothelioma (PILA)
(Dabska tumor) shows a
polypoid lesion in the skin with
irregular dilated vascular
spaces ﬊. (Right) This shows a
dilated vascular space filled
with red blood cells overlying
a smaller space with a
prominent papillary
intralymphatic projection lined
by hobnailed cells ﬊.

Intraluminal Papillary Structures Hobnail Cells

(Left) Prominent
intralymphatic projections of
papillary structures with
hyaline cores are lined by
plump hyperchromatic-
staining cells, some of which
contain cytoplasmic
hemosiderin pigment ﬈.
(Right) Another example at
high-power examination
shows papillae lined by mildly
enlarged hobnailed cells
projecting into the vascular
lumina. The cells show
vesicular chromatin, small
nucleoli, and occasional
grooves ﬉.

456
 Papillary Intralymphatic Angioendothelioma

Vascular Tumors (Including Lymphatics)

• Typically associated with surrounding lymphoid infiltrate
TERMINOLOGY and sclerotic collagen
Abbreviations • Vessels often extend into subcutaneous tissues
• Papillary intralymphatic angioendothelioma (PILA) • Associated lymphatic or vascular tumor or malformation in
some cases
Synonyms
• Dabska tumor ANCILLARY TESTS
• Endovascular papillary angioendothelioma
Immunohistochemistry
Definitions • CD31, CD34, and FVIIIRAg (+)
• Low-grade malignant vascular tumor composed of • Most cases also show expression of lymphatic markers D2-
hobnailed endothelial cells 40 and VEGFR-3

ETIOLOGY/PATHOGENESIS DIFFERENTIAL DIAGNOSIS

Unknown Retiform Hemangioendothelioma
• May be associated with vascular or lymphatic • Most cases occur in adults, but some present in children
tumor/malformation • Proliferation of vessels forming distinct elongated rete-like
structures lined by hobnail cells
CLINICAL ISSUES • Some cases of retiform hemangioendothelioma (RHE)
Epidemiology show significant overlap with PILA, with prominent papillary
structures
• Incidence
○ Rare tumors Composite Hemangioendothelioma
• Age • By definition, composed of at least 2 distinct types of
○ Typically occur in children (minority in adults) hemangioendothelioma
• Sex ○ Predominant histologic components usually are
○ Slight female predominance epithelioid hemangioendothelioma and RHE
Site Kaposi Sarcoma
• Distal extremities most common but may occur in other • Much more common, associated with HIV infection and
sites AIDS in most cases
• Proliferation of small, slit-like vascular spaces lined by
Presentation
spindle cells, lacking papillary pattern of PILA
• Plaque-like lesion of dermis + subcutis • HHV8(+)
○ May show overlying violaceous skin discoloration
Angiosarcoma
Treatment
• Typically occurs in older adults or post mastectomy
• Complete surgical excision recommended • Proliferation of atypical spindled or epithelioid endothelial
Prognosis cells forming anastomosing vascular spaces and showing
infiltrative features
• High rate of local recurrence, rare metastasis (to lymph
nodes)
DIAGNOSTIC CHECKLIST
MACROSCOPIC Pathologic Interpretation Pearls
General Features • Dermal proliferation of vessels with papillary projections
lined by enlarged, cuboidal endothelial cells
• Dermal-based infiltrative tumor with extension into
subcutis
SELECTED REFERENCES
Size 1. Gambarotti M et al: Intraosseous papillary intralymphatic
• Can be quite large (average: 7 cm) angioendothelioma (PILA): one new case and review of the literature. Clin
Sarcoma Res. 8:1, 2018
2. Kugler A et al: Papillary intralymphatic angioendothelioma (PILA), also
MICROSCOPIC referred to as Dabska tumour, in an 83-year-old woman. J Eur Acad
Dermatol Venereol. 30(10):e59-e61, 2016
Histologic Features 3. Neves RI et al: Endovascular papillary angioendothelioma (Dabska tumor):
• Dermal proliferation of vessels lined by enlarged, cuboidal underrecognized malignant tumor in childhood. J Pediatr Surg. 46(1):e25-8,
2011
endothelial cells
4. Emanuel PO et al: Dabska tumor arising in lymphangioma circumscriptum. J
○ Intravascular papillary projections with hyaline cores Cutan Pathol. 35(1):65-9, 2008
○ Endothelial cells show prominent hobnail features with 5. Fukunaga M: Expression of D2-40 in lymphatic endothelium of normal
tissues and in vascular tumours. Histopathology. 46(4):396-402, 2005
plump, rounded profiles protruding into lumina
6. Fanburg-Smith JC et al: Papillary intralymphatic angioendothelioma (PILA): a
– Hobnail cells show high N:C ratio; nuclei may show report of twelve cases of a distinctive vascular tumor with phenotypic
grooves features of lymphatic vessels. Am J Surg Pathol. 23(9):1004-10, 1999
○ Cytoplasmic vacuolation may be seen 7. Dabska M: Malignant endovascular papillary angioendothelioma of the skin
in childhood. Clinicopathologic study of 6 cases. Cancer. 24(3):503-10, 1969
○ Mitotic figures absent or rare
457
 Retiform Hemangioendothelioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY • Often show papillary-like intraluminal projections, some of

• Synonym: Hobnail hemangioendothelioma
• Low-grade malignant vascular tumor composed of
elongated vessels resembling rete testis
CLINICAL ISSUES
• Typically presents in middle-aged adults but may occur in
children
• More common in females
• Treatment: Wide local excision
• Local recurrences common if not completely excised
• Very rare metastases reported (regional lymph nodes)
which may have hyaline core
• Vascular spaces are lined by endothelial cells with
characteristic hobnail morphology
○ Hobnail cells with oval nuclei with mild hyperchromasia
• Very prominent lymphocytic infiltrate in most cases
• Some cases show significant overlap with papillary
intralymphatic angioendothelioma (Dabska tumor)
ANCILLARY TESTS
• Vascular markers: CD31(+), CD34(+), and FVIIIRAg(+)
• Usually D2-40(-) and VEGFR-3(-)

MACROSCOPIC TOP DIFFERENTIAL DIAGNOSES

• Typically poorly circumscribed dermal &/or subcutaneous • Papillary intralymphatic angioendothelioma (Dabska tumor)
tumor • Composite hemangioendothelioma
• Kaposi sarcoma
MICROSCOPIC • Angiosarcoma
• Distinctive, elongated, arborizing blood vessels resembling
rete testis

Retiform Hemangioendothelioma Hobnailed Endothelial Cells

(Left) This cutaneous retiform
hemangioendothelioma (RHE)
shows superficial dermal
involvement by elongated,
irregularly branching vascular
spaces ﬈. Focal papillary
structures are present ﬊.
(Right) RHE features a
proliferation of elongated
vessels lined by
hyperchromatic-staining
hobnailed endothelial cells ﬉.
The surrounding stroma shows
fibrosis and scattered
lymphocytes.

Cytologic Features Stromal Lymphocytic Infiltrate

(Left) High-magnification view
of RHE shows hyperchromatic
endothelial cells with hobnail
features, nuclear crowding ﬊,
and focally enlarged nucleoli
﬉. (Right) H&E of the deep
aspect of a RHE shows
elongated vascular spaces
surrounded by prominent
lymphoid aggregates ﬊. Note
the hobnailed endothelial
cells.

458
 Retiform Hemangioendothelioma

Vascular Tumors (Including Lymphatics)

• Very prominent lymphocytic infiltrate reported in most
TERMINOLOGY cases
Abbreviations • May show invasion of subcutaneous tissues
• Retiform hemangioendothelioma (RHE) • Some cases show significant overlap with Dabska tumor
(both have hobnailed cells) with prominent papillary
Synonyms structures and hyaline cores
• Hobnail hemangioendothelioma
Definitions ANCILLARY TESTS
• Low-grade malignant vascular tumor composed of Immunohistochemistry
elongated vessels resembling rete testis • Vascular markers: CD31(+), CD34(+), and FVIIIRAg(+)
• Usually D2-40(-) and VEGFR-3(-)
ETIOLOGY/PATHOGENESIS
Unknown DIFFERENTIAL DIAGNOSIS
• Rare cases associated with lymphedema or preceding Papillary Intralymphatic Angioendothelioma (Dabska
radiation Tumor)
• 1 case reported to be positive for HHV8 • More common in children, but cases in young adults also
reported
CLINICAL ISSUES • Papillary structures more common
Epidemiology • Typically do not show prominent rete-like, elongated
vessels of RHE
• Incidence
• Some cases show significant overlap with RHE (both have
○ Rare
hobnailed cells)
• Age
○ Typically middle-aged adults but may occur in children Composite Hemangioendothelioma
• Sex • By definition, composed of at least 2 distinct
○ More common in females hemangioendothelioma types
Site ○ Predominant histologic components usually are
epithelioid hemangioendothelioma and RHE
• Trunk or extremities
Kaposi Sarcoma
Presentation
• Much more common, associated with HIV/AIDS or other
• Large, nodular to plaque-like lesion forms of immunosuppression
Treatment • Proliferation of small, slit-like vascular spaces lined by
• Wide local excision is necessary to prevent recurrence spindle cells lacking rete-like pattern of RHE
• HHV8(+) (only 1 case of RHE reported to be positive)
Prognosis
Angiosarcoma
• Locally aggressive, often with multiple recurrences if not
completely excised • Typically occurs in older adults or post mastectomy and
• Very rare metastases reported (regional lymph nodes) irradiation
• No deaths from disease reported • Proliferation of atypical spindled or epithelioid endothelial
cells, often forming anastomosing vascular spaces and
showing infiltrative features
MACROSCOPIC
General Features DIAGNOSTIC CHECKLIST
• Typically poorly circumscribed dermal &/or subcutaneous Pathologic Interpretation Pearls
tumor
• Proliferation of distinctive elongated blood vessels (lined by
Size hobnail cells) resembling rete testis
• May be large tumors (up to 12 cm)
SELECTED REFERENCES
MICROSCOPIC 1. Kiyohara T et al: Retiform hemangioendothelioma presenting as a
pedunculated nodule on the site of an inguinal pyoderma chronica. J
Histologic Features Dermatol. ePub, 2018
• Dermal-based infiltrative proliferation of distinctive, 2. Arriola AG et al: Atypical retiform hemangioendothelioma arising in a patient
with Milroy disease: a case report and review of the literature. J Cutan
elongated, arborizing blood vessels resembling rete testis Pathol. 44(1):98-103, 2017
• Vascular spaces are lined by endothelial cells with 3. Mota A et al: Clinical, dermoscopic and histopathologic findings of retiform
characteristic hobnail morphology hemangioendothelioma. Dermatol Pract Concept. 3(4):11-4, 2013
4. Keiler SA et al: Retiform hemangioendothelioma treated with Mohs
○ Endothelial cells show hyperchromasia, but typically do micrographic surgery. J Am Acad Dermatol. 65(1):233-5, 2011
not show prominent cytologic atypia 5. Parsons A et al: Retiform hemangioendotheliomas usually do not express
○ Hobnail cells with oval nuclei with mild hyperchromasia D2-40 and VEGFR-3. Am J Dermatopathol. 30(1):31-3, 2008
○ Mitotic figures may be present but are usually rare

459
 Composite Hemangioendothelioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY MACROSCOPIC
• Endothelial neoplasm of low malignant potential • Red to purple, nodular or multinodular mass
composed of admixture of histologically benign, • Infiltrative border
intermediate, and malignant components • Average: 5 cm; range: 1-30 cm
ETIOLOGY/PATHOGENESIS MICROSCOPIC
• Can arise from preexisting or congenital vascular • Complex admixture of variety of vasoformative patterns
malformation • Retiform hemangioendothelioma (HE) pattern
CLINICAL ISSUES ○ Most common and usually dominant
• Very rare • Epithelioid HE pattern
• Acral extremities most common ○ 2nd most common pattern
• Enlarging nodular erythematous or violaceous mass • Well-differentiated angiosarcoma pattern
• Treatment: Wide local excision • Spindle cell hemangioma pattern
• Local recurrence (up to 50%) TOP DIFFERENTIAL DIAGNOSES
• Metastases (15%) • Retiform HE
• No reports of death from disease to date • Epithelioid HE
• Well-differentiated angiosarcoma
• Spindle cell hemangioma

Retiform Hemangioendothelioma
Composite Hemangioendothelioma Component
(Left) Composite
hemangioendothelioma (HE)
usually presents as a
dermal/subcutaneous tumor
on an acral extremity. It has
complex histology with
admixtures of various
elements, most often retiform
﬈ and epithelioid HE ﬉.
(Right) Retiform HE is the
most common component of
composite HE, composed of
elongated, thin-walled
channels lined by endothelial
cells that protrude into the
lumen, forming a hobnail
pattern ﬉.

Epithelioid Hemangioendothelioma
Component Angiosarcoma-Like Areas
(Left) An epithelioid HE
component is present in most
composite HEs and consists of
cords of cells with abundant
eosinophilic cytoplasm ﬈
within hyalinized or myxoid
matrix. Cells with
intracytoplasmic vacuoles
mimic lipoblasts (inset).
(Right) Angiosarcoma-like
areas are present in some
tumors and are characterized
by irregular anastomosing
channels lined by atypical
endothelial cells ﬊. This
pattern is not associated with
a worse prognosis.

460
 Composite Hemangioendothelioma

Vascular Tumors (Including Lymphatics)

○ Long, branching, thin-walled vessels
TERMINOLOGY
○ Single layer of bland endothelial cells that protrude
Abbreviations intraluminally (hobnail pattern)
• Hemangioendothelioma (HE) ○ Intraluminal papillary structures in some
• Epithelioid HE pattern
Definitions
○ 2nd most common
• Endothelial neoplasm of low malignant potential ○ Cords, strands, or sheets of epithelioid endothelial cells
composed of admixture of histologically benign, – Abundant eosinophilic cytoplasm
intermediate, and malignant components
– Intracytoplasmic vacuoles
– Hyalin or myxoid stroma
ETIOLOGY/PATHOGENESIS
• Well-differentiated angiosarcoma pattern
Developmental Anomaly ○ Anastomosing spaces lined by atypical cells, often
• Can arise from preexisting or congenital vascular multilayered
malformation ○ Dissecting growth pattern
○ Minor component when present
CLINICAL ISSUES • Spindle cell hemangioma pattern
Epidemiology ○ Sheets and fascicles of spindle-shaped endothelial cells
○ Slit-like vascular spaces
• Incidence
○ Cavernous spaces, often with organizing thrombi and
○ Very rare
phleboliths
Site • Composite HE with neuroendocrine marker expression
• Dermis and subcutis ○ Variant tumor with synaptophysin staining and focal
○ Acral extremities most common nested pattern
– Foot/ankle region (50%) ○ Usually negative for chromogranin (< 10%) and CD56 (<
– Hand/forearm (25%) 50%)
• Oral mucosa (12%) ○ Often deep seated
• Other reported sites: Thigh, hip, upper arm, back, inguinal ○ More aggressive than convention variant
lymph nodes, mediastinum, scalp, kidney, manubrium, neck,
nose, spleen, hypopharynx, periaortic tissue, vertebra, DIFFERENTIAL DIAGNOSIS
pulmonary vein, liver Retiform Hemangioendothelioma
Presentation • Skin and soft tissue of acral extremities
• Enlarging nodular or multinodular erythematous or • Pure pattern, lacks other vascular components
violaceous mass Epithelioid Hemangioendothelioma
○ Satellite nodules, ulceration, bleeding, edema
• Various skin, soft tissue, osseous, and visceral sites
Natural History • Pure pattern, lacks other vascular components
• High local recurrence rate (up to 50%) Well-Differentiated Angiosarcoma
○ Often many years after primary excision
• Most often cutaneous tumor on scalp/face of elderly
• Metastases (15%)
patient
○ Usually to regional lymph nodes
• Dissecting channels lined by atypical, multilayered
Treatment endothelial cells
• Wide local excision Spindle Cell Hemangioma
Prognosis • Skin and soft tissue of acral extremities
• No reports of death from disease to date • Spindle cell, cavernous and epithelioid patterns
• Thrombi and phleboliths
MACROSCOPIC Kaposi Sarcoma
General Features • Fascicles of atypical spindle cells
• Red to purple, nodular or multinodular mass with • Slit-like, blood-filled spaces
infiltrative border • HHV8(+)
Size
SELECTED REFERENCES
• Average: 5 cm; range: 1-30 cm
1. Perry KD et al: Composite hemangioendothelioma with neuroendocrine
marker expression: an aggressive variant. Mod Pathol. 30(11):1589-1602,
MICROSCOPIC 2017
2. Requena L et al: Cutaneous composite hemangioendothelioma with
Histologic Features satellitosis and lymph node metastases. J Cutan Pathol. 35(2):225-30, 2008
• Complex admixture of variety of vasoformative patterns 3. Nayler SJ et al: Composite hemangioendothelioma: a complex, low-grade
vascular lesion mimicking angiosarcoma. Am J Surg Pathol. 24(3):352-61,
• Retiform HE pattern 2000
○ Most common and usually dominant
461
 Pseudomyogenic Hemangioendothelioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY
• Synonym: Epithelioid sarcoma-like hemangioendothelioma
• Distinctive vascular neoplasm of borderline malignant
potential that shows morphologic features reminiscent of
myoid neoplasm or epithelioid sarcoma
CLINICAL ISSUES
• Most common in young adults (mean: 30 years)
• Male predilection
• Most arise in extremities (particularly lower limb)
• Multicentric in over 50% of patients
○ May present in superficial &/or deep soft tissue
• Treatment: Complete surgical excision
• Generally indolent clinical course
○ Local recurrence common
○ True metastasis very rare
MACROSCOPIC
• Usually < 3 cm
MICROSCOPIC
• Ill-defined nodules, sheets, and fascicles
• Plump spindled and epithelioid cells with abundant
eosinophilic cytoplasm
• Usually scant mitoses
• Brisk neutrophilic infiltrate common
• Well-developed vasoformation absent
ANCILLARY TESTS
• Cytokeratin AE1/AE3(+), ERG(+), FLI-1(+)
• CD31(+) in 50% of cases
• Retained nuclear INI1
• t(7;19)(q22;q13) with SERPINE1-FOSB fusion
TOP DIFFERENTIAL DIAGNOSES
• Epithelioid sarcoma
• Sarcomatoid squamous cell carcinoma
• Epithelioid hemangioendothelioma
• Cellular fibrous histiocytoma (fibrous histiocytoma)

Pseudomyogenic Hemangioendothelioma Sheets, Nodules, and Fascicles

(Left) Pseudomyogenic
hemangioendothelioma (PMH)
﬈, a.k.a. epithelioid sarcoma-
like hemangioendothelioma, is
a distinctive vascular
neoplasm that, in > 1/2 of
cases, shows
multicentric/multifocal
nodular growth that often
involves multiple tissue planes,
including dermis, subcutis,
muscle, and even bone. (Right)
PMH typically grows in sheets,
ill-defined nodules, &/or
fascicles. Some areas contain
tumor cells that are tightly
packed ﬉, while others show
loose dyscohesion ﬊.

Pseudomyogenic Cells and Neutrophils Cytokeratin AE1/AE3 Expression

(Left) Tumor cells in PMH are
generally plump and spindled
and feature abundant, brightly
eosinophilic cytoplasm,
reminiscent of myoid cells.
Some larger cells can resemble
rhabdomyoblasts ﬉. A brisk
neutrophilic infiltrate ﬊ is
seen in ~ 50% of cases and is a
helpful diagnostic feature.
(Right) Strong cytokeratin
AE1/AE3 expression is
characteristic of PMH and can
lead to obvious confusion with
epithelioid sarcoma. The
latter, however, is positive for
CD34 (50% of cases), negative
for CD31, and shows loss of
INI1.

462
 Pseudomyogenic Hemangioendothelioma

Vascular Tumors (Including Lymphatics)

TERMINOLOGY
Abbreviations
• Pseudomyogenic hemangioendothelioma (PMH)
Synonyms
• Epithelioid sarcoma-like hemangioendothelioma
Definitions
• Distinctive vascular neoplasm of borderline malignant
potential that shows morphologic features reminiscent of
myoid neoplasm or epithelioid sarcoma
CLINICAL ISSUES
Epidemiology
• Age
○ Most common in young adults (mean: 30 years)
– Infrequent > 40 years
• Sex
○ Male predilection
Site
• Most common in lower extremity
• Also upper extremity, trunk, head/neck
Presentation
• Painful or painless nodule(s)
• Multicentric in > 50% of patients
• May present in superficial or deep soft tissue
○ Not uncommon for multiple tissue planes to be involved
– Skin, subcutis, muscle, &/or bone
○ Cutaneous lesions may be ulcerated
○ Intracytoplasmic lumen formation rare and usually focal
○ Some cells may resemble rhabdomyoblasts
○ Usually scant mitoses
• Fibrous or desmoplastic stroma; rarely myxoid
• Brisk neutrophilic infiltrate common
• Well-developed vasoformation absent
• Intralesional hemorrhage uncommon
• Some tumors contain foci of necrosis or vascular invasion
ANCILLARY TESTS
Immunohistochemistry
• Cytokeratin AE1/AE3(+), ERG(+), FLI-1(+)
○ Often negative for other keratins
• CD31(+) in 50% of cases
• FOSB(+)
• Retained nuclear INI1
• Focal SMA(+) in up to 30%
• CD34, EMA, S100 protein, desmin, myogenin, CAMTA1 (-)
Molecular Genetics
• Characteristic recurring t(7;19)(q22;q13)
○ Results in SERPINE1-FOSB fusion
DIFFERENTIAL DIAGNOSIS
Epithelioid Sarcoma
• Nodular growth predominates, often with necrosis
• Multicentric disease uncommon
• Loss of nuclear INI1
• Keratin (+), EMA(+); CD34(+) in 50% of tumors
• CD31 and FLI-1 (-)

Treatment Sarcomatoid Squamous Cell Carcinoma

• Complete surgical excision • Overlying in situ component may be present
• Usually more pronounced cytologic atypia
Prognosis • p63(+); CD31(-)
• Generally indolent clinical course
• Local recurrence common
Epithelioid Hemangioendothelioma
○ Often multiple; can occur over long time period • Cords and small aggregates of small epithelioid cells
• True metastasis very rare ○ Intracytoplasmic lumina common
○ Reported sites include lung, bone, lymph node, scalp • Characteristic myxohyaline stroma
○ Multicentricity may be mistaken for locoregional • CD31(+), CD34(+), ERG(+), FLI-1(+)
metastases • CAMTA1(+) by immunohistochemistry
• Characteristic t(1;3) with WWTR1-CAMTA1 fusion
MACROSCOPIC Cellular Fibrous Histiocytoma (Fibrous Histiocytoma)
General Features • Lacks plump, myoid-appearing tumor cells and brisk
• Poorly demarcated neutrophilic infiltrate
• Tan-white to gray cut surface • Negative for keratin
Size SELECTED REFERENCES
• Usually < 3 cm
1. Raftopoulos E et al: Pseudomyogenic hemangioendothelioma: case report
and review of the literature. Am J Dermatopathol. 40(8):597-601, 2018
MICROSCOPIC 2. Hung YP et al: FOSB is a useful diagnostic marker for pseudomyogenic
hemangioendothelioma. Am J Surg Pathol. 41(5):596-606, 2017
Histologic Features 3. Walther C et al: A novel SERPINE1-FOSB fusion gene results in
• Infiltrative borders transcriptional up-regulation of FOSB in pseudomyogenic
haemangioendothelioma. J Pathol. 232(5):534-40, 2014
• Ill-defined nodules, sheets, and fascicles 4. Hornick JL et al: Pseudomyogenic hemangioendothelioma: a distinctive,
• Plump spindled and epithelioid cells with abundant often multicentric tumor with indolent behavior. Am J Surg Pathol.
eosinophilic cytoplasm 35(2):190-201, 2011
5. Billings SD et al: Epithelioid sarcoma-like hemangioendothelioma. Am J Surg
○ Round, vesicular nuclei with variable nucleoli Pathol. 27(1):48-57, 2003
– Usually mild to moderate atypia; rarely marked
463
 Pseudomyogenic Hemangioendothelioma
Vascular Tumors (Including Lymphatics)

Myoid Appearance Cytologic Features

(Left) Sheets of plump
eosinophilic spindled cells may
naturally bring to mind a
myogenic tumor, such as
rhabdomyosarcoma or
leiomyosarcoma. PMH,
however, is negative for
desmin and myogenin and
does not show diffuse SMA
positivity. (Right) Tumor cell
nuclei are mostly round to
ovoid, but elongated forms
can be seen as well. They
contain vesicular chromatin
with variably prominent
nucleoli. Atypia is generally
mild, but occasional cases can
show focal marked atypia or
nuclear pleomorphism.

Loosely Cellular Areas Myxoid Stroma

(Left) In addition to tightly
packed, cellular areas, foci of
apparent cellular dyscohesion
are common in PMH. The
stroma varies from fibrous to
myxoid and can appear
desmoplastic, as depicted.
(Right) Myxoid stroma may be
seen in PMH but is usually
focal. Note the prominent
eosinophilic cytoplasm of the
tumor cells in this H&E.

Fascicular Growth Thinner Spindled Cells

(Left) A loose fascicular
architecture is common in
PMH and can result in the
tumor being misinterpreted as
a spindled epithelioid sarcoma
(fibroma-like variant).
Fascicles may be better
developed in some tumors but
rarely to the degree that a
fibroblastic sarcoma is
considered. Vague storiform
growth may also be seen.
(Right) Tumor cells in this
fascicular area of PMH are
more slender than plump, but
more typical cells ﬈ can still
be identified upon close
inspection. Note the subtle
scattered neutrophils ﬉.

464
 Pseudomyogenic Hemangioendothelioma
Deceptively Bland Areas
Epithelioid Cytomorphology
Frozen Section Tissue
Vascular Tumors (Including Lymphatics)
Bony Involvement
(Left) Several foci containing
slender, spindled tumor cells,
as depicted, were found
adjacent to the main tumor
nodule in this case of PMH. At
low power, these areas may be
misconstrued as reactive
fibroblastic proliferations and
not taken into consideration
when evaluating the margin
status. (Right) PMH can
involve superficial and deep
soft tissues, including bone, as
depicted. This patient had
separate discontiguous tumor
nodules in the skin, subcutis,
muscle, and bone of the foot
and ankle.
Infiltrative Growth
(Left) A distinct epithelioid
cytomorphology is usually
present in PMH but is often
focal. In conjunction with
cytokeratin AE1/AE3
expression, squamous cell
carcinoma and epithelioid
sarcoma are potential serious
misdiagnoses. (Right) Tumor
nodules in PMH are generally
poorly defined and often show
infiltrative borders
microscopically. This H&E
shows an intramuscular mass
featuring an irregular border
with surrounding mature
skeletal muscle ﬉.
CD31 Expression
(Left) Characteristic features
of PMH can often be identified
even on frozen section. Note
the plump tumor cells,
scattered rhabdomyoblast-like
cells ﬉, and scattered
neutrophils ﬈. (Right) CD31
positivity is seen in 50% of
cases of PMH and shows a true
endothelial pattern of
expression (strong, linear
membranous staining) in
contrast to weak, granular
staining in histiocytes. ERG
and FLI-1 are also positive in
PMH; however, CD34 is
negative.
465
 Epithelioid Hemangioendothelioma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY
• Malignant angiocentric vascular neoplasm composed of
epithelioid endothelial cells within characteristic
myxohyaline stromal matrix
CLINICAL ISSUES
• Most common: 30-50 years
• Wide distribution in soft tissue
• Also visceral organs (particularly liver and lung)
• Solitary, often painful mass
○ Multicentricity at presentation likely represents
locoregional metastases
• Treatment: Wide surgical excision with negative margins
• Indolent clinical course in majority of cases
• Metastases in 20-30%
• Overall mortality rate of 10-20%
○ High-risk tumors are > 3 cm with > 3 mitoses/50 HPF
– Associated with significant decrease in survival
MICROSCOPIC
• Infiltrative growth with absence of defined lobularity
• Epithelioid eosinophilic cells arranged in cords, nests
○ Intracytoplasmic vacuoles common ("blister cells")
• Well-formed vascular channels typically absent
• Characteristic myxoid to hyaline stromal matrix
• Involvement of larger vessels common
ANCILLARY TESTS
• CD31, CD34, ERG, FLI-1, CAMTA1 (+)
• Nuclear TFE3(+) observed in distinctive genetic subset
• Keratin (+) in up to 35% of cases, often focal
• Molecular: t(1;3)(p36;q25) with WWTR1-CAMTA1
○ Distinctive subset contains YAP1-TFE3 fusion
TOP DIFFERENTIAL DIAGNOSES
• Epithelioid hemangioma
• Epithelioid angiosarcoma
• Composite hemangioendothelioma

Epithelioid Hemangioendothelioma Intracytoplasmic Vacuoles

(Left) Epithelioid
hemangioendothelioma (EHE)
is a distinctive malignant
vascular neoplasm
characterized by predominant
cords of epithelioid tumor cells
within a characteristic myoid
to hyaline matrix. (Right)
Another characteristic finding
in EHE is the presence of
intracytoplasmic vacuoles ﬉.
Despite their resemblance to
fat cells, these spaces actually
represent immature vascular
lumina and may at times
contain erythrocytes ﬈.

Vessel Involvement Endothelial Marker Expression

(Left) EHE is an angiocentric
neoplasm, and evidence of
origin from a larger vessel may
be evident histologically. Note
the residual smooth muscle
wall ﬈ in this hematoxylin
and eosin. Tumor cells often
extend outward from the
involved vessel into the
surrounding tissues. (Right)
EHE shows expression of
endothelial markers, including
CD31 (shown), CD34, ERG, and
FLI-1. Nuclear CAMTA1(+) is
also present in tumors with
CAMTA1 gene fusion. Focal
keratin positivity is seen in up
to 1/3 of cases.

466
 Epithelioid Hemangioendothelioma

Vascular Tumors (Including Lymphatics)

TERMINOLOGY MACROSCOPIC
Abbreviations General Features
• Epithelioid hemangioendothelioma (EHE) • Well-circumscribed nodular lesion
• Firm, tan-gray cut surface
Synonyms
• Intravascular tumors may simulate organizing thrombi
• Intravascular bronchioloalveolar tumor (lung)
Size
Definitions
• Wide range
• Malignant angiocentric vascular neoplasm composed of
○ Mean: 2.5 cm in one large series
epithelioid endothelial cells within characteristic
myxohyaline stromal matrix
MICROSCOPIC
CLINICAL ISSUES Histologic Features
Epidemiology • Infiltrative growth with absence of defined lobularity
• Epithelioid cells arranged in cords, singly, and in small
• Incidence
aggregates or nests
○ Rare
○ Pale to densely eosinophilic cytoplasm
• Age
– Intracytoplasmic vacuoles representing primitive
○ Wide range affected
vascular lumina (blister cells)
– Most common: 30-50 years
□ May contain erythrocytes
– Rare in childhood
○ Small, vesicular nuclei ± small nucleoli
• Sex
– Occasional tumors show marked nuclear
○ Slight female predominance pleomorphism and hyperchromasia
Site ○ Mitotic rate usually low (< 3 figures per 50 HPF)
• Wide distribution in soft tissue ○ Occasional spindled cytomorphology
○ Extremities, head/neck region, others • Well-formed vascular channels typically absent
• Visceral organs (particularly liver and lung) • Characteristic myxoid to hyaline stromal matrix
○ Contains sulfated acid mucopolysaccharides
Presentation • Involvement of larger vessels common
• Solitary, often painful mass ○ Obliteration of lumina
○ Superficial or deep ○ Outward growth of tumor cells into surrounding tissue
○ Rarely cutaneous • Metaplastic calcification &/or ossification in some cases
• Apparent multicentricity at time of presentation (up to 50% • Necrosis infrequent
of cases) • Site-specific unique features (visceral EHE)
○ Recent molecular data supports conclusion of ○ Lung
locoregional metastases over multiple primary lesions – Characteristic alveolar-filling pattern
• Occlusion of vessels – Central necrosis common
○ 30-50% of cases arise in or are associated with ○ Liver
preexisting vessel – Distinct tumor nodules common
○ May cause more profound vasoocclusive symptoms, – Entrapped hepatocytes and bile ducts common
including edema
Morphologic/Genetic Variant
Treatment
• EHE with YAP1-TFE3 fusion
• Wide surgical excision with negative margins
○ Tumor cells often feature more abundant eosinophilic
• No proven role for adjuvant chemo-/radiotherapy cytoplasm
Prognosis ○ Vasoformation more developed
• Indolent clinical course in majority of cases
○ Local recurrence in 10-15% ANCILLARY TESTS
• Metastases in 20-30% Immunohistochemistry
○ Usually liver, bone, lungs • CD31, CD34, ERG, FLI-1 (+)
○ Occasionally regional lymph nodes • CAMTA1(+) in tumors with CAMTA1 fusion
• Overall mortality rate of 10-20% ○ Nuclear TFE3(+) observed in YAP1-TFE3 fusion subset
• Proposed risk assessment • Keratin (+) in up to 35% of cases, often focal
○ High-risk EHE features size > 3 cm and > 3 mitoses per 50 • FOSB, S100 protein, SMA, desmin, CD117, EMA, HMB-45 (-)
HPF
– Significant decrease in survival in these cases Molecular Genetics
• Characteristic t(1;3)(p36;q25) in most cases (90%)
○ Results in WWTR1-CAMTA1 fusion
• Distinctive subset (5%) contains YAP1-TFE3 fusion

467
 Epithelioid Hemangioendothelioma
Vascular Tumors (Including Lymphatics)
DIFFERENTIAL DIAGNOSIS
Epithelioid Hemangioma
• Lobular architecture
• Well-formed vascular channels present; plump endothelial
cells
• Complete rim of SMA(+) pericytes
• Characteristic mixed chronic inflammatory infiltrate,
particularly eosinophils
• FOSB(+) by immunohistochemistry
• Lacks genetic signatures of EHE
Epithelioid Angiosarcoma
• Background of conventional angiosarcoma often present
• Large epithelioid tumor cells in nests or lining irregular
vascular spaces
• Mitoses common, include atypical forms
• Frequent tumor necrosis
Composite Hemangioendothelioma
• Rare tumor
• Most occur on distal extremities, particularly hands and feet
• Contains components of at least 2 vascular neoplasms
○ Often retiform hemangioendothelioma and EHE
○ Also, well-differentiated angiosarcoma, spindle cell
hemangioma, others
Pseudomyogenic Hemangioendothelioma
• Sheets and fascicles of predominantly plump spindled cells
• Neutrophilic infiltrate common
• Keratin (+) usually diffuse; CD34(-)
• FOSB(+) by immunohistochemistry
Myoepithelioma of Soft Tissue
• Epithelial differentiation evidence in subset (mixed tumor)
• Lacks angiocentric growth
• Usually diffuse keratin (+)
• S100 protein (+) in most cases
• Variable expression of SMA, GFAP, several other markers
• CD31, CD34, ERG (-)
Epithelioid Sarcoma
• Most common in distal extremities of younger patients
• May show granuloma-like growth pattern with centralized
necrosis
• Diffuse expression of keratins and EMA
• CD31 (-)
• Loss of nuclear INI1 expression
Extraskeletal Myxoid Chondrosarcoma
• Prominent lobular growth with fibrous septa
• Fibrous pseudocapsule common
• Small, rounded to spindled tumor cells with uniform nuclei
• Prominent myxoid, hypovascular stroma
• Keratin, CD31, CD34, ERG (-)
• Fusions involving NR4A3 (most commonly to EWSR1)
Metastatic Carcinoma
• Clinical history of primary tumor
• Usually higher degree of atypia
• Strong, diffuse keratin (+)
• CD31 and CD34 (-)
468
Chondroid Lipoma
• Lobular, often encapsulated
• Conspicuous lipogenic component (mature adipocytes,
lipoblasts)
• CD31, CD34, keratins (-)
SELECTED REFERENCES
1. Studer LL et al: Hepatic epithelioid hemangioendothelioma. Arch Pathol Lab
Med. 142(2):263-267, 2018
2. Thway K et al: Multicentric visceral epithelioid hemangioendothelioma, with
extremity dermal deposits, unusual late recurrence on the nasal bridge, and
TFE3 gene rearrangement. Hum Pathol. 72:153-159, 2018
3. Sugita S et al: Diagnostic utility of FOSB immunohistochemistry in
pseudomyogenic hemangioendothelioma and its histological mimics. Diagn
Pathol. 11(1):75, 2016
4. Anderson T 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. 39(1):132-
9, 2015
5. Doyle LA et al: Nuclear expression of CAMTA1 distinguishes epithelioid
hemangioendothelioma from histologic mimics. Am J Surg Pathol. 40(1):94-
102, 2015
6. Patel NR et al: Molecular characterization of epithelioid
haemangioendotheliomas identifies novel WWTR1-CAMTA1 fusion variants.
Histopathology. 67(5):699-708, 2015
7. Puls F et al: YAP1-TFE3 epithelioid hemangioendothelioma: a case without
vasoformation and a new transcript variant. Virchows Arch. 466(4):473-8,
2015
8. Shibuya R et al: CAMTA1 is a useful immunohistochemical marker for
diagnosing epithelioid hemangioendothelioma. Histopathology. 67(6):827-
35, 2015
9. Flucke U et al: Epithelioid Hemangioendothelioma: clinicopathologic,
immunhistochemical, and molecular genetic analysis of 39 cases. Diagn
Pathol. 9:131, 2014
10. Antonescu CR et al: Novel YAP1-TFE3 fusion defines a distinct subset of
epithelioid hemangioendothelioma. Genes Chromosomes Cancer.
52(8):775-84, 2013
11. Chevreau C et al: Sorafenib in patients with progressive epithelioid
hemangioendothelioma: a phase 2 study by the French Sarcoma Group
(GSF/GETO). Cancer. 119(14):2639-44, 2013
12. Mistry AM et al: Diagnostic and therapeutic challenges in hepatic epithelioid
hemangioendothelioma. J Gastrointest Cancer. 43(4):521-5, 2012
13. Wang LR et al: Clinical experience with primary hepatic epithelioid
hemangioendothelioma: retrospective study of 33 patients. World J Surg.
36(11):2677-83, 2012
14. Murali R et al: Cytologic features of epithelioid hemangioendothelioma. Am
J Clin Pathol. 136(5):739-46, 2011
15. Woelfel C et al: Molecular cytogenetic characterization of epithelioid
hemangioendothelioma. Cancer Genet. 204(12):671-6, 2011
16. Gill R et al: Utility of immunohistochemistry for endothelial markers in
distinguishing epithelioid hemangioendothelioma from carcinoma
metastatic to bone. Arch Pathol Lab Med. 133(6):967-72, 2009
17. Clarke LE et al: Cutaneous epithelioid hemangioendothelioma. J Cutan
Pathol. 35(2):236-40, 2008
18. Deyrup AT et al: Epithelioid hemangioendothelioma of soft tissue: a
proposal for risk stratification based on 49 cases. Am J Surg Pathol.
32(6):924-7, 2008
19. Celikel C et al: Epithelioid hemangioendothelioma with multiple organ
involvement. APMIS. 115(7):881-8, 2007
20. Bagan P et al: Prognostic factors and surgical indications of pulmonary
epithelioid hemangioendothelioma: a review of the literature. Ann Thorac
Surg. 82(6):2010-3, 2006
21. Tsarouha H et al: Chromosome analysis and molecular cytogenetic
investigations of an epithelioid hemangioendothelioma. Cancer Genet
Cytogenet. 169(2):164-8, 2006
22. Mendlick MR et al: Translocation t(1;3)(p36.3;q25) is a nonrandom
aberration in epithelioid hemangioendothelioma. Am J Surg Pathol.
25(5):684-7, 2001
23. Quante M et al: Epithelioid hemangioendothelioma presenting in the skin: a
clinicopathologic study of eight cases. Am J Dermatopathol. 20(6):541-6,
1998
24. Mentzel T et al: Epithelioid hemangioendothelioma of skin and soft tissues:
clinicopathologic and immunohistochemical study of 30 cases. Am J Surg
Pathol. 21(4):363-74, 1997
25. Weiss SW et al: Epithelioid hemangioendothelioma: a vascular tumor often
mistaken for a carcinoma. Cancer. 50(5):970-81, 1982
 Epithelioid Hemangioendothelioma
Nested Growth
Spindled Cytomorphology
Hepatic Epithelioid
Hemangioendothelioma
Vascular Tumors (Including Lymphatics)
Increased Cellularity
(Left) In addition to growth in
cords and chains, tumor cells
in EHE may also be arranged in
small aggregates and nests, as
depicted. Note the
intracytoplasmic vacuoles ﬊.
Also note that the stroma is
more hyaline than myxoid in
this hematoxylin and eosin.
(Right) Some cases of EHE
feature areas of increased
cellularity, as depicted. Note
also that some tumor cells can
appear to contain multiple
intracytoplasmic vacuoles ﬉,
mimicking true lipoblastic
cells.
Metaplastic Bone Formation
(Left) Spindling of tumor cells
is seen in a minor proportion
of cases of EHE. Areas of more
conventional epithelioid
morphology are usually also
present. Increased nuclear
atypia may also be seen but
does not correlate well with
more aggressive behavior. In
contrast, increased size and
mitotic activity do appear to
correlate with reduced
survival. (Right) Foci of
metaplastic ossification ﬊
may be seen in up to 10% of
EHE.
Pulmonary Epithelioid
Hemangioendothelioma
(Left) Hepatic EHE shows a
similar morphology to soft
tissue EHE; however,
entrapped hepatocytes and
reactive bile ducts ﬉ are
often present. Growth as
multiple distinct nodules is
also more common in this site.
(Right) Pulmonary EHE shows
a characteristic alveolar-filling
pattern by tumor nodules ﬈.
Central necrosis within tumor
nodules is also relatively
common.
469
 Angiosarcoma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY • Overall poor prognosis (overall survival rate: 30%)

• Malignant neoplasm showing morphologic &/or ○ Epithelioid angiosarcoma is often more aggressive
immunophenotypic evidence of vascular/endothelial MICROSCOPIC
differentiation
• Infiltrative tumors with dissecting growth through fat and
ETIOLOGY/PATHOGENESIS collagen characteristic
• Subsets associated with prior radiotherapy, chronic • Histologic appearance depends upon degree of
lymphedema, exposure to certain chemicals, certain vasoformation
syndromes • Lesional endothelial cells show variable nuclear atypia;
often multilayering
CLINICAL ISSUES • Morphologic variant: Epithelioid angiosarcoma
• Wide age range overall (more common in adults)
• Various clinical features depending upon subset ANCILLARY TESTS
○ Cutaneous scalp/face in elderly, cutaneous breast with • CD31(+), CD34(+), ERG(+), FLI-1(+)
history of radiotherapy or chronic lymphedema, • Keratin (+) in significant subset of epithelioid angiosarcoma
parenchymal breast in young women TOP DIFFERENTIAL DIAGNOSES
○ Deep soft tissue forms most common in lower extremity
• Hemangioma
• Treatment: Aggressive surgical resection with widely
negative margins • Atypical vascular lesion
• Kaposi sarcoma

Angiosarcoma Angiosarcoma
(Left) Angiosarcoma is an
aggressive vascular
malignancy that occurs most
commonly in adults, especially
in cutaneous sites (particularly
the scalp and face), but can
also involve the breast, deep
soft tissues, bone, and visceral
organs. (Right) Depending
upon the degree of
vasoformation in a given case,
some areas of angiosarcoma
may appear more clearly
vascular (with luminal spaces
﬈), and others may appear
less well differentiated ﬉.

Infiltrating, Dissecting Growth Atypical Endothelial Cells

(Left) Infiltrative and
dissecting growth through
collagenous connective tissue
and adipose tissue by
irregularly shaped and
anastomosing vascular
channels is a characteristic
feature of angiosarcoma. The
depth and extent of
infiltration can be striking.
(Right) The lesional
endothelial cells in many cases
of angiosarcoma show at least
mild nuclear enlargement and
hyperchromasia. Multilayering
﬈ &/or tufting of nuclei is
also a common feature.

470
 Angiosarcoma

Vascular Tumors (Including Lymphatics)

• Breast
TERMINOLOGY
○ May be cutaneous or parenchymal
Synonyms – Cutaneous
• Hemangiosarcoma □ Macroscopically similar to other cutaneous forms
• Malignant hemangioendothelioma □ Often history of irradiation to breast or chest wall
area (short latency, usually < 7 years)
Definitions
□ Occurrence in setting of postsurgical lymphedema
• Malignant neoplasm showing morphologic &/or (Stewart-Treves syndrome)
immunophenotypic evidence of vascular/endothelial – Parenchymal
differentiation □ Solitary or multiple breast masses
• Many clinicopathologic subsets (cutaneous, deep soft □ May show purple discoloration of overlying skin
tissue, radiation or lymphedema associated, breast
• Deep soft tissue
parenchymal, others)
○ Slow-growing, often large, painful mass
ETIOLOGY/PATHOGENESIS ○ Hematologic abnormalities (e.g., coagulopathy) in up to
1/3 of cases
Developmental Anomaly ○ May also arise within field of previous irradiation
• Develops rarely in association with genetic syndromes
Treatment
○ Klippel-Trenaunay, Maffucci, neurofibromatosis
• Aggressive surgical resection with widely negative margins
○ Often deep soft tissue angiosarcoma
• Chemotherapy
Environmental Exposure
Prognosis
• Associated with exposure to radiation or certain chemicals
(e.g., polyvinyl chloride) • Overall poor prognosis (overall survival rate: 30%)
• Can arise within setting of chronic lymphedema ○ Local recurrences and distant metastases common
• Rarely develops adjacent to foreign material or synthetic – Cutaneous disease is often more extensive than
vascular grafts clinically/macroscopically apparent
– Metastases to lung, brain, bone, soft tissue sites,
Tumor Associations others
• May rarely arise in benign nerve sheath tumors, malignant ○ High mortality rate
nerve sheath tumors, germ cell tumors, others • In general, prognosis unrelated to histologic grade
○ Possible exception: Breast parenchymal tumors
CLINICAL ISSUES • Adverse prognostic factors for deep soft tissue cases: Older
Epidemiology age, larger size, high proliferation rate, retroperitoneal
origin
• Incidence
• Tumors with prominent epithelioid morphology are often
○ Rare (< 1-2% of all sarcomas)
more clinically aggressive than conventional forms
– Cutaneous angiosarcoma is most common form
• Age MACROSCOPIC
○ Wide age range overall
– Cutaneous: 60-80 years most common General Features
– Breast parenchymal: 30-40 years most common • Poorly demarcated or nodular
○ Rare in childhood • Red to brown hemorrhagic cut surface
• Sex Size
○ Male predominance in nonbreast cutaneous and deep
• Highly variable but often large
soft tissue
○ Female predominance in breast (cutaneous and
MICROSCOPIC
parenchymal)
Histologic Features
Site
• Often highly infiltrative and not well demarcated
• Most common site overall is scalp and face (cutaneous type)
○ Poorly differentiated areas are often more nodular and
○ Superficial cutaneous tumors may also arise elsewhere, better demarcated
including breast and lower extremity
• Apparent multifocality within same tissue section is
• Deep soft tissue tumors are most common in deep muscles common
of lower extremity
• Morphologic appearance depends heavily upon degree of
○ Also retroperitoneum, abdominal cavity, mesentery vasoformation
• Also arises in breast parenchyma, spleen, liver, heart, bone, ○ Formation of irregular, anastomosing vascular channels
other viscera in well-differentiated areas
Presentation – Vessels characteristically appear to dissect through
• Cutaneous collagen, fat, and other soft tissues
○ Dark red or purple nodules, plaques, or bruise-like areas □ May entrap fragments of collagen and form
○ May be multifocal intraluminal papillary structures

471
 Angiosarcoma
Vascular Tumors (Including Lymphatics)
– Endothelial cell lining may show multilayering or
intraluminal tufting
□ Nuclear atypia varies, but hyperchromasia,
enlargement, and irregularity are often present
□ Mitotic activity variable, often conspicuous
□ Intracytoplasmic lumina may be present focally
– Back-to-back vascular channels may appear sieve-like
○ Solid growth in more poorly differentiated areas
– Cells may be spindled, epithelioid, or pleomorphic
○ Intraluminal erythrocytes and hemorrhage common
○ Stromal lymphoid infiltrate may be present
○ Pericytes usually absent
• Rare findings: Solid spindle, granular, clear cell, or foamy
cell morphology; prominent inflammation
Morphologic Variants
• Epithelioid angiosarcoma
○ More frequent in deep soft tissues
○ Predominantly large epithelioid cells in nests and sheets
– Abundant eosinophilic cytoplasm
– Large vesicular nuclei with prominent macronucleoli
○ Irregular vascular spaces lined by protuberant epithelioid
cells may also be seen
○ Mitoses often numerous; necrosis common
ANCILLARY TESTS
Immunohistochemistry
• Endothelial differentiation
○ CD31(+), CD34(+), ERG(+), FLI-1(+)
– Multistain panel recommended, as sensitivity varies
○ Variable D2-40 (podoplanin)
• Keratin (+) in significant subset of epithelioid angiosarcoma
• SMA, desmin, HHV8, CAMTA1 (-)
• Retention of nuclear INI1 expression
Molecular Genetics
• High-level MYC (8q24) amplification in radiation-
/lymphedema-associated (secondary) tumors
• FLT4 (VEGFR3) (5q35) amplification in 25% of secondary
tumors
DIFFERENTIAL DIAGNOSIS
Hemangioma
• Well-defined lobular architecture
○ No peripheral infiltrative or dissecting growth
• Well-formed vascular channels with bland endothelial cells
○ No endothelial multilayering and tufting
Atypical Vascular Lesion
• Small, solitary, or multiple lesion(s) in previously irradiated
skin
○ Small size (median 0.5 cm) of atypical vascular lesion is
helpful feature
• Histologically resemble lymphangioma
• Usually no multilayering or significant nuclear atypia
Kaposi Sarcoma
• Predominantly spindled cellular morphology
• Vasoformation generally less developed than in
angiosarcoma
472
• Characteristically HHV8(+)
Retiform Hemangioendothelioma
• Most common in extremities of younger patients
• Slit-like spaces lined by hobnail tumor cells
• Absence of nuclear pleomorphism and multilayering
Atypical Fibroxanthoma
• Small lesion; lacks vasoformation
• CD31, CD34, ERG (-)
○ CD31 stains histiocytes
Papillary Endothelial Hyperplasia
• Generally small lesions
• Bulk of lesion confined to lumen of vessel
• Lacks nuclear atypia, mitoses, and necrosis
Giant Cell Fibroblastoma
• Most common in children
• Cleft-like pseudovascular spaces lined by mononuclear and
multinucleated giant cells
• CD34(+) but CD31 and ERG (-)
• Related to dermatofibrosarcoma protuberans
Epithelioid Hemangioendothelioma
• Included in differential diagnosis of epithelioid
angiosarcoma
• Lacks well-developed vasoformation
• Characteristic chondromyxoid stroma
• Recurrent t(1;3) involving CAMTA1 and WWTR1
Metastatic Carcinoma or Melanoma
• Can resemble epithelioid angiosarcoma
• Lacks vasoformation
• Diffuse keratin (+) in carcinoma
• Diffuse S100 protein (+) in melanoma
Epithelioid Sarcoma (Proximal Type)
• Can resemble epithelioid angiosarcoma
• Diffuse keratin (+); CD34(+) in 50% of cases
• May express ERG but CD31(-)
• Loss of nuclear INI1 expression
SELECTED REFERENCES
1. Requena C et al: Immunohistochemical and fluorescence in situ hybridization
analysis of MYC in a series of 17 cutaneous angiosarcomas: A Single-center
study. Am J Dermatopathol. 40(5):349-354, 2018
2. Gervais MK et al: Clinical outcomes in breast angiosarcoma patients: a rare
tumor with unique challenges. J Surg Oncol. 116(8):1056-1061, 2017
3. Shustef E et al: Cutaneous angiosarcoma: a current update. J Clin Pathol.
70(11):917-925, 2017
4. Patel SH et al: Angiosarcoma of the scalp and face: the Mayo Clinic
experience. JAMA Otolaryngol Head Neck Surg. 141(4):335-40, 2015
5. Suchak R et al: Primary cutaneous epithelioid angiosarcoma: a
clinicopathologic study of 13 cases of a rare neoplasm occurring outside the
setting of conventional angiosarcomas and with predilection for the limbs.
Am J Surg Pathol. 35(1):60-9, 2011
6. Lucas DR: Angiosarcoma, radiation-associated angiosarcoma, and atypical
vascular lesion. Arch Pathol Lab Med. 133(11):1804-9, 2009
7. Nascimento AF et al: Primary angiosarcoma of the breast: clinicopathologic
analysis of 49 cases, suggesting that grade is not prognostic. Am J Surg
Pathol. 32(12):1896-904, 2008
8. Fayette J et al: Angiosarcomas, a heterogeneous group of sarcomas with
specific behavior depending on primary site: a retrospective study of 161
cases. Ann Oncol. 18(12):2030-6, 2007
9. Meis-Kindblom JM et al: Angiosarcoma of soft tissue: a study of 80 cases. Am
J Surg Pathol. 22(6):683-97, 1998
 Angiosarcoma
Subtle Nuclear Atypia
Papillary-Like Structures
Infiltration of Adipose Tissue
Vascular Tumors (Including Lymphatics)
Papillary-Like Structures
(Left) In highly differentiated
areas of angiosarcoma, the
lesional endothelial cells may
show very little atypia;
however, the irregular and
dissecting growth can help
establish the diagnosis. (Right)
A common finding in
angiosarcoma is variably sized,
papillary-like structures ﬉
composed of collagen lined by
lesional endothelial cells.
These structures can also
appear to float freely ﬊
within the open vascular
spaces.
Infiltration of Adipose Tissue
(Left) In some areas, the
papillary-like structures may
be abundant and resemble
papillary endothelial
hyperplasia. (Right)
Angiosarcoma can infiltrate
normal subcutaneous adipose
tissue and may show extensive
or subtle involvement. Note
the irregular, infiltrating
vascular channels ﬊.
Subtle Cutaneous Involvement
(Left) H&E of angiosarcoma
shows a highly fat-infiltrative
tumor with extensive
hemorrhage, somewhat
obscuring the malignant
tumor cells. (Right)
Conspicuous vascular lumina
are not present in all areas of
angiosarcoma, and
identification of subtle tumor
foci ﬊ can be challenging.
This appearance can be
problematic when evaluating
margins by frozen section at
the time of surgery.
473
 Angiosarcoma
Vascular Tumors (Including Lymphatics)

Prominent Nuclear Atypia Marked Nuclear Pleomorphism

(Left) In some cases of
angiosarcoma, the lesional
endothelial cells show a much
greater degree of nuclear
enlargement and
hyperchromasia. (Right) In
occasional cases, there is
marked nuclear pleomorphism
in angiosarcoma. This may
lead to consideration of other
malignant entities in solid
areas in a small biopsy.

Variable Vasoformation Solid Growth

(Left) A variable degree of
vasoformation is a common
occurrence in angiosarcoma.
Note the more well-
differentiated, vasoformative
areas (right) and less-
differentiated, more solid
areas (left). (Right) Poorly
differentiated areas of
angiosarcoma often show a
greater degree of solid
growth; however,
vasoformation ﬊ is still
evident, at least focally.

Sieve-Like Pattern Hemorrhage

(Left) A sieve-like or lattice-
like growth pattern may be
seen in some areas of
angiosarcoma. These back-to-
back channels may also
contain abundant
erythrocytes. (Right)
Hemorrhage is not uncommon
in angiosarcoma and may be
prominent in some cases. It
can occasionally be so
extensive that the neoplastic
cells are obscured and
underrecognized.

474
 Angiosarcoma
Spindled Morphology
Epithelioid Angiosarcoma Prominent Epithelioid Morphology
Macronucleoli
Vascular Tumors (Including Lymphatics)
Prominent Inflammation
(Left) A spindled morphology
may be seen in poorly
differentiated areas of
angiosarcoma. It can also be
the dominant pattern in rare
tumors. (Right) Stromal
chronic inflammatory cells,
particularly lymphocytes and
plasma cells, may be seen in
angiosarcoma, particularly in
cutaneous forms. When
extensive, it may obscure the
underlying neoplasm. Note the
hyperchromatic endothelial
cell nuclei ﬊.
(Left) The lesional endothelial
cells of angiosarcoma may
show an epithelioid
morphology in some cases;
rarely, is it a predominant
feature of the tumor. In the
latter scenario, the term
epithelioid angiosarcoma is
often utilized. (Right)
Epithelioid angiosarcoma may
mimic a variety of epithelioid
neoplasms, including,
carcinoma, melanoma, and
epithelioid sarcoma.
Immunohistochemistry is often
necessary.
Epithelioid Angiosarcoma
(Left) A characteristic finding
in epithelioid angiosarcoma is
the presence of enlarged
vesicular nuclei with
prominent macronucleoli ﬈.
(Right) In some cases of
epithelioid angiosarcoma, the
malignant cells form diffuse
sheets. Prominent nucleoli ﬈
and mitotic figures ﬉ are
evident even at this
magnification.
475
 Kaposi Sarcoma

KEY FACTS
Vascular Tumors (Including Lymphatics)

TERMINOLOGY • Tumor stage

• Vascular neoplasm (usually low grade) caused by HHV8 ○ Nodules with intersecting fascicles of spindle cells
○ Blood-filled, slit-/sieve-like spaces between spindle cells
CLINICAL ISSUES
ANCILLARY TESTS
• Sites: Skin (majority), mucosa, lymph nodes, organs
• Clinical variants • Positive HHV8 (LANA1) in essentially 100%
○ Classic: Lower legs/feet of elderly (M > F); indolent TOP DIFFERENTIAL DIAGNOSES
○ African/endemic: Children/adults in equatorial Africa • Angiosarcoma
○ Iatrogenic: Immunosuppressed patients of any age • Severe vascular stasis (acroangiodermatitis)
○ AIDS associated: Aggressive (often disseminated) • Hobnail (targetoid hemosiderotic) hemangioma
• Many modalities for symptom control but no cure • Microvenular hemangioma
MICROSCOPIC • Spindle cell hemangioma
• Patch stage • Kaposiform hemangioendothelioma
○ Infiltrative interconnected vascular channels dissect • Acquired tufted angioma
dermal collagen; scattered plasma cells (useful clue) • Progressive lymphangioma
• Plaque stage • Cellular fibrous histiocytoma
○ Spindle cell proliferation infiltrating dermis and • Leiomyosarcoma (cutaneous)
invading/destroying eccrine glands

Classic Kaposi Sarcoma Infiltrating Vascular Channels

(Left) Classic Kaposi sarcoma
is shown presenting as diffuse
erythematous and
hyperpigmented plaques and
nodules on the lower
extremities of this elderly
male patient. (Courtesy J.
McMichael, MD.) (Right)
Earlier lesions of Kaposi
sarcoma display increased
numbers of irregular vascular
channels infiltrating the
dermis. Hemorrhage is evident
even at low power ﬈.

Infiltrative Growth Slit- and Sieve-Like Spaces

(Left) In addition to vascular
channels, infiltrative spindle
cells with hemorrhage are
present in the plaque stage of
Kaposi sarcoma. These have a
tendency to infiltrate and
destroy the eccrine sweat
coils. (Right) In later stage
lesions of Kaposi sarcoma,
spindled endothelial cells form
fascicles with intervening slit-
and sieve-like vascular spaces
containing numerous
erythrocytes.

476
 Kaposi Sarcoma
TERMINOLOGY
Abbreviations
• Kaposi sarcoma (KS)
Definitions
• Locally aggressive vascular proliferation (usually low grade)
caused by human herpes virus 8 (HHV8)
ETIOLOGY/PATHOGENESIS
Infectious Agents
• All forms of KS are caused by HHV8
○ HHV8 detectable in 100% of KS
○ HHV8 present in tumor cells and peripheral blood
CLINICAL ISSUES
Presentation
• Most cases involve skin
○ Also can involve mucosa, lymph nodes, visceral organs
• Multiple lesions may arise in different sites simultaneously
○ Multifocality does not necessarily represent metastatic
spread in a classic sense
• 3 stages
○ Patch stage: Red or violaceous macules coalescing into
patches
○ Plaque stage: Thickened red/blue/purple/brown plaques
○ Tumor stage: Larger nodules arise from plaques; may
ulcerate and simulate pyogenic granuloma clinically
• Stages are same regardless of clinical variant of KS; stages
may coexist with one another
Natural History
• Clinical variants of KS
○ Classic
– Elderly men (90%), usually nodules/plaques on feet
and lower legs
– Most prevalent regions: Mediterranean, East
European, and central equatorial Africa
□ Rare in USA
– Often associated with underlying malignancy, usually
hematologic
– Indolent behavior: Slow growth over years
□ Lymph node or organ involvement uncommon
○ African (endemic)
– Young children and middle-aged adults in equatorial
Africa
– May be associated with podoconiosis (endemic
lymphedema from barefoot soil exposure)
– Not associated with HIV
– Multiple skin nodules/tumors of lower legs
progressing over many years
– Aggressive, often fatal, disease if lymph node
involvement (lymphadenopathic form)
○ Iatrogenic
– Occurs in immunosuppressed patients of any age
– Skin and mucosal involvement common; may be
disseminated with organ involvement
– Variable behavior
○ AIDS associated
– Occurs in patients coinfected by HIV-1 and HHV8
Vascular Tumors (Including Lymphatics)
□ Specific predilection for homosexual men and IV
drug users with HIV
□ In Africa, has equal M:F incidence among HIV-
positive patients
– Usually patch stage at presentation with subsequent
progression
– Predilection for skin of face, genitals, lower
extremities
– Frequently disseminated with involvement of mucosa,
lymph nodes, organs 
– Most aggressive type of KS
Treatment
• No cure for KS
• Wide variety of treatment options for symptom reduction,
prevention of disease progression, &/or cosmesis
○ Surgical excision (only for individual more symptomatic
lesions, not for complete excision of all lesions)
○ External beam radiation
○ Cryo-, laser, or photodynamic therapy
○ Topical or intralesional drugs
○ Systemic chemotherapy only in more severe scenarios
• In AIDS-associated KS, lesions may regress or flare with
antiretroviral therapy
• In Iatrogenic KS, lesions may regress (sometimes entirely)
once immunosuppression removed
Prognosis
• Depends on epidemiological/clinical type of KS
• Strongly related to stage of disease
• Strongly related to coexisting infectious diseases
MICROSCOPIC
Histologic Features
• Differ by stage of disease but not by
clinical/epidemiological type
• Distinction of stages not required by pathologist but are
useful for recognition of varying histologic patterns in KS
• Patch stage
○ Increased "jagged" interconnected vascular channels in
reticular dermis
– Dissecting/wrapping collagen bundles
– Growing around adnexa
– Growing around normal vessels ("promontory" sign is
characteristic but uncommon finding)
– Lined by uniform endothelial cells with minimal atypia
○ Scattered plasma cells (very useful clue) and lymphocytes
○ Extravasated erythrocytes and hemosiderin deposits
• Plaque stage
○ More extensive vascular proliferation
○ Increased inflammatory infiltrate with plasma cells
○ Spindle cell proliferation infiltrating dermis and
invading/destroying eccrine glands
• Tumor stage
○ Nodules of spindle cells arranged in intersecting
fascicles 
○ Blood-filled slit- and sieve-like spaces between spindle
cells
– When blood-filled spaces absent, may be difficult to
recognize as vascular tumor
477
 Kaposi Sarcoma
Vascular Tumors (Including Lymphatics)
○ Mitoses often prominent, but nuclear atypia only mild-
moderate usually
– If severe atypia, consider spindled angiosarcoma
– In AIDS, KS may have more atypical areas similar to
angiosarcoma
○ Intracytoplasmic hyaline globules in spindle cells
– Some suggest these are degenerated erythrocytes
○ Inflammatory infiltrate with plasma cells usually present
• Other unique histologic variants
○ Lymphangioma-like: Bulla-like clinical appearance, dilated
lymphatic-like channels similar to lymphangioma
○ Hemangioma-like: Larger dilated blood-filled spaces
similar to hemangioma
○ Poorly differentiated: Pleomorphism and numerous
mitoses (more common in Africa)
ANCILLARY TESTS
Immunohistochemistry
• Positive for endothelial and lymphatic markers
○ CD31, CD34, ERG, D2-40 (podoplanin), PROX1, FLI1
• Nuclear HHV8 (LANA1) positive in essentially 100%
(punctate, speckled, or granular pattern of nuclear staining
is classic)
○ Essentially all other vascular proliferations are HHV8
negative
DIFFERENTIAL DIAGNOSIS
Angiosarcoma
• Different clinical scenario
• Anastomosing infiltrating vascular channels lined by
markedly atypical endothelium with multilayering
○ Negative for HHV8
Severe Vascular Stasis (Acroangiodermatitis)
• Very similar clinical and histologic appearance to KS
○ Violaceous plaques on lower extremities
○ Increased vascular channels and spindle cells in dermis
○ Extravasated RBCs and hemosiderin
• Dermal spindle cells are fibroblasts (not spindled
endothelial cells like KS)
○ Negative for vascular markers: CD31, ERG, etc.
• Negative for HHV8 (in vessels and spindle cells)
Hobnail (Targetoid Hemosiderotic) Hemangioma
• Solitary vascular lesion of skin
• Dilated lymphatic-like channels with bland hobnail
endothelium in superficial dermis
• Compressed vessels trickle into underlying dermis
○ Apparently "infiltrative" thin vessels can mimic KS
• Negative for HHV8
Microvenular Hemangioma
• Solitary vascular lesion of skin
• Compressed vascular channels trickle between dermal
collagen (similar to hobnail hemangioma)
○ Apparently "infiltrative" thin vessels can mimic KS
• Negative for HHV8
Spindle Cell Hemangioma
• Subcutaneous (or dermal) nodule(s), usually in leg
• Biphasic pattern
478
○ Cavernous zone: Similar to cavernous hemangioma
○ Cellular zone: Spindled endothelium and compressed
vascular spaces can resemble KS
– No mitoses, hemorrhage, plasma cells
– Epithelioid endothelium with vacuoles resembling
miniature adipocytes (not seen in KS)
• Negative for HHV8
Kaposiform Hemangioendothelioma
• Infants and young children (vast majority)
○ Very rare in skin of adults
• Whorled nodules of spindled endothelium with slit-like
vascular channels
○ No mitoses, hemorrhage, plasma cells
○ Whorled nodular pattern not seen in KS
• Negative for HHV8
Acquired Tufted Angioma
• Solitary skin lesion in adults
• Histologically identical to kaposiform
hemangioendothelioma
• Negative for HHV8
Progressive Lymphangioma (Benign
Lymphangioendothelioma)
• Slowly growing, solitary, patch or plaque
• Infiltrative channels with bland lymphatic endothelium
• No spindle cells, hemorrhage, plasma cells
• Negative for HHV8
Cellular Fibrous Histiocytoma (Cellular
Dermatofibroma)
• Dermatofibroma with intersecting hypercellular fascicles
○ Similar fascicles in paucivascular tumor stage KS
• Epidermal hyperplasia, peripheral collagen trapping, and
other features of dermatofibroma present
• Lacks infiltrative vascular channels
• Negative for HHV8 and vascular markers
Leiomyosarcoma (Superficial/Cutaneous)
• Intersecting fascicles of atypical smooth muscle cells
○ Similar fascicles in paucivascular tumor stage KS
• SMA and desmin positive
• Negative for HHV8 and vascular markers
SELECTED REFERENCES
1. Vangipuram R et al: Epidemiology of Kaposi sarcoma: review and description
of the nonepidemic variant. Int J Dermatol. ePub, 2018
2. Schnebelen AM et al: Benign lymphangioendothelioma presenting as a giant
flank mass. J Cutan Pathol. 42(3):217-21, 2015
3. Chadburn A et al: Molecular and immunohistochemical detection of Kaposi
sarcoma herpesvirus/human herpesvirus-8. Methods Mol Biol. 999:245-56,
2013
4. Dittmer DP et al: Kaposi sarcoma associated herpesvirus pathogenesis
(KSHV)--an update. Curr Opin Virol. 3(3):238-44, 2013
5. Radu O et al: Kaposi sarcoma. Arch Pathol Lab Med. 137(2):289-94, 2013
6. Miettinen M et al: Prox1 transcription factor as a marker for vascular tumors-
evaluation of 314 vascular endothelial and 1086 nonvascular tumors. Am J
Surg Pathol. 36(3):351-9, 2012
7. Rosado FG et al: Utility of immunohistochemical staining with FLI1, D2-40,
CD31, and CD34 in the diagnosis of acquired immunodeficiency syndrome-
related and non-acquired immunodeficiency syndrome-related Kaposi
sarcoma. Arch Pathol Lab Med. 136(3):301-4, 2012
8. Grayson W et al: Histological variants of cutaneous Kaposi sarcoma. Diagn
Pathol. 3:31, 2008
 Kaposi Sarcoma
Nodules of Classic Kaposi Sarcoma
Early Kaposi Sarcoma
Classic Kaposi Sarcoma
Vascular Tumors (Including Lymphatics)
AIDS-Associated Kaposi Sarcoma
(Left) Classic Kaposi sarcoma
arising in an elderly man who
presented with multiple
violaceous and hyperkeratotic
nodules on the foot. (Right)
Photograph shows an HIV-
positive patient exhibiting
multiple erythematous to
violaceous patches and
coalescing papules on the
thigh.
Patch Stage Kaposi Sarcoma
(Left) Early forms of Kaposi
sarcoma may be subtle and
difficult to diagnose clinically.
This elderly patient developed
multiple erythematous
macules and slightly elevated
papules on the toe. (Right)
Patients with AIDS-associated
Kaposi sarcoma may present
with lesions at unusual
anatomic sites, as did this
young patient who developed
small erythematous patches
on his upper eyelid.
Patch Stage Kaposi Sarcoma
(Left) Photograph shows
multiple erythematous
nodules and plaques of classic
Kaposi sarcoma in an elderly
male patient. (Courtesy J.
McMichael, MD.) (Right) A 30-
year-old male patient with HIV
presented with an irregularly
shaped erythematous to
violaceous patch on the upper
arm. The lesion proved to be
Kaposi sarcoma.
479
 Kaposi Sarcoma
Vascular Tumors (Including Lymphatics)

Increased Numbers of Vessels Inflammation

(Left) Earlier lesions of Kaposi
sarcoma display increased
numbers of irregular vascular
channels and spindle cells
infiltrating the dermis.
Hemorrhage is present. Some
preexisting dermal vessels
protrude into the lumen of
dilated Kaposi sarcoma
vascular channels (promontory
sign) ﬈. (Right) Increased
numbers of irregular vascular
channels infiltrate the dermis.
Mixed inflammation is also
present.

Promontory Sign Infiltrative Spindle Cells

(Left) Vessels protrude into
the lumen of larger vascular
channels (promontory sign)
giving a vessel within a vessel
appearance. This finding is
characteristic of Kaposi
sarcoma, although it is
relatively uncommon. (Right)
Bland spindle cells with
associated hemorrhage
infiltrate the dermis in plaque-
stage Kaposi sarcoma. Most of
these are endothelial cells, not
fibroblasts, and will thus be
highlighted on IHC by CD31,
ERG, CD34, and other vascular
markers.

Infiltration of Eccrine Coils Disruption of Eccrine Coils

(Left) Spindled endothelial
cells often infiltrate and
disrupt the eccrine coils ﬇, a
very characteristic finding in
Kaposi sarcoma. (Right) Bland
spindled endothelial cells
infiltrate and disrupt the
eccrine coils in Kaposi
sarcoma, intervening between
individual eccrine ducts ﬈.
Scattered extravasated
erythrocytes are present.

480
 Kaposi Sarcoma

Vascular Tumors (Including Lymphatics)

Early Kaposi Sarcoma Spindle Cells and Inflammation
(Left) Early Kaposi sarcoma
displays infiltrating, irregular,
thin-walled vascular channels;
scattered spindle cells; and
brisk inflammation. (Right)
Spindled endothelial cells ﬊
infiltrate the dermis.
Extravasated erythrocytes are
present, and there are
aggregates of lymphocytes
and plasma cells ﬈.

Mitoses Plasma Cells

(Left) At high-power
magnification, narrow
vascular spaces and
cytologically bland spindled
cells are seen. Note the
presence of inflammatory cells
and scattered mitoses ﬊.
(Right) The inflammatory
infiltrate in Kaposi sarcoma
usually contains plasma cells
﬊.

Dilated Cavernous Channels Dissection of Dermal Collagen

(Left) Larger, dilated, blood-
filled vessels may be present in
some cases of Kaposi sarcoma,
as depicted. These unique
cases have been described as
hemangioma-like variants of
Kaposi sarcoma. (Right)
Infiltrative, dilated vascular
channels dissect between
dermal collagen in this H&E.
This growth may be so
extensive that individual
collagen bundles appear to be
suspended within empty
spaces ﬈. Angiosarcoma can
also produce this pattern.

481
 Kaposi Sarcoma
Vascular Tumors (Including Lymphatics)

Tumor-Stage Kaposi Sarcoma Cellular Fascicles of Spindle Cells

(Left) Low-power view of
tumor-stage Kaposi sarcoma
shows an ulcerated, exophytic,
pedunculated, and
hypercellular dermal nodule
with hemorrhage. (Right)
Tumor-stage Kaposi sarcoma
displays cellular fascicles of
relatively uniform spindle cells
with intervening slit- or sieve-
like spaces filled with
erythrocytes.

Intersecting Fascicles Mitoses but Minimal Nuclear Atypia

(Left) Short fascicles of spindle
cells intersect one another in
tumor-stage Kaposi sarcoma.
Abundant erythrocytes are
present between tumor cells.
(Right) Kaposi sarcoma
displays tumor cells with
relatively uniform, spindled
nuclei that typically have
minimal nuclear atypia.
Mitoses are usually seen ﬇.
Small, sieve-like spaces
containing erythrocytes are
seen between the spindled
cells ﬈.

Hemorrhage and Hemosiderin Minimal Hemorrhage

(Left) Abundant erythrocyte
extravasation is seen.
Hemosiderin is often present
﬈. Mitoses are readily
identified st. (Right) Tumor-
stage Kaposi sarcoma
sometimes has minimal or
completely absent
erythrocyte-filled spaces or
hemorrhage. These cases may
be easily confused with other
fascicular-patterned,
nonvascular spindle cell
tumors.

482
 Kaposi Sarcoma
Fascicles Without Erythrocytes
Nuclear HHV8 Expression
CD34 Expression
Vascular Tumors (Including Lymphatics)
Plasma Cells Characteristic
(Left) This tumor-stage Kaposi
sarcoma is composed of
cellular fascicles of uniform
spindle cells but is essentially
devoid of erythrocytes.
Recognizing the endothelial
nature of these cells is very
challenging in areas like this.
(Right) In tumor-stage Kaposi
sarcoma lacking erythrocytes,
the presence of plasma cells
﬈ is a very important clue to
the diagnosis.
HHV8: Granular Nuclear Staining
(Left) Nuclear HHV8
expression is present in
essentially 100% of Kaposi
sarcoma but is absent in all
other vascular proliferations.
(Right) HHV8 immunostain
often displays a punctate
granular stippled/speckled
nuclear staining pattern.
Podoplanin (D2-40) Expression
(Left) Fascicles of spindle cells
are diffusely positive for CD34
in this case of tumor-stage
Kaposi sarcoma. CD31 is also
typically expressed. (Right)
Most cases of Kaposi sarcoma
have a lymphatic endothelial
phenotype resulting in
podoplanin expression
detected on D2-40
immunostaining.
483
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 SECTION 11

Chondroosseous Tumors

Benign
Soft Tissue Chondroma 486
Synovial Chondromatosis 492

Malignant
Extraskeletal Osteosarcoma 496
Extraskeletal Mesenchymal Chondrosarcoma 500
 Soft Tissue Chondroma

KEY FACTS
Chondroosseous Tumors

TERMINOLOGY • Variable amounts of calcification

• Benign hyaline cartilage neoplasm of soft tissue with • Ossification common
predilection for hands and feet • Granulomatous inflammation in 15% of cases
• Rare tumors with extensive xanthogranulomatous
CLINICAL ISSUES inflammation
• Low recurrence rate (15-20%) • Myxoid matrix common (myxochondroma)
• Recurrences controlled by reexcision • Rare tumors with extensive stromal fibrosis
IMAGING (fibrochondroma)
• Morphologic variant: Chondroblastoma-like chondroma
• Small, well demarcated
• Mineralized soft tissue mass TOP DIFFERENTIAL DIAGNOSES
• Acral extremity • Synovial chondromatosis
MACROSCOPIC • Tophaceous pseudogout
• Tumoral calcinosis
• Median size: 1.6 cm
• Extraskeletal myxoid chondrosarcoma
• Range: 0.3-6.5 cm
• Calcifying aponeurotic fibroma
MICROSCOPIC • Myxochondroid metaplasia of plantar foot
• Well circumscribed and lobulated • Cutaneous mixed tumor with chondroid metaplasia
• Mostly composed of mature hyaline cartilage • Tenosynovial giant cell tumor

Soft Tissue Chondroma Lobular Architecture

(Left) Soft tissue chondroma
typically occurs in the digits of
the hands and feet. It presents
as a painless, well-
demarcated, mineralized
mass, as demonstrated in this
CT of a dorsal index finger
lesion. Note the peripheral
distribution of mineralization
﬈. (Right) Soft tissue
chondroma typically has a
lobular architecture with
islands of hyaline cartilage ﬉
separated by fibrous bands ﬈.
Matrix calcification ﬊ and
ossification ﬈ are common.

Cytologic Features Calcified Hyaline Cartilage

(Left) High-power micrograph
illustrates the typical cytologic
features of soft tissue
chondroma. The chondrocytes
are often arranged in clusters,
situated in lacunar spaces
within pale blue hyaline
matrix, and have uniform,
round nuclei and abundant
eosinophilic cytoplasm. Rare
binucleated cells can be seen
﬈. Mitoses are rare. (Right)
Areas of very dense
calcification are common,
illustrated by heavy basophilic
stippling ſt of the cartilage
matrix.

486
 Soft Tissue Chondroma

Chondroosseous Tumors
• Morphology
TERMINOLOGY
○ Most are calcified or ossified
Synonyms ○ Sometimes erode and deform underlying bone
• Extraskeletal chondroma
• Chondroma of soft parts MACROSCOPIC
• Fibrochondroma General Features
• Osteochondroma
• Well demarcated and bosselated
• Myxochondroma
• Spherical or oval
• Chondroblastoma-like chondroma
• Rubbery or hard
Definitions • Sometimes soft, friable, gelatinous, or cystic
• Benign hyaline cartilage neoplasm of soft tissue with Size
predilection for hands and feet
• Median: 1.6 cm
○ Range: 0.3-6.5 cm
ETIOLOGY/PATHOGENESIS
Neoplasm MICROSCOPIC
• Rearrangement of 12q13-15 Histologic Features
• Trisomy 5
• Well circumscribed and lobulated
• Aberrations of chromosome 11
• Mostly composed of mature hyaline cartilage
• HMGA2 abnormalities
• Chondrocytes located in lacunae
○ Arranged diffusely or in small clusters
CLINICAL ISSUES
○ Some have enlarged nuclei and moderate pleomorphism
Epidemiology ○ Very low mitotic rate
• Incidence • Variable amounts of calcification
○ Uncommon ○ Granular stippled calcification that surrounds
– Exact incidence unknown chondrocytes in lace-like pattern
• Age ○ Some with extensive calcification
○ Median: 4th decade – Deep basophilia of cartilage
– Range: Infancy to 9th decade • Ossification common
• Sex • Granulomatous inflammation in 15% of cases
○ M=F ○ Epithelioid macrophages and osteoclastic giant cells
○ Most pronounced in heavily calcified tumors
Presentation
• Myxoid areas and cystic degeneration in some
• Painless mass • Rare tumors with extensive xanthogranulomatous
• Most common in hands and feet (60-95%) inflammation
○ Especially in fingers ○ Mimics fibrous histiocytoma or tenosynovial giant cell
• Rare sites tumor
○ Proximal extremities, trunk, head and neck, oral cavity, • Rare tumors with extensive stromal fibrosis
ear, upper aerodigestive tract, dura/extradural, skin, (fibrochondroma)
fallopian tube, bladder, scrotum, orbit, eyelid
Morphologic Variant
Treatment
• Chondroblastoma-like chondroma
• Simple surgical excision ○ Abundant myxoid matrix
Prognosis ○ Immature chondrocytes
• Low recurrence rate (15-20%) – Resemble cells of chondroblastoma of bone
○ Recurrences controlled by reexcision □ Polygonal or elongated cells
• No reports of malignant degeneration □ Abundant eosinophilic or vacuolated cytoplasm
□ Eccentrically located, grooved or reniform nuclei
IMAGING
ANCILLARY TESTS
General Features
Immunohistochemistry
• Best diagnostic clue
○ Small, well demarcated • S100 and ERG (+)
○ Mineralized soft tissue mass • Keratin and SMA (-)
○ Acral extremity
• Location DIFFERENTIAL DIAGNOSIS
○ Hands and feet Synovial Chondromatosis
○ Often in vicinity of joint or tendon • Larger tumors
○ No intraarticular or subperiosteal localization by • Most often in synovium of large joints, especially knee
definition
487
 Soft Tissue Chondroma
Chondroosseous Tumors

○ Also found in tenosynovium of acral extremities ○ Extensive calcification and ossification

• More discrete lobular architecture and chondrocyte ○ Granulomatous or xanthogranulomatous reaction
clusters ○ Fibrous and myxoid areas
• Intrarticular loose bodies ○ Chondroblastoma-like features
Tophaceous Pseudogout
SELECTED REFERENCES
• Wide distribution, including acral extremities
1. Sugiura Y et al: Convexity dural chondroma: a case report with pathological
○ Predilection for temporomandibular joint and molecular analysis. Clin Neuropathol. 34(1):13-8, 2015
• Heavily calcified lesions with metaplastic cartilage 2. Pace J et al: Extradural chondroma presenting as lumbar mass with
formation compressive neuropathy. J Craniovertebr Junction Spine. 5(3):131-3, 2014
• Rhomboid-shaped calcium pyrophosphate dihydrate 3. Shon W et al: ERG expression in chondrogenic bone and soft tissue tumours.
J Clin Pathol. 68(2):125-9, 2014
(CPPD) crystals 4. Vescovi P et al: Soft tissue chondroma of the oral cavity: an extremely rare
○ Positive birefringence under polarized light tumour localized on the hard palate. Case Rep Med. 2014:414861, 2014
5. Choi Y et al: A case of auricular chondroma. Korean J Audiol. 17(3):156-8,
Tumoral Calcinosis 2013
• Predilection for large joints 6. Choi Y et al: Extraskeletal chondroma of the scalp: an atypical location. Indian
J Dermatol Venereol Leprol. 79(3):435-6, 2013
• Calcium hydroxyapatite crystals (psammomatous) 7. Raparia K et al: Chondroblastoma-like chondroma of soft tissue: report of
• Histiocytic giant cells with intracytoplasmic calcifications the first case in the base of skull. Ann Diagn Pathol. 17(3):298-301, 2013
• Familial and nonfamilial cases 8. Shon W et al: Myxochondroid metaplasia of the plantar foot: a distinctive
pseudoneoplastic lesion resembling nuchal fibrocartilaginous pseudotumor
Extraskeletal Myxoid Chondrosarcoma and the equine digital cushion. Mod Pathol. 26(12):1561-7, 2013
9. Smith EJ et al: Case presentation of soft tissue parapharyngeal chondroma
• Large, lobulated soft tissue mass in a pediatric patient. Am J Otolaryngol. 34(6):720-3, 2013
• Abundant myxoid matrix 10. Thompson J et al: Cutaneous mixed tumor with extensive chondroid
metaplasia: a potential mimic of cutaneous chondroma. Dermatol Online J.
• Thick fibrous septa 18(3):9, 2012
• Interconnecting cords of neoplastic cells 11. Kim HS et al: A true chondroma cutis. J Eur Acad Dermatol Venereol.
• Lacks true cartilage 23(5):612-3, 2009
12. Khedhaier A et al: Soft tissues chondromas of the hand: a report of five
• Necrosis cases. Acta Orthop Belg. 73(4):458-61, 2007
Calcifying Aponeurotic Fibroma 13. Hondar Wu HT et al: Imaging and pathological correlation of soft-tissue
chondroma: a serial five-case study and literature review. Clin Imaging.
• Hands and feet 30(1):32-6, 2006
○ Especially palms of children 14. Dahlén A et al: Fusion, disruption, and expression of HMGA2 in bone and
soft tissue chondromas. Mod Pathol. 16(11):1132-40, 2003
• Geographic areas of calcification surrounded by chondroid 15. Fetsch JF et al: Tenosynovial (extraarticular) chondromatosis: an analysis of
cells 37 cases of an underrecognized clinicopathologic entity with a strong
• Fibromatous areas predilection for the hands and feet and a high local recurrence rate. Am J
Surg Pathol. 27(9):1260-8, 2003
Myxochondroid Metaplasia of Plantar Foot 16. Tallini G et al: Correlation between clinicopathological features and
karyotype in 100 cartilaginous and chordoid tumours. A report from the
• All reports from plantar foot, including toes Chromosomes and Morphology (CHAMP) Collaborative Study Group. J
• Fibromyxoid background Pathol. 196(2):194-203, 2002
17. Cates JM et al: Chondroblastoma-like chondroma of soft tissue: an
• Areas with distinct stromal basophilia and chondroid underrecognized variant and its differential diagnosis. Am J Surg Pathol.
appearance 25(5):661-6, 2001
• Cystic change common 18. Ishida T et al: Tophaceous pseudogout (tumoral calcium pyrophosphate
dihydrate crystal deposition disease). Hum Pathol. 26(6):587-93, 1995
• Reactive, nonneoplastic
19. Pollock L et al: Childhood soft tissue chondroma: a case report. Pediatr
Pathol Lab Med. 15(3):437-41, 1995
Cutaneous Mixed Tumor With Chondroid Metaplasia
20. Bridge JA et al: Biologic and clinical significance of cytogenetic and
• Massive chondroid metaplasia molecular cytogenetic abnormalities in benign and malignant cartilaginous
• Epithelial glandular structures lesions. Cancer Genet Cytogenet. 69(2):79-90, 1993
21. Humphreys S et al: Soft tissue chondroma--a study of 15 tumours.
Tenosynovial Giant Cell Tumor Histopathology. 10(2):147-59, 1986
22. Chung EB et al: Chondroma of soft parts. Cancer. 41(4):1414-24, 1978
• Similar location, most common in fingers 23. Dahlin DC et al: Cartilaginous tumors of the soft tissues of the hands and
• Calcified soft tissue chondromas can have extensive feet. Mayo Clin Proc. 49(10):721-6, 1974
granulomatous inflammation
• Osteoclastic giant cells
• Xanthoma cells

DIAGNOSTIC CHECKLIST
Clinically Relevant Pathologic Features
• Predilection for acral extremities
Pathologic Interpretation Pearls
• Features that can lead to misdiagnosis
○ Chondrocyte atypia
○ Increased cellularity

488
 Soft Tissue Chondroma

Chondroosseous Tumors
Soft Tissue Chondroma Calcification
(Left) Soft tissue chondroma is
typically a well-circumscribed
tumor composed of hyaline
cartilage lobules ﬈, areas of
calcification ﬉, and sharp
demarcation from adjacent
soft tissue (top). (Right)
Calcification is very common in
soft tissue chondroma. It
appears as granular basophilic
stippling of the matrix, which
often surrounds individual
chondrocytes to form a
reticular pattern ﬈.

Granulomatous Inflammation and Giant

Dense Calcification Cells
(Left) This medium-power
micrograph depicts very dense
mineralization of the cartilage
matrix, consisting of coarse,
basophilic particles of calcium
﬈. (Right) Granulomatous
inflammation is often present
in heavily calcified tumors.
This micrograph illustrates
epithelioid macrophages ſt
and osteoclastic giant cells ﬈
in a calcified tumor. When
extensive, it mimics
tenosynovial giant cell tumor.

Xanthogranulomatous Inflammation Ossification

(Left) Xanthogranulomatous
inflammation can be present
in soft tissue chondroma,
consisting of sheets or clusters
of foamy histiocytes ﬈. When
extensive, such a tumor can be
mistaken for fibrous
histiocytoma or tenosynovial
giant cell tumor. (Right)
Ossification ﬈ is common in
soft tissue chondroma and can
sometimes be extensive, as
illustrated here. It can be
located either at the center or
periphery of the tumor and is
formed via endochondral
ossification of calcified
cartilage matrix ﬉.

489
 Soft Tissue Chondroma
Chondroosseous Tumors

Soft Tissue Chondroma of Foot Lobular Architecture and Calcification

(Left) CT depicts a mineralized
soft tissue chondroma ﬈
involving the plantar soft
tissue adjacent to the 4th
metatarsal. Soft tissue
chondroma has a predilection
for the hands and feet, often
near a joint or tendon. (Right)
This low-power micrograph
illustrates well-defined,
lobular architecture in a soft
tissue chondroma, consisting
of cartilaginous lobules ﬈
separated by fibrous bands ﬉.
Note the deeply basophilic
calcium deposits within the
center of the lobules ﬈.

Calcified Cartilage Matrix Myxoid Matrix

(Left) This high-power
micrograph of a densely
calcified tumor depicts finely
granular ﬈ and coarse ﬉
calcium deposits. The hyaline
matrix is degenerated, and the
chondrocytes ﬈ are no longer
contained within lacunae.
(Right) Some tumors have
extensive myxoid matrix
where chondrocytes assume
elongated and stellate
configurations, sometimes
interconnecting with each
other to form a network,
mimicking extraskeletal
myxoid chondrosarcoma. Such
tumors have been called
myxochondromas.

Stellate and Chondroblastoma-Like Cells Fibrocollagenous Matrix

(Left) In myxoid areas, the
chondrocytes lose their
lacunae and assume stellate
shapes ﬈ and rounded cells
that resemble chondroblasts
with abundant eosinophilic
cytoplasm and eccentric
grooved or reniform nuclei ﬉.
(Right) Soft tissue chondroma
can have extensive fibrosis
exemplified by numerous
collagen bundles traversing
this tumor ﬈. Tumors with
extensive fibrosis are
sometimes referred to as
fibrochondromas.

490
 Soft Tissue Chondroma
Circumscription and Lobular Architecture
Increased Cellularity
Chondroblastoma-Like Features
Chondroosseous Tumors
Calcification and Increased Cellularity
(Left) Soft tissue chondroma is
well circumscribed and well
demarcated from adjacent
soft tissues ﬈. It typically has
a multilobular architecture, as
shown, and zones of
calcification ﬉. (Right) This
micrograph illustrates a zone
of calcified matrix ﬈
surrounded by an area of
increased cellularity. The
cellular area is composed by a
mixture of chondrocytes
devoid of lacunae ﬉ and
mononuclear inflammatory
cells ﬊ and resembles
tenosynovial giant cell tumor.
Cellular Atypia
(Left) Areas of increased
cellularity can be present in
soft tissue chondroma, as
exemplified, and does not
portend a more aggressive
behavior. (Right) Degenerative
cytologic atypia is not
uncommon in soft tissue
chondroma. This high-power
micrograph illustrates
chondrocytes with nuclear
enlargement ﬈ and
pleomorphism, which, out of
context, would be suspicious
for chondrosarcoma.
Cystic Degeneration
(Left) This heavily calcified
soft tissue chondroma
contains cells with abundant
eosinophilic cytoplasm and
eccentric nuclei with reniform
and grooved shapes ﬈,
resembling the cells of a
chondroblastoma. (Right)
Cystic degeneration can occur
in some tumors consisting of
liquefaction of the hyaline
cartilage matrix, as seen in
this foot lesion ﬈.
491
 Synovial Chondromatosis

KEY FACTS
Chondroosseous Tumors

TERMINOLOGY
• Benign, multinodular proliferation of hyaline cartilage
within articular synovium, tendon sheath, or bursa
• Usually diffuse and associated with loose bodies
CLINICAL ISSUES
• Site
○ Knee, hip, and elbow most common
○ Temporomandibular joint
○ Tenosynovium of acral extremities
• Benign with propensity for local recurrence
• Very rare chondrosarcomatous transformation
IMAGING
• Diffuse, punctate and ring-like calcifications
• Intense T2 signal on MR
MACROSCOPIC
• Multiple small, cartilaginous nodules (0.1-1.0 cm) that
coalesce into larger conglomerates
• Diffuse lesions stud synovial membrane
MICROSCOPIC
• Multiple discrete nodules of hyaline cartilage
• Chondrocytes arranged in small clusters
• Cytologic atypia and increased cellularity in some
• Matrix usually hyaline but may be myxoid or heavily
calcified
• Can undergo endochondral ossification
• Temporomandibular joint tumors often calcified and have
cytological atypia
TOP DIFFERENTIAL DIAGNOSES
• Osteocartilaginous loose bodies
• Soft tissue chondroma
• Synovial chondrosarcoma

Synovial Chondromatosis Radiology

(Left) Synovial chondromatosis
has a well-defined,
multinodular architecture,
characterized by discrete
nodules of hyaline cartilage
within subsynovial tissue. The
chondrocytes are arranged in
small clusters ﬈. (Right) The
knee is the most common site
of synovial chondromatosis.
Radiographically, it appears as
periarticular punctate
calcifications ﬈. Other
common sites are the hip,
elbow, shoulder, and
temporomandibular joint
(TMJ).

High-Power Features Gross Appearance

(Left) Proliferating cells are
benign-appearing
chondrocytes with uniform,
small nuclei situated within
lacunar spaces. Note the
clustered arrangement of the
cells and occasional lacunae
containing 2 cells ﬈. (Right)
Grossly, synovial
chondromatosis has a very
distinctive multinodular
pattern characterized by
small, opalescent,
cartilaginous nodules, which
coalesce into larger
conglomerates.

492
 Synovial Chondromatosis

Chondroosseous Tumors
TERMINOLOGY MACROSCOPIC
Synonyms General Features
• Primary synovial chondromatosis, synovial • Multiple small, cartilaginous nodules (0.1-1.0 cm) that
osteochondromatosis, synovial chondroma, synovial coalesce into larger conglomerates
chondrometaplasia ○ Diffuse lesions stud synovial membrane
Definitions ○ Detached loose bodies
• Benign, multinodular proliferation of hyaline cartilage MICROSCOPIC
within articular synovium, tendon sheath, or bursa
○ Usually diffuse and associated with loose bodies, with Histologic Features
propensity for local recurrence • Multiple nodules of hyaline cartilage
• Nodules underlie flattened synovium
CLINICAL ISSUES • Chondrocytes arranged in small clusters
Epidemiology ○ Binucleation common
• Incidence ○ Cytologic atypia and increased cellularity in some lesions
○ Rare but exact incidence unknown • Hyaline cartilage matrix
• Age ○ Can be focally myxoid
○ Peak age: 5th decade but wide variation (1st-7th ○ Calcification common
decades) – Some lesions heavily calcified
• Sex ○ Nodules may undergo endochondral ossification
○ M:F = 2:1
• Etiology
DIFFERENTIAL DIAGNOSIS
○ Unknown, possibly neoplastic Osteocartilaginous Loose Bodies
– Clonal chromosomal changes, chromosome 6, 1, 5 • Concentric laminations of variably calcified/ossified
abnormalities reported cartilage
○ IDH1 and IDH2 mutations absent • Associated with degenerative joint disease, trauma,
Site osteochondritis dissecans
• Virtually any joint may be involved Soft Tissue Chondroma
○ Knee is most common site • Lacks well-defined, multinodular architecture
○ Hip, elbow, and shoulder common • Predilection for hands and feet
○ Temporomandibular joint
Juxtaarticular Chondroma
• Soft tissue around joints
○ Tenosynovium of acral extremities • Most common in subpatellar knee
○ Bursae • Often heavily ossified
• Can be multifocal Synovial Chondrosarcoma
Presentation • Very rare
• Painful or painless mass • May arise within synovial chondromatosis or de novo
• Impaired range of motion • Loss of clustered growth, prominent myxoid matrix,
necrosis, peripheral spindling
Treatment
• Synovectomy and removal of loose bodies DIAGNOSTIC CHECKLIST
Prognosis Clinically Relevant Pathologic Features
• Benign; 15-20% local recurrence rate • Tissue distribution
• Chondrosarcomatous transformation very rare Pathologic Interpretation Pearls
• Multinodularity
IMAGING
• Clustered chondrocytes
Radiographic Findings
• Multifocal, punctate and ring-like calcifications involving SELECTED REFERENCES
joint, tendon sheath, or bursa 1. Shah SB et al: Synovial chondromatosis of temporomandibular joint: journey
○ Early lesions lack calcification through 25 decades and a case report. J Oral Maxillofac Surg. 69(11):2795-
814, 2011
○ Older lesions may become heavily mineralized with
2. Fetsch JF et al: Tenosynovial (extraarticular) chondromatosis: an analysis of
ossified bodies 37 cases of an underrecognized clinicopathologic entity with a strong
○ Can erode adjacent bone predilection for the hands and feet and a high local recurrence rate. Am J
Surg Pathol. 27(9):1260-8, 2003
MR Findings 3. Sciot R et al: Synovial chondromatosis: clonal chromosome changes provide
further evidence for a neoplastic disorder. Virchows Arch. 433(2):189-91,
• Lobulated mass with intense T2 signal 1998

493
 Synovial Chondromatosis
Chondroosseous Tumors

Multinodular Architecture Subsynovial Location

(Left) Low-power micrograph
depicts the characteristic well-
defined, multinodular
architecture of synovial
chondromatosis consisting of
hyaline cartilage nodules that
contain clusters of
chondrocytes ﬈. (Right) Low-
power micrograph depicts
discrete nodules of synovial
chondromatosis within
subsynovial tissue. Note the
overlying synovial membrane
﬉ and nodules of cartilage
with sharp borders, separated
by fibrovascular tissue ﬈.

Hyaline Cartilage Matrix and Cell Clusters Intraarticular Loose Bodies

(Left) In most cases of synovial
chondromatosis, the matrix
consists of pale blue or pink
hyaline cartilage, and the
chondrocytes are arranged in
small clusters, as shown.
(Right) Intraarticular loose
bodies frequently occur in
synovial chondromatosis.
Unlike the osteocartilaginous
loose bodies associated with
degenerative joint disease,
they lack concentric
laminations and maintain the
clustered arrangement of
chondrocytes.

Calcification Endochondral Ossification

(Left) Calcification is common
in synovial chondromatosis ﬈,
as depicted. This pattern
correlates with the punctate
calcifications seen on
radiographs. (Right) Calcified
nodules may be transformed
into ring-like, ossified
structures via endochondral
ossification. Note the
remnants of calcified cartilage
﬈ peripheral to the bone ﬉.
Such ossified nodules
correspond to the ring-like
structures seen on
radiographs.

494
 Synovial Chondromatosis
Cytological Atypia
Gross Appearance
Temporomandibular Joint Tumor
Chondroosseous Tumors
Synovial Chondromatosis of Hip
(Left) Degenerative
cytological atypia may be seen
in synovial chondromatosis.
This high-power micrograph
depicts large chondrocytes
with eccentric cytoplasm and
pleomorphic nuclei with
smudged chromatin. (Right)
Synovial chondromatosis
typically presents as a calcified
mass in a large, weight-
bearing joint, such as the hip.
It usually presents as multiple
diffuse punctate or ring-like
calcifications ﬈.
Nodules Separated by Fibrous Stroma
(Left) Gross photograph
depicts tissue removed at knee
synovectomy. Note the
characteristic multinodular
appearance as well as how it
studs the synovial membrane
﬈. Detached loose bodies
typically accompany such
specimens. (Right) In some
cases, the cartilaginous
nodules are separated by
abundant fibrous stroma ﬈,
as depicted in this low-power
micrograph. Note the sharp
demarcation between the
nodules and stroma.
Synovial Chondromatosis of
Temporomandibular Joint
(Left) T2-weighted MR depicts
bright signaling in a case of
synovial chondromatosis ﬈ of
the TMJ. In this location,
synovial chondromatosis
presents with pain, swelling,
and deviation. It frequently
recurs and rarely can invade
intracranially. (Right) Synovial
chondromatosis of the TMJ is
often heavily calcified ﬈ and
has increased cellularity and
degenerative cytologic atypia
﬉, as is seen in this H&E.
495
 Extraskeletal Osteosarcoma

KEY FACTS
Chondroosseous Tumors

TERMINOLOGY IMAGING
• Soft tissue sarcoma in which neoplastic cells produce • Calcification in 50%
osteoid or bone ○ Spotty to massive
ETIOLOGY/PATHOGENESIS MACROSCOPIC
• Radiation associated (10%) • Average size: 8 cm; range: 1-50 cm
CLINICAL ISSUES MICROSCOPIC
• 1-2% of soft tissue sarcomas • Wide histologic variation; mixed patterns common
• Affects adults almost exclusively ○ Osteoblastic, chondroblastic, fibroblastic
• Mostly deep seated (70-90%) ○ Giant cell rich, small cell
• Thigh most common site (30-50%) ○ Well differentiated
• Upper extremity, including shoulder girdle (20%)
TOP DIFFERENTIAL DIAGNOSES
• Retroperitoneum (10%)
• Poor prognosis: 5-year survival (30%) • Undifferentiated pleomorphic sarcoma
○ Local recurrence (35-50%) • Dedifferentiated liposarcoma
○ Metastasis (60%) • Sarcomatoid carcinoma
○ Age < 40 years and smaller tumor size associated with • Myositis ossificans
better prognosis

Extraskeletal Osteosarcoma Radiographic Appearance

(Left) Extraskeletal
osteosarcoma (ESOS) is a rare
soft tissue tumor found almost
exclusively in adult patients. It
is histologically identical to
skeletal osteosarcoma,
consisting of irregular, lace-
like osteoid matrix ſt and
high-grade malignant cells
with brisk mitotic activity st.
(Right) ESOS typically presents
as a massive soft tissue tumor,
most commonly in the thigh,
as shown in this CT scan.
Calcifications ſt are common
and highly variable in extent.

Malignant Bone Formation Fibroblastic Osteosarcoma

(Left) Most ESOS are high-
grade sarcomas and are
characterized by direct
production of malignant
osteoid and bone by the
neoplastic cells. Note the lace-
like pattern of mineralization
﬈. (Right) Fibroblastic ESOS
resembles undifferentiated
pleomorphic or spindle cell
sarcoma. Identification of
osteoid ﬉ is required for
diagnosis. However, it can be
sparse and hard to distinguish
from hyalinized fibrous matrix.
Osteoclastic giant cells ﬈ are
often present.

496
 Extraskeletal Osteosarcoma

Chondroosseous Tumors
TERMINOLOGY IMAGING
Abbreviations General Features
• Extraskeletal osteosarcoma (ESOS) • Large mass
• Calcifications in 50%
Synonyms
• May secondarily involve periosteum or bone
• Soft tissue osteosarcoma
• Extraosseous osteogenic sarcoma MACROSCOPIC
Definitions General Features
• Soft tissue sarcoma in which neoplastic cells produce • Circumscribed or infiltrative
osteoid or bone • Firm, fleshy, gritty, or hard
○ Can produce cartilage in addition to osseous matrix ○ Ossification
○ No other lines of differentiation – Diffuse, focal, or undetectable
– Tends to be located in center of tumor
ETIOLOGY/PATHOGENESIS • Cystic hemorrhagic spaces &/or geographic necrosis
Environmental Exposure • Satellite nodules
• Radiation associated (10%) Size
• Trauma history in some
• Average: 8 cm; range: 1-50 cm
• Rare tumors arise in myositis ossificans
MICROSCOPIC
CLINICAL ISSUES
Histologic Features
Epidemiology
• Identical to skeletal osteosarcoma
• Incidence
• Vast majority are high grade
○ 1-2% of soft tissue sarcomas
• Striking variation in amount of osteoid
○ 2-4% of osteosarcomas
• Wide histologic variation, mixed patterns common
• Age
○ Osteoblastic
○ Affects adults almost exclusively
– Polygonal cells with eccentric nuclei
– Average: 50 years; range: 20-80 years
– Abundant malignant osteoid or bone
• Sex
– Fine, lace-like osteoid
○ M:F = 2:1
– Wide osseous trabeculae
Site ○ Fibroblastic
• Mostly deep seated (70-90%) – Resembles undifferentiated pleomorphic sarcoma or
• Lower extremity (50-70%) fibrosarcoma
○ Thigh most common site (30-50%) – Osteoid can be sparse
○ Pelvic girdle, buttocks, leg ○ Chondroblastic
• Upper extremity (20%) – Pleomorphic chondrocytes within lobules of hyaline
○ Shoulder girdle and upper arm common cartilage
• Retroperitoneum (10%) – Peripheral lobular hypercellularity
• Rare sites: Hand, foot, larynx, tongue, spermatic cord, penis, – Often mixed with osteoblastic areas
pleura, lung, heart, breast, colon, CNS, liver, pancreas, skin ○ Giant cell rich
– Pleomorphic sarcoma with numerous osteoclastic
Presentation giant cells
• Painless mass – Osteoclasts may obscure underlying malignant
• Progressive enlargement histology
Treatment – Osteoid can be sparse
○ Telangiectatic
• Wide local excision, resection, or amputation
– Very rare in pure form
• Radiation therapy may be used for local control or palliation
– Telangiectatic or cystic hemorrhagic areas common in
• Efficacy of chemotherapy not proven
conventional ESOS
Prognosis ○ Well differentiated
• Poor; 5-year survival: 30% – Very rare
• Local recurrence: 35-50% – Cytologically bland, fibrogenic spindle cells
• Metastasis: 60% – Wide seams of osteoid and woven bone
○ Occurs within 2-3 years – Resembles parosteal or low-grade central
○ Lungs most common site osteosarcoma
○ Also bone, soft tissue, lymph nodes, liver, brain ○ Small cell
• Favorable prognostic factors: Size < 5 cm, age < 40 years, – Very rare
chondroblastic histology, low MIB-1 – Resembles Ewing sarcoma

497
 Extraskeletal Osteosarcoma
Chondroosseous Tumors
ANCILLARY TESTS
Immunohistochemistry
• Osteocalcin and SATB2 are sensitive and specific markers
for general osteoblastic differentiation
○ Not specific for osteosarcoma
• Variable, nonspecific expression of SMA, CD99, EMA,
desmin
Cytogenetics
• Complex karyotype
DIFFERENTIAL DIAGNOSIS
Undifferentiated Pleomorphic Sarcoma
• Can show significant morphologic overlap with ESOS
• Stromal hyalinization can mimic osteoid
• Can have osteoclast-like giant cells
• Distinction from fibroblastic ESOS sometimes arbitrary
Dedifferentiated Liposarcoma
• Heterologous osteosarcomatous differentiation
sometimes present
○ Usually in retroperitoneal tumors
• Identification of well-differentiated liposarcomatous
component rules out ESOS
• MDM2 and CDK4 amplification detectable by
immunohistochemistry or fluoroscopic in situ hybridization
(FISH)
Extraskeletal Mesenchymal Chondrosarcoma
• Small round blue or spindle cell tumor
• Neoplastic cells produce cartilage that can ossify
• Pericytic vascular pattern
Extraskeletal Ewing Sarcoma
• Small round blue cell tumor
• Fibrinous matrix can mimic osteoid
• CD99(+) characteristically diffuse and membranous
• Cytogenetic [t(11;22), t(7;22), t(21;22), t(2;22)] and
molecular (EWS-FLI-1, EWS-ERG) confirmation
Giant Cell Tumor of Soft Tissue
• Numerous osteoclastic giant cells and mononuclear stromal
cells
• Can produce bone, usually at periphery of tumor
• Lacks high-grade cytologic atypia and atypical mitoses
• Lacks lace-like osteoid
Myositis Ossificans
• Nonneoplastic, usually post trauma
• Benign, reactive myofibroblasts and osteoblasts
○ Can have brisk mitotic activity
○ Lacks malignant cytologic atypia
• Temporal and peripheral bony maturation
○ Increased bone formation and maturation with time
○ More mature bone forms at periphery of tumor
Fibroosseous Pseudotumor of Digits
• Affects digits
• Benign, reactive fibroblasts and osteoblasts
• Often lack peripheral zonal maturation
498
Synovial Sarcoma
• Uniform spindle cells
• May have stromal fibrosis with heterotopic ossification
• TLE1, CD99, cytokeratin, and EMA (+) in most
• Cytogenetic t(X;18) and molecular (SSX-SYT) confirmation
Malignant Peripheral Nerve Sheath Tumor
• Hyperchromatic spindle cells in fascicles
• May have heterologous osseous, chondroid, or
osteosarcomatous elements
• Usually S100(+) (50-60%)
• Frequent history of neurofibromatosis type 1 (50%)
Osteogenic Melanoma
• Rare melanoma with heterologous osteosarcomatous
element
• S100(+)
• Often HMB-45(+) or Melan-A(+)
Ossifying Fibromyxoid Tumor
• Ovoid mesenchymal cells arranged in cords and clusters
• Fibromyxoid stroma
• Usually encased by peripheral shell of bone
• Usually bland but can show cytologic atypia
Sarcomatoid Carcinoma
• Uterus, kidney, lung, others
• Cytokeratin in most
○ However, some osteosarcomas express cytokeratin
DIAGNOSTIC CHECKLIST
Clinically Relevant Pathologic Features
• Tissue distribution
Pathologic Interpretation Pearls
• Microscopically identical to skeletal osteosarcoma
SELECTED REFERENCES
1. Longhi A et al: Extraskeletal osteosarcoma: a European Musculoskeletal
Oncology Society study on 266 patients. Eur J Cancer. 74:9-16, 2017
2. Choi LE et al: Analysis of outcomes in extraskeletal osteosarcoma: a review
of fifty-three cases. J Bone Joint Surg Am. 96(1):e2, 2014
3. von Baer A et al: Immunohistochemical and FISH analysis of MDM2 and
CDK4 in a dedifferentiated extraskeletal osteosarcoma arising in the vastus
lateralis muscle: differential diagnosis and diagnostic algorithm. Pathol Res
Pract. 210(10):698-703, 2014
4. Conner JR et al: SATB2 is a novel marker of osteoblastic differentiation in
bone and soft tissue tumours. Histopathology. 63(1):36-49, 2013
5. Kyriazoglou AI et al: 12q amplification defines a subtype of extraskeletal
osteosarcoma with good prognosis that is the soft tissue homologue of
parosteal osteosarcoma. Cancer Genet. 205(6):332-6, 2012
6. Yang JY et al: Small cell extraskeletal osteosarcoma. Orthopedics. 32(3):217,
2009
7. Konishi E et al: Extraskeletal osteosarcoma arising in myositis ossificans.
Skeletal Radiol. 30(1):39-43, 2001
8. Fanburg-Smith JC et al: Osteocalcin and osteonectin immunoreactivity in
extraskeletal osteosarcoma: a study of 28 cases. Hum Pathol. 30(1):32-8,
1999
9. Lucas DR et al: Osteogenic melanoma. A rare variant of malignant
melanoma. Am J Surg Pathol. 17(4):400-9, 1993
10. Chung EB et al: Extraskeletal osteosarcoma. Cancer. 60(5):1132-42, 1987
11. Allan CJ et al: Osteogenic sarcoma of the somatic soft tissues.
Clinicopathologic study of 26 cases and review of literature. Cancer.
27(5):1121-33, 1971
 Extraskeletal Osteosarcoma
Extraskeletal Osteosarcoma
Chondroblastic Osteosarcoma
Giant Cell-Rich Osteosarcoma
Chondroosseous Tumors
Osteoblastic Osteosarcoma
(Left) This low-power
micrograph shows a flank
mass in a 42-year-old man. It
depicts classic features of
osteosarcoma comprised by
solid sheets and lace-like
configurations of osteoid ﬈
and large, pleomorphic spindle
cells arranged in fascicles and
storiform arrays st. (Right)
Osteoblastic osteosarcoma is
characterized by polygonal
osteoblastic cells with
eccentric nuclei ﬈ that
produce osteoid or woven
bone, often with an irregular,
lace-like pattern as shown ﬉.
Hemorrhagic Cystic Spaces
(Left) Chondroblastic
osteosarcoma has
pleomorphic chondrocytes st
in lacunar spaces embedded
within a pale blue chondroid
matrix ſt. This pattern is
often admixed with others,
such as osteoblastic ﬊ or
fibroblastic patterns. (Right)
Large, blood-filled cystic
spaces are often found in
ESOS. This micrograph depicts
a space filled with red blood
cells ﬈ adjacent to tumor.
Note the lace-like osteoid
matrix st.
Well-Differentiated Osteosarcoma
(Left) Giant cell-rich
osteosarcoma contains
numerous benign osteoclastic
giant cells ﬈. In such tumors,
one needs to search carefully
for atypical cells ﬉, atypical
mitotic figures (not shown),
and osteoid ﬇ to establish
the diagnosis. (Right) Only a
handful of well-differentiated
ESOS have been reported.
These tumors are
microscopically identical to
parosteal or low-grade central
osteosarcomas, composed of
cytologically bland, fibrogenic
spindle cells ﬉ in between a
broad trabeculae of woven
bone ﬈.
499
 Extraskeletal Mesenchymal Chondrosarcoma

KEY FACTS
Chondroosseous Tumors

TERMINOLOGY MICROSCOPIC
• Bimorphic soft tissue sarcoma characterized by • Bimorphic pattern
undifferentiated small round or spindle cells, islands of • Small round or spindle cells
well-differentiated hyaline cartilage, and recurrent HEY1- • Hyperchromatic coarse chromatin
NCOA2 fusion • Thin-walled, branching (pericytomatous) vascular pattern
CLINICAL ISSUES • Hyaline cartilage islands
• Rare: < 1% of soft tissue sarcomas • Calcifications and endochondral ossification
• Age: Mostly 2nd and 3rd decades • CD99(+) and SOX9(+)
• Wide range of soft tissue and visceral locations TOP DIFFERENTIAL DIAGNOSES
• Common locations • Ewing sarcoma
○ Head and neck region • Synovial sarcoma
○ Cranial and spinal dura • Solitary fibrous tumor (cellular/malignant)
• Clinical course can be protracted • Osteosarcoma
IMAGING • Malignant peripheral nerve sheath tumor with
heterologous cartilage
• Calcifications in most
• Atypical teratoid rhabdoid tumor
• Sclerosing rhabdomyosarcoma

Extraskeletal Mesenchymal
Chondrosarcoma Radiographic Appearance
(Left) Extraskeletal
mesenchymal chondrosarcoma
(EMC) has a bimorphic
histology consisting of small
round cell areas and islands of
hyaline cartilage st. Most
tumors have a prominent
pericytomatous vascular
pattern ﬊. (Right) EMC
typically presents as a
circumscribed, calcified mass.
Although most common in
cranial and spinal meninges, it
occurs at widely variable sites.
In this case, CT shows a tumor
﬈ in the retrocrural area with
stippled calcification.

Cytologic Features CD99

(Left) Most EMCs are
composed of closely spaced
small cells with rather
distinctive cytologic features
consisting of round or oval
nuclei with dense, coarse
chromatin and scant, indistinct
cytoplasm. (Right) Diffuse,
strong CD99 immunoreactivity
characterizes EMC. In this
example, anti-CD99 shows a
cytoplasmic membrane
staining pattern, which can
lead to a misdiagnosis of
Ewing sarcoma. Note that the
cells within the cartilage
island are negative ﬈.

500
 Extraskeletal Mesenchymal Chondrosarcoma

Chondroosseous Tumors
TERMINOLOGY IMAGING
Abbreviations Radiographic Findings
• Extraskeletal mesenchymal chondrosarcoma (EMC) • Well-defined soft tissue mass
• Dural-based intracranial/intraspinal tumor
Definitions
• Calcifications in most
• Bimorphic soft tissue (or bone) sarcoma characterized by
○ Stipples, rings and arcs, streaks
undifferentiated small round or spindle cells, islands of
well-differentiated hyaline cartilage, and HEY1-NCOA2
MACROSCOPIC
fusion
○ Microscopically identical to primary skeletal General Features
mesenchymal chondrosarcoma • Multilobulated and well circumscribed
• Periphery soft and fleshy
CLINICAL ISSUES • Center often with gritty texture or cartilaginous foci
Epidemiology • Necrosis and hemorrhage in some
• Incidence Size
○ Rare: < 1% of soft tissue sarcomas • Variable: 2-37 cm
○ Only 1/3 of EMCs present as primary soft tissue tumors
– Most are primary bone tumors MICROSCOPIC
• Age
Histologic Features
○ Wide range: 0-70 years
– Mostly 2nd and 3rd decades • Bimorphic pattern
– Average: 30 years ○ Small round or spindle cells
– Rare congenital cases – Clusters or fascicles
• Sex – Uniform round, oval, or spindle-shaped nuclei
○ Women and men equally affected □ Hyperchromatic coarse chromatin
□ Scant cytoplasm (may be clear in some cells)
Site □ Variable mitotic rate
• Head and neck region – Thin-walled branching (pericytomatous) vascular
○ Cranial dura pattern
– Most common extraskeletal site – Necrosis or hemorrhage in some
○ Orbit ○ Hyaline cartilage
• Lower extremities – Variable-sized islands
• Reported in wide array of soft tissue and visceral locations – Large sheets in some
Presentation – Small hyperchromatic cells in lacunar spaces
– Often low-grade or bland cytologic features
• Painful or painless mass in extremity tumors
– Calcifications and endochondral ossification common
• Headache and neurologic symptoms in meningeal tumors
□ Bone formation sometimes extensive
• Proptosis and visual changes in orbital tumors
– Sharp demarcation or gradual transition between
Natural History cellular areas and cartilage
• Fully malignant and aggressive
• Frequent metastases ANCILLARY TESTS
○ Lungs most common Immunohistochemistry
○ Can have late metastases • CD99(+), SOX9(+), desmin (+) in 50%, EMA(+) in 35%
– Up to 20 years following initial presentation • S100 protein and ERG expressed in cartilage only
• Behavior regarded as unpredictable • Osteocalcin expressed in areas of ossification only
Treatment • β-catenin may be expressed at interface of cartilage and
tumor cells
• Complete surgical resection when possible
• Retention of nuclear SNF5 (INI1)
• Role of chemotherapy poorly defined
• Negative for FLI-1, STAT6, CD45, SMA, GFAP, keratin,
• Radiation may benefit local control
myogenin (very rare focal positivity), MYOD1 (very rare
Prognosis focal positivity)
• Overall poor outcome Molecular Genetics
○ 50% 5-year survival
• Recurrent HEY1-NCOA2 fusion detectable by RT-PCR (or
○ 25% 10-year survival FISH)
• Clinical course can be protracted ○ IRF2BP2-CDX1 fusion reported

501
 Extraskeletal Mesenchymal Chondrosarcoma
Chondroosseous Tumors

• Desmin (-), MYOD1(+), myogenin (+/-)

DIFFERENTIAL DIAGNOSIS
○ EMC desmin (+) in 50% of cases
Ewing Sarcoma ○ Very rare EMCs reported as focally positive for MYOD1
• Uniform small round cells or myogenin
• Softer, less coarse chromatin Extraskeletal Myxoid Chondrosarcoma
• Lacks cartilage
• Abundant myxoid matrix
• Lacks pericytomatous vascular pattern
• Epithelioid or spindle cells arranged in cords
• Glycogen-rich clear cell cytoplasm in most
• Well-formed hyaline cartilage rarely present
• CD99(+), FLI-1(+), ERG(+)
• SOX9(-)
• SOX9(+/-)
• EWSR1 break-apart by FISH
SELECTED REFERENCES
• EWS-FLI1 or EWS-ERG fusion by RT-PCR
1. Arora K et al: Extraskeletal mesenchymal chondrosarcoma. Arch Pathol Lab
Synovial Sarcoma Med. 142(11):1421-4, 2018
2. Frezza AM et al: Mesenchymal chondrosarcoma: prognostic factors and
• Spindle or small round cells outcome in 113 patients. A European Musculoskeletal Oncology Society
• Softer, less coarse chromatin study. Eur J Cancer. 51(3):374-81, 2015
• Pericytomatous vascular pattern 3. Andersson C et al: Primary spinal intradural mesenchymal chondrosarcoma
with detection of fusion gene HEY1-NCOA2: a paediatric case report and
• Hyalinized and calcified stroma review of the literature. Oncol Lett. 8(4):1608-12, 2014
• Metaplastic ossification in some 4. Cheah AL et al: STAT6 rabbit monoclonal antibody is a robust diagnostic tool
for the distinction of solitary fibrous tumour from its mimics. Pathology.
• Lacks hyaline cartilage 46(5):389-95, 2014
• Keratin (+), EMA(+), CD99(+), TLE1(+), SOX9(+) 5. Kawaguchi S et al: Radiation therapy is associated with fewer recurrences in
• SYT break-apart by FISH mesenchymal chondrosarcoma. Clin Orthop Relat Res. 472(3):856-64, 2014
• SSX-SYT fusion by RT-PCR 6. Moriya K et al: Mesenchymal chondrosarcoma diagnosed on FISH for HEY1-
NCOA2 fusion gene. Pediatr Int. 56(5):e55-7, 2014
Solitary Fibrous Tumor (Cellular/Malignant) 7. Panagopoulos I et al: Chromosome aberrations and HEY1-NCOA2 fusion
gene in a mesenchymal chondrosarcoma. Oncol Rep. 32(1):40-4, 2014
• Spindle cells in haphazard or storiform arrays 8. Fritchie KJ et al: Are meningeal hemangiopericytoma and mesenchymal
• Wire-like collagen bundles chondrosarcoma the same?: a study of HEY1-NCOA2 fusion. Am J Clin
Pathol. 140(5):670-4, 2013
• Pericytomatous vascular pattern 9. Nakayama R et al: Detection of HEY1-NCOA2 fusion by fluorescence in-situ
• Occurs in meninges, as does EMC hybridization in formalin-fixed paraffin-embedded tissues as a possible
• Lacks hyaline cartilage diagnostic tool for mesenchymal chondrosarcoma. Pathol Int. 62(12):823-6,
2012
• CD99(+) 10. Shakked RJ et al: Mesenchymal chondrosarcoma: clinicopathologic study of
• CD34(+/-) 20 cases. Arch Pathol Lab Med. 136(1):61-75, 2012
• CD10(+) 11. Wang L et al: Identification of a novel, recurrent HEY1-NCOA2 fusion in
mesenchymal chondrosarcoma based on a genome-wide screen of exon-
• STAT6(+) level expression data. Genes Chromosomes Cancer. 51(2):127-39, 2012
12. Cajaiba MM et al: Sox9 expression is not limited to chondroid neoplasms:
Osteosarcoma variable occurrence in other soft tissue and bone tumors with frequent
• Can have small cell or chondroblastic features expression by synovial sarcomas. Int J Surg Pathol. 18(5):319-23, 2010
13. Fanburg-Smith JC et al: Immunoprofile of mesenchymal chondrosarcoma:
• Rare as primary soft tissue tumor aberrant desmin and EMA expression, retention of INI1, and negative
• SOX9(-) estrogen receptor in 22 female-predominant central nervous system and
musculoskeletal cases. Ann Diagn Pathol. 14(1):8-14, 2010
• Osteocalcin (+)
14. Fanburg-Smith JC et al: Reappraisal of mesenchymal chondrosarcoma: novel
Malignant Peripheral Nerve Sheath Tumor morphologic observations of the hyaline cartilage and endochondral
ossification and beta-catenin, Sox9, and osteocalcin immunostaining of 22
• Rare cases featuring heterologous cartilage cases. Hum Pathol. 41(5):653-62, 2010
• Fascicular spindle cell pattern most common 15. Dantonello TM et al: Mesenchymal chondrosarcoma of soft tissues and bone
in children, adolescents, and young adults: experiences of the CWS and
• Can have small round cell pattern COSS study groups. Cancer. 112(11):2424-31, 2008
• Can have pericytomatous vascular pattern 16. Gengler C et al: Desmin and myogenin reactivity in mesenchymal
• S100 protein (+) in 50% of tumors, usually focal chondrosarcoma: a potential diagnostic pitfall. Histopathology. 48(2):201-3,
2006
Atypical Teratoid Rhabdoid Tumor 17. Wehrli BM et al: Sox9, a master regulator of chondrogenesis, distinguishes
mesenchymal chondrosarcoma from other small blue round cell tumors.
• Intracranial location Hum Pathol. 34(3):263-9, 2003
• Small round cells 18. Granter SR et al: CD99 reactivity in mesenchymal chondrosarcoma. Hum
Pathol. 27(12):1273-6, 1996
• More abundant eosinophilic cytoplasm 19. Nakashima Y et al: Mesenchymal chondrosarcoma of bone and soft tissue. A
• Lacks cartilage review of 111 cases. Cancer. 57(12):2444-53, 1986
• Keratin (+) 20. Bertoni F et al: Mesenchymal chondrosarcoma of bone and soft tissues.
Cancer. 52(3):533-41, 1983
• Loss of nuclear SNF5 (INI1)
21. Huvos AG et al: Mesenchymal chondrosarcoma. A clinicopathologic analysis
of 35 patients with emphasis on treatment. Cancer. 51(7):1230-7, 1983
Sclerosing Rhabdomyosarcoma
• Small round or spindle cells
• Hyalinized matrix can mimic cartilage; well-formed cartilage
absent
• Rhabdomyoblasts often sparse

502
 Extraskeletal Mesenchymal Chondrosarcoma
Pericytomatous Vascular Pattern
Round Cells Admixed With Chondroid
Ossification
Islands of Hyaline Cartilage
Chondroosseous Tumors
Large Area of Hyaline Cartilage
(Left) The amount of cartilage
﬈ is variable in EMC. In most
tumors, cellular areas
predominate as depicted. Note
the prominent pericytomatous
vascular pattern ﬉ and
central calcification of the
cartilage. (Right) In some
EMCs, hyaline cartilage forms
the predominant element, as
depicted ﬈. The cartilage is
often pink instead of light blue
and can be heavily mineralized
﬉.
Matrix
(Left) Endochondral
ossification is often seen in
EMC. This micrograph depicts
an island of neoplastic hyaline
cartilage ﬈ transitioning into
woven bone ﬉. Such tumors
can sometimes be
misdiagnosed as
osteosarcoma. Note the sharp
interface between cellular
area and cartilage ﬊. (Right)
In some tumors, the malignant
cells are intimately admixed
with chondroid matrix ﬈,
which appears pale blue in the
tumor.
Spindle Cells
(Left) Multiple small islands of
hyaline cartilage ﬈ blend
with small round cells in this
EMC, creating a multinodular
pattern. (Right) In some
tumors, the cells are spindle-
shaped and arranged in
fascicles ﬈. However, spindle
cell areas generally account
for only a portion of a given
tumor. Fibrotic stroma is also
occasionally seen as
illustrated ﬉.
503
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 SECTION 12

Peripheral Nerve Sheath Tumors

Benign
Solitary Circumscribed Neuroma 506
Schwannoma 508
Neurofibroma 522
Perineurioma 530
Hybrid Nerve Sheath Tumor 536
Granular Cell Tumor 540
Dermal Nerve Sheath Myxoma 546
Ganglioneuroma 550
Neuromuscular Choristoma 554

Intermediate
Melanotic Schwannoma 556

Malignant
Malignant Peripheral Nerve Sheath Tumor 558
Epithelioid Malignant Peripheral Nerve Sheath Tumor 566
Ectomesenchymoma 570
 Solitary Circumscribed Neuroma

KEY FACTS
Peripheral Nerve Sheath Tumors

TERMINOLOGY • Relatively uniform cellularity

• Synonym: Palisaded encapsulated neuroma • Cells may form vague palisades
• Benign dermal/subcutaneous intraneural proliferation of ○ Usually not as dramatic as seen in Verocay bodies
Schwann cells and axons • Usually only minimal focal myxoid change
• Often connected to nerve
CLINICAL ISSUES • Likely intraneural proliferation that distends and expands
• Common nerve
• Middle-aged to elderly adults
ANCILLARY TESTS
• Most common sites: Face, especially cheeks, nasolabial
folds, and nose • S100 protein and SOX10 (+) Schwann cells
• Less common sites: Oral mucosae, acral skin, eyelid, penis • Neurofilament (+) axons throughout lesion
• Completely benign • EMA, claudin-1, GLUT-1 (+) perineurial cells in capsule
• No association with NF1 or MEN 2B TOP DIFFERENTIAL DIAGNOSES
MICROSCOPIC • Schwannoma
• Sharply circumscribed dermal nodule with thin capsule • Mucosal neuroma
○ May be plexiform or multinodular • Traumatic neuroma
• Composed of Schwann cells arranged into short • Plexiform neurofibroma
fascicles/bundles with intervening clefting artifact

Solitary Circumscribed Dermal Nodule Characteristic Clefting Artifact

(Left) Solitary circumscribed
neuroma (SCN) usually
presents as a sharply
demarcated dermal nodule
composed of bundles or
fascicles of spindled Schwann
cells. (Right) Bland spindled
Schwann cells are arranged in
fascicles/bundles, which are
divided from one another by
very characteristic artifactual
clefts ﬈. The spindle cells
may form palisades ﬈,
although these are usually less
well developed in SCN than
those of a schwannoma.

Palisading and Peripheral "Capsule" Plexiform Growth Pattern

(Left) Bland spindled Schwann
cells may form vague
palisades ﬈ in SCN. A thin
peripheral layer ("capsule") of
perineurium often surrounds
the lesion ﬊. (Right) The
plexiform pattern of SCN is
composed of multiple
circumscribed nodules, each of
which has the typical features
of conventional SCN. Clefting
artifact is visible here even
from low power ﬈.

506
 Solitary Circumscribed Neuroma

Peripheral Nerve Sheath Tumors

– Not usually striking palisading like Verocay bodies of
TERMINOLOGY schwannoma
Abbreviations ○ Usually only minimal focal myxoid change
• Solitary circumscribed neuroma (SCN) • Often connected to nerve
○ Likely represents intraneural proliferation that distends
Synonyms and expands nerve
• Palisaded encapsulated neuroma
Definitions ANCILLARY TESTS
• Benign dermal/subcutaneous intraneural proliferation of Immunohistochemistry
Schwann cells and axons • S100 protein and SOX10 (+) in Schwann cells
• Neurofilament protein (+) axons throughout lesion
CLINICAL ISSUES • Perineurial cells in capsule (+) for EMA, claudin-1, GLUT1
Epidemiology • GFAP, SMA, keratin (-)
• Incidence
○ Common DIFFERENTIAL DIAGNOSIS
• Middle-aged to elderly adults Schwannoma
Site • Alternating hyper- and hypocellular areas
• Hyalinized or myxoid stromal change
• Face most common site, especially
• Hyalinized vessel walls
○ Cheeks
• More prominent palisading (Verocay bodies)
○ Nasolabial folds
• Lacks bundles with intervening clefting artifact
○ Nose
• May have some axons
• Less common sites
○ Axons usually limited to area beneath capsule
○ Oral mucosa
○ Acral skin Mucosal Neuroma
○ Eyelid • Neural proliferations of oral cavity and gastrointestinal tract
○ Penis • Thickened tortuous nerve bundles scattered throughout
Presentation submucosa
• Poorly circumscribed
• Skin-colored papule (may mimic basal cell carcinoma
• May be associated with MEN 2B
clinically)
• Rare hybrid lesions show overlap between SCN and
• Usually asymptomatic
mucosal neuroma; unclear if these are related to MEN 2B
Treatment
Traumatic Neuroma
• Simple excision usually curative
• Neural proliferations in dermis near site of injury or
Prognosis amputation
• Completely benign • Thickened nerve bundles intertwined with one another
• No association with NF1 or MEN 2B • Often poorly circumscribed
• Rare plexiform SCN on acral skin may be associated with Plexiform Neurofibroma
Cowden syndrome (PTEN mutation)
• Can mimic multinodular pattern of SCN
• Less cellular and less organized than SCN
MICROSCOPIC
• More myxoid background, scattered disorganized spindle
Histologic Features cells
• Sharply circumscribed dermal nodule • Virtually diagnostic of NF1
○ May be plexiform or multinodular ○ Very important to not confuse plexiform neurofibroma
○ May extend into subcutis with SCN or vice versa
○ Thin, peripheral capsule of perineurium
– Mass often only partially surrounded by perineurium SELECTED REFERENCES
• Composed of Schwann cells arranged into short 1. Harris E et al: Acral plexiform palisaded encapsulated neuromas as the initial
fascicles/bundles cutaneous manifestation of Cowden syndrome. Pediatr Dermatol.
34(4):e219-20, 2017
○ Intervening clefting artifact between bundles is very 2. Jokinen CH et al: Expanding the clinicopathologic spectrum of palisaded
characteristic encapsulated neuroma. J Cutan Pathol. 37(1):43-8, 2010
○ Relatively uniform cellularity 3. Koutlas IG et al: Palisaded encapsulated ("solitary circumscribed") neuroma
of the oral cavity: a review of 55 cases. Head Neck Pathol. 4(1):15-26, 2010
○ Cells have buckled nuclei and scant cytoplasm
4. Megahed M: Palisaded encapsulated neuroma (solitary circumscribed
○ Majority of cells are bland but may be hyperchromatic neuroma). A clinicopathologic and immunohistochemical study. Am J
– As with other Schwann cell proliferations, focal Dermatopathol. 16(2):120-5, 1994
degenerative nuclear pleomorphism may be seen 5. Argenyi ZB: Immunohistochemical characterization of palisaded,
encapsulated neuroma. J Cutan Pathol. 17(6):329-35, 1990
○ Mitotic activity is very low 6. Fletcher CD: Solitary circumscribed neuroma of the skin (so-called palisaded,
○ Cells may form vague palisades encapsulated neuroma). Am J Surg Pathol. 13(7):574-80, 1989

507
 Schwannoma

KEY FACTS
Peripheral Nerve Sheath Tumors

TERMINOLOGY • Morphologic variants: Ancient, cellular, plexiform,

• Encapsulated, benign peripheral nerve sheath tumor
composed predominantly of Schwann cells
CLINICAL ISSUES
• Any age
○ Most common: 20-50 years
• Most occur in superficial soft tissues of head/neck and
upper or lower extremities
○ Also retroperitoneum, posterior mediastinum, and
viscera [gastrointestinal (GI) tract, kidney, etc.]
• Surgical excision is generally curative and recurrences are
rare
MICROSCOPIC
• Well-circumscribed, nodular mass with fibrous capsule
• Hallmark: Variable amounts of hypercellular Antoni A and
hypocellular Antoni B areas
epithelioid, pseudoglandular, neuroblastoma-like,
microcystic/reticular
• Schwannomas in neurofibromatosis type 2 (NF2) and
schwannomatosis
○ Similar morphologically to sporadic tumors
ANCILLARY TESTS
• Diffuse, strong S100(+) and SOX10(+) is characteristic of all
schwannoma variants
• Type IV collagen is present around individual cells and small
groups of cells
• Cytokeratin AE1/AE3 and GFAP expression common in
tumors of retroperitoneum, posterior mediastinum, and GI
tract
TOP DIFFERENTIAL DIAGNOSES
• Neurofibroma
• Malignant peripheral nerve sheath tumor
• Pleomorphic hyalinizing angiectatic tumor

Schwannoma Encapsulation Common

(Left) Schwannoma is a well-
circumscribed, encapsulated
peripheral nerve sheath tumor
that, in its conventional form,
shows a variable admixture of
zones of high and low
cellularity, imparting a
somewhat marbled
appearance at low
magnification. (Right) Most
schwannomas are surrounded
by a thick or thin fibrous
capsule that contains
epineurium and residual nerve
fibers.

Classic Alternating Cellularity Antoni A and Antoni B Zones

(Left) The classic marbled
appearance of schwannoma is
created by interfaces between
the cellular Antoni A zones ſt
and the loose edematous or
myxoid Antoni B zones ﬊.
This interface may be
discretely abrupt or a gradual
transition. (Right) Antoni A
zones ﬈ are more cellular and
organized than Antoni B
zones. Most schwannomas
show a complex admixture of
these 2 types of zones, but
occasional cases are composed
predominantly of either
Antoni A or B.

508
 Schwannoma

Peripheral Nerve Sheath Tumors

– Common between 20-50 years
TERMINOLOGY
• Sex
Synonyms ○ Affects male and female patients equally
• Neurilemmoma
Site
Definitions • Most occur in superficial soft tissues of head/neck and
• Encapsulated, benign peripheral nerve sheath tumor upper or lower extremities
composed predominantly of Schwann cells ○ Deep-seated soft tissue tumors much less common
• Retroperitoneum and mediastinum (often large)
ETIOLOGY/PATHOGENESIS • May also be seen in gastrointestinal (GI) tract and
Molecular Aberrations parenchymal organs (kidney, pancreas, etc.)
• May involve cranial nerve VIII in setting of NF2
• Somatic NF2 gene mutations present in most tumors (vestibular/acoustic neuroma)
• Bilateral vestibular schwannomas occur in setting of
germline NF2 gene mutations Presentation
Associated Syndromes • Slow-growing, painless mass
○ Large tumors may be painful
• Neurofibromatosis type 2 (NF2)
• Cystic tumors may show fluctuation in size
○ Inactivating germline mutations of NF2 gene on
• Examples that occur in neck often confused clinically for
chromosome 22
lymph nodes
○ Autosomal dominant condition
– Incidence around 1:30,000-40,000 Treatment
○ Bilateral vestibular schwannomas are characteristic and • Surgical excision, often nerve sparing
diagnostic
Prognosis
– Schwannomas involving other cranial nerves may be
present • Benign
○ CNS tumors, such as meningioma, ependymoma, and • Excision is generally curative, and recurrences are rare
gliomas, are also part of disease spectrum (usually deep-seated tumors)
○ Schwannomas in NF2 resemble their sporadic
counterparts MACROSCOPIC
– Of note, plexiform schwannomas are not diagnostic General Features
of NF2
• Surrounded by true capsule consisting of epineurium
• Schwannomatosis
• Eccentric growth off of large nerve, or less likely, as nodular
○ Rare sporadic or familial (autosomal dominant) condition or fusiform mass seemingly unassociated with nerve
characterized by formation of multiple peripheral
○ Dumbbell-shaped tumors occur in vertebral canal,
schwannomas
usually in posterior mediastinum
– Familial cases that follow autosomal dominant
• Variable size (often < 5 cm)
inheritance with reduced penetrance occur but are
• Cut surface is gray-tan-white to yellow
less common
• Large tumors may show cystic change, hemorrhage, or
– Schwannomatosis locus identified on chromosome 22
calcification on cut section
proximal to NF2 gene
– Not associated with germline mutations in NF1 or NF2
MICROSCOPIC
genes
– Some cases of inherited and sporadic Histologic Features
schwannomatosis may be associated with germline • Well-circumscribed, nodular mass with fibrous capsule
SMARCB1 mutations • Hallmark: Variable amounts of admixed cellular Antoni A
○ By definition, patients do not have bilateral vestibular and hypocellular Antoni B areas
schwannomas and lack other criteria for NF2 ○ Antoni A
○ Morphology similar to sporadic schwannomas – Spindle cells in short or interconnecting fascicles,
loosely or tightly formed
CLINICAL ISSUES – Generally indistinct cytoplasmic borders
Epidemiology – Nuclear palisading or whorling is common
• Incidence □ Verocay bodies: Compact rows of palisaded nuclei
separated by fibrillary processes
○ 90% are sporadic
– May contain lymphocytic infiltrate
○ 10% are syndromic
○ Antoni B
– ~ 3% with NF2
– Less orderly than Antoni A
– 2% with schwannomatosis
– Spindle or ovoid cells with indistinct cytoplasmic
– 5% with multiple meningiomas
borders
– Very rarely in association with NF1
– Loose edematous or myxoid matrix with cystic change
• Age
and inflammatory cells, particularly lymphocytes and
○ All ages
histiocytes
509
 Schwannoma
Peripheral Nerve Sheath Tumors
□ Presence of scattered collagen bundles may impart
resemblance to neurofibroma
– Large vessels with thick hyalinized walls and luminal
thrombi ± hemosiderin deposition
• Nuclei are either thin and elongated with buckled or carrot-
like shape or plump and ovoid
○ Intranuclear inclusions may be seen
• Mitotic rate is generally low to absent with no atypical
forms
○ Cellular schwannomas may show more conspicuous
mitotic activity
• Longstanding lesions often show degenerative changes
○ Nuclear atypia (ancient change) but without increase in
mitotic activity
○ Cystic change may be focal or widespread with abundant
hemorrhage
○ Stromal hyalinization or marked hypocellularity
○ Calcification ± metaplastic bone formation
○ Infarct-type necrosis may be present
– True coagulative necrosis is rarely seen in cellular
schwannoma (usually focal)
• Malignant transformation in schwannomas extremely rare
○ Usually epithelioid malignant peripheral nerve sheath
tumor (MPNST), also epithelioid angiosarcoma
Morphologic Variants
• Ancient schwannoma
○ Demonstrates marked nuclear atypia of degenerative
type (often "smudgy")
○ Lacks mitotic activity
○ Cystic change, hemorrhage, calcification, and
hyalinization present
○ Usually seen in tumors of long duration (particularly
deep-seated cases)
• Cellular schwannoma
○ By definition, composed almost exclusively of
hypercellular Antoni A areas, which lack Verocay bodies
○ Encapsulated tumors; some may be multinodular or
plexiform in architecture
– Many show subcapsular &/or intratumoral lymphoid
aggregates
○ Short to long sweeping fascicles of spindle-shaped cells
– Cells may appear round/ovoid in fascicles that are cut
in cross section
○ Mitotic activity is low (< 4/10 HPF)
○ Small foci of necrosis may be present
○ More common in mediastinum, retroperitoneum, and GI
tract
• Plexiform schwannoma
○ Encapsulated tumors with striking multinodular or
plexiform architecture
○ Often more cellular than ordinary schwannoma
– Highly cellular examples reported in infants and
children (cellular plexiform schwannoma)
○ Usually occur in skin or superficial soft tissues
○ Most common in head and neck region; infrequent in
deeper locations
○ Association with NF syndromes is weak (unlike plexiform
neurofibroma)
• Epithelioid schwannoma
510
○ Epithelioid or polygonal Schwann cells with sharp cell
borders and variable amount of eosinophilic cytoplasm
○ Arranged in clusters, cords, or as single cells in variably
myxoid or collagenous stroma
○ Foci of conventional schwannoma may be present
○ Small, bland nuclei
– Degenerative nuclear atypia may be seen
○ Lacks mitotic activity
• Pseudoglandular schwannoma
○ Contains cystic spaces that are lined by small round
tumor cells, resembling epithelial surfaces
– Cells may show "apical" cytoplasm
□ May mimic glandular or ductal epithelium
○ Often contains areas of conventional schwannoma
• Neuroblastoma-like schwannoma
○ Contains rosette-like structures composed of round to
ovoid Schwann cells around acellular collagen cores
– Collagen cores may lack peripheral cells
– Structures may be centered around small vessels
○ Mimics rosettes seen in neuroblastoma
• Microcystic/reticular schwannoma
○ Anastomosing strands of eosinophilic spindle cells in
myxoid, fibrillary, or collagenous matrix
○ Predilection for visceral locations, particularly GI tract
○ Foci of conventional schwannoma or other schwannoma
variants may be present
ANCILLARY TESTS
Immunohistochemistry
• Diffuse, strong S100 protein (+) is characteristic
○ Applies to all morphologic variants
○ SOX10 shows similar diffuse expression in nuclei
• Type IV collagen is present around individual cells and small
groups of cells
• Loss of nuclear INI1 in up to 1/2 of epithelioid
schwannomas
• Nuclear H3K27me3 expression generally intact
• Neurofilament protein expression is often limited to
entrapped axons at periphery of tumor but may be also
seen within tumor in some cases
• Cytokeratin AE1/AE3 and GFAP expression common in
tumors of retroperitoneum, posterior mediastinum, and GI
tract
○ In peripheral sites, GFAP expression is rare, and CK
AE1/AE3 has not been reported
○ CK AE1/AE3 expression due to cross reactivity with GFAP
• CD34, EMA, claudin-1, GLUT1 (-)
○ Mixed expression of S100 protein with 1 or more of
these markers may indicate hybrid peripheral nerve
sheath tumor
○ EMA expression often seen in capsule of schwannoma
DIFFERENTIAL DIAGNOSIS
Neurofibroma
• Unencapsulated and lacks Antoni A areas
○ Antoni B areas of schwannoma can look very similar to
neurofibroma
• Composed of mixture of Schwann cells, fibroblasts, and
perineurial cells
 Schwannoma
• S100 protein is diffusely positive but less striking overall
compared to schwannoma (due to lower cellularity)
• CD34 is commonly positive in admixed population of
fibroblasts
Malignant Peripheral Nerve Sheath Tumor
• Often larger and more deep seated than schwannoma
• Cytology varies from monomorphic to highly pleomorphic,
and mitotic activity is generally high and conspicuous
• Tumor necrosis common
• S100 protein expression is characteristically negative or at
most focal
○ Lower grade MPNST may show more extensive S100
positivity
○ Very rare cases of high-grade MPNST are diffusely
S100(+)
• Loss of nuclear H3K27me3 expression by IHC in majority of
cases
• Most likely to be confused with cellular, plexiform, and
ancient schwannoma variants
○ Cellular examples of plexiform schwannoma may be
mistaken for MPNST arising in plexiform neurofibroma
• Epithelioid MPNST is larger and more cellular than
epithelioid schwannoma and contains larger nuclei with
prominent macronucleoli
Malignant/Metastatic Melanoma
• Always consider in dermal tumors and in patients with
history of melanoma
• Lack admixed Antoni A and Antoni B zones
• Primary melanoma often contains cutaneous junctional
component
• Spindle cell melanoma may be relatively bland but often
shows at least focal nuclear atypia and mitotic activity
• Epithelioid melanoma cells are often cytologically
malignant with prominent, eosinophilic, cherry red nucleoli
• Strong expression of S100 protein and SOX10; often
diffuse
• Variable expression of melanocytic markers (HMB-45,
MART1/melan-A, MITF, tyrosinase)
○ Focal expression is significant in HMB-45 and
MART1/melan-A and can be easily missed
○ Desmoplastic melanomas are characteristically HMB-45
and MART-1 (-)
Pleomorphic Hyalinizing Angiectatic Tumor
• Can show markedly similar appearance to ancient
schwannoma
• S100 protein (-); CD34(+) (~ 50% of cases)
• Predilection for foot, ankle, and leg
• Significant risk of local recurrence with simple excision
Leiomyoma
• Generally very pink microscopic appearance
• Lack admixed Antoni A and Antoni B zones
• Composed of fascicles of plump, eosinophilic spindle cells
with cigar-shaped nuclei
○ May show epithelioid morphology
• SMA, caldesmon, and desmin expression
• S100 protein (-)
Peripheral Nerve Sheath Tumors
SELECTED REFERENCES
1. Jo VY et al: SMARCB1/INI1 loss in epithelioid schwannoma: a
clinicopathologic and immunohistochemical study of 65 cases. Am J Surg
Pathol. 41(8):1013-22, 2017
2. Hart J et al: Epithelioid schwannomas: an analysis of 58 cases including
atypical variants. Am J Surg Pathol. 40(5):704-13, 2016
3. Luzar B et al: Cutaneous microcystic/reticular schwannoma: a poorly
recognized entity. J Cutan Pathol. 43(2):93-100, 2015
4. Pekmezci M et al: Morphologic and immunohistochemical features of
malignant peripheral nerve sheath tumors and cellular schwannomas. Mod
Pathol. 28(2):187-200, 2014
5. Zong S et al: Treatment results in the differential surgery of intradural
extramedullary schwannoma of 110 cases. PLoS One. 8(5):e63867, 2013
6. Carter JM et al: Epithelioid malignant peripheral nerve sheath tumor arising
in a schwannoma, in a patient with "neuroblastoma-like" schwannomatosis
and a novel germline SMARCB1 mutation. Am J Surg Pathol. 36(1):154-60,
2012
7. Harder A et al: Hybrid neurofibroma/schwannoma is overrepresented
among schwannomatosis and neurofibromatosis patients. Am J Surg Pathol.
36(5):702-9, 2012
8. Rezanko T et al: Epithelioid schwannoma of soft tissue: unusual
morphological variant causing a diagnostic dilemma. Ann Diagn Pathol.
16(6):521-6, 2012
9. Voltaggio L et al: Gastric schwannoma: a clinicopathologic study of 51 cases
and critical review of the literature. Hum Pathol. 43(5):650-9, 2012
10. Chetty R: Reticular and microcystic schwannoma: a distinctive tumor of the
gastrointestinal tract. Ann Diagn Pathol. 15(3):198-201, 2011
11. Gaudi S et al: Intravascular schwannoma. Am J Dermatopathol. 33(8):850-4,
2011
12. Agaimy A et al: Peripheral nerve sheath tumors of the gastrointestinal tract:
a multicenter study of 58 patients including NF1-associated gastric
schwannoma and unusual morphologic variants. Virchows Arch. 456(4):411-
22, 2010
13. Küsters-Vandevelde HV et al: Improved discrimination of melanotic
schwannoma from melanocytic lesions by combined morphological and
GNAQ mutational analysis. Acta Neuropathol. 120(6):755-64, 2010
14. Santos PP et al: Clinicopathologic analysis of 7 cases of oral schwannoma and
review of the literature. Ann Diagn Pathol. 14(4):235-9, 2010
15. Trufant JW et al: Melanotic schwannoma arising in association with nevus of
Ota: 2 cases suggesting a shared mechanism. Am J Dermatopathol.
31(8):808-13, 2009
16. Liegl B et al: Microcystic/reticular schwannoma: a distinct variant with
predilection for visceral locations. Am J Surg Pathol. 32(7):1080-7, 2008
17. Fanburg-Smith JC et al: Keratin expression in schwannoma; a study of 115
retroperitoneal and 22 peripheral schwannomas. Mod Pathol. 19(1):115-21,
2006
18. MacCollin M et al: Diagnostic criteria for schwannomatosis. Neurology.
64(11):1838-45, 2005
19. Woodruff JM et al: Congenital and childhood plexiform (multinodular)
cellular schwannoma: a troublesome mimic of malignant peripheral nerve
sheath tumor. Am J Surg Pathol. 27(10):1321-9, 2003
20. McMenamin ME et al: 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. 25(1):13-25, 2001
21. Antinheimo J et al: Population-based analysis of sporadic and type 2
neurofibromatosis-associated meningiomas and schwannomas. Neurology.
54(1):71-6, 2000
22. Kindblom LG et al: Benign epithelioid schwannoma. Am J Surg Pathol.
22(6):762-70, 1998
23. Chan JK et al: Pseudoglandular schwannoma. Histopathology. 29(5):481-3,
1996
24. Goldblum JR et al: Neuroblastoma-like neurilemoma. Am J Surg Pathol.
18(3):266-73, 1994
25. Brooks JJ et al: Benign glandular schwannoma. Arch Pathol Lab Med.
116(2):192-5, 1992
26. Carney JA: Psammomatous melanotic schwannoma. A distinctive, heritable
tumor with special associations, including cardiac myxoma and the Cushing
syndrome. Am J Surg Pathol. 14(3):206-22, 1990
27. Fletcher CD et al: Cellular schwannoma: a distinct pseudosarcomatous
entity. Histopathology. 11(1):21-35, 1987
28. Fletcher CD et al: Benign plexiform (multinodular) schwannoma: a rare
tumour unassociated with neurofibromatosis. Histopathology. 10(9):971-80,
1986
511
 Schwannoma
Peripheral Nerve Sheath Tumors

Antoni A Zones Antoni A Cytologic Features

(Left) Antoni A zones of
schwannoma are cellular and
relatively organized. Not all
Antoni A zones exhibit nuclear
palisading, Verocay body
formation, or whorling. (Right)
The spindle cells in Antoni A
zones of schwannoma
typically show indistinct
cytoplasmic borders and
elongated, buckled, wavy, or
twisted nuclei. The matrix is
fine, fibrillary, and
eosinophilic.

Nuclear Palisading in Antoni A Morphology of Verocay Bodies

(Left) A characteristic finding
in some Antoni A zones of
schwannoma is the presence
of focal to prominent nuclear
palisading ﬈. This finding is
not pathognomonic, however,
as other unrelated tumors can
show similar morphology.
(Right) In schwannoma, the
term Verocay body is used to
describe the finding of
eosinophilic fibrillary cell
processes ﬈ between 2 rows
of palisading Schwann cell
nuclei.

Whorling Architecture in Some Cases Schwann Cell Nuclear Features

(Left) In addition to nuclear
palisading, a whorling
architecture may be identified
within Antoni A zones of
schwannoma. (Right)
Cytologically, most Schwann
cell nuclei are bland,
elongated, and often tapered
at one or both ends. Nucleoli
are inconspicuous. Clear
nuclear pseudoinclusions (not
pictured) are also seen in some
cases. Mitotic figures ſt are
rarely identified in
schwannoma and, if present,
are never atypical.

512

Stromal Inflammation Common
Antoni B Zones
Hypocellularity or Myxoid Change in
Antoni B
Schwannoma
Peripheral Nerve Sheath Tumors
Variable Stromal Collagen
(Left) A chronic inflammatory
infiltrate is not uncommon in
schwannoma and usually
consists of predominantly
reactive lymphocytes. This
finding varies in prominence
and may be seen in both
Antoni A and Antoni B zones.
(Right) Some areas in a
schwannoma may show a
typical loose fascicular growth
of Antoni A but with increased
stromal collagen. This finding
is a feature of some cellular
schwannomas.
Antoni B Collagen Distribution
(Left) Antoni B zones in
schwannoma are distinctly
less cellular than Antoni A
zones and demonstrate a
loose edematous or myxoid
matrix with scattered collagen
fibers. (Right) In some areas of
schwannoma, the distribution
of collagen fibers in Antoni B
zones may closely resemble
that of a neurofibroma,
particularly the plexiform
type; however, the
characteristic multinodular
growth pattern of the latter is
generally absent.
Strong and Diffuse S100 Protein
Expression
(Left) Antoni B zones in
schwannoma may be
significantly myxoid and
hypocellular and easily
confused with a variety of
other low-grade myxoid
neoplasms, such as myxoma or
neurofibroma. (Right) S100
protein expression is
essentially always strong and
diffuse in schwannoma and
characteristic of all variants.
The staining pattern is
typically both nuclear and
cytoplasmic.
513
 Schwannoma
Peripheral Nerve Sheath Tumors

Hyperplastic Vascular Changes in Some

Hyalinized Vessels Characteristic Tumors
(Left) An often conspicuous
and characteristic finding in
schwannoma is the presence
of single or clusters of
irregular vascular channels
with hyalinized walls. These
vessels predominate in Antoni
B zones but may occasionally
be identified in cellular Antoni
A zones. (Right) A variety of
benign vascular changes may
be identified in the vessels of
schwannoma, including
papillary endothelial
hyperplasia and thrombosis.

Occasional Vessels With Fibrinoid Changes Myxoid Areas in Schwannoma

(Left) Occasional vessels in
schwannoma may show
fibrinoid change in the wall ±
thrombosis. This finding is
most commonly seen in
ancient schwannoma. Similar
vascular changes can be seen
in other tumors, particularly
pleomorphic hyalinizing
angiectatic tumor. (Right)
Some examples of
schwannoma show an
interesting morphologic
arrangement of relatively
eosinophilic Antoni A zones
and highly myxoid Antoni B.
The overall marbled pattern is
characteristic of most cases of
conventional schwannoma.

Rare, Prominent Myxoid Stroma Stromal Hyalinization in Antoni B

(Left) This particular case of
schwannoma shows large
areas of myxoid matrix,
resembling other low-grade
myxoid neoplasms. S100
protein positivity was helpful
in supporting the diagnosis of
schwannoma. (Right) Antoni B
zones in schwannoma may be
markedly hyalinized and
hypocellular, particularly
longstanding tumors or those
with abundant other
degenerative features.

514

Diffuse Stromal Sclerosis in Older Tumors
Metaplastic Bone Formation Uncommon
Cystic Change in Degenerative
Schwannoma
Schwannoma
Peripheral Nerve Sheath Tumors
Calcification in Degenerative Schwannoma
(Left) Diffuse stromal
hyalinization or sclerosis may
be seen in degenerative
schwannoma, and areas of
conventional morphology ﬈
may be focal or absent
altogether. (Right)
Calcification is not uncommon
in schwannoma and is often
associated with other
degenerative changes,
including vascular
hyalinization, stromal
sclerosis, cystic change, and
hemosiderin deposition.
Foamy Histiocytes
(Left) Metaplastic bone
formation is an uncommon
event in schwannoma but is
more likely to be seen in
longstanding cases. (Right)
Foamy histiocytes ﬈ may be
identified in some cases of
schwannoma, particularly
cellular variants. They can also
be seen as a component of
Antoni B zones.
Rare Prominent Cystic Change
(Left) Cystic change is not
uncommon in schwannoma
but is more frequently
encountered in
ancient/degenerative tumors.
Clinically larger schwannomas
are more likely to have central
cystic hemorrhage. (Right)
Rare cases of schwannoma are
predominantly or exclusively
cystic and may be challenging
to diagnose. This type of
schwannoma is usually very
hemorrhagic intraoperatively,
clinically suggesting a vascular
neoplasm.
515
 Schwannoma
Peripheral Nerve Sheath Tumors

Hemosiderin Deposition Common Degenerative Microcystic Stromal Change

(Left) Hemosiderin deposition
﬈ is common in schwannoma,
particularly cases with
intratumoral hemorrhage.
Rare cases show abundant
hemosiderin and blood,
simulating a hematoma or
vascular neoplasm. (Right)
Microcystic stromal changes
may be seen in some cases of
schwannoma. The microcysts
vary in size and are often more
prominent around large cystic
spaces. Note the hyalinized
vessels ﬈.

Microcystic Stromal Change Associated

With Inflammation "Smudgy" Degenerative Nuclear Changes
(Left) Microcystic stromal
change in degenerative
schwannomas may be
associated with a brisk chronic
inflammatory infiltrate as well
as hyalinized vessels and
histiocytes. (Right) A common
finding in many schwannomas
is the presence of scattered
enlarged cells with
hyperchromatic, "smudgy"
nuclei ſt, termed ancient
change. Another common
finding in these cases is
lipofuscin pigment ﬊.

Ancient Schwannoma Variant Atypical, "Smudgy" Nuclei in Schwannoma

(Left) Ancient change in a
schwannoma may be very
prominent in some cases,
mostly in Antoni B areas but
even in Antoni A zones. This
finding may lead one to
suspect malignancy; however,
mitoses are discrepantly rare,
and there is no tumor necrosis.
(Right) At high magnification,
the degenerative nuclei are
often hyperchromatic and
irregular with "smudgy"
contours and may show
nuclear vacuolization. Mitoses
are inconspicuous or absent.

516

Cellular Schwannoma Variant
Cellular Whorls
Rare Nuclear Palisading in Cellular Tumors
Schwannoma
Peripheral Nerve Sheath Tumors
Short Fascicles and Whorls
(Left) The cellular variant of
schwannoma is defined as
being composed exclusively or
predominantly of Antoni A
zones. Focal Antoni B zones
may be identified but usually
do not comprise > 10% of the
tumor. (Right) Cellular
schwannoma often shows the
formation of short fascicular
or vague whorling
architectures. Mitoses are
more likely to be identified in
this variant; however, they are
generally not numerous.
Stromal Collagen in Cellular Schwannoma
(Left) A notable finding in
some cases of cellular
schwannoma is the formation
of cellular whorls ﬈ by the
tumor cells. This finding may
also be seen in malignant
peripheral nerve sheath
tumor; however, it is
uncommon. (Right) Some
examples of cellular
schwannoma show increased
stromal collagen and are
overall more eosinophilic in
appearance. Gastrointestinal
schwannomas in particular
routinely show this
morphology.
Microtrabecular Pattern in Cellular
Schwannoma
(Left) In contrast to Antoni A
zones in conventional
schwannoma, those of cellular
schwannoma often lack
distinct nuclear palisading and
Verocay body formation. Rare
herringbone fascicular
architecture ﬈ may be
identified focally in some
cases. (Right) A
microtrabecular architecture
is another interesting and
recurrent pattern that can be
seen in cellular schwannoma.
It is characterized by discrete,
small clusters or rows of
spindled Schwann cells.
517
 Schwannoma
Peripheral Nerve Sheath Tumors

Collections of Foamy Histiocytes Lymphoid Aggregates Common

(Left) Collections or
aggregates of foamy
histiocytes are a common
finding in cellular
schwannoma and can be
diagnostically helpful in
identifying this particular
variant. (Right) Lymphoid
aggregates are a very common
and characteristic feature of
most cellular schwannomas.
These aggregates are often
subcapsular, pericapsular, or
intratumoral and may show
reactive germinal center
formation.

Plexiform Schwannoma Variant Plexiform Schwannoma With Palisading

(Left) The plexiform variant of
schwannoma has a distinct
multinodular or serpentine
growth pattern. It shows a
predilection for the skin and is
rarely at deep sites. Unlike
plexiform neurofibroma,
plexiform schwannoma is not
diagnostic of
neurofibromatosis type 1.
(Right) Plexiform schwannoma
generally contains minimal
Antoni B and therefore has an
overall cellular appearance.
Typical features of Antoni A,
including nuclear palisading
﬈, may be seen.

Plexiform Schwannoma Without Palisading Epithelioid Schwannoma Variant

(Left) Some examples of
plexiform schwannoma may
show diffuse cellularity
without nuclear palisading. In
the context of a plexiform
growth pattern, this
appearance may lead to
misdiagnosis of malignant
peripheral nerve sheath tumor
in a plexiform neurofibroma;
however, mitotic activity is
low, and there is no tumor
necrosis. (Right) Epithelioid
cellular change in a
schwannoma is seen focally in
many cases. Rarely, this
morphology may be diffuse
and warrant classification as
an epithelioid schwannoma.

518

Epithelioid Schwannoma With Clusters of
Small Cells
Mixed Epithelioid and Spindled Cells
Schwann Cell Lining Resembles Gland
Formation
Schwannoma
Peripheral Nerve Sheath Tumors
Bland Nuclei in Epithelioid Tumors
(Left) Epithelioid schwannoma
may show clusters of small,
bland tumor cells in small
clusters or linear arrays within
a myxoid matrix. Mitotic
figures are rare or absent.
(Right) Cytologically, the cells
of epithelioid schwannoma are
generally small and show
bland nuclei. Features of
epithelioid malignant
peripheral nerve sheath
tumor, including enlarged
nuclei with prominent
macronucleoli and
conspicuous mitoses, are not
seen.
Pseudoglandular Spaces in Schwannoma
(Left) Foci of epithelioid
Schwann cells ﬈ may be seen
in the background of an
otherwise typical spindle cell
schwannoma. (Right)
Schwannomas with cystic
change may show a lining ﬈
that is very reminiscent of
glandular epithelium. This
lining is clearly schwannian, as
evidenced by strong S100
protein expression and
negative keratin staining. Also,
there is an absence of
intracytoplasmic mucin.
Pseudoglandular Schwannoma Variant
(Left) The basal polarity of the
Schwann cell nuclei lining the
cystic spaces helps impart a
pseudoglandular appearance.
(Right) In some rare cases of
schwannoma, the
pseudoglandular change is
extensive or predominant,
warranting classification as a
pseudoglandular
schwannoma. Other areas of
more typical schwannoma are
often present.
519
 Schwannoma
Peripheral Nerve Sheath Tumors

Neuroblastoma-Like Schwannoma Variant Radial Cellular Arrangement in Rosettes

(Left) Variably sized,
hyalinized, rosette-like
structures lined by peripheral
Schwann cell nuclei are a rare
finding in schwannoma and
may be numerous. (Right) The
neuroblastoma-like rosettes
seen in rare cases of
schwannoma are formed by
rounded Schwann cells
radially oriented around a
collagen core. The nuclei of
these cells are cytologically
banal.

Rosettes With Spindled Cells in

Focal Perivascular Arrangement Schwannoma
(Left) In some cases of
neuroblastoma-like
schwannoma, the rosette
structures are formed around
what appear to be tiny
vascular channels ﬈. (Right)
The radially oriented cells of
neuroblastoma-like
schwannoma may rarely be
spindled rather than
epithelioid, warranting
consideration of low-grade
fibromyxoid sarcoma
(hyalinizing spindle cell tumor
with giant rosette
morphology).

Cytoplasmic Eosinophilia in Reticular

Microcystic/Reticular Schwannoma Variant Schwannoma
(Left) Rare cases of
schwannoma show a striking
reticular growth pattern in a
myxoid to hyalinized stroma.
This morphology may be
predominant or associated
with areas of more
conventional schwannoma
morphology. (Right) The
cytoplasmic eosinophilia is
more conspicuous in this
example of
microcystic/reticular
schwannoma.

520
 Schwannoma
Focal Microcystic/Reticular Change in
Microcyst Formation
Rare Presence of Eosinophilic Granular
Bodies
Adjacent Ganglion in Schwannoma
Mimicking Ganglioneuroma
Peripheral Nerve Sheath Tumors
Otherwise Typical Schwannoma
(Left) Microcyst formation ﬈
may also be identified in
association with the reticular
morphology in some
schwannomas. Similar to other
forms of schwannoma, this
morphologic variant strongly
and diffusely expresses S100
protein. (Right) This case of
schwannoma showed small
focal areas demonstrating
reticulated growth within a
myxoid stroma intermixed
with areas of more
conventional schwannoma.
Direct Association With Nerve
(Left) Eosinophilic, granular
body-like structures ſt are a
rare finding in schwannoma
but appear to be more
prevalent in schwannomas of
the vestibulocochlear nerve
(acoustic schwannoma) along
with Rosenthal fibers. (Right)
Occasionally, a small or
incipient schwannoma may be
detected intraoperatively as a
small nodule growing on an
otherwise unremarkable
nerve. This H&E shows the
tumor ﬈ arising in a
background of peripheral
nerve ﬊.
Very Rare Malignant Change in
Schwannoma
(Left) Schwannomas that arise
in the immediate vicinity of a
ganglion will often show
scattered collections of benign
ganglion cells ﬈ in or
adjacent to the peripheral
capsule. This pattern differs
from a true ganglioneuroma,
in which ganglion cells are
widely scattered throughout
the tumor. (Right) Malignant
change in schwannoma is an
extremely rare event. Most
well-documented cases of this
transformation are in the form
of an epithelioid malignant
peripheral nerve sheath tumor
(pictured) or epithelioid
angiosarcoma.
521
 Neurofibroma

KEY FACTS
Peripheral Nerve Sheath Tumors

TERMINOLOGY
• Benign peripheral nerve sheath tumor composed of
Schwann cells, fibroblasts, perineurial-like cells, and residual
nerve axons within extracellular matrix
CLINICAL ISSUES
• Most common peripheral nerve sheath tumor
○ 3 main types: Localized (cutaneous or intraneural),
diffuse, and plexiform
– Plexiform type is essentially pathognomonic for
neurofibromatosis type 1 (NF1)
• Wide age range
○ Diffuse and plexiform types most common in young
• Most (90%) neurofibromas are sporadic
• Benign; very rare local recurrence
• Malignant transformation usually occurs in setting of NF1
(up to 10% of patients)
MICROSCOPIC
• Loosely arranged spindle cells in haphazard arrangement
○ Small, hyperchromatic, wavy or buckled nuclei
○ Variable myxoid to collagenous matrix
• Diffuse type: Ill-defined, dermal and subcutaneous
proliferation that entraps adnexa
○ Pseudomeissnerian bodies are characteristic
• Plexiform: Multinodular/serpentine growth pattern
• Malignant transformation: Combination of increased
cellularity, nuclear atypia, mitotic activity, &/or necrosis
ANCILLARY TESTS
• Mixture of S100(+), CD34(+), and EMA(+) cells
TOP DIFFERENTIAL DIAGNOSES
• Malignant peripheral nerve sheath tumor
• Dermatofibrosarcoma protuberans
• Schwannoma
• Perineurioma

Neurofibroma Localized Neurofibroma

(Left) Grossly, neurofibroma
often appears as an ovoid or
fusiform mass and usually
shows a pale, wavy to
gelatinous cut surface. The
gross degenerative changes
often seen in schwannomas
are seldom present in
neurofibroma. Note the
transected nerve fibers ſt at
both ends of the mass. (Right)
Localized cutaneous
neurofibroma forms a well-
circumscribed, but
unencapsulated, dermal
proliferation. This lesion may
also occur in the nerve
(intraneural localized
neurofibroma).

Small Elongated Spindle Cells S100 Expression in Schwann Cells

(Left) All forms of
neurofibroma are cytologically
similar and are characterized
by small, elongated spindled
cells in a variably collagenous
background stroma. Rare
tumors show epithelioid
features (not shown). (Right)
Consistent S100 protein
expression is seen in all forms
of neurofibroma; however, it is
usually less impressive than
that seen in schwannoma due
to the lower overall cellularity
and mixture of cell types in the
former (e.g., fibroblasts,
perineurial-like cells).

522
 Neurofibroma

Peripheral Nerve Sheath Tumors

• Diffuse type
TERMINOLOGY
○ Poorly defined, plaque-like growth, often large
Definitions ○ 10% of cases associated with NF1
• Benign peripheral nerve sheath tumor composed of • Plexiform
Schwann cells, fibroblasts, perineurial-like cells, and residual ○ Considered pathognomonic for NF1
nerve axons within extracellular matrix – Occurs in up to 40% of NF1 patients
○ 4 major types: Localized cutaneous, localized intraneural, ○ Irregular, nodular mass with bag of worms appearance
diffuse, and plexiform ○ Entire extremity may be involved (elephantiasis
– Plexiform neurofibroma is essentially pathognomonic neuromatosa)
of neurofibromatosis type 1 (NF1) • Rare, massive soft tissue neurofibromas may result in large,
pendulous folds of neurofibromatous tissue (localized
ETIOLOGY/PATHOGENESIS gigantism)
Histogenesis Treatment
• Sporadic in ~ 90% of cases; others are syndromic in • Complete surgical excision
association with NF1
○ NF1 results from germline mutation in NF1 gene on Prognosis
chromosome 17q11.2 • Benign
– NF1 gene encodes for neurofibromin protein, which is ○ All forms (including atypical/bizarre neurofibroma)
GTPase-activating protein • Local recurrence very rare
○ Sporadic tumors arise from somatic mutations in NF1 • Malignant transformation
○ Usually occurs in setting of NF1 (rare in sporadic tumors)
CLINICAL ISSUES – Seen in 5-10% of NF1 patients
Epidemiology ○ Plexiform and localized intraneural types are most
frequent precursors to malignant peripheral nerve
• Incidence
sheath tumor (MPNST)
○ Most common peripheral nerve sheath tumor
– Essentially no risk for localized cutaneous type
– Localized type most common among neurofibromas
– Very low risk for diffuse type
• Age
○ Wide range (most common in young to middle-aged MACROSCOPIC
adults)
– Plexiform and diffuse variants occur more often in General Features
younger age groups, including children • Most are well circumscribed or well demarcated
• Sex ○ Diffuse type is ill defined, plaque-like, cutaneous growth
○ M=F • Unencapsulated
• Gray-tan firm/fibrous to gelatinous cut surface
Site
• Generally lack degenerative changes (hemorrhage, cystic
• Localized change)
○ Usually skin of trunk, head/neck, extremities
○ Less common in deeply situated nerves, nerve plexi, Size
major nerve trunks, viscera • Wide range
• Diffuse ○ Localized cutaneous types usually small (< 2 cm)
○ Skin &/or subcutaneous tissue of head/neck ○ Diffuse type often large
• Plexiform ○ Rare tumors may be massive
○ Superficial or deep soft tissues, large nerve trunks
○ Head/neck, trunk, extremities MICROSCOPIC
Presentation Histologic Features
• Most (90%) neurofibromas are sporadic and unassociated • Localized type (cutaneous or intraneural)
with NF1 ○ Well circumscribed, unencapsulated; grenz zone in skin
• Usually slow-growing masses overall – Intraneural tumors may have peripheral rim of
○ Rapid growth in preexisting neurofibroma is worrisome perineurium or thickened epineurium
for malignant transformation ○ Usually low or moderate cellularity
• Localized ○ Loosely arranged spindle cells in haphazard arrangement
○ Usually small, sporadic, solitary mass – Poorly defined cytoplasmic borders/processes
– Deep lesions may be large – Small, hyperchromatic, wavy or buckled nuclei
○ Rarely associated with NF1 – Scattered nuclei may show degenerative changes
– Numerous localized neurofibromas; however, usually (pleomorphic, hyperchromatic, "smudgy" nuclei)
indicate NF1 □ Described as atypical (or bizarre) neurofibroma
○ Intraneural tumors present as fusiform swellings ○ Variable myxoid to collagenous matrix
– Often cause sensory or motor disturbances related to – Coarse collagen bundles often described as having
affected nerve shredded-carrot appearance

523
 Neurofibroma
Peripheral Nerve Sheath Tumors
○ Mast cells are common
○ Rarely contain small nerve twigs
○ Many rare variants described: Cellular, epithelioid,
lipomatous, granular cell, dendritic cell, others
• Diffuse type
○ Ill-defined, expansive dermal and subcutaneous
proliferation
– Proliferates around cutaneous adnexal structures,
entrapping them
□ Entrapped nerve twigs are often hypertrophic or
edematous
– Extends into subcutaneous tissue along connective
tissue septa and infiltrates fat
○ Loosely arranged spindle cells in haphazard arrangement
– Small, hyperchromatic, wavy or buckled nuclei
– Some cases have epithelioid cytomorphology, at least
focally
○ Evenly distributed, fibrillar collagenous stroma
– May be myxoid
○ Pseudomeissnerian bodies are characteristic
– Individual or aggregates of whorled eosinophilic
fibrillary clusters
– Vary in number and distribution
○ Rare cases show scattered dendritic cells containing
melanin pigment
• Plexiform
○ Defined by growth pattern
– Multiple, irregularly arranged structures resembling
hypertrophic nerve fascicles
□ Imparts mixed multinodular and serpentine
appearance
□ Usually markedly myxoid or edematous with
abundant collagen bundles
○ May also show areas indistinguishable from diffuse-type
neurofibroma
○ May show scattered nuclear atypia (degenerative)
without increased mitoses or necrosis
• Hybrid neurofibroma/schwannoma
○ Schwannoma-like nodules within otherwise typical
neurofibroma
○ Identified in some patients with NF1, per recent reports
• Malignant transformation (MPNST)
○ Many cases are clear cut and high grade with increased
cellularity, generalized nuclear pleomorphism and
hyperchromasia, high mitotic activity, &/or necrosis
○ Low-grade MPNST can be challenging to diagnose
– Cases of neurofibroma with nuclear atypia alone are
not MPNST
– One study (Miettinen 2017) has proposed term
"atypical neurofibromatous neoplasm of uncertain
biologic potential" (ANNUBP)
□ Defined as neurofibroma with 2 of following 4
features: Nuclear atypia, loss of neurofibroma
architecture, high cellularity, mitotic activity > 1/50
HPF but < 3/10 HPF
□ Tumors with features of ANNUBP but with 3-9
mitoses per 10 HPF and no necrosis considered
low-grade MPNST
□ ANNUBP associated with local recurrence but not
metastasis
524
ANCILLARY TESTS
Immunohistochemistry
• S100(+) and SOX10(+) in ~ 50% of total cells (Schwann cells)
• CD34(+) admixed spindled fibroblasts
• EMA(+) admixed perineurial cells
• Neurofilament protein highlights intratumoral axons
• Ki-67, p53, and p16 markers are of limited utility
DIFFERENTIAL DIAGNOSIS
Malignant Peripheral Nerve Sheath Tumor
• Usually large, deep tumors
• Variable combination of high cellularity with nuclear atypia,
mitotic figures, &/or necrosis
• Perivascular tumor cell accentuation
• May contain peripheral component of preexisting
neurofibroma
• Diffuse loss of h3k27me3 by IHC
Dermatofibrosarcoma Protuberans
• Cellular, highly infiltrative tumor with honeycomb
infiltration of subcutaneous fat
• Usually prominent storiform architecture
• Diffuse CD34(+), S100(-)
• PDGFB rearrangements
Schwannoma
• Biphasic, encapsulated tumor with Antoni A and Antoni B
areas
• Verocay body formation, perivascular hyalinization
• Diffuse, uniform S100(+) and SOX10(+)
• Cellular plexiform schwannoma may be mistaken for
MPNST arising in plexiform neurofibroma
Desmoplastic Melanoma
• Junctional component may be present
• HMB-45(+), MART-1(+)
• p53(+) by IHC
Perineurioma
• Usually prominent storiform, whorling, or lamellar
architecture
• EMA(+), claudin-1 (+), GLUT1(+)
○ Expression is often more diffuse than in neurofibroma
(focal, patchy)
• S100(-), CD34(+/-)
SELECTED REFERENCES
1. Elsensohn A et al: Distinguishing neurofibroma from desmoplastic
melanoma: the value of p53. Am J Surg Pathol. 42(3):372-5, 2018
2. Miettinen MM et al: Histopathologic evaluation of atypical
neurofibromatous tumors and their transformation into malignant
peripheral nerve sheath tumor in neurofibromatosis 1 patients - a consensus
overview. Hum Pathol. 67:1-10, 2017
3. Jokinen CH et al: Atypical neurofibroma of the skin and subcutaneous tissue:
clinicopathologic analysis of 11 cases. J Cutan Pathol. 37(1):35-42, 2010
4. Magro G et al: Multinucleated floret-like giant cells in sporadic and NF1-
associated neurofibromas: a clinicopathologic study of 94 cases. Virchows
Arch. 456(1):71-6, 2010
5. Spurlock G et al: Molecular evolution of a neurofibroma to malignant
peripheral nerve sheath tumor (MPNST) in an NF1 patient: correlation
between histopathological, clinical and molecular findings. J Cancer Res Clin
Oncol. 136(12):1869-80, 2010

Classic Neural Cytologic Features
Low to Moderate Cellularity
Rare, Multinucleated, Floret-Like Giant
Cells
Neurofibroma
Peripheral Nerve Sheath Tumors
Mast Cells
(Left) The lesional Schwann
cell nuclei of neurofibroma are
generally elongated with
pointed or tapered ends and
often appear wavy ﬈ or
buckled (comma-shaped ﬊).
Mitotic activity is essentially
nonexistent. (Right) Mast cells
﬈ are commonly identified in
neurofibromas, particularly
localized and diffuse forms.
They may be sparse or
relatively abundant.
Myxoid Stromal Change
(Left) Neurofibroma is
generally a low to moderately
cellular neoplasm. Some cases
are heavily edematous
(shown). Even at low power,
the characteristic wavy nuclei
are apparent. (Right) Myxoid
stromal change is not
uncommon in neurofibroma.
Note the numerous separated
pink collagen fibers, which
somewhat resemble shredded
carrots. Examples in which
myxoid change is extensive
may show morphologic
overlap with myxoma or
spindle cell lipoma.
Rare Tumor With Increased Cellularity
(Left) Multinucleated, floret-
like giant cells ﬈, similar to
those seen in pleomorphic
lipoma, are occasionally
encountered in neurofibroma.
They are seen in both sporadic
tumors and those associated
with neurofibromatosis type 1
(NF1) and are typically
CD34(+) and S100(-). (Right)
Rare cases of neurofibroma
show increased cellularity.
Importantly, mitotic activity
and high-grade cytologic
atypia are absent.
525
 Neurofibroma
Peripheral Nerve Sheath Tumors

Diffuse-Type Neurofibroma Intralesional Adipose Tissue

(Left) Diffuse-type
neurofibroma usually presents
as an ill-defined, cutaneous
plaque in the head and neck. It
is characteristically highly
infiltrative and grows around
normal anatomic structures.
(Right) Intralesional adipose
tissue may rarely be identified
within localized cutaneous
neurofibroma; however, it is
far more common in diffuse-
type neurofibroma (due to
peripheral infiltration of
subcutaneous fat).

Entrapment of Cutaneous Adnexa Infiltration of Fat and Muscle

(Left) The lesional tissue of
diffuse-type neurofibroma
characteristically grows
around and entraps cutaneous
adnexa, such as hair follicles
and eccrine structures
(shown). Note that there is no
destruction of these normal
structures. (Right) Infiltration
of peripheral soft tissues,
including fat and skeletal
muscle, is commonly seen in
diffuse-type neurofibroma.

Infiltration of Fat Diffuse-Type Neurofibroma Cytology

(Left) Some cases of diffuse-
type neurofibroma grow as
thin rays ﬈ of lesional tissue
within abundant fat,
resembling fibrous septa. This
morphology can mimic
lipofibromatosis or
fibrolipoma. (Right) The nuclei
of Schwann cells in diffuse-
type neurofibroma are
identical to those of other
forms. Note the admixed non-
schwannian nuclei, which are
larger ﬈ and paler.

526
 Neurofibroma

Peripheral Nerve Sheath Tumors

Rounded Nuclei Very Rare Nuclear Palisading
(Left) Lesional Schwann cells
with a rounded nuclear profile
may be seen in some cases of
diffuse-type neurofibroma.
This appearance is more
common in this subtype than
in the others. (Right) Nuclear
palisading is very uncommon
in neurofibroma. This unusual
case of otherwise typical
diffuse-type neurofibroma had
focal areas of increased
cellularity with vague
palisading ﬈.

Wagner-Meissner Bodies Morphology of Wagner-Meissner Bodies

(Left) Wagner-Meissner
(pseudomeissnerian) bodies ﬈
are very characteristic of
diffuse-type neurofibroma and
may arrange in small
aggregates, linear arrays, or
larger sheets. (Right) Wagner-
Meissner (pseudomeissnerian)
bodies are composed of
spherical, layered clusters of
thin and elongated spindled
cells with long delicate
cytoplasmic processes. They
resemble Meissner corpuscles.

Scattered Wagner-Meissner Bodies Pigmented Neurofibroma

(Left) Diffuse-type
neurofibroma may contain
large zones of predominantly
mature adipose tissue with
scattered small Wagner-
Meissner bodies ﬈. This
finding may be the only clue to
the diagnosis in a small biopsy.
(Right) Rare cases of diffuse-
type neurofibroma contain
collections of pigmented
Schwann cells ﬈ with
intracytoplasmic melanin.
Most of these tumors occur in
the setting of NF1, and some
may also show a plexiform
morphology.

527
 Neurofibroma
Peripheral Nerve Sheath Tumors

Plexiform Neurofibroma Expanded Nerves

(Left) Plexiform neurofibroma
is identified by a characteristic
irregular, multinodular, and
serpentine growth pattern of
expanded nerves. This variant
usually first arises in childhood
and is virtually diagnostic of
NF1. (Right) Many of the
expanded nerves in plexiform
neurofibroma contain a
centralized core ﬈ of residual
nerve within otherwise typical
neurofibromatous tissue.

Myxoid Change Collagen Fibers

(Left) Myxoid change is
common in plexiform
neurofibroma, and collagen
fibers are typically splayed
apart throughout each
expanded nerve, reminiscent
of shredded carrots. This
morphology is similar to other
forms of neurofibroma. (Right)
Collagen fibers may be thicker
in some foci of plexiform
neurofibroma. Note the small
core ﬈ of centralized residual
nerve.

Combined Diffuse and Plexiform

Prominent Collagen Morphologies
(Left) This example of
plexiform neurofibroma shows
foci with extensive bundled
collagen between clusters of
lesional spindled cells. (Right)
Many cases of plexiform
neurofibroma show extension
﬈ of lesional tissue out of the
expanded nerves ﬊ in
plexiform areas and into the
surrounding tissue. The
morphology of this
extraneural tissue is
indistinguishable from diffuse-
type neurofibroma.

528
 Neurofibroma
Degenerative Changes Include Foamy
Degenerative Nuclear Atypia
Central Cellularity in Atypical
Neurofibroma
Malignant Transformation in
Neurofibroma
Peripheral Nerve Sheath Tumors
Histiocytes
(Left) Degenerative nuclear
atypia, identical to the ancient
change seen in schwannoma,
may be seen in localized or
plexiform neurofibroma. The
nuclei generally show
"smudgy" chromatin and
commonly contain
pseudoinclusions. When this
change is prominent, these
tumors may be referred to as
atypical (or bizarre)
neurofibroma. (Right)
Collections of foamy
histiocytes ﬈ may also be
seen in degenerative
(atypical/bizarre)
neurofibromas.
Increased Cellularity in Atypical
Neurofibroma
(Left) Large examples of
localized soft tissue
neurofibroma may show
centralized increases in
cellularity ﬈. These areas
should be evaluated at higher
power for other features that
might indicate possible
malignant transformation.
(Right) Increased cellularity in
atypical (bizarre)
neurofibroma does not
necessarily imply malignant
transformation. However,
marked cellularity with
generalized nuclear atypia and
more than rare mitoses
suggests transformation into
an MPNST.
MPNST Arising in Neurofibroma
(Left) This image shows
transformation of a localized
soft tissue neurofibroma ﬈
into an MPNST ﬊. Note the
marked increase in cellularity
from benign to malignant
zones. (Right) This image
shows the MPNST portion of a
neurofibroma with malignant
transformation, as evidenced
by the significant nuclear
atypia and several mitotic
figures ﬈ in 1 field. Necrosis
may or may not be present
(not shown).
529
 Perineurioma

KEY FACTS
Peripheral Nerve Sheath Tumors

TERMINOLOGY MICROSCOPIC
• Benign mesenchymal neoplasm composed exclusively of • Well circumscribed and unencapsulated
perineural cells • Bland, elongated spindle cells in various growth patterns
(storiform, whorling, lamellar, fascicular)
CLINICAL ISSUES
○ Nuclei range from thin and wavy to round and pale
• Wide age range (usually adults)
• Collagenous to myxoid stroma
• Sclerosing perineurioma shows marked male predilection
• Variants: Intraneural, sclerosing, reticular, plexiform
• Usually occurs in superficial soft tissues of extremities or
trunk ANCILLARY TESTS
○ Sclerosing perineurioma very common in hands/fingers • EMA(+), claudin-1 (+), GLUT-1(+)
• Solitary, slow-growing, usually painless mass • Variable CD34(+)
• No clear association with neurofibromatosis syndromes • Negative for S100 protein, keratin, SMA, desmin, MUC4
• Treatment: Complete, but conservative surgical excision
TOP DIFFERENTIAL DIAGNOSES
• Benign; excellent prognosis
• Hybrid nerve sheath tumor
MACROSCOPIC • Dermatofibrosarcoma protuberans
• Well circumscribed, nodular • Schwannoma
• Wide size range (mean: 4 cm) • Neurofibroma
• Low-grade fibromyxoid sarcoma

Perineurioma Storiform Whorling Growth

(Left) Perineurioma is a rare,
well-circumscribed peripheral
nerve sheath tumor of
perineurial origin. It often
contains abundant stromal
blood vessels ﬈ easily
identified at low
magnification. Rare cases
show microscopically
infiltrative margins. (Right) A
storiform architecture is
commonly identified in soft
tissue perineurioma along
with lamellar and fascicular
patterns. Although certainly
not pathognomonic, this
morphologic pattern should
always engender
consideration of perineurioma.

Whorls Bland Cytologic Features

(Left) Architectural whorls,
particularly around small
blood vessels ﬊, is highly
characteristic of perineurioma
and should always lead to
consideration of the diagnosis.
(Right) The lesional cells of
perineurioma are cytologically
banal and vary from slender
and elongated ﬉ to rounded
and pale ﬊. An admixed mild
lymphocytic infiltrate may be
present in some cases, and
occasionally mast cells are
seen.

530
 Perineurioma

Peripheral Nerve Sheath Tumors

TERMINOLOGY MICROSCOPIC
Synonyms Histologic Features
• Extraneural soft tissue perineurioma • Well circumscribed and unencapsulated
• Storiform perineural fibroma ○ Rare tumors have infiltrative growth
• Localized hypertrophic neuropathy of limbs (intraneural • Bland, elongated spindle cells in various growth patterns
perineurioma) (storiform, whorling, lamellar, fascicular)
○ Nuclei range from thin and wavy to round and pale
Definitions
○ Nuclear pseudoinclusions common
• Benign mesenchymal neoplasm composed exclusively of
○ Scattered cells with nuclear atypia may occasionally be
perineural cells
present (likely degenerative)
○ Mitotic figures usually rare
CLINICAL ISSUES
• Overall cellularity varies widely
Epidemiology • Collagenous to myxoid stroma
• Age • Unusual findings: Intratumoral mature adipose tissue,
○ Wide range (usually adults) metaplastic bone/cartilage, granular cell change,
– Intraneural and sclerosing perineuriomas occur in pseudolipoblastic morphology
younger age group • Very rare cases show overtly malignant cytologic atypia,
– Rare in children numerous mitotic figures, &/or necrosis
• Sex ○ May be referred to as malignant perineurioma or
○ Sclerosing perineurioma shows marked male perineurial malignant peripheral nerve sheath tumor
predilection Morphologic Variants
– M = F for most other types
• Intraneural perineurioma
Site ○ Hypercellular, expanded nerve tissue with bland
• Usually superficial soft tissues of extremities or trunk perineurial cells forming concentric layers around
○ Up to 30% arise in deep soft tissues or visceral locations preexisting nerve axons ("onion-bulb" structures)
○ Occasional dermal origin – Identified in histologic cross sections of lesion
• Sclerosing perineurioma very common in hands/fingers • Sclerosing perineurioma
○ Plump spindled &/or epithelioid tumor cells in corded,
Presentation trabecular, or whorled patterns
• Solitary, slow-growing, usually painless mass ○ Diffusely hyalinized stroma containing thin-walled blood
• No clear association with neurofibromatosis syndromes vessels
• Intraneural perineurioma often presents with symptoms • Reticular perineurioma
related to neurologic defects ○ Anastomosing cords of thin, fusiform spindle cells in lace-
○ Fusiform segmental enlargement of affected nerve like pattern
– Pseudocystic spaces may be present
Treatment
○ Usually prominent myxedematous stroma
• Complete but conservative surgical excision • Plexiform perineurioma
• Excision with nerve grafting may be attempted in ○ Multinodular, serpentine growth pattern
intraneural perineurioma
○ Standard histologic features of perineurioma
Prognosis
• Benign (including variants) ANCILLARY TESTS
• Local recurrence is very rare Immunohistochemistry
• Predictive histologic features • EMA(+), claudin-1 (+), GLUT1(+)
○ Mildly atypical features (scattered pleomorphic cells, ○ EMA expression may be weak &/or focal, requiring
infiltrative growth) do not appear to affect excellent careful examination
prognosis ○ Use of 2 or 3 markers recommended for screening
○ Overtly malignant cytologic features and high mitotic • Variable CD34(+)
rate diffusely present in large perineurioma indicates
• Negative for S100 protein, keratin, SMA, desmin, MUC4
increased risk of aggressive behavior and malignant
○ SMA may be (+) in sclerosing variants
potential
Molecular Genetics
MACROSCOPIC • Abnormalities involving chromosome 22q most frequent
General Features finding
○ 17q deletions less common
• Well circumscribed, nodular
• Rearrangements &/or deletions of 10q in sclerosing
• Tan-white fibrous to gelatinous cut surface
perineurioma
Size • Frequent TRAF7 mutations in intraneural perineurioma
• Wide size range (mean: 4 cm)

531
 Perineurioma
Peripheral Nerve Sheath Tumors
DIFFERENTIAL DIAGNOSIS
Hybrid Nerve Sheath Tumor
• Most commonly perineurioma-schwannoma hybrid
○ Overall cytoarchitectural features of perineurioma
– Immunohistochemistry usually required for diagnosis
• S100 protein (+) in Schwann cells
• EMA(+), claudin-1 (+) in perineurial cells
Neurofibroma
• Usually less cellular than perineurioma
• S100 protein (+)
• May show scattered EMA(+) intratumoral perineurial cells
Schwannoma
• Most are encapsulated
• Antoni A and B regions
• Diffuse S100 protein (+)
• EMA(-), claudin-1 (-)
○ May be (+) in peripheral capsule
Ectopic Meningioma
• Occurs predominantly in head and neck sites
• Often shows significant morphologic overlap with soft
tissue perineurioma
• EMA(+), progesterone receptor (+)
• Usually claudin-1 (-), GLUT-1(-)
Dermatofibrosarcoma Protuberans
• Diffuse infiltration of dermis and subcutis ("honeycomb"
infiltration)
• Storiform growth pattern often present, at least focally
• Diffuse CD34(+)
• EMA(-), claudin-1 (-)
• Characteristic t(17;22) translocation involving COL1A1 and
PDGFB
Solitary Fibrous Tumor
• Absence of storiform, whorling growth
• Characteristic hemangiopericytoma-like ectatic vasculature
• Diffuse CD34(+), nuclear STAT6(+)
• EMA(-), claudin-1 (-)
Low-Grade Fibromyxoid Sarcoma
• Usually large, deeply located tumors
• Can show histologic overlap with perineurioma
• Cells lack long cytoplasmic processes
• Arcades of small blood vessels may be seen in myxoid areas
• MUC4(+)
• EMA (variable), claudin-1 (variable)
○ Neither are useful for distinguishing from perineurioma
• FUS gene fusions
Desmoid Fibromatosis
• Ill-defined, infiltrative neoplasms
• Long fascicles of bland spindled tumor cells; lacks whorling
growth
• Nuclear β-catenin (+) in most cases
• EMA(-), claudin-1 (-)
532
Juxtaarticular Myxoma
• Absence of storiform, whorling growth
• Often shows highly mucoid foci, at least focally
• EMA(-); claudin-1 (-)
Myoepithelioma
• Nests and clusters of epithelioid (less commonly spindled)
cells in myxoid to collagenous stroma
• Keratin (+), S100 protein (+) in majority of cases
• EWSR1 gene translocations in some cases
Extraskeletal Myxoid Chondrosarcoma
• Large, deeply located tumors
• May resemble reticular perineurioma
• EMA(-)
• Translocations involving 9q22.3 [NR4A3 (TEC)]
SELECTED REFERENCES
1. Carter JM et al: Recurrent genomic alterations in soft tissue perineuriomas.
Am J Surg Pathol. 42(12):1708-14, 2018
2. Klein CJ et al: Genomic analysis reveals frequent TRAF7 mutations in
intraneural perineuriomas. Ann Neurol. 81(2):316-21, 2017
3. Torres-Mora J et al: Pseudolipoblastic perineurioma: an unusual
morphological variant of perineurioma that may simulate liposarcoma. Hum
Pathol. 57:22-7, 2016
4. Agaimy A et al: Comparative study of soft tissue perineurioma and
meningioma using a five-marker immunohistochemical panel.
Histopathology. 65(1):60-70, 2014
5. Fox MD et al: Extra-acral cutaneous/soft tissue sclerosing perineurioma: an
under-recognized entity in the differential of CD34-positive cutaneous
neoplasms. J Cutan Pathol. 37(10):1053-6, 2010
6. Hornick JL et al: Hybrid schwannoma/perineurioma: clinicopathologic
analysis of 42 distinctive benign nerve sheath tumors. Am J Surg Pathol.
33(10):1554-61, 2009
7. Macarenco AC et al: Cutaneous lipomatous sclerosing perineurioma. Am J
Dermatopathol. 30(3):291-4, 2008
8. Macarenco RS et al: Perineurioma: a distinctive and underrecognized
peripheral nerve sheath neoplasm. Arch Pathol Lab Med. 131(4):625-36,
2007
9. Hornick JL et al: Soft tissue perineurioma: clinicopathologic analysis of 81
cases including those with atypical histologic features. Am J Surg Pathol.
29(7):845-58, 2005
10. Mentzel T et al: Reticular and plexiform perineurioma: clinicopathological
and immunohistochemical analysis of two cases and review of perineurial
neoplasms of skin and soft tissues. Virchows Arch. 447(4):677-82, 2005
11. Michal M et al: A benign neoplasm with histopathological features of both
schwannoma and retiform perineurioma (benign schwannoma-
perineurioma): a report of six cases of a distinctive soft tissue tumor with a
predilection for the fingers. Virchows Arch. 445(4):347-53, 2004
12. Yamaguchi U et al: Sclerosing perineurioma: a clinicopathological study of
five cases and diagnostic utility of immunohistochemical staining for GLUT1.
Virchows Arch. 443(2):159-63, 2003
13. Folpe AL et al: Expression of claudin-1, a recently described tight junction-
associated protein, distinguishes soft tissue perineurioma from potential
mimics. Am J Surg Pathol. 26(12):1620-6, 2002
14. Graadt van Roggen JF et al: Reticular perineurioma: a distinctive variant of
soft tissue perineurioma. Am J Surg Pathol. 25(4):485-93, 2001
15. Fetsch JF et al: 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. 21(12):1433-42, 1997
16. Giannini C et al: Soft-tissue perineurioma. Evidence for an abnormality of
chromosome 22, criteria for diagnosis, and review of the literature. Am J
Surg Pathol. 21(2):164-73, 1997
 Perineurioma

Peripheral Nerve Sheath Tumors

Artifactual Cracking Mixed Elongated and Epithelioid Nuclei
(Left) Artifactual cracking, or
microclefting ﬈, of the
stroma is not uncommon in
perineurioma and may be
arranged in a storiform
architecture. This finding can
be particularly prominent in
cases with abundant stromal
collagen. (Right) A useful
histologic finding for raising
the possibility of perineurioma
is the presence of thin, wavy
nuclei ﬉ closely admixed with
rounder, pale nuclei ﬊.

Scattered Pleomorphic Nuclei EMA Expression

(Left) Although the vast
majority of cases of
perineurioma are cytologically
banal, rare cases may show
scattered pleomorphic nuclei
﬈, often with
pseudoinclusions. This change
is likely degenerative and
similar to ancient change seen
in schwannoma. Importantly,
mitotic figures are rare to
absent. (Right) Epithelial
membrane antigen (EMA)
expression is present (at least
focally) in most cases of
perineurioma. However,
expression can be weak &/or
focal, necessitating careful
evaluation.

Cellular Perineurioma Cellular Perineurioma

(Left) Some areas, or cases, of
soft tissue perineurioma are
quite cellular and may raise
differential diagnosis concerns
of other neoplasms, including
malignancies. Note the sharp
circumscription ﬈ that is
characteristic of most
examples. (Right) Storiform,
lamellar, and fascicular
growth patterns may all be
seen in cellular areas of
perineurioma. Despite the
cellularity, the lesional nuclei
of perineurioma are
cytologically bland, and
mitotic figures are generally
rare to absent.

533
 Perineurioma
Peripheral Nerve Sheath Tumors

Nuclear Pseudoinclusions Vague Fascicular Growth

(Left) Bland nuclear cytology is
typical of most cases of
perineurioma. Pale to clear
nuclear pseudoinclusions ﬊
are also commonly identified.
(Right) This image shows a
focal, loose fascicular growth
pattern in a soft tissue
perineurioma. This pattern
may raise considerations of
malignant peripheral nerve
sheath tumor, synovial
sarcoma, or even desmoid
fibromatosis.

Wavy Morphology Cellular Whorls

(Left) Cytologic layering with
prominent wavy nuclei is a
feature of some cases of
perineurioma. This pattern is
not unique, however, and can
be seen in other neural (and
nonneural) tumors. (Right)
Cellular whorls are common
features of perineurioma and
may be quite diffuse and
prominent in some cases.
Whorls often arise around
small stromal vascular
channels ﬊.

Meningothelial-Like Clusters Myxoid Change

(Left) Cellular, tightly whorled
clusters ﬊ of spindled cells
may occasionally be seen in
soft tissue perineurioma,
somewhat reminiscent of
meningioma. Ectopic
meningioma tends to occur in
locations different from
perineurioma, however.
(Right) Myxoid stromal change
is not uncommon in
perineurioma, but diffusely
myxoid tumors are rare. The
elongated, fine, cytoplasmic
processes of the lesional
perineurial cells are nicely
evident ﬈ in this case.

534
 Perineurioma
Reticular Perineurioma
Sclerosing Perineurioma
Rare Plexiform Perineurioma
Peripheral Nerve Sheath Tumors
Sclerosing Perineurioma
(Left) Reticular perineurioma
is a rare variant of soft tissue
perineurioma that is
characterized by prominent
myxoid stromal changes and
lace-like or net-like growth
pattern. The neoplastic cells
contain very thin and
elongated cell processes.
(Right) The sclerosing variant
of perineurioma is most
common in acral locations and
is characterized by an even
distribution of abundant
stromal collagen. The lesional
cells vary from spindled to
epithelioid.
Sclerosing Perineurioma
(Left) This example of
sclerosing perineurioma shows
scattered lesional cells with
round, pale nuclei. Small
stromal capillary channels ﬈
are usually conspicuous in this
variant. (Right) This example
of sclerosing perineurioma is
composed of rather plump,
epithelioid tumor cells set in
collagenous, sclerosing
stroma. Note the perivascular
arrangement of the neoplastic
cells.
Intraneural Perineurioma
(Left) Rare cases of plexiform
perineurioma have been
reported. This case arose on
the lower lip of a 60-year-old
woman and shows the unique
multinodular and serpentine
growth pattern. (Right) The
rare intraneural perineurioma
usually presents as a fusiform
growth within a nerve and is
characterized histologically by
whorls of perineurial cells ﬊
around preexisting nerve
fibers/axons ("onion bulbs").
These features can only be
seen on cross section.
535
 Hybrid Nerve Sheath Tumor

KEY FACTS
Peripheral Nerve Sheath Tumors

TERMINOLOGY MICROSCOPIC
• Benign composite neoplasm demonstrating morphologic • Usually well circumscribed and unencapsulated
&/or immunohistochemical features of > 1 type of nerve • Morphology depends upon composition
sheath tumor ○ Schwannoma, perineurioma, neurofibroma, very rarely
CLINICAL ISSUES others
○ Components may be intimately intermixed or distinct
• Rare, but incidence may be underestimated
• Mitoses rare to absent
• Wide age range
• Wide distribution but most common in extremities ANCILLARY TESTS
• Most arise in superficial soft tissue, but some are deeply • S100(+) in Schwann cells
located or visceral • EMA(+), claudin-1 (+) in perineurial cells
• Slow-growing, often painless mass
TOP DIFFERENTIAL DIAGNOSES
• Treatment: Simple surgical excision
• Benign; local recurrence very rare • Malignant peripheral nerve sheath tumor (low grade)
• Perineurioma
MACROSCOPIC • Schwannoma
• Most < 5 cm in size • Neurofibroma

Hybrid Nerve Sheath Tumor Hybrid Nerve Sheath Tumor

(Left) Hybrid nerve sheath
tumors are well circumscribed,
unencapsulated, benign
neoplasms characterized by
mixed features of various
nerve sheath tumors. Their
incidence is likely
underestimated given their
morphologic overlap with pure
nerve sheath tumors. (Right)
Hybrid
perineurioma/schwannoma
appears to be the most
common hybrid nerve sheath
tumor. It often resembles
perineurioma architecturally
yet contains an admixed
Schwann cell component ﬈.

S100 Protein Expression Expression of Perineurial Markers

(Left) S100 protein expression
is common in hybrid tumors
due to the presence of
Schwann cells, as in this
example of hybrid
perineurioma/schwannoma.
Expression is often greater
than that of perineurial
markers; however, in some
cases it is less abundant.
(Right) Claudin-1 (shown) and
EMA expression is seen in this
case of hybrid
perineurioma/schwannoma.
Note the Schwann cells in the
background that are not
staining.

536
 Hybrid Nerve Sheath Tumor

Peripheral Nerve Sheath Tumors

– Nodules or zones of typical Antoni A schwannoma
TERMINOLOGY within larger zones of neurofibroma
Definitions – May appear plexiform
• Benign composite neoplasm demonstrating morphologic ○ Neurofibroma/perineurioma, granular cell
&/or immunohistochemical features of > 1 type of nerve tumor/perineurioma, and perineurioma/cellular
sheath tumor neurothekeoma also described
○ Most often schwannoma and perineurioma • Mitoses rare to absent
• No coagulative necrosis
CLINICAL ISSUES
Epidemiology
ANCILLARY TESTS
• Incidence Immunohistochemistry
○ Rare • S100(+) in Schwann cells
– However, incidence likely underestimated • EMA(+), claudin-1 (+), GLUT-1(+) in perineurial cells
• Age • CD34(+) in perineurial cells and fibroblasts (neurofibroma)
○ Wide range
• Sex DIFFERENTIAL DIAGNOSIS
○ No apparent predilection Malignant Peripheral Nerve Sheath Tumor (Low
Site Grade)
• Wide distribution but most common in extremities • Areas of increased cellularity with mitotic activity common
• Most arise in superficial soft tissue, but some are deeply • Nuclear atypia that is not degenerative
located or visceral • Usually EMA(-), claudin-1 (-)

Presentation
• Slow-growing, often painless mass
• May have clinical features of syndromes, such as
neurofibromatosis or schwannomatosis
○ Reports of some cases of hybrid
neurofibroma/schwannoma associated with these
syndromes
Treatment
• Simple surgical excision
Prognosis
• Benign
• Local recurrence rare
MACROSCOPIC
General Features
• Firm, rubbery mass with tan/white/yellow cut surface
Size
• Most < 5 cm
MICROSCOPIC
Histologic Features
• Usually well circumscribed and unencapsulated
• Morphology depends upon composition
○ Schwannoma/perineurioma (most common)
– Overall storiform, lamellar, or whorled growth pattern
– Intimate admixture of spindled Schwann cells with
plump nuclei and slender, more inconspicuous
perineurial cells with bipolar processes
□ Some cases are composed of discrete areas of one
type of nerve sheath tumor within zones of another
– Variable collagenous or myxoid stroma
– Degenerative nuclear atypia ("ancient change") &/or
multinucleation may be seen
○ Schwannoma/neurofibroma
Perineurioma
• Can appear very similar to hybrid
perineurioma/schwannoma
• Purely composed of perineurial cells
• EMA(+), claudin-1 (+), CD34 (variable), S100 protein (-)
Schwannoma
• Most are encapsulated
• Most show classic Antoni A and B zonation
○ Also Verocay bodies
• Diffuse S100 protein (+), EMA(-), claudin (-), CD34(-)
Neurofibroma
• Mixture of Schwann cells, fibroblasts, perineurial cells, and
variable axons
○ Perineurial component usually minor
• S100 protein (+) but less so than typical schwannoma
SELECTED REFERENCES
1. Ud Din N et al: Hybrid peripheral nerve sheath tumors: report of five cases
and detailed review of literature. BMC Cancer. 17(1):349, 2017
2. Kacerovska D et al: Hybrid epithelioid schwannoma/perineurioma. Am J
Dermatopathol. 38(7):e90-2, 2016
3. Linos K et al: Benign cutaneous biphasic hybrid tumor of perineurioma and
cellular neurothekeoma: a case report expanding the clinical and
histopathologic features of a recently described entity. Am J
Dermatopathol. 37(4):319-22, 2015
4. Fletcher C et al: WHO Classification of Tumours of Soft Tissue and Bone.
Lyon: IARC Press, 2013
5. Kacerovska D et al: Hybrid peripheral nerve sheath tumors, including a
malignant variant in type 1 neurofibromatosis. Am J Dermatopathol.
35(6):641-9, 2013
6. Harder A et al: Hybrid neurofibroma/schwannoma is overrepresented
among schwannomatosis and neurofibromatosis patients. Am J Surg Pathol.
36(5):702-9, 2012
7. Pusiol T et al: Routine use of immunohisto-chemistry may increase the
frequency of hybrid peripheral nerve sheath tumors. Am J Dermatopathol.
33(6):634-6, 2011
8. Hornick JL et al: Hybrid schwannoma/perineurioma: clinicopathologic
analysis of 42 distinctive benign nerve sheath tumors. Am J Surg Pathol.
33(10):1554-61, 2009
9. Kazakov DV et al: Hybrid peripheral nerve sheath tumors: schwannoma-
perineurioma and neurofibroma-perineurioma. A report of three cases in
extradigital locations. Ann Diagn Pathol. 9(1):16-23, 2005

537
 Hybrid Nerve Sheath Tumor
Peripheral Nerve Sheath Tumors

Stromal Collagen Collagen Fibers

(Left) The stroma in hybrid
nerve sheath tumors varies
from collagenous to myxoid.
Hybrid
schwannoma/perineurioma
often contains areas of
prominent collagenization ﬊,
as shown. (Right) This hybrid
nerve sheath tumor showed
conspicuous collagen fibers,
such as those often seen in
neurofibroma.
Immunohistochemically,
however, EMA and claudin-1
stained the majority of the
cells, and a subpopulation
expressed S100 protein.

Neurofibroma-Like Appearance Myxocollagenous Stroma

(Left) Prominent collagen
fibers are displayed in this
focus of hybrid nerve sheath
tumor. Note the appearance
of "cracking" due to the
presence of slender perineurial
cells between the fibers.
Immunostains for EMA &/or
claudin-1 can highlight these
cells. (Right) Some cases of
hybrid nerve sheath tumor are
extensively myxoid and may
histologically and clinically
mimic a myxoma. Stromal
collagen ﬊, however, is more
frequent in hybrid tumors.

Diffuse Myxoid Stroma Neurofibroma-Like Areas

(Left) This example of a hybrid
nerve sheath tumor
demonstrates diffuse myxoid
stromal change. There is
minimal to no cytologic atypia,
and there are no mitotic
figures or necrosis. (Right)
Areas of hybrid nerve sheath
tumor may resemble myxoid
neurofibroma, particularly
when discrete collagen fibers
are present, as depicted in this
image.

538
 Hybrid Nerve Sheath Tumor
Corded S100 Expression Pattern
Rare Nodular/Plexiform Growth
Cellularity
Peripheral Nerve Sheath Tumors
Minor S100 Protein Expression
(Left) A cord-like pattern of
S100 protein expression may
be seen in hybrid
perineurioma/schwannoma
due to alternating rows and
thin layers of Schwann cells
and perineurial cells. A dual
chromogen S100/EMA cocktail
(not shown) can nicely
demonstrate the 2 distinct
populations of cells. (Right)
Although it often appears to
stain the majority of the cells
in hybrid nerve sheath tumor,
S100 protein may only be
expressed in the minority of
cells, as was seen in this case.
Degenerative Atypia
(Left) This case of superficial
hybrid nerve sheath tumor
grew in a conspicuous
multinodular/plexiform
pattern. Other findings
included focal multinucleated
tumor cells and metaplastic
bone (not shown). (Right)
Degenerative nuclear atypia
("ancient change") and
multinucleated tumor cells ﬈
may be seen in some cases of
hybrid nerve sheath tumor,
similar to pure nerve sheath
tumors. Mitoses are very rare
to absent.
Hybrid Schwannoma/Neurofibroma
(Left) Schwannian areas in
hybrid nerve sheath tumor
may show increased
cellularity, similar to cellular
schwannomas. A minor
component of perineurial cells
is often present too, though
they are difficult to see
without immunostains. (Right)
This tumor had features of
schwannoma ﬈ and
neurofibroma ﬉ with a
nodular architecture
reminiscent of a plexiform
growth pattern. Of note, some
of these particular tumors may
be associated with
neurofibromatosis or
schwannomatosis.
539
 Granular Cell Tumor

KEY FACTS
Peripheral Nerve Sheath Tumors

TERMINOLOGY
• Benign tumor of putative schwannian origin composed of
cells with abundant granular cytoplasm
CLINICAL ISSUES
• Wide age range (peak: 40-60 years)
○ Female predilection
○ More prevalent in African Americans
• Wide anatomic distribution, usually arises in skin and
subcutaneous tissue
○ Head and neck region common (particularly tongue and
oral cavity)
• Usually solitary, slowly growing, painless nodule, plaque, or
mass
○ Multicentricity in 10% of cases
• Treatment: Complete surgical excision
• Overall excellent prognosis for benign lesions
• Malignant granular cell tumor (GrCT) (rare) metastasizes in
up to 50% of cases
MACROSCOPIC
• Usually small (mean: 1-2 cm)
MICROSCOPIC
• Nonencapsulated, usually with irregular borders
• Overlying pseudoepitheliomatous hyperplasia in 30%
• Sheets, nests, and cords of plump, polygonal cells with
abundant eosinophilic granular cytoplasm
• Typically prominent collagenous stroma
• Malignant GrCT shows ≥ 3 atypical features (pleomorphism,
prominent nucleoli, increased mitoses, etc.)
ANCILLARY TESTS
• PAS(+), diastase-resistant cytoplasmic granules
• Strong, diffuse S100 protein (+), SOX10(+)
TOP DIFFERENTIAL DIAGNOSES
• Congenital granular cell epulis
• Nonneural GrCT

Granular Cell Tumor Granular Cell Tumor

(Left) Granular cell tumor
(GrCT) is a benign tumor of
putative Schwann cell origin
that occurs at a variety of
anatomic sites but shows a
predilection for the head and
neck region, particularly the
tongue and oral cavity. Most
cases are dermal or
subcutaneous, and some may
extend directly up under the
overlying epidermis. (Right)
This tumor is composed of
sheets, nests, and cords of
plump, polygonal cells with
abundant eosinophilic
granular cytoplasm within a
collagenous stroma.

Cytologic Features S100 Protein Expression

(Left) Cytologically, the cells
of GrCT show prominent
granular cytoplasm, which
represents numerous
lysosomal structures. Nuclei
are generally small and may
be dark with dense chromatin
or vesicular with a small
nucleolus. Occasional
scattered larger nuclei and
nucleoli may be seen in
otherwise benign GrCT. (Right)
Strong, diffuse S100 protein
expression is characteristic of
GrCT and can help to
distinguish it from most
entities in its differential
diagnosis.

540
 Granular Cell Tumor

Peripheral Nerve Sheath Tumors

TERMINOLOGY MACROSCOPIC
Abbreviations General Features
• Granular cell tumor (GrCT) • Cutaneous lesions may show hyperplastic/verrucous
appearance
Synonyms
• Cut surface firm, pale yellow, or cream colored
• Granular cell myoblastoma
• Abrikossoff tumor Size
• Granular cell schwannoma • Usually small (mean: 1-2 cm)
○ Deep lesions often larger (5-6 cm)
Definitions
• Benign tumor of putative schwannian origin composed of MICROSCOPIC
cells with abundant granular cytoplasm
Histologic Features
CLINICAL ISSUES • Nonencapsulated, usually with irregular borders
○ May appear to infiltrate adjacent tissues (dermal
Epidemiology
collagen, adipose tissue, skeletal muscle)
• Incidence – Tumor cells often appear to entrap small nerves
○ Benign GrCT not uncommon ○ Can extend directly up to surface epithelium
– Malignant GrCT rare – May incite overlying pseudoepitheliomatous
• Age hyperplasia (30% of cases)
○ Any (peak: 40-60 years) □ Can mimic invasive squamous cell carcinoma in
• Sex superficial biopsies
○ Male predilection ○ Rare plexiform growth pattern in dermis
– Malignant GrCT more frequent in females • Sheets, nests, and cords of plump, polygonal cells
• Ethnicity ○ Abundant granular, eosinophilic cytoplasm
○ More prevalent in African Americans – Enlarged, denser granules with halos
Site (phagolysosomes) frequent
– Cell membrane often indistinct; appears syncytial
• Wide distribution, usually arises in skin and subcutaneous
○ Central small nuclei with variable dense to vesicular
tissue
nuclei
○ Rarely in deep soft tissue sites
– Small, subtle nucleoli may be present
• Head and neck region common
– Mitoses absent
○ Particularly tongue and oral cavity
• Typically prominent collagenous stroma
• Also breast, bronchus, larynx, neurohypophysis, other
○ May be fibrotic or desmoplastic in longstanding lesions
viscera
• Intratumoral lymphoid aggregates in some cases
• Rarely in nerve, lymph node
• Necrosis absent
Presentation • Atypical features
• Usually solitary, slowly growing, painless nodule, plaque, or ○ Pleomorphism, prominent nucleoli, high
mass nuclear:cytoplasmic ratio, spindling of cells
○ Multicentric in ~ 10% of cases – Should be prominent in tumor, not focal
– May appear synchronously or metachronously ○ Mitoses > 2 per 10 HPF
– May rarely arise in association with Noonan syndrome ○ Necrosis
or LEOPARD syndrome • Malignant GrCT shows ≥ 3 atypical features
• Oral cavity/tongue lesions may show concurrent candidiasis ○ Tumors with 1 or 2 prominent atypical features may be
regarded as atypical GrCT
Treatment
• Complete surgical excision ANCILLARY TESTS
Prognosis Histochemistry
• Overall excellent prognosis for benign lesions • PAS(+), diastase-resistant cytoplasmic granules
○ Local recurrence < 10% of cases ○ Diffuse, chunky staining
• Multicentric tumors usually benign
• Malignant GrCT Immunohistochemistry
○ Up to 30% recur • Strong, diffuse S100 protein (+) and nuclear SOX10(+)
○ Up to 50% metastasize • Calretinin (+), CD68(+), inhibin (+), nestin (+), MITF (+)
○ Adverse prognostic factors • Nuclear TFE3(+) in majority of cases
– Local recurrence, metastasis • Type IV collagen (+) around nests of cells
– Tumor size (> 5 cm), older patient age (> 50 years) • SMA(-), desmin (-), myogenin (-), ALK(-), GFAP(-), HMB-45(-),
neurofilament (-)

541
 Granular Cell Tumor
Peripheral Nerve Sheath Tumors
DIFFERENTIAL DIAGNOSIS
Congenital Granular Cell Epulis
• Can be histologically indistinguishable from GrCT
• Arises in gingiva of newborns (congenital)
• S100 protein and SOX10 (-)
Nonneural Granular Cell Tumor (Primitive Polypoid
Granular Cell Tumor)
• Cutaneous lesion, often polypoid with epidermal collarette
• Sheet-like growth of spindled to epithelioid cells with
abundant granular, eosinophilic cytoplasm
• Variable nuclear atypia and mitotic activity
• ALK (+); S100 protein and SOX10 (-)
Hibernoma
• Sheets and lobules of multivacuolated brown fat cells
○ Often contains areas of white fat cells
• Most common in subcutis (not cutaneous)
• Cells lack intracytoplasmic phagolysosomes
Malignant Melanoma
• Junctional component usually present
• Melanin pigment in some cases
• Granular cell change rare
• HMB-45(+), MART-1(+) in most cases
Granular Cell Dermatofibroma (Fibrous
Histiocytoma)
• Other typical features of dermatofibroma
• Lacks prominent overlying pseudoepitheliomatous
hyperplasia
• S100 protein (-)
Reactive Granular Cell Change
• Collections of granular histiocytes
• Occurs at sites of trauma or prior surgical procedures
• Lack diffuse S100 protein expression
Leiomyoma
• Rare granular cell change
• Areas of conventional smooth muscle cytology
• SMA(+) and desmin (+)
• S100 protein (-)
Alveolar Soft Part Sarcoma
• Deep, usually large mass
• Compartmentalized growth; pseudoalveolar pattern
common
• Rare granular cell change
• Majority of cases show PAS(+), diastase resistant
intracytoplasmic rod-like crystals
• S100 protein, SOX10, and nestin (-)
• Nuclear TFE3(+), like GrCT
Adult-Type Rhabdomyoma
• Sheets of polygonal cells with homogeneous, eosinophilic
cytoplasm
• Desmin (+), myogenin (+)
• S100 protein (-)
542
SELECTED REFERENCES
1. Cohen JN et al: Cutaneous non-neural granular cell tumors harbor recurrent
ALK gene fusions. Am J Surg Pathol. 42(9):1133-42, 2018
2. Mirza FN et al: Epidemiology of malignant cutaneous granular cell tumors: a
US population-based cohort analysis using the Surveillance, Epidemiology,
and End Results (SEER) database. J Am Acad Dermatol. 78(3):490-7.e1, 2018
3. Tsukamoto S et al: Malignant granular cell tumor of the median nerve: a case
report with a literature review of 157 cases. Skeletal Radiol. 48(2): 307-16,
2018
4. Fernandez-Flores A et al: Cutaneous dermal non-neural granular cell tumor is
a granular cell dermal root sheath fibroma. J Cutan Pathol. 44(6):582-7, 2017
5. Stemm M et al: Typical and atypical granular cell tumors of soft tissue: a
clinicopathologic study of 50 patients. Am J Clin Pathol. 148(2):161-6, 2017
6. Battistella M et al: Vascular invasion and other invasive features in granular
cell tumours of the skin: a multicentre study of 119 cases. J Clin Pathol.
67(1):19-25, 2014
7. Chamberlain BK et al: Alveolar soft part sarcoma and granular cell tumor: an
immunohistochemical comparison study. Hum Pathol. 45(5):1039-44, 2014
8. Gomes CC et al: Evidence for loss of heterozygosity (LOH) at chromosomes
9p and 17p in oral granular cell tumors: a pilot study. Oral Surg Oral Med
Oral Pathol Oral Radiol. 115(2):249-53, 2013
9. Izquierdo F et al: Perineurial cells in granular cell tumors and neoplasms with
perineural invasion: an immunohistochemical study. Am J Dermatopathol.
34(8):800-9, 2012
10. Covington MF et al: Pituicytoma, spindle cell oncocytoma, and granular cell
tumor: clarification and meta-analysis of the world literature since 1893.
AJNR Am J Neuroradiol. 32(11):2067-72, 2011
11. Nasser H et al: Malignant granular cell tumor: a look into the diagnostic
criteria. Pathol Res Pract. 207(3):164-8, 2011
12. Papalas JA et al: Recurrence risk and margin status in granular cell tumors of
the breast: a clinicopathologic study of 13 patients. Arch Pathol Lab Med.
135(7):890-5, 2011
13. Rejas RA et al: The neural histogenetic origin of the oral granular cell tumor:
an immunohistochemical evidence. Med Oral Patol Oral Cir Bucal. 16(1):e6-
10, 2011
14. Shintaku M: Immunohistochemical localization of autophagosomal
membrane-associated protein LC3 in granular cell tumor and schwannoma.
Virchows Arch. 459(3):315-9, 2011
15. Papalas JA et al: Isolated and synchronous vulvar granular cell tumors: a
clinicopathologic study of 17 cases in 13 patients. Int J Gynecol Pathol.
29(2):173-80, 2010
16. Aldabagh B et al: Plexiform pattern in cutaneous granular cell tumors. J
Cutan Pathol. 36(11):1174-6, 2009
17. Rose B et al: Granular cell tumours: a rare entity in the musculoskeletal
system. Sarcoma. 2009:765927, 2009
18. Vered M et al: Granular cell tumor of the oral cavity: updated
immunohistochemical profile. J Oral Pathol Med. 38(1):150-9, 2009
19. Bhattacharyya I et al: Granular cell leiomyoma of the oral cavity. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod. 102(3):353-9, 2006
20. Zarovnaya E et al: Distinguishing pseudoepitheliomatous hyperplasia from
squamous cell carcinoma in mucosal biopsy specimens from the head and
neck. Arch Pathol Lab Med. 129(8):1032-6, 2005
21. Chrysomali E et al: Immunohistochemical evaluation of cell proliferation
antigen Ki-67 and apoptosis-related proteins Bcl-2 and caspase-3 in oral
granular cell tumor. Oral Surg Oral Med Oral Pathol Oral Radiol Endod.
96(5):566-72, 2003
22. Becelli R et al: Abrikossoff's tumor. J Craniofac Surg. 12(1):78-81, 2001
23. Philipp K et al: Eagle syndrome produced by a granular cell tumor. Arch
Otolaryngol Head Neck Surg. 127(12):1499-501, 2001
24. van der Meij EH et al: Granular cells in oral lichen planus. Oral Dis. 7(2):116-8,
2001
25. Fanburg-Smith JC et al: Malignant granular cell tumor of soft tissue:
diagnostic criteria and clinicopathologic correlation. Am J Surg Pathol.
22(7):779-94, 1998
26. Junquera LM et al: Granular-cell tumours: an immunohistochemical study. Br
J Oral Maxillofac Surg. 35(3):180-4, 1997
27. Collins BM et al: Multiple granular cell tumors of the oral cavity: report of a
case and review of the literature. J Oral Maxillofac Surg. 53(6):707-11, 1995
28. Gordon AB et al: Granular cell tumour of the breast. Eur J Surg Oncol.
11(3):269-73, 1985
 Granular Cell Tumor
Large Intracytoplasmic Granules
Prominent Eosinophilia
Entrapped Nerve Fibers
Peripheral Nerve Sheath Tumors
Large Intracytoplasmic Granules
(Left) A frequent finding in
GrCT is the presence of
distinctive large granular
structures ﬈ (large lysosomal
aggregates) that appear more
densely eosinophilic and often
show a surrounding clear halo.
(Right) Large intracytoplasmic
granular structures are
common in GrCT but vary
widely in number from case to
case. In some tumors, they are
abundant.
Pale Granular Cells
(Left) Some cases of GrCT
show markedly granular and
intensely eosinophilic
cytoplasm. Note the lack of
clear cytoplasmic borders,
imparting a syncytial
appearance. This lesion arose
within the breast parenchyma
of a middle-aged woman.
(Right) Occasional cases of
GrCT contain scattered tumor
cells ﬈ with pale cytoplasm.
Entrapped Nerve Fibers
(Left) In keeping with the
likely schwannian origin of this
lesion, entrapped nerve fibers
﬈ are commonly identified in
GrCT, both within the tumor
and around the periphery.
However, to the unwary, this
finding may suggest perineural
invasion by a malignant
process. (Right) This image of
GrCT shows almost complete
entrapment of a nerve fiber
﬈ by lesional tumor cells.
543
 Granular Cell Tumor
Peripheral Nerve Sheath Tumors

Pseudoepitheliomatous Hyperplasia Pseudoepitheliomatous Hyperplasia

(Left) In ~ 1/3 of cases of
cutaneous GrCT, the overlying
squamous epithelium shows
marked hyperplasia and may
very closely simulate the
appearance of an invasive
well-differentiated squamous
cell carcinoma. Detection of
the GrCT component is critical
on a superficial biopsy. (Right)
Note the irregular, small nests
of keratinizing squamous
epithelial cells ﬈ that, out of
the context of GrCT, would be
highly suspicious for invasive
carcinoma.

Surface Ulceration Rare Plexiform Growth

(Left) Occasional cases of
GrCT may show surface
ulceration and inflammation
and may obscure the actual
diagnosis. Note the subtle
eosinophilic granular cells ﬈
underlying the ulceration.
(Right) Some cases of dermal
GrCT can show a multinodular
growth pattern with satellite
nodules. Rarely, an apparent
plexiform pattern is seen
(shown).

Infiltrative Appearance Intratumoral Lymphoid Aggregates

(Left) Most cases of GrCT are
characterized by an ill-defined
proliferation of tumor cells
that appear to infiltrate
adjacent tissues, including
dermal collagen, adipose
tissue, and skeletal muscle
(shown). This finding should
not be equated with
malignancy. (Right) Scattered
intratumoral lymphoid
aggregates may be seen in
occasional cases of GrCT,
similar to what is seen in some
examples of schwannoma.

544
 Granular Cell Tumor
Longstanding Lesions
Degenerative Atypia
Malignant Granular Cell Tumor
Peripheral Nerve Sheath Tumors
Longstanding Lesions
(Left) The stroma in GrCT is
characterized in most cases by
prominent, dense collagen. In
older lesions, this stroma may
appear even more
collagenous, fibrotic, or even
desmoplastic, and lesional
cells may be identified singly
&/or in scattered small
aggregates or cords. (Right)
Longstanding cases of GrCT
may show subtle diagnostic
findings that are easily
overlooked. This image shows
a subtle tumor cell infiltrate
﬈ without the classic
overlying marked epidermal
changes.
Focal Cellular Spindling
(Left) Degenerative nuclear
atypia ﬈ may be seen in
occasional cases of GrCT and is
rarely prominent. This finding
is similar to what is seen in
other nerve sheath tumors.
(Right) Although most cases of
GrCT are composed of
polygonal tumor cells,
occasional tumors show focal
cellular spindling. This finding,
when focal and in isolation, is
of no prognostic significance.
Of note, spindling is not
uncommon in GI tract GrCT.
Malignant Granular Cell Tumor
(Left) Malignant examples of
GrCT are extremely rare and
usually show diffuse atypical
features, such as large
vesicular nuclei with
prominent nucleoli, high
nuclear:cytoplasmic ratio,
pleomorphism, and increased
mitoses ﬊ (> 2 figures per 10
HPF). Necrosis, both single-cell
and geographic types, is also
common. (Right) Areas of
prominent spindling, increased
cellularity, and an overall
sarcomatoid appearance are
common features of
malignant GrCT.
545
 Dermal Nerve Sheath Myxoma

KEY FACTS
Peripheral Nerve Sheath Tumors

TERMINOLOGY • Stellate and vacuolated cells common

• Benign, cutaneous nerve sheath tumor with Schwann cell • No atypia, very low mitotic rate
differentiation, abundant myxoid matrix, and well-defined ANCILLARY TESTS
lobular architecture
• Diffuse S100(+)
CLINICAL ISSUES • GFAP(+) in most
• Fingers and hand most common sites • SMA, desmin, CD68, HMB-45, synaptophysin,
○ Pretibial skin also common chromogranin-A, CD31 (-)
○ Uncommon on face TOP DIFFERENTIAL DIAGNOSES
• Benign, but up to 50% recur
• Neurothekeoma
• Rare intraoral, orbital, intradural, and paraspinal cases
• Superficial angiomyxoma
MICROSCOPIC • Digital mucoid cyst
• Multiple lobules with abundant myxoid matrix • Myxoid neurofibroma
• Well-defined, lobular architecture and dense fibrous septa • Superficial acral fibromyxoma
• Usually limited to dermis and subcutis • Myxoid dermatofibrosarcoma protuberans
• Spindle-shaped and epithelioid cells • Myxofibrosarcoma (low grade)
• Interconnecting cords, networks, syncytial nests, ring-like
structures

Dermal Nerve Sheath Myxoma Dermal Papule

(Left) Dermal nerve sheath
myxoma has a very distinctive
architecture, consisting of
well-defined myxoid lobules. It
is typically centered within the
dermis and can involve the
underlying subcutis as well.
(Right) Dermal nerve sheath
myxoma typically presents as
a firm papule that varies from
0.5-4.5 cm in size. It usually
occurs in adults. Common
locations are the fingers,
hand, and pretibial skin.

Schwann Cells S100 Expression

(Left) The cells in dermal nerve
sheath myxoma have
schwannian differentiation.
They have uniform, spindle-
shaped or oval nuclei, evenly
distributed chromatin, and
long, fibrillary cytoplasmic
processes ﬈ forming bipolar
and stellate configurations.
(Right) Dermal nerve sheath
myxomas are strongly S100(+),
consonant with Schwann cell
differentiation. This
immunohistochemically
stained section depicts diffuse
and intense nuclear ﬈ and
cytoplasmic ﬉ reactivity.

546
 Dermal Nerve Sheath Myxoma

Peripheral Nerve Sheath Tumors

• Spindle and large, plump epithelioid cells; ill-defined
TERMINOLOGY cytoplasm
Definitions • Lacks cords, syncytial aggregates, vacuolated cells
• Benign cutaneous nerve sheath tumor with Schwann cell • S100(-)
differentiation, abundant myxoid matrix, and well-defined • Predilection for face
lobular architecture
Superficial Angiomyxoma
CLINICAL ISSUES • Poorly circumscribed, extends into adjacent tissue
• Fibroblastic cells, often bi- or multinucleated
Epidemiology • Prominent vascularity; small, thin-walled, curvilinear,
• Incidence congested vessels
○ Rare; fewer than 100 reports • Sparse dispersed inflammation, often neutrophils
• Age • S100(-)
○ Mostly adults; median: 34 years
Cutaneous Myxoma in Carney Complex
Site • Indistinguishable from superficial angiomyxoma
• Extremities • Predilection for ear, eyelid, nipple
○ Fingers and hand most common • Spotty pigmentation, endocrine overactivity,
○ Pretibial skin common psammomatous melanotic schwannoma
• Rare intraoral, orbital, intradural, and paraspinal cases
Digital Mucoid Cyst
• Uncommon on face
• Extruded myxoid material, possibly from underlying joint
Presentation • Limited to fingers over dorsal aspect of distal
• Slowly growing, painless mass interphalangeal joints
Prognosis Myxoid Neurofibroma
• Benign and nonaggressive but often excised with positive • Small spindle cells with buckled, wavy nuclei and ill-defined
margins cytoplasm
○ Up to 50% recur • Lacks lobular architecture; may be plexiform or diffuse
• Collagen bundles within myxoid stroma
MACROSCOPIC
Superficial Acral Fibromyxoma
Size • Variable fibrous and myxoid areas
• 0.5-4.5 cm • Lacks well-defined lobules
• CD34(+), S100(-)
MICROSCOPIC • Acral extremities, often periungual
Histologic Features Myxoid Dermatofibrosarcoma Protuberans
• Multiple myxoid lobules • Storiform or fascicular, lacks lobular architecture
○ Well-defined borders separated by dense fibrous septa • Infiltrates subcutis, classic honeycomb pattern
• Usually limited to dermis and subcutis • Plexiform vascular pattern
• Paucicellular proliferation of bland spindle cells • CD34(+), S100(-)
○ Interconnecting cords, networks, syncytial nests, ring-like
structures, Verocay-like bodies Myxofibrosarcoma (Low Grade)
• Variable lobular architecture
Cytologic Features
• Infiltrative growth into dermis and subcutis
• Spindle-shaped and epithelioid Schwann cells • Pleomorphism and mitotic figures in most cases
• Stellate and vacuolated cells • S100(-)
• No atypia, very low mitotic rate
SELECTED REFERENCES
ANCILLARY TESTS
1. Sheth S et al: Differential gene expression profiles of neurothekeomas and
Immunohistochemistry nerve sheath myxomas by microarray analysis. Mod Pathol. 24(3):343-54,
2011
• S100 diffusely (+) in 100% of tumors 2. Nishioka M et al: Nerve sheath myxoma (neurothekeoma) arising in the oral
• GFAP(+) in most cavity: histological and immunohistochemical features of 3 cases. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod. 107(5):e28-33, 2009
• SMA, desmin, CD68, HMB-45, synaptophysin,
3. Fetsch JF et al: Nerve sheath myxoma: a clinicopathologic and
chromogranin-A, CD31 (-) immunohistochemical analysis of 57 morphologically distinctive, S-100
protein- and GFAP-positive, myxoid peripheral nerve sheath tumors with a
predilection for the extremities and a high local recurrence rate. Am J Surg
DIFFERENTIAL DIAGNOSIS Pathol. 29(12):1615-24, 2005
Neurothekeoma 4. Carney JA et al: Cutaneous myxomas. A major component of the complex of
myxomas, spotty pigmentation, and endocrine overactivity. Arch Dermatol.
• Multinodular but less myxoid matrix and less-defined 122(7):790-8, 1986
border
• Whorling pattern common
547
 Dermal Nerve Sheath Myxoma
Peripheral Nerve Sheath Tumors

Lobular Architecture Fibrous Septa

(Left) This scanning-power
micrograph of a dermal nerve
sheath myxoma illustrates its
well-defined, lobular
architecture composed of
rounded lobules containing
copious, pale blue myxoid
matrix. (Right) The lobular
architecture in dermal nerve
sheath myxoma is defined by
thick fibrous septa ﬈, which
separate the myxoid lobules
﬉.

Thick Fibrous Septum Verocay-Like Body

(Left) This medium-power view
of a dermal nerve sheath
myxoma depicts a thick
fibrous septum composed of
dense, mature collagen ﬈ in
between myxoid lobules.
(Right) Verocay-like bodies
consist of parallel arrays of
spindle cells ﬈ surrounding a
fine fibrillary matrix ﬉.
Although rarely seen in dermal
nerve sheath myxomas, they
provide additional evidence of
schwannian differentiation.

Syncytial Nests and Vacuoles Ring-Like Structures

(Left) The neoplastic cells of
nerve sheath myxoma consist
of spindle and epithelioid cells
with uniform, bland, oval, and
elongated nuclei and
abundant eosinophilic
cytoplasm. They are
frequently arranged in
syncytial nests and often have
intracytoplasmic vacuoles ﬈,
as depicted. (Right) The
spindle cells may interconnect
via elongated cytoplasmic
processes to form ring-like
structures ﬈.

548
 Dermal Nerve Sheath Myxoma

Peripheral Nerve Sheath Tumors

Papule Cohesive Structures
(Left) This scanning-power
micrograph depicts a dermal
nerve sheath myxoma with a
raised, exophytic pattern due
to an expansile myxoid lobule
﬈ in the superficial dermis.
Clinically, it presented as a
papule. Note the peripheral
epidermal collarette ﬉.
(Right) Dermal nerve sheath
myxomas often form cohesive
structures ﬈ floating within a
myxoid matrix ﬉. Note the
thick fibrous septum at the
bottom, which divides the
adjacent lobules ﬊.

Reticulated Pattern Multilobular and Plexiform Architecture

(Left) This micrograph shows
bipolar ﬈ and stellate ﬉
spindle cells in a dermal nerve
sheath myxoma with
abundant eosinophilic
cytoplasm and long,
interconnecting cell processes,
forming a reticulated or
network pattern. (Right) This
low-power micrograph
highlights a multilobular and
plexiform pattern in a dermal
nerve sheath myxoma,
consisting of sharply
demarcated, serpiginous
myxoid lobules ﬈ situated
within dense fibroconnective
tissue ﬉.

S100 Expression CD34(+) Fibroblasts

(Left) S100 immunostain in a
dermal nerve sheath myxoma
shows diffuse nuclear and
cytoplasmic staining, which
highlights its long, delicate
cytoplasmic processes ﬈.
(Right) Immunohistochemical
stain for CD34 highlights the
long, slender cell processes ﬈
of intraneurial fibroblasts,
which are frequently detected
in dermal nerve sheath
myxoma. In addition, EMA(+)
perineurial cells (not depicted)
are also detected in most
tumors.

549
 Ganglioneuroma

KEY FACTS
Peripheral Nerve Sheath Tumors

TERMINOLOGY MICROSCOPIC
• Benign, well-differentiated neoplasm of neural crest origin • Uniform spindled Schwann cells in collagenous stroma
containing ganglion cells and arising from sympathetic or ○ Fascicles or patternless arrays
peripheral nerves ○ Elongated or wavy nuclei
CLINICAL ISSUES • Intermixed ganglion cells of variable size and number
○ Occur in clusters, nests, and singly
• Most common: 10-30 years of age
• Primitive neuroblasts absent
• Posterior mediastinum and retroperitoneum most
common • May show myxoid stromal change, cystic change, fibrosis,
lymphoid aggregates, or calcification
○ Less common in adrenal gland
• Usually solitary, painless mass ANCILLARY TESTS
• Treatment: Complete, conservative excision • S100 protein (+) in Schwann cell component
• Benign; rare local recurrence • Synaptophysin (+) in ganglion cells
○ Very rare described cases with malignant transformation
TOP DIFFERENTIAL DIAGNOSES
MACROSCOPIC • Neurofibroma
• Wide size range (mean: 8 cm) • Cellular schwannoma
• Leiomyoma
• Ganglioneuroblastoma

Ganglioneuroma 2 Components
(Left) Ganglioneuroma is a
well-circumscribed, benign
neoplasm that occurs most
commonly in the posterior
mediastinum and
retroperitoneum. In the latter
location, the tumor ﬈ may be
extraadrenal (shown) or
intraadrenal (much less
common). It may or may not
have a thin fibrous capsule.
(Right) Ganglioneuroma is
composed of ganglion cells ﬈
within a mature schwannian
stroma.

Schwannian Stroma Ganglion Cells

(Left) The stroma of
ganglioneuroma is composed
of mature Schwann cells with
typical neural cytologic
features (elongated nuclei
with tapered or pointed ends)
within a collagenous and
variably edematous
background. The overall
morphology may closely
simulate neurofibroma. (Right)
The number of ganglion cells
seen in ganglioneuroma varies
from case to case and ranges
from sparse or rare to
numerous, as is seen in this
H&E.

550
 Ganglioneuroma

Peripheral Nerve Sheath Tumors

TERMINOLOGY MICROSCOPIC
Abbreviations Histologic Features
• Ganglioneuroma (GN) • Generally well circumscribed with thin fibrous capsule
○ Rare limited infiltration of surrounding tissue
Definitions
• Uniform spindled Schwann cells in collagenous stroma
• Benign, well-differentiated neoplasm of neural crest origin
○ Fascicles or patternless arrays
containing ganglion cells and arising from sympathetic or
○ Elongated or wavy nuclei
peripheral nerves
○ May be indistinguishable from neurofibroma
ETIOLOGY/PATHOGENESIS • Intermixed ganglion cells of variable size and number
○ Round, vesicular, sometimes multiple nuclei
Associated Conditions – May show mild to moderate atypia
• Most develop de novo ○ Abundant eosinophilic or amphophilic cytoplasm
• Some develop from maturation of neuroblastoma ○ Occur in clusters, nests, and singly
• Solitary polypoid GN in gastrointestinal tract may be – May contain fine granular cytoplasmic pigment
associated with Cowden syndrome, juvenile polyposis, or ○ Maturation varies
tuberous sclerosis – Primitive neuroblasts absent
○ Multiple polypoid GN in gastrointestinal tract may be • May show myxoid stromal change, cystic change, fibrosis,
associated with neurofibromatosis type 1 and multiple lymphoid aggregates, or calcification
endocrine neoplasia (MEN) type 2B • Rare intralesional mature adipose tissue
• Rare composite tumors
CLINICAL ISSUES ○ GN with pheochromocytoma/paraganglioma
Epidemiology • Very rare malignant degeneration to MPNST
• Age
○ Most common: 10-30 years ANCILLARY TESTS
Site Immunohistochemistry
• Posterior mediastinum and retroperitoneum most • S100 protein (+) in Schwann cell component
common • Neurofilament protein (+) axons
○ Less common in adrenal gland • Synaptophysin (+) in ganglion cells
○ Very rarely in skin, parapharynx, and paratestis
• May occur as small polyps in gastrointestinal tract DIFFERENTIAL DIAGNOSIS
Presentation Neurofibroma
• Usually solitary, painless mass • Some areas may be virtually indistinguishable from GN
○ Rarely multifocal • Generally lacks discrete bundles of Schwann cells
• Rare urinary catecholamine secretion in larger tumors • Ganglion cells absent
○ Symptoms: Diarrhea, sweating • Most occur in somatic sites

Treatment Cellular Schwannoma

• Complete, conservative excision • May be seen in retroperitoneum or posterior mediastinum
• Ganglion cells absent
Prognosis • Strong, diffuse S100 protein (+)
• Benign
Leiomyoma
○ Rare "metastatic" GN foci described in lymph nodes
– Presumably represent metastatic neuroblastoma that • No ganglion cells
matured • Smooth muscle actin (+), desmin (+)
• Local recurrence is rare • S100 protein (-)
• Very rare described cases with malignant transformation Ganglioneuroblastoma
○ Resembles malignant peripheral nerve sheath tumor • Contains islands of immature neuroblasts
(MPNST)
• Generally seen in younger age group than GN
MACROSCOPIC SELECTED REFERENCES
General Features 1. Silveira CRS et al: Magnetic resonance neurography in the diagnosis of a
• Well-defined, smooth, encapsulated mass retroperitoneal ganglioneuroma: Case report and literature review. Radiol
Case Rep. 13(2):380-385, 2018
• Gray-white or yellow cut surface 2. Gupta S et al: Composite pheochromocytoma/paraganglioma-
• May have calcification ganglioneuroma: a clinicopathologic study of eight cases with analysis of
succinate dehydrogenase. Endocr Pathol. 28(3):269-275, 2017
• Hemorrhage and necrosis absent
3. Hu J et al: Retroperitoneal composite pheochromocytoma-ganglioneuroma
Size : a case report and review of literature. Diagn Pathol. 8:63, 2013

• Wide range (mean: 8 cm)

551
 Ganglioneuroma
Peripheral Nerve Sheath Tumors

Multinucleation Intracytoplasmic Pigment

(Left) Multinucleation ﬈ is a
common finding in
ganglioneuroma, and some
cells may show as many as 3
distinct nuclei. Mild to
moderate nuclear atypia may
be seen. (Right) Some of the
ganglion cells in
ganglioneuroma may show
accumulation of brown,
granular intracytoplasmic
pigment ﬈ that resembles
lipofuscin or neuromelanin.

Size Variation Large Clusters or Nests

(Left) Ganglion cells vary
widely in size from tumor to
tumor, and the cytoplasm
ranges from pale to deeply
eosinophilic. Most importantly,
no immature neuroblastic cells
are present. (Right) Although
ganglion cells may be
identified singly in many cases
of ganglioneuroma, clusters or
large nests of ganglion cells
are also common.

Fascicle Formation Fascicle Formation (Cross Section)

(Left) The lesional cells of
ganglioneuroma may be more
compact and bundled in areas,
resembling irregular nerve
fibers. (Right) H&E of
ganglioneuroma shows
fascicular bundles of lesional
cells cut in cross section,
appearing reminiscent of
normal nerve.

552
 Ganglioneuroma
Cellular Fascicles
Myxoid Stromal Change
Intralesional Adipose Tissue
Peripheral Nerve Sheath Tumors
Myxoid Stroma
(Left) Some cases of
ganglioneuroma contain more
cellular, fascicular foci. This
morphology may mimic
cellular schwannoma;
however, note the presence of
a ganglion cell ﬈. Also, the
nuclei are cytologically bland,
and there is no mitotic activity.
(Right) Rare examples of
ganglioneuroma demonstrate
bundles of lesional Schwann
cells separated within a
myxoid stroma.
Mild Degenerative Atypia
(Left) H&E shows a myxoid
focus of ganglioneuroma in
which the lesional cells are
individually separated from
one another rather than in
bundles. A lymphocytic
infiltrate is also seen. (Right)
Similar to other benign neural
tumors, such as schwannoma
and neurofibroma,
ganglioneuroma may contain
rare, isolated cells with
slightly enlarged and
hyperchromatic nuclei ﬈. This
finding is likely degenerative.
Calcification
(Left) A component of mature
adipose tissue may be
identified within the substance
of ganglioneuroma, but it is
rare. Fat is more likely to be
present near the periphery
where the tumor interfaces
with surrounding soft tissue.
(Right) Calcification may be
seen in ganglioneuroma. It can
also be seen in
ganglioneuroblastoma, and
therefore a thorough search
for neuroblastic elements is
warranted in these cases.
553
 Neuromuscular Choristoma

KEY FACTS
Peripheral Nerve Sheath Tumors

TERMINOLOGY MACROSCOPIC
• Benign endoneurial tumor composed of mature skeletal • Fusiform expansion of affected nerve with multifascicular
muscle fibers intermixed with peripheral nerve cells often involvement
associated with desmoid-type fibromatosis (DTF)
MICROSCOPIC
• Synonyms: Benign triton tumor, neuromuscular hamartoma
• Enlarged nerve fascicles containing abundant skeletal
CLINICAL ISSUES muscle fibers
• Arises in early childhood in most cases ○ Rarely contains smooth muscle fibers
○ Mean age: 10 years (range: Birth to 68 years) • Surrounded by dense, hypocellular fibrous tissue
• Affects major peripheral nerves • Areas of DTF (18-32% of cases)
○ Brachial plexus and sciatic nerve most frequent
ANCILLARY TESTS
• Symptoms related to mass effect, sensory/motor deficits,
or musculoskeletal deformity • Nuclear β-catenin (+)
• Local recurrence in 33% • Exon 3 CTNNB1 mutations
○ Most recurrent cases associated with DTF TOP DIFFERENTIAL DIAGNOSES
IMAGING • Primary DTF
• T1 and T2 signal intensities similar to muscle and nerve • Lipomatosis of nerve (fibrolipomatous hamartoma)
• Low signal in areas of fibrosis/fibromatosis

Neuromuscular Choristoma Multifascicular Pattern

(Left) Neuromuscular
choristoma (NMC) is composed
of mature skeletal muscle
fibers ﬈ admixed with
peripheral nerve cells ﬉ and
has a multifascicular pattern
in cross section, as shown.
(Courtesy J. Carter, MD, PhD.)
(Right) On cross section of the
affected nerve, NMC displays a
lobular pattern consisting of
fascicles of skeletal muscle
fibers ﬈ within a peripheral
nerve with areas of fibrosis
﬉. (Courtesy J. Carter, MD,
PhD.)

Fibrous Area Desmoid-Type Fibromatosis

(Left) In addition to fascicles
of skeletal muscle and nerve
sheath cells, hypocellular
fibrous areas ﬈ are common
in NMC. (Courtesy J. Carter,
MD, PhD.) (Right) Desmoid-
type fibromatosis is often
associated with NMC. It may
appear de novo or at
recurrence and often behaves
in an aggressive manner. It is
indistinguishable from primary
desmoid-type fibromatosis,
consisting of fascicles of bland
myofibroblasts and fibrous
stroma. (Courtesy J. Carter,
MD, PhD.)

554
 Neuromuscular Choristoma

Peripheral Nerve Sheath Tumors

• Usually solitary, but may be multifocal
TERMINOLOGY
Abbreviations MICROSCOPIC
• Neuromuscular choristoma (NMC) Histologic Features
Synonyms • Enlarged nerve fascicles containing abundant skeletal
• Benign triton tumor muscle fibers
• Neuromuscular hamartoma ○ Rarely contain smooth muscle fibers
○ Surrounded by dense, hypocellular fibrous tissue
Definitions • Areas of DTF
• Benign endoneurial tumor composed of mature skeletal ○ 18-32% of cases
muscle fibers intermixed with peripheral nerve cells often ○ Usually in vicinity of NMC
associated with desmoid-type fibromatosis (DTF) ○ May appear in recurrent NMC
○ May be iatrogenically induced by biopsy
ETIOLOGY/PATHOGENESIS
Developmental Anomaly ANCILLARY TESTS
• Etiology poorly understood Immunohistochemistry
○ Developmental malformation, most likely • Both NMC and associated DTF have nuclear β-catenin
staining
CLINICAL ISSUES
Genetic Testing
Epidemiology
• Most NMC &/or associated DTF have exon 3 CTNNB1
• Incidence mutations
○ Very rare, only 30 reported cases
• Age DIFFERENTIAL DIAGNOSIS
○ Early childhood in most cases
– Usually before 2 years (mean 10 years)
Primary Desmoid Fibromatosis
– Rare cases in adults • Lacks entrapped NMC
– Range: Birth to 68 years Lipomatosis of Nerve (Fibrolipomatous Hamartoma)
Site • Usually perineural, not intraneural
• Major peripheral nerves • Contains adipose tissue, whereas NMC does not
○ Brachial plexus and sciatic nerve most frequent
○ Head and neck, lumbar plexus, spinal nerves, subcutis DIAGNOSTIC CHECKLIST
Presentation Clinically Relevant Pathologic Features
• Fusiform enlargement of major nerve
• Symptoms related to mass effect or sensory/motor deficits
• Early childhood
• Progressive neuropathy or plexopathy
• Secondary musculoskeletal deformity Pathologic Interpretation Pearls
○ Cavus deformity of foot in sciatic nerve tumors • Skeletal muscle fibers within nerve fascicle
Treatment • Often associated with DTF
• Complete surgical excision
SELECTED REFERENCES
Prognosis 1. Stone JJ et al: Recurrent desmoid-type fibromatosis associated with
• Local recurrence in 33% underlying neuromuscular choristoma. J Neurosurg. 1-9, 2018
2. Carter JM et al: CTNNB1 mutations and estrogen receptor expression in
○ Most recurrent cases are associated with DTF neuromuscular choristoma and its associated fibromatosis. Am J Surg
○ 80% develop DTF in cases with long-term clinical follow- Pathol. 40(10):1368-74, 2016
up 3. Hébert-Blouin MN et al: Fibromatosis: a potential sequela of neuromuscular
choristoma. J Neurosurg. 116(2):399-408, 2012
○ Development of DTF may be iatrogenically precipitated
4. Daley TD et al: Benign triton tumor of the tongue. Oral Surg Oral Med Oral
by biopsy Pathol Oral Radiol Endod. 105(6):763-6, 2008
5. Tiffee JC et al: Neuromuscular hamartomas of the head and neck. Arch
IMAGING Otolaryngol Head Neck Surg. 124(2):212-6, 1998
6. Bassett GS et al: Cavus deformity of the foot secondary to a neuromuscular
MR Findings choristoma (hamartoma) of the sciatic nerve. A case report. J Bone Joint
Surg Am. 79(9):1398-401, 1997
• T1 and T2 signal intensities similar to muscle and nerve 7. Awasthi D et al: Neuromuscular hamartoma (benign "triton" tumor) of the
• Low signal in areas of fibrosis/fibromatosis brachial plexus. Case report. J Neurosurg. 75(5):795-7, 1991
8. O'Connell JX et al: Multiple cutaneous neuromuscular choristomas. Report
of a case and a review of the literature. Am J Surg Pathol. 14(1):93-6, 1990
MACROSCOPIC
9. Chen KT: Neuromuscular hamartoma. J Surg Oncol. 26(3):158-60, 1984
General Features 10. Bonneau R et al: Neuromuscular choristoma. A clinicopathologic study of
two cases. Am J Surg Pathol. 7(6):521-8, 1983
• Fusiform expansion of affected nerve with multifascicular
involvement

555
 Melanotic Schwannoma

KEY FACTS
Peripheral Nerve Sheath Tumors

TERMINOLOGY MACROSCOPIC
• Synonym: Psammomatous melanotic schwannoma • Variable tan-gray to black cut surface
• Unusual Schwann cell neoplasm containing variable • Usually < 5 cm
melanin pigment and showing potential for malignant
MICROSCOPIC
behavior
• Lobular growth but often peripherally infiltrative
ETIOLOGY/PATHOGENESIS • Sheets and fascicles of spindled to epithelioid cells
• Subset of cases associated with Carney complex • Mitoses rare to absent
CLINICAL ISSUES • Variably prominent melanin pigment
• Psammoma bodies (50% of cases)
• Most common: 20-45 years of age
• Posterior spinal nerve roots (most common) ANCILLARY TESTS
○ Subset arise in gastrointestinal tract • S100 protein (+), SOX10(+), HMB-45(+), MART-1(+)
• Treatment: Complete surgical excision with negative • Keratin (-), EMA(-), GFAP(-)
margins
• Local recurrence in 1/3 of cases TOP DIFFERENTIAL DIAGNOSES
• Metastasis in 15-42% of reported cases • Metastatic melanoma
• Overall 15% mortality rate • Schwannoma (conventional or gastrointestinal)
• No correlation between morphology and clinical behavior • Clear cell sarcoma

Melanotic Schwannoma Sheets and Fascicles

(Left) Melanotic schwannoma
is an unusual neoplasm that
shows combined schwannian
and melanocytic features and
shows a predilection for the
posterior spinal nerve roots.
Tumor cells are spindled to
epithelioid and associated
with a highly variable amount
of melanin pigment ﬉.
Mitoses are rare. (Right)
Tumor cells are arranged in
sheets and fascicles and often
show mild atypia. Nuclear
palisading ﬈ may be seen in
occasional cases but is usually
much less prominent as
compared to conventional
schwannoma.

Psammoma Bodies Heavy Melanin Pigment

(Left) Spherical, lamellated
calcifications (psammoma
bodies) ﬊ are seen in up to
50% of cases of melanotic
schwannoma and range from
sparse to abundant. Cells with
cytoplasmic vacuolization ﬉
may also be seen in some
cases and can mimic adipose
tissue when prominent. (Right)
The amount and distribution
of melanin pigment is highly
variable in melanotic
schwannoma. This case
showed areas of extensive
pigmentation that obscured
underlying cytologic features.

556
 Melanotic Schwannoma
TERMINOLOGY
Synonyms
• Psammomatous melanotic schwannoma
• Malignant melanotic schwannian tumor (proposed)
Definitions
• Unusual Schwann cell neoplasm containing variable
melanin pigment and showing potential for malignant
behavior
ETIOLOGY/PATHOGENESIS
Common Association With Carney Complex
• Up to 50% of cases (much lower in some series)
• Familial; autosomal dominant
• Other manifestations include myxomas (cutaneous,
cardiac), cutaneous hyperpigmentation, and endocrine
tumors/abnormalities
CLINICAL ISSUES
Epidemiology
• Incidence
○ Rare
• Age
○ Most common: 20-45 years
• Sex
○ Slight female predominance
Site
• Posterior spinal nerve roots and paraspinal ganglia
○ Particularly cervical and thoracic
• Subset arise in gastrointestinal tract
• Very rarely bone or other sites
Presentation
• May be associated with pain or sensory defects
• Usually solitary
○ May be multicentric in Carney complex
Treatment
• Complete surgical excision with negative margins
• Indefinite, long-term clinical follow-up recommended
Prognosis
• Local recurrence in 1/3 of cases
• Metastasis in 15-42% of reported cases
○ May occur late in clinical course
○ Sites include lung, brain, liver
• Overall 15% mortality rate
• No established correlation between morphology and
clinical behavior
MACROSCOPIC
General Features
• Well circumscribed, round to fusiform
• May or may not be encapsulated
• Variable tan-gray to black cut surface
Size
• Usually < 5 cm
Peripheral Nerve Sheath Tumors
MICROSCOPIC
Histologic Features
• Lobular growth but often peripherally infiltrative
• Sheets and fascicles of spindled to epithelioid cells with
ample pale eosinophilic cytoplasm
○ Mildly atypical, vesicular nuclei with small nucleoli
– Nuclear pseudoinclusions or grooves in some cells
○ Occasional cases show nuclear enlargement,
multinucleation, or prominent nucleoli
○ Mitoses rare to absent
• Psammoma bodies (50% of cases)
○ Spherical, concentrically laminar calcifications
○ Can range from sparse to numerous
• Variably prominent melanin pigment
○ May be sparse to focal or abundant and obscuring
• Nuclear palisading, scattered hyalinized vessels rare
• Necrosis in minority of cases
• Degenerative changes include stromal fibrosis, myxoid
changes, symplastic nuclear atypia, cytoplasmic
vacuolizations
• Malignant behavior difficult to predict histologically
○ However, mitotic rate > 2 mitoses/10 HPF may be
associated with increased risk
ANCILLARY TESTS
Immunohistochemistry
• Strong, diffuse S100 protein (+), SOX10(+)
○ Rare cases are entirely negative
• HMB-45(+), MART-1(+), tyrosinase (+)
• Pericellular collagen type IV (+) and laminin (+)
• Keratin (-), EMA(-), GFAP(-)
DIFFERENTIAL DIAGNOSIS
Metastatic Melanoma
• Often marked nuclear atypia with abundant mitoses
• Current or prior clinical history
• Lacks psammoma bodies
Schwannoma (Conventional or Gastrointestinal)
• Lacks psammoma bodies and prominent melanin pigment
• No expression of melanocytic markers
Clear Cell Sarcoma
• Most common in distal extremities of young adults
• Lacks psammoma bodies and heavy melanin pigment
• Osteoclast-like multinucleated giant cells common
• EWSR1 translocations
SELECTED REFERENCES
1. Alexiev BA et al: Pathology of melanotic schwannoma. Arch Pathol Lab Med.
ePub, 2018
2. Torres-Mora J 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. 38(1):94-105, 2014
3. Chetty R et al: Psammomatous melanotic schwannoma presenting as
colonic polyps. Virchows Arch. 451(3):717-20, 2007
4. Carney JA: Psammomatous melanotic schwannoma. A distinctive, heritable
tumor with special associations, including cardiac myxoma and the Cushing
syndrome. Am J Surg Pathol. 14(3):206-22, 1990
557
 Malignant Peripheral Nerve Sheath Tumor

KEY FACTS
Peripheral Nerve Sheath Tumors

TERMINOLOGY
• Malignant neoplasm showing evidence of nerve sheath
(mostly schwannian) cellular differentiation
○ May arise from peripheral nerve or preexisting benign
nerve sheath tumor or within context of NF1
• Term malignant triton tumor may be used for MPNST with
rhabdomyoblastic differentiation
ETIOLOGY/PATHOGENESIS
• 50% of cases associated with NF1
CLINICAL ISSUES
• Wide age range (most common: 20-50 years)
• Extremities (often proximal), trunk, and head/neck
○ Most (70%) arise in major nerve trunks
• Treatment: Complete surgical resection
• Overall poor prognosis
○ Local recurrence in up to 40%
○ Metastasis: 30-60%
MICROSCOPIC
• Most tumors are histologically high grade
• Fascicles and broad whorls of relatively uniform, spindled
cells of variable cellularity
○ Alternating zones of cellularity ("marbled") and
perivascular tumor cell accentuation common
○ Hyperchromatic, elongated to pleomorphic nuclei
• Mitoses often numerous and necrosis is common
• May show origin from benign nerve sheath tumor
• Heterologous differentiation in 10-15% of cases
ANCILLARY TESTS
• Focal S100 protein (+) &/or SOX10(+) in up to 50%
• Loss of nuclear H3K27me3 expression by IHC
TOP DIFFERENTIAL DIAGNOSES
• Synovial sarcoma
• Cellular schwannoma
• Atypical neurofibroma

Malignant Peripheral Nerve Sheath Tumor Gross Photograph

(Left) Malignant peripheral
nerve sheath tumor (MPNST)
is a neurogenic neoplasm that
may occur sporadically or
within the setting of
neurofibromatosis type 1. This
intraoperative photograph of
MPNST shows a large fusiform
tumor mass arising from and
incorporating the femoral
nerve ſt. (Right) MPNSTs tend
to form bulky, circumscribed,
and pseudoencapsulated
masses often with a
variegated cut surface,
including firm, white-tan areas
of viable tumor ﬊, yellow
necrotic areas ﬉, and cystic
hemorrhagic foci ﬈.

Marbled or Tapestry-Like Pattern Nuclear Atypia Common

(Left) Although the
morphologic spectrum is
relatively broad, the classic
low-power appearance of
MPNST shows alternating
zones of varying cellularity
that imparts a marbled or
tapestry-like pattern, as
depicted. (Right) Most MPNSTs
are high-grade neoplasms, and
nuclear atypia and
pleomorphism ﬉ are
common. This is in contrast to
synovial sarcoma, which shows
nuclear monomorphism.
Mitotic figures ﬊ are often
easily identified in MPNST as
well.

558
 Malignant Peripheral Nerve Sheath Tumor
TERMINOLOGY
Abbreviations
• Malignant peripheral nerve sheath tumor (MPNST)
Synonyms
• Neurofibrosarcoma, malignant schwannoma, neurogenic
sarcoma
Definitions
• Malignant neoplasm showing evidence of nerve sheath
(mostly schwannian) cellular differentiation
○ Common settings: Origin from peripheral nerve, or
preexisting benign nerve sheath tumor, or in patient
with neurofibromatosis type 1 (NF1)
– May also arise outside of these classic settings
• Term malignant triton tumor may be used for MPNST with
rhabdomyoblastic differentiation
ETIOLOGY/PATHOGENESIS
Genetic Predisposition
• 50% of cases associated with NF1
○ Lifetime risk: 5-10%
• 40% of cases are sporadic
Molecular Pathogenesis
• NF1 caused by germline mutation of NF1 tumor suppressor
gene (17q11.2)
○ Somatic loss of 2nd NF1 allele required for tumorigenesis
• Malignant transformation in both NF1-associated and
sporadic MPNST often involves CDKN2A and TP53 and their
downstream pathways
Environmental Exposure
• 10% of cases associated with history of radiation
CLINICAL ISSUES
Epidemiology
• Incidence
○ Uncommon (5% of soft tissue sarcomas)
• Age
○ Wide range (most common: 20-50 years)
– Younger average age in NF1 patients
• Sex
○ Male predominance in NF1-associated tumors
Site
• Extremities (often proximal), trunk, and head/neck
○ Most are deep seated
• Most (70%) arise in major nerve trunks
○ Sciatic nerve most common
○ Also brachial plexus, sacral plexus, paraspinal nerves
Presentation
• Enlarging painless or painful mass
○ Rapid enlargement of preexisting nerve sheath tumor in
NF1 patient suggests malignant transformation
• Neurogenic symptoms (e.g., weakness, tingling) in some
patients
Treatment
• Complete surgical resection
Peripheral Nerve Sheath Tumors
• Postoperative radiotherapy
• Generally poor response to chemotherapy
○ Recent studies suggest efficacy of rapamycin (mTOR
inhibitor) ± AKT inhibitors
Prognosis
• Overall poor prognosis
○ Local recurrence in up to 40%
○ Metastasis: 30-60%
– Lungs, bone, pleura most common
○ 5-year survival rate: 26-60%
– NF1-associated tumors associated with worse survival
than sporadic tumors
• Adverse prognostic factors: Centralized/truncal location,
larger size (> 5 cm), high-grade histology, local recurrence
• Malignant triton tumors usually show very aggressive
clinical course
MACROSCOPIC
General Features
• Often large, fusiform mass
○ Origin from nerve or benign nerve sheath tumor may be
evident
– Particularly plexiform neurofibroma in NF1
• Tan-white-gray, firm, gelatinous to fleshy cut surface
• Necrosis and hemorrhage common
Size
• Most > 5 cm
MICROSCOPIC
Histologic Features
• Fascicles and broad whorls of relatively uniform, spindled
cells
○ Pale eosinophilic cytoplasm with ill-defined cytoplasmic
borders
○ Hyperchromatic, elongated nuclei with dispersed coarse
chromatin
– Wavy, tapered, or "buckled" contours in some cells
– Nuclear pleomorphism not uncommon
□ May rarely be marked and extensive
– Focal epithelioid cytomorphology may be present
– Rare primitive, small-cell morphology
• Cellularity characteristically varies
○ Alternating cellular fascicles and hypocellular areas
(tapestry or marbled pattern)
– Cellular areas may show herringbone, palisading, or
neuroid whorling patterns
○ Increased cellular density and prominence around some
stromal vessels
– Cells may appear to herniate into vascular lumen
• Vascularized, variable myxoid to collagenous stroma
○ Hemangiopericytoma-like vascular pattern in some
○ Distinct clusters of small vessels may be seen
• Mitoses often numerous
• Coagulative necrosis is common
○ May be geographic with perivascular sparing
(peritheliomatous pattern)
• Most are histologically high grade
○ 10-15% are low grade (few mitoses, no necrosis)
559
 Malignant Peripheral Nerve Sheath Tumor
Peripheral Nerve Sheath Tumors
• Origin from peripheral nerve may be evident
○ Tumor may track along nerve bundles
• Origin from preexisting benign nerve sheath tumor in some
cases
○ Neurofibroma most common
– Plexiform (in NF1) and solitary soft tissue types; rarely
others
– Transitional areas of increased cellularity and atypia
may be seen
○ Rarely schwannoma, ganglioneuroma,
ganglioneuroblastoma, or pheochromocytoma
• Heterologous mesenchymal differentiation in 10-15% of
cases
○ Rhabdomyoblastic (malignant triton tumor)
○ Osteosarcomatous, chondrosarcomatous
○ Rarely angiosarcomatous, liposarcomatous
• Epithelial elements (e.g., glands) very rare
○ Usually seen within context of NF1
ANCILLARY TESTS
Immunohistochemistry
• S100 protein (+) &/or SOX10 (+) in up to 50%,
characteristically focal
○ Diffuse expression very rare (except in low-grade
MPNST)
• Loss of nuclear H3K27me3 expression is supportive
○ Usually diffuse loss; rarely heterogeneous
○ Greater sensitivity in sporadic and radiation-induced
MPNST than in NF1-related tumors
• Variable CD34(+), GFAP(+)
• Keratin, SMA, desmin, HMB45, MART-1 (-)
○ Heterologous rhabdomyoblasts elements are desmin (+),
myogenin (+)
Genetic Testing
• Complex structural and numeric chromosomal
abnormalities
○ No consistent differences between NF1-associated and
sporadic tumors
• No MDM2 amplification
DIFFERENTIAL DIAGNOSIS
Synovial Sarcoma (Monophasic)
• Characteristic uniform, cytologic and architectural features
• Presence of stromal "wiry collagen" and calcifications
• Cytokeratin (+) and EMA(+) but usually focal or patchy
• Focal S100(+) in 30% of cases
• Diffuse nuclear TLE1(+)
• Characteristic t(X;18) involving SS18 (SYT)
Cellular Schwannoma
• Lacks malignant cytological atypia
• Patchy subcapsular lymphoid aggregates &/or foamy
macrophages
• Necrosis uncommon but may be present focally
• Strong, diffuse S100(+) and SOX10(+)
• Retention of nuclear H3K27me3 by IHC
Atypical Neurofibroma
• Usually retains cytoarchitectural features of neurofibroma
560
• Scattered, enlarged nuclei with degenerative, "smudgy"
chromatin
• Lacks fascicular growth and marked cellularity
• Mitoses rare to absent
Malignant Melanoma
• May have previous clinical history
• Pure spindled morphology uncommon
• Diffusely S100 protein (+)
• Expression of HMB-45 and other melanocytic markers
Dedifferentiated Liposarcoma
• Heterogeneous morphologic appearance
• Lacks perivascular accentuation of tumor cells
• Identification of well-differentiated liposarcoma
component very helpful
• MDM2 amplification (best supportive test)
• General retention of nuclear H3K27me3 by IHC (lost in rare
cases)
Leiomyosarcoma
• Smooth muscle cytomorphology
• SMA(+), variable desmin (+)
• S100 protein (-)
Spindle Cell Rhabdomyosarcoma
• Usually does not arise in association with large nerve or
within context of NF1
• Desmin (+), myogenin (+) tumor cells are more evenly
distributed
SELECTED REFERENCES
1. Makise N et al: Clarifying the distinction between malignant peripheral nerve
sheath tumor and dedifferentiated liposarcoma: a critical reappraisal of the
diagnostic utility of MDM2 and H3K27me3 status. Am J Surg Pathol.
42(5):656-64, 2018
2. Le Guellec S 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. 40(7):896-908, 2016
3. Prieto-Granada CN et al: Loss of H3K27me3 expression is a highly sensitive
marker for sporadic and radiation-induced MPNST. Am J Surg Pathol.
40(4):479-89, 2016
4. Schaefer IM et al: Loss of H3K27 trimethylation distinguishes malignant
peripheral nerve sheath tumors from histologic mimics. Mod Pathol. 29(1):4-
13, 2016
5. Pekmezci M et al: Morphologic and immunohistochemical features of
malignant peripheral nerve sheath tumors and cellular schwannomas. Mod
Pathol. 28(2):187-200, 2014
6. Endo M et al: Conventional spindle cell-type malignant peripheral nerve
sheath tumor arising in a sporadic schwannoma. Hum Pathol. 44(12):2845-8,
2013
7. Kolberg M et al: Survival meta-analyses for >1800 malignant peripheral
nerve sheath tumor patients with and without neurofibromatosis type 1.
Neuro Oncol. 15(2):135-47, 2013
8. Wakely PE Jr et al: The cytopathology of malignant peripheral nerve sheath
tumor: a report of 55 fine-needle aspiration cases. Cancer Cytopathol.
120(5):334-41, 2012
9. Kroep JR et al: First-line chemotherapy for malignant peripheral nerve
sheath tumor (MPNST) versus other histological soft tissue sarcoma
subtypes and as a prognostic factor for MPNST: an EORTC soft tissue and
bone sarcoma group study. Ann Oncol. 22(1):207-14, 2011
10. Mills AM et al: Endocervical fibroblastic malignant peripheral nerve sheath
tumor (neurofibrosarcoma): report of a novel entity possibly related to
endocervical CD34 fibrocytes. Am J Surg Pathol. 35(3):404-12, 2011
11. Moretti VM et al: Early outcomes for malignant peripheral nerve sheath
tumor treated with chemotherapy. Am J Clin Oncol. 34(4):417-21, 2011
12. Gottfried ON et al: Neurofibromatosis type 1 and tumorigenesis: molecular
mechanisms and therapeutic implications. Neurosurg Focus. 28(1):E8, 2010
 Malignant Peripheral Nerve Sheath Tumor

Peripheral Nerve Sheath Tumors

Cytologic Features Cytologically Low-Grade Areas
(Left) General nuclear features
of neural tumors, including
elongated, tapered/pointed,
wavy, or buckled nuclei are
often seen at least focally in
MPNST. The characteristic
cytology may be difficult to
appreciate in higher grade
areas. (Right) It is not
uncommon for an otherwise
high-grade MPNST to contain
areas that are cytologically
lower grade, as depicted. In a
minority of cases, low-grade
morphology makes up most or
all of the tumor (low-grade or
well-differentiated MPNST).

Perivascular Accentuation Perivascular Accentuation

(Left) A characteristic and
helpful diagnostic feature of
MPNST is the tendency of
tumor cells to become larger
and more rounded around the
stromal blood vessels ﬊. This
pattern often makes the
vessels stand out at low power
and may even superficially
resemble epithelial
islands/nests. (Right) In some
cases of MPNST, the larger
tumor cells around the vessels
appear to push ﬊ or
"herniate" into the lumen.

Myxoid Stroma Collagenous Stroma

(Left) This H&E shows a
myxoid area of MPNST
featuring nuclear
pleomorphism, neural
cytologic features, and
stromal vessels with mild
perivascular tumor cell
accentuation ﬊. (Right) Some
areas of MPNST may contain
more stromal collagen and
appear more fibroblastic, as
depicted, which may lead to
consideration of a fibroblastic
sarcoma or synovial sarcoma.

561
 Malignant Peripheral Nerve Sheath Tumor
Peripheral Nerve Sheath Tumors

Coagulative Necrosis Geographic Necrosis

(Left) Coagulative tumor
necrosis ﬉ is common in
MPNST. (Right) Necrosis may
be extensive and geographic in
MPNST. In these situations, a
common finding is the
preservation of tumor cells
only around vessels ﬊
(peritheliomatous pattern)
with necrosis of the
intervening cells. Although in
no way pathognomonic, this
pattern should always raise
the possibility of MPNST.

Fascicular Growth Fascicular Growth

(Left) A fascicular pattern of
growth is common in MPNST.
In occasional cases, a
herringbone architecture may
be identified, as shown. Note
the prominent nuclear
pleomorphism ﬊, which is not
a feature of synovial sarcoma
or adult-type fibrosarcoma.
(Right) Fascicular growth may
also be seen in areas with
more collagenous stroma or
myxoid stroma. Note the
absence of nuclear
pleomorphism in this H&E,
which is not uncommon in
MPNST.

Marked Anaplasia Perineurial Morphology

(Left) Rare cases of MPNST
show marked nuclear
anaplasia and may mimic
other pleomorphic sarcomas.
Demonstration of origin from
a nerve or benign nerve sheath
tumor (mainly neurofibroma)
is very helpful. (Right) A loose,
whorling morphology similar
to perineurioma may be seen
in MPNST and is evidence of
perineurial differentiation. IHC
(EMA, Claudin-1) can be used
to highlight this
differentiation, though it is of
no clinical significance.

562
 Malignant Peripheral Nerve Sheath Tumor
S100 Protein Expression
Origin From Nerve
Origin From Neurofibroma
Peripheral Nerve Sheath Tumors
Origin From Nerve
(Left) S100 protein &/or
SOX10 expression is only seen
in ~ 50% of cases of MPNST
and is characteristically focal
or patchy. Diffuse expression
of either marker is generally
very rare and should raise the
possibility of melanoma or
cellular schwannoma. (Right)
Origin from a nerve ﬊ may be
evident grossly &/or
histologically in MPNST ﬉;
however, in some cases,
imaging or intraoperative
reports can provide this
information. In yet other
cases, nerve origin cannot be
clearly demonstrated.
Origin From Neurofibroma
(Left) This H&E shows cross
sections of large nerve fibers
being expanded and replaced
by MPNST. Note the cellularity
and marked pleomorphism.
(Right) Certain forms of
neurofibroma (particularly
plexiform and large soft tissue
ſt types) are well known to
carry a risk for malignant
transformation into MPNST.
This change ﬊ is often
heralded by a combination of
increased cellularity, nuclear
atypia, mitoses, &/or necrosis.
Origin From Neurofibroma
(Left) This case of MPNST
arising in a neurofibroma
shows a more abrupt
transition between the benign
(right) and malignant (left)
components. (Right) At high
magnification, the increased
cellularity, atypia, and mitoses
indicate transformation from
neurofibroma (top) into
MPNST (bottom).
563
 Malignant Peripheral Nerve Sheath Tumor
Peripheral Nerve Sheath Tumors

Heterologous Mesenchymal Elements Malignant Triton Tumor

(Left) Up to 15% of cases of
MPNST contain evidence of
heterologous mesenchymal
differentiation. The formation
of bone ﬉ and cartilage ﬊
can be seen in this example.
(Right) An MPNST with
heterologous
rhabdomyoblastic elements
﬊ is also referred to as a
malignant triton tumor. This
distinction from conventional
MPNST is important, as
malignant triton tumors are
generally more aggressive.

Heterologous Angiosarcoma Rare Glandular Elements

(Left) Rare cases of MPNST
may contain areas of
angiosarcoma, as
demonstrated in this H&E by
irregular vascular channels
lined by pleomorphic,
hyperchromatic cells. IHC may
be utilized to confirm the
endothelial origin of the cells
[CD31(+) &/or CD34(+)].
(Right) Rarely, MPNST can
contain heterologous
glandular elements. The
glands may or may not show
evidence of mucin production
﬊ and can sometimes show
focal neuroendocrine
differentiation.

Prominent Vasculature Hemangiopericytoma-Like Vessels

(Left) The stromal vasculature
is generally conspicuous in
MPNST and is often
highlighted by the
characteristic perivascular
tumor cell accentuation. Some
vessels, however, lack this
change, and others may
appear more dilated ﬉ or
even staghorn. (Right) Rare
cases of MPNST show a more
developed
hemangiopericytoma-like
vasculature, as depicted,
reminiscent of a solitary
fibrous tumor.

564
 Malignant Peripheral Nerve Sheath Tumor
Small Cell Morphology
Rare Nuclear Palisading
Rare Findings
Peripheral Nerve Sheath Tumors
Small Cell Morphology
(Left) Small cell change is an
uncommon morphology in
MPNST but when present can
lead to consideration of a
variety of other small round
blue cell tumors, particularly
on limited biopsy. (Right)
MPNST can have prominent
small round blue cell areas,
mimicking Ewing sarcoma or
poorly differentiated synovial
sarcoma. Appropriate use of
IHC and molecular analysis can
resolve these differential
diagnoses in most instances.
Rare Findings
(Left) Despite the neural origin
of MPNST, nuclear palisading
is an uncommon finding. Of
note, this pattern can also be
seen in other entities on the
differential of MPNST,
including synovial sarcoma
and GI stromal tumor. Note
the presence of nuclear
pleomorphism ﬇. (Right)
Discrete, thickened collagen
bundles ﬉ may rarely be seen
in MPNST.
Rare Findings
(Left) Small, rosette-like
structures may rarely be seen
in MPNST, as depicted. Similar
structures may be seen in the
neuroblastoma-like variant of
schwannoma; however, the
latter lacks the other cytologic
and architectural features of
MPNST. (Right)
Multinucleated giant cells ﬉
are a very rare finding in
MPNST.
565
 Epithelioid Malignant Peripheral Nerve Sheath Tumor

KEY FACTS
Peripheral Nerve Sheath Tumors

TERMINOLOGY
• Distinctive subtype of malignant peripheral nerve sheath
tumor (MPNST) composed predominantly of epithelioid
tumor cells and characterized in most cases by strong,
diffuse S100 protein expression
ETIOLOGY/PATHOGENESIS
• No association with neurofibromatosis type 1
CLINICAL ISSUES
• Rare subtype of MPNST
• Affects mainly adults (median: 44 years)
• Usually involves extremities or trunk
○ Subcutaneous tissue > deep soft tissue
• Treatment: Complete surgical resection with negative
margins
• Prognosis: Potential for aggressive clinical behavior
○ Local recurrence and distant metastasis in subset
MICROSCOPIC
• Lobular or multinodular growth common
• Sheets, nests, and cords of large epithelioid cells
• Large, irregular nucleus with vesicular chromatin and
prominent nucleolus
• Variable collagenous to myxoid stroma
ANCILLARY TESTS
• Strong, diffuse S100 protein (+)
• Loss of nuclear INI1 in 50-60% of cases
• HMB-45, MART-1, SMA, desmin, CD31, CD34 (-)
• Intact nuclear expression of H3K27me3
TOP DIFFERENTIAL DIAGNOSES
• Epithelioid schwannoma
• Malignant melanoma
• Clear cell sarcoma
• Malignant myoepithelioma

Epithelioid Malignant Peripheral Nerve

Sheath Tumor Typical Features
(Left) Epithelioid malignant
peripheral nerve sheath tumor
(EMPNST) is a distinctive
subtype of malignant
peripheral nerve sheath tumor
(MPNST) that shows no clear
association with
neurofibromatosis type 1.
Multinodular growth, as seen
in this H&E, is a common
feature of these tumors.
(Right) The usual appearance
of EMPNST is that of sheets,
nests, and cords of large cells
with eosinophilic to
amphophilic cytoplasm within
a myxoid to collagenous
matrix.

Prominent Nucleoli S100 Protein Expression

(Left) The lesional cells of
EMPNST characteristically
contain a large, vesicular
nucleus with a prominent
nucleolus. Mitotic figures ﬊
are usually easily identified
and may be
atypical/abnormal. (Right) In
contrast to a conventional
MPNST, the epithelioid
subtype typically shows strong
and diffuse expression of S100
protein, as shown. Due to this
feature, epithelioid
schwannoma and malignant
melanoma must always be
considered and excluded.

566
 Epithelioid Malignant Peripheral Nerve Sheath Tumor

Peripheral Nerve Sheath Tumors

TERMINOLOGY MICROSCOPIC
Abbreviations Histologic Features
• Epithelioid malignant peripheral nerve sheath tumor • Lobular or multinodular growth common
(EMPNST) ○ Superficial tumors may appear encapsulated
Synonyms • Sheets, nests, and cords of large epithelioid cells
○ Abundant eosinophilic to amphophilic cytoplasm
• Malignant epithelioid schwannoma
– May show rhabdoid cytomorphology
Definitions – Rare clear cell change
• Distinctive subtype of malignant peripheral nerve sheath ○ Large, irregular nucleus with vesicular chromatin and
tumor (MPNST) composed predominantly of epithelioid prominent nucleolus
tumor cells and characterized in most cases by strong, – Mitoses common
diffuse S100 protein expression • Minor areas showing spindled morphology may be present
• Variable collagenous to myxoid stroma
ETIOLOGY/PATHOGENESIS • Coagulative necrosis may be present
Genetics • May arise in background of benign peripheral nerve sheath
tumor, particularly schwannoma
• No association with neurofibromatosis type 1
• Rare tumors demonstrate overall low histologic grade
CLINICAL ISSUES
ANCILLARY TESTS
Epidemiology
Immunohistochemistry
• Incidence
• Strong, diffuse S100 protein (+) in majority
○ Rare subtype of MPNST
• Loss of nuclear INI1 in 50-60% of cases
– ~ 5% of cases
• HMB-45, MART-1, SMA, desmin, CD31, CD34 (-)
• Age
• Intact nuclear expression of H3K27me3
○ Usually adults (median: 44 years)
Site DIFFERENTIAL DIAGNOSIS
• Subcutaneous tissue more common than deep soft tissue Epithelioid Schwannoma
○ May infrequently arise in dermis • Usually clinically small lesions
• Usually involves extremities (particularly lower) • Small nuclei lacking diffuse atypia, macronucleoli, atypical
○ Nearly 1/2 of cases arise in association with large nerve mitoses, and necrosis
• Also trunk; occasionally other sites
Malignant Melanoma
Presentation
• Clinical history or junctional component may be present
• Slowly growing, painful or painless mass • Often significant nuclear pleomorphism/atypia
Treatment • S100 protein (+), HMB-45(+), MART-1(+)
• Complete surgical resection with negative margins Clear Cell Sarcoma
• Postoperative tumor bed radiation may be utilized • S100 protein (+), HMB-45(+), MART-1(+)
Prognosis • Characteristic t(12;22) with EWSR1 rearrangement
• Potential for aggressive clinical behavior Malignant Myoepithelioma
○ Low to moderate risk of local recurrence • Often keratin (+) &/or EMA(+) as well as S100 protein (+)
○ Distant metastases to lung, pleura, other sites in 10-50% ○ May also express SMA, GFAP, calponin, desmin, others
• Superficial tumors may exhibit better overall prognosis with • May show formation of epithelial (ductal) structures
lower risk of adverse outcome • EWSR1 translocation in 50% of cases
○ However, recent study suggests that superficial and
deep tumors show same potential for aggressive Other Epithelioid Malignancies
behavior • e.g., lymphoma, epithelioid sarcoma, angiosarcoma,
extrarenal rhabdoid tumor, rhabdomyosarcoma
MACROSCOPIC • Each can be distinguished by immunohistochemistry
General Features
SELECTED REFERENCES
• Multinodular, well demarcated
• Firm, fleshy, tan-gray cut surface 1. Asano N et al: Immunohistochemistry for trimethylated H3K27 in the
diagnosis of malignant peripheral nerve sheath tumours. Histopathology.
70(3):385-93, 2017
Size
2. Jo VY et al: Epithelioid malignant peripheral nerve sheath tumor:
• Median: 3 cm (range: 0.4-20.0 cm) clinicopathologic analysis of 63 cases. Am J Surg Pathol. 39(5):673-82, 2015
3. Carter JM et al: Epithelioid malignant peripheral nerve sheath tumor arising
in a schwannoma, in a patient with "neuroblastoma-like" schwannomatosis
and a novel germline SMARCB1 mutation. Am J Surg Pathol. 36(1):154-60,
2012

567
 Epithelioid Malignant Peripheral Nerve Sheath Tumor
Peripheral Nerve Sheath Tumors

Lobulated Appearance Solid Sheets

(Left) Lobular or nodular
architecture is common in
EMPNST. In some cases, the
tumor cell nodules are
separated by thick fibrous
septa, as seen in this H&E.
(Right) Solid growth may be
seen in EMPNST, either focally
or in most of the tumor.
Together with the cytologic
features, this morphology can
raise suspicions for melanoma.
Immunohistochemical
evaluation with melanocytic
markers is often very helpful.

Necrosis Prominent Myxoid Matrix

(Left) Coagulative necrosis
may be seen in EMPNST;
however, in general, it is not
as common as in other high-
grade sarcomas. Necrosis may
be focal ﬈, as depicted, or
rarely geographic. (Right)
Myxoid matrix is a relatively
common finding in EMPNST
and varies widely in amount
and distribution. Extensively
myxoid examples can closely
resemble soft tissue
myoepithelioma or
myoepithelial carcinoma.

Hypocellular Areas Abundant Cytoplasm

(Left) Some areas in EMPNST
may be less cellular and show
small clusters or individual
cells within a myxoid or
collagenous matrix. Note the
prominent nucleoli. (Right)
This case of EMPNST had
areas containing nests of
tumor cells showing more
abundant eosinophilic
cytoplasm, all within a loose
myxoid matrix.

568
 Epithelioid Malignant Peripheral Nerve Sheath Tumor

Peripheral Nerve Sheath Tumors

Spindled Morphology Spindled and Epithelioid Morphology
(Left) The presence of
spindling in otherwise
cytologically typical tumor
cells is not uncommon in
EMPNST and can resemble
conventional spindle cell
MPNST. (Right) This EMPNST
contained minor areas of
spindled tumor cells with
scattered nests and clusters of
epithelioid cells ﬊. The
majority of the tumor,
however, showed a prominent
epithelioid morphology.

Clear Cell Change Rhabdoid Cells

(Left) Prominent clear cell
change may be seen in some
cases of EMPNST and may
lead to confusion with clear
cell sarcoma. (Right) Rhabdoid
cells can be seen in EMPNST
and should raise consideration
of other tumors that may
show a rhabdoid
cytomorphology, including
melanoma. Of note, ~ 50-60%
of cases of EMPNST show loss
of nuclear INI1.

Rare Nuclear Pleomorphism Loss of Nuclear INI1

(Left) Significant nuclear
pleomorphism is generally
uncommon in EMPNST;
however, rare cases may
contain cells with bizarre
nuclei, as depicted. (Right)
Nuclear loss ﬉ of INI1 can be
seen in 40-60% of cases of
EMPNST. Scattered
inflammatory cells ﬈ are
often positive for the marker
and should be ignored.

569
 Ectomesenchymoma

KEY FACTS
Peripheral Nerve Sheath Tumors

TERMINOLOGY MICROSCOPIC
• Synonym: Malignant ectomesenchymoma • Combination of RMS with variable neural component
• Tumor composed of rhabdomyosarcoma (RMS) and neural ○ Components often intermingled
or neuronal elements • RMS component often embryonal type
ETIOLOGY/PATHOGENESIS • Variable neural/neuronal component
○ Ganglioneuroma, neuroblastoma, malignant peripheral
• Possible origin from pluripotent embryologic migratory
nerve sheath tumor (MPNST), PNET
neural crest cells
ANCILLARY TESTS
CLINICAL ISSUES
• Desmin (+) and myogenin (+) in RMS component
• Usually childhood (< 4 years)
• S100 protein (+) in Schwann cell component
• Head and neck, paratesticular region, abdomen, pelvis
• NB84(+), synaptophysin (+), CD56(+) in neuroblastic
• Treatment: Generally approached like RMS
component
○ International Rhabdomyosarcoma Group (IRSG) protocol
• Usually aggressive clinical course TOP DIFFERENTIAL DIAGNOSES
• Embryonal RMS
MACROSCOPIC
• Malignant triton tumor
• Median: 5 cm
• Neuroblastoma
• Ganglioneuroma

Ectomesenchymoma Ectomesenchymoma
(Left) Ectomesenchymoma is a
very rare and often clinically
aggressive tumor that
typically features a
combination of
rhabdomyosarcoma (RMS),
usually embryonal type, and
neural or neuronal elements
(such as ganglion cells or
neuroblastic cells). (Right) This
H&E shows a single ganglion
cell ﬊ amidst rounded cells
with small hyperchromatic
nuclei dispersed in a fibrillary
background. Typically, the
elements of
ectomesenchymoma are
randomly intermingled.

Rhabdomyoblastic Elements Schwann Cell Component

(Left) The RMS component of
ectomesenchymoma is most
often embryonal type, but
spindle cell and alveolar RMS
may also be seen.
Rhabdomyoblastic elements
﬊ are often readily
identifiable. (Right)
Ectomesenchymoma may
contain areas showing
fascicles of differentiated
Schwann cells, as depicted,
similar to ganglioneuroma or
even cellular schwannoma.
S100 protein expression is
seen in these areas.

570
 Ectomesenchymoma

Peripheral Nerve Sheath Tumors

TERMINOLOGY MICROSCOPIC
Synonyms Histologic Features
• Malignant ectomesenchymoma • Combination of RMS with variable neural component
• Gangliorhabdomyosarcoma ○ Components often intermingled
○ RMS
Definitions
– Sheets, nests, or cords of small round cells
• Tumor composed of rhabdomyosarcoma (RMS) and neural
□ Can resemble embryonal, alveolar, or spindle cell
or neuronal elements
RMS
– Spindled or rounded rhabdomyoblasts with
ETIOLOGY/PATHOGENESIS eosinophilic cytoplasm
Uncertain Etiology ○ Variable neural/neuronal component
• Possible origin from pluripotent embryologic migratory – Ganglioneuroma
neural crest cells □ Ganglion cells in variable numbers
• Possible RMS variant □ Differentiated Schwann cells in fascicles or whorls
○ Ganglion cells reported in rare cases of both metastatic – Neuroblastoma
and treated RMS □ Clusters or nodules of small primitive cells
○ Gene expression profiling suggests genetic link to RMS – Primitive neuroectodermal tumor
– Malignant peripheral nerve sheath tumor
CLINICAL ISSUES
Epidemiology ANCILLARY TESTS
• Incidence Immunohistochemistry
○ Extremely rare • Desmin (+) and myogenin (+) in RMS component
• Age • S100 protein (+) in Schwann cell component
○ Usually childhood (< 4 years) • NB84(+), synaptophysin (+), CD56(+) in neuroblastic
component
Site
• Retained H3K27me3 expression
• Head and neck
○ Nasal cavity, orbit Genetic Testing
• Paratesticular region • HRAS mutations common
• Abdomen, pelvis
• CNS DIFFERENTIAL DIAGNOSIS
Presentation Embryonal Rhabdomyosarcoma
• Often, rapidly growing mass • Can be impossible to distinguish from ectomesenchymoma
• Superficial or deep soft tissues on limited biopsy
○ Embryonal RMS is far more common, however
Treatment • Absence of neural/neuroectodermal component
• Generally approached like RMS
Malignant Triton Tumor
○ Treated per International Rhabdomyosarcoma Group
(IRSG) protocols • MPNST with heterologous rhabdomyoblastic elements
○ Rhabdomyoblastic component often discrete rather
Prognosis than diffusely intermingled
• Usually aggressive clinical course • Lacks ganglion cells and other neural/neuroectodermal
• Favorable prognostic factors component
○ Tumor size < 10 cm, superficial location, low stage at
Neuroblastoma
presentation
○ Absence of alveolar RMS component • Arises along sympathetic chain
• Lacks rhabdomyosarcomatous component
MACROSCOPIC Ganglioneuroma
General Features • Mixture of Schwann cells and mature ganglion cells
• Lobular • Lacks component of RMS or neuroblastoma
• Well circumscribed or infiltrative
• Hemorrhage and necrosis SELECTED REFERENCES
1. Griffin BB et al: Malignant ectomesenchymoma: series analysis of a
Size histologically and genetically heterogeneous tumor. Int J Surg Pathol.
• Median: 5 cm 1066896917734915, 2017
2. Huang SC et al: Frequent HRAS mutations in malignant
ectomesenchymoma: overlapping genetic abnormalities with embryonal
rhabdomyosarcoma. Am J Surg Pathol. 40(7):876-85, 2016

571
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 SECTION 13

Genital Stromal Tumors

Fibroepithelial Stromal Polyp 574

Angiomyofibroblastoma 576
Cellular Angiofibroma 580
Deep (Aggressive) Angiomyxoma 584
 Fibroepithelial Stromal Polyp

KEY FACTS
Genital Stromal Tumors

TERMINOLOGY • Spindle to stellate cells

• Benign polypoid fibroblastic proliferation, usually involving ○ Multinucleation and nuclear enlargement common
vagina in women of reproductive age • Fibrous, edematous, or myxoid stroma
• Can be alarmingly cellular with nuclear pleomorphism and
CLINICAL ISSUES mitotic figures
• Occurs in women, usually in vagina or vulva ○ Most often seen in pregnancy
• Wide age range (particularly reproductive years)
ANCILLARY TESTS
• 1/2 of patients are asymptomatic
• Significant association with pregnancy • Immunophenotype
• Treatment: Simple excision ○ Desmin (+), ER(+), PR(+)
• Benign; rare recurrences ○ Variable CD34(+) and SMA(+)
○ Myogenin (-), MYOD1(-)
MACROSCOPIC
TOP DIFFERENTIAL DIAGNOSES
• Often polypoid
• Usually 1-3 cm • Aggressive angiomyxoma
• Angiomyofibroblastoma
MICROSCOPIC • Cellular angiofibroma
• No grenz zone between lesion and overlying squamous • Botryoid rhabdomyosarcoma
mucosa • Genital rhabdomyoma

Fibroepithelial Stromal Polyp Grenz Zone Absent

(Left) Fibroepithelial stromal
polyp (FSP) most often
presents as a small, polypoid
mass on the vagina or vulva.
Most cases are hypocellular
and contain a myxoid or
edematous stroma. The
overlying epidermis is usually
unremarkable or reactive.
(Right) A helpful feature for
identifying FSP is the absence
of a grenz zone (normal
subepithelial tissue) between
the lesion and overlying
squamous mucosa. This is in
direct contrast to other benign
genital stromal tumors.

Nuclear Morphology Pseudosarcomatous Change

(Left) The cells of FSP have
eosinophilic cytoplasm and are
usually spindled with bipolar
processes. Stellate and
multinucleated forms ﬈ are
common and are often seen
close to the overlying mucosa.
(Right) Occasional cases of
FSP (particularly those that
occur during pregnancy) show
marked cellularity and nuclear
pleomorphism. Mitotic figures,
including atypical forms, may
also be seen. This variant has
been described as cellular
pseudosarcomatous
fibroepithelial stromal polyp.
Note the absence of a grenz
zone ﬈.

574
 Fibroepithelial Stromal Polyp

Genital Stromal Tumors

• Fibrous, edematous, or myxoid stroma
TERMINOLOGY
• Thick- or thin-walled vessels more prominent in center of
Abbreviations lesion
• Fibroepithelial stromal polyp (FSP) • Larger lesions can undergo torsion
○ Imparts striking edema/myxoid change
Synonyms
• Can be alarmingly cellular with nuclear pleomorphism and
• Mesodermal stromal polyp mitotic figures
• Cellular pseudosarcomatous fibroepithelial stromal polyp; ○ Most often seen in pregnancy
pseudosarcoma botryoides
Definitions ANCILLARY TESTS
• Benign polypoid fibroblastic proliferation, usually involving Immunohistochemistry
vagina in women of reproductive age • Desmin (+), ER(+), PR(+)
• Variable CD34(+) and SMA(+)
CLINICAL ISSUES • Myogenin (-), MYOD1(-)
Epidemiology
• Incidence DIFFERENTIAL DIAGNOSIS
○ Relatively common Aggressive Angiomyxoma
• Age • Poorly circumscribed, large, deep masses
○ Wide range (particularly reproductive years) • Medium- and large-caliber vessels common throughout
• Sex lesion
○ Women • Multinucleated cells uncommon
Site • Similar immunophenotype to FSP
• Usually vagina or vulva Angiomyofibroblastoma
○ Rarely cervix • Well-circumscribed mass rather than polyp
Presentation • Grenz zone in superficial lesions
• Plump epithelioid to spindled cells proliferating around
• 1/2 of patients are asymptomatic
vessels
• May present with vaginal bleeding or local pain
• Similar immunophenotype to FSP
• Association with pregnancy
○ Likely hormone related Cellular Angiofibroma
○ Polyps may be multiple • Occurs in both men and women
Treatment • Well-circumscribed mass rather than polyp
• Grenz zone in superficial lesions
• Simple excision
• Uniformly cellular spindle cells in myxocollagenous stroma
Prognosis • Medium-sized vessels with hyalinized vessels common
• Benign • CD34(+), ER/PR(+); usually desmin (-); loss of Rb protein
• Recurrence is rare Botryoid-Type Embryonal Rhabdomyosarcoma
○ May be associated with subsequent pregnancies or
• Young patients, polypoid masses
presence of atypical features
• Cellular subepithelial layer ("cambium layer")
• Regression reported in some infants
• Cytologically malignant cells
MACROSCOPIC • Desmin (+), myogenin (+), MYOD1(+)

General Features Genital Rhabdomyoma

• Often polypoid • Similar clinical presentation to FSP
• Smooth or villiform surface • Contains variable number of rhabdomyoblasts

Size SELECTED REFERENCES

• Usually 1-3 cm 1. Madueke-Laveaux OS et al: Giant fibroepithelial stromal polyp of the vulva:
largest case reported. Ann Surg Innov Res. 7:8, 2013
MICROSCOPIC 2. Song JS et al: Cellular pseudosarcomatous fibroepithelial stromal polyp of
the vagina during pregnancy: a lesion that is overdiagnosed as a malignant
Histologic Features tumor. Korean J Pathol. 46(5):494-8, 2012
3. Wani Y et al: A vulvar fibroepithelial stromal polyp appearing in infancy. Am J
• Overlying squamous mucosa is often unremarkable or Dermatopathol. 31(5):465-7, 2009
reactive 4. Nucci MR et al: Vulvovaginal soft tissue tumours: update and review.
○ No grenz zone between lesion and overlying mucosa Histopathology. 36(2):97-108, 2000
5. Nucci MR et al: Cellular pseudosarcomatous fibroepithelial stromal polyps of
• Spindle to stellate cells the lower female genital tract: an underrecognized lesion often
○ Tapering cytoplasmic processes misdiagnosed as sarcoma. Am J Surg Pathol. 24(2):231-40, 2000
○ Multinucleation and nuclear enlargement common
– May have wreath-like appearance
575
 Angiomyofibroblastoma

KEY FACTS
Genital Stromal Tumors

TERMINOLOGY • Plump epithelioid, ovoid, or plasmacytoid tumor cells with

• Benign genital stromal tumor composed of fibroblasts eosinophilic cytoplasm
oriented around prominent capillary vasculature ○ Cells characteristically cluster around thin-walled
capillaries
CLINICAL ISSUES • In postmenopausal patients, cells are more spindled and
• Occurs in women between 35-60 years (median: 46) overall cellularity is low
• Vulva and vagina most common sites • Mature adipose tissue component in minority of cases
• Slow-growing, painless mass • Some cases show morphologic overlap with cellular
• Treatment: Simple local excision angiofibroma
• Benign ANCILLARY TESTS
MACROSCOPIC • Desmin (+), ER(+), PR(+)
• Superficial, well-circumscribed, solid mass • Usually CD34(-) and SMA(-)
MICROSCOPIC TOP DIFFERENTIAL DIAGNOSES
• Nonencapsulated • Deep (aggressive) angiomyxoma
• Alternating zones of cellularity • Cellular angiofibroma
• Prominent vascular component • Fibroepithelial stromal polyp

Angiomyofibroblastoma Circumscription
(Left) Angiomyofibroblastoma
is a distinctive, benign
neoplasm of the lower female
genital tract. At low
magnification, the classic
morphologic pattern is that of
irregular zones of cellularity
within a myxoid or fibrous
stroma. (Right) Some areas of
angiomyofibroblastoma are
less myxoid and more fibrous,
as seen here. Note the sharp
circumscription ﬈, a feature
seen in most examples.

Alternating Zones of Cellularity Perivascular Organization

(Left) The neoplastic cells of
angiomyofibroblastoma are
characteristically clustered
around small thin-walled
capillary channels ﬈, which
can often be recognized by the
presence of intraluminal
erythrocytes. The intervening
myxoid stroma is hypocellular.
(Right) In classic cases of
angiomyofibroblastoma, the
tumor cells are epithelioid,
ovoid, or plasmacytoid and
form small nests or clusters
around capillary channels. This
perivascular orientation is
characteristic of this tumor.

576
 Angiomyofibroblastoma

Genital Stromal Tumors

• Some cases of AMFB show morphologic overlap with
TERMINOLOGY cellular angiofibroma
Abbreviations • Very rare reports describing malignant transformation
• Angiomyofibroblastoma (AMFB)
ANCILLARY TESTS
Definitions
• Benign genital stromal tumor composed of fibroblasts
Immunohistochemistry
oriented around prominent capillary vasculature • Desmin (+)
• Often ER(+) and PR(+)
CLINICAL ISSUES • Usually CD34(-) and SMA(-)
• Negative for keratin and S100 protein
Epidemiology
• Retained nuclear Rb1 expression
• Age
○ Generally 35-60 years (median: 46) DIFFERENTIAL DIAGNOSIS
• Sex
○ Affects women almost exclusively Deep (Aggressive) Angiomyxoma
• Often large and deeply located
Site • Infiltrative margins
• Vulva (most common) and vagina • Uniform cellularity (lacks perivascular orientation of AMFB)
• Rarely perineum or inguinal region • Contains medium- to large-sized vessels
Presentation ○ Overall less vascular than AMFB
• Slow-growing, painless mass • Lacks epithelioid cells
○ Often mistaken clinically for Bartholin cyst • Aberrations involving 12q13-15 (HMGA2)

Treatment Cellular Angiofibroma

• Simple local excision • Some cases may show considerable overlap with AMFB
○ May appropriately classify as "benign genital stromal
Prognosis tumor"
• Benign • More uniformly cellular
• Very rare recurrences reported ○ May show formation of short fascicles
• Contains medium-sized vessels, often with hyalinization
MACROSCOPIC ○ Overall less vascular than AMFB
General Features • Lacks epithelioid cells with perivascular orientation
• Often CD34(+); most cases desmin negative
• Well-circumscribed solid mass
• Loss of RB1 (13q14)
• Tan-white coloration
• Rubbery or mucoid cut surface Fibroepithelial Stromal Polyp
Size • Young to middle-aged women
• Typically very superficial and polypoid
• Usually < 5 cm
○ Overlying squamous epithelium
○ No grenz zone
MICROSCOPIC
• Stellate and multinucleate cells are characteristic
Histologic Features ○ Often located beneath epithelial surface at epithelial-
• Nonencapsulated stromal interface
• Alternating zones of cellularity • Some cases are associated with pregnancy
○ Hypocellular zones often myxoid or edematous ○ May contain bizarre nuclear atypia and mitoses
• Prominent vascular component (pseudosarcomatous stromal polyp)
○ Numerous thin-walled capillaries • Desmin (+), ER(+), PR(+)
• Plump epithelioid, ovoid, or plasmacytoid tumor cells with
eosinophilic cytoplasm SELECTED REFERENCES
○ Singly, in cords, or small nests 1. Schoolmeester JK et al: Genital soft tissue tumors. J Cutan Pathol. 42(7):441-
○ Cells characteristically cluster around thin-walled 51, 2015
capillaries 2. Magro G et al: Vulvovaginal angiomyofibroblastomas: morphologic,
immunohistochemical, and fluorescence in situ hybridization analysis for
○ Cells may show multinucleation deletion of 13q14 region. Hum Pathol. 45(8):1647-55, 2014
• Mast cells common 3. Kairi-Vassilatou E et al: Angiomyofibroblastoma of the vulva: a
clinicopathological and immunohistochemical analysis of a rare benign
• In postmenopausal patients mesenchymal tumor. Eur J Gynaecol Oncol. 32(3):353-5, 2011
○ Often less cellular 4. Laskin WB et al: Angiomyofibroblastoma of the female genital tract: analysis
○ Cells are more spindled than epithelioid of 17 cases including a lipomatous variant. Hum Pathol. 28(9):1046-55, 1997
5. Fletcher CD et al: Angiomyofibroblastoma of the vulva. A benign neoplasm
○ Increased stromal collagen distinct from aggressive angiomyxoma. Am J Surg Pathol. 16(4):373-82,
• Mature adipose tissue component in minority of cases 1992

577
 Angiomyofibroblastoma
Genital Stromal Tumors

Epithelioid Cytomorphology Cording Growth

(Left) The tumor cell nuclei of
angiomyofibroblastoma are
cytologically bland and may
show small, inconspicuous
nucleoli. Multinucleated forms
are not uncommon. Mitoses
are rare. (Right) In addition to
small clusters and nests, the
tumor cells in
angiomyofibroblastoma may
show a linear, corded growth
pattern. This pattern may
mimic the growth of lobular
carcinoma of the breast or a
Sertoli cell tumor.

Mature Adipose Tissue Vasculature

(Left) A component of mature
adipose tissue is seen in a
minority (~ 10%) of cases of
angiomyofibroblastoma.
These tumors have been
referred to as "lipomatous
angiomyofibroblastoma"
when the fat is prominent.
(Right) Although the vast
majority of vessels in
angiomyofibroblastoma are
thin-walled capillaries, larger
thicker-walled vessels are
occasionally seen.

Vasculature Chronic Inflammatory Infiltrate

(Left) In rare cases of
angiomyofibroblastoma,
larger dilated vessels forming
an ectatic "staghorn" pattern
may be apparent. This finding
is generally nonspecific, but it
may raise the consideration of
a solitary fibrous tumor.
(Right) A mild chronic
inflammatory infiltrate may
be seen in
angiomyofibroblastoma and
tends to be accentuated
around the vessels. Mast cells
are also a common finding.

578
 Angiomyofibroblastoma
Postmenopausal Angiomyofibroblastoma
Subtle Perivascular Arrangement
Cellular Angiofibroma
Genital Stromal Tumors
Stromal Collagen
(Left) In postmenopausal
patients,
angiomyofibroblastoma often
shows a drop in cellularity as
well as a tendency for the
tumor cells to be more
spindled and less epithelioid.
Note, however, that the
perivascular orientation is still
maintained. (Right) Some
examples of postmenopausal
angiomyofibroblastoma are
markedly hypocellular and
may show prominent collagen
or hyalinization. Note the
numerous thin-walled
capillary channels ﬈.
Desmin Expression
(Left) This image of
angiomyofibroblastoma in a
postmenopausal patient
demonstrates a marked drop
in overall cellularity but also
shows how the tumor cells
(more spindled rather than
epithelioid) congregate
around the capillary channels.
(Right) The tumor cells of
angiomyofibroblastoma
usually show diffuse
expression of desmin. Estrogen
receptor and progesterone
receptor stains are often
positive as well. CD34 is
usually negative.
Deep (Aggressive) Angiomyxoma
(Left) In contrast to
angiomyofibroblastoma,
cellular angiofibroma is more
uniformly cellular. The vessels
are often of a larger caliber
and usually show at least focal
hyalinization. CD34 is also
typically expressed. (Right)
Deep angiomyxoma differs
from angiomyofibroblastoma
in that it is often larger, more
deeply located, and
demonstrates a prominent
component of medium- to
large-size thick-walled vessels.
The uniform hypocellularity
and myxoedematous stroma
are also characteristic.
579
 Cellular Angiofibroma

KEY FACTS
Genital Stromal Tumors

TERMINOLOGY • Prominent component of small- to medium-sized blood

• Synonym: Angiomyofibroblastoma-like tumor of male vessels, often with hyalinized walls
genital tract • May contain component of mature adipose tissue
• Benign, often moderately cellular genital stromal neoplasm • Rare examples with atypical or sarcomatous features
composed of spindled cells and often containing small- to ANCILLARY TESTS
medium-sized vessels with hyalinized walls
• Diffuse CD34(+) in majority of cases
CLINICAL ISSUES • Loss of nuclear Rb protein expression
• Middle-aged to older adults (median: 52 years) • STAT6(-)
• Occurs in both sexes • Usually desmin, smooth muscle actin, and S100 protein (-)
• Usually subcutaneous tissue of vulva/vagina (women) and • Molecular: Loss of 13q14 region (RB1)
inguinoscrotal region (men) TOP DIFFERENTIAL DIAGNOSES
○ Can also arise in anogenital region and pelvic soft tissues
in both sexes • Aggressive angiomyxoma
• Benign; recurrences rare • Angiomyofibroblastoma
• Mammary-type myofibroblastoma
MICROSCOPIC • Spindle cell lipoma
• Well-marginated and evenly cellular bland spindle cell • Solitary fibrous tumor
neoplasm

Cellular Angiofibroma Conspicuous Vasculature

(Left) Cellular angiofibroma is
a well-circumscribed ﬈
benign neoplasm of genital
stromal fibroblasts. Unlike
angiomyofibroblastoma and
aggressive angiomyxoma,
cellular angiofibroma is well
described in men. (Right)
Medium- to large-sized blood
vessels are often conspicuous
in cellular angiofibroma, and
many show some degree of
perivascular hyalinization ﬈.
Cellularity can vary widely
from field to field; however,
cells are usually evenly
distributed regardless of the
overall cellularity.

Hyalinized Vessels Even Cellular Distribution

(Left) Perivascular
hyalinization ﬈ or fibrosis is
seen at least focally in most
cases of cellular angiofibroma
and may affect both small and
larger vessels. In some cases,
the extent of change can be
striking. (Right) The cellularity
of cellular angiofibroma is
generally more evenly
distributed than is seen in
angiomyofibroblastoma, in
which cells tend to cluster
around capillary vascular
channels.

580
 Cellular Angiofibroma

Genital Stromal Tumors

○ Scattered cells with marked nuclear atypia or foci
TERMINOLOGY resembling various pleomorphic sarcomas or well-
Synonyms differentiated liposarcoma
• Angiomyofibroblastoma-like tumor of male genital tract
ANCILLARY TESTS
Definitions
Immunohistochemistry
• Benign, often moderately cellular genital stromal neoplasm
composed of spindled cells and often containing small • Diffuse CD34(+) in majority of cases, rare desmin (+)
vessels with hyalinized walls • ER(+), PR(+) in most cases in women (less common in men)
• Loss of nuclear Rb protein expression
CLINICAL ISSUES • Usually smooth muscle actin and S100 protein (-)
Epidemiology Molecular Genetics
• Age • Monoallelic or biallelic loss of 13q14 region (RB1)
○ Middle-aged to older adults (median: 52 years) ○ Identical aberration to that seen in spindle cell lipoma
• Sex and mammary-type myofibroblastoma
○ Occurs in both sexes
DIFFERENTIAL DIAGNOSIS
Site
• Women: Usually vulva or vagina
Deep (Aggressive) Angiomyxoma
• Men: Scrotal or inguinal region • Large, deeply located tumors
• Can also arise in anogenital region and pelvic soft tissues in • Infiltrative, paucicellular tumor with spindled to stellate
both sexes cells
• Rare cases reported in retroperitoneum • Prominent medium- to large-sized stromal blood vessels
• Desmin (+), CD34 variable
Presentation
• Well-circumscribed, painless mass
Angiomyofibroblastoma
• May simulate Bartholin cyst in women or hernia in men • Tumor cells are more epithelioid than spindled and cluster
around prominent capillary vascular channels
Prognosis • Alternating zones of cellularity and hypocellularity
• Benign • Desmin (+), variable CD34(+)
○ Rare examples with sarcomatous features have also
exhibited benign behavior
Mammary-Type Myofibroblastoma
• Recurrences rare • Can show morphologic and immunohistochemical overlap
with cellular angiofibroma
MACROSCOPIC ○ However, mammary-type myofibroblastoma is often
desmin (+)
General Features
• Well circumscribed ("shelled out") and lobulated
Spindle Cell Lipoma
• Dermal or subcutaneous • Can show morphologic and immunohistochemical overlap
• Firm to rubbery, gray-white cut surface with cellular angiofibroma
• Commonly arise in region of neck, shoulder, and upper back
Size
Solitary Fibrous Tumor
• Median: 2-3 cm in females
• Median: 6-7 cm in males • Usually prominent component of ectatic "staghorn" blood
vessels
MICROSCOPIC • Diffuse CD34(+), STAT6(+), retained Rb protein expression

Histologic Features SELECTED REFERENCES

• Well marginated and variably but evenly cellular
• Uniform spindle cells, often with bipolar processes
○ May be arranged randomly, in loose whorls, in palisades,
or in short fascicles
• Fibrous to myxoid stroma with wispy collagen
• Prominent component of small- to medium-sized blood
vessels
○ Hyalinized vessels common and characteristic
• Mitotic activity generally low
• Stromal lymphocytes are common
• May contain component of mature adipose tissue
• Rare examples with atypical or sarcomatous features
1. Mandato VD et al: Cellular angiofibroma in women: a review of the
literature. Diagn Pathol. 10:114, 2015
2. Chen BJ 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.
36(8):1119-28, 2012
3. Flucke U et al: Cellular angiofibroma: analysis of 25 cases emphasizing its
relationship to spindle cell lipoma and mammary-type myofibroblastoma.
Mod Pathol. 24(1):82-9, 2011
4. Chen E et al: Cellular angiofibroma with atypia or sarcomatous
transformation: clinicopathologic analysis of 13 cases. Am J Surg Pathol.
34(5):707-14, 2010
5. Iwasa Y et al: Cellular angiofibroma: clinicopathologic and
immunohistochemical analysis of 51 cases. Am J Surg Pathol. 28(11):1426-
35, 2004
6. Laskin WB et al: Angiomyofibroblastoma-like tumor of the male genital tract:
analysis of 11 cases with comparison to female angiomyofibroblastoma and
spindle cell lipoma. Am J Surg Pathol. 22(1):6-16, 1998

581
 Cellular Angiofibroma
Genital Stromal Tumors

Bland Spindle Cells Cytologic Features

(Left) The lesional cells of
cellular angiofibroma are
generally spindled with bipolar
processes and may show a
wavy, undulating morphology.
The background stroma is
often filled with fine collagen
fibers. (Right) The spindle cells
of cellular angiofibroma are
generally devoid of significant
nuclear atypia. Nonspecific
findings, such as small, pale
intranuclear pseudoinclusions
or nuclear grooving, may be
seen.

Moderate Cellularity Various Architectural Patterns

(Left) Cellular angiofibroma
often shows zones of
moderate cellularity, which
can vary from focal to
extensive. In these areas, there
is no significant nuclear
atypia, and mitotic figures are
generally inconspicuous.
(Right) Cellular areas of
cellular angiofibroma may
show a variety of architectural
patterns, including short
fascicles, loose
whorling/storiform growth, or
haphazard arrays.

Stromal Inflammation Mast Cells

(Left) A subtle to brisk chronic
inflammatory infiltrate is a
common finding in cellular
angiofibroma and is composed
of mostly lymphocytes. Mast
cells are also frequently
identified. (Right) As seen in
other genital stromal
neoplasms, scattered mast
cells ﬈ are commonly
identified in most cases of
cellular angiofibroma. In rare
cases, they may be numerous.

582
 Cellular Angiofibroma
Myxoedematous Stromal Change
Spindle Cell Lipoma-Like Morphology
DDx: Angiomyofibroblastoma
Genital Stromal Tumors
Mature Adipose Tissue
(Left) Stromal edema or
myxoid changes are seen in
some cases of cellular
angiofibroma and vary in
extent. Other typical features,
including hyalinized vessels
and a chronic inflammatory
infiltrate, are often present.
(Right) Mature adipose tissue
﬊ may be identified as a
component of cellular
angiofibroma in a minority of
cases (~ 10%) and is usually
found near the periphery of
the tumor.
Sarcomatous Features
(Left) Occasional cases of
cellular angiofibroma may
show cellular regions
containing mature adipose
tissue, a morphology
reminiscent of a spindle cell
lipoma. Interestingly, recent
evidence suggests that these
tumors are histogenetically
related. (Right) Rare cases of
otherwise conventional
cellular angiofibroma show
solitary or multiple nodules of
increased cellularity and
nuclear atypia, suggestive of
pleomorphic sarcoma ﬈. In
fact, in one study, several foci
resembled well-differentiated
or pleomorphic liposarcoma.
DDx: Deep (Aggressive) Angiomyxoma
(Left) In contrast to cellular
angiofibroma,
angiomyofibroblastoma
demonstrates more of an
alternating pattern of
cellularity with the epithelioid
to spindled tumor cells
predominantly clustering
around capillary vascular
channels. (Right) In contrast to
cellular angiofibroma, deep
angiomyxoma is usually evenly
hypocellular and shows
prominent blood vessels that
are, on average, larger in
caliber. The clinical features of
these 2 tumors are also very
different.
583
 Deep (Aggressive) Angiomyxoma

KEY FACTS
Genital Stromal Tumors

TERMINOLOGY • Prominent myxoedematous stroma rich in collagen fibers

• Hypocellular locally aggressive myxoedematous neoplasm • Numerous blood vessels with sizes ranging from capillaries
with prominent vessels, typically of deep pelvic tissues to thick-walled larger vessels
• Stromal mast cells and extravasated erythrocytes are
CLINICAL ISSUES common
• Vast majority occur in women
ANCILLARY TESTS
• Sites: Vulva, perineum, pelvic cavity
• Deep, slow-growing mass • Immunophenotype: Desmin (+), ER(+), PR(+)
• Treatment: Surgical excision &/or adjuvant hormone ○ Variable SMA; CD34(-)
therapy • Molecular: Various rearrangements involving HMGA2
• Benign, but local recurrences common (12q13-15)

MACROSCOPIC TOP DIFFERENTIAL DIAGNOSES

• Usually large (> 10 cm) • Angiomyofibroblastoma
• Cellular angiofibroma
MICROSCOPIC • Superficial angiomyxoma
• Overall low cellularity • Desmoid fibromatosis
• Infiltrative growth pattern • Leiomyoma
• Small spindled to stellate cells

Deep Angiomyxoma Medium to Large Vessels

(Left) Deep angiomyxoma is a
locally aggressive genital
stromal neoplasm that occurs
predominantly in women in
the perineopelvic region. This
tumor is typically large and
deeply located, and it is
characterized by a
myxoedematous stroma with
prominent blood vessels.
(Right) A characteristic finding
is the presence of prominent
medium- to large-sized blood
vessels within the stroma. In
some cases, these vessels may
also have mature smooth
muscle cells radiating away
from the vessel wall (not
shown).

Cytologic Features Desmin Expression

(Left) Deep angiomyxoma is
generally a hypocellular tumor
and is composed of small
spindled or stellate cells
without significant atypia or
mitotic activity. Some cases
feature areas with a mild to
moderate increase in
cellularity. (Right) Desmin is
often expressed by the lesional
cells in deep angiomyxoma.
Smooth muscle actin (SMA) is
negative; however, it will
highlight any mature smooth
muscle cells within the lesion.

584
 Deep (Aggressive) Angiomyxoma

Genital Stromal Tumors

• Stromal mast cells and extravasated erythrocytes are
TERMINOLOGY common
Definitions
• Hypocellular locally aggressive myxoedematous neoplasm ANCILLARY TESTS
with prominent vessels, typically of deep pelvic tissues Immunohistochemistry
• Desmin (+), ER(+), PR(+)
CLINICAL ISSUES
• Variable SMA; CD34(-)
Epidemiology • Keratin (-) , S100 protein (-), myogenin (-)
• Age
Genetic Testing
○ Wide range (most common: 20-50 years)
• Various rearrangements involving HMGA2 (12q13-15)
• Sex
○ t(8;12) and t(11;12) have been reported
○ Vast majority occur in women
Site DIFFERENTIAL DIAGNOSIS
• Vulva, perineum, pelvic cavity Angiomyofibroblastoma
○ May simulate Bartholin cyst or inguinal hernia clinically
• Well marginated, small, and superficial
○ Often infiltrates perirectal or perivaginal soft tissues
• Zones of cellularity and hypocellularity
• Inguinopelvic or scrotal region in men (very rare)
• Plump epithelioid to spindled cells with enhanced cellularity
Presentation around prominent capillary vasculature
• Deep, slow-growing mass Cellular Angiofibroma
Treatment • Well marginated, superficial
• Surgical excision • May be seen in both men and women
○ May be impossible to completely resect due to • Evenly dispersed small- to medium-sized vessels
infiltrative nature of tumor ○ Perivascular hyalinization may be seen
• Also, may utilize adjuvant hormone therapy, including • CD34(+), ER(+), PR(+), desmin (-)
gonadotrophin-releasing hormone agonists and Superficial Angiomyxoma
antiestrogens
• Less common in genital sites
Prognosis • Usually small and superficial
• Benign • Arborizing thin-walled vasculature
• Recurrences common (30-40%) • Stromal neutrophils common
○ Aggressive, complete surgical resection may be
Desmoid Fibromatosis
associated with lower risk
• May show prominent myxoid change
MACROSCOPIC ○ Usually contains zones of more conventional fascicular
architecture
General Features • Nuclear β-catenin expression in majority of cases
• Variable circumscription • Desmin (-), ER(-), PR(-)
• Lobulated or polypoid mass
Leiomyoma
• Rubbery, myxoid, or gelatinous cut surface
• May show prominent myxoid stromal change
Size • Smooth muscle cytology
• Usually large (> 10 cm) • Diffuse smooth muscle actin (+) and desmin (+)

MICROSCOPIC SELECTED REFERENCES

Histologic Features
• Overall low cellularity
○ May show foci of increased cellularity, particularly in
recurrent lesions
• Infiltrative growth pattern
○ May contain adipose tissue &/or small nerve twigs
• Small spindled to stellate cells
○ No significant nuclear atypia or mitotic activity
• Prominent myxoedematous stroma rich in collagen fibers
• Numerous blood vessels with sizes ranging from capillaries
to thick-walled larger vessels
○ Some vessels may show perivascular smooth muscle
proliferation
1. Chen H et al: Clinicopathological features and differential diagnosis of
aggressive angiomyxoma of the female pelvis: 5 case reports and literature
review. Medicine (Baltimore). 96(20):e6820, 2017
2. Smith HG et al: Selective marginal resections in the management of
aggressive angiomyxomas. J Surg Oncol. 114(7):828-832, 2016
3. Sutton BJ et al: Aggressive angiomyxoma. Arch Pathol Lab Med. 136(2):217-
21, 2012
4. Bigby SM et al: Aggressive angiomyxoma [corrected] of the female genital
tract and pelvis--clinicopathologic features with immunohistochemical
analysis. Int J Gynecol Pathol. 30(5):505-13, 2011
5. McCluggage WG et al: HMGA2 is a sensitive but not specific
immunohistochemical marker of vulvovaginal aggressive angiomyxoma. Am
J Surg Pathol. 34(7):1037-42, 2010
6. McCluggage WG et al: Aggressive angiomyxoma of the vulva: dramatic
response to gonadotropin-releasing hormone agonist therapy. Gynecol
Oncol. 100(3):623-5, 2006

585
 Deep (Aggressive) Angiomyxoma
Genital Stromal Tumors

Low to Mild Cellularity Fat Infiltration

(Left) Deep angiomyxoma is
typically a diffusely
hypocellular neoplasm;
however, a mild increase in
cellularity is not uncommon.
On average, recurrent tumors
tend to be more cellular.
(Right) Given its infiltrative
nature, deep angiomyxoma
can show involvement of
regional mature adipose
tissue. In some areas, the fat
may be so prominent as to
mimic the pattern of myxoid
dermatofibrosarcoma
protuberans.

Entrapment of Nerves Extravasated Red Blood Cells

(Left) Deep angiomyxoma is a
locally infiltrative tumor,
which is often evidenced by
the presence of intratumoral
adipose tissue or nerve twigs
﬈. Clinically, this tumor often
shows involvement of the
perivaginal or perirectal soft
tissues. (Right) Given the
vascularity of deep
angiomyxoma, extravasated
red blood cells ﬈ are a
frequent finding, similar to
nodular fasciitis. Focal
hemosiderin-laden
macrophages ﬉ may be
identified as well.

Smooth Muscle Proliferation Mast Cells

(Left) A common finding in
deep angiomyxoma is the
presence of smooth muscle
cells ﬉ proliferating around
and near stromal blood
vessels. These cells can be
highlighted by smooth muscle
actin (SMA) as well as desmin.
(Right) Mast cells ﬈ are
frequently identified in deep
angiomyxoma and are not
specific for the lesion.
Scattered lymphocytes can be
seen as well.

586
 Deep (Aggressive) Angiomyxoma
Estrogen Receptor (ER) Expression
CD34 Negativity
Perivascular Smooth Muscle
Genital Stromal Tumors
S100 Protein Negativity
(Left) Estrogen receptor (ER) is
often expressed in the nuclei
of lesional cells in deep
angiomyxoma. Progesterone
receptor (PR) is also positive in
most cases. (Right) Although
some areas of deep
angiomyxoma can resemble a
peripheral nerve sheath
tumor, such as neurofibroma,
the lesional cells are negative
for S100. Note the entrapped
nerve twig ﬉ serving as an
internal positive control for
this marker.
Hypocellularity
(Left) CD34 highlights the
prominent vascular
component of deep
angiomyxoma; however, the
lesional spindle cells are often
negative (or, at most, focally
positive). (Right) Some regions
of deep angiomyxoma can
show marked hypocellularity,
resembling a cutaneous or
intramuscular myxoma.
However, deep angiomyxoma
is localized to the genital
region.
Focal Nuclear Atypia
(Left) This image of deep
angiomyxoma shows smooth
muscle cells spinning off of a
blood vessel that they encircle.
This particular case also shows
mildly atypical nuclei but is
devoid of mitoses. (Right)
Focal nuclear atypia, in the
form of hyperchromasia or
multinucleation, may be
identified in deep
angiomyxoma but is generally
very rare. This image was
taken from a recurrent tumor
in the perineum.
587
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 SECTION 14

Tumors of Mesothelial Cells

Benign
Adenomatoid Tumor 590
Multicystic Peritoneal Mesothelioma 592
Well-Differentiated Papillary Mesothelioma 594

Malignant
Malignant Mesothelioma 598
 Adenomatoid Tumor

KEY FACTS
Tumors of Mesothelial Cells

TERMINOLOGY • Several architectural patterns in varying concentrations and

• Benign, localized proliferation of mesothelial cells distributions
○ Tubular, gland-like, cords, nests
CLINICAL ISSUES • Epithelioid or flattened, cytologically bland mesothelial cells
• Young to middle-aged adults • Fibrous stroma
• Occurs in both males and females
ANCILLARY TESTS
○ Epididymis, spermatic cord, uterus, fallopian tube,
adrenal gland, others • Keratin (+), EMA(+)
• Painless, firm mass • Calretinin (+), CK5/6(+), WT1(+), D2-40(+)
• Treatment: Simple surgical excision TOP DIFFERENTIAL DIAGNOSES
• Benign • Metastatic adenocarcinoma
MACROSCOPIC • Well-differentiated papillary mesothelioma
• Usually < 2 cm • Multicystic peritoneal mesothelioma
• Malignant mesothelioma
MICROSCOPIC • Lymphangioma
• Well circumscribed but may show peripheral, infiltrative
growth

Adenomatoid Tumor Cytoplasmic "Bridging"

(Left) Adenomatoid tumor is a
benign proliferation of
mesothelial cells that is often
discovered incidentally. It is
characterized by a variety of
structural patterns, including
tubular, pseudoglandular,
angiomatoid, cord, and nest
formation. Lymphoid
aggregates ﬈ may be present
in some cases. (Right)
Cytoplasmic "bridging" ﬊, or
the presence of very thin
cytoplasmic extensions
between cells, is a unique and
fairly consistent finding in an
adenomatoid tumor.

Cytoplasmic Vacuolization Smooth Muscle Bundles

(Left) Cytoplasmic
vacuolization ﬈ is a common
cytologic feature of an
adenomatoid tumor. (Right) In
some cases of adenomatoid
tumor, bundles of mature
smooth muscle can be
identified between the tubular
structures, as depicted in this
image. Given that
adenomatoid tumors often
occur in tissues that contain
smooth muscle, these bundles
likely represent normal
nonlesional tissue.

590
 Adenomatoid Tumor

Tumors of Mesothelial Cells

○ Thin or thick cords
TERMINOLOGY
○ Angiomatoid growth
Definitions • Cytologically bland mesothelial cells
• Benign, localized proliferation of mesothelial cells ○ May be plump and epithelioid or small and flattened
○ May show vacuolated cytoplasm or have signet ring
CLINICAL ISSUES morphology
Epidemiology ○ Desquamated cells may be present within dilated spaces
• Fibrous stroma
• Incidence
○ May contain scattered lymphoid aggregates or subtle
○ Uncommon lymphoid infiltrate
• Age ○ Can contain smooth muscle bundles
○ Young to middle-aged adults • Rare infarction with necrosis, calcification, or cystic change
– Rare < 20 years • Mitoses rare
• Sex
○ Occurs in both males and females ANCILLARY TESTS
Site Immunohistochemistry
• In males • Keratin (+), EMA(+)
○ Epididymis, spermatic cord • Mesothelial: Calretinin (+), CK5/6(+), WT1(+), D2-40(+)
○ Testis (tunica albuginea, body of testis)
○ Prostate Genetic Testing
• In females • TRAF7 gene mutations
○ Uterus or fallopian tube
○ Occasionally in ovary DIFFERENTIAL DIAGNOSIS
• In either sex Metastatic Adenocarcinoma
○ Adrenal gland • Usually shows nuclear pleomorphism and mitotic activity
○ Mesentery, pancreas • History of prior carcinoma often present
○ Pleura, mediastinum • Absence of expression of mesothelial
○ Lymph node immunohistochemical markers
• Usually solitary; rarely multiple • Expression of specific epithelial markers (e.g., colon,
Presentation prostate)
• Painless, firm mass Well-Differentiated Papillary Mesothelioma
○ Scrotal tumors may cause hydrocele • Papillary architecture
• Often discovered incidentally • Can involve peritoneum and omentum
Treatment Multicystic Peritoneal Mesothelioma
• Simple surgical excision • Usually involves peritoneal surface
Prognosis • Larger cysts but histologic features can overlap with
adenomatoid tumor
• Benign
• Local recurrence rare Malignant Mesothelioma
• No reports of malignant transformation • Larger, more diffuse, or multiple lesions
• Infiltrates adjacent tissues
MACROSCOPIC • Nuclear atypia, mitoses, necrosis variably present
General Features Lymphangioma
• Well circumscribed • Spaces contain lymphatic fluid
• Smooth, firm, tan-yellow cut surface • D2-40(+), keratin (-)
• May rarely show cystic change
Size SELECTED REFERENCES
• Usually < 2 cm 1. Goode B et al: Adenomatoid tumors of the male and female genital tract are
defined by TRAF7 mutations that drive aberrant NF-kB pathway activation.
Mod Pathol. 31(4):660-673, 2018
MICROSCOPIC 2. Terada T: An immunohistochemical study of adenomatoid tumors of the
uterus and fallopian tube. Appl Immunohistochem Mol Morphol. 20(2):173-
Histologic Features 6, 2012
• Well circumscribed but may show peripheral, infiltrative 3. Wachter DL et al: Adenomatoid tumors of the female and male genital tract.
A comparative clinicopathologic and immunohistochemical analysis of 47
growth cases emphasizing their site-specific morphologic diversity. Virchows Arch.
• Several architectural patterns in varying concentrations and 458(5):593-602, 2011
distributions 4. Amin W et al: Adenomatoid tumor of testis. Clin Med Pathol. 2:17-22, 2009
5. Sangoi AR et al: Adenomatoid tumors of the female and male genital tracts:
○ Dilated gland-like tubules a clinicopathological and immunohistochemical study of 44 cases. Mod
○ Solid nests Pathol. 22(9):1228-35, 2009

591
 Multicystic Peritoneal Mesothelioma

KEY FACTS
Tumors of Mesothelial Cells

TERMINOLOGY MACROSCOPIC
• Definition: Benign multicystic proliferation originating from • Thin-walled, semitransparent cysts or multicystic mass(es)
peritoneal mesothelium ○ Conglomerate masses can be well over 5 cm
• Synonym: Multilocular peritoneal inclusion cyst
MICROSCOPIC
CLINICAL ISSUES • Cystic spaces lined by single layer of cuboidal or flattened
• Predominantly in 2nd-6th decades mesothelial cells
• More common in females ○ Cysts may contain pale eosinophilic granular fluid
• Mostly arise on visceral peritoneum • Loose fibrovascular stroma between cysts
○ Serosal surfaces of uterus, bladder, rectum
ANCILLARY TESTS
• Many patients have history of prior abdominal surgery,
endometriosis, or pelvic inflammatory disease • Mesothelial lining cells
• May present with vague abdominal pain ± other obstructive ○ Keratin (+), calretinin (+), EMA(+) in lining cells
symptoms ○ CD31(-), CD34(-)
• Treatment TOP DIFFERENTIAL DIAGNOSES
○ Complete surgical excision, if possible, or debulking • Cystic lymphangioma (lymphatic malformation)
• Benign; rare local recurrences • Malignant mesothelioma
• Adenomatoid tumor

Multicystic Peritoneal Mesothelioma Mesothelial Cell Lining

(Left) Multicystic peritoneal
mesothelioma (MPM)
generally displays a prominent
multicystic appearance at low
magnification and can show
significant morphologic
overlap with a lymphatic
malformation. (Right) Unlike
the typically flat endothelial
cells that line lymphatic
channels, the lining cells of
MPM are mesothelial and are
often plump and epithelioid.
Hobnailing of cells into the
cystic spaces is common, and
occasionally, focal tufting may
be seen.

Intracystic Fluid Cytokeratin Expression

(Left) Some of the cystic
spaces in MPM may contain
pale granular eosinophilic fluid
with occasional inflammatory
cells, similar to lymph seen in
cystic lymphangioma
(lymphatic malformation).
(Right) Given the mesothelial
origin of the lining cells,
diffuse expression of CK5/6
(shown) and calretinin is
typical in MPM. Endothelial
and lymphatic markers, such
as CD31, are negative.

592
 Multicystic Peritoneal Mesothelioma

Tumors of Mesothelial Cells

TERMINOLOGY MICROSCOPIC
Abbreviations Histologic Features
• Multicystic peritoneal mesothelioma (MPM) • Cystic spaces lined by single layer of cuboidal or flattened
mesothelial cells
Synonyms
○ Variable size and number of cysts
• Benign MPM (BMPM) – Often contain pale eosinophilic, granular
• Benign cystic mesothelioma proteinaceous fluid
• Multilocular peritoneal inclusion cyst ○ Uniform, but variably orientated nuclei without cytologic
Definitions atypia
– May show bi- or multinucleation
• Benign multicystic proliferation originating from peritoneal
mesothelium ○ Hobnailing, tufting, or small papillations sometimes
present
CLINICAL ISSUES • Loose fibrovascular stroma between cysts
○ May contain lymphocytes &/or occasional lymphoid
Epidemiology aggregates
• Incidence ○ Occasionally contains small mesothelial cell clusters,
○ Rare resembling invasive carcinoma
• Age • Rare focal calcifications or hyaline globules
○ Predominantly in 2nd-6th decades • Occasionally, cases show areas reminiscent of adenomatoid
• Sex tumor
○ More common in females
ANCILLARY TESTS
Site
• Mostly on visceral peritoneum, including surfaces of pelvic
Immunohistochemistry
organs • Keratin (+), calretinin (+), EMA(+) in lining cells
○ Uterus, bladder, rectum • D2-40 (variable)
○ Rarely involves other viscera, mesentery, omentum • CD31(-), CD34(-)
• Can form detached intraperitoneal mass
• Extraperitoneal sites very rare DIFFERENTIAL DIAGNOSIS
○ Pericardium, pleura, cesarean section scar Cystic Lymphangioma (Lymphatic Malformation)
Presentation • Most common in male children
• Many patients have history of prior abdominal surgery, • Stromal lymphoid aggregates more common
endometriosis, or pelvic inflammatory disease • Smooth muscle may be present around cystic spaces
• Vague abdominal pain ± other obstructive symptoms • Lining cells are CD31(+), CD34(+), D2-40(+) and keratin (-)
• May be incidental finding Malignant Mesothelioma
Treatment • Usually solid or papillary growth, rarely cystic
• Complete surgical excision, if possible, or debulking • Presence of cytologic atypia and mitotic activity
• Also in situ ablation with sclerosing agents or laser therapy • Stromal invasion
• Intraperitoneal chemotherapy has been utilized for Adenomatoid Tumor
intractable cases
• Well circumscribed, often small
Prognosis • Pattern of dilated tubules within fibrous stroma
• Benign • Cuboidal or flattened mesothelial cell lining
• May recur, or spread, especially if incompletely excised • Generally lacks large cystic spaces of BMPM
• Very rare reported cases have been associated with diffuse
epithelioid malignant mesothelioma SELECTED REFERENCES
1. Rapisarda AMC et al: Benign multicystic mesothelioma and peritoneal
MACROSCOPIC inclusion cysts: are they the same clinical and histopathological entities? A
systematic review to find an evidence-based management. Arch Gynecol
General Features Obstet. ePub, 2018
2. Momeni M et al: Multicystic benign cystic mesothelioma presenting as a
• Thin-walled, semitransparent cysts or multicystic mass(es) pelvic mass. Case Rep Obstet Gynecol. 2014:852583, 2014
○ Cysts often numerous 3. Elbouhaddouti H et al: Benign cystic mesothelioma of the peritoneum: a
– Contain clear or hemorrhagic fluid case report and literature review. World J Emerg Surg. 8(1):43, 2013
4. Wang TB et al: Diagnosis and treatment of benign multicystic peritoneal
Size mesothelioma. World J Gastroenterol. 19(39):6689-92, 2013
5. Psoinos CM et al: Multicystic peritoneal mesothelioma in an octogenarian:
• Conglomerate masses can be well over 5 cm diagnosis, natural history, and treatment. Int J Surg Pathol. 20(1):92-6, 2012
○ Individual cysts range from 1 mm to > 1 cm

593
 Well-Differentiated Papillary Mesothelioma

KEY FACTS
Tumors of Mesothelial Cells

TERMINOLOGY MICROSCOPIC
• Well-differentiated papillary mesothelioma (WDPM) • Well-formed papillary structures
• Synonym: Benign mesothelioma ○ Occasional solid nests, tubules, cords
• Uniform cuboidal cells with central, rounded nuclei
CLINICAL ISSUES
• Loose fibrous cores
• Rare
○ Occasional multinucleated cells in stroma
• Incidental finding
• Very low mitotic rate
• Peritoneal lesions mostly in women
• Invasive foci in some cases
• Pleural lesions show no sex predilection
• Can arise in paratesticular location (tunica vaginalis) ANCILLARY TESTS
• Solitary or multiple • Positive: Calretinin, CK5/6, WT1, D2-40, pax-8
○ Solitary lesions generally benign • Negative: MOC31, BerEP4, desmin, BAP1
• Some rarely recur after long period as malignant
TOP DIFFERENTIAL DIAGNOSES
mesothelioma
• Tumors with invasive foci more likely to recur • Malignant mesothelioma
• Mesothelial hyperplasia
MACROSCOPIC • Implants of serous borderline tumor
• Multiple papillary nodules studding surface of omentum, • Serous carcinoma
peritoneum, etc.

Well-Differentiated Papillary
Mesothelioma Papillary Architecture
(Left) Well-differentiated
papillary mesothelioma
(WDPM) consists of exophytic
papillary fronds that arise
from mesothelial surfaces as
depicted in this scanning-
power micrograph. It can be
solitary or multifocal and is
usually discovered incidentally
during surgical operations,
most often on the peritoneum
in women. (Right) WDPM is
composed of well-formed,
branching papillary structures
or blunt processes arising from
the peritoneal, pleural, or
paratesticular mesothelium.

Fibromyxoid Stroma Cytologic Features

(Left) Stromal core of WDPM
is characterized by loose
fibrous or fibromyxoid stroma
﬈ with bland fibroblasts and
a few blood vessels. Note the
uniform papillary structures
with simple lining ﬊. (Right)
Papillary cores are lined by a
single layer of uniform
cuboidal cells with eosinophilic
cytoplasm, round nuclei with
bland cytologic features ﬈,
and very low mitotic activity.

594
 Well-Differentiated Papillary Mesothelioma

Tumors of Mesothelial Cells

• Loose fibrous cores
TERMINOLOGY
○ May be myxoid
Abbreviations ○ Occasional multinucleated giant cells
• Well-differentiated papillary mesothelioma (WDPM) • Invasive foci
○ Simple, bland-appearing glands invading papillary stalks
Synonyms
○ Solid foci of higher cytologic grade
• Benign mesothelioma • Rare tumors with mixed adenomatoid tumor, cystic
• Mesothelioma of low malignant potential mesothelioma, or malignant mesothelioma

ETIOLOGY/PATHOGENESIS ANCILLARY TESTS

Neoplasm Immunohistochemistry
• Single familial case with germline BAP1 mutation • Positive: Calretinin, CK5/6, WT1, D2-40, pax-8
Environmental Exposure • Negative: MOC-31, BerEP4, desmin, BAP1 (intact)
• Some patients have history of asbestos exposure
○ Mostly with pleural tumors DIFFERENTIAL DIAGNOSIS
Malignant Mesothelioma
CLINICAL ISSUES • Multilayering
Epidemiology • Nuclear atypia, prominent nucleoli, mitoses, necrosis
• Incidence • Stromal invasion
○ Rare Mesothelial Hyperplasia
• Age • Can have papillary architecture mimicking WDPM
○ Predominantly 30-50 years • Scant amount of fibroconnective tissue in their cores
• Sex • Reactive/inflammatory changes in adjacent serosa
○ Peritoneal lesions arise mostly in women
– Reproductive age Implants of Serous Borderline Tumor
○ Pleural lesions show no sex predilection • Complex hierarchical branching papillae
• Micropapillary tufting
Site
• Cytologically bland
• Peritoneum, omentum, pleura, pericardium • Psammoma bodies
• Paratesticular (tunica vaginalis)
Metastatic or Primary Peritoneal Serous Carcinoma
Presentation
• Cytologically malignant
• Incidental finding • Psammoma bodies
○ Rarely symptomatic • Positive: pax-8, ER, WT1, MOC-31
Treatment • Negative: Calretinin
• Surgical excision of localized lesion
• Chemotherapy for multiple or widespread lesions SELECTED REFERENCES
1. Lee HE et al: BAP1 loss is unusual in well-differentiated papillary
Prognosis mesothelioma and may predict development of malignant mesothelioma.
Hum Pathol. 79:168-76, 2018
• Vast majority discovered incidentally; solitary and have
2. Sun M et al: Well-differentiated papillary mesothelioma: a 17-year single
excellent prognosis institution experience with a series of 75 cases. Ann Diagn Pathol. 38:43-50,
• Multiple or widespread lesions can be progressive 2018
• Some recur after long period as frank malignant 3. Churg A et al: Well-differentiated papillary mesothelioma with invasive foci.
Am J Surg Pathol. 38(7):990-8, 2014
mesothelioma 4. Chen X et al: Well-differentiated papillary mesothelioma: a
• Tumors with invasive foci more likely to recur clinicopathological and immunohistochemical study of 18 cases with
additional observation. Histopathology. 62(5):805-13, 2013
5. Ribeiro C et al: Well-differentiated papillary mesothelioma: clustering in a
MACROSCOPIC Portuguese family with a germline BAP1 mutation. Ann Oncol. 24(8):2147-
50, 2013
General Features
6. Malpica A et al: Well-differentiated papillary mesothelioma of the female
• Multiple papillary nodules studding surface of omentum, peritoneum: a clinicopathologic study of 26 cases. Am J Surg Pathol.
peritoneum, etc. 36(1):117-27, 2012
7. Tolhurst SR et al: Well-differentiated papillary mesothelioma occurring in the
tunica vaginalis of the testis with contralateral atypical mesothelial
MICROSCOPIC hyperplasia. Urol Oncol. 24(1):36-9, 2006
8. Hoekstra AV et al: Well-differentiated papillary mesothelioma of the
Histologic Features peritoneum: a pathological analysis and review of the literature. Gynecol
• Well-formed papillary structures Oncol. 98(1):161-7, 2005
9. Butnor KJ et al: Well-differentiated papillary mesothelioma. Am J Surg
○ Lined by single layer of uniform cuboidal cells Pathol. 25(10):1304-9, 2001
– Central, rounded, benign nuclei 10. Perez-Ordonez B et al: Mesothelial lesions of the paratesticular region.
○ Occasional solid nests, tubules, cords Semin Diagn Pathol. 17(4):294-306, 2000
11. Xiao SY et al: Benign papillary mesothelioma of the tunica vaginalis testis.
○ Compressive crowding can mimic invasion Arch Pathol Lab Med. 124(1):143-7, 2000

595
 Well-Differentiated Papillary Mesothelioma
Tumors of Mesothelial Cells

Papillary Architecture Cytologic Features

(Left) WDPM is composed of
uniform papillary structures
with fibrous cores lined by a
simple layer of cytologically
benign mesothelial cells.
(Right) High-power
micrograph depicts a papilla
covered by a single layer of
uniform cuboidal mesothelial
cells with rounded, central
nuclei and eosinophilic
cytoplasm ﬈. Note collagen
fibers in the papillary core ﬊.

Papillary Architecture Elongated Papillae

(Left) Medium-power
micrograph shows the simple
papillary architecture of
WDPM consisting of a broad,
central fibrovascular core ﬈
and smaller branches ﬉ lined
by a single layer of cells ﬊.
(Right) Although the papillary
structures are usually short
and blunt ended, occasionally
they can be villiform and
pointed ﬈, as illustrated.

Myxoid Papillary Stroma Calretinin

(Left) Stroma in WDPM
frequently contains an
abundant myxoid matrix ﬈,
rich in proteoglycan, that
acquires a pale blue color on
hematoxylin and eosin. (Right)
Diffuse, strong, nuclear, and
cytoplasmic calretinin
expression is present in the
lining cells of WDPM ﬈,
supportive of mesothelial
origin.

596
 Well-Differentiated Papillary Mesothelioma

Tumors of Mesothelial Cells

Gross Specimen Reactive Fibroblastic Stroma
(Left) Gross appearance of
WDPM involving the omentum
depicts multiple papillary
nodules studding the surface.
(Right) In this example, the
stroma is expanded by a
reactive proliferation of
spindle-shaped fibroblasts
arranged in fascicles ﬈
resembling that of nodular
fasciitis.

Compressive Crowding Giant Cells

(Left) Compressive crowding in
WDPM represents an artifact
of surgical biopsy/excision in
which the papillae are
squeezed together and can
mimic invasive infiltration.
Note the intact papilla with
fibromyxoid stroma ﬈. (Right)
Multinucleated cells are
sometimes present within the
papillary stroma and base of
the lesion. Note both
collagenous ﬈ and more
myxoid ﬉ areas.

Multiple Invasive Foci Invasive Foci

(Left) Invasive foci are rarely
found in WDPM. When
present, they consist of simple,
bland-appearing glands within
the papillary stalks that are
often multifocal, as indicated
﬈. (Courtesy H. Tazelaar,
MD.) (Right) Invasive foci
usually consist of benign-
appearing glands ﬈.
However, rare examples with
higher cytologic grade have
been reported. Invasive foci,
when present, are associated
with greater risk for recurrent
disease and rarely
transformation to life-
threatening disease. (Courtesy
H. Tazelaar, MD.)

597
 Malignant Mesothelioma

KEY FACTS
Tumors of Mesothelial Cells

TERMINOLOGY ○ Sheet-like, tubular, papillary, glandular, adenomatoid, or

• Aggressive, malignant tumor of mesothelial cells arising in mixed patterns
pleura, peritoneum, or pericardium • Sarcomatoid type: Variably pleomorphic spindled cells in
sheets and fascicles
ETIOLOGY/PATHOGENESIS ○ May contain heterologous elements
• Asbestos exposure closely linked to development • Desmoplastic sarcomatoid type: Prominent stromal fibrosis,
hyalinization, sclerosis
CLINICAL ISSUES
• Biphasic type: Mixed epithelioid and sarcomatoid
• Most cases occur > 50 years of age
• M>F ANCILLARY TESTS
• Treatment: Multimodal therapy more effective than • Variable mesothelial immunophenotype
surgery alone ○ Use of multistain panel recommended
• Overall poor prognosis and high mortality
TOP DIFFERENTIAL DIAGNOSES
MACROSCOPIC • Reactive mesothelial proliferations
• Multiple small nodules, growths, and plaques • Adenocarcinoma
MICROSCOPIC • Synovial sarcoma
• Solitary fibrous tumor
• Epithelioid cytomorphology most common
• Epithelioid hemangioendothelioma
○ Polygonal dyscohesive cells with eosinophilic cytoplasm

Malignant Mesothelioma Pattern Variety

(Left) Pleural malignant
mesothelioma (MM) is
generally characterized by
patchy or diffuse thickening of
the pleura ﬊. The tumor also
extends along fissures and
septa ﬈. (Right)
Mesothelioma can show a
variety of morphologic
patterns, including
microglandular, tubular, and
papillary growth. A stromal
reaction may or may not be
present, depending upon the
site and extent of
involvement.

Papillary Growth Invasion

(Left) Papillary or
tubulopapillary growth is
common in MM and is often
prominent. Small,
micropapillary-like clusters
may also be seen ﬈ and can
sometimes resemble rosette-
like structures. (Right) Invasion
of normal soft tissues or
structures is typical of MM and
is often the best clue to the
diagnosis in small biopsies of
subtle, well-differentiated
tumors. Cytologically, even
malignant cells can appear
bland.

598
 Malignant Mesothelioma

Tumors of Mesothelial Cells

○ Metastases to lung, lymph nodes, liver, other organs
TERMINOLOGY
• Histologic features associated with poorer prognosis
Abbreviations ○ Nonepithelioid morphology
• Malignant mesothelioma (MM) ○ Marked nuclear pleomorphism
○ Loss of p16 by FISH
Synonyms
• Desmoplastic variant of sarcomatoid MM is most aggressive
• Diffuse mesothelioma • Nuclear grading (degree of nuclear atypia and mitotic
Definitions activity) has been shown to predict overall survival in
• Aggressive, malignant tumor of mesothelial cells arising in epithelioid MM
pleura, peritoneum, or pericardium
IMAGING
ETIOLOGY/PATHOGENESIS General Features
Environmental Exposure • Pleural effusion
• Asbestos • Diffuse pleural thickening extending into fissures
○ Closely linked to development of mesothelioma • Peritoneal thickening
○ Occupational exposure • Mass lesion
– Mining, construction, vehicle maintenance,
shipbuilding MACROSCOPIC
– Risk relates to intensity and duration of exposure General Features
○ Amphibole fiber types most carcinogenic • Multiple small nodules, growths, and plaques
– Persist in lung ± tissue reaction ○ Rare cases solitary
– Crocidolite and amosite have highest risk • May encase lung or abdominal organs
– Longer, thinner fibers more oncogenic • Firm, white tissue
○ Latent period: 15-40 years
• Occasionally, other fiber types implicated (e.g., erionite) MICROSCOPIC
Infectious Agents Histologic Features
• SV40 DNA oncogenic virus • Usually diffuse, infiltrative
○ Viral sequences found in some mesotheliomas • Epithelioid cytomorphology most common
Radiation Exposure ○ Polygonal or cuboidal dyscohesive cells with eosinophilic
cytoplasm
• Therapy for other cancer (e.g., lymphoma, carcinoma)
– Mild nuclear pleomorphism; variable mitoses
• Contrast media (e.g., thorium dioxide)
○ Variety of morphologic patterns
– Solid, tubular, papillary, glandular,
CLINICAL ISSUES adenomatoid/microglandular, or mixed patterns
Epidemiology ○ Variable stromal collagen and inflammation
• Incidence – Occasional myxoid/mucoid change
○ Geographic variation ○ Psammoma bodies may be seen
– In USA, ~ 3,000 cases diagnosed per year ○ Asbestos bodies may be identified in adjacent lung tissue
– Higher rates reported in UK, Netherlands, and (pleural mesothelioma)
Australia ○ Rare variants: Clear cell, small cell, deciduoid, signet ring,
– Lower rates reported in Japan and Central Europe pleomorphic, micropapillary, lymphohistiocytoid,
• Age rhabdoid
○ Most > 50 years • Sarcomatoid MM
○ Occasional cases at any age ○ Variably pleomorphic spindled cells in sheets and
• Sex fascicles
○ M>F ○ Necrosis common
○ May contain heterologous osteosarcoma,
Presentation rhabdomyosarcoma, chondrosarcoma, or angiosarcoma
• Pleural: Dyspnea, chest pain, cough, weight loss ○ Desmoplastic variant
• Peritoneal: Abdominal pain, distension, vague mass – Prominent stromal fibrosis, hyalinization, sclerosis
– Storiform architecture common
Treatment
– Disorganized, nonuniform growth
• Multimodal therapy more effective than surgery alone
– Usually low cellularity
○ Surgery and chemotherapy ± radiotherapy
□ Can show deceptively bland foci
Prognosis • Some tumors may show mixed epithelioid and sarcomatoid
• Overall poor morphology (biphasic)
○ Median survival: 7 months
○ Mortality rate: 100%

599
 Malignant Mesothelioma
Tumors of Mesothelial Cells
ANCILLARY TESTS
Immunohistochemistry
• Diffuse pancytokeratin (+)
• Variable mesothelial immunophenotype
○ Panel of expected positive and negative markers
strongly recommended
– Usually positive: Calretinin, CK 5/6, D2-40, WT1,
glypican-1, GATA3, CK7, mesothelin, thrombomodulin
– Usually negative: BER-EP4, MOC31, B72.3, TTF-1,
CD34, pax-8
• Loss of nuclear BAP1 favors MM over reactive/atypical
mesothelial proliferation
○ Only occurs in ~ 50% of cases, however, and is even
much less common in sarcomatoid/desmoplastic MM
• Keratin expression may be only demonstrable marker in
sarcomatoid/desmoplastic mesothelioma
○ Use of multiple keratins (e.g., AE1/AE3, CAM 5.2, OSCAR)
recommended
○ Pitfall: Submesothelial fibroblasts often express keratin
Molecular Genetics
• BAP1 gene deletion in majority of cases showing loss of
BAP1 expression by IHC
• Deletion of p16 (CDKN2A) by FISH in up to 80% of cases of
pleural MM and 25% of peritoneal MM
○ Most commonly identified in sarcomatoid MM but also
majority of epithelioid and biphasic types
• Rare cases reported of EWSR1-ATF1, FUS-ATF1, and EWSR1-
YY1 fusions
DIFFERENTIAL DIAGNOSIS
Reactive Mesothelial Proliferations
• Absence of invasion, necrosis
• Usually lacks complicated architectural growth
• Does not form macroscopic lesion or mass
• Retained nuclear BAP1 expression (but also in 50% of MM)
Fibrous Pleurisy
• Can mimic desmoplastic mesothelioma
• Uniform growth of fibroblasts; storiform pattern absent
• No stromal invasion
• Pitfall: Can also show keratin (+)
Adenocarcinoma (Pulmonary)
• Usually positive: BER-EP4, MOC-31, TTF-1
• Usually negative: Calretinin, CK5/6, WT1, glypican-1
• Clinical history and imaging helpful
Adenocarcinoma (Serous Ovarian)
• pax-8(+), ER(+), BER-EP4(+), MOC31(+)
• Calretinin (-)
Synovial Sarcoma
• Highly cellular but monomorphic spindle cell neoplasm
• Can feature epithelial nests or glandular structures
• Spindled cells often keratin (+) but usually focal
• Calretinin (+) and TLE1(+) but also seen in MM
• Demonstration of t(X;18) or SS18 (SYT) rearrangement
most useful
600
Solitary Fibrous Tumor
• Patternless array of cellular and fibrous areas
• CD34(+), STAT6(+)
• Keratin (-), calretinin (-)
Epithelioid Hemangioendothelioma
• Cords or nests of cells in chondromyxoid stroma
○ Intracytoplasmic vacuoles ("blister cells")
• CD34(+), CD31(+)
Epithelioid Angiosarcoma
• Sheets of atypical cells with prominent nucleoli
• Hemorrhage and necrosis common
• CD34(+), CD31(+), ERG(+)
SELECTED REFERENCES
1. Amatya VJ et al: Glypican-1 immunohistochemistry is a novel marker to
differentiate epithelioid mesothelioma from lung adenocarcinoma. Mod
Pathol. 31(5):809-15, 2018
2. Brcic L et al: Reproducibility of malignant pleural mesothelioma
histopathologic subtyping. Arch Pathol Lab Med. 142(6):747-52, 2018
3. Hjerpe A et al: Cytopathologic diagnosis of epithelioid and mixed-type
malignant mesothelioma: ten years of clinical experience in relation to
international guidelines. Arch Pathol Lab Med. 142(8):893-901, 2018
4. Husain AN et al: Guidelines for pathologic diagnosis of malignant
mesothelioma 2017 update of the consensus statement from the
International Mesothelioma Interest Group. Arch Pathol Lab Med. 142(1):89-
108, 2018
5. Klebe S et al: Pleural malignant mesothelioma versus pleuropulmonary
synovial sarcoma: a clinicopathological study of 22 cases with molecular
analysis and survival data. Pathology. 50(6):629-34, 2018
6. Monaco S et al: Recent advances in the diagnosis of malignant
mesothelioma: focus on approach in challenging cases and in limited tissue
and cytologic samples. Adv Anat Pathol. 25(1):24-30, 2018
7. Pelosi G et al: Pathologic grading of malignant pleural mesothelioma: an
evidence-based proposal. J Thorac Oncol. 13(11):1750-61, 2018
8. Pillappa R et al: Loss of BAP1 Expression in Atypical Mesothelial
Proliferations Helps to Predict Malignant Mesothelioma. Am J Surg Pathol.
42(2):256-63, 2018
9. Rosen LE et al: Nuclear grade and necrosis predict prognosis in malignant
epithelioid pleural mesothelioma: a multi-institutional study. Mod Pathol.
31(4):598-606, 2018
10. Tandon RT et al: Immunohistochemistry in peritoneal mesothelioma: a
single-center experience of 244 cases. Arch Pathol Lab Med. 142(2):236-42,
2018
11. Vivero M et al: Clinicopathologic and genetic characteristics of young
patients with pleural diffuse malignant mesothelioma. Mod Pathol.
31(1):122-31, 2018
12. Berg KB et al: GATA3 immunohistochemistry for distinguishing sarcomatoid
and desmoplastic mesothelioma from sarcomatoid carcinoma of the lung.
Am J Surg Pathol. 41(9):1221-5, 2017
13. Desmeules P et al: A subset of malignant mesotheliomas in young adults are
associated with recurrent EWSR1/FUS-ATF1 fusions. Am J Surg Pathol.
41(7):980-8, 2017
14. Hwang HC et al: BAP1 immunohistochemistry and p16 fish in the diagnosis
of sarcomatous and desmoplastic mesotheliomas. Am J Surg Pathol.
40(5):714-8, 2016
15. Hwang HC et al: Utility of BAP1 immunohistochemistry and p16 (CDKN2A)
FISH in the diagnosis of malignant mesothelioma in effusion cytology
specimens. Am J Surg Pathol. 40(1):120-6, 2016
16. Cigognetti M et al: BAP1 (BRCA1-associated protein 1) is a highly specific
marker for differentiating mesothelioma from reactive mesothelial
proliferations. Mod Pathol. 28(8):1043-57, 2015
17. Pavlisko EN et al: Sarcomatoid Peritoneal mesothelioma: clinicopathologic
correlation of 13 cases. Am J Surg Pathol. 39(11):1568-75, 2015
18. Panagopoulos I et al: RNA sequencing identifies fusion of the EWSR1 and
YY1 genes in mesothelioma with t(14;22)(q32;q12). Genes Chromosomes
Cancer. 52(8):733-40, 2013
19. Betta PG et al: Immunohistochemistry and molecular diagnostics of pleural
malignant mesothelioma. Arch Pathol Lab Med. 136(3):253-61, 2012
20. Klebe S et al: Sarcomatoid mesothelioma: a clinical-pathologic correlation of
326 cases. Mod Pathol. 23(3):470-9, 2010
 Malignant Mesothelioma

Tumors of Mesothelial Cells

Invasion Malignant Mesothelioma
(Left) Clear-cut invasion of
subpleural or subperitoneal
soft tissues by atypical
mesothelial cells is essentially
diagnostic of malignancy. This
H&E shows infiltrating tubular
structures within the adipose
tissue of the chest wall.
(Right) H&E shows ill-defined,
invasive, glandular formations
﬈ in a paratesticular
mesothelioma. Note the
absence of a desmoplastic
stromal reaction in this field.

Glandular Pattern Solid and Papillary Growth

(Left) H&E of a peritoneal MM
shows an irregular,
infiltrating, gland-like
morphology in the muscularis
propria of the large bowel,
mimicking adenocarcinoma.
Note also the foci of tubular
﬈ morphology. (Right) H&E
shows MM with a mixture of
solid sheets of epithelioid cells
and papillae with fibrous cores
﬈. Note the small psammoma
body ﬊.

Solid and Papillary Growth Adenomatoid Pattern

(Left) The papillary structures
in this case of MM were filled
with solid sheets of neoplastic
mesothelial cells. (Right)
Another type of growth in MM
is a microcystic pattern with
areas of cytoplasmic
"bridging" ﬈. This pattern
resembles that of an
adenomatoid tumor. Clinically,
the presentations of these 2
lesions are very different.

601
 Malignant Mesothelioma
Tumors of Mesothelial Cells

Epithelioid Mesothelioma Myxoid Stroma

(Left) An epithelioid cellular
morphology is quite common
in MM. This H&E shows sheets
of polygonal cells and a
sprinkling of lymphocytes.
(Right) Some cases of
mesothelioma contain a
myxoid or mucoid stroma,
which rarely may be very
prominent and mimic
mucinous adenocarcinoma.
Tumor cells exist singly or
form clusters or loose
aggregates and appear to
float freely.

Epithelioid Cells Psammoma Bodies

(Left) The rare deciduoid
variant of mesothelioma is
characterized by diffuse sheets
of large polygonal cells with
abundant pale or deep
eosinophilic cytoplasm,
resembling decidual cells.
(Right) Psammoma bodies ﬈
may be identified in MM,
particularly cases with a
papillary architecture.

Sarcomatoid Mesothelioma Heterologous Osteosarcoma

(Left) Sarcomatoid
mesothelioma is characterized
by sheets and fascicles of
spindled or pleomorphic tumor
cells as depicted. Some tumors
are biphasic and also contain
an epithelioid component.
(Right) Heterologous elements
may be identified in
sarcomatoid mesothelioma
and usually appear as
rhabdomyosarcomatous,
osteosarcomatous ﬊, or
chondrosarcomatous foci.

602
 Malignant Mesothelioma
Desmoplastic Mesothelioma
Lymphohistiocytoid Mesothelioma
Electron Microscopy
Tumors of Mesothelial Cells
Desmoplastic Mesothelioma
(Left) The desmoplastic
variant of sarcomatoid
mesothelioma shows
scattered atypical cells
amongst abundant collagen or
sclerosis. Areas of storiform
growth may also be seen. If
not considered, this variant
may be mistaken for a benign,
reactive fibroblastic process.
(Right) Despite the prominent
hyalinization/sclerosis and
overall hypocellularity of
desmoplastic mesothelioma,
there is often at least focal
nuclear atypia ﬈ and
hyperchromasia that should
raise concern for this
diagnosis.
Cytokeratin Expression
(Left) H&E of the rare
lymphohistiocytoid
mesothelioma shows mixed
chronic inflammatory cells
obscuring scattered malignant
mesothelial cells ﬊, which
may resemble histiocytes. The
inflammatory infiltrate is
typically dense, and the
overall pattern may be similar
to thymoma. (Right)
Cytokeratin AE1/AE3 shows
diffuse expression in most
cases of MM, regardless of its
morphology. Other more
specific markers are generally
required to confirm the
diagnosis.
Malignant Mesothelioma
(Left) Transmission electron
microscopy high-power image
of mesothelioma cells exhibits
the classic features of zonula
adherens junctions ﬇ joining
otherwise separated cell
surfaces on which are
microvilli of various lengths
﬈. Cells are oriented on the
basal lamina ﬉. (Right)
Unenhanced CT of the chest
shows typical increased
thickness of the pleura ſt
from MM. It will frequently
have a multifocal appearance,
as in this case.
603
This page intentionally left blank
 SECTION 15

Hematopoietic Tumors in Soft Tissue

Solitary Extramedullary Plasmacytoma 606

Myeloid Sarcoma 608
Lymphoma of Soft Tissue 610
 Solitary Extramedullary Plasmacytoma

KEY FACTS
Hematopoietic Tumors in Soft Tissue

TERMINOLOGY IMAGING
• Mass-forming proliferation of clonal (neoplastic) plasma • No lytic lesions in skeleton
cells arising outside of bone marrow
MICROSCOPIC
○ Signs or diagnostic features of multiple myeloma must
be absent • Sheets and nests of variably differentiated plasma cells
○ Nuclear atypia varies with grade of tumor
CLINICAL ISSUES
ANCILLARY TESTS
• Usually older adults (median age: 58 years)
○ 2:1 male predominance • CD138(+), keratin (-), S100 protein (-), CD20(-)
• Head and neck most common site overall • Shows λ- or κ-light chain restriction by in situ hybridization
○ Upper aerodigestive tract, including sinonasal cavity, TOP DIFFERENTIAL DIAGNOSES
sinuses, and oropharynx
• Myoepithelioma of soft tissue
• Symptoms related to location of mass
• Metastatic carcinoma
• Treatment: Radiation therapy; surgical excision in some
• Multiple myeloma
cases
• Epithelioid sarcoma
• Low risk of local recurrence following radiation (up to 7%)
• Malignant melanoma
• Risk of progression to myeloma (10-30% at 10 years)

Solitary Extramedullary Plasmacytoma Plasma Cells

(Left) Solid extramedullary
plasmacytoma (SEP) is
characterized by a clonal
proliferation of plasma cells
occurring outside of the bone
marrow. Also, by definition, no
clinical evidence of multiple
myeloma can be present.
(Right) In general, the degree
of nuclear atypia depends
upon the grade of the tumor;
however, in most cases, the
lesional cells are easily
identified as plasma cells if
attention is paid to cytologic
features (eccentric nuclei with
"clockface" chromatin).

Nests and Sheets In Situ Hybridization

(Left) The lesional cells of SEP
form diffuse sheets and nests
within a variable collagenous
stroma. In some cases, foci of
stromal sclerosis may impart
an appearance similar to
carcinoma or myoepithelioma.
(Right) In situ hybridization
studies are usually utilized to
demonstrate light chain
restriction in SEP. This
particular case shows κ
restriction (blue).

606
 Solitary Extramedullary Plasmacytoma

Hematopoietic Tumors in Soft Tissue

TERMINOLOGY MICROSCOPIC
Abbreviations Histologic Features
• Solitary extramedullary plasmacytoma (SEP) • Sheets and nests of variably differentiated plasma cells
○ Eccentric nuclei, presence of perinuclear hof, classic
Synonyms
clockface chromatin pattern
• Solitary extraosseous plasmacytoma – Nuclear atypia varies with grade of tumor
Definitions ○ Variable mitotic rate
• Mass-forming proliferation of clonal (neoplastic) plasma • Stroma may show sclerotic areas
cells arising outside of bone marrow
• Signs or diagnostic features of multiple myeloma must be ANCILLARY TESTS
absent Immunohistochemistry
○ Including no evidence of anemia, hypercalcemia, renal • CD138(+)
insufficiency, or lytic bone lesions
• Keratin (-), S100 protein (-), CD20(-)
CLINICAL ISSUES In Situ Hybridization
Epidemiology • Shows λ- or κ-light chain restriction
• Incidence
DIFFERENTIAL DIAGNOSIS
○ Rare (3% of all plasma cell neoplasms)
• Age Myoepithelioma of Soft Tissue
○ Usually older adults (median age: 58 years) • Tumor cells may be plasmacytoid with eosinophilic
• Sex cytoplasm
○ 2:1 male predominance • Myxoid stroma common; often prominent
• Keratin (+), EMA(+), S100 protein (+)
Site
• Head and neck most common overall Metastatic Carcinoma
○ Upper aerodigestive tract, including sinonasal cavity, • Clinical history of primary tumor often present
sinuses, and oropharynx • Keratin (+)
– May spread to regional lymph nodes (15% of cases) • Pitfall: CD138(+) in some types of carcinoma
• Also gastrointestinal tract, skin, soft tissue, liver, central
Multiple Myeloma
nervous system, lung
• Does not involve bone • Median age older than in SEP
• > 1 lesion present
Presentation • Lytic skeletal lesions common
• Symptoms related to location of mass • Presence of 10% or more clonal plasma cells in bone
○ Epistaxis and nasal-obstructive symptoms in upper marrow
airway tumors
Epithelioid Sarcoma
• Minority of patients have small M-protein (usually IgA)
• Sheets of epithelioid tumor cells, often with foci of central
Treatment necrosis
• Radiation therapy • Keratin (+); CD34 (variable); loss of nuclear INI1
• Complete surgical excision in some cases
Malignant Melanoma
○ Incomplete excisions followed by radiation
• Clinical history of primary tumor may or may not be present
Prognosis • Often marked nuclear atypia, mitotic activity, and necrosis
• Overall good prognosis • S100 protein (+)
○ Head and neck location and size < 5 cm may be good • 1 or more melanocytic markers (HMB-45, MART-1, etc.)
prognostic factors often present
• Low risk of local recurrence following radiation (up to 7%) • May show focal CD138(+)
• Risk of progression to myeloma (10-30% at 10 years)
SELECTED REFERENCES
IMAGING 1. Ghodke K et al: A retrospective study of correlation of morphologic patterns,
MIB1 proliferation index, and survival analysis in 134 cases of plasmacytoma.
MR and Bone Scan Ann Diagn Pathol. 19(3):117-23, 2015
• No lytic lesions in skeleton 2. Comfere NI et al: Cutaneous extramedullary plasmacytoma: clinical,
prognostic, and interphase cytogenetic analysis. Am J Dermatopathol.
35(3):357-63, 2013
MACROSCOPIC 3. Gerry D et al: Epidemiologic evidence of superior outcomes for
extramedullary plasmacytoma of the head and neck. Otolaryngol Head Neck
Size Surg. 148(6):974-81, 2013
• Variable range 4. Kilciksiz S et al: A review for solitary plasmacytoma of bone and
extramedullary plasmacytoma. ScientificWorldJournal. 2012:895765, 2012

607
 Myeloid Sarcoma

KEY FACTS
Hematopoietic Tumors in Soft Tissue

TERMINOLOGY • Uniform, medium-sized cells with little cytoplasm

• Tumoral mass of myeloid blasts ± maturation occurring
outside of bone marrow
• Synonyms: Granulocytic sarcoma, chloroma
CLINICAL ISSUES
• Wide age range (children to older adults)
• Skin, bone, lymph node, testis most common sites
• Solitary mass
○ May arise de novo or concurrently with acute myeloid
leukemia, myeloproliferative neoplasm, or
myelodysplastic syndrome
• Prognosis does not seem to be influenced by age, sex, site,
histologic features, immunophenotype, or cytogenetic
findings
MICROSCOPIC
• Diffuse, sheet-like growth that effaces normal tissue
architecture
○ Round to oval nucleus with prominent nucleolus
○ Cytoplasm may contain eosinophilic granules
○ May show monoblastic, monocytic, myelomonocytic
morphologies depending on origin
ANCILLARY TESTS
• CD43(+), lysozyme (+), CD45(+), CD34 (variable)
• Myeloid differentiation: Myeloperoxidase (+), CD117(+)
• Monocytic differentiation: CD68(+), CD13(+)
• CD3(-), CD20(-), keratin (-), S100(-), desmin (-)
• Molecular: Chromosomal aberrations detected in ~ 50% of
cases
TOP DIFFERENTIAL DIAGNOSES
• Lymphoma
• Poorly differentiated carcinoma or melanoma
• Various small round blue cell tumors
• Epithelioid angiosarcoma

Myeloid Sarcoma Uniform Myeloblasts

(Left) Myeloid sarcoma (a.k.a.
granulocytic sarcoma) is an
extramedullary tumoral mass
of myeloid blasts ± evidence of
maturation. Histologically, it is
composed of diffuse sheets of
uniform cells that efface
normal tissue architecture.
(Right) The lesional cells of
myeloid sarcoma are uniform
myeloblasts with fine
chromatin and variably
prominent nucleoli. Taken
together, this appearance is
often morphologically
indistinguishable from
lymphoma.

Larger Nucleoli Eosinophilic Myelocytes

(Left) Some cases of myeloid
sarcoma show larger cells with
very prominent nucleoli. The
differential diagnosis in these
cases naturally includes poorly
differentiated carcinoma and
melanoma but also sarcomas,
such as epithelioid
angiosarcoma. (Right)
Myelocytes with eosinophilic
cytoplasm may be present in
some cases of myeloid
sarcoma and can be a helpful
clue to suggest myeloid origin.
Immunohistochemistry,
however, is diagnostic.

608
 Myeloid Sarcoma

Hematopoietic Tumors in Soft Tissue

TERMINOLOGY ANCILLARY TESTS
Synonyms Immunohistochemistry
• Granulocytic sarcoma • CD43(+), lysozyme (+), CD45(+), CD34 (variable)
• Extramedullary myeloid tumor • Myeloid differentiation: Myeloperoxidase (+), CD117(+)
• Chloroma • Monocytic differentiation: CD68(+), CD13(+)
• CD3(-), CD20(-), CD79a(-), keratin (-), S100(-), desmin (-)
Definitions
• Tumoral mass of myeloid blasts ± maturation occurring Molecular Genetics
outside of bone marrow • Chromosomal abnormalities detected in ~ 50% of cases
○ t(8;21)(q22;q22) and inv(16) are recurrent aberrations
CLINICAL ISSUES ○ Trisomy 8, monosomy 16, many others
Epidemiology ○ Some show NPM1 mutations
• Incidence
○ Rare
DIFFERENTIAL DIAGNOSIS
• Age Lymphoma
○ Wide range (children to older adults) • B cell, T cell, or NK cell
• Sex • Can show significant morphologic overlap
○ Slight male predominance • May present without leukemic manifestations
Site • Specific B-, T-, or NK-cell immunophenotypes
• Can occur anywhere Poorly Differentiated Carcinoma
○ Skin, bone, lymph node, testis most common • Shows more cohesive growth pattern
Presentation • Keratin (+)
• Solitary mass Malignant Melanoma
○ < 10% of cases are multifocal • May have small round cell morphology
• May arise de novo or concurrently with acute myeloid • S100(+), HMB45(+), MART-1(+)
leukemia, myeloproliferative neoplasm, or myelodysplastic • Necrosis common
syndrome
Various Small Round Blue Cell Tumors
Treatment • Particularly in children
• Chemotherapy • Includes alveolar rhabdomyosarcoma, neuroblastoma,
• Possibly surgical excision for isolated lesions without extrarenal rhabdoid tumor, Ewing sarcoma
previous or current evidence of hematogenous disease • Immunohistochemistry must be utilized
Prognosis • Molecular analysis may be helpful
• Does not seem to be influenced by age, sex, site, histologic Epithelioid Angiosarcoma
features, immunophenotype, or cytogenetic findings • CD31(+), ERG(+), CD34(+)
• Isolated extramedullary tumors without concomitant • Sheets and clusters of epithelioid cells with macronucleoli
hematologic disease may fare better
○ Rare reports of isolated tumors in patients who never SELECTED REFERENCES
develop hematogenous disease
1. Almond LM et al: Myeloid sarcoma: presentation, diagnosis, and treatment.
Clin Lymphoma Myeloma Leuk. 17(5):263-267, 2017
MACROSCOPIC 2. Seifert RP et al: A practical approach to diagnose soft tissue myeloid
sarcoma preceding or coinciding with acute myeloid leukemia. Ann Diagn
Size Pathol. 18(4):253-260, 2014
• Varies 3. Campidelli C et al: Myeloid sarcoma: extramedullary manifestation of
myeloid disorders. Am J Clin Pathol. 132(3):426-37, 2009
4. Alexiev BA et al: Myeloid sarcomas: a histologic, immunohistochemical, and
MICROSCOPIC cytogenetic study. Diagn Pathol. 2:42, 2007
5. Pileri SA et al: Myeloid sarcoma: clinico-pathologic, phenotypic and
Histologic Features cytogenetic analysis of 92 adult patients. Leukemia. 21(2):340-50, 2007
• Diffuse, sheet-like growth that effaces normal tissue 6. Breccia M et al: Clinico-pathological characteristics of myeloid sarcoma at
architecture diagnosis and during follow-up: report of 12 cases from a single institution.
Leuk Res. 28(11):1165-9, 2004
• Uniform, medium-sized cells with little cytoplasm
○ Round to oval nucleus with prominent nucleolus
○ Cytoplasm may contain eosinophilic granules
• May contain larger cells with more abundant cytoplasm
• Differentiating tumors show > 10% neutrophils
• Necrosis is rare
• May show monoblastic, monocytic, myelomonocytic
morphologies depending on origin

609
 Lymphoma of Soft Tissue

KEY FACTS
Hematopoietic Tumors in Soft Tissue

TERMINOLOGY ○ Also precursor lymphoblastic lymphoma, anaplastic large

• Group of malignant lymphoid proliferations that arise in cell lymphoma, small cell lymphomas, others
soft tissue as primary site without evidence of lymph node ANCILLARY TESTS
or skin involvement
• Most CD45/LCA(+)
CLINICAL ISSUES • ~ 80-85% of primary soft tissue lymphoid neoplasms
• True primary soft tissue lymphoma is rare originate from B cells and therefore express B-cell markers
○ Soft tissue manifestation/deposit of systemic lymphoma (e.g., CD19, CD20, CD79a)
more common • Anaplastic large cell lymphoma: CD30(+), ALK (variable)
• Most common in extremities, particularly leg • Flow cytometry is useful adjunct to immunohistochemistry
• Usually older adults TOP DIFFERENTIAL DIAGNOSES
• Treatment: Chemotherapy &/or radiotherapy • Poorly differentiated synovial sarcoma
○ Surgery not indicated • Ewing sarcoma
• Prognosis depends upon type of lymphoma • Malignant melanoma
MICROSCOPIC • Myeloid sarcoma
• Depends upon type of lymphoma • Merkel cell carcinoma
○ Diffuse large B-cell lymphoma (most common overall)

Lymphoma Muscle Infiltration

(Left) Lymphoma
characteristically grows in
diffuse sheets of dyscohesive
atypical lymphoid cells. The
degree of atypia and mitotic
activity vary depending upon
whether the lymphoma is low
or high grade. (Right) When
lymphoma arises in or near
muscle, it often shows diffuse
infiltration between the
muscle fibers ﬈, splaying
them apart. This pattern of
infiltration may be referred to
as checkerboard.

High-Grade Lymphoma Anaplastic Large Cell Lymphoma

(Left) This high-grade B-cell
lymphoma of the proximal
thigh shows diffuse sheets of
markedly atypical
lymphocytes with numerous
mitotic figures ﬈. (Right)
Anaplastic large cell
lymphoma is composed of
sheets of malignant polygonal
cells. In soft tissue sites, this
tumor can be easily mistaken
for carcinoma, melanoma, or
some form of pleomorphic or
round cell sarcoma.

610
 Lymphoma of Soft Tissue
TERMINOLOGY
Definitions
• Group of malignant lymphoid proliferations that arise in
soft tissue as primary site without evidence of lymph node
or skin involvement
CLINICAL ISSUES
Epidemiology
• Incidence
○ True primary soft tissue lymphoma is rare
○ Soft tissue manifestation/deposit of systemic lymphoma
more common
• Age
○ Usually older adults
– Lymphoblastic lymphomas more common in children
and young adults
Site
• Most common in extremities, particularly leg
Presentation
• Suddenly enlarging mass
○ Systemic symptoms may be present
Treatment
• Chemotherapy &/or radiotherapy
• Surgical excision not indicated
Prognosis
• Depends upon type of lymphoma
○ Diffuse large B-cell lymphoma of soft tissue is often
highly aggressive
MICROSCOPIC
Histologic Features
• Depends upon type of lymphoma
○ Diffuse large B-cell lymphoma (most common overall)
– Diffuse sheets of medium-to-large malignant
lymphoid cells
□ May resemble poorly differentiated carcinoma or
melanoma
– Mitotic figures usually abundant
– Necrosis common
– Heterogeneous population of smaller lymphoid cells
may be intermixed
○ Lymphoblastic lymphoma/leukemia
– Diffuse sheets of small primitive lymphocytes
□ May resemble various small round blue cell tumors,
e.g., Ewing sarcoma, neuroblastoma, alveolar
rhabdomyosarcoma
○ Anaplastic large cell lymphoma
– Diffuse sheets of large epithelioid lymphoid cells
□ May resemble poorly differentiated carcinoma or
melanoma
□ May rarely show "mesenchymal" features, such as
myxoid stroma
• Other types include Burkitt lymphoma, follicular
lymphoma, extranodal NK-/T-cell lymphoma, and various
small cell lymphomas
Hematopoietic Tumors in Soft Tissue
ANCILLARY TESTS
Immunohistochemistry
• Most CD45/LCA(+)
○ May be (-) in precursor B-cell lymphoma, which is often
TdT(+)
• ~ 80-85% of primary soft tissue lymphoid neoplasms
originate from B cells
○ CD20, CD79-α, others
○ Additional markers (e.g., CD5, CD10) useful for further
classification
• T-cell lymphomas
○ CD2, CD3, CD4, CD7, CD8, others
• Anaplastic large cell lymphoma
○ CD30(+), ALK (variable)
Flow Cytometry
• Useful adjunct to immunohistochemistry
DIFFERENTIAL DIAGNOSIS
Poorly Differentiated Synovial Sarcoma
• May show small round blue cell tumor morphology
• Focal keratin (+) and EMA(+) in some cases
• TLE1(+), CD45(-)
• t(X;18) involving SS18 (SYT) gene
Malignant Melanoma
• Patient may or may not have past history
• S100 protein(+), SOX10(+) in vast majority of cases
• HMB-45(+), MART-1(+), other melanocytic markers
○ May be (-) in some cases
Ewing Sarcoma
• FLI-1(+), CD45(-), TdT(-)
• CD99(+)
○ Can also be expressed in precursor lymphoblastic
lymphomas and anaplastic large cell lymphoma
• t(11;22) and other translocations involving EWSR1 gene
Merkel Cell Carcinoma
• CK20(+) in perinuclear dot-like pattern
• Synaptophysin (+), chromogranin (+)
Myeloid Sarcoma
• Often history of previous or active acute myeloid leukemia
• Eosinophilic myelocytes may be interspersed
• CD117(+), CD34(+), myeloperoxidase (+) in many cases
SELECTED REFERENCES
1. Gupta P et al: Primary cutaneous non-Hodgkin's lymphoma, clinically
mimicking a soft tissue sarcoma. Cytojournal. 15:2, 2018
2. Derenzini E et al: Non-hodgkin lymphomas presenting as soft tissue masses:
a single center experience and meta-analysis of the published series. Clin
Lymphoma Myeloma Leuk. 13(3):258-65, 2013
3. Knowles B et al: Extra-nodal lymphoma presenting as a mimic of soft-tissue
sarcoma. ANZ J Surg. 73(1-2):26-30, 2003
4. Salamao DR et al: Lymphoma in soft tissue: a clinicopathologic study of 19
cases. Hum Pathol. 27(3):253-7, 1996
5. Lanham GR et al: Malignant lymphoma. A study of 75 cases presenting in
soft tissue. Am J Surg Pathol. 13(1):1-10, 1989
6. Travis WD et al: Primary extranodal soft tissue lymphoma of the extremities.
Am J Surg Pathol. 11(5):359-66, 1987
611
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 SECTION 16

Tumors of Uncertain Differentiation

Benign
Intramuscular Myxoma 614
Juxtaarticular Myxoma 618
Superficial Angiomyxoma 620
Acral Fibromyxoma 624
Pleomorphic Hyalinizing Angiectatic Tumor 626
Aneurysmal Bone Cyst of Soft Tissue 630
Ectopic Hamartomatous Thymoma 632

Intermediate (Locally Aggressive)

Hemosiderotic Fibrolipomatous Tumor 634

Intermediate (Rarely Metastasizing)

Atypical Fibroxanthoma 636
Angiomatoid Fibrous Histiocytoma 642
Ossifying Fibromyxoid Tumor 650
Myoepithelioma of Soft Tissue 656
Phosphaturic Mesenchymal Tumor 664

Malignant
Synovial Sarcoma 666
Epithelioid Sarcoma 678
Alveolar Soft Part Sarcoma 684
Clear Cell Sarcoma 688
Perivascular Epithelioid Cell Tumor (PEComa) 692
Desmoplastic Small Round Cell Tumor 700
Extraskeletal Ewing Sarcoma 706
Extraskeletal Myxoid Chondrosarcoma 712
Extrarenal Rhabdoid Tumor 716
Intimal Sarcoma 720
 Intramuscular Myxoma

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY MICROSCOPIC
• Benign mesenchymal neoplasm arising within muscle and • Often shows peripheral infiltration of skeletal muscle fibers
composed of bland spindled cells within abundant myxoid (sometimes checkerboard pattern)
and hypovascular matrix • Overall uniform, hypocellular, haphazard proliferation of
small spindled to stellate cells
CLINICAL ISSUES
• Abundant extracellular myxoid matrix
• Usually adults (most common 40-70 years)
• Vasculature is characteristically sparse
• Female predilection
• Mitoses very rare; no necrosis
• Usually large muscles of thigh, buttock, shoulder, upper
• Morphologic variant: Cellular myxoma
arm
• Arise sporadically or within context of Mazabraud ANCILLARY TESTS
syndrome • Molecular: Activating missense mutations in codon 201 of
• Treatment: Simple surgical excision GNAS gene
• Does not recur if excised completely
TOP DIFFERENTIAL DIAGNOSES
MACROSCOPIC • Myxofibrosarcoma (low grade)
• Lobulated, gelatinous cut surface • Low-grade fibromyxoid sarcoma
• Most < 10 cm in greatest dimension • Benign peripheral nerve sheath tumors
• Myxoid liposarcoma

Intramuscular Myxoma Low-Power Appearance

(Left) Intramuscular myxoma
presents as a circumscribed
and lobulated mass, most
commonly within large
muscles, typically showing a
gray-white, glistening, or
gelatinous cut surface. Note
the smooth interface with
surrounding skeletal muscle
﬈. (Right) At low power,
intramuscular myxoma is
characterized by an abundant
myxoid matrix and is generally
diffusely hypocellular and
hypovascular. The interface
with adjacent skeletal muscle
may be sharp and distinct (as
shown) or irregular and
infiltrative-appearing.

Infiltrative Appearance Common Hypocellular and Cytologically Bland

(Left) Infiltration of tumor
cells between bundles of
skeletal muscle is a common
finding at the periphery of
intramuscular myxoma. Not
infrequently, the lesional cells
grow between individual
muscle fibers, imparting a
checkerboard appearance.
(Right) The lesional cells of
intramuscular myxoma are
characteristically small,
spindled to stellate in shape,
and show small amounts of
eosinophilic cytoplasm. Nuclei
are often small, dark, and
bland. Mitoses are very rare.

614
 Intramuscular Myxoma

Tumors of Uncertain Differentiation

• Vasculature is characteristically sparse and inconspicuous
TERMINOLOGY
• Areas with finely fibrillar stromal collagen may be seen
Definitions • Vacuolated macrophages may be present
• Benign mesenchymal neoplasm arising within muscle and • Mitoses very rare; no necrosis
composed of bland spindled cells within abundant myxoid
Morphologic Variant
and hypovascular matrix
• Cellular myxoma
CLINICAL ISSUES ○ Focal to diffuse areas of increased cellularity and
vascularity
Epidemiology ○ Cytologically identical to noncellular tumors
• Age – Very rare mitoses; no necrosis
○ Usually adults (most common 40-70 years) ○ Stroma often more collagenous
• Sex
○ Female predilection ANCILLARY TESTS
Site Immunohistochemistry
• Usually large muscles • Variable CD34(+), variable SMA(+)
○ Thigh (most common) • Negative for S100 protein, desmin, EMA, MUC4, claudin-1
○ Also buttock, shoulder, upper arm, rarely others
Genetic Testing
Presentation • Activating missense mutations in codon 201 of GNAS gene
• Slow-growing, solitary, painless mass ○ Detected in both cellular and noncellular forms, in both
• Most are sporadic sporadic tumors, and those occurring in Mazabraud
○ Subset arise in association with fibrous dysplasia syndrome
(Mazabraud syndrome)
– Multiple myxomas may be seen DIFFERENTIAL DIAGNOSIS
– Often arise in same anatomic region as fibrous Low-Grade Myxofibrosarcoma
dysplasia lesion(s)
• Usually older adults and elderly
Treatment • More often superficial (subcutis) than deep
• Simple surgical excision • Usually contains tumor cells with nuclear atypia and
pleomorphism, at least focally
Prognosis • Vascularity more pronounced (curvilinear vessels)
• Typically does not recur if excised completely
○ Local recurrence very rare even if incompletely excised Low-Grade Fibromyxoid Sarcoma
• No significant prognostic difference between cellular and • Alternating myxoid and collagenous zones
conventional types ○ Vascularity often more pronounced in myxoid areas
• Does not metastasize or show malignant transformation • MUC4(+)
• Characteristic t(7;16) with FUS-CREB3L2
MACROSCOPIC Benign Peripheral Nerve Sheath Tumors
General Features • Includes neurofibroma, perineurioma, and hybrid nerve
• Appears well circumscribed sheath tumor
○ May show subtle infiltration of adjacent skeletal muscle ○ All can feature myxoid stroma
on closer inspection • S100 protein (+) in neurofibroma
• Lobulated, gelatinous cut surface • EMA(+) &/or claudin-1 (+) in perineurioma
• Cystic spaces may be present • Admixed S100 protein (+) and EMA/claudin-1 (+) cells in
hybrid nerve sheath tumor
Size
• Most < 10 cm in greatest dimension Myxoid Liposarcoma
○ Can measure up to 20 cm • Characteristic plexiform chicken-wire vasculature
• Uni- and multivacuolated lipoblasts often present
MICROSCOPIC • Characteristic t(12;16) with FUS-DDIT3 fusion
Histologic Features
SELECTED REFERENCES
• Often shows peripheral infiltration of skeletal muscle fibers
(sometimes checkerboard pattern) 1. Rachidi S et al: Intramuscular myxoma of the paraspinal muscles: a case
report and systematic review of the literature. Oncol Lett. 11(1):466-470,
• Overall uniform, hypocellular, haphazard proliferation of 2016
small spindled to stellate cells 2. Delaney D et al: GNAS1 mutations occur more commonly than previously
○ Small, bland, oval nuclei ± inconspicuous nucleoli thought in intramuscular myxoma. Mod Pathol. 22(5):718-24, 2009
3. Nielsen GP et al: Intramuscular myxoma: a clinicopathologic study of 51
○ Tapered, eosinophilic, fibrillary cytoplasm cases with emphasis on hypercellular and hypervascular variants. Am J Surg
• Abundant extracellular myxoid matrix Pathol. 22(10):1222-7, 1998
○ May appear "frothy" &/or contain microcystic spaces

615
 Intramuscular Myxoma
Tumors of Uncertain Differentiation

Cytologic Features Rare Tumor Cells

(Left) Some of the tumor cells
in intramuscular myxoma are
slightly larger and more ovoid
and show somewhat darker
eosinophilic cytoplasm ﬊.
Nuclei are often eccentric.
(Right) Rare tumor cells in
intramuscular myxoma,
particularly those that are
stellate in shape, may
somewhat resemble the
"floret-like" cells that are seen
in other tumors, such as
pleomorphic lipoma and
myxofibrosarcoma. The latter,
in particular, should always be
thoroughly excluded.

Foamy Histiocytes Frothy Myxoid Matrix

(Left) Occasionally, small
histiocytes with foamy,
vacuolated cytoplasm may be
encountered in intramuscular
myxoma. These cells should
not be confused for lipoblasts.
(Right) A frothy or bubbly
quality to the myxoid matrix
may be seen in intramuscular
myxoma. This finding may
simulate lipoblastic
differentiation.

Abundant Mucoid Material Cystic Change

(Left) Given its highly myxoid
nature, slide preparations of
an intramuscular myxoma may
contain large globs of mucoid
material, as shown in this
image. This finding is
particularly common in frozen
section preparations. (Right)
Cystic change is not
uncommon in intramuscular
myxoma and may be grossly
evident in some cases. This
finding is encountered more
frequently in cellular forms of
intramuscular myxoma as well
as in the unrelated
juxtaarticular myxoma.

616
 Intramuscular Myxoma
Variable Fine Stromal Collagen
Cellular Intramuscular Myxoma
Cellular Intramuscular Myxoma
Tumors of Uncertain Differentiation
Increased Collagen
(Left) Although the abundant
myxoid matrix often
dominates the histologic
picture, areas containing fine,
fibrillary stromal collagen ﬊
may also be seen in
intramuscular myxoma. Large
bundled collagen fibers are
uncommon. (Right) Increased
stromal collagen may be seen
around the periphery, as in this
image, and may impart a
vague nodular appearance.
Cellular Intramuscular Myxoma
(Left) Cellular examples of
intramuscular myxoma are
characterized by regions of
increased cellularity with an
often concomitant increase in
the prominence of stromal
collagen and blood vessels ﬊.
Cellular areas may be focal or
comprise most of a given
tumor. (Right) Cellular
intramuscular myxoma often
shows slightly more
architectural organization of
the tumor cells compared with
typical forms. As a rule, low-
grade fibromyxoid sarcoma
should always be excluded
before a diagnosis of cellular
myxoma is made.
Cellular Intramuscular Myxoma
(Left) Cellular intramuscular
myxoma generally lacks the
haphazard or patternless
growth of tumor cells that
characterize conventional
cases. (Right) Importantly, the
tumor cells in cellular
intramuscular myxoma are
still very bland and
cytologically identical to cells
in conventional tumors.
Mitotic figures are very rare.
617
 Juxtaarticular Myxoma

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY ○ Mitotic figures rare or absent

• Benign lesion occurring in region of large joints that is ○ Hypovascular myxoid stroma
histologically similar to cellular intramuscular myxoma ○ Areas of increased cellularity common
• Cystic, ganglion-like spaces present in many cases
CLINICAL ISSUES
• Usually adults (predominantly 20-50 years) ANCILLARY TESTS
• 90% occur around knee joint • Variable CD34 and SMA
• Benign; local recurrence in 30% • Negative for S100 protein, MUC4
• Genetics: Lacks mutations of GNAS gene
MACROSCOPIC
• Myxoid, gelatinous cut surface TOP DIFFERENTIAL DIAGNOSES
• Cystic areas common • Intramuscular myxoma
• Mean size: 3.5 cm • Myxofibrosarcoma (low grade)
• Low-grade fibromyxoid sarcoma
MICROSCOPIC • Deep (aggressive) angiomyxoma
• Peripheral borders often ill defined with infiltration of • Superficial angiomyxoma
adjacent tissue • Myxoid neurofibroma
• Histologically very similar to cellular intramuscular myxoma
○ Proliferation of bland spindle or stellate cells

Juxtaarticular Myxoma Cystic Spaces

(Left) Juxtaarticular myxoma
(JAM) is histologically similar
to the cellular form of
intramuscular myxoma and
contains areas showing low
cellularity (left) and higher
cellularity (right). The cells are
embedded in patternless
distributions within stroma
that is myxoid and
hypovascular. (Right) Stromal
cysts can be a prominent
feature ﬉ of JAM. In some
cases, large ganglion-like
spaces are present. The
hypovascularity of the myxoid
matrix is also notable.

Increased Cellularity Hypovascular Stroma

(Left) Despite the increased
cellularity, the cells of JAM are
cytologically bland, and
mitotic activity is
characteristically low or
absent. The stroma is typically
myxoid or myxocollagenous.
(Right) Unlike many low-grade
myxoid sarcomas, the stroma
in JAM is characteristically
hypovascular. Note the rare
scattered small blood vessels
﬊ in this image.

618
 Juxtaarticular Myxoma

Tumors of Uncertain Differentiation

○ Fibrin deposition
TERMINOLOGY
○ Variable mild chronic inflammatory cell infiltrate
Abbreviations ○ Reactive fibroblastic proliferation
• Juxtaarticular myxoma (JAM)
ANCILLARY TESTS
Definitions
• Benign lesion occurring in region of large joints that is Immunohistochemistry
histologically similar to cellular intramuscular myxoma • Similar immunoprofile to intramuscular myxoma
○ Variable expression of CD34 and SMA
ETIOLOGY/PATHOGENESIS ○ Negative for S100 protein, MUC4
Environmental Exposure Genetic Testing
• Lesions have been associated with trauma • Lack mutations of GNAS gene typically found in
• May also occur adjacent to osteoarthritic joint intramuscular myxoma
○ Therefore, genetically distinct from intramuscular
CLINICAL ISSUES myxoma
Epidemiology
DIFFERENTIAL DIAGNOSIS
• Age
○ Usually adults (predominantly 20-50 years) Intramuscular Myxoma
• Sex • Most common in large muscles of lower limb
○ M>F • Many contain mutations of GNAS gene
Site Myxofibrosarcoma (Low Grade)
• Occurs adjacent to large joints • Often subcutaneous location in older/elderly patients
○ 90% occur around knee joint • Multinodular growth
○ Also shoulder, elbow, ankle, and hip • Atypical, hyperchromatic nuclei
• Can involve periarticular tendons, ligaments, joint capsules, • Prominent "curvilinear" vasculature in most cases
muscles, and subcutis
Low-Grade Fibromyxoid Sarcoma
Presentation • Admixed fibrous and myxoid zones
• Painful or painless mass ○ Myxoid zones more cellular than in JAM
○ Lesion duration varies • MUC4(+)
• Characteristic t(7;16) or t(11;16)
Prognosis
• Local recurrence in ~ 30% Deep (Aggressive) Angiomyxoma
• No reports of malignant transformation • Adult women
• Deep soft tissues of vulvovaginal region
MACROSCOPIC • Numerous vessels of varying sizes
General Features Superficial Angiomyxoma
• Myxoid, gelatinous cut surface • Trunk, head and neck, or vulvovaginal sites
• Cystic areas common • Prominent vasculature
Size • Can have neutrophilic infiltrate
• May contain admixed epithelial structures
• Varies from < 1 cm to > 10 cm
○ Mean size: 3.5 cm Myxoid Neurofibroma
• Buckled, elongated nuclei
MICROSCOPIC • S100 protein (+)
Histologic Features
• Peripheral borders often ill defined with infiltration of
SELECTED REFERENCES
adjacent tissue 1. Ye ZX et al: Juxta-articular myxoma of the temporomandibular joint. J
Craniofac Surg. 26(8):e695-6, 2015
• Histologically very similar to cellular intramuscular myxoma
2. Wakely Jr PE et al: The cytopathology of soft tissue mxyomas: ganglia, juxta-
○ Proliferation of spindle or stellate fibroblast-like cells articular myxoid lesions, and intramuscular myxoma. Am J Clin Pathol.
– Cytologically bland 123(6):858-65, 2005
3. Okamoto S et al: Juxta-articular myxoma and intramuscular myxoma are
– Mitotic figures rare or absent two distinct entities. Activating Gs alpha mutation at Arg 201 codon does
○ Hypovascular myxoid stroma not occur in juxta-articular myxoma. Virchows Arch. 440(1):12-5, 2002
○ Areas of increased cellularity common 4. Allen PW: Myxoma is not a single entity: a review of the concept of myxoma.
Ann Diagn Pathol. 4(2):99-123, 2000
• Cystic, ganglion-like spaces present in many cases 5. Sciot R et al: Clonal chromosomal changes in juxta-articular myxoma.
○ Lined by fibrin or collagen Virchows Arch. 434(2):177-80, 1999
• Other findings 6. Meis JM et al: Juxta-articular myxoma: a clinical and pathologic study of 65
cases. Hum Pathol. 23(6):639-46, 1992
○ Hemorrhage with hemosiderin deposition

619
 Superficial Angiomyxoma

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY • Hypocellular spindle and stellate cells in abundant myxoid

• Synonym: Cutaneous myxoma background
• Benign, cutaneous myxoid lesion, sometimes associated • Arborizing/plexiform thin-walled vessels
with Carney complex • Neutrophils present in subset of cases
• Entrapped benign epithelial elements in up to 25% 
CLINICAL ISSUES
ANCILLARY TESTS
• Mean age: 3rd-5th decades
• Trunk, head and neck, lower extremities, and genital area • CD34(+); S100 protein (-)
• Ear canal, eyelid, nipple common sites in Carney complex TOP DIFFERENTIAL DIAGNOSES
• Benign but local recurrence in 30-40% if incompletely • Digital mucous cyst
excised
• Cutaneous focal mucinosis
MACROSCOPIC • Dermal nerve sheath myxoma
• Typically small (up to 5 cm) • Myxoid neurofibroma
• Multinodular gelatinous cut surface with thin fibrous septa • Superficial acral (digital) fibromyxoma
• Deep (aggressive) angiomyxoma
MICROSCOPIC • Myxoid liposarcoma
• Dermal nodule, sometimes extending to subcutis • Low-grade myxofibrosarcoma
• Multiple vague lobules divided by thin fibrous septa • Low-grade fibromyxoid sarcoma

Superficial Angiomyxoma Plexiform Vessels

(Left) In this example of
superficial angiomyxoma,
multiple hypocellular myxoid
lobules in the dermis are
divided by thin fibrous septa.
(Right) As seen here, the
branching thin vessels may be
quite striking in superficial
angiomyxoma; however, they
are usually not as thin or
delicate as the vessels of
myxoid liposarcoma.

Bland Spindle and Stellate Cells CD34 Expression

(Left) Bland spindle and
stellate cells st with
eosinophilic cytoplasm are
arranged in a myxoid
background in superficial
angiomyxoma. A variable
amount of collagen fibers may
be present. Scattered
neutrophils are also
characteristically seen ﬈.
(Right) There is strong
expression of CD34 within
spindle and stellate cells. Note
also the prominent
vasculature ﬈.

620
 Superficial Angiomyxoma

Tumors of Uncertain Differentiation

TERMINOLOGY ANCILLARY TESTS
Synonyms Immunohistochemistry
• Cutaneous myxoma • CD34(+); occasionally focal SMA or desmin
• S100 protein, keratin, ER, PR (-)
Definitions
• Benign myxoid lesion of skin, sometimes associated with DIFFERENTIAL DIAGNOSIS
Carney complex
Digital Mucous Cyst
CLINICAL ISSUES • Typically on dorsum of fingers near nail
Epidemiology • May show mucin-/myxoid-filled pseudocyst &/or noncystic
loose myxoid change in dermis
• Age
• Lacks plexiform vessels and neutrophils; not multilobular
○ Any age but mostly in middle-aged adults (mean: 20-40
years) Cutaneous Focal Mucinosis
Site • Small papule; usually limited to mid-/upper dermis
• Similar histology but vasculature usually less pronounced
• Trunk, head/neck, lower extremities, genital region
• Ear canal, eyelid, nipple common sites in Carney complex Dermal Nerve Sheath Myxoma
Presentation • Strikingly lobular architecture
• Spindle cells arranged in whorled chains/cords
• Incidental, painless papule/nodule or polyp
• Strongly SOX10 and S100 protein (+)
○ Clinically similar to skin tag, neurofibroma, or cyst
Myxoid Neurofibroma
Treatment
• Buckled, elongated nuclei; minimal cytoplasm
• Local excision with follow-up
• SOX10 and S100 protein (+)
Prognosis
Superficial Acral (Digital) Fibromyxoma
• Benign but local recurrence in 30-40% if incompletely
• Acral sites, especially fingers; often periungual
excised (median time to recurrence: 12 months)
• More cellularity and more fibrous background
• No metastatic potential
• May show loss of RB1/13q abnormalities
MACROSCOPIC Deep (Aggressive) Angiomyxoma
General Features • Large, deep pelvic/perineal mass, usually in females
• Usually solitary • Different vascular pattern: Vessels vary in size
○ Often multiple in Carney complex Myxoid Liposarcoma
• Multinodular gelatinous cut surface with thin fibrous septa • Large, deep mass; very rare in dermis/subcutis
• May be poorly circumscribed • Also has plexiform vessels but usually more thin/delicate
• May contain cysts with keratin debris • Uniform, round/oval cells with minimal cytoplasm
Size • Uni- and bivacuolated lipoblasts usually present
• Typically small (up to 5 cm) • Characteristic gene fusions: FUS-DDIT3 or EWSR1-DDIT3
Low-Grade Myxofibrosarcoma
MICROSCOPIC • Always has at least focal nuclear atypia/pleomorphism
Histologic Features • Spindle cells aggregate near long "curvilinear" vessels
• Dermal nodule, sometimes extending to subcutis Low-Grade Fibromyxoid Sarcoma
• Multiple vague lobules divided by thin fibrous septa
• Usually large/deep, rarely may be small/superficial
• Hypocellular spindle/stellate cells in myxoid background
• Varying cellularity with hypo- and hypercellular areas
○ Bland, round/reniform nuclei, sometimes with nuclear
• Alternating fibrous and myxoid background
vacuoles
• Bland spindle cells with minimal cytoplasm; MUC4(+)
○ Often bi- or multinucleated
• Characteristic translocations: FUS-CREB3L2 and others
○ Mitoses rare
○ Perinuclear protruding "belly" of eosinophilic cytoplasm
SELECTED REFERENCES
• Arborizing/plexiform thin-walled vessels often prominent
1. Aberdein G et al: Mohs micrographic surgery for the treatment of superficial
• Scattered mixed inflammatory cells, especially neutrophils angiomyxoma. Dermatol Surg. 42(8):1014-6, 2016
○ Neutrophils absent in other dermal myxoid tumors 2. Calonje E et al: Superficial angiomyxoma: clinicopathologic analysis of a
• Entrapped benign epithelial elements in up to 25% series of distinctive but poorly recognized cutaneous tumors with tendency
for recurrence. Am J Surg Pathol. 23(8):910-7, 1999
○ Follicular/"epidermoid" cysts, often with keratin debris
3. Carney JA: Carney complex: the complex of myxomas, spotty pigmentation,
• May have overlying basaloid proliferation in epidermis  endocrine overactivity, and schwannomas. Semin Dermatol. 14(2):90-8, 1995
○ Can mimic basal cell carcinoma 4. Allen PW et al: Superficial angiomyxomas with and without epithelial
components. Report of 30 tumors in 28 patients. Am J Surg Pathol.
12(7):519-30, 1988

621
 Superficial Angiomyxoma
Tumors of Uncertain Differentiation

Myxoid Dermal Nodule Vasculature

(Left) Superficial
angiomyxoma is a dermal
hypocellular myxoid nodule. In
this example, the tumor has
infiltrative borders and lacks
fibrous septa. (Right) Bland
spindle and stellate cells are
scattered in a pale myxoid
background with elongated
thin vessels. Vessels are often
prominent but do not always
display branching/plexiform
arrangement.

Branching Vessels Hypocellularity

(Left) The branching vessels
and hypocellular myxoid
background can bear vague
resemblance to myxoid
liposarcoma. (Right) A
hypocellular proliferation of
bland spindle and stellate cells
are scattered in a pale myxoid
background. Some cases of
superficial angiomyxoma have
very little collagen, as seen
here.

Bland Nuclei "Bellies" of Eosinophilic Cytoplasm

(Left) Superficial
angiomyxoma is composed of
a hypocellular proliferation of
spindle to stellate cells with
bland nuclei lacking atypia or
significant mitotic activity. The
background contains a
variable amount of blue
mucin. (Right) The spindle
cells of superficial
angiomyxoma often have
reniform nuclei and an
adjacent globular "belly" of
eosinophilic cytoplasm ﬈.

622
 Superficial Angiomyxoma
Scattered Neutrophils
Entrapped Cystic Sweat Duct
Entrapped Follicular Cyst
Tumors of Uncertain Differentiation
Entrapped Epithelial Elements
(Left) Unlike most other
cutaneous myxoid neoplasms,
superficial angiomyxoma
often contains scattered
neutrophils ﬈. (Right) A
cystically dilated sweat duct
﬊ is entrapped at the edge of
this superficial angiomyxoma.
Entrapped benign epithelial
elements are seen in up to
25% of cases.
Entrapped Sweat Duct Elements
(Left) A cystically dilated
sweat ductal structure ﬉ is
entrapped at the periphery of
this superficial angiomyxoma.
(Right) The lining ﬈ of this
entrapped cystic duct
alternates between
keratinocytes and apocrine
cells. There is fibrosis within
the adjacent lesion.
Entrapped Follicular Cyst
(Left) Entrapped cystic
epithelial structures similar to
follicular cysts (so-called
epidermal inclusion cysts) may
be present. (Right) The lining
of this entrapped cyst is
composed of benign
keratinocytes similar to the
lining of a typical follicular
cyst. Fibrosis may be
prominent in some superficial
angiomyxomas, as seen here.
623
 Acral Fibromyxoma

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY MICROSCOPIC
• Synonyms: Digital fibromyxoma, cellular digital fibroma • Moderately cellular proliferation of spindled to stellate
• Benign fibroblastic neoplasm that occurs in hands and feet, fibroblastic cells in randomly arranged, loose fascicles or
particularly nail bed region storiform arrays
• Nuclear atypia minimal to absent
CLINICAL ISSUES
• Rare mitoses; no necrosis
• Most common > 40 years • Variable myxoid, myxocollagenous, or collagenous stroma
• Male predilection
• Vast majority arise fingers and toes ANCILLARY TESTS
○ Particularly in or near nail bed • CD34(+)
• Solitary, slowly growing, and often longstanding lesion • Loss of nuclear RB1 expression
• Treatment: Complete excision • Negative for S100 protein, desmin, keratin, claudin-1,
• Excellent prognosis MUC4, STAT6
• Low rate of recurrence, usually related to incomplete TOP DIFFERENTIAL DIAGNOSES
excision
• Dermatofibroma (fibrous histiocytoma)
MACROSCOPIC • Perineurioma
• Usually < 5 cm (median: 1.5 cm) • Dermatofibrosarcoma protuberans
• Myxoid neurofibroma

Acral Fibromyxoma Stromal Collagen

(Left) Acral fibromyxoma (AF),
also referred to as digital
fibromyxoma, is a benign
fibroblastic tumor that shows
a marked predilection for the
fingers and toes, particularly
the nail bed region.
Histologically, it is
characterized by bland,
spindled, and stellate cells
arranged in random, loose
fascicles and storiform arrays
within a variable myxoid to
fibrous stroma. (Right) Some
areas of AF feature prominent
stromal collagen, as depicted.

Loose Storiform Growth CD34 Expression

(Left) AF may also
demonstrate a loose
arrangement of cells in a more
vascularized stroma,
somewhat resembling
perineurioma. Despite its usual
dermal origin, in some cases,
AF shows superficial extension
into subcutaneous fat ﬈.
(Right) CD34 expression is
seen in most cases of AF, but
the extent of this positivity
varies. Focal EMA and SMA
may also be seen in rare cases.
S100 protein, claudin-1,
desmin, and keratins are
negative.

624
 Acral Fibromyxoma

Tumors of Uncertain Differentiation

○ Occasional multinucleated cells
TERMINOLOGY
○ Rare cases with increased cellularity
Abbreviations • Variable myxoid, myxocollagenous, or collagenous stroma
• Acral fibromyxoma (AF) • Small blood vessels common
• Mast cells common
Synonyms
• Rare mitoses; no necrosis
• Superficial AF
• Digital fibromyxoma ANCILLARY TESTS
• Cellular digital fibroma
Immunohistochemistry
Definitions • CD34(+)
• Benign fibroblastic neoplasm that occurs in hands and feet, • Loss of nuclear RB1 expression
particularly nail bed region • Occasional focal reactivity for EMA or SMA
• Generally negative for S100 protein, desmin, keratin,
CLINICAL ISSUES claudin-1, MUC4, STAT6
Epidemiology In Situ Hybridization
• Age • RB1 gene deletion by FISH
○ Wide range
– Most common in patients > 40 years DIFFERENTIAL DIAGNOSIS
• Sex
○ Male predilection Dermatofibroma (Fibrous Histiocytoma)
• Peripheral collagen trapping
Site • Chronic inflammation, foamy histiocytes common
• Almost exclusively hands and feet • Generally negative for CD34 and EMA
○ Vast majority in fingers and toes
– Particularly subungual or periungual region (nail bed) Perineurioma
• Extremely rare in nonacral sites • Can show morphologic overlap with AF
• Whorled (perivascular) growth pattern often prominent
Presentation • Claudin-1 (+), EMA(+), variable CD34(+)
• Solitary, slowly growing, and often longstanding lesion
○ Associated with pain in up to 40-50% of cases Dermatofibrosarcoma Protuberans
• Superficial, dermal based • Prominent infiltration of subcutaneous fat
• Characteristic prominent storiform growth pattern
Treatment • Homogeneous CD34(+)
• Complete excision • t(17;22) with COL1A1-PDGFB fusion
Prognosis Myxoid Neurofibroma
• Excellent prognosis • Elongated, wrinkled or buckled nuclei
• Recurrences have been reported in up to 22% • Loose fascicular or storiform growth uncommon
○ Usually related to incomplete excision • S100 protein (+), variable CD34(+)
• No reported case of metastasis or progression
Superficial Angiomyxoma
MACROSCOPIC • Lobular growth
• Blood vessels with slightly fibrosed walls
General Features
• Prominent myxoid stroma with perivascular neutrophils
• May appear dome-shaped, polypoid, or verrucoid
• Overlying mucosa intact or ulcerated Solitary Fibrous Tumor
• Rare tumors can erode underlying bone • Acral extremity involvement very rare
• CD34(+), STAT6(+)
Size
• Retained nuclear RB1 expression
• Usually < 5 cm (median: 1.5 cm)
SELECTED REFERENCES
MICROSCOPIC
1. Agaimy A et al: Superficial acral fibromyxoma: clinicopathological,
Histologic Features immunohistochemical, and molecular study of 11 cases highlighting
frequent Rb1 loss/deletions. Hum Pathol. 60:192-198, 2017
• Nodular, lobular, or irregular/infiltrative growth 2. Cullen D et al: Superficial acral fibromyxoma: report of 13 cases with new
○ Superficial involvement of subcutis and fat in some immunohistochemical findings. Am J Dermatopathol. 39(1):14-22, 2017
tumors 3. Hollmann TJ et al: Digital fibromyxoma (superficial acral fibromyxoma): a
detailed characterization of 124 cases. Am J Surg Pathol. 36(6):789-98, 2012
• Moderately cellular proliferation of spindled to stellate
4. Al-Daraji WI et al: Superficial acral fibromyxoma: a clinicopathological analysis
fibroblastic cells in randomly arranged, loose fascicles or of 32 tumors including 4 in the heel. J Cutan Pathol. 35(11):1020-6, 2008
storiform arrays 5. Fetsch JF et al: Superficial acral fibromyxoma: a clinicopathologic and
○ Nuclear atypia generally minimal to absent immunohistochemical analysis of 37 cases of a distinctive soft tissue tumor
with a predilection for the fingers and toes. Hum Pathol. 32(7):704-14, 2001
– Rare cases with scattered pleomorphic nuclei
625
 Pleomorphic Hyalinizing Angiectatic Tumor

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY
• Locally recurring but nonmetastasizing mesenchymal
neoplasm characterized by atypical spindled cells amidst
clusters of dilated, hyalinized vascular spaces
○ Possible pathogenetic relationship exists with other
entities: Hemosiderotic fibrolipomatous tumor (HFLT)
and myxoinflammatory fibroblastic sarcoma
CLINICAL ISSUES
• Median age: 51 years
• Usually lower leg, ankle, or foot
• Slow-growing, subcutaneous mass
• Treatment: Complete surgical excision
• Local recurrence in 30-50% of cases
○ May rarely progress to frank myxoid sarcoma
• No metastases reported
MACROSCOPIC
• Usually poorly circumscribed
MICROSCOPIC
• Unencapsulated
• Variably cellular, pleomorphic spindle cell proliferation
○ Intracytoplasmic hemosiderin
○ Intranuclear pseudoinclusions common
• Clusters of ectatic, thin-walled, hyalinized blood vessels
• Inflammatory infiltrate common
• Mitoses rare to absent and no necrosis
• Most cases show peripheral areas resembling HFLT
○ Infiltrative, bland, spindled cells with hemosiderin
ANCILLARY TESTS
• CD34(+) in most cases; S100 protein (-)
TOP DIFFERENTIAL DIAGNOSES
• Schwannoma
• HFLT
• Undifferentiated pleomorphic sarcoma

Pleomorphic Hyalinizing Angiectatic

Tumor Characteristic Vessels and Pleomorphism
(Left) Pleomorphic hyalinizing
angiectatic tumor (PHAT) is a
distinctive, locally recurring
but nonmetastasizing soft
tissue neoplasm with an
unusual predilection for the
distal lower extremity. Classic
cases feature a variably
cellular, pleomorphic spindle
cell proliferation, hemosiderin
pigment ﬉, and dilated, thin-
walled blood vessels with
fibrinoid change and
hyalinization. (Right) Classic
PHAT features pleomorphic
spindled cells ﬊ and ectatic
vessels ﬈ with fibrinoid
change, hyalinization, or
thrombosis.

HFLT-Like Areas (Early Pleomorphic

Hemosiderin and Inflammatory Cells Hyalinizing Angiectatic Tumor)
(Left) High-power H&E of
PHAT shows characteristic
hyperchromatic, pleomorphic
nuclei ﬉ as well as
hemosiderin pigment ﬊ and
chronic inflammatory cells,
including mast cells ſt and
lymphocytes. (Right) A bland,
infiltrative spindle cell
proliferation ﬊ with
hemosiderin ﬈ is commonly
seen at the periphery of PHAT
and is generally considered a
precursor lesion (early PHAT).
It resembles (or is likely
identical to) hemosiderotic
fibrolipomatous tumor (HFLT).

626
 Pleomorphic Hyalinizing Angiectatic Tumor
TERMINOLOGY
Abbreviations
• Pleomorphic hyalinizing angiectatic tumor (PHAT)
Definitions
• Locally recurring but nonmetastasizing mesenchymal
neoplasm characterized by atypical spindled cells amidst
clusters of dilated, hyalinized vascular spaces
○ Possible pathogenetic relationship exists between PHAT,
hemosiderotic fibrolipomatous tumor (HFLT), and
myxoinflammatory fibroblastic sarcoma (MIFS)
– Hybrid tumors: HFLT/PHAT or PHAT/MIFS (rare)
– Current data suggests that HFLT and PHAT are related
lesions, whereas PHAT and classic MIFS are not
□ Hybrid PHAT/MIFS cases likely represent PHAT with
sarcomatous progression rather than classic MIFS
CLINICAL ISSUES
Epidemiology
• Age
○ Wide range: 10-80 years (median: 51 years)
• Sex
○ Slight female predominance
Site
• Usually lower leg, ankle, or foot
• Rarely thigh or other sites
Presentation
• Slow-growing, often painless mass
○ Usually subcutaneous; rarely deep
Treatment
• Complete surgical excision
• Reexcision of local recurrences
Prognosis
• Local recurrence in 30-50% of cases
○ Rare cases progress to frank myxoid sarcoma
• No metastases reported in PHAT or HFLT/PHAT
MACROSCOPIC
General Features
• Usually poorly circumscribed
• Tan-gray to dark brown or red
Size
• Wide range (median: 6 cm)
MICROSCOPIC
Histologic Features
• Unencapsulated
• Variably cellular proliferation of spindle cells
○ Nuclear hyperchromasia and pleomorphism common
○ Prominent intranuclear cytoplasmic inclusions
○ Intracytoplasmic hemosiderin pigment
– May be abundant and striking in some cases
○ Mitoses rare to absent
• Clusters of ectatic, thin-walled blood vessels
Tumors of Uncertain Differentiation
○ Fibrinoid and hyaline material in vessel walls
• Hyalinized to myxoid stroma
○ Inflammatory infiltrate common
– Particularly mast cells
• Necrosis absent
• Most cases show peripheral areas resembling HFLT
○ Infiltrative, bland, spindled cells associated with
hemosiderin
○ Appears to represent precursor lesion of PHAT
• Rare cases progress to frank myxoid sarcoma
○ Increased cellularity and mitotic activity
○ May resemble MIFS
ANCILLARY TESTS
Immunohistochemistry
• CD34(+) in most cases
• S100 protein, keratin, desmin (-)
Molecular Genetics
• TGFBR3 &/or MGEA5 gene rearrangements reported in
PHAT and HFLT
DIFFERENTIAL DIAGNOSIS
Schwannoma
• Encapsulated
• Occurs at variety of sites beyond lower extremity
• Verocay body formation in many
• Areas with degenerative/ancient changes may resemble
PHAT
• Strong, diffuse S100 protein (+); CD34(-)
Hemosiderotic Fibrolipomatous Tumor
• Appears to be histogenetically related to PHAT
○ Tumors often show hybrid features of HFLT and PHAT
• Lacks large, dilated vessels with fibrinoid material
• Prominent adipose tissue component
Undifferentiated Pleomorphic Sarcoma
• May contain areas with large, hyalinized vessels
• Usually large, deeply situated mass; necrosis common
• High cellularity and nuclear grade; atypical mitoses
Myxoinflammatory Fibroblastic Sarcoma
• Classically, mixture of myxoid, hyalinized, and inflammatory
zones
• Large, ganglion-like cells, virocyte-like macronucleoli;
pseudolipoblasts
SELECTED REFERENCES
1. Boland JM et al: Hemosiderotic fibrolipomatous tumor, pleomorphic
hyalinizing angiectatic tumor, and myxoinflammatory fibroblastic sarcoma:
related or not? Adv Anat Pathol. 24(5):268-77, 2017
2. Carter JM et al: TGFBR3 and MGEA5 rearrangements in pleomorphic
hyalinizing angiectatic tumors and the spectrum of related neoplasms. Am J
Surg Pathol. 38(9):1182-992, 2014
3. Illueca C 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. 20(1):96-101, 2012
4. Folpe AL et al: Pleomorphic hyalinizing angiectatic tumor: analysis of 41
cases supporting evolution from a distinctive precursor lesion. Am J Surg
Pathol. 28(11):1417-25, 2004
627
 Pleomorphic Hyalinizing Angiectatic Tumor
Tumors of Uncertain Differentiation

Gross Specimen Prominent Ectatic Vasculature

(Left) This PHAT is partially
circumscribed ﬊ but focally
extends into fat st. An
infiltrative peripheral border is
common in this tumor. The
tumor is reddish-brown due to
a combination of old and
recent hemorrhage. (Right)
The characteristic ectatic or
dilated vasculature is
generally conspicuous in
PHAT; however, in more
cellular or solid tumors, these
vessels may be only focally
prominent. Note the fibrinoid
change ﬉ and hyalinization
apparent even at low power.

Partial Thrombosis and Hemosiderin Clusters of Hyalinized Vessels

(Left) Thrombosis ﬈ within
vessels is relatively common in
PHAT. Focal intraluminal
papillary endothelial
hyperplasia or recanalization
may also be seen in some
cases. (Right) In this PHAT,
there are aggregates of
angiectatic blood vessels with
hyalinized walls that have
fused ﬈. This resembles the
vascular changes in ancient
schwannoma.

Prominent Thrombosed Vasculature Infiltrative Border

(Left) This case of PHAT
features predominantly large,
thrombosed vascular spaces
﬈ separated by cellular
fibrous tissue ﬊. The lesion
infiltrates subcutaneous fat at
the periphery ﬉. (Right) PHAT
often shows an infiltrative
periphery with tumor cells
infiltrating between mature
adipocytes ﬈, as shown in
this H&E. These peripheral
areas typically show features
of HFLT (early PHAT).

628
 Pleomorphic Hyalinizing Angiectatic Tumor
Nuclear Pseudoinclusions
Rare Mitotic Figures Minimally Pleomorphic Areas
Solid/Cellular Areas
Tumors of Uncertain Differentiation
Hemosiderin
(Left) Intranuclear
pseudoinclusions ﬈ are
common in PHAT and may
appear pale or deeply
eosinophilic depending upon
the color of the cytoplasm of
the cell. (Right)
Intracytoplasmic hemosiderin
﬈ is common in PHAT but
varies widely in amount and
distribution. Some cases
feature extensive hemosiderin
readily apparent at low
magnification, and others
require a histochemical stain
in order for iron to fully
appreciate them.
(Left) Mitoses ﬉ are rare in
PHAT. More than an
occasional mitotic figure
should raise concerns for a
true pleomorphic sarcoma.
Very rare cases have been
reported of PHAT recurring as
frank sarcoma with abundant
mitoses and necrosis. (Right)
Although characteristic of
classic PHAT, pleomorphic
nuclei may be subtle or absent
in some areas, as depicted
here.
Myxoid Areas
(Left) Solid areas of PHAT with
an absent ectatic vasculature
may be easily confused for
frank sarcoma; however, the
cytologic features are
identical to those in more
conventional areas, and
mitotic figures remain sparse
or absent. (Right) Myxoid
stroma is uncommon in PHAT.
This unusual case also shows
areas somewhat reminiscent
of myxoinflammatory
fibroblastic sarcoma or
myxofibrosarcoma, including
pseudolipoblasts ﬈. This rare
phenomenon likely represents
sarcomatous progression in
PHAT.
629
 Aneurysmal Bone Cyst of Soft Tissue

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY MICROSCOPIC
• Benign, primary soft tissue counterpart of intraosseous • Well circumscribed, noninfiltrative
aneurysmal bone cyst (ABC) • Histologically identical to intraosseous ABC
CLINICAL ISSUES ○ Variable-sized cystic spaces filled with blood
○ Cystic walls and septa composed of cytologically bland
• Very rare
spindled cells
• Range: 7-57 years (median: 29 years)
○ Clusters of osteoclast-like giant cells common
• 2:1 = F:M
○ Immature (woven) bone common in septa and around
• Deep soft tissues of upper extremity, shoulder, and thigh periphery of lesion
• Usually no history of trauma reported
• Treatment: Complete surgical excision ANCILLARY TESTS
• Benign; excellent prognosis • Molecular: Various rearrangements involving USP6 (17p13)
IMAGING TOP DIFFERENTIAL DIAGNOSES
• Oval-shaped, variably ossified soft tissue mass • Myositis ossificans
• Intralesional septations and fluid levels • Nodular fasciitis
• Giant cell tumor of soft tissue
MACROSCOPIC
• Extraskeletal osteosarcoma
• Range: 2-9 cm (median: 5.2 cm)

Aneurysmal Bone Cyst of Soft Tissue Peripheral Bone Formation

(Left) Soft tissue ABC is a form
of ABC that occurs exclusively
in soft tissue sites without
bony involvement. It is
morphologically nearly
identical to intraosseous ABC,
and at low power, it shows a
multicystic, hemorrhagic
lesion with variably cellular
septa, as depicted. (Right) A
peripheral rim of immature or
mature bone ﬇ is a frequent
feature of soft tissue ABC. This
finding can lead to histologic,
clinical, and radiologic
confusion with myositis
ossificans. Note the
centralized hemorrhagic cavity
﬈.

Classic Features Loose Fibromyxoid Stroma

(Left) The septa and cyst walls
of soft tissue ABC are
composed of bland spindled
fibroblastic cells admixed with
scattered, osteoclast-like giant
cells ﬈ and foci of immature
(woven) bone formation ﬇. A
mild chronic inflammatory
infiltrate may also be present
in some cases. (Right) The
stroma in soft tissue ABC is
characteristically loose and
fibromyxoid in quality,
imparting a reactive
appearance. This morphology
is similar to what is seen in
early forms of nodular
fasciitis.

630
 Aneurysmal Bone Cyst of Soft Tissue

Tumors of Uncertain Differentiation

TERMINOLOGY MICROSCOPIC
Abbreviations Histologic Features
• Aneurysmal bone cyst (ABC) • Well circumscribed, noninfiltrative
• Histologically identical to intraosseous ABC
Definitions
○ Variable-sized cystic spaces filled with blood
• Benign, primary soft tissue counterpart of intraosseous
– Lack endothelial cell lining
ABC
○ Cystic walls and septa composed of cytologically bland
spindled cells
ETIOLOGY/PATHOGENESIS
– Storiform or fascicular growth
Neoplasm – Loose fibromyxoid stroma
• Characterized by recurrent rearrangements of USP6 gene ○ Clusters of osteoclast-like giant cells common
○ Not present in secondary, reactive ABC-like lesions ○ Variable mitotic rate (usually low)
○ Immature (woven) bone common in septa and around
CLINICAL ISSUES periphery of lesion
Epidemiology – Occasional mature bone at periphery

• Incidence ANCILLARY TESTS

○ Very rare
• Age Molecular Genetics
○ Range: 7-57 years (median: 29 years) • Various rearrangements involving USP6 (17p13)
• Sex ○ USP6 rearrangements also detected in nodular fasciitis
○ 2:1 = F:M (most frequently MYH9-USP6)

Site DIFFERENTIAL DIAGNOSIS

• Deep soft tissues of upper extremity, shoulder, and thigh
Myositis Ossificans
○ Groin, abdominal wall also reported
• May closely mimic ABC clinically and radiologically
Presentation • History of trauma often present
• Generally short time to presentation (weeks to several • Solid growth; lacks prominent hemorrhagic cysts
months) • Characteristic zonal maturation
• Painful or painless mass • Lacks USP6 rearrangements
• Usually no history of trauma reported
Nodular Fasciitis
Treatment • Small, rapidly growing superficial lesion
• Complete surgical excision • Generally lacks prominent hemorrhagic cysts
Prognosis • Peripheral bone formation not feature
• Distinctive MYH9-USP6 rearrangement
• Benign; excellent prognosis
○ Not yet described in soft tissue ABC
• Usually cured by complete excision
○ 1 reported case of local recurrence following incomplete Giant Cell Tumor of Soft Tissue
excision • Osteoclast-like giant cell component more prominent
• No evidence of malignant transformation • Lacks USP6 rearrangements

IMAGING Extraskeletal Osteosarcoma

• Malignant cytologic atypia and atypical mitoses
General Features
• Lacks USP6 rearrangements
• Oval-shaped soft tissue mass
• Variable ossification, often peripheral SELECTED REFERENCES
• No skeletal involvement
1. Lopez LV et al: Extraskeletal aneurysmal bone cyst: report of a case and
MR Findings review of the literature. Pathol Res Pract. 213(11):1445-1449, 2017
2. Jacquot C et al: Soft-tissue aneurysmal bone cyst with translocation
• Intralesional septations and fluid levels t(17;17)(p13;q21) corresponding to COL1A1 and USP6 loci. Skeletal Radiol.
44(11):1695-9, 2015
MACROSCOPIC 3. Pietschmann MF et al: Aneurysmal bone cysts of soft tissue represent true
neoplasms: a report of two cases. J Bone Joint Surg Am. 93(9):e45, 2011
General Features 4. Sukov WR et al: Frequency of USP6 rearrangements in myositis ossificans,
brown tumor, and cherubism: molecular cytogenetic evidence that a subset
• Peripheral rim of thin bone often present of "myositis ossificans-like lesions" are the early phases in the formation of
• Red-brown cystic, hemorrhagic tissue soft-tissue aneurysmal bone cyst. Skeletal Radiol. 37(4):321-7, 2008
5. Ellison DA et al: Soft-tissue aneurysmal bone cyst: report of a case with
Size t(5;17)(q33;p13). Pediatr Dev Pathol. 10(1):46-9, 2007
6. Nielsen GP et al: Soft tissue aneurysmal bone cyst: a clinicopathologic study
• Range: 2-9 cm (median: 5.2 cm) of five cases. Am J Surg Pathol. 26(1):64-9, 2002

631
 Ectopic Hamartomatous Thymoma

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY
• Definition: Rare benign tumor composed of spindle,
epithelial, and adipose tissue elements that occurs mainly in
lower neck region
• Synonym: Branchial anlage mixed tumor
CLINICAL ISSUES
• Occurs in adults (median: 40 years)
• Male predominance (4:1)
• Arises in subcutaneous tissue of lower neck, supraclavicular,
or suprasternal region
• Painless, slowly enlarging mass, often of long duration
• Treatment: Conservative surgical excision
• Benign; local recurrence very rare
MACROSCOPIC
• Usually 2-8 cm in size (average: 5 cm)
MICROSCOPIC
• Well circumscribed, unencapsulated
• Haphazard admixture of spindle cells, epithelial cells, and
mature adipose tissue in varying proportions
○ Spindle cells form sheets, short fascicles, or storiform
arrays
○ Solid, cystic, or glandular epithelial components
ANCILLARY TESTS
• Diffuse keratin (+) in both epithelial and spindle cells
• Variable CD34(+) and SMA(+) in spindle cells
• S100 protein (-), desmin (-), STAT6(-), and pax-8(-)
TOP DIFFERENTIAL DIAGNOSES
• Pleomorphic adenoma
• Synovial sarcoma (biphasic)
• Sarcomatoid carcinoma
• Solitary fibrous tumor

Ectopic Hamartomatous Thymoma Epithelial Elements

(Left) Ectopic hamartomatous
thymoma (EHT) is a distinctive
soft tissue tumor that occurs
primarily in the neck region of
adult men. It classically shows
3 components (epithelial,
spindled, and adipose tissue) in
varying proportions. (Right)
The epithelial component is
often characterized by solid
nests or trabeculae of
squamous cells, but glandular
or ductular differentiation is
also seen. Clear cell change,
sebaceous differentiation, and
frank keratinization may also
be identified.

Cystic Epithelial Elements Spindle Cell Component

(Left) The epithelial elements
can also show cystic dilation
and may contain eosinophilic
material. Note also the
associated spindle cell and
mature adipose tissue
components. (Right) The
spindle cell component of EHT
is made up of bland and
relatively monomorphic cells
with elongated nuclei.
Cellularity varies, and sheets,
short fascicles, and storiform
architectural arrays can be
seen. Of note, both the
epithelial and spindle cell
components show diffuse
expression of keratin.

632
 Ectopic Hamartomatous Thymoma

Tumors of Uncertain Differentiation

○ Spindle cells
TERMINOLOGY
– Sheets, short fascicles, or storiform arrays
Abbreviations □ Variable cellularity
• Ectopic hamartomatous thymoma (EHT) – Bland, elongated, sometimes tapering nuclei
○ Epithelial cells
Synonyms
– Solid, cystic, or glandular components
• Branchial anlage mixed tumor – Squamous elements are usually predominant
Definitions □ May show keratinization
• Rare benign tumor composed of spindle, epithelial, and – Epithelial-lined cysts are seen focally in many cases
adipose tissue elements that occurs mainly in lower neck ○ Mature adipose tissue
region – May be relatively abundant
• Generally low mitotic rate
ETIOLOGY/PATHOGENESIS • Subtle stromal lymphoid infiltrate may be present
Developmental Anomaly
ANCILLARY TESTS
• Suggested derivation from sequestered branchial
epithelium Immunohistochemistry
• Possible origin from thymic anlage remnants • Diffuse keratin (+) in both epithelial and spindle cells
○ Includes low- and high-molecular-weight keratins
CLINICAL ISSUES • Variable CD34(+) and SMA(+) in spindle cells
Epidemiology • S100 protein (-), desmin (-), STAT6(-), and pax-8(-)
• Incidence
DIFFERENTIAL DIAGNOSIS
○ Very rare
• Age Pleomorphic Adenoma
○ Adults (median: 40 years) • Salivary gland origin
• Sex • Chondromyxoid stroma &/or cartilaginous differentiation
○ Male predominance (4:1) • Spindle cells are keratin (+), S100(+), EMA(+), CD34(-)
• PLAG1 gene rearrangements
Site
• Subcutaneous tissue of lower neck, supraclavicular, or Synovial Sarcoma (Biphasic)
suprasternal region • Squamous nests and intratumoral adipose tissue
○ May also arise subfascially uncommon
• Keratin (+) in spindled tumor cells is usually patchy or focal
Presentation
• Nuclear TLE1(+), CD34(-)
• Painless, slowly enlarging mass, often of long duration
• Characteristic t(X;18) involving SS18 (SYT)
○ Clinical presentation and diagnostic imaging may
suggest malignancy Sarcomatoid Carcinoma
Treatment • Usually overtly cytologically malignant
• Mitoses and necrosis common
• Conservative surgical excision
Solitary Fibrous Tumor
Prognosis
• Lacks epithelial elements
• Benign
• STAT6(+)
• Local recurrence is very rare if completely excised
• Keratins (-)
• Does not metastasize
○ Very rare cases of carcinoma arising in EHT have been SELECTED REFERENCES
reported in literature
1. Sato K et al: Ectopic hamartomatous thymoma: a review of the literature
with report of new cases and proposal of a new name: biphenotypic
MACROSCOPIC branchioma. Head Neck Pathol. 12(2):202-9 2017
2. Weissferdt A et al: Ectopic hamartomatous thymoma-new insights into a
General Features challenging entity: a clinicopathologic and immunohistochemical study of 9
• Well circumscribed, lobulated cases. Am J Surg Pathol. 40(11):1571-1576, 2016
3. Jing H et al: Ectopic hamartomatous thymoma: report of a case and review
• Tan-white to yellow, firm cut surface of literature. Int J Clin Exp Pathol. 8(9):11776-84, 2015
Size 4. Liang PI et al: Ectopic hamartomatous thymoma is distinct from lipomatous
pleomorphic adenoma in lacking PLAG1 aberration. Histopathology.
• Usually 2-8 cm (average: 5 cm) 62(3):518-22, 2013
5. Kushida Y et al: Ectopic hamartomatous thymoma: a case report with
immunohistochemical study and review of the literature. J Cutan Pathol.
MICROSCOPIC 33(5):369-72, 2006
Histologic Features 6. Fetsch JF et al: Ectopic hamartomatous thymoma: a clinicopathologic and
immunohistochemical analysis of 21 cases with data supporting
• Well circumscribed, unencapsulated reclassification as a branchial anlage mixed tumor. Am J Surg Pathol.
28(10):1360-70, 2004
• Haphazard admixture of spindle cells, epithelial cells, and
mature adipose tissue in varying proportions
633
 Hemosiderotic Fibrolipomatous Tumor

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY MICROSCOPIC
• Synonym: Hemosiderotic fibrohistiocytic lipomatous lesion • Unencapsulated
• Locally aggressive but nonmetastasizing neoplasm • Lobules of mature adipose tissue with loose fascicles of
featuring mixture of mature adipose tissue, bland spindled bland spindled cells in septal, perilobular, or periadipocytic
cells, abundant hemosiderin, and chronic inflammatory cells arrangement
○ Possible pathogenetic relationship exists with other • Hemosiderin always present and often abundant
entities: Pleomorphic hyalinizing angiectatic tumor • Mitoses absent to scarce
(PHAT) and myxoinflammatory fibroblastic sarcoma
(MIFS) ANCILLARY TESTS
• CD34(+)
CLINICAL ISSUES • Keratins, EMA, S100 protein, SMA, desmin (-)
• Most common: 40-60 years • Molecular: t(1;10)(p22;q24) involving rearrangements of
• Marked female predominance TGFBR3 &/or MGEA5
• Predominantly affects distal extremities
TOP DIFFERENTIAL DIAGNOSES
○ Particularly foot or ankle
• Treatment: Complete surgical excision • Spindle cell lipoma
• Local recurrence in up to 50% • PHAT
• No metastases • MIFS
• Dermatofibrosarcoma protuberans

Hemosiderotic Fibrolipomatous Tumor Prominent Hemosiderin

(Left) Hemosiderotic
fibrolipomatous tumor (HFLT)
features lobules of mature
adipose tissue admixed with
variably cellular fascicles of
spindle cells, often along septa
and around or within lobules.
This appearance may resemble
a reactive, rather than
neoplastic, process.
Hemosiderin ﬉ is often
prominent and appreciable
even at low power. (Right)
Hemosiderin deposition is a
characteristic feature of HFLT
and is usually quite prominent.
Note also the irregular septal
and perilobular growth around
the mature adipose tissue.

Bland Spindle Cells Occasional Multinucleated Giant Cells

(Left) In general, tumor cells in
HFLT are cytologically banal;
however, occasional enlarged
or pleomorphic
hyperchromatic nuclei (similar
to what is seen in pleomorphic
hyalinizing angiectatic tumor)
may be seen in some cases.
Mitoses are absent. Note the
hemosiderin ﬉. (Right)
Multinucleated giant cells may
be seen in HFLT and are often
of the osteoclastic variety ﬊.
Note also the hemosiderin
pigment ﬈.

634
 Hemosiderotic Fibrolipomatous Tumor

Tumors of Uncertain Differentiation

TERMINOLOGY
Abbreviations
• Hemosiderotic fibrolipomatous tumor (HFLT)
Synonyms
• Hemosiderotic fibrohistiocytic lipomatous lesion
Definitions
• Locally aggressive but nonmetastasizing neoplasm
featuring mixture of mature adipose tissue, bland spindled
cells, abundant hemosiderin, and chronic inflammatory cells
○ Possible pathogenetic relationship exists between HFLT,
pleomorphic hyalinizing angiectatic tumor (PHAT), and
myxoinflammatory fibroblastic sarcoma (MIFS)
– "Hybrid" tumors: HFLT with PHAT or HFLT with MIFS
– Current data suggests that HFLT and PHAT are related
lesions, whereas HFLT and classic MIFS are not
□ Hybrid HFLT/MIFS cases likely represent HFLT with
sarcomatous progression rather than classic MIFS
• Occasional osteoclast-type multinucleated giant cells
• Chronic inflammatory cells, including lymphocytes, foamy
histiocytes, plasma cells, and mast cells
• Focal features suggestive of PHAT or MIFS may be present
○ PHAT: Scattered pleomorphic nuclei with
pseudoinclusions; ectatic hyalinized blood vessels
○ MIFS: Larger atypical cells with prominent macronucleoli
in variable myxoid stroma
ANCILLARY TESTS
Immunohistochemistry
• CD34(+)
• Keratins, EMA, S100 protein, SMA, desmin (-)
Molecular Genetics
• t(1;10)(p22;q24) with rearrangements of TGFBR3 &/or
MGEA5
• To date, no BRAF mutations reported in pure HFLT or
hybrid HFLT/MIFS

CLINICAL ISSUES DIFFERENTIAL DIAGNOSIS

Epidemiology Spindle Cell Lipoma
• Age • Most common in neck, shoulder, upper back
○ Most common: 40-60 years • Bundles of "ropey" collagen
• Sex • Lacks abundant hemosiderin
○ Marked female predominance Pleomorphic Hyalinizing Angiectatic Tumor
Site • Likely related to HFLT
• Predominantly distal extremities (particularly foot or ankle) • Variable cellular, solid proliferation of pleomorphic spindle
• Less frequent: Calf, cheek, thigh cells with nuclear pseudoinclusions
• Characteristic clusters of ectatic hyalinized vessels
Presentation
• Slow-growing subcutaneous mass Myxoinflammatory Fibroblastic Sarcoma
• Classically, mixture of myxoid, hyalinized, and inflammatory
Treatment zones
• Complete surgical excision • Large ganglion-like cells, virocyte-like macronucleoli;
Prognosis pseudolipoblasts
• Cases reported of HFLT with areas resembling MIFS
• Local recurrence in up to 50%
○ Likely represent HFLT with sarcomatous progression,
○ Often related to incomplete excision
unrelated to classic MIFS
• No metastases reported
Dermatofibrosarcoma Protuberans
MACROSCOPIC • Usually prominent storiform growth pattern
General Features • Lacks abundant inflammation and hemosiderin
• t(17;22) with COL1A1-PDGFRB fusion
• Poorly defined fatty proliferation
•  Dark yellow-brown cut surface
SELECTED REFERENCES
Size 1. Boland JM et al: Hemosiderotic fibrolipomatous tumor, pleomorphic
• Wide size range (average: 7.7 cm) hyalinizing angiectatic tumor, and myxoinflammatory fibroblastic sarcoma:
related or not? Adv Anat Pathol. 24(5):268-277, 2017
2. Kao YC et al: Recurrent BRAF gene rearrangements in myxoinflammatory
MICROSCOPIC fibroblastic sarcomas, but not hemosiderotic fibrolipomatous tumors. Am J
Surg Pathol. 41(11):1456-1465, 2017
Histologic Features 3. Zreik RT et al: TGFBR3 and MGEA5 rearrangements are much more common
• Unencapsulated in "hybrid" hemosiderotic fibrolipomatous tumor-myxoinflammatory
fibroblastic sarcomas than in classical myxoinflammatory fibroblastic
• Subcutaneous lobules of homogeneous fat sarcomas: a morphological and fluorescence in situ hybridization study. Hum
• Loose fascicles of spindled cells in septal, perilobular, or Pathol. 53:14-24, 2016
periadipocytic arrangement 4. Browne TJ et al: Haemosiderotic fibrolipomatous tumour (so-called
haemosiderotic fibrohistiocytic lipomatous tumour): analysis of 13 new cases
○ Cytologically bland; usually no significant pleomorphism in support of a distinct entity. Histopathology. 48(4):453-61, 2006
○ Mitoses absent to scarce 5. Marshall-Taylor C et al: Hemosiderotic fibrohistiocytic lipomatous lesion: ten
cases of a previously undescribed fatty lesion of the foot/ankle. Mod Pathol.
• Hemosiderin always present and often abundant 13(11):1192-9, 2000
○ May be seen in spindle cells or histiocytes

635
 Atypical Fibroxanthoma

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY
• Atypical fibroxanthoma (AFX)
• Strictly defined, dermal-based mesenchymal neoplasm
showing no specific lineage of differentiation
○ Should be negative for markers of melanocytic (i.e.,
S100, SOX10, melan-A), epithelial (i.e., cytokeratins and
p63), and vascular (i.e., CD34, ERG) differentiation
○ Not allowed: Invasion into deep subcutaneous tissue and
beyond, tumor necrosis, lymphovascular invasion, and
perineurial involvement
○ Can only be diagnosed on complete excision (diagnosis
of exclusion)
CLINICAL ISSUES
• Mass lesion, may be ulcerated or bleeding
• Often rapidly growing tumor in head and neck region of
elderly adult
• Rate of local recurrence is low (< 10% reported)
MICROSCOPIC
• Highly atypical and pleomorphic dermal-based proliferation
of spindled to epithelioid-appearing cells
• Scattered large, bizarre-appearing, multinucleated cells
often seen
• Variants include spindle cell, clear cell, granular, others
• Numerous mitoses, including highly atypical forms
ANCILLARY TESTS
• IHC is essential to exclude other, more specific diagnoses
• Negative for cytokeratins (especially high-molecular-weight
cytokeratins), p63, and melanocytic, myogenic, and vascular
markers
TOP DIFFERENTIAL DIAGNOSES
• Sarcomatoid carcinoma
• Spindle cell melanoma
• Pleomorphic dermal sarcoma
• Leiomyosarcoma and other sarcomas

Atypical Fibroxanthoma at Low

Atypical Fibroxanthoma Magnification
(Left) Clinical photograph
shows an atypical
fibroxanthoma (AFX) on the
ear of an elderly patient. Note
that the surface is ulcerated
and shows focal serum crust
﬊. (Right) Histologic section
of AFX at low magnification
shows a large, dermal-based,
nodular to sheet-like
collection of atypical tumor
cells with diffuse overlying
ulceration. The dermis shows
several congested dilated
vessels and hemorrhage ﬉.

Atypical Fibroxanthoma at High CD10 Immunohistochemical Stain in

Magnification Atypical Fibroxanthoma
(Left) High magnification of
AFX shows a proliferation of
markedly atypical and
pleomorphic-appearing,
spindled and large, bizarre-
appearing, multinucleated ﬇
tumor giant cells. (Right) CD10
shows very strong and diffuse
staining in most cases of AFX.
Although this is a nonspecific
marker, in junction with
negative staining for all of the
more specific markers, it
supports the diagnosis of AFX.

636
 Atypical Fibroxanthoma
TERMINOLOGY
Abbreviations
• Atypical fibroxanthoma (AFX)
Definitions
• Strictly defined, dermal-based mesenchymal neoplasm
showing no specific lineage of differentiation
○ Should be negative for markers of melanocytic (i.e.,
S100, SOX10, melan-A), epithelial (i.e., cytokeratins and
p63), and vascular (i.e., CD31, ERG) differentiation
○ Not allowed: Invasion into deep subcutaneous tissue or
beyond, tumor necrosis, lymphovascular invasion, or
perineurial involvement (features which are compatible
with pleomorphic dermal sarcoma)
○ Can only be diagnosed on complete excision (diagnosis
of exclusion)
ETIOLOGY/PATHOGENESIS
Environmental Exposure
• Likely related to UV exposure, as most cases occur in elderly
patients in sun-damaged skin
• Some cases reported following radiation therapy
CLINICAL ISSUES
Epidemiology
• Age
○ Typically occurs in elderly patients
○ Rare cases in children with xeroderma pigmentosum or
Li-Fraumeni syndrome
• Sex
○ May have slight male predominance
Site
• Head and neck in general is most commonly affected area
○ Scalp is most common location
• Uncommonly occurs on trunk or extremities
Presentation
• Skin nodule, asymptomatic in most cases
○ Often rapidly growing lesion
○ Dermal-based nodule
○ Often shows overlying ulceration or crusting
Treatment
• Complete and wide surgical excision is typically pursued
○ Mohs surgery is also effective
Prognosis
• Very good in most cases
• Progressive lesion; does not regress without treatment
• Rate of local recurrence is low (< 10% reported)
• Vast majority of cases do not metastasize
○ Cases with more than minimal superficial involvement of
subcutis are considered pleomorphic sarcoma and have
metastatic potential
MACROSCOPIC
General Features
• Large, nodular, unencapsulated, dermal-based tumor
Tumors of Uncertain Differentiation
Size
• < 2 cm in greatest dimension in most cases
MICROSCOPIC
Histologic Features
• Nodular, dermal-based proliferation of atypical,
pleomorphic spindled and epithelioid-shaped cells
○ Cells are markedly enlarged and often bizarre appearing
○ Show atypical, hyperchromatic-staining nuclei
– Irregular nuclear borders and prominent nucleoli
○ Cytoplasm of tumor cells is abundant, eosinophilic, and
sometimes foamy/vacuolated appearing
○ Variants include spindle cell, clear cell, granular,
chondroid, and osteoid
• May show limited superficial pushing extension into
subcutis but nothing deeper
• No tumor necrosis, lymphovascular invasion, or perineurial
involvement
• Scattered large, bizarre-appearing, multinucleated giant
cells typically present
• Numerous mitoses, including highly atypical forms, usually
easily found
• No evidence of associated/overlying carcinoma or
melanoma in situ
○ Often separated from epidermis by thin grenz zone
ANCILLARY TESTS
Immunohistochemistry
• IHC is key in confirming diagnosis
○ Essential to exclude other, more specific diagnoses
• Negative for S100, SOX10, melanocytic markers,
cytokeratins (especially high-molecular-weight
cytokeratins), p63, p40, SMA, desmin, myogenin, CD31,
CD34, ERG
○ Focal/weak SMA expression or granular CD31 positivity
(in histiocytes) may be seen
• Positive for nonspecific markers, including CD10 (usually
very strong and diffuse), CD68 (may be focal/weak), CD99,
and vimentin
DIFFERENTIAL DIAGNOSIS
Sarcomatoid Carcinoma
• Typically squamous cell carcinoma (SCC), but poorly
differentiated adnexal carcinomas and metastatic
carcinomas should also be considered
• Positive: High-molecular-weight cytokeratins (CK5/6,
CK903/34βE12), p63, and p40 (especially primary
cutaneous tumors)
○ May or may not show staining for pancytokeratin,
AE1/AE3, EMA, and CAM5.2 (low-molecular-weight
cytokeratin)
Pleomorphic, Spindle Cell, and Desmoplastic
Melanoma
• Overlying junctional component/melanoma in situ is
present in majority of cases (> 70%)
• Positive: S100 and SOX10; ± MART-1/melan-A, HMB-45,
tyrosinase, and MITF
637
 Atypical Fibroxanthoma
Tumors of Uncertain Differentiation

Immunohistochemistry Table
Antibody Reactivity Staining Pattern Comment
CD10 Positive Cell membrane & Usually strongly and diffusely positive
cytoplasm
CD68 Positive Cell membrane & Usually positive, may be weak/focal
cytoplasm
CK-PAN Negative Positive control staining of epidermis and adnexal structures
CK-HMW-NOS Negative Positive control staining of epidermis and adnexal structures
p63 Negative Rare cases reportedly positive; must be CK negative
S100 Negative Entrapped dendritic cells positive
Melan-A Negative Junctional melanocytes serve as positive control
HMB-45 Negative Junctional melanocytes serve as positive control
Desmin Negative
CD34 Negative Highlights stromal vessels
CD31 Negative Highlights stromal vessels
Actin-sm Equivocal Cytoplasmic May be weakly positive in some cases, likely indicating
myofibroblastic differentiation
MITF Equivocal Nuclear Rare cases may be weakly/focally positive
CD99 Equivocal Cell membrane & Some cases positive, but often weak or negative
cytoplasm

○ S100 and SOX10 often only positive markers in spindle

cell and desmoplastic melanoma
○ Scattered S100-positive dendritic cells are present in
AFX, may be numerous in some cases, and should not be
misinterpreted as melanoma
Pleomorphic Dermal Sarcoma
• Contains features incompatible with diagnosis of AFX
○ Tumor necrosis, deep subcutaneous invasion (or
beyond), lymphovascular invasion, perineural
involvement
• Often shows clinical and histologic overlap with AFX
Leiomyosarcoma
• Proliferation of atypical spindle cells with elongated, blunt-
ended, or cigar-shaped nuclei
• Cells show abundant, eosinophilic-staining cytoplasm and
perinuclear vacuoles
• Positive: MSA, SMA, desmin (although up to 30% can be
negative)
Other Sarcomas
• Much less likely considerations (but differential may include
both primary and metastatic sarcomas)
• Angiosarcoma: Irregular, anastomosing vascular spaces;
CD31 and CD34 positive
• Malignant peripheral nerve sheath tumor (MPNST)
○ Usually deep-seated lesions but can rarely involve dermis
○ S100 positive in 50-70% of cases, usually focal/weak, may
show CD56 and nestin positive
• Fibrosarcoma (FS)
○ Usually arises in dermatofibrosarcoma protuberans
(DFSP) in dermis or superficial subcutis
○ Prominent herringbone pattern in FS areas, storiforming
in DFSP areas
SELECTED REFERENCES
1. Gaiser T et al: MYC gene amplification is a rare event in atypical
fibroxanthoma and pleomorphic dermal sarcoma. Oncotarget. 9(30):21182-
9, 2018
2. Griewank KG et al: Atypical fibroxanthoma and pleomorphic dermal sarcoma
harbor frequent NOTCH1/2 and FAT1 mutations and similar DNA copy
number alteration profiles. Mod Pathol. 31(3):418-28, 2018
3. Helbig D et al: Immunohistochemical expression of melanocytic and
myofibroblastic markers and their molecular correlation in atypical
fibroxanthomas and pleomorphic dermal sarcomas. J Cutan Pathol.
45(12):880-5, 2018
4. Polcz MM et al: Atypical fibroxanthoma management: recurrence,
metastasis and disease-specific death. Australas J Dermatol. 59(1):10-25,
2018
5. Tolkachjov SN et al: Atypical fibroxanthoma: systematic review and meta-
analysis of treatment with Mohs micrographic surgery or excision. J Am
Acad Dermatol. 79(5):929-34.e6, 2018
6. Nguyen CM et al: Clear cell atypical fibroxanthoma: a case report and review
of the literature. J Cutan Pathol. 43(6):538-42, 2016
7. Lai K et al: Genomic analysis of atypical fibroxanthoma. PLoS One.
12(11):e0188272, 2017
8. Henderson SA et al: p40 is more specific than p63 for the distinction of
atypical fibroxanthoma from other cutaneous spindle cell malignancies. Am
J Surg Pathol. 38(8):1102-10, 2014
9. Tongdee E et al: Keloidal atypical fibroxanthoma: case and review of the
literature. Case Rep Dermatol. 8(2):156-63, 2016
10. Lee SM et al: Atypical fibroxanthoma arising in a young patient with Li-
Fraumeni syndrome. J Cutan Pathol. 41(3):303-7, 2014
11. Tallon B et al: MITF positivity in atypical fibroxanthoma: a diagnostic pitfall.
Am J Dermatopathol. 36(11):888-91, 2014
12. Thum C et al: Atypical fibroxanthoma with pseudoangiomatous features: a
histological and immunohistochemical mimic of cutaneous angiosarcoma.
Ann Diagn Pathol. 17(6):502-7, 2013
13. Kanner WA et al: CD10, p63 and CD99 expression in the differential
diagnosis of atypical fibroxanthoma, spindle cell squamous cell carcinoma
and desmoplastic melanoma. J Cutan Pathol. 37(7):744-50, 2010
14. Mirza B et al: Atypical fibroxanthoma: a clinicopathological study of 89 cases.
Australas J Dermatol. 46(4):235-8, 2005

638
 Atypical Fibroxanthoma
Overlying Ulceration in Atypical
Fibroxanthoma
Multinucleated Tumor Cells
Superficial Atypical Fibroxanthoma
Tumors of Uncertain Differentiation
Spindle Cell Variant of Atypical
Fibroxanthoma
(Left) Histologic section of AFX
at low magnification shows a
large, dermal-based, nodular
to sheet-like collection of
atypical tumor cells with
overlying ulceration and dense
serum crust with cellular
debris ﬉. (Right)
Intermediate-power
examination of a spindle cell
variant of AFX shows a
proliferation of atypical,
hyperchromatic-staining
spindle cells forming dense,
short fascicles.
Atypical Mitoses
(Left) High magnification of
the same case shows a
proliferation of highly atypical
and pleomorphic-appearing,
spindled and focally
multinucleated ﬇ tumor cells.
(Right) High magnification of
another example of AFX
shows highly atypical cells
with numerous mitoses st,
including frankly atypical
forms ﬊.
Granular Cell Variant of Atypical
Fibroxanthoma
(Left) Histologic examination
of the superficial portion of an
AFX shows a proliferation of
markedly atypical, spindled
and epithelioid-shaped cells
with numerous large,
multinucleated tumor cells st.
The tumor closely abuts, but
does not involve, the overlying
epidermis ﬊. (Right) High
magnification of an example
of a rare granular cell variant
of AFX shows large, bizarre-
appearing histiocytoid cells
containing abundant granular
cytoplasm, similar to a
malignant granular cell tumor.
Mitoses ﬉ are easily found.
639
 Atypical Fibroxanthoma
Tumors of Uncertain Differentiation

Clear Cell Atypical Fibroxanthoma at Low Clear Cell Variant of Atypical

Magnification Fibroxanthoma at High Magnification
(Left) Clear cell AFX is a rare
variant of AFX, which can be
confused with other malignant
clear cell tumors. This example
shows diffuse overlying
ulceration with dense serum
crust ﬊. (Right) This is a rare
clear cell variant of AFX, which
shows a proliferation of large,
atypical, clear-staining cells
with multiple bizarre-
appearing, hyperchromatic-
staining nuclei ﬉.

Keratin Expression in Atypical

Fibroxanthoma S100 Expression in Atypical Fibroxanthoma
(Left) High-molecular-weight
cytokeratin
immunohistochemical stain
shows positivity within the
epidermis and adnexal ducts
﬊ but is negative within the
tumor cells. (Right) S100 IHC
shows no staining of the
tumor cells but highlights a
few scattered small
intradermal dendritic cells ﬈.

Focal SMA Expression in Atypical CD68 Expression in Atypical

Fibroxanthoma Fibroxanthoma
(Left) SMA stain shows
scattered positive cytoplasmic
staining ﬈ in a few of the
large cells, likely indicating
myofibroblastic
differentiation. (Right) CD68 is
a nonspecific marker but is
typically positive in AFX. This
example shows moderate to
strong cytoplasmic staining of
most of the tumor cells,
especially the large
multinucleated tumor giant
cells ﬉.

640
 Atypical Fibroxanthoma

Tumors of Uncertain Differentiation

DDx: Melanoma DDx: Melanoma With S100 Positivity
(Left) Melanoma should
always be considered in the
differential diagnosis with
AFX, especially spindle
cell/desmoplastic and
metastatic melanomas, which
can lack epidermal
attachments, be amelanotic,
and show striking atypia and
pleomorphism, including
multinucleated tumor giant
cells ﬊ similar to AFX. (Right)
S100 IHC shows diffuse, strong
nuclear and cytoplasmic
staining in a pleomorphic
melanoma. This finding would
exclude the possibility of AFX.

DDx: Poorly Differentiated Squamous Cell
Carcinoma
DDx: Squamous Cell Carcinoma and p63
Staining
(Left) This is a poorly
differentiated squamous cell
carcinoma (SCC) composed of
enlarged, markedly atypical
epithelioid cells with
abundant, pale to eosinophilic-
staining cytoplasm ﬈.
Scattered pleomorphic
multinucleated tumor cells ﬉
can be seen in some cases of
SCC. (Right) This is a high-
magnification view of a p63
stain in a poorly differentiated
SCC. High-molecular-weight
cytokeratin and p63 are the
most sensitive markers for
poorly differentiated and
spindle cell SCC and are
typically negative in AFX.

DDx: Leiomyosarcoma Showing Desmin

DDx: Leiomyosarcoma Staining
(Left) Leiomyosarcoma is
composed of large, atypical,
spindle-shaped cells with oval
to elongated, cigar-shaped
nuclei ﬉ and abundant,
eosinophilic-staining
cytoplasm. (Right) Desmin
immunostain shows strong
cytoplasmic labeling in this
leiomyosarcoma. Most cases
are positive for both SMA and
desmin, although up to 30% of
cases can be desmin negative.

641
 Angiomatoid Fibrous Histiocytoma

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY • Sheets, nodules, and aggregates of ovoid to spindled cells

• Distinctive, rarely metastasizing mesenchymal neoplasm • Most cells are cytologically bland with vesicular nuclei;
composed of nodules and sheets of spindled and mitoses infrequent
histiocytoid cells ○ Scattered cells with nuclear hyperchromasia and
○ Often demonstrates pseudoangiomatous spaces and pleomorphism are common
peripheral lymphoplasmacytic cuff • Variably sized, blood-filled pseudovascular spaces in
majority of cases
CLINICAL ISSUES
ANCILLARY TESTS
• Predominantly children and young adults
• Most often arises in superficial extremities • Desmin (+) in 50-60% of cases
• Constitutional symptoms in subset (e.g., fever, malaise, • ALK (+) by IHC common
anemia) • Variable, nonspecific expression of EMA, CD68, CD99, SMA
• Treatment: Wide local excision with follow-up • Molecular: t(2:22) with EWSR1-CREB1 fusion most common
• ≤ 15% recur locally TOP DIFFERENTIAL DIAGNOSES
• Rare cases metastasize (< 5%)
• Aneurysmal variant of fibrous histiocytoma
MICROSCOPIC • Nodal metastasis
• Fibrous pseudocapsule with lymphoplasmacytic cuff (80% • Follicular dendritic cell sarcoma
of cases) • Granulomatous lesions

Angiomatoid Fibrous Histiocytoma Nodular/Lobular Growth

(Left) Angiomatoid fibrous
histiocytoma (AFH) most
commonly occurs in the
subcutaneous tissue or deep
dermis of the extremities.
Most examples demonstrate a
fibrous pseudocapsule
associated with a patchy
chronic inflammatory
infiltrate ﬈. The overall
pattern may mimic a lymph
node metastasis. (Right) Many
cases of AFH show a
multinodular or lobular
growth pattern. The fibrous
septa are extensions of the
characteristic fibrous
pseudocapsule ﬈ surrounding
the tumor.

Lymphoplasmacytic Cuff Lymphoplasmacytic Cuff

(Left) The majority of cases of
AFH have a
lymphoplasmacytic cuff of
varying extent and thickness in
and around the pseudocapsule
﬈. Reactive germinal centers
﬊ may also be seen, further
simulating the appearance of
a lymph node containing
metastatic tumor. (Right) The
chronic inflammatory
infiltrate ﬉ that makes up
the characteristic peripheral
cuff of AFH is composed of a
mixture of nonclonal B- and T-
lymphocytes and polytypic
plasma cells.

642
 Angiomatoid Fibrous Histiocytoma
TERMINOLOGY
Abbreviations
• Angiomatoid fibrous histiocytoma (AFH)
Synonyms
• Angiomatoid malignant fibrous histiocytoma
○ Term "malignant" removed due to relatively indolent
clinical behavior (2013 WHO classification)
Definitions
• Distinctive, rarely metastasizing mesenchymal neoplasm
composed of nodules and sheets of spindled and
histiocytoid cells
○ Often demonstrates pseudoangiomatous spaces and
peripheral lymphoplasmacytic cuff
ETIOLOGY/PATHOGENESIS
Lineage Uncertain
• Postulated nodal fibroblastic reticulum cell differentiation
• Myoid, myofibroblastic, endothelial, or histiocytic
differentiation not proven
CLINICAL ISSUES
Epidemiology
• Incidence
○ Rare
• Age
○ Predominantly children and young adults
○ Rare in adults > 40 years
– More likely to arise in extrasomatic locations
• Sex
○ Slight female predilection
Site
• Most common in superficial extremities (deep dermis and
subcutis)
○ Rarely arise in deep soft tissue
• Also trunk and head/neck, including scalp
• Rare extrasomatic cases reported in lung, bone,
mediastinum, retroperitoneum, brain, ovary, and vulva
Presentation
• Slowly growing, painless mass
○ Rapid growth uncommon and likely attributable to
intratumoral hemorrhage
• Constitutional symptoms in subset (e.g., fever, malaise,
anemia)
○ May be more common in extrasomatic tumors
○ Possibly related to tumoral cytokine production
Treatment
• Wide surgical excision
• Radiotherapy and chemotherapy may be indicated for rare
metastatic or unresectable tumors
• Indefinite long-term clinical follow-up recommended
Prognosis
• Majority of lesions are clinically indolent
• Regional recurrence rate up to 15%
○ Higher rate reported in extrasomatic tumors (up to 33%)
Tumors of Uncertain Differentiation
○ May be related to site (difficulty of excision) and tumors
showing infiltrative margins
• Rare metastasis (< 5% of reported cases)
○ Most frequently to regional lymph nodes
○ Very rare reports of death due to late distant metastases
• At present, no firm morphologic or clinical indicators of
behavior
MACROSCOPIC
General Features
• Well circumscribed
• Lobulated or multinodular
• Blood-filled cystic cavities may be apparent grossly
Size
• Usually small (2-4 cm)
MICROSCOPIC
Histologic Features
• Uni- or multinodular growth
• Fibrous pseudocapsule
○ Contains patchy, dense peripheral lymphoplasmacytic
cuff in up to 80%
• Sheets, nodules, and aggregates of ovoid to spindled cells
○ Variety of patterns: Loose swirling, storiform, short
fascicles
• Majority of cells are cytologically bland with vesicular nuclei
○ Scattered cells with conspicuous nuclear pleomorphism
or atypia are common and likely degenerative
○ Minority of cases show diffuse nuclear pleomorphism
• Fibrosclerotic to myxoid stroma
• Mitotic figures usually infrequent
○ Rare cases may show conspicuous mitotic activity or
isolated atypical mitoses
• Variably sized, blood-filled pseudoangiomatous spaces in
majority of cases
○ Lined by tumor cells, not endothelial cells
○ Scattered osteoclast-like giant cells common near these
areas
• Stromal chronic inflammatory infiltrate may be present
○ May contain variable number of eosinophils
• Less common and exceptional features
○ Myxoid/reticular, clear cell, epithelioid, small cell, and
focal palisading patterns
○ Rhabdoid morphology, pulmonary edema-like foci,
hyalinized vessels, hemangioendothelioma-like foci
ANCILLARY TESTS
Immunohistochemistry
• Desmin (+) in 50-60% of cases
○ Varies from focal to diffuse cytoplasmic
○ Dendritic process-like staining in many cases
○ Scattered desmin (+) cells may be present within
peripheral lymphoid proliferation
• ALK (+) in majority of cases, often with moderate to strong
staining
• Variable and nonspecific expression of EMA, CD68, CD99,
SMA, calponin
• Negative for myogenin, MyoD1, CD31, and S100 protein
643
 Angiomatoid Fibrous Histiocytoma
Tumors of Uncertain Differentiation
○ Isolated reports of focal CD34, CD21, and keratin
expression
Molecular Genetics
• 3 characteristic chromosomal translocations identified
○ t(2:22)(q33:q12); EWSR1-CREB1
– Most common overall (90% of cases)
○ t(12:22)(q13:q12); EWSR1-ATF1
– More common in extrasomatic cases of AFH
○ t(12:16)(q13:p11); FUS-ATF1
– Infrequent
• EWSR1-ATF1 and EWSR1-CREB1 also identified in clear cell
sarcoma of soft tissue and malignant gastrointestinal
neuroectodermal tumor
DIFFERENTIAL DIAGNOSIS
Aneurysmal Fibrous Histiocytoma
• Morphologic variant of benign fibrous histiocytoma
(dermatofibroma)
• Dermal localization, often with overlying epidermal
changes
• No pseudocapsule or lymphoplasmacytic cuff
• Peripheral collagen trapping often present
• Mixed cell population, including chronic inflammatory cells,
siderophages, and giant cells
• Desmin (-)
Undifferentiated Pleomorphic Sarcoma (Malignant
Fibrous Histiocytoma)
• Older age group
• Mostly large, deeply located masses
• Often profound nuclear atypia
• Atypical mitoses and tumor necrosis are common
Nodal Metastasis
• Metastatic melanoma in particular can mimic AFH
• Arises in regions populated by lymph nodes
• True nodal architecture present
○ Subcapsular and medullary sinuses
• History of malignancy may or may not be present
Follicular Dendritic Cell Sarcoma
• Most arise in lymph nodes
• Infiltrating lymphocytes are common
• CD21(+), CD23(+), CD35(+), EMA(+)
• Desmin (-)
Granulomatous Lesions
• Lack solid growth pattern of AFH
○ Granulomas are usually dispersed and discrete or
irregular and confluent
• Large granulomas often show central necrosis and lack
cystic hemorrhage
• May contain foreign body-type giant cells
• Predisposing factors may be noted clinically (exposure to
infectious agents, etc.)
• CD68(+), CD168(+); desmin (-)
Rhabdomyosarcoma
• May be confused with AFH due to age and desmin (+)
• Morphologic appearance depends upon specific subtype
• Myogenin (+), MyoD1(+)
644
Kaposi Sarcoma (Nodular)
• May involve lymph nodes
• Predisposing factors often present (AIDS history)
• Moderately cellular neoplasm of spindled endothelial cells
• CD34(+), CD31(+), D2-40 (podoplanin) (+), HHV8(+)
• Desmin (-)
Spindle Cell Hemangioma
• Distal extremities, particularly acral
• No pseudocapsule or lymphoplasmacytic cuff
• Resembles cavernous hemangioma with cellular septa
composed of spindle cells
• CD31(+), CD34(+), SMA(+)
• Desmin (-)
Intranodal Palisaded Myofibroblastoma
• Occurs in lymph nodes, predominantly in inguinal region in
male patients
• Fascicles of spindle cells with nuclear palisading and
amianthoid fibers characteristic
• SMA(+); desmin (-)
Nodular Fasciitis
• Lacks thick fibrous pseudocapsule and lymphoplasmacytic
cuff
• Spindle and stellate myofibroblasts with tissue culture
appearance
• SMA(+); desmin (-) (rarely focal)
• MYH9-USP6 fusion
SELECTED REFERENCES
1. Cheah AL et al: ALK expression in angiomatoid fibrous histiocytoma: a
potential diagnostic pitfall. Am J Surg Pathol. 43(1):93-101, 2019
2. Zaccarini DJ et al: TLE-1-positive angiomatoid fibrous histiocytoma
mimicking synovial sarcoma. Appl Immunohistochem Mol Morphol. 27(1):e1-
e4, 2019
3. Saito K et al: Angiomatoid fibrous histiocytoma: a series of seven cases
including genetically confirmed aggressive cases and a literature review.
BMC Musculoskelet Disord. 18(1):31, 2017
4. Justin Wong SB et al: Angiomatoid fibrous histiocytoma with prominent
myxoid stroma: a case report and review of the literature. Am J
Dermatopathol. 37(8):623-31, 2015
5. Shi H et al: Clinicopathological features of angiomatoid fibrous histiocytoma:
a series of 21 cases with variant morphology. Int J Clin Exp Pathol. 8(1):772-8,
2015
6. Thway K et al: Angiomatoid fibrous histiocytoma: comparison of
fluorescence in situ hybridization and reverse transcription polymerase chain
reaction as adjunct diagnostic modalities. Ann Diagn Pathol. 19(3):137-42,
2015
7. Bohman SL et al: Angiomatoid fibrous histiocytoma: an expansion of the
clinical and histological spectrum. Pathology. 46(3):199-204, 2014
8. Kao YC et al: Angiomatoid fibrous histiocytoma: clinicopathological and
molecular characterisation with emphasis on variant histomorphology. J Clin
Pathol. 67(3):210-5, 2014
9. Schaefer IM et al: Myxoid variant of so-called angiomatoid "malignant
fibrous histiocytoma": clinicopathologic characterization in a series of 21
cases. Am J Surg Pathol. 38(6):816-23, 2014
10. Chen G et al: Angiomatoid fibrous histiocytoma: unusual sites and unusual
morphology. Mod Pathol. 24(12):1560-70, 2011
11. Matsumura T et al: Angiomatoid fibrous histiocytoma including cases with
pleomorphic features analysed by fluorescence in situ hybridisation. J Clin
Pathol. 63(2):124-8, 2010
12. Thway K: Angiomatoid fibrous histiocytoma: a review with recent genetic
findings. Arch Pathol Lab Med. 132(2):273-7, 2008
13. Fanburg-Smith JC et al: Angiomatoid "malignant" fibrous histiocytoma: a
clinicopathologic study of 158 cases and further exploration of the myoid
phenotype. Hum Pathol. 30(11):1336-43, 1999
14. Costa MJ et al: Angiomatoid malignant fibrous histiocytoma. A follow-up
study of 108 cases with evaluation of possible histologic predictors of
outcome. Am J Surg Pathol. 14(12):1126-32, 1990
 Angiomatoid Fibrous Histiocytoma
Bland Nuclear Features
Focal Nuclear Atypia
Nuclear Grooves
Tumors of Uncertain Differentiation
Mitoses Uncommon
(Left) In a typical case of AFH,
the tumor cells are spindled to
ovoid with generally bland
nuclei containing pale or
vesicular chromatin with small
nucleoli and showing minimal
to mild pleomorphism. They
often appear histiocytoid. The
overall cellularity varies
widely from case to case.
(Right) The mitotic rate in AFH
is generally low, and mitotic
figures ﬈ are often small and
difficult to find. In rare cases,
they are more numerous, but
this does not appear to affect
prognosis. In exceptional
cases, atypical mitotic figures
may be identified.
Marked Nuclear Atypia
(Left) It is common for AFH to
contain scattered tumor cells
﬉ with nuclear enlargement,
hyperchromasia, and
pleomorphism. Intranuclear
pseudoinclusions may be
identified. These changes are
likely degenerative in nature.
(Right) In some cases,
pleomorphic tumor cells are
more prominent in number
and distribution. Coupled
together with an increase in
cellularity, these cases may be
misdiagnosed as an
undifferentiated pleomorphic
sarcoma. Notably, however,
mitotic activity is
disproportionately low.
Pseudovascular Spaces
(Left) Nuclear irregularity with
the presence of grooves ﬈ or
folds is not an uncommon
finding in AFH and may even
be quite prominent in rare
cases. (Right) Most cases of
AFH show at least focal
hemorrhage and often the
formation of dilated blood-
filled spaces, similar to what is
seen in the unrelated
aneurysmal fibrous
histiocytoma. These spaces
may predominate in rare
cases, clinically and
pathologically simulating a
hematoma. Thorough
histologic examination is
required in these cases.
645
 Angiomatoid Fibrous Histiocytoma
Tumors of Uncertain Differentiation

Pseudovascular Space Lining Osteoclast-Like Giant Cells

(Left) The dilated vascular
spaces seen in AFH are not
true vessels or cysts, as they
lack endothelial and epithelial
linings, respectively, but rather
are lined by tumor cells.
Osteoclast-like giant cells ﬉
are commonly identified near
these spaces and, very rarely,
may be numerous. (Right)
Osteoclast-like giant cells ﬈
are generally infrequent in
AFH and may be sparsely
scattered throughout the
tumor; however, when
present, they are most
typically identified adjacent to
or near hemorrhagic foci and
pseudovascular spaces.

Hemosiderin Variable Architecture

(Left) Hemosiderin pigment ﬈
is a common finding in AFH
and varies in distribution from
case to case. It is most
commonly seen around
regions of hemorrhage and
pseudovascular space
formation and may be seen in
the stroma or within the
cytoplasm of the tumor cells.
(Right) The overall growth
pattern of AFH varies widely
from one tumor to the next, as
does the cellularity. Tumor
cells may form sheets, short
fascicles, loose storiform
arrays, or a variety of other
unusual patterns.

Loose Storiform Growth Myxoid Stromal Change

(Left) The growth pattern in
this AFH shows a mixture of
short irregular fascicles and a
vague, loose storiform
architecture. It also contained
regions of prominent myxoid
stromal change (not shown).
(Right) Myxoid stromal change
is uncommon in AFH, and
when present, varies from
focal to diffuse in extent. Even
when these changes are
diffuse, other typical
pathologic features of AFH,
such as the characteristic
pseudocapsule and
inflammatory cuff, can usually
be identified to aid in a correct
diagnosis.

646
 Angiomatoid Fibrous Histiocytoma
Myxoid/Reticulated Pattern
Prominent Vasculature
Stromal Sclerosis
Tumors of Uncertain Differentiation
Pulmonary Edema-Like Pattern
(Left) In some examples of
myxoid AFH, the tumor cells
are small, spindled to stellate,
and form an interconnecting,
reticulated growth pattern.
This morphology may cause
confusion with a variety of
other myxoid neoplasms,
particularly extraskeletal
myxoid chondrosarcoma.
(Right) Variably dilated, cyst-
like foci ﬈ containing
homogeneous eosinophilic
material may be seen in AFH.
This appearance is reminiscent
of edema filling pulmonary
alveoli. Scattered vacuolar
forms are also seen at the
periphery ﬊.
Stromal Hyalinization
(Left) A rare finding in some
cases of myxoid AFH are thin-
walled branching vessels ﬊
with a curvilinear appearance
similar to that seen in low-
grade fibromyxoid sarcoma
and myxofibrosarcoma. Other,
more typical areas of AFH may
be present and should be
sought out. (Right) AFH may
show regions of stromal
hyalinization or
hypocellularity, which can vary
from focal to extensive.
Chronic inflammatory cells are
often identified within the
stroma, as is hemosiderin.
Hemangioendothelioma-Like Foci
(Left) In extreme cases,
extensive stromal sclerosis
may lead to diagnostic
difficulties. In particular,
tissue-separation artifact may
lead to an appearance
suggestive of a vascular
neoplasm or even a
nonneoplastic sclerosing
process. (Right) This unusual
case of AFH shows foci
containing irregular stromal
clefts between tumor cells,
imparting a
hemangioendothelioma-like
appearance. Erythrocytes may
be seen within these clefts,
furthering mimicking a
vascular lesion.
647
 Angiomatoid Fibrous Histiocytoma
Tumors of Uncertain Differentiation

Whorled Perineurioma-Like Growth Stromal Inflammation

(Left) Occasional cases of AFH
demonstrate areas of tight
whorling or storiform growth,
mimicking soft tissue
perineurioma.
Immunohistochemical
expression of EMA in AFH may
further confound the issue.
(Right) A mixed chronic
inflammatory infiltrate is
usually present to some
degree in AFH; however, it
varies from subtle to
prominent. Most of the
constituent inflammatory cells
are lymphocytes and plasma
cells, but eosinophils may also
be present.

Stromal Eosinophils Small Cell Morphology

(Left) Eosinophils ﬈ are not a
common finding in AFH and
are usually sparsely
distributed, but in very rare
cases they can be surprisingly
abundant. (Right) Small cell
morphology may also be seen
and is characterized by tumor
cells with minimal cytoplasm
and increased nuclear density.
When nuclear monomorphism
is prominent, this morphology
may resemble Ewing sarcoma,
a major pitfall given that the
tumor may both express CD99
and show EWSR1 gene
fusions.

Fascicular Growth Rare Vascular Hyalinization

(Left) A conspicuous short
fascicular growth pattern may
rarely be seen in AFH and, in
combination with small cell
morphology and nuclear
monomorphism, may resemble
other more aggressive tumors,
such as synovial sarcoma.
(Right) Focal vascular
hyalinization ﬈ may be seen
in some cases of AFH and can
simulate the Antoni B zones of
schwannoma. In some
reported cases, this finding has
been associated with focal
nuclear palisading, further
mimicking schwannoma.

648
 Angiomatoid Fibrous Histiocytoma
Carcinoma-Like Morphology
Hyaline Eosinophilic Globules
Desmin Expression
Tumors of Uncertain Differentiation
Rhabdoid-Like Morphology
(Left) This image shows AFH
with sheet-like areas of larger
eosinophilic tumor cells with
diffuse pleomorphism,
somewhat mimicking a poorly
differentiated carcinoma. A
background of stromal
sclerosis or fibromyxoid
change can also complicate
the issue. (Right) Epithelioid
tumor cells ﬉ with glassy,
eosinophilic cytoplasm and
eccentric nuclei, resembling
rhabdomyoblasts, are a rare
finding in AFH. Given the usual
age of the patient, care should
be taken to avoid a
misdiagnosis of
rhabdomyosarcoma.
Predominantly Cystic Tumors
(Left) Intracytoplasmic
eosinophilic globules are a
rare finding in AFH and vary
from tiny clusters ſt to larger,
pale globs ﬊. The latter form
resembles the hyaline globules
seen in Kaposi sarcoma.
(Right) Some cases of AFH are
extensively cystic and appear
to be a large blood cyst with a
collagenous fibrous
pseudocapsule, thus closely
mimicking a hematoma. Close
inspection of the fibrous rind
and inflammatory infiltrate
often reveals small nodules ﬉
of diagnostic tumor cells.
ALK Expression
(Left) Approximately half of
cases of AFH show expression
of desmin within tumor cells,
which varies from focal to
extensive, and often shows
areas of stellate, dendritic
process-like staining st.
Isolated desmin (+) cells may
be identified in the peripheral
lymphoplasmacytic infiltrate
as well. (Right) ALK expression
by IHC has been recently
reported as a common finding
in angiomatoid fibrous
histiocytoma and may lead to
misdiagnosis as IMT,
particularly on small biopsy.
Notably, rearrangements of
the ALK gene are absent.
649
 Ossifying Fibromyxoid Tumor

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY
• Distinctive mesenchymal neoplasm of intermediate
malignant potential arising predominantly in superficial soft
tissues and featuring uniform, bland, round to ovoid cells
embedded in fibromyxoid stroma, often with incomplete,
peripheral shell of bone
CLINICAL ISSUES
• Wide age range (mean: 50 years)
○ ~ 2:1 male predominance
• Extremities (particularly lower), trunk, head/neck
○ Usually originates in subcutaneous tissue
• Slow-growing, often longstanding, painless mass
• Treatment: Complete surgical excision
• Overall good prognosis for most tumors with conventional
histologic features
○ Rare, histologically malignant forms show increased risk
of local recurrence and metastatic disease
MICROSCOPIC
• Pseudocapsule with metaplastic bone in 75% of cases
• Low to moderately cellular proliferation of uniform, oval to
round tumor cells in cords, nests, clusters, or sheets
○ Bland nuclear features
○ Mitoses are rare (< 2 figures per 50 HPF)
• Variable myxoid, fibromyxoid, or hyalinized stroma
• Absence of necrosis and vascular invasion
• Malignant forms show severe nuclear atypia or high
cellularity with increased mitotic activity
ANCILLARY TESTS
• S100 protein (+); variable desmin (+)
• Molecular: Rearrangements of 6p21 involving PHF1
TOP DIFFERENTIAL DIAGNOSES
• Schwannoma (epithelioid variant)
• Myoepithelioma of soft tissue
• Extraskeletal myxoid chondrosarcoma

Ossifying Fibromyxoid Tumor Metaplastic Bone

(Left) Ossifying fibromyxoid
tumor (OFMT) is a distinctive,
rarely metastasizing
mesenchymal neoplasm that
most commonly arises in
subcutaneous tissue, as
depicted, and usually features
a thick, fibrous pseudocapsule
﬈. (Right) Metaplastic bone
formation ﬈ is seen in the
majority of cases of OFMT,
typically at the periphery
within the fibrous
pseudocapsule but
occasionally within the
intratumoral fibrous septa. It
may be focal, partial, or
extensively present.

Growth Patterns S100 Protein Expression

(Left) Tumor cells in OFMT are
typically small, uniform, and
bland and are arranged in a
variety of patterns, including
branching cords, trabeculae,
nests, clusters, or loose sheets.
The stroma has a fine,
fibrillary fibromyxoid quality.
(Right) S100 protein
expression is seen in most (but
not all) cases of OFMT and
typically shows both nuclear
and cytoplasmic staining.
Positivity is often diffuse but
can occasionally be patchy.

650
 Ossifying Fibromyxoid Tumor

Tumors of Uncertain Differentiation

TERMINOLOGY IMAGING
Abbreviations Specimen Radiographic Findings
• Ossifying fibromyxoid tumor (OFMT) • Partial rim of bone around tumor in many cases
Synonyms
MACROSCOPIC
• OFMT of soft parts
General Features
Definitions
• Well-circumscribed, lobular or multinodular mass
• Distinctive mesenchymal neoplasm of intermediate • Most show peripheral fibrous pseudocapsule ± bone
malignant potential arising predominantly in superficial soft ○ Bone, if present, may be identifiable grossly
tissues and featuring uniform, bland, round to ovoid cells
• Firm or rubbery, tan-white or gray cut surface
embedded in fibromyxoid stroma, often with incomplete,
peripheral shell of bone Size
○ Characterized by recurrent rearrangements of PHF1 in • Usually < 5 cm (mean: 4 cm)
50-80% of cases ○ Can grow quite large (> 15 cm)

ETIOLOGY/PATHOGENESIS MICROSCOPIC
Specific Differentiation Unproven Histologic Features
• Various lineages suggested • Most show lobulated or nodular growth
○ Neural (Schwann cell), chondroid, myoepithelial, ○ May show formation of peripheral satellite nodules
osteogenic • Peripheral fibrous pseudocapsule common, often with
intratumoral septal extensions
CLINICAL ISSUES ○ Incomplete/partial rim of metaplastic bone (often
Epidemiology lamellar) in 75% of cases
• Incidence – Ossification may extend inward along septa
○ Rare – Occasional cartilage component
• Age • Low to moderately cellular proliferation of uniform, oval to
○ Wide range (mean: 50 years) round tumor cells in cords, nests, clusters, or sheets
– Rare < 20 years ○ Oval to rounded, bland nuclei ± small pinpoint nucleoli
• Sex ○ Pale eosinophilic cytoplasm
○ ~ 2:1 male predominance ○ Mitoses are rare (< 2 figures per 50 HPF)
○ Rare spindled cytomorphology, fascicular growth
Site • Variable myxoid, fibromyxoid, or hyalinized stroma
• Extremities most common (particularly lower) • Occasional cystic change
• Also head/neck region and trunk • Absence of necrosis and vascular invasion
• Rarely other sites
Malignant Ossifying Fibromyxoid Tumor
Presentation • Per published criteria of Folpe and Weiss
• Slow-growing, often longstanding, painless mass ○ High nuclear grade or
• Solitary subcutaneous mass ○ High cellularity with > 2 mitoses per 50 HPF
○ Rarely involves skin or deep soft tissues – Overlapping nuclei with loss of intercellular matrix in
at least one 4x microscopic field
Treatment
• Areas with malignant histologic features often associated
• Complete surgical excision with areas of conventional OFMT
• Reexcision with negative margins for tumors with atypical ○ However, malignant OFMT may arise in pure form or in
or malignant features recurrence of conventional/atypical OFMT
• Indefinite long-term clinical follow-up warranted for all • Necrosis, vascular invasion, infiltrative growth more
cases of OFMT common in malignant OFMT
Prognosis • Atypical OFMT deviates from conventional OFMT but does
not reach criteria for malignant OFMT
• Overall good prognosis for conventional OFMT
○ Most are clinically benign
ANCILLARY TESTS
○ Infrequent local recurrence
○ Very rare metastases (< 5% of cases) Immunohistochemistry
• Atypical OFMT shows increased risk of local recurrence • S100 protein (+) in majority
○ Tumors may recur many years after primary surgery ○ Less frequent expression in malignant OFMT
• Malignant OFMT shows increased risk of aggressive local • Desmin (+) in up to 40%
recurrence and metastatic disease • Occasional focal expression of keratin, EMA, SMA
○ Metastases often to lung or other soft tissue sites • Focal MUC4(+) in minor subset

651
 Ossifying Fibromyxoid Tumor
Tumors of Uncertain Differentiation
• Nuclear INI1 expression lost in some but not all tumor cells
(mosaic pattern)
Molecular Genetics
• Rearrangements of 6p21 involving PHF1 (50-80% of
reported cases)
○ EP400-PHF1 fusion most commonly reported
○ MEAF6-PHF1, EPC1-PHF1, and ZC3H7B-BCOR fusions also
reported
• PHF1 rearrangements identified in all forms (conventional,
atypical, and malignant) of OFMT
• 2 additional fusions reported: CREBBP-BCORL1 and KDM2A-
WWTR1
DIFFERENTIAL DIAGNOSIS
Schwannoma (Epithelioid Variant)
• Can show close morphologic overlap with OFMT
• May contain areas of conventional schwannoma histology
• Generally lacks metaplastic bone formation
• Strong diffuse S100 protein (+); desmin (-)
• No rearrangements of PHF1
Myoepithelioma of Soft Tissue
• Wider range of morphologic patterns
• Keratin (+) and S100 protein (+) in many cases
• Variably (+) for SMA, desmin, GFAP, calponin
• EWSR1 rearrangements in some tumors
• No rearrangements of PHF1
Extraskeletal Myxoid Chondrosarcoma
• Large mass arising in deep soft tissues
• Lacks pseudocapsule and peripheral metaplastic bone
formation
• Prominent myxoid stroma
• S100 protein (+), often focal/weak
• NR4A3 gene rearrangements
Extraskeletal Osteosarcoma
• Arises in deep soft tissues
• Marked nuclear atypia and pleomorphism common
• Atypical mitoses and necrosis
• Neoplastic bone formation is often centralized rather than
peripheral
Epithelioid Malignant Peripheral Nerve Sheath
Tumor
• Origin from large nerve may be demonstrated
• Prominent macronucleoli characteristic
• Lacks metaplastic bone formation
• Desmin (-)
• No rearrangements of PHF1
Sclerosing Epithelioid Fibrosarcoma
• Occurs in deep soft tissues
• Matrix usually densely sclerotic rather than myxoid or
fibromyxoid
• Clear cell morphology is common
• Negative for S100 protein and desmin
• MUC4(+)
○ However, of limited utility given MUC4(+) in subset of
OFMT
• EWSR1 and CREB3L1 rearrangements predominate
652
Low-Grade Fibromyxoid Sarcoma
• Spindle cells usually predominate; occasional epithelioid
cytomorphology
• Negative for S100 protein and desmin
• MUC4(+)
○ However, of limited utility given MUC4(+) in subset of
OFMT
• Most cases show t(7;16) with FUS-CREB3L2 fusion
Glomus Tumor
• Uniform epithelioid cells arranged around prominent blood
vessels
• Generally lacks metaplastic bone formation
• SMA(+)
• S100 protein (-)
• No rearrangements of PHF1
SELECTED REFERENCES
1. Velasco IA et al: Ossifying fibromyxoid tumor of soft parts in head and neck:
case report and literature review. Diagn Pathol. 13(1):21, 2018
2. Dantey K et al: Ossifying fibromyxoid tumor: a study of 6 cases of atypical
and malignant variants. Hum Pathol. 60:174-9, 2017
3. Kao YC et al: Expanding the molecular signature of ossifying fibromyxoid
tumors with two novel gene fusions: CREBBP-BCORL1 and KDM2A-WWTR1.
Genes Chromosomes Cancer. 56(1):42-50, 2017
4. Bakiratharajan D et al: Ossifying fibromyxoid tumor: an update. Arch Pathol
Lab Med. 140(4):371-5, 2016
5. Schneider N et al: Ossifying fibromyxoid tumor: morphology, genetics, and
differential diagnosis. Ann Diagn Pathol. 20:52-8, 2016
6. Atanaskova Mesinkovska N et al: Ossifying fibromyxoid tumor: a
clinicopathologic analysis of 26 subcutaneous tumors with emphasis on
differential diagnosis and prognostic factors. J Cutan Pathol. 42(9):622-31,
2015
7. Antonescu CR 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. 53(2):183-93, 2014
8. Asirvatham JR et al: Ossifying fibromyxoid tumor of the breast mimicking
fibroadenoma: a case report and differential diagnoses. Arch Pathol Lab
Med. 138(8):1098-100, 2014
9. Endo M et al: Ossifying fibromyxoid tumor presenting EP400-PHF1 fusion
gene. Hum Pathol. 44(11):2603-8, 2013
10. Graham RP 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. 37(11):1751-5, 2013
11. Gebre-Medhin S et al: Recurrent rearrangement of the PHF1 gene in
ossifying fibromyxoid tumors. Am J Pathol. 181(3):1069-77, 2012
12. Graham RP et al: Ossifying fibromyxoid tumor of soft parts: a
clinicopathologic, proteomic, and genomic study. Am J Surg Pathol.
35(11):1615-25, 2011
13. Miettinen M et al: 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.
32(7):996-1005, 2008
14. Folpe AL et al: Ossifying fibromyxoid tumor of soft parts: a clinicopathologic
study of 70 cases with emphasis on atypical and malignant variants. Am J
Surg Pathol. 27(4):421-31, 2003
15. Zámecník M et al: Ossifying fibromyxoid tumor of soft parts: a report of 17
cases with emphasis on unusual histological features. Ann Diagn Pathol.
1(2):73-81, 1997
16. Kilpatrick SE et al: Atypical and malignant variants of ossifying fibromyxoid
tumor. Clinicopathologic analysis of six cases. Am J Surg Pathol. 19(9):1039-
46, 1995
17. Fisher C et al: Ossifying fibromyxoid tumor of soft parts with stromal cyst
formation and ribosome-lamella complexes. Ultrastruct Pathol. 18(6):593-
600, 1994
18. Schofield JB et al: Ossifying fibromyxoid tumour of soft parts:
immunohistochemical and ultrastructural analysis. Histopathology.
22(2):101-12, 1993
19. Enzinger FM et al: Ossifying fibromyxoid tumor of soft parts. A
clinicopathological analysis of 59 cases. Am J Surg Pathol. 13(10):817-27,
1989
 Ossifying Fibromyxoid Tumor
Lobular, Fibromyxoid Appearance
Satellite Nodules
Bland Cytology
Tumors of Uncertain Differentiation
Prominent Bone Formation
(Left) Multilobular growth is
common in OFMT, with
lobules separated by fibrous
septa ﬇. The stroma shows
variable composition ranging
from myxoid to fibromyxoid
﬉ to hyalinized ﬈. (Right)
H&E shows an OFMT with an
extensive rim of mature bone
﬊ with septal extensions ﬉
into the tumor mass. This
degree of bone formation is
often first noticeable during
gross examination and
sectioning.
Microcystic Change
(Left) Some cases of OFMT
feature a distinctly
multinodular or plexiform
growth, as depicted here.
There are also several smaller
extracapsular satellite nodules
extending into the
subcutaneous fat ﬊. (Right)
Formation of stromal
microcysts ﬉ is common in
OFMT. These foci may be of a
fibrous, fibromyxoid, or
myxoid quality.
Increased Cellularity
(Left) The lesional cells of
OFMT are typically
monomorphic and contain
small, round to ovoid, bland
nuclei ± small pinpoint
nucleoli. Cellularity is
generally low, and mitotic
figures are typically sparse to
absent. (Right) Areas of
moderately increased
cellularity, as shown here, are
not uncommon in OFMT and
have no prognostic
significance. Note the lack of
cytologic atypia. In contrast,
malignant OFMT often feature
highly cellular areas with
conspicuous mitotic activity or
severe nuclear atypia.
653
 Ossifying Fibromyxoid Tumor
Tumors of Uncertain Differentiation

Myxoid Matrix Hyalinized Matrix

(Left) Areas with a prominent
myxoid stroma may be seen in
OFMT. When a myxoid
morphology is prominent and
diffuse, other tumors, such as
extraskeletal myxoid
chondrosarcoma and
myoepithelioma, must be
excluded. (Right) Prominent
fibrous zones may be seen in
OFMT, as shown here. Some
longstanding tumors may
show extensive hyalinization
and overall paucicellularity.

Hyalinized Stroma Spindle Cells

(Left) This case of OFMT
features densely hyalinized or
sclerotic stroma, as depicted
here. Note the retained
branching cord pattern that is
commonly seen in this tumor.
(Right) Tumor cells
occasionally adopt a spindled
cytomorphology in OFMT;
however, it is rarely a
prominent or diffuse change.
Cellular fascicles with mitotic
activity have also been
reported in histologically
malignant forms of OFMT.

Clear Cell Morphology Hyalinized Foci

(Left) Clear cell change is an
uncommon finding in OFMT
and can vary from focal and
inconspicuous to prominent.
(Right) Vague hyalinized
nodules ﬉ are sometimes
noted in cases of otherwise
conventional OFMT. These foci
are somewhat similar to the
rosette-like structures seen in
some schwannoma variants
and in low-grade fibromyxoid
sarcoma; however, the latter
structures often show a
condensed peripheral rim of
tumor cells.

654
 Ossifying Fibromyxoid Tumor
Desmin Expression
Malignant Ossifying Fibromyxoid Tumor
Sclerosing Epithelioid Fibrosarcoma-Like
Foci
Tumors of Uncertain Differentiation
Malignant Ossifying Fibromyxoid Tumor
(Left) Desmin expression is
seen in up to 50% of cases of
OFMT. Unlike S100 protein,
desmin expression is often
limited to focal or patchy
positivity, as depicted. (Right)
Per criteria set forth by Folpe
and Weiss, histologic features
of malignancy in OFMT include
either high nuclear grade or
high cellularity with > 2
mitoses per 50 HPF. As
depicted here, areas of high
cellularity feature prominent
nuclear overlapping and loss
of intercellular matrix/stroma.
Mitoses were numerous in this
case.
Malignant Ossifying Fibromyxoid Tumor
(Left) Mitoses ﬉ are generally
sparse or absent in typical
cases of OFMT; however,
tumors with ≥ 2 mitoses per
50 HPF show an increased risk
for local recurrence and, if
associated with high
cellularity, are probably best
considered as having
malignant potential
(malignant OFMT). (Right)
Malignant forms of OFMT
often retain the lobular
configuration of conventional
OFMT; however, note the
markedly increased cellularity
﬈ evident here even at low
power.
Lung Metastasis
(Left) Some cases of malignant
OFMT contain areas of
sclerotic stroma ﬈ with
variable clear cell change
resembling sclerosing
epithelioid fibrosarcoma.
(Right) Malignant OFMT may
metastasize to the lung (as
shown here) or other soft
tissue sites. Notably,
metastases often closely
resemble the primary tumor
morphologically. Bone
formation may be particularly
prominent in some
metastases.
655
 Myoepithelioma of Soft Tissue

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY
• Soft tissue neoplasm composed exclusively or
predominantly of cells demonstrating myoepithelial
phenotype
• Synonyms: Parachordoma, mixed tumor
CLINICAL ISSUES
• Wide age range (median: 40 years)
○ Significant number of cases (20%) arise in children
• Most common in limbs and limb girdles (lower > upper)
• Treatment: Complete surgical excision
• Most neoplasms are benign; may locally recur (20%)
• Histologically malignant examples behave aggressively
(metastases in up to 50%)
MACROSCOPIC
• Wide size range (mean: 4-6 cm)
MICROSCOPIC
• Well-demarcated, nodular or lobular growth
• Epithelioid, spindled, plasmacytoid, or clear cells
• Cells arranged in nests, cords, sheets, clusters, or singly
• Chondromyxoid to collagenous/hyalinized stroma
• Moderate to severe nuclear atypia in malignant cases
• Variants: Parachordoma, mixed tumor, syncytial
ANCILLARY TESTS
• Variable myoepithelial immunophenotype
• Molecular: Rearrangement of EWSR1 gene (22q12) in ~
50% of cases
TOP DIFFERENTIAL DIAGNOSES
• Extraskeletal myxoid chondrosarcoma
• Soft tissue chondroma
• Ossifying fibromyxoid tumor
• Epithelioid malignant peripheral nerve sheath tumor
• Metastatic carcinoma/melanoma

Myoepithelioma of Soft Tissue Myoepithelioma of Soft Tissue

(Left) Soft tissue
myoepithelioma may arise in
subcutaneous or deep soft
tissue sites and is usually well
circumscribed and nodular
with a variably firm,
gelatinous, fibrotic, or fleshy
cut surface. (Right)
Myoepithelioma is a
heterogeneous neoplasm and
has a broad morphologic
spectrum. It shares many
histologic patterns with
myoepithelioma of salivary
gland origin.

Myxoid Matrix Myoepithelial Immunophenotype

(Left) A myxoid matrix is very
common in myoepithelioma
and is often quite prominent.
The lesional cells have
eosinophilic cytoplasm, vary
from epithelioid to spindled in
shape, and may form a variety
of architectural patterns.
(Right) Most myoepitheliomas
express S100 protein (shown),
calponin, and epithelial
markers, such as pankeratin
and EMA. Other markers, such
as GFAP, SMA, and p63, are
variably positive.

656
 Myoepithelioma of Soft Tissue

Tumors of Uncertain Differentiation

TERMINOLOGY MICROSCOPIC
Synonyms Histologic Features
• Parachordoma • Well-demarcated, nodular or lobular growth
• Mixed tumor • Epithelioid, spindled, plasmacytoid, or clear cells
• Ectomesenchymal chondromyxoid tumor (of tongue) ○ Minimal nuclear pleomorphism; vesicular nuclei; small
• Myoepithelial carcinoma (malignant myoepithelioma) nucleoli
○ Few mitoses are usually present (< 2 mitoses per 10 HPF)
Definitions
• Significant architectural heterogeneity
• Soft tissue neoplasm composed exclusively or ○ Cells arranged in nests, cords, sheets, clusters, or singly
predominantly of cells demonstrating myoepithelial
• Usually prominent chondromyxoid to
phenotype
collagenous/hyalinized stroma
○ May also contain evidence of ductal differentiation
• Minority of cases (10%) show foci of cartilaginous or
(mixed tumor)
osseous metaplasia
○ May contain population of larger epithelioid cells with
○ Adipocytic or squamous elements rare
heavily vacuolated cytoplasm (parachordoma)
• Malignant myoepithelioma (myoepithelial carcinoma)
○ Tumors with diffuse, moderate to severe nuclear atypia
○ Diffuse, moderate to severe nuclear atypia appears to be
classified as malignant myoepithelioma (myoepithelial
most reliable criterion
carcinoma)
– Nuclear pleomorphism, vesicular or coarse chromatin,
and prominent nucleoli
CLINICAL ISSUES
– Often associated with high mitotic rate and
Epidemiology coagulative necrosis
• Incidence ○ Tend to be larger tumors and show more infiltrative
○ Rare margins
• Age ○ In children, tumors may contain undifferentiated round
○ Wide range (median: 40 years) cell component
– Significant number of cases (20%) arise in children < ○ May contain areas of more conventional, benign-
10 years old appearing morphology
□ Higher incidence of malignancy (myoepithelial Morphologic Variants
carcinoma) in this age group
• Parachordoma
Site ○ Contains population of larger epithelioid cells with
• Most common in limbs and limb girdles (lower > upper) prominent cytoplasmic vacuolization
○ Also trunk and head/neck region ○ Similar features to conventional myoepithelioma
• Subcutaneous and deep soft tissue • Mixed tumor
○ Occasionally in skin ○ Contain foci of epithelial (ductal) differentiation
○ Rarely in bone and viscera ○ Similar features to conventional myoepithelioma
• Cutaneous syncytial myoepithelioma
Presentation ○ Small, dermal-based lesions
• Painless, often palpable mass ○ Solid, sheet-like proliferation of ovoid to spindled cells
Treatment with pale eosinophilic, syncytial cytoplasm
○ No nuclear atypia; mitoses rare to absent
• Complete surgical excision
○ Adipocytic metaplasia &/or lymphoplasmacytic
Prognosis inflammation may be seen
• Most neoplasms behave in benign fashion
○ Conventional, benign-appearing neoplasms recur in 20% ANCILLARY TESTS
of cases and rarely metastasize Immunohistochemistry
• Histologically malignant examples behave aggressively
• Variable myoepithelial immunophenotype
○ Recur and metastasize in up to 50% of cases
• Loss of nuclear INI1 in many cases of myoepithelial
○ Metastatic sites: Lung, bone, soft tissue, lymph nodes carcinoma

MACROSCOPIC Molecular Genetics

General Features • Rearrangement of EWSR1 gene (22q12) in ~ 50% of cases
○ Reported gene partners: POU5F1 (6p21), PBX1 (1q23),
• Usually well circumscribed and nodular
ZNF44 (19q13), others
• Firm, fleshy, or gelatinous cut surface
• Subset show FUS rearrangements (FUS-KLF17 fusion most
Size common)
• Wide range (mean: 4-6 cm) • PLAG1 gene rearrangements identified in myoepitheliomas
with ductal differentiation (mixed tumor)
○ Similar to pleomorphic adenoma (benign mixed tumor)
of salivary gland
657
 Myoepithelioma of Soft Tissue
Tumors of Uncertain Differentiation

Immunohistochemistry Table
Antibody Reactivity Staining Pattern Comment
S100 Positive Nuclear & cytoplasmic Positive in most cases (90%)
CK-PAN Positive Cytoplasmic Positive in most cases (90%); often negative in cutaneous
syncytial type
Calponin Positive Cytoplasmic Positive in most cases (80%)
EMA Positive Cell membrane and Positive in most cases (60%)
cytoplasm
GFAP Positive Cytoplasmic Positive in 50% of cases
Actin-sm Positive Cytoplasmic Positive in 50% of cases
CD34 Negative
Brachyury Negative
p63 Equivocal Nuclear Positive in some cases (30-45%)
Desmin Equivocal Cytoplasmic Positive in some cases (15%)
INI1 Equivocal Nuclear Loss of nuclear INI1 in some cases of myoepithelial carcinoma

• Chondromyxoid stroma rare in both entities

DIFFERENTIAL DIAGNOSIS
Extraskeletal Myxoid Chondrosarcoma
• Can show striking morphologic overlap with
myoepithelioma
• Lacks strong, diffuse keratin and EMA expression
• Variable S100 protein (+), often focal
• NR4A3 (9q22) gene rearrangements characteristic
○ Most common fusion partner is EWSR1
• Tumors with rhabdoid features may show loss of INI1
Soft Tissue Chondroma
• Most common in acral locations
• Nodules of well-developed cartilage
• No expression of epithelial markers
Ossifying Fibromyxoid Tumor
• Can show morphologic overlap with myoepithelioma
• Majority show incomplete peripheral rim of bone
• S100 protein (+) in most cases; desmin (+) in 50%
• No expression of epithelial markers (or at most focal)
• PHF1 (6p21) gene rearrangements in majority
Epithelioid Malignant Peripheral Nerve Sheath
Tumor
• Sheets and nodules of large epithelioid cells with
prominent macronucleoli, often in myxoid stroma
• May contain areas of more conventional spindle cell MPNST
• Demonstration of origin from nerve is helpful
• Strong, diffuse S100 protein (+)
• Lacks expression of epithelial markers (or at most focal
positivity)
• Lacks EWSR1 gene rearrangements
Schwannoma (Epithelioid Variant)
• Small, epithelioid Schwann cells with bland nuclei within
myxoid or fibrillary stroma
• Strong, diffuse S100 protein (+)
• No expression of epithelial markers
Metastatic Carcinoma/Melanoma
• Expression of epithelial markers (and absence of other
myoepithelial markers) in carcinoma
○ TTF-1, pax-8, CDX-2, etc. in carcinomas from various sites
• Expression of melanocytic markers in melanoma
Epithelioid Sarcoma
• Myxoid stroma uncommon but described
• Proximal-type epithelioid sarcoma show rhabdoid
morphology with prominent nucleoli
• Strong expression of epithelial markers; CD34(+) in 50%
• S100 protein (-)
• Complete loss of nuclear INI1 common
• Lacks EWSR1 gene rearrangements
Chordoma
• In soft tissues sites, more likely to be metastasis from bone
tumor than soft tissue primary
• Multivacuolated "physaliferous" cells
• Keratin (+), EMA(+), S100 protein (+), brachyury (+)
Myxofibrosarcoma (Epithelioid Variant)
• Eosinophilic epithelioid tumor cells in background of
conventional myxofibrosarcoma
• No expression of S100 protein and epithelial markers
SELECTED REFERENCES
1. Kravtsov O et al: Myoepithelioma of soft tissue: a cytological-pathological
correlation with literature review. Ann Diagn Pathol. 27:14-7, 2017
2. Jo VY et al: Myoepithelial neoplasms of soft tissue: an updated review of the
clinicopathologic, immunophenotypic, and genetic features. Head Neck
Pathol. 9(1):32-8, 2015
3. Jo VY et al: Cutaneous syncytial myoepithelioma: clinicopathologic
characterization in a series of 38 cases. Am J Surg Pathol. 37(5):710-8, 2013
4. Antonescu CR 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 common involvement of the EWSR1 gene.
Genes Chromosomes Cancer. 49(12):1114-24, 2010
5. Gleason BC et al: Myoepithelial carcinoma of soft tissue in children: an
aggressive neoplasm analyzed in a series of 29 cases. Am J Surg Pathol.
31(12):1813-24, 2007
6. Hornick JL et al: Myoepithelial tumors of soft tissue: a clinicopathologic and
immunohistochemical study of 101 cases with evaluation of prognostic
parameters. Am J Surg Pathol. 27(9):1183-96, 2003

• Clinical history of primary tumor often present

658
 Myoepithelioma of Soft Tissue

Tumors of Uncertain Differentiation

Epithelioid Cells Corded Growth
(Left) H&E of myoepithelioma
shows predominantly
epithelioid cells in a prominent
myxoid matrix. Nuclei are
relatively uniform and
vesicular and may or may not
show small nucleoli. Mitotic
activity is low or absent.
(Right) Cords or thin
trabeculae of cells is a
common pattern in
myoepithelioma. These cords
may interconnect or appear
separated from one another.

Reticular Pattern Micronodular Pattern

(Left) Myoepithelioma can
show a finely reticular pattern
of growth in highly myxoid
tumors. Tumors with a
prominent collagenous or
hyalinized/sclerotic matrix
may also show this
morphology. (Right) The
lesional cells may form small
nests or aggregates and
impart an overall
micronodular appearance. The
background stroma is variably
myxoid and collagenous.

Variable Cellularity Spindled Morphology

(Left) H&E shows
hypercellularity and density in
a myoepithelioma. This finding
does not correlate with
malignant potential; however,
malignant myoepitheliomas
are often more cellular than
benign types. Importantly,
there is no significant nuclear
atypia or increased mitotic
rate. (Right) Spindled
myoepithelial cells may form
loose or tight fascicles and
may raise the possibility of a
smooth muscle, neural, or
myofibroblastic neoplasm.

659
 Myoepithelioma of Soft Tissue
Tumors of Uncertain Differentiation

Nodular or Nested Growth Monomorphic Cytology

(Left) Variably sized, solid
nests within a loose or dense
collagenous stroma
characterize occasional cases
of myoepithelioma. Areas of
intratumoral hemorrhage are
seen ﬈. (Right) Regardless of
whether the cells in
myoepithelioma are
epithelioid or spindled, the
nuclei are minimally atypical
and relatively uniform.
Nucleoli ﬈ are often present
but should be small and
inconspicuous.

Clear Cell Change Clear Cell Change

(Left) Clear cell change ﬈ is
not uncommon in
myoepithelioma and may be
prominent in some cases.
Rarely is a tumor composed
entirely of clear cells. (Right)
H&E of myoepithelioma shows
sheets of epithelioid cells,
many of which show
cytoplasmic clearing. Clear cell
change in a soft tissue
neoplasm should always raise
the possibility of a
myoepithelial neoplasm.

Hyalinized Stroma Pseudovascular Spaces

(Left) Some cases of
myoepithelioma contain a
stroma that is less myxoid and
more collagenous and may
even be diffusely hyalinized.
Lesional myoepithelial cells ﬈
are arranged in a variety of
patterns, including cords or
trabeculae, similar to
predominantly myxoid
examples. (Right) In some
hyalinized myoepitheliomas,
irregular nests and cords of
cells show central cellular loss
or dyscohesion ﬈ resembling
vascular spaces.

660
 Myoepithelioma of Soft Tissue
Aggregates of Clear Cells
Hypocellularity
Plasmacytoid Cytomorphology
Tumors of Uncertain Differentiation
Storiform Architecture
(Left) This myoepithelioma
contained prominent stromal
collagen and shows nests and
aggregates of neoplastic cells
demonstrating abundant clear
cytoplasm, thus, raising the
possibility of a metastatic
clear cell carcinoma. (Right)
Spindled myoepithelial cells in
a collagenous stroma may
occasionally adopt a loose
storiform architecture. The
area depicted somewhat
resembles a perineurioma.
Plasmacytoid Cytomorphology
(Left) This example of
myoepithelioma shows diffuse
stromal hyalinization and
relatively low cellularity
overall. Scattered cords and
small aggregates of neoplastic
myoepithelial cells are evident
in scattered patches. (Right) A
plasmacytoid morphology is
not uncommon in soft tissue
myoepithelioma and may be
the predominant
cytomorphology in some
cases. The cells may form
nests, sheets, or cords in a
myxoid or collagenous stroma.
Osteoid-Like Hyalinization
(Left) Plasmacytoid
myoepithelial cells are
characterized by eccentric
nuclei with tiny nucleoli and
an eosinophilic
intracytoplasmic inclusion ﬊.
Some larger cells may
resemble rhabdoid cells.
(Right) This soft tissue
myoepithelioma shows loose
aggregates of plasmacytoid
myoepithelial cells within a
dense, osteoid-like sclerotic
matrix reminiscent of
osteosarcoma.
661
 Myoepithelioma of Soft Tissue
Tumors of Uncertain Differentiation

Sclerotic Matrix Epithelioid Cell Nests

(Left) This myoepithelioma is
composed of cords and
aggregates of plasmacytoid
myoepithelial cells within a
densely sclerotic stroma
resembling infiltrating lobular
carcinoma of the breast.
(Right) This myoepithelioma is
composed of dense nests and
aggregates of plump
epithelioid and plasmacytoid
cells, some of which show
clear cytoplasm (bottom
right).

Parachordoma Morphology Epithelial Differentiation

(Left) Some variants of soft
tissue myoepithelioma show a
population of larger
epithelioid cells with heavily
vacuolated cytoplasm ﬈
reminiscent of physaliferous
cells. These tumors are
sometimes referred to as
parachordoma but are
currently considered a
morphologic variant of
myoepithelioma. (Right)
Approximately 10% of cases of
soft tissue myoepithelioma
show evidence of epithelial
differentiation, usually in the
form of ductular structures
﬈. These tumors are also
referred to as mixed tumors.

Cutaneous Syncytial Myoepithelioma Scattered Atypical Nuclei

(Left) This case of cutaneous
myoepithelioma is composed
predominantly of spindle-
shaped tumor cells with a
syncytial growth pattern. Note
the focal adipocytic
metaplasia and scattered
chronic inflammatory cells.
(Right) Scattered, enlarged,
hyperchromatic nuclei, in an
otherwise conventional soft
tissue myoepithelioma, does
not imply aggressive behavior.
In contrast, diffuse nuclear
atypia, particularly with
prominent nucleoli, correlates
well.

662
 Myoepithelioma of Soft Tissue
Malignant Myoepithelioma
Rhabdoid Morphology
Malignant Myoepithelioma
Tumors of Uncertain Differentiation
Nuclear Atypia and Mitoses
(Left) A rare case of malignant
myoepithelioma of deep soft
tissues with gray-white cut
surfaces and extensive areas
of tumor necrosis ﬊ is shown.
(Right) This case of clinically
malignant and metastatic
myoepithelioma shows diffuse
nuclear atypia in the form of
coarse chromatin and
prominent nucleoli. Mitotic
figures ﬉ are also increased
in the tumor.
Necrosis
(Left) This malignant
myoepithelioma with a
predominant plasmacytoid
morphology shows prominent
nucleoli imparting a rhabdoid
appearance. Note the mitotic
figures ﬈. A subset of
malignant cases show loss of
nuclear INI1 similar to
epithelioid sarcoma and other
rhabdoid tumors. (Right)
Coagulative necrosis ﬉ is a
common feature of malignant
myoepithelioma.
Undifferentiated Morphology
(Left) Malignant forms of
myoepithelioma are often
more cellular than benign
types, and the mitotic rate is
typically elevated. Coagulative
necrosis is also not
uncommon. Diffuse nuclear
atypia, however, correlates
best with malignant potential.
(Right) An undifferentiated
round cell component may be
seen in some cases of
malignant myoepithelioma, as
depicted, particularly in those
that occur in children.
663
 Phosphaturic Mesenchymal Tumor

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY • Rare malignant PMT can metastasize and cause death

• Rare distinctive mesenchymal neoplasm of soft tissue and MICROSCOPIC
bone that is often associated in most cases with tumor-
• Loose arrays of spindled to stellate cells
induced osteomalacia
• Chondromyxoid or hyalinized matrix with characteristic
CLINICAL ISSUES granular, flocculent calcification
• Most common in middle-aged adults • Well-developed stromal capillary vasculature
• Predilection for extremities, particularly thigh and foot • Osteoclast-like multinucleated giant cells common
○ Also bony sites ANCILLARY TESTS
• Most patients have symptoms related to osteomalacia
• Detection of FGF23 mRNA or expression by
○ Labs: Hypophosphatemia, hyperphosphaturia, immunohistochemistry
normocalcemia
• ERG(+), SATB2(+), CD56(+)
○ Some patients have no clinical or laboratory evidence of
• FN1-FGFR1 gene fusion in 40-50% of cases
osteomalacia
• Treatment: Complete surgical excision TOP DIFFERENTIAL DIAGNOSES
○ Tumor-induced osteomalacia often resolves following • Solitary fibrous tumor
resection of tumor • Soft tissue chondroma
• Most are clinically benign • Mesenchymal chondrosarcoma
○ Local recurrence common

Phosphaturic Mesenchymal Tumor Bland Cytologic Features

(Left) Phosphaturic
mesenchymal tumor (PMT) is a
rare neoplasm of soft tissue
and bone that is associated in
most cases with clinical
features of osteomalacia. A
characteristic finding is
variable-sized deposits ﬊ of
amorphous, lightly basophilic
calcification. (Right) The
lesional cells of PMT are
spindled to stellate and
usually cytologically bland;
however, rare malignant cases
do occur. Osteoclast-like giant
cells ﬉ are common. Note the
deposit ﬊ of granular
calcification.

Distinctive Calcification Vascular Stroma

(Left) The distinctive and
characteristic foci of
calcification in PMT appear
lightly basophilic and granular
or flocculent in quality.
Sometimes it is referred to as
"grungy" calcification. (Right)
The stroma in PMT is often
quite vascular, and dilated
capillaries or larger channels
are usually readily evident and
may even impart a
hemangioma-like appearance.
Larger, ectatic, "staghorn"
vessels are also not
uncommon.

664
 Phosphaturic Mesenchymal Tumor

Tumors of Uncertain Differentiation

• Loose arrays of spindled to stellate cells, often of low
TERMINOLOGY cellularity
Abbreviations ○ Bland nuclei without atypia
• Phosphaturic mesenchymal tumor (PMT) ○ Mitoses rare
• Chondromyxoid "smudgy" or hyalinized matrix
Synonyms
○ Characteristic granular, flocculent, "grungy" calcification
• PMT mixed connective tissue variant ○ May show areas resembling osteoid or cartilage
Definitions • Well-developed, stromal capillary vasculature
• Rare distinctive mesenchymal neoplasm of soft tissue and ○ Larger, ectatic, "staghorn" vessels common
bone that is often associated with tumor-induced • Osteoclast-like multinucleated giant cells common
osteomalacia • Adipose tissue, microcystic change, hemorrhage may be
present
CLINICAL ISSUES • No necrosis
• Rare cases can show features similar to chondromyxoid
Epidemiology
fibroma, giant cell reparative granuloma, or sinonasal
• Incidence glomangiopericytoma
○ Very rare • Malignant PMT
• Age ○ Usually shows increased cellularity with high nuclear
○ Wide range (middle-aged adults most common) grade and frequent mitoses (> 5 per 10 HPF)
• Sex
○ Male = female ANCILLARY TESTS
Site Immunohistochemistry
• Predilection for extremities, particularly thigh and foot, but • FGF23(+) in most tumors
can occur at any soft tissue site • ERG(+), SATB2(+), CD56(+)
○ Superficial or deep soft tissues • CD34(-), STAT6(-), S100(-), desmin (-), keratin (-), DOG1(-)
○ May arise in acral locations
Molecular Genetics
• Occurs with roughly equal frequency in bony sites
• Also sinonasal tract • Detection of FGF23 mRNA in lesional cells
○ Supports diagnosis within appropriate histologic and
Presentation clinical setting
• Most patients have symptoms related to osteomalacia • FN1-FGFR1 gene fusion in 40-50% of cases
○ Pain, stress fractures ○ FGFR1 rearrangement detectable by FISH
• Labs: Hypophosphatemia, hyperphosphaturia,
normocalcemia DIFFERENTIAL DIAGNOSIS
○ Related to oversecretion of fibroblastic growth factor-23 Solitary Fibrous Tumor
(FGF23)
• Lacks characteristic "grungy" calcified matrix of PMT
– Inhibits phosphate reabsorption by proximal renal
tubules • STAT6(+), CD34(+)
• Some patients have no clinical or laboratory evidence of Soft Tissue Chondroma
osteomalacia • Most common in fingers and hand
Treatment • May be calcified and contain giant cells
• Complete surgical excision • Lacks bland spindle cells and adipose tissue, as seen in PMT

Prognosis Mesenchymal Chondrosarcoma

• Most are clinically benign • Sheets of malignant small round cells with admixed islands
○ Rare malignant PMT can metastasize and cause death of cartilage
• Local recurrence common • Lacks characteristic "grungy" calcified matrix of PMT
○ Clinically malignant tumors most commonly arise within • Recurrent HEY1-NCOA2 gene arrangement
setting of local recurrence; often repeated
• Tumor-induced osteomalacia often resolves following SELECTED REFERENCES
resection of tumor 1. Agaimy A et al: Phosphaturic mesenchymal tumors: clinicopathologic,
immunohistochemical and molecular analysis of 22 cases expanding their
morphologic and immunophenotypic spectrum. Am J Surg Pathol.
MACROSCOPIC 41(10):1371-80, 2017
2. Lee JC et al: Characterization of FN1-FGFR1 and novel FN1-FGF1 fusion
Size genes in a large series of phosphaturic mesenchymal tumors. Mod Pathol.
• Mean: 3.9 cm 29(11):1335-46, 2016
3. Bahrami A et al: RT-PCR analysis for FGF23 using paraffin sections in the
diagnosis of phosphaturic mesenchymal tumors with and without known
MICROSCOPIC tumor induced osteomalacia. Am J Surg Pathol. 33(9):1348-54, 2009
4. Folpe AL et al: Most osteomalacia-associated mesenchymal tumors are a
Histologic Features single histopathologic entity: an analysis of 32 cases and a comprehensive
• Usually well circumscribed review of the literature. Am J Surg Pathol. 28(1):1-30, 2004

665
 Synovial Sarcoma

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY
• Malignant mesenchymal spindle cell neoplasm with variable
epithelial differentiation, including gland formation, and
characterized by specific chromosomal translocation
t(X;18)(p11;q11)
CLINICAL ISSUES
• Most common in young adults
• Most arise in deep soft tissues of extremities
○ Most common near joints (particularly knee)
• Also head/neck, trunk, many other sites
• Treatment: Complete surgical resection with negative
margins
• Adjuvant therapy in some cases
• Local recurrence common
• Metastasis in up to 50% of cases
• Unfavorable prognostic factors
○ High stage, age > 40 years, poorly differentiated
histology
MICROSCOPIC
• Predominantly monophasic or biphasic morphologies
• Dense cellular sheets or vague fascicles of uniform spindle
cells without significant pleomorphism
• Stromal calcifications, prominent vasculature in some
• Biphasic tumors also contain epithelial structures
• Subset show poorly differentiated areas
ANCILLARY TESTS
• Keratin (+), EMA(+), usually focal/patchy
• Strong, diffuse nuclear TLE-1(+)
• CD56(+), CD99(+)
• CD34, SMA, desmin, synaptophysin, TTF-1 (-)
• Molecular: Characteristic t(X;18)(p11;q11)
TOP DIFFERENTIAL DIAGNOSES
• Malignant peripheral nerve sheath tumor
• Fibrosarcomatous dermatofibrosarcoma protuberans
• Solitary fibrous tumor

Synovial Sarcoma Monophasic Morphology

(Left) Macroscopically,
synovial sarcoma (SS) often
appears as a nodular,
circumscribed mass located in
skeletal muscle beneath the
deep fascia ﬈. The cut
surface varies from tan to
white or pink and may display
focal hemorrhage st or cystic
change. (Right) Monophasic SS
is the most common form of
SS and is characterized by an
exclusive spindle cell
morphology (no epithelial
structures). Sheet-like or
fascicular growth is typical of
this form, and the cells are
always cytologically uniform.

High Cellularity Keratin/EMA Expression

(Left) Most cases of SS show
areas with a high degree of
cellularity, which imparts an
overall blue or purple color to
the tumor tissue at lower
magnifications due to the
increased nuclear density.
Nuclear overlapping is a
frequent feature. (Right) The
majority of cases of SS show
keratin &/or EMA positivity;
however, expression is
characteristically focal or
patchy, often in a single-cell
distribution, as depicted.
Diffuse keratin or EMA
expression in a spindle cell
neoplasm should raise
concerns for a different entity.

666
 Synovial Sarcoma

Tumors of Uncertain Differentiation

TERMINOLOGY Prognosis
• Local recurrence common, especially following incomplete
Abbreviations resection
• Synovial sarcoma (SS) • Metastasis in up to 50% of cases
Synonyms ○ Lung most common site
– Late metastases can appear after many years
• Obsolete terms: Synovial cell sarcoma, malignant
synovioma ○ Small subset (5-10%) can spread to lymph nodes
• 5-year survival rate (50-85%)
Definitions ○ Higher rate in children/adolescents
• Malignant mesenchymal spindle cell neoplasm with variable • Prognostic factors
epithelial differentiation, including gland formation, and ○ Favorable
characterized by specific chromosomal translocation – Small tumor size (< 5 cm)
t(X;18)(p11;q11) □ Tumors < 1 cm have excellent prognosis
○ Despite its name, tumor does not arise from or – Occurrence in childhood
differentiate toward synovium ○ Unfavorable
– Age > 40 years
CLINICAL ISSUES – Large tumor size
Epidemiology – Poorly differentiated histology (> 20% component)
• Incidence □ More common in elderly patients
○ 5-10% of all soft tissue sarcomas – High stage at presentation
• Age ○ Biphasic vs. monophasic morphology has no prognostic
○ Most common in young adults (majority 10-40 years) relevance
– Rare over 50 years
• Sex MACROSCOPIC
○ Slight male predominance General Features
– SS of peripheral nerve more common in females • Well circumscribed; can be multinodular
Site • Soft to firm, tan, gray, yellow, or pink cut surface
• Most arise in deep soft tissues of extremities • Cystic change not uncommon
○ Most common near joints (particularly knee) • Calcification &/or ossification may be seen
• Head and neck Size
○ Parapharynx, oral cavity, tonsil • Usually 3-10 cm
• Trunk ○ Can be minute (< 1 cm) or > 15 cm
• Rare subsets
○ Viscera (kidney, pleura, lung, other organs) MICROSCOPIC
○ Retroperitoneum, mediastinum
Histologic Features
○ Tumors arising within peripheral nerve
○ Male and female genital tracts • Monophasic SS
○ Central nervous system, bone ○ Dense cellular sheets or vague fascicles of uniform
spindle cells with scanty cytoplasm
Presentation – Relatively uniform, ovoid, bland nuclei, often
• Deeply situated, slowly growing mass overlapping
○ Very rare superficial tumors □ Lack significant pleomorphism
• 1/2 of cases associated with pain – Highly variable mitotic rate (from sparse to numerous)
• History of local trauma sometimes present ○ Rare herringbone or focal palisaded growth patterns
• Can be present for long period: 2-20 years ○ Variable collagenous stroma, often inconspicuous
– Thickened bundles of "wiry" collagen can be seen
Treatment
– Myxoid stromal changes in some tumors (may be
• Complete surgical resection with negative margins prominent)
○ Usually limb sparing; amputation rarely required – Extensive stromal fibrosis and associated
• Resection of recurrences hypocellularity common in irradiated tumors
○ May necessitate radical surgery, including amputation ○ Stromal calcifications are identified in 30% of cases
• Pulmonary metastasectomy for small numbers of surgically – Helpful diagnostic clue
accessible metastases – May also show metaplastic bone formation
• Role of adjuvant therapy ○ Stromal vasculature can be prominent
○ Preoperative irradiation for large or initially unresectable – Also, focally "staghorn" or hemangiopericytoma-like
primary tumor ○ Mast cells common (may be prominent in some tumors)
○ Chemotherapy for disseminated disease ○ Necrosis uncommon
○ Tumors arising within peripheral nerve often strikingly
multinodular
667
 Synovial Sarcoma
Tumors of Uncertain Differentiation
• Biphasic SS
○ Contains same spindle cell population as monophasic SS
(at least focally)
○ Additionally features epithelial structures
– Can be focal/subtle or extensive/prominent
– Glands (well or poorly formed), ducts, nests, and cords
□ Glandular lumina may contain eosinophilic
secretions or mucin
□ Epithelial cells show more abundant cytoplasm
– Rare squamous differentiation or granular cell change
• Poorly differentiated histology
○ Can be seen within monophasic or biphasic SS
– May be focal or extensive
○ Characterized by hypercellularity, high-grade nuclear
features, and increased mitoses
– Nuclei often show irregular contours and "chunky"
chromatin or prominent nucleoli
○ Spindle cell pattern can be highly fascicular
○ Round cell pattern resembles Ewing sarcoma
○ Necrosis more common
• Rare: Rhabdoid cells, clear cell change, rosette-like
structures
ANCILLARY TESTS
Immunohistochemistry
• Keratin (+), EMA(+)
○ Characteristic focal/patchy expression in spindled cells
○ Strong expression in epithelial components (biphasic SS)
• Strong, diffuse nuclear TLE1(+)
○ Focal or weak expression is nonspecific
○ Diffuse TLE1 expression also reported in solitary fibrous
tumor and biphenotypic sinonasal sarcoma (rare)
• Focal S100 protein (+) &/or SOX10(+) in up to 40% of cases
• CD56(+), CD99(+)
• Calretinin (+) in 40-70% of cases (may be diffuse)
• CD34, SMA, desmin, myogenin, PAX3, synaptophysin, TTF-
1, NKX2.2 (-)
• Retention of H3K27me3 in most cases
Molecular Genetics
• Characteristic t(X;18)(p11;q11) in vast majority of tumors
○ One of SSX genes at Xp11 fuses to SS18 gene (formerly
termed SYT) at 18q11
– May involve SSX1 (most common), SSX2, or SSX4
○ Can utilize break-apart FISH for SS18 (SYT) or RT-PCR for
fusion transcripts
• Rare SS18L1-SSX1 fusion variant reported (not detectable
by standard SS18 FISH)
DIFFERENTIAL DIAGNOSIS
Malignant Peripheral Nerve Sheath Tumor
• Can arise in association with neurofibromatosis type 1
• Nuclei wavy, buckled, or arrowhead-shaped
• Variable CD34(+) common
• Loss of nuclear H3K27me3 by IHC
• Keratin (-)
○ May show focal or weak TLE1(+)
• Lacks SS18 (SYT) rearrangements
668
Fibrosarcomatous Dermatofibrosarcoma
Protuberans (DFSP)
• Predominantly affects superficial soft tissues
• May be associated with areas of low-grade DFSP
• CD34(+) in some cases (may be patchy or absent)
• Keratin and TLE1 (-)
• Characteristic COL1A1-PDGFB fusion
Solitary Fibrous Tumor
• Characteristic dilated, irregular staghorn vasculature
• Stromal collagen usually prominent
• Strong, diffuse CD34(+), STAT6(+); keratin (-)
• Rare tumors can show diffuse TLE1(+)
• Characteristic NAB2-STAT6 fusion
Ewing Sarcoma
• Can mimic poorly differentiated SS
• Small round cell morphology without spindle cells or
epithelial structures
• Diffuse membranous CD99(+); also, NKX2.2(+)
• CD56(-)
• EWSR1 translocations in vast majority of cases
BCOR-CCNB3 (Ewing-Like) Sarcoma
• Can mimic poorly differentiated SS
• CD99(+), TLE-1 (variable)
• Lacks SS18 (SYT) rearrangement
Leiomyosarcoma
• Most tumors show prominent eosinophilic cytoplasm
• Nuclear pleomorphism common
• SMA(+), H-caldesmon (+), variable desmin (+)
• Generally keratin and EMA (-)
Biphasic Sinonasal Sarcoma
• Closely resembles monophasic SS
• Some tumors feature rhabdomyoblastic differentiation
• Expression of myogenic markers (SMA, desmin, myogenin)
• PAX3(+); S100 protein (+); SOX10(-)
• Characterized by PAX3-MAML3 fusion
SELECTED REFERENCES
1. Terra SBSP et al: Mediastinal synovial sarcoma: clinicopathologic analysis of
21 cases with molecular confirmation. Am J Surg Pathol. 42(6):761-766,
2018
2. Chrisinger JSA et al: Synovial sarcoma of peripheral nerves: analysis of 15
cases. Am J Surg Pathol. 41(8):1087-96, 2017
3. El Beaino M et al: Synovial sarcoma: advances in diagnosis and treatment
identification of new biologic targets to improve multimodal therapy. Ann
Surg Oncol. 24(8):2145-2154, 2017
4. Kao YC et al: BCOR upregulation in a poorly differentiated synovial sarcoma
with SS18L1-SSX1 fusion-a pathologic and molecular pitfall. Genes
Chromosomes Cancer. 56(4):296-302, 2017
5. Schaefer IM et al: Loss of H3K27 trimethylation distinguishes malignant
peripheral nerve sheath tumors from histologic mimics. Mod Pathol. 29(1):4-
13, 2016
6. Thway K et al: Synovial sarcoma: defining features and diagnostic evolution.
Ann Diagn Pathol. 18(6):369-80, 2014
7. Shi W et al: Long-term treatment outcomes for patients with synovial
sarcoma: a 40-year experience at the University of Florida. Am J Clin Oncol.
36(1):83-8, 2013
8. Knösel T et al: TLE1 is a robust diagnostic biomarker for synovial sarcomas
and correlates with t(X;18): analysis of 319 cases. Eur J Cancer. 46(6):1170-6,
2010
9. Michal M et al: Minute synovial sarcomas of the hands and feet: a
clinicopathologic study of 21 tumors less than 1 cm. Am J Surg Pathol.
30(6):721-6, 2006
 Synovial Sarcoma
Monomorphic Cytology
Fascicular Growth
Loose, Hypocellular Areas
Tumors of Uncertain Differentiation
Variations in Cellularity
(Left) Relatively bland,
hyperchromatic, and
monomorphic nuclei are a
constant feature of SS, and
significant nuclear
pleomorphism in a spindle cell
sarcoma should lead to
consideration of another
diagnosis, such as MPNST.
Optically clear nuclear
pseudoinclusions ﬊ are
common and may be
numerous. (Right) Although
many cases of SS are evenly
cellular, variations in
cellularity may also be seen, as
depicted, creating an
alternating marbled pattern
similar to MPNST.
Neural-Like Fascicles
(Left) Vague or loose
fascicular growth is common
in SS. In some cases, fascicles
are well formed and quite
prominent and can even show
a focal herringbone pattern of
growth, as demonstrated in
this H&E. (Right) On occasion,
the spindle cells of
monophasic SS may appear
highly compressed and with
hyperchromatic, wavy nuclei,
imparting a neural
cytomorphology, as shown. A
diagnosis of MPNST should
always be considered and
excluded in these cases.
Stromal Calcifications
(Left) Most cases of SS are not
diffusely cellular. Some areas
are hypocellular secondary to
stromal edema, myxoid
change, or fibrosis. Familiarity
with the entire spectrum of
cellularity in SS is important to
avoid underdiagnosis. (Right)
Stromal calcifications ﬊ are a
characteristic feature of SS
and can be seen in up to 30-
40% of cases. They are usually
unassociated with
hemorrhage or evidence of
trauma. In helpful contrast,
these calcifications are not
generally a feature of the
morphologically similar
MPNST.
669
 Synovial Sarcoma
Tumors of Uncertain Differentiation

Wiry Stromal Collagen Prominent Stromal Collagen

(Left) Although not always
apparent due to the frequent
high cellularity of the tumor, a
fine eosinophilic collagenous
stroma is present in SS.
Variably conspicuous,
irregular, thin collagen fibers
﬈ are often described as wiry
but can appear as thicker
bundles. (Right) In some cases
of SS, the stromal collagen is
more prominent and may
appear as hyalinized bands, as
depicted. Note the presence of
stromal calcifications.

Diffuse Hyalinization Diffuse Hyalinization

(Left) Diffuse stromal
hyalinization or sclerosis may
be seen de novo in rare cases
of SS. However, this
morphology is much more
frequent following radiation
therapy or chemotherapy.
(Right) Diffusely hyalinized or
fibrotic cases of SS show
marked hypocellularity
compared to conventional
forms and maintain the
characteristic cellular
monomorphism. A vague
fascicular pattern may also be
present in these cases.

Metaplastic Bone Formation Metaplastic Bone Formation

(Left) Metaplastic bone ﬈
may be seen in a minority of
cases of SS and often shows a
mature, lamellar composition
with mineralization. This H&E
was taken from a pulmonary
metastasis of SS following
chemotherapy. Note the
diffuse fibrosis. (Right) In rare
cases of SS, calcification &/or
metaplastic bone formation
﬈ is extensive and dominates
the histologic picture, as
shown. The cellularity of this
variant is often less than usual
and, therefore, may be
potentially misdiagnosed as a
benign neoplasm.

670
 Synovial Sarcoma

Tumors of Uncertain Differentiation

Myxoid Stroma Diffuse Myxoid Stroma
(Left) Myxoid stroma ﬈ is a
relatively common finding in
SS but is often minor and
overshadowed by more
conventional highly cellular
areas. The interface between
myxoid and nonmyxoid zones
may be gradual or abrupt.
(Right) In rare cases of SS,
myxoid stroma is diffuse and
prominent and may easily lead
to confusion with a variety of
other myxoid sarcomas.
Identification of areas of more
typical morphology or
utilization of ancillary studies
can be very helpful.

Myxoid Stroma Stromal Vasculature

(Left) The characteristic
cellular uniformity or
monomorphism of SS is
maintained even in highly
myxoid areas, as depicted in
this H&E. Note the relative
blandness of the nuclei,
mimicking a low-grade or
benign neoplasm. (Right)
Infrequently, some areas of SS
may show a more loose,
fibromyxoid stroma in which
thin-walled blood vessels ﬈
become more prominent. On
biopsy, this appearance can
lead to confusion with low-
grade fibromyxoid sarcoma or
myxofibrosarcoma.

Pleural Synovial Sarcoma Lung Metastasis

(Left) This unusual case of SS
arising in the pleura shows a
prominent myxoid stroma and
a more ovoid cytomorphology.
Cytologic atypia was mild, and
mitoses were not abundant.
FISH analysis confirmed the
presence of an SS18 (SYT)
rearrangement. (Right) The
most common site of
metastasis for synovial
sarcoma is the lung. Although
often histologically similar to
the primary tumor, cases of
treated/irradiated SS can
produce metastatic deposits
that are heavily collagenized,
resembling pulmonary or
subpleural scars.

671
 Synovial Sarcoma
Tumors of Uncertain Differentiation

TLE1 Expression CD56 Expression

(Left) Nuclear expression of
TLE1 has been found to be a
highly sensitive marker of SS.
It is also relatively specific
when the staining is strong
and diffuse, as shown.
However, solitary fibrous
tumor can occasionally show
similar positivity. Weak &/or
focal expression is nonspecific
and may be seen in a variety of
other tumors. (Right) Strong
CD56 expression is a common
finding in SS. Awareness of
this expression is important to
avoid confusion with high-
grade neuroendocrine
carcinoma, particularly in
poorly differentiated SS.

CD99 Expression Mast Cells

(Left) CD99 expression is often
present in SS. Notably, in
poorly differentiated forms
with a round cell morphology,
membranous expression of
this antigen can lead to
consideration of Ewing
sarcoma. Molecular evaluation
is diagnostic in this scenario.
(Right) Mast cells ﬈ are a
frequent finding in SS;
however, the exact number
varies widely from tumor to
tumor. In some cases, they can
be quite prominent, as
depicted in this H&E.

Mast Cells Hemorrhage

(Left) Mast cells ﬈ may also
be noted in hypocellular
fibrous or myxoid areas of SS.
Given the additional feature of
elongated and wavy nuclei, as
seen in this H&E, a tumor of
neural origin may be
considered. (Right)
Hemorrhage may be seen in
SS, both grossly and
microscopically. In occasional
tumors, the presence of
extravasated red blood cells
among uniform spindled cells
can impart an appearance
somewhat reminiscent of
Kaposi sarcoma.

672
 Synovial Sarcoma

Tumors of Uncertain Differentiation

Multinodular Growth Occasional Whorling Pattern
(Left) A vaguely nodular
growth pattern may be seen in
rare cases of monophasic SS
and may lead to confusion
with other entities, including
low-grade fibromyxoid
sarcoma. A multinodular
pattern is also typical of SS
arising from the peripheral
nerve. (Right) Whorled foci ﬈
are a rare and unusual finding
in SS and may be seen in either
hypercellular or hypocellular
collagenous areas. However,
this finding should prompt
exclusion of a neural
neoplasm, particularly MPNST.

Biphasic Morphology Well-Formed Glands

(Left) Biphasic SS is best
conceptualized as a typical
monophasic spindled SS but
with the formation of
epithelial structures, including
glands ﬈, ducts, or nests. The
conventional spindled
component ﬉ is essentially
always present but may be
extremely focal. (Right) The
epithelial cells of biphasic SS
may be arranged as well-
formed glands or ducts, as
depicted. This appearance may
at first suggest a well- or
moderately differentiated
adenocarcinoma; however,
note the spindle cell
component ﬈.

Cystic Glands Pseudopapillary Appearance

(Left) Glandular structures in
biphasic SS may exhibit cystic
change and may become quite
prominent in some cases.
Larger cysts can often be
identified grossly. (Right)
Occasionally, the glandular
component of biphasic SS
appears ramifying and
labyrinthine, creating a
pseudopapillary appearance.
This pattern can resemble that
seen in malignant phyllodes
tumor of the breast.

673
 Synovial Sarcoma
Tumors of Uncertain Differentiation

Intraluminal Eosinophilic Secretions Intraluminal Mucin

(Left) A characteristic finding
in biphasic SS is the presence
of inspissated eosinophilic
secretions ﬈ within the
glandular or ductular lumina
of the tumor. Also note the
cytologic features of the
epithelial component: Round
to oval nuclei without
significant pleomorphism.
(Right) Mucin ﬈ may also be
produced by glands in biphasic
SS. This particular case also
shows epithelial cells with
clear cytoplasm ﬊ focally.

Adenocarcinoma-Like Morphology Predominant Biphasic Morphology

(Left) The glandular
component of biphasic SS may
appear highly complex and, in
conjunction with the presence
of granular eosinophilic
secretions ﬊ (resembling
necrosis), can easily mimic
primary or metastatic
adenocarcinoma, depending
on the site. (Right) The
epithelial component of
biphasic SS may comprise the
vast majority of a given tumor
suggesting the existence of a
pure "monophasic epithelial"
SS; however, focal spindle cell
areas ﬈ are essentially
always found if carefully
sought.

Focal Pseudodesmoplastic Stroma Nests and Poorly Formed Glands

(Left) Some cases of biphasic
SS may show focal myxoid
stromal changes ﬈ around
the glands, mimicking a
desmoplastic response to the
tumor often seen in many
forms of invasive carcinoma.
(Right) Glands may be poorly
formed in biphasic SS and
appear as distinct, variably
sized nests of epithelioid cells,
as depicted. Note the presence
of eosinophilic secretions ﬉,
revealing subtle lumina
formation.

674
 Synovial Sarcoma
Poorly Formed Epithelial Nests/Cords
Subtle Biphasic Component
Rare Squamous Metaplasia
Tumors of Uncertain Differentiation
Syncytia-Like Trabecular Morphology
(Left) In some cases of biphasic
SS, the epithelial component is
very poorly formed and can
appear as irregular nests or
cords ﬊ of enlarged tumor
cells. These vague structures
are often strongly keratin and
EMA (+). (Right) Biphasic SS
may contain an extensive
epithelial component ﬈ that
manifests histologically as
broad, serpentine trabeculae
or sheets of large, pale cells in
a syncytia-like arrangement,
admixed with a more
conventional spindle cell
component ﬉.
Biphasic With Sclerosis
(Left) At 1st glance, this H&E
of SS may appear monophasic;
however, closer inspection
reveals subtle gland formation
(with secretions ﬈) within a
very vague and poorly
developed epithelial
component. Note the focal
spindled component ﬉.
(Right) This unusual case of
biphasic SS showed the
characteristic epithelial
component ﬈ but within a
markedly hyalinized/sclerotic
stromal matrix.
Strong Keratin Expression
(Left) Squamous metaplasia
with central keratinization is a
rare, but well-described
finding in the epithelial
component of biphasic SS.
(Right) Keratin (shown) and
EMA are typically strongly
expressed within the epithelial
component of biphasic SS, as
depicted, similar to
conventional epithelial cells. In
contrast, the spindle cell
component is often focally
positive ﬈ in a single cell
pattern, as is seen in pure
monophasic SS.
675
 Synovial Sarcoma
Tumors of Uncertain Differentiation

Poorly Differentiated Morphology Severe Nuclear Atypia

(Left) Poorly differentiated
areas may be present within
otherwise typical monophasic
or biphasic SS and are often
hypercellular with abundant
mitotic figures st. In some
cases, the entire tumor is
poorly differentiated. The
morphology may be
spindled/fascicular or round
cell. (Right) Poorly
differentiated foci in SS are
most readily identified by the
presence of severe nuclear
atypia, including nuclear
enlargement and contour
irregularity, and a "chunky" or
"clumpy" chromatin ﬈
distribution.

Prominent Nucleoli Coagulative Necrosis

(Left) Prominent nucleoli st
are also a common finding in
poorly differentiated SS and
can aid in recognition of these
higher grade areas. (Right)
Coagulative tumor necrosis ﬊
is not a frequent finding in
conventional monophasic or
biphasic SS; however, it is
much more common in poorly
differentiated areas, as
depicted. The necrosis may be
focal or rarely extensive and
geographic.

Round Cell Morphology Nested Round Cell Morphology

(Left) Poorly differentiated SS
can manifest histologically
with a round cell morphology
(center) similar to a variety of
"round blue cell tumors,"
including Ewing sarcoma,
alveolar rhabdomyosarcoma,
and neuroendocrine
carcinoma. These round cell
areas often "stick out" from
more conventional areas ſt of
SS, if present. (Right) The
round cell pattern of poorly
differentiated SS can appear
as nests and cords within a
fibrocollagenous or myxoid
stroma, as depicted.
Cytologically, these cells differ
from those of biphasic SS.

676

Poorly Differentiated With Sclerosis
Rare Clear Cell Change
Prominent, Ectatic Stromal Vasculature
Synovial Sarcoma
Tumors of Uncertain Differentiation
Rhabdoid Cells
(Left) Stromal hyalinization
may be seen in areas of poorly
differentiated SS with round
cell morphology, as depicted.
In general, however,
prominent stromal collagen is
more common in conventional
SS. (Right) A distinctive
rhabdoid cytomorphology may
be identified in some cases of
poorly differentiated SS.
Rare Nuclear Palisading
(Left) H&E shows a rare case
of poorly differentiated SS
with areas of clear cell
change. (Right) Vague nuclear
palisades ſt may be seen in
rare cases of SS (often in
poorly differentiated areas);
however, in general, the
palisades are not as well
formed as what is typically
seen in some neural tumors.
Rare Hemangiopericytoma-Like Pattern
(Left) Scattered, dilated
stromal blood vessels are not
uncommon in SS; however,
they are more common and
often more prominent in
poorly differentiated areas. A
staghorn appearance may also
be present, as depicted.
(Right) Rarely, the vasculature
of SS is impressively
prominent, as depicted, and
can lead to confusion with a
cellular solitary fibrous tumor
(previously termed
hemangiopericytoma).
677
 Epithelioid Sarcoma

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY ○ Epithelioid and spindled cells with eosinophilic cytoplasm

• Distinctive malignant mesenchymal neoplasm that often and uniform, irregular, mildly atypical nuclei
shows epithelioid cytomorphology and demonstrates ○ Rare predominantly spindled tumors (fibroma-like ES)
evidence of epithelial differentiation • Proximal-type ES
○ Classic ES most commonly affects adolescents and ○ Large, cellular nodules of polygonal cells with prominent
young adults and arises in distal extremities macronucleoli
○ Proximal-type ES tends to affect older age groups ○ Rhabdoid morphology common
(median: 40 years), arises in proximal locations, and is ANCILLARY TESTS
often more clinically aggressive
• Keratin (+); also, CD34(+) in 50%
CLINICAL ISSUES • Complete loss of nuclear INI1 protein expression
• Classic ES may appear clinically as nonhealing ulcer • Molecular: High frequency of SMARCB1 (INI1) deletion
• Clinically aggressive sarcoma (22q11)
○ High rate of recurrence and metastases TOP DIFFERENTIAL DIAGNOSES
– Metastases to lymph nodes, lung, and skin
• Granulomatous processes
MICROSCOPIC • Carcinoma or melanoma
• Classic ES • Extrarenal rhabdoid tumor
○ Nodules with central necrosis (granuloma like) • Epithelioid angiosarcoma

Epithelioid Sarcoma Pseudogranulomatous Morphology

(Left) Epithelioid sarcoma (ES)
is a distinctive malignant
mesenchymal neoplasm that
classically arises on the distal
extremities of adolescents and
young adults and shows
immunohistochemical
evidence of epithelial
differentiation. Overlying
ulceration, though not shown
here, may be present and can
lead to clinical misdiagnosis as
an infection or chronic
reactive process. (Right) The
nodules of ES ﬉ often contain
centralized necrosis ﬈,
imparting an appearance
reminiscent of a true
granulomatous process.

Classic Epithelioid Sarcoma Immunophenotype

(Left) The classic type of ES is
composed of small- to
medium-sized epithelioid cells
with eosinophilic cytoplasm.
Admixed small spindled cells
﬈ can also be identified and
often appear more
conspicuous at the periphery
of a nodule. Note the central
tumor necrosis ﬊. (Right) ES
is notable among most
mesenchymal tumors for its
expression of epithelial
markers, including most
keratins and EMA (shown).
CD34 is coexpressed in 50% of
cases. Complete loss of
nuclear INI1 is also
characteristic of ES cells.

678
 Epithelioid Sarcoma

Tumors of Uncertain Differentiation

○ > 70% recur
TERMINOLOGY
– Successive recurrences often extend more proximally
Abbreviations in limbs
• Epithelioid sarcoma (ES) ○ ~ 50% metastasize
– Lymph nodes and lungs
Definitions
– Also skin and other soft tissue sites
• Distinctive malignant mesenchymal neoplasm that often ○ 5-year survival (70%), 10-year survival (40%)
shows epithelioid cytomorphology and demonstrates • Proximal-type ES has worse prognosis
evidence of epithelial differentiation
○ Up to 75% metastasize
○ Classic ES most commonly affects adolescents and
○ 5-year survival (35-65%)
young adults and arises in distal extremities
• Adverse prognostic factors
○ Proximal-type ES tends to affect older age groups, arises
○ Proximal location
in proximal locations, and is often more clinically
aggressive ○ Male sex
○ Size > 5 cm
CLINICAL ISSUES ○ Localization to deep soft tissue sites

Epidemiology MACROSCOPIC
• Incidence
General Features
○ Rare
– Accounts for ~ 1% of all soft tissue sarcomas • Uni- or multinodular firm lesion
– Classic ES is more common than proximal-type ES • Tan/white/gray cut surface
• Age • Hemorrhage and necrosis common in proximal-type ES
○ Classic ES Size
– Adolescents and young adults (median: 26 years) • Classic ES: Usually < 5 cm
○ Proximal-type ES • Proximal-type ES: Wide range (1-20 cm)
– Affects middle-aged to older adults (median: 40 years)
• Sex MICROSCOPIC
○ More frequent in male patients (both types)
Histologic Features
Site • Classic ES
• Classic ES ○ Dermal/subcutaneous nodule(s), ± central necrosis
○ Most common in distal extremities, especially hand, – Can simulate granulomatous process at low
wrist, forearm, lower leg magnification
○ Also head and neck, genital sites – Peripheral infiltration of connective tissue is common
• Proximal-type ES – Deeply extending lesions often involve and track
○ Proximal limb girdles along tendons/aponeuroses
○ Perineum, pelvis, mediastinum ○ Small- to medium-sized epithelioid cells with eosinophilic
○ Trunk cytoplasm
– Irregular but uniform, mildly atypical nuclei with small
Presentation
nucleoli
• Classic ES – Admixed cells with spindled morphology common
○ Slow-growing, often painless (particularly at periphery)
○ Indurated dermal or subcutaneous nodule(s) □ May rarely predominate (termed fibroma-like
– Can appear to track up limb variant of ES)
○ May appear as nonhealing ulcer □ Can show storiform growth
– Can closely mimic infection clinically ○ Variable mitotic activity, often low
– Raised "sealing wax" margins ○ Mixed chronic inflammatory infiltrate common
• Proximal-type ES ○ Other findings
○ Subcutaneous or deep soft tissue mass – Densely hyalinized collagenous stroma
○ Can appear and grow more rapidly than classical ES – Rare myxoid change
Treatment – Osteoclast-like giant cells, calcification, metaplastic
bone formation
• Wide surgical excision and reexcision
– Pseudogland formation
○ Amputation in some cases
– Pseudovascular morphology
• Chemotherapy can be palliative but currently of limited
• Proximal-type ES
therapeutic benefit
○ More infiltrative with less-defined peripheral borders
○ Preclinical models suggest possible therapeutic benefit
of EGFR-TK, mTOR, and c-MET inhibitors ○ Multiple large nodules
○ Large polygonal cells with abundant eosinophilic
Prognosis cytoplasm
• Clinically aggressive sarcoma – Rhabdoid morphology common

679
 Epithelioid Sarcoma
Tumors of Uncertain Differentiation
○ Vesicular nuclei with prominent macronucleoli
○ Mitoses common
○ Necrosis and hemorrhage common
ANCILLARY TESTS
Immunohistochemistry
• High- and low-molecular weight keratins (+), EMA(+),
vimentin (+)
○ However, CK5/6(-)
• CD34(+) in 50%
• ERG(+) in 40% of cases; GLUT1(+) in 50% of cases
• Complete loss of nuclear INI1 protein expression
• Negative for CD31, S100 protein, p63, desmin, FLI-1, and
PROX1
Molecular Genetics
• High frequency of SMARCB1 (INI1) deletion (22q11)
○ Both classic and proximal-type ES
DIFFERENTIAL DIAGNOSIS
Granulomatous Processes
• Particularly granuloma annulare
• Lacks infiltrative or invasion growth
• Lacks coagulative tumor cell necrosis
• Keratin (-) and EMA(-)
• Retained nuclear INI1 expression
Squamous Cell Carcinoma
• Overlying in situ component may be identifiable
• Prior clinical history may be present
• Usually more pleomorphic than ES
• CK5/6(+) and p63(+)
• CD34(-)
• Retained nuclear INI1 expression
Extrarenal Rhabdoid Tumor
• Can show significant morphologic overlap with proximal-
type ES
• Most common in infants and young children
• Keratin(+) but less prominent than in ES
• Consistent loss of nuclear INI1 expression
• Mutation of SMARCB1 gene
Melanoma
• Junctional component or prior clinical history may be
present
• Usually larger, more pleomorphic cells than classic ES
• S100 protein (+), SOX10(+); variable HMB45(+) or MART-
1(+)
• Retained nuclear INI1 expression
Epithelioid Angiosarcoma
• Can show significant morphologic overlap with proximal-
type ES
• Foci of vasoformation often present at least focally
• CD31(+), CD34(+), FLI1(+)
• May be keratin (+), though usually not diffuse
• Retained nuclear INI1 expression
680
Pseudomyogenic (Epithelioid Sarcoma-Like)
Hemangioendothelioma
• Commonly involves multiple tissue planes
• Predominantly spindled morphology
• Neutrophilic infiltrate characteristic
• Keratin (+), CD31(+)
• CD34(-)
• Retained nuclear INI1 expression
Malignant Myoepithelioma (Myoepithelial
Carcinoma)
• Can show morphologic overlap with proximal-type ES
• Myxoid stroma common
• Keratin (+), EMA(+), S100 protein (+)
• Loss of nuclear INI1 expression in subset of cases
Cellular Fibrous Histiocytoma (Dermatofibroma)
• Can show morphologic overlap with predominantly
spindled forms of ES
• Keratin (-)
• Retained nuclear INI1 expression
SELECTED REFERENCES
1. Kohashi K et al: SWI/SNF chromatin-remodeling complex status in
SMARCB1/INI1-preserved epithelioid sarcoma. Am J Surg Pathol. 42(3):312-
8, 2018
2. Alikhan MB et al: Primary epithelioid sarcoma of the kidney and adrenal
gland: report of 2 cases with immunohistochemical and molecular
cytogenetic studies. Hum Pathol. 61:158-63, 2017
3. Thway K et al: Epithelioid sarcoma: diagnostic features and genetics. Adv
Anat Pathol. 23(1):41-9, 2016
4. Coates SJ et al: Epidermotropic metastatic epithelioid sarcoma: a potential
diagnostic pitfall. J Cutan Pathol. 41(8):672-6, 2014
5. Folpe AL: Selected topics in the pathology of epithelioid soft tissue tumors.
Mod Pathol. 27 Suppl 1:S64-79, 2014
6. Imura Y et al: Combined targeting of mTOR and c-MET signaling pathways
for effective management of epithelioid sarcoma. Mol Cancer. 13:185, 2014
7. Stockman DL et al: ERG and FLI1 protein expression in epithelioid sarcoma.
Mod Pathol. 27(4):496-501, 2014
8. Miettinen M et al: ERG expression in epithelioid sarcoma: a diagnostic pitfall.
Am J Surg Pathol. 37(10):1580-5, 2013
9. Sullivan LM et al: Epithelioid sarcoma is associated with a high percentage of
SMARCB1 deletions. Mod Pathol. 26(3):385-92, 2013
10. Kosemehmetoglu K et al: Intra-articular epithelioid sarcoma showing mixed
classic and proximal-type features: report of 2 cases, with
immunohistochemical and molecular cytogenetic INI-1 study. Am J Surg
Pathol. 35(6):891-7, 2011
11. Flucke U et al: Myxoid epithelioid sarcoma: a diagnostic challenge. A report
on six cases. Histopathology. 57(5):753-9, 2010
12. Armah HB et al: Epithelioid sarcoma. Arch Pathol Lab Med. 133(5):814-9,
2009
13. Chbani L et al: Epithelioid sarcoma: a clinicopathologic and
immunohistochemical analysis of 106 cases from the French sarcoma group.
Am J Clin Pathol. 131(2):222-7, 2009
14. Hornick JL et al: Loss of INI1 expression is characteristic of both conventional
and proximal-type epithelioid sarcoma. Am J Surg Pathol. 33(4):542-50, 2009
15. Jawad MU et al: Prognostic factors for survival in patients with epithelioid
sarcoma: 441 cases from the SEER database. Clin Orthop Relat Res.
467(11):2939-48, 2009
16. Orrock JM et al: INI1 and GLUT-1 expression in epithelioid sarcoma and its
cutaneous neoplastic and nonneoplastic mimics. Am J Dermatopathol.
31(2):152-6, 2009
17. Miettinen M et al: Epithelioid sarcoma: an immunohistochemical analysis of
112 classical and variant cases and a discussion of the differential diagnosis.
Hum Pathol. 30(8):934-42, 1999
18. Guillou L et al: "Proximal-type" epithelioid sarcoma, a distinctive aggressive
neoplasm showing rhabdoid features. Clinicopathologic,
immunohistochemical, and ultrastructural study of a series. Am J Surg
Pathol. 21(2):130-46, 1997
 Epithelioid Sarcoma

Tumors of Uncertain Differentiation

Cytologic Features Typical Cytology
(Left) The lesional cells of ES
show eosinophilic cytoplasm
and contain mildly atypical but
relatively uniform nuclei.
Significant nuclear
pleomorphism is very
uncommon in this tumor. Note
that some cells ﬊ are
compressed and appear to
have darker cytoplasm and
more hyperchromatic nuclei.
(Right) This high-power image
shows typical cytologic
features of ES. Mitotic activity
varies but is often low in
classic forms.

Spindled Morphology Infiltrative Growth

(Left) Admixed tumor cells
with a spindled rather than
epithelioid morphology are
common in ES. Occasionally,
this morphology is more
prominent and a vague
storiform or fascicular growth
pattern may be seen. (Right)
Most cases of ES show
infiltrative growth at the
periphery of the main tumor
mass. Small nests and cords of
cells st within fibrotic
connective tissue, as depicted,
can mimic infiltrating
carcinoma.

Stromal Hyalinization/Sclerosis Osteoid-Like Collagen

(Left) Some cases of ES show
prominent stromal
hyalinization or sclerosis, as
depicted. Entrapped tumor
cells ﬊ may appear singly or
as irregular clusters,
aggregates, or cords. (Right)
Hyalinized stromal collagen
may appear as irregular,
thickened bundles imparting
an appearance reminiscent of
osteoid deposition in
osteosarcoma.

681
 Epithelioid Sarcoma
Tumors of Uncertain Differentiation

Chronic Inflammatory Infiltrate Proximal-Type Epithelioid Sarcoma

(Left) A mixed chronic
inflammatory infiltrate may
be seen in ES and rarely can be
so prominent as to obscure the
underlying neoplasm.
Lymphocytes are
predominantly seen in this
image. (Right) In contrast to
the classic type, the proximal-
type variant of ES usually
shows a larger, more solid and
cellular nodular growth
pattern. Clinically, this form of
ES generally affects an older
age group and arises in
proximal locations.

Macronucleoli Rhabdoid Cytomorphology

(Left) The cells of proximal-
type ES are larger and
plumper than those of classic
ES and show more abundant
eosinophilic cytoplasm.
Vesicular nuclei with
prominent macronucleoli are
characteristic of this variant
and aid in its histologic
recognition. (Right) Rhabdoid
cytomorphology, as shown, is
not uncommon in proximal-
type ES and can lead to
significant morphologic
overlap with malignant
extrarenal rhabdoid tumor;
however, the clinical scenarios
for these 2 entities are often
very different.

Osteoclast-Like Giant Cells Loss of Nuclear INI1

(Left) Rare cases of ES may
contain a population of
reactive multinucleated
osteoclast-like giant cells ﬊
scattered within otherwise
typical lesional cells (proximal-
type ES in this image). This is
usually a focal finding. (Right)
Complete loss of nuclear INI1
protein expression by IHC is
characteristic of epithelioid
sarcoma and is a helpful
feature for supporting the
diagnosis. Note that the large
cells ﬈ are negative in this
image, whereas the
inflammatory cells (bottom
left) are positive.

682
 Epithelioid Sarcoma

Tumors of Uncertain Differentiation

Pseudoglandular Foci Pseudovascular Morphology
(Left) Central loss of cellular
cohesion ﬊ in ES can lead to a
pseudoglandular appearance,
as depicted. Note the larger
lesional cells with prominent
nucleoli and scattered
rhabdoid forms ﬈, identifying
this tumor as a proximal-type
ES. (Right) A loosely
dyscohesive, pseudovascular
pattern is a rare finding in ES
but can resemble
angiosarcoma. The absence of
CD31 &/or FLI1 expression in
ES is helpful in the distinction.

Myxoid Stroma Rare Fibroma-Like Variant

(Left) Myxoid stromal change
is a very rare finding in ES and
is usually focal if present.
Exceptional cases show diffuse
myxoid change. (Right)
Although spindled tumor cells
are common in classic ES, rare
tumors show a predominant or
exclusive spindled
morphology. This variant has
been described as fibroma-like
ES and may lead to
consideration of cellular
fibrous histiocytoma (cellular
dermatofibroma).

Lymph Node Metastases Cutaneous Metastases

(Left) ES is one of the few
mesenchymal neoplasms that
is well known to metastasize
to lymph nodes. Spread to the
lungs is also common. Overall,
metastasis occurs in up to 50%
of cases. (Right) Cutaneous ﬊
and soft tissue metastases are
not uncommon in ES and may
present as small nodules or
bumps that do not
immediately raise clinical
suspicion for malignancy. In
some cases, the relatively
bland cytologic features may
lead to tumor cells getting
overlooked.

683
 Alveolar Soft Part Sarcoma

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY • Polygonal tumor cells with eosinophilic, granular cytoplasm

• Malignant neoplasm composed of large eosinophilic cells in
variable pseudoalveolar growth pattern and characterized
by specific chromosomal translocation and fusion gene
CLINICAL ISSUES
• Infants, children, and young adults
• Most common in lower extremity (particularly anterior
thigh and buttock)
○ Also head and neck (particularly tongue and orbit)
• Slow-growing, painless intramuscular mass
• Treatment: Aggressive surgical resection
• Fully malignant; indefinite long-term follow-up mandatory
○ Late recurrence and metastases (lung, brain) common
MICROSCOPIC
• Prominent compartmentalization
○ Lobules and nests delineated by fibrous septa and
sinusoidal blood vessels
○ Central or eccentric nuclei with prominent nucleoli
• Pseudoalveolar growth pattern (focal or prominent)
○ Some variants show sheet-like growth
• Mitotic rate low; necrosis uncommon
ANCILLARY TESTS
• PAS-D(+) intracytoplasmic crystals in most cases
• Nuclear TFE3(+); negative for S100 and myogenin
• Molecular: der(17)t(X;17)(p11.2;q25) translocation
with ASPSCR1-TFE3 gene fusion
TOP DIFFERENTIAL DIAGNOSES
• Metastatic renal cell carcinoma
• Malignant melanoma
• Paraganglioma
• PEComa
• Granular cell tumor
• Rhabdomyoma

Alveolar Soft Part Sarcoma Peripheral Dilated Veins

(Left) Alveolar soft part
sarcoma (ASPS) is a rare
malignant mesenchymal
neoplasm that predominantly
affects children and young
adults. It is characteristically
compartmentalized with
variably thick fibrous septa
dividing and subdividing
lobules of tumor cells. (Right)
Dilated veins ﬈ are a
common finding at the
periphery of ASPS and attest
in part to the vascularity of
this neoplasm.

Nested Growth Pseudoalveolar Growth

(Left) A nested growth pattern
is commonly seen in ASPS.
Conspicuous delicate, thin-
walled vascular channels ﬊
are widespread and often
readily apparent. (Right)
Central loss of cellular
cohesion ﬉ within a tumor
nest imparts a pseudoalveolar
appearance. This morphology
can be identified at least
focally in most cases and may
sometimes be extensive.

684
 Alveolar Soft Part Sarcoma
TERMINOLOGY
Abbreviations
• Alveolar soft part sarcoma (ASPS)
Definitions
• Malignant neoplasm composed of large eosinophilic cells in
variable pseudoalveolar growth pattern and characterized
by der(17)t(X;17)(p11;q25) resulting in ASPSCR1-TFE3
fusion
CLINICAL ISSUES
Epidemiology
• Age
○ Predominantly infants, children, and young adults
• Sex
○ 2:1 = F:M
Site
• Most common in lower extremity (particularly anterior
thigh and buttock)
• Head and neck (particularly tongue and orbit)
○ Most common sites in infants and children
Presentation
• Slow-growing, painless intramuscular mass
• Significant proportion of patients (> 50%) have metastases
at presentation
Treatment
• Aggressive surgical resection
• Radiation and systemic chemotherapy not shown to be
helpful in most studies
• Indefinite, long-term clinical follow-up mandatory
Prognosis
• May have deceptively indolent clinical course initially
• Fully malignant; overall poor prognosis
○ Majority of patients present with high-stage disease
○ Late recurrence and metastases (lung, brain) common
• Most important favorable prognostic parameters
○ Smaller tumor size (< 5 cm), absence of metastases at
presentation, younger age at diagnosis (< 10 years)
MACROSCOPIC
Size
• Often 3-10 cm in extremities
• Head and neck cases often smaller (1-3 cm)
MICROSCOPIC
Histologic Features
• Prominent compartmentalization
○ Lobules and nests delineated by fibrous septa
○ Nests separated by sinusoidal vascular channels
• Dilated veins usually present at periphery of mass, often
with at least focal involvement by tumor
• Polygonal tumor cells with eosinophilic, granular cytoplasm
○ Central or eccentric nuclei with prominent nucleoli
○ Some cells have clear cytoplasm (may be extensive)
○ Nuclear pleomorphism is rare but may be marked
Tumors of Uncertain Differentiation
• Pseudoalveolar growth pattern (focal or prominent)
○ Tumor cell nests with empty centers due to
degeneration or loss of cellular cohesion
• Some variants show sheet-like growth
○ Most common morphology in infants and children
• Mitotic rate low; necrosis uncommon
ANCILLARY TESTS
Histochemistry
• PAS(+), diastase-resistant intracytoplasmic crystals in most
cases (may be absent)
Immunohistochemistry
• Nuclear TFE3(+); variable desmin (+)
• Negative for vimentin, myogenin, MYOD1, keratin, S100
protein, HMB-45, SMA
Molecular Genetics
• Characteristic der(17)t(X;17)(p11.2;q25) translocation
resulting in fusion of ASPSCR1 (ASPL) and TFE3 genes
DIFFERENTIAL DIAGNOSIS
Metastatic Renal Cell Carcinoma
• Older patients (> 40 years), often with history of renal mass
• Keratin (+), pax-8(+), vimentin (+)
• Subtype of pediatric renal cell carcinoma has similar
morphology to ASPS, is TFE3(+), and contains t(X;17)
Malignant Melanoma
• Usually shows significant mitotic activity and necrosis
• S100(+); HMB-45(+); MART-1(+)
Paraganglioma
• Generally more nuclear atypia than ASPS
• Synaptophysin (+); chromogranin (+)
PEComa
• Most tumor cells are spindled and with stringy eosinophilic
to clear cytoplasm
• Usual coexpression of SMA and HMB-45 or MART-1
• Rare cases may be TFE3(+)
Granular Cell Tumor
• Cells have distinctly granular, PAS-D(+) cytoplasm
• Diffuse S100 protein (+); TFE3(+) in many cases
Rhabdomyoma
• Lacks pseudoalveolar growth
• Diffuse desmin (+), myogenin (+), MYOD1(+)
SELECTED REFERENCES
1. Flores RJ et al: Alveolar soft part sarcoma in children and young adults: a
report of 69 cases. Pediatr Blood Cancer. 65(5):e26953, 2018
2. Schoolmeester JK et al: Alveolar soft part sarcoma of the female genital
tract: a morphologic, immunohistochemical, and molecular cytogenetic
study of 10 cases with emphasis on its distinction from morphologic mimics.
Am J Surg Pathol. 41(5):622-32, 2017
3. Jaber OI et al: Alveolar soft part sarcoma. Arch Pathol Lab Med.
139(11):1459-62, 2015
4. Chamberlain BK et al: Alveolar soft part sarcoma and granular cell tumor: an
immunohistochemical comparison study. Hum Pathol. 45(5):1039-44, 2014
5. Cho YJ et al: Alveolar soft part sarcoma: clinical presentation, treatment and
outcome in a series of 19 patients. Clin Orthop Surg. 6(1):80-6, 2014
6. Folpe AL et al: Alveolar soft-part sarcoma: a review and update. J Clin Pathol.
59(11):1127-32, 2006
685
 Alveolar Soft Part Sarcoma
Tumors of Uncertain Differentiation

Pseudoalveolar Growth Cytologic Features

(Left) Delicate, thin-walled
sinusoidal vascular channels
separate nests of tumor cells
in ASPS. Note the flat,
inconspicuous endothelial cell
nuclei ﬈. (Right) The tumor
cells of ASPS are large,
polygonal, and demonstrate
eosinophilic cytoplasm. They
typically show 1 or more
eccentric nuclei with
prominent nucleoli.

Intracytoplasmic Crystals Intracytoplasmic Crystals

(Left) The majority of cases of
ASPS show an
intracytoplasmic accumulation
of rod-shaped crystals ﬈.
These crystals vary widely
from numerous to focal or
may be completely absent.
(Right) A PAS-diastase special
stain nicely highlights the
intracytoplasmic crystals ﬉ in
ASPS and serves as a useful
screening stain. These crystals
are known to contain CD147
and monocarboxylate
transporter 1 (MCT1).

Nuclear Notch Solid Growth

(Left) An interesting feature of
ASPS is the presence of a
nuclear indentation or notch
﬈. This appearance has been
colorfully described by some
as resembling an apple with a
bite taken out of it. (Right) In
the minority of cases, the
nested growth is less
conspicuous or seemingly
absent, imparting a solid
morphology. This pattern is
particularly common in infants
and children in the head and
neck region.

686
 Alveolar Soft Part Sarcoma
Nuclear and Cytologic Pleomorphism
Granular Cytoplasm
Vascular Invasion
Tumors of Uncertain Differentiation
Ectatic "Staghorn" Vessels
(Left) Increased cytologic &/or
nuclear pleomorphism is
uncommon in ASPS but is well
described. In rare cases, it can
be marked and striking. Most
conventional cases show
relatively little variation in
tumor cell size. (Right) In
addition to smaller sinusoidal
vascular channels, large
ectatic vessels with a
"staghorn" morphology ﬈
may also be seen in ASPS and
may be quite prominent.
Clear Cell Change
(Left) In ASPS, the
combination of solid sheets or
nests of eosinophilic cells with
granular cytoplasm may mimic
a granular cell tumor. Of note,
TFE3 expression can be seen in
both tumors. Diffuse S100
protein expression, however, is
not a feature of ASPS. (Right)
Degenerative clear cell change
may be seen in ASPS and,
when extensive, may closely
mimic a metastatic carcinoma,
particularly clear cell renal cell
carcinoma.
Nuclear TFE3 Expression
(Left) Vascular invasion can be
identified in the majority of
cases of ASPS and is often
seen in vessels near the
periphery of the tumor mass,
as depicted. (Right) TFE3 often
shows strong nuclear
expression in ASPS. Although
once thought to be relatively
specific for ASPS, it has now
been reported in several
morphologically similar
entities (such as granular cell
tumor), somewhat limiting its
usefulness.
687
 Clear Cell Sarcoma

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY • Prominent central nucleoli

• Synonym: Melanoma of soft parts
• Translocation-associated sarcoma of soft tissues showing
melanocytic differentiation
CLINICAL ISSUES
• Young adults (3rd-4th decades)
• > 90% arise on extremities, especially feet
• Usually in subcutis or deeper, often involves
tendon/aponeurosis
• Poor prognosis but often prolonged clinical course
• Late recurrence or metastasis at 10-20 years is common
• Unlike most sarcomas, lymph node metastases common
• Treatment/prognosis of clear cell sarcoma different than
melanoma
MICROSCOPIC
• Uniform, ovoid to spindled cells arranged in nests and
fascicles with intervening collagen
• Clear to pale eosinophilic cytoplasm
• Scattered wreath-like multinucleated tumor giant cells
ANCILLARY TESTS
• Essentially identical to melanoma on IHC
○ Positive for S100 protein, SOX10, MART-1, HMB-45
• Molecular: Translocations detected via FISH or RT-PCR
○ t(12;22) with EWSR1-ATF1 fusion
○ t(2;22) with EWSR1-CREB1 alternate fusion
TOP DIFFERENTIAL DIAGNOSES
• Metastatic melanoma
• Cellular blue nevus
• Paraganglioma-like dermal melanocytic tumor
• PEComa
• Malignant peripheral nerve sheath tumor
• Monophasic synovial sarcoma

Clear Cell Sarcoma Dermal Involvement

(Left) Clear cell sarcoma (CCS)
of soft tissue often presents as
a nodule arising from a tendon
or aponeurosis ﬈. (Right)
Nests and large aggregates of
tumor cells are divided by
thick eosinophilic fibrous
septa; this appearance is
classic for CCS. Some cases
may involve the dermis, as
depicted, leading to potential
misdiagnosis as melanoma.

Nested Growth Pattern Prominent Nucleoli

(Left) Elongated nests and
fascicles of clear or pale tumor
cells are divided by prominent
intervening fibrous septa in
CCS, as shown in this H&E.
(Right) Nuclei in CCS are
usually relatively uniform,
oval/round to spindled in
shape, and characteristically
feature prominent nucleoli.
Wreath-like multinucleated
tumor giant cells ﬈ with
identical nuclear features are
also a common finding in CCS.

688
 Clear Cell Sarcoma

Tumors of Uncertain Differentiation

• Unlike most sarcomas, lymph node metastasis is common
TERMINOLOGY (50%)
Abbreviations ○ Role of sentinel lymph node biopsy for CCS still uncertain
• Clear cell sarcoma (CCS) • Most important poor prognostic factors
○ Local recurrence
Synonyms
○ Size > 5 cm
• CCS of tendon and aponeurosis ○ Necrosis
• Melanoma of soft parts (formerly) • Early stage tumors < 2.5 cm associated with 5-year disease-
Definitions free survival
• Translocation-associated sarcoma of soft tissues showing • Distinction of CCS from melanoma important for treatment
melanocytic differentiation and prognosis
○ Not related to CCS of kidney
○ Probably distinct from malignant gastrointestinal
MACROSCOPIC
neuroectodermal tumor (GNET) (formerly CCS-like tumor General Features
of GI tract) • Lobulated, gray-white masses, often attached to
tendon/aponeurosis
CLINICAL ISSUES ○ Sometimes with dark brown/black melanin deposits
Epidemiology Size
• Incidence • Usually 2-6 cm (range: 1-15 cm)
○ Rare
• Age MICROSCOPIC
○ Young adults (3rd-4th decades) (median: 39 years)
• Ethnicity
Histologic Features
○ 78% Caucasian and 15% African ancestry • Uniform, spindled to ovoid cells arranged in nests and
fascicles with intervening collagen
Presentation ○ Clear to pale eosinophilic cytoplasm
• Pain in up to 50% of cases ○ Prominent central nucleoli
• Usually affects extremities (> 90%) ○ Melanin pigment present in 50% but may be only focal
○ Foot most common site • As with most translocation sarcomas, nuclei are
○ Very uncommon in head, neck, or trunk monotonous not pleomorphic
• Often attached to tendon or aponeurosis ○ Pleomorphism may be seen in recurrence or metastasis
• Usually in subcutis or deeper, unlike primary cutaneous • Variable mitotic rate (range: 0-43/10 HPF; mean: 4/10 HPF)
melanoma • Scattered wreath-like multinucleated tumor giant cells very
○ Rare cases involve dermis or even epidermis; melanoma characteristic finding
must be excluded by molecular testing • Intervening collagen between nests/fascicles may be
• Occasional visceral examples delicate or dense/sclerotic (especially if tumor embedded in
○ GI tract most common visceral site; must be tendon)
distinguished from GNET by IHC and other features
ANCILLARY TESTS
Treatment
• Surgical resection is mainstay of treatment Immunohistochemistry
• Usually chemotherapy resistant • Essentially identical to melanoma on IHC
• Some may respond to tyrosine kinase inhibitors (crizotinib, ○ Positive for S100 protein, SOX10, MART-1/Melan-A,
sorafenib, sunitinib) HMB-45, MITF
• Rare reported response to PD1 blockade (pembrolizumab) ○ Sometimes positive for synaptophysin, CD56, CD57,
plus radiation EMA, BCL-2, C-kit, CD34, cytokeratin AE1/AE3 (rare)
Prognosis Molecular Genetics
• Poor prognosis, although clinical course often prolonged • Most cases possess translocations that can be detected by
○ 5-year survival: 50-67% FISH or RT-PCR
○ 10-year survival: 30-33% ○ EWSR1-ATF1 fusion from t(12;22) (> 90%)
○ 20-year survival: 10% ○ EWSR1-CREB1 alternate fusion from t(2;22) (6%)
• Late recurrence or metastasis at 10-20 years is common • Identical gene fusions found in variety of tumors, including
○ Late metastases more common in patients with multiple angiomatoid fibrous histiocytoma and GNET
local recurrences ○ Diagnosis of CCS requires combination of clinical,
– Local control of tumor is thus important histologic, IHC, and molecular findings
– Risk of local recurrence correlates with incomplete ○ As with many tumors, molecular results cannot be used
initial resection in isolation for diagnosis
• Lung most common site of metastasis

689
 Clear Cell Sarcoma
Tumors of Uncertain Differentiation
DIFFERENTIAL DIAGNOSIS
Metastatic Melanoma
• Similar presentation: Dermal/subcutaneous/deep nodule
without epidermal involvement
○ CCS should always be considered in differential diagnosis
of skin/soft tissue metastatic melanoma, especially in
extremities of young patients who lack known history of
primary melanoma
• Immunophenotype may be identical to CCS
○ Positive for S100 protein, SOX10, MART-1/Melan-A,
HMB-45, MITF
○ Often CD117(+) (unlike CCS)
• Usually more pleomorphic and mitotically active than CCS
• Often has BRAF or NRAS mutations (very rare in CCS)
• Lacks EWSR1-ATF1 and EWSR1-CREB1 fusions
Cellular Blue Nevus
• Dermal nodule, often with dumbbell-shaped protrusion
into subcutis
• Buttocks most common site (50%) but can occur almost
anywhere, including extremities
• Clear spindle cells in fascicles/nests divided by dense
collagen
○ Usually has areas of typical blue nevus in dermis at
periphery of lesion (useful clue)
• May have wreath-like tumor giant cells similar to CCS
• Often more melanin than CCS but may be hypopigmented
or amelanotic
• Immunophenotype may be identical to CCS
○ Positive for S100 protein, SOX10, MART-1/Melan-A,
HMB-45, MITF
• Cytology is key: Prominent nucleoli lacking, minimal nuclear
atypia, low mitotic rate
• Often positive for GNAQ mutation (unlike CCS)
• Lacks EWSR1-ATF1 and EWSR1-CREB1 fusions
Paraganglioma-Like Dermal Melanocytic Tumor
• Dermal/subcutaneous nodule, usually small and
circumscribed
• Cells arranged into packets, nests, cords with intervening
collagen
• Spindled or round cells with pale/clear cytoplasm
○ Minimal atypia or mitotic activity
• S100 protein (+), MART-1(+), HMB-45(+)
• Lacks EWSR1-ATF1 and EWSR1-CREB1 fusions
PEComa
• Distinctive group of tumors with overlapping smooth
muscle and melanocytic differentiation
• Epithelioid or spindle cells with abundant pale/clear often
granular cytoplasm
• May be arranged into packets/nests with intervening
collagen
• Positive for MART-1 &/or HMB-45 plus SMA &/or desmin
• S100 protein (+) in some but SOX-10(-)
• Lacks EWSR1-ATF1 and EWSR1-CREB1 fusions
Malignant Peripheral Nerve Sheath Tumor
• Large sarcoma of deep soft tissue, usually arises from
nerve, from neurofibroma, or in neurofibromatosis type 1
○ Dermal involvement very rare
690
• Relatively uniform spindle cells in fascicles, often
herringbone pattern
○ Usually lacks distinct fascicles/nests with intervening
collagen seen in CCS
• Immunophenotype easily distinguishes malignant
peripheral nerve sheath tumor (MPNST) from CCS
○ Paradoxically, S100 protein (-) or only focally (+) in
MPNST
○ Other melanocytic markers (-)
○ H3K27me3 loss in many MPNSTs but also in some CCS
• Lacks EWSR1-ATF1 and EWSR1-CREB1 fusions
Monophasic Synovial Sarcoma
• Sarcoma often arising in deep soft tissue of distal
extremities (rare in skin)
• Uniform, plump spindle cells in fascicles
• May have brisk mitotic activity, but prominent nucleoli
usually absent
• Immunophenotype distinguishes synovial sarcoma (SS)
from CCS
○ Keratin (+), EMA(+), TLE-1(+)
– S100 protein (+) in subset of SS
○ Other melanocytic markers (-)
• Fusions of SS18 (SYT) with SSX1, SSX2, or SSX4 genes
• Lacks EWSR1-ATF1 and EWSR1-CREB1 fusions
DIAGNOSTIC CHECKLIST
Clinically Relevant Pathologic Features
• Late recurrence and metastasis
○ Metastasizes to lymph nodes and lungs
Pathologic Interpretation Pearls
• Consider CCS before diagnosing metastatic melanoma in
young patient, in extremity, &/or if no known primary
melanoma
SELECTED REFERENCES
1. Gonzaga MI et al: The epidemiology and survivorship of clear cell sarcoma: a
National Cancer Database (NCDB) review. J Cancer Res Clin Oncol.
144(9):1711-6, 2018
2. Schöffski P et al: Activity and safety of crizotinib in patients with advanced
clear-cell sarcoma with MET alterations: European Organization for Research
and Treatment of Cancer phase II trial 90101 'CREATE'. Ann Oncol.
28(12):3000-8, 2017
3. Lee HL et al: Prognostic factors associated with clear cell sarcoma in 14
Chinese patients. J Orthop Surg (Hong Kong). 22(2):236-9, 2014
4. Kiuru M et al: Compound clear cell sarcoma misdiagnosed as a Spitz nevus. J
Cutan Pathol. 40(11):950-4, 2013
5. Hocar O et al: Clear cell sarcoma (malignant melanoma) of soft parts: a
clinicopathologic study of 52 cases. Dermatol Res Pract. 2012:984096, 2012
6. Mir O et al: Objective response to sorafenib in advanced clear-cell sarcoma.
Ann Oncol. 23(3):807-9, 2012
7. Hisaoka M et al: Clear cell sarcoma of soft tissue: a clinicopathologic,
immunohistochemical, and molecular analysis of 33 cases. Am J Surg Pathol.
32(3):452-60, 2008
8. Garcia JJ et al: Utility of CD117 immunoreactivity in differentiating
metastatic melanoma from clear cell sarcoma. Arch Pathol Lab Med.
130(3):343-8, 2006
9. Antonescu CR 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. 4(1):44-52, 2002
10. Lucas DR et al: Clear cell sarcoma of soft tissues. Mayo Clinic experience with
35 cases. Am J Surg Pathol. 16(12):1197-204, 1992
11. Montgomery E et al: Clear cell sarcoma of tendons and aponeuroses. A
clinicopathologic study of 58 cases with analysis of prognostic factors. Int J
Surg Pathol. 1:89-100, 1992
 Clear Cell Sarcoma
Prominent Fibrous Septa
Fascicular Growth
Tumor Giant Cells
Tumors of Uncertain Differentiation
Thin Fibrous Septa
(Left) Dense fibrous bands
divide nests and fascicles of
tumor cells in CCS. These
septa can be quite prominent
in some tumors, as seen in this
H&E. (Right) In areas, the
tumor cells have round or oval
nuclei and are arranged into
nests, packets, or large
aggregates. The intervening
fibrous septa are sometimes
thin and delicate instead of
thick and sclerotic ﬈.
Eosinophilic Cytoplasm
(Left) When cut longitudinally,
the tumor cells have a more
spindled appearance and are
arranged in long fascicles.
Delicate fibrous septa are also
present. (Right) Despite its
name, CCS does not always
feature clear cells. In many
cases, the cells often have pale
or eosinophilic cytoplasm, as
depicted. Areas of dyscohesion
﬈ may be seen imparting a
pseudoalveolar pattern.
Less Prominent Nucleoli
(Left) In this H&E of CCS, the
tumor cells have clear to pale
eosinophilic cytoplasm and
nuclei that contain prominent
nucleoli but lack
pleomorphism. Wreath-like
multinucleated tumor giant
cells ﬊ are also seen and are
a helpful diagnostic feature of
this tumor. (Right) Spindled
pale tumor cells in this area of
CCS have mostly small
indistinct nucleoli. The classic
large prominent nucleoli are
not present in all cases.
Mitoses are often seen ﬈.
691
 Perivascular Epithelioid Cell Tumor (PEComa)

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY • Clinically malignant tumors exists but are uncommon

• Distinctive mesenchymal neoplasm arising from ○ Criteria have been proposed for assessing risk
perivascular epithelioid cells that usually demonstrates MICROSCOPIC
combined myomelanocytic immunophenotype
• Nests, trabeculae, or sheets of epithelioid to spindled cells
○ PEComa family includes other defined clinical subtypes
with clear to eosinophilic cytoplasm
that arise in specific organs
• Association with walls of larger vessels in many cases
– Angiomyolipoma (AML), clear cell sugar tumor (CCST),
• Malignant tumors often feature prominent nuclear atypia,
lymphangioleiomyomatosis (LAM)
pleomorphism, and mitotic activity
ETIOLOGY/PATHOGENESIS • Variants: Sclerosing PEComa, fibroma-like PEComa
• Deletions of TSC2 gene with activation of mTOR pathway ANCILLARY TESTS
• AML, CCST, and LAM associated with tuberous sclerosis
• Variable expression of SMA, desmin, melanocytic markers
complex
• Subset of cases show nuclear TFE3(+)
○ Most other PEComas are sporadic
TOP DIFFERENTIAL DIAGNOSES
CLINICAL ISSUES
• Leiomyosarcoma or leiomyoma
• Wide age range (median: 45 years)
• Carcinoma or melanoma
• Marked female predominance
• Clear cell sarcoma
• Overall good prognosis
• Alveolar soft part sarcoma

PEComa Epithelioid Cells

(Left) The term perivascular
epithelioid cell tumor
(PEComa) identifies a family of
related neoplasms that
includes entities such as
angiomyolipoma (AML) and
lymphangioleiomyomatosis
(LAM). PEComas, other than
AML and LAM, arise in a
variety of soft tissue and
visceral sites and often show a
nested architecture at low
power, which may be well
formed ﬈ or more subtle ﬊.
(Right) PEComa is most
commonly composed of
epithelioid cells with variable
eosinophilic to clear
cytoplasm.

Spindle Cells Myomelanocytic Immunophenotype

(Left) Spindled tumor cells are
common in PEComa but are
overall less frequent than
epithelioid cells. They are
arranged in bundles and
fascicles and show variable
eosinophilic to clear
cytoplasm. Note the
resemblance to smooth
muscle cells. (Right) PEComa
characteristically shows a
combined myomelanocytic
immunophenotype and shows
variable expression of a
variety of myoid and
melanocytic markers
(particularly SMA and HMB-
45). HMB-45 expression is seen
here.

692
 Perivascular Epithelioid Cell Tumor (PEComa)

Tumors of Uncertain Differentiation

TERMINOLOGY Prognosis
• Overall good prognosis
Abbreviations ○ Clinically malignant tumors exists but are uncommon
• Perivascular epithelioid cell tumor (PEComa) – Generally aggressive sarcomas
Synonyms – Metastases to lung, liver, lymph nodes, bone
• Clear cell myomelanocytic tumor • Criteria have been proposed for assessing risk for malignant
behavior (Folpe criteria)
• Primary extrapulmonary sugar tumor
○ High-risk features
• Extrarenal epithelioid angiomyolipoma (AML)
– Size > 5 cm
• Abdominopelvic sarcoma of perivascular epithelioid cells
– High nuclear grade and cellularity, readily identifiable
Definitions mitotic figures
• Distinctive mesenchymal neoplasm arising from – Infiltrative growth, necrosis, vascular invasion
perivascular epithelioid cells that usually demonstrates ○ Risk categories
combined myomelanocytic immunophenotype – Likely benign
○ PEComa family includes defined clinical subtypes that □ Size < 5 cm and < 2 high-risk features
arise in specific organs – Uncertain malignant potential
– AML (kidney and liver) □ Size ≥ 5 cm with no other high-risk features or
– Clear cell sugar tumor (CCST) (lung) □ Nuclear pleomorphism/multinucleated giant cells
– Lymphangioleiomyomatosis (LAM) (lung) only
– Malignant
ETIOLOGY/PATHOGENESIS □ ≥ 2 high-risk features
Genetics
MACROSCOPIC
• Frequent deletions of TSC2 gene with activation of mTOR
pathway General Features
• AML, CCST, and LAM show association with tuberous • Well-demarcated, firm mass
sclerosis complex (TSC) • Fleshy or fibrous cut surface
○ Most other PEComas are sporadic
– Subset associated with TFE3 rearrangements/fusions
Size
• Wide range (average: 6 cm)
CLINICAL ISSUES
MICROSCOPIC
Epidemiology
• Incidence
Histologic Features
○ Rare • Nests, trabeculae, or sheets of epithelioid to spindled cells
• Age ○ Clear to granular, lightly eosinophilic cytoplasm
○ Wide range (median: 45 years) – Cytoplasm sometimes described as moth-eaten or
• Sex stringy
○ Marked female predominance – Some larger epithelioid cells may appear spider-like
○ Round to oval nuclei with small nucleoli
Site – Limited pleomorphism may be seen
• May arise in almost any site • Thin-walled capillary vessels between nests of tumor cells
○ Retroperitoneum, abdomen, pelvis • Association with walls of larger vessels often present, at
○ Uterus, GI tract least focally
○ Kidney, liver (AML) ○ Cells appear to radiate outward from lumen
○ Lung (CCST, LAM) • Perivascular hyalinization not common
○ Uncommon in extremities, bone, skin • Multinucleated giant cells in some cases
Presentation • Intracytoplasmic melanin pigment in some cases
• TFE3-rearranged PEComa
• Usually painless mass
○ Epithelioid cells with clear cytoplasm
• Site-specific symptoms
○ Distinctive nested or alveolar growth pattern
○ Vaginal bleeding with uterine tumors
• Malignant PEComa
○ Obstructive symptoms or hematochezia with GI tumors
○ Proposed predictive criteria exist (Folpe)
• May present with signs/symptoms of TSC, if affected
○ Most cases of malignant PEComa show overtly
○ e.g., seizures, developmental delay, behavioral problems malignant features
Treatment – Marked cellularity with prominent nuclear
• Complete surgical excision pleomorphism/atypia and abundant mitoses
• Indefinite, long-term clinical follow-up recommended – Also, infiltrative growth, necrosis, vascular invasion
• mTOR inhibitors (e.g., sirolimus) may have efficacy in • Unique features of specific clinical subtypes
malignant PEComa ○ AML often contains component of mature adipose tissue

693
 Perivascular Epithelioid Cell Tumor (PEComa)
Tumors of Uncertain Differentiation
○ LAM of lung features cystic spaces associated with
bundles of spindled cells
– Localized tumors (lymphangiomyoma) show
prominent pericytic growth
Morphologic Variants
• Sclerosing PEComa
○ Not associated with tuberous sclerosis
○ Prominent densely collagenous stroma
○ Cords, nests, and trabeculae of epithelioid cells
○ Most common in retroperitoneum
• Fibroma-like PEComa
○ Affects patients with tuberous sclerosis
○ Bland spindled to stellate cells within abundant
collagenous stroma
○ Epithelioid cells rare or absent
ANCILLARY TESTS
Immunohistochemistry
• Classic combined myomelanocytic immunophenotype
○ SMA(+), desmin (+), caldesmon (+)
– SMA is most sensitive
○ HMB-45(+), MART-1/melan-A (+), MITF(+)
– HMB-45 is most sensitive
• Overall expression pattern is highly variable
○ Most tumors do not express all myomelanocytic antigens
○ Occasional tumors lack expression of either myoid
markers or melanocytic markers
• Subset of cases show nuclear TFE3(+)
○ These tumors often have negative myoid markers
• Focal S100 protein (+) or CD117(+) in minority of cases
• Keratin, CD34, myogenin, DOG1 (-)
Molecular Genetics
• Subset lacking TSC2 mutations show TFE3 gene fusions
○ Suggests different pathogenesis for some types of
PEComa
○ SFPQ-TFE3 fusion most common
– DVL2-TFE3 and NONO-TFE3 fusions rare
DIFFERENTIAL DIAGNOSIS
Leiomyosarcoma (and Leiomyoma)
• Can show morphologic overlap with spindle cell-
predominant PEComa
• Perpendicularly oriented fascicles and bundles of spindled
cells with brightly eosinophilic cytoplasm and blunt-ended
nuclei
• Perivascular hyalinization &/or stromal sclerosis uncommon
• HMB-45, MART-1, MITF (-)
Carcinoma
• Particularly renal cell, adrenocortical, hepatocellular
• Lacks particular association with vessel walls
• Usually strong expression of epithelial antigens (keratin,
EMA)
• May express markers of specific differentiation (pax-8, Hep-
Par1, etc.)
• Myoid and melanocytic markers (-)
694
Melanoma
• Previous clinical history may be present
• Marked cytologic atypia with prominent nucleoli common
• Most show strong, diffuse S100 protein (+)
• Usually myoid markers (-)
Clear Cell Sarcoma
• Most common in distal extremities of young adults
• Nests of uniform cells with clear to pale eosinophilic
cytoplasm and uniform nuclei with single large nucleolus
• May feature multinucleated giant cells
• S100 protein, HMB-45, MART-1 (+)
• SMA and desmin (-)
• t(12;22) with EWSR1-ATF1 (most common)
Alveolar Soft Part Sarcoma
• Deep soft tissue of extremities in young adults
• Head/neck region in children
• Nests of large eosinophilic or clear epithelioid cells with
variable central loss of cellular cohesion
○ Spindle cells absent
• Nuclear TFE3(+)
• Focal expression of SMA or desmin in some cases
• HMB-45, MART-1, MITF (-)
• t(X;17) with ASPSCR1-TFE3 fusion
Granular Cell Tumor
• Diffuse cytoplasmic granularity
• Strongly S100 protein (+)
• Myoid and melanocytic markers (-)
• TFE3(+) in majority of cases
SELECTED REFERENCES
1. Bennett JA et al: Uterine PEComas: a morphologic, immunohistochemical,
and molecular analysis of 32 tumors. Am J Surg Pathol. 42(10):1370-83,
2018
2. Larque AB et al: Fibroma-like PEComa: a tuberous sclerosis complex-related
lesion. Am J Surg Pathol. 42(4):500-5, 2018
3. Maloney N et al: Expanding the histomorphologic spectrum of TFE3
rearranged PEComas. Hum Pathol. 82:125-30, 2018
4. McGregor SM et al: Melanotic PEComa of the sinonasal mucosa with NONO-
TFE3 fusion: an elusive mimic of sinonasal melanoma. Am J Surg Pathol.
41(5):717-22, 2017
5. Agaram NP et al: Dichotomy of genetic abnormalities in PEComas with
therapeutic implications. Am J Surg Pathol. 39(6):813-25, 2015
6. Schoolmeester JK et al: TFE3 translocation-associated perivascular
epithelioid cell neoplasm (PEComa) of the gynecologic tract: morphology,
immunophenotype, differential diagnosis. Am J Surg Pathol. 39(3):394-404,
2015
7. Shen Q et al: Perivascular epithelioid cell tumor (PEComa) with TFE3 gene
rearrangement: clinicopathological, immunohistochemical, and molecular
features. Virchows Arch. 465(5):607-13, 2014
8. Doyle LA et al: PEComa of the gastrointestinal tract: clinicopathologic study
of 35 cases with evaluation of prognostic parameters. Am J Surg Pathol.
37(12):1769-82, 2013
9. Bleeker JS et al: "Malignant" perivascular epithelioid cell neoplasm: risk
stratification and treatment strategies. Sarcoma. 2012:541626, 2012
10. Folpe AL et al: Perivascular epithelioid cell neoplasms: pathology and
pathogenesis. Hum Pathol. 41(1):1-15, 2010
11. Hornick JL et al: Sclerosing PEComa: clinicopathologic analysis of a distinctive
variant with a predilection for the retroperitoneum. Am J Surg Pathol.
32(4):493-501, 2008
12. Folpe AL et al: Perivascular epithelioid cell neoplasms of soft tissue and
gynecologic origin: a clinicopathologic study of 26 cases and review of the
literature. Am J Surg Pathol. 29(12):1558-75, 2005
 Perivascular Epithelioid Cell Tumor (PEComa)
Cytologic Features
Clear Cells
Pale Granular Cells Eosinophilic Granular Cells
Tumors of Uncertain Differentiation
Nested Growth
(Left) Nuclei in PEComa are
generally round to ovoid and
contain small nucleoli. Note
that the cytoplasm often
varies from eosinophilic to
clear and may show a "frayed"
quality that has been
described as stringy or moth-
eaten. (Right) Nested growth
of tumor cells is common in
PEComa, but trabecular and
sheet-like patterns may also
be seen. Nests are often
demarcated by variably
prominent, thin-walled
capillary channels ﬉, similar
to that seen in renal cell
carcinoma.
Spider Cells
(Left) Tumor cells with
abundant clear cytoplasm may
be diffuse and prominent in
some cases of PEComa, as
depicted. Note the vague
nested architecture with
intervening capillaries. This
appearance can mimic clear
cell renal cell carcinoma.
(Right) Some larger epithelioid
tumor cells in PEComa may
show centralized cytoplasmic
retraction ﬉, similar to the
"spider cells" seen in adult-
type rhabdomyoma.
(Left) PEComa may contain
epithelioid tumor cells with
pale, eosinophilic and finely
granular cytoplasm,
reminiscent of histiocytes or
possibly even an
adrenocortical neoplasm.
(Right) Finely granular
cytoplasm with more
distinctive eosinophilia may be
encountered in PEComa,
reminiscent of granular cell
tumor. This tumor arose in the
uterus.
695
 Perivascular Epithelioid Cell Tumor (PEComa)
Tumors of Uncertain Differentiation

Prominent Alveolar Growth Eosinophilic Epithelioid Cells

(Left) A prominent alveolar
growth pattern, as depicted, is
seen in a subset of PEComa.
These particular tumors are
more likely to harbor TFE3
gene fusions and show nuclear
TFE3 immunoreactivity. Note
the resemblance to alveolar
soft part sarcoma, another
tumor with TFE3 gene fusion.
(Right) This PEComa shows
predominantly smaller
epithelioid cells with
exclusively eosinophilic
cytoplasm. In visceral organs,
this morphology may lead to
confusion with carcinoma.

Trabecular Pattern Multinucleated Giant Cells

(Left) Trabecular growth may
be conspicuous in PEComa,
although areas with a nested
pattern are usually also
present. (Right)
Multinucleated tumor giant
cells ﬈ are focally present in
some cases of PEComa, and
they can adopt a variety of
cytomorphologies, including
wreath-like, Touton,
osteoclastic, and Langhans.
The presence of these cells
does not appear to affect
behavior unless there are
other atypical features
(mitoses, significant nuclear
atypia, etc.).

Perivascular Hyalinization Vessel Wall Association

(Left) Perivascular
hyalinization ﬉ or sclerosis is
not uncommon in PEComa and
may be prominent and
extensive in some cases, as
shown in this H&E. (Right) An
interesting finding seen in
many cases of PEComa is the
association of tumor cells with
blood vessel walls, often with
a outward-radiating
arrangement ﬉. This finding
is particularly evident in renal
PEComa (AML).

696
 Perivascular Epithelioid Cell Tumor (PEComa)
Stromal Hyalinization
Sclerosing PEComa
Myoid Marker Expression
Tumors of Uncertain Differentiation
Stromal Sclerosis
(Left) Although thin fibrous
septa are not uncommon
between nests of tumor cells
in PEComa, more extensive
seams and bands of glassy
hyalinized collagen may be
present in some cases. (Right)
In this case of PEComa,
paucicellular areas of dense
sclerosis ﬈ are seen adjacent
to more conventional areas
featuring tumor cells with
prominent clear cytoplasm.
Sclerosing PEComa
(Left) Sclerosing PEComa is a
morphologic variant
characterized by a prominent,
densely hyalinized or sclerotic
stroma. Tumor cells may
appear in small nests, cords,
clusters, or even singly. (Right)
This case of sclerosing
PEComa shows thin
anastomosing cords of
epithelioid tumor cells within
an abundant collagenous
stroma. This particular variant
is most frequent in the
retroperitoneum, particularly
near the kidneys.
Cutaneous PEComa
(Left) SMA expression (shown)
is seen in most cases of
PEComa. Other myoid markers
(such as MSA, desmin, and
caldesmon) are usually less
consistently expressed. Rare
cases are completely negative
for all of these markers.
(Right) Although rare, PEComa
may also arise in the skin, as
depicted. Although similar in
many respects to more deeply
situated and visceral tumors,
cutaneous PEComa does not
appear to harbor TFE3 gene
fusions or express nuclear
TFE3.
697
 Perivascular Epithelioid Cell Tumor (PEComa)
Tumors of Uncertain Differentiation

Cutaneous PEComa Angiomyolipoma

(Left) Clear cytoplasm is
usually prominent in cases of
cutaneous PEComa, as shown.
Note the dermal collagen
fibers ﬉. (Right) Primary
renal PEComa (better known
as AML) contains spindled
tumor cells similar to those of
other forms of PEComa;
however, it also usually
contains mature adipose tissue
﬈ and shows a more
conspicuous association with
intratumoral blood vessels ﬉.
Epithelioid variants also exist.

Lymphangioleiomyomatosis Lymphangiomyoma
(Left) Pulmonary LAM is a
form of PEComa that affects
female patients almost
exclusively and features
bundles ﬈ of uniform,
spindled myomelanocytic cells,
often associated with
prominent cystic spaces.
(Right) Rare, localized forms of
LAM (known as
lymphangiomyoma) may arise
outside of the lungs, mainly
within the retroperitoneum or
mediastinum, and often in
association with large
lymphatic ducts or lymph
nodes.

Lymphangiomyoma Malignant PEComa

(Left) Lymphangiomyoma
features bundles of uniformed,
spindled cells arranged around
endothelial-lined channels ﬈,
creating a pericytic growth
pattern. Scattered
lymphocytes &/or lymphoid
aggregates are common.
Dilated spaces ﬉ containing
lymphatic fluid are also
frequently seen. (Right)
Clinically malignant PEComa is
uncommon but is generally
aggressive. Criteria have been
proposed for risk assessment
that include tumor size as well
as significant nuclear atypia
(shown), among other
features.

698
 Perivascular Epithelioid Cell Tumor (PEComa)
Cellular Malignant PEComa
Clear Cell Malignant PEComa
Spindle Cell Malignant PEComa
Tumors of Uncertain Differentiation
Vessel Wall Association
(Left) Malignant PEComa
usually features significant
nuclear atypia and
pleomorphism, and mitotic
figures ﬉ are often readily
identified, including atypical
forms. (Right) The
characteristic finding of vessel
wall involvement in typical
PEComa can also be seen in
malignant forms, as depicted.
Note the radial arrangement
of tumor cells ﬈.
Coagulative Necrosis
(Left) Malignant PEComa can
show features of any form of
typical PEComa, including a
diffuse clear cell morphology.
This large tumor contained
numerous mitoses and diffuse
nuclear atypia. (Right)
Coagulative necrosis ﬈ is rare
in PEComa but is more
frequently seen in malignant
forms. Vascular invasion and
infiltrative growth are also
atypical findings and should be
considered when assessing risk
of malignant behavior.
Deceptively Bland Malignant PEComa
(Left) Malignant PEComa may
also contain areas showing a
fascicular, spindled
morphology and may be
difficult to distinguish from
leiomyosarcoma. (Right) This
PEComa from the thigh
demonstrates mostly
relatively uniform, pale,
granular tumor cells,
suggesting benignity;
however, mitoses were
abundant, including atypical
forms ﬈. Areas of increased
nuclear atypia were present
very focally. This tumor
metastasized to the
mediastinum 2 years after
initial complete resection.
699
 Desmoplastic Small Round Cell Tumor

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY MICROSCOPIC
• Malignant mesenchymal neoplasm of polyphenotypic • Nests, sheets, and trabeculae of small undifferentiated cells
differentiation composed of primitive cells embedded in • Characteristic abundant desmoplastic fibrous stroma
abundant desmoplastic stroma • Mitoses and necrosis common
CLINICAL ISSUES • Other findings: Rosette-like structures, tubule/gland
formation, clear cell change
• Usually children and young adults (median age: 20 years)
○ Strong male predilection ANCILLARY TESTS
• Abdominal cavity most common site • Polyphenotypic differentiation, with keratin (+), desmin (+),
○ Peritoneum, retroperitoneum, omentum, mesentery NSE(+)
• Treatment: Multimodality therapy with ○ Key finding: Perinuclear dot-like desmin expression
surgery/chemotherapy • Molecular: Characteristic recurrent t(11;22)(p13;q12)
• Overall poor prognosis involving EWSR1 and WT1 genes
MACROSCOPIC TOP DIFFERENTIAL DIAGNOSES
• Bulky, diffuse multinodular or solitary • Ewing sarcoma
• Wide range, usually large (often > 10 cm) • Alveolar rhabdomyosarcoma
• Neuroendocrine carcinoma

Desmoplastic Small Round Cell Tumor Undifferentiated Cells

(Left) Desmoplastic small
round cell tumor (DSRCT) is an
aggressive malignant
neoplasm that most
commonly affects children and
young adults, particularly
males. Morphologically, it is
characterized by nests, sheets,
and cords of relatively
monomorphic cells in a
prominent desmoplastic
fibrous stroma. (Right) The
lesional cells of DSRCT are
generally small, relatively
monomorphic, and appear
undifferentiated. Nucleoli are
inconspicuous and mitoses are
common.

Desmin Expression Keratin Expression

(Left) Diffuse desmin
expression is common in
DSRCT and characteristically
manifests as dot-like staining
adjacent to the nucleus.
Diffuse cytoplasmic expression
may also be seen in this tumor.
(Right) Cytokeratins are
usually strongly expressed in
DSRCT and vary in pattern
from diffuse cytoplasmic ﬈ to
perinuclear dot-like ﬊ (less
common). A similar pattern of
reactivity is seen with
vimentin.

700
 Desmoplastic Small Round Cell Tumor

Tumors of Uncertain Differentiation

• Desmoplastic stroma is characteristic
TERMINOLOGY
○ Fibroblasts/myofibroblasts within loose extracellular
Abbreviations matrix or collagen
• Desmoplastic small round cell tumor (DSRCT) ○ May show myxoid change or hyalinization
○ Variably prominent stromal vascularity
Synonyms
• Variety of architectural configurations
• DSRCT with divergent differentiation ○ Nests (individual or confluent), sheets, cords, trabeculae,
• Polyphenotypic small round cell tumor organoid, others
• Intraabdominal DSRCT – Central necrosis and cystic change common; may
Definitions occasionally be diffuse
• Small, relatively monomorphic, round to oval cells with
• Malignant mesenchymal neoplasm of polyphenotypic
scant eosinophilic cytoplasm
differentiation composed of primitive cells embedded in
abundant desmoplastic stroma ○ Small hyperchromatic nuclei with inconspicuous nucleoli
– Nuclear pleomorphism may be present (focal or
CLINICAL ISSUES diffuse) in some cases
○ Mitotic figures often numerous
Epidemiology ○ Cells may be epithelioid with more abundant cytoplasm
• Incidence – Also cytoplasm may be vacuolated or show clear cell
○ Rare change
• Age ○ Intracytoplasmic paranuclear hyaline inclusions in some
○ Usually children and young adults (median: 20 years) tumors
– Occasionally older adults ○ Focal cytoplasmic spindling rare
• Sex • Rare focal epithelial differentiation: Rosette-like structures,
○ Strong male predilection tubule/gland formation, papillary areas
Site ANCILLARY TESTS
• Abdominal cavity most common
Immunohistochemistry
○ Peritoneum, retroperitoneum, pelvis, omentum,
mesentery • Polyphenotypic differentiation (see table)
• Sporadic involvement of extraabdominal sites, including • Key finding: Perinuclear dot-like desmin expression
paratesticular region, thoracic cavity, and many others • Nuclear WT1 expression only seen with antibodies directed
against carboxy (C) terminus of WT1
Presentation
• Abdominal distention, pain, weight loss, obstructive Molecular Genetics
symptoms • Characteristic recurrent t(11;22)(p13;q12) involving EWSR1
• Diffuse serosal involvement by multiple tumor nodules and WT1 genes
common ○ Rare isolated reports of EWSR1-ERG and EWSR1-FLI1
fusions
Treatment – Appear to be hybrid tumors with features of DSRCT
• Multimodality therapy, including surgical and Ewing sarcoma
resection/debulkment and chemotherapy
Prognosis DIFFERENTIAL DIAGNOSIS
• Overall poor prognosis Extraskeletal Ewing Sarcoma
○ Nearly uniformly fatal • Lacks prominent desmoplastic stroma
○ Median survival: 24 months • Strong, membranous CD99(+)
• Frequent local recurrence; occasionally metastasizes ○ Variety of other small blue cell tumors, such as DSRCT,
can show patchy cytoplasmic positivity
MACROSCOPIC • Negative for desmin, EMA, and WT1
General Features • FLI-1(+); may show focal keratin (+)
• EWSR1 translocation in most cases
• Large, bulky, multinodular or solitary
○ Most commonly t(11;22)(q24;q12) involving EWSR1 and
• Firm tan-white homogeneous cut surface
FLI1
• Foci of necrosis &/or hemorrhage
– Distinct from t(11;22)(p13;q12) of DSRCT, which
Size involves WT1 instead of FLI1
• Wide range, usually large (often > 10 cm) Alveolar Rhabdomyosarcoma
• Nests with central dyscohesion and divided by fibrous septa
MICROSCOPIC
• Lacks prominent desmoplastic stroma
Histologic Features • May contain multinucleated (wreath-like) giant cells
• Nests of small undifferentiated cells within abundant • Diffuse desmin (+), myogenin (+), MYOD1(+)
desmoplastic fibrous stroma • May show focal keratin (+)

701
 Desmoplastic Small Round Cell Tumor
Tumors of Uncertain Differentiation

Immunohistochemistry Table
Antibody Reactivity Staining Pattern Comment
AE1/AE3 Positive Cytoplasmic May also show perinuclear dot-like staining
Desmin Positive Dot positivity Cytoplasmic expression also common
Vimentin Positive Cytoplasmic May also show perinuclear dot-like staining
EMA Positive Cell membrane
NSE Positive Cytoplasmic Very nonspecific marker
Actin-sm Negative Cytoplasmic Expressed in stromal myofibroblasts but not tumor cells
Synaptophysin Negative Cytoplasmic Rare focal positivity
CD56 Negative
Myogenin Negative
MYOD1 Negative
WT1 Equivocal Nuclear Selective carboxy-terminus immunoreactivity only
CD99 Equivocal Cell membrane and Usually cytoplasmic, if present; rarely membranous
cytoplasm
NB84 Equivocal Cytoplasmic Usually focal, if present

• Characteristic t(2;13) or t(1;13) involving FOXO1 2. Subbiah V et al: Multimodality treatment of desmoplastic small round cell
tumor: chemotherapy and complete cytoreductive surgery improve patient
Metastatic Neuroendocrine Carcinoma survival. Clin Cancer Res. 24(19):4865-73, 2018
3. Mohamed M et al: Desmoplastic small round cell tumor: evaluation of
• Clinical history of primary tumor reverse transcription-polymerase chain reaction and fluorescence in situ
• Lacks prominent desmoplastic stroma separating tumor hybridization as ancillary molecular diagnostic techniques. Virchows Arch.
471(5):631-40, 2017
cell nests
4. de Alava E et al: Birth and evolution of the desmoplastic small round-cell
• Has distinctive smudged or salt and pepper chromatin tumor. Semin Diagn Pathol. 33(5):254-61, 2016
pattern 5. Thway K et al: Desmoplastic small round cell tumor: pathology, genetics, and
• Synaptophysin (+), chromogranin (+), CD56(+) potential therapeutic strategies. Int J Surg Pathol. 24(8):672-84, 2016
6. Arnold MA et al: Diagnostic pitfalls of differentiating desmoplastic small
• Negative for desmin and WT1 round cell tumor (DSRCT) from Wilms tumor (WT): overlapping morphologic
• Can show perinuclear dot-like expression of keratins and immunohistochemical features. Am J Surg Pathol. 38(9):1220-6, 2014
7. Wong HH et al: Desmoplastic small round cell tumour: characteristics and
Extrarenal Rhabdoid Tumor prognostic factors of 41 patients and review of the literature. Clin Sarcoma
Res. 3(1):14, 2013
• Affects infants and children 8. Dufresne A et al: Desmoplastic small round cell tumor: current management
• Sheets of epithelioid cells with prominent rhabdoid and recent findings. Sarcoma. 2012:714986, 2012
differentiation 9. Jordan AH et al: Management of desmoplastic small round-cell tumors in
children and young adults. J Pediatr Hematol Oncol. 34 Suppl 2:S73-5, 2012
○ Rhabdoid morphology may be less prominent in small
10. Bono F et al: Desmoplastic small cell tumor with bizarre giant nuclei. Int J
cell variant Surg Pathol. 19(6):843-6, 2011
• Desmin (-) 11. Yin WH et al: Desmoplastic small round cell tumor of the submandibular
• Loss of nuclear INI1 by immunohistochemistry gland--a rare but distinctive primary salivary gland neoplasm. Hum Pathol.
41(3):438-42, 2010
Malignant Lymphoma 12. Saab R et al: Desmoplastic small round cell tumor in childhood: the St. Jude
Children's Research Hospital experience. Pediatr Blood Cancer. 49(3):274-9,
• Dyscohesive pattern of growth without striking 2007
desmoplasia 13. Chang F: Desmoplastic small round cell tumors: cytologic, histologic, and
immunohistochemical features. Arch Pathol Lab Med. 130(5):728-32, 2006
• Expresses hematolymphoid markers (e.g., CD45, CD3,
14. Lae ME et al: Desmoplastic small round cell tumor: a clinicopathologic,
CD20, CD30, CD43) immunohistochemical, and molecular study of 32 tumors. Am J Surg Pathol.
• Negative for keratin, desmin, nuclear WT1 26(7):823-35, 2002
• Lymphoblastic lymphoma in children and adolescents 15. Ordóñez NG: Desmoplastic small round cell tumor: I: a histopathologic study
of 39 cases with emphasis on unusual histological patterns. Am J Surg
shows nuclear positivity for TdT and is positive for CD99 Pathol. 22(11):1303-13, 1998
16. Ordóñez NG: Desmoplastic small round cell tumor: II: an ultrastructural and
Neuroblastoma immunohistochemical study with emphasis on new immunohistochemical
• Most diagnosed < 5 years of age markers. Am J Surg Pathol. 22(11):1314-27, 1998
17. Gerald WL et al: Intra-abdominal desmoplastic small round-cell tumor.
• NB84(+) Report of 19 cases of a distinctive type of high-grade polyphenotypic
• Negative for desmin and keratins malignancy affecting young individuals. Am J Surg Pathol. 15(6):499-513,
• Lacks EWSR1 translocation 1991

SELECTED REFERENCES
1. Stiles ZE et al: Desmoplastic small round cell tumor: a nationwide study of a
rare sarcoma. J Surg Oncol. 117(8):1759-67, 2018

702
 Desmoplastic Small Round Cell Tumor
Variably Sized Nests
Clear Cell Change
Desmoplastic Fibrous Stroma
Tumors of Uncertain Differentiation
Infiltrative Areas
(Left) Although the exact
pattern varies from case to
case, most examples of DSRCT
show nests of varying sizes
and shapes. Note the
desmoplastic background
stroma that is characteristic of
this tumor. (Right) In some
areas of DSRCT, particularly at
the periphery, the tumor cells
may adopt a less cellular and
corded morphologic pattern
that resembles infiltrating
carcinoma.
Central Necrosis
(Left) Tumor cells with
cytoplasmic clearing ﬊ are
seen in some cases of DSRCT
and may be focal or extensive.
Vacuolated cytoplasm or a
signet ring-like cytologic
appearance may also be seen
in some tumors. (Right) Larger
nests in DSRCT often show
central necrosis ﬊. Rarely, a
tumor may show extensive,
zonal coagulative necrosis
with scattered islands of
viable cells.
Collagenous Stroma
(Left) The desmoplastic fibrous
stroma of DSRCT is composed
of spindled fibroblasts and
myofibroblasts within a loose
extracellular matrix. It
characteristically surrounds
and separates tumor cell nests
﬊. (Right) The stroma of
DSRCT may occasionally
appear less desmoplastic and
more fibrous and collagenous,
as depicted.
703
 Desmoplastic Small Round Cell Tumor
Tumors of Uncertain Differentiation

Stromal Vasculature Focal Stromal Hyalinization

(Left) The fibrous stroma of
DSRCT often contains a large
number of blood vessels
ranging in size from capillaries
to larger channels. Of note,
complex capillary
proliferations ﬊ may be
identified in some cases.
(Right) Rarely, cases of DSRCT
with collagenous stroma may
show foci of dense
hyalinization, as depicted.

Large Confluent Nests Occasional Nuclear Molding

(Left) Larger nests with areas
of confluency may be seen in
DSRCT, although it is usually
not a prominent feature. This
morphology may suggest a
poorly differentiated
carcinoma. Note the 2 foci ﬊
of centralized coagulative
necrosis. (Right) Nuclear
molding is not generally a
feature of DSRCT but may be
seen in rare cases.
Neuroendocrine carcinoma
should be excluded; however,
in this image, the desmoplastic
stroma provides a clue to the
diagnosis of DSRCT.

Intracytoplasmic Hyaline Inclusions Epithelial Architectures

(Left) Not uncommonly, some
of the tumor cells in DSRCT
may contain paranuclear
eosinophilic hyaline inclusions
﬈ reminiscent of rhabdoid
cells. This is often a focal
finding. (Right) Epithelial
architectural arrangements ﬈
such as a glandular or tubular
appearance are an uncommon
finding in DSRCT and are often
focal if present.

704
 Desmoplastic Small Round Cell Tumor
Abundant Cytoplasm
Rare Rosette Pattern
Rare Bizarre Atypia
Tumors of Uncertain Differentiation
Dense Nested Growth
(Left) The tumor cells of
DSRCT generally contain scant
eosinophilic cytoplasm;
however, in some cases it is
more abundant and
prominent, as depicted.
Confusion with carcinoma is
more likely in this setting.
(Right) A rare finding in DSRCT
with larger tumor cells is the
presence of tightly nested
growth with scant stroma and
fibrovascular septa. This
morphology may closely mimic
urothelial carcinoma or the
zellballen pattern of
paraganglioma.
Rare Nuclear Pleomorphism
(Left) This image shows a
rosette pattern ﬊ in DSRCT.
This morphology is focal, when
present, and is overall a rare
finding. (Right) Nuclei in
DSRCT are generally uniform
in most cases; however, some
cases show scattered nuclear
atypia in the form of
enlargement and
pleomorphism, as shown. This
finding is often focal and
inconspicuous but may rarely
be diffuse and prominent.
Submesothelial Fibroblasts
(Left) Frankly bizarre nuclear
atypia ﬊ is an exceptionally
rare, but reported, finding in
DSRCT. (Right) Many cases of
DSRCT arise near a peritoneal
surface, as evidenced by a
mesothelial lining ﬈ in this
image from a cytokeratin
AE1/AE3 immunostain. Note
that spindled submesothelial
fibroblasts ﬊ also stain for
keratin.
705
 Extraskeletal Ewing Sarcoma

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY ANCILLARY TESTS

• Malignant small round blue cell neoplasm of bone and soft
tissue characterized by specific EWSR1 mutations
• Ewing sarcoma (ES) and primitive neuroectodermal tumor
(PNET) represent continuous morphologic spectrum
CLINICAL ISSUES
• Children, adolescents, and young adults
• Aggressive with propensity for early metastases
• 10-year survival
○ Localized disease at presentation: 67%
○ Metastatic disease at presentation: 28%
MICROSCOPIC
• Sheets of densely packed cells with round, uniform nuclei
• Scant, glycogen-rich cytoplasm with indistinct cell
membranes
• Homer Wright rosettes may be seen (PNET)
• CD99(+), characteristically strong, diffuse, and membranous
• Nuclear FLI-1(+)
• Myogenin, BCOR, TdT, CD45, CD56, WT1 (-)
• Molecular: Multiple balanced translocations and fusions
involving EWSR1 gene on chromosome 22
○ Most fusion transcripts are EWSR1-FLI1 (90-95%) and
EWSR1-ERG (5-10%)
TOP DIFFERENTIAL DIAGNOSES
• Alveolar rhabdomyosarcoma
• Poorly differentiated synovial sarcoma
• Undifferentiated sarcoma with CIC-DUX4 translocation
• BCOR-CCNB3 fusion-positive sarcoma
• Desmoplastic small round cell tumor
• Neuroblastoma
• Lymphoma

Ewing Sarcoma Cellular, Uniform Morphology

(Left) Ewing sarcoma (ES) is a
highly cellular, high-grade
sarcoma with a dense, solid to
sheet-like distribution of cells,
as depicted. Most tumors are
diagnosed on small biopsy
prior to treatment with
chemotherapy, and large,
preserved sections, as shown,
are uncommon. (Right) Tumor
cells in ES are generally very
uniform, and overlapping of
nuclei is quite common.
Chromatin is finely and evenly
distributed, and nucleoli are
small, if present.

Clear Cytoplasm Common Diffuse, Membranous CD99 Expression

(Left) Accumulation of
intracytoplasmic glycogen is
common in ES and results in a
conspicuous clear cell
appearance. This morphology
may be focal, patchy, or
diffuse in any given tumor.
(Right) ES characteristically
shows strong, diffuse
membranous staining for
CD99 (MIC2), as shown. Once
thought to be specific for ES,
CD99 has since been well
described in many other small
round blue cell tumors;
however, expression is usually
weak or focal in these other
entities.

706
 Extraskeletal Ewing Sarcoma

Tumors of Uncertain Differentiation

– 10-year survival for metastatic disease at presentation:
TERMINOLOGY 28%
Abbreviations • Prognostic factors associated with decreased survival
• Ewing sarcoma (ES) ○ Metastatic disease at presentation
○ Axial tumor location
Synonyms
○ Tumor size > 10 cm
• Primitive neuroectodermal tumor (PNET) ○ Patient age > 19 years
• Askin tumor
Definitions MACROSCOPIC
• Malignant small round blue cell neoplasm of bone and soft General Features
tissue characterized by specific EWSR1 mutations • Tan to gray, friable cut surfaces
• ES and PNET represent continuous morphologic spectrum • Hemorrhage and necrosis common
○ Overlapping morphologic features, immunophenotype, • May display cystic change with necrotic, semiliquid contents
and molecular/genetic alterations
○ PNET displays morphologic evidence of neuronal Size
differentiation • Variable, up to 20 cm
• Askin tumor refers to ES/PNET of chest wall or
thoracopulmonary region MICROSCOPIC
Histologic Features
CLINICAL ISSUES
• Sheets of densely packed cells with round, uniform nuclei
Epidemiology • Dispersed fine chromatin and inconspicuous nucleoli
• Incidence • Scant cytoplasm with indistinct cell membranes
○ Rare ○ Can be clear due to glycogen content
• Age • Neuroectodermal differentiation (Homer Wright rosettes)
○ Children, adolescents, and young adults (median: 15 may be seen in PNET
years) ○ Central fibrillary core without lumen
○ Peak incidence in 2nd decade of life • Rarely have focal spindled morphology
• Sex • Minimal intercellular collagen or reticulin
○ Slight male predominance (M:F ratio = 1.4:1.0) • Rare myxoid change with microcyst formation may be seen
• Ethnicity • Necrosis frequently seen with perivascular preservation of
○ More common in Caucasians tumor cells
○ Very rare in Africans and African Americans • Rare morphologic variants
○ Atypical (large cell) variant
Site
– Larger, vesicular nuclei with irregular nuclear contours
• Trunk (lung, mediastinum, paravertebral region) – Conspicuous nucleoli
• Extremities (deep soft tissues) – Pleomorphism and spindling
○ Primary bone tumor can extend into and present in soft ○ Adamantinoma-like variant occurs mostly in bone
tissue
○ Sclerosing and clear cell variants described
• Head and neck
• Retroperitoneum ANCILLARY TESTS
Presentation Histochemistry
• Painful or swelling at site of involvement • PAS(+) intracytoplasmic glycogen
• Constitutional symptoms (fever, anemia, leukocytosis) • Reticulin (-)
often seen ○ Staining pattern: Minimal or no intercellular reticulin
Treatment except around blood vessels
• Multimodality therapy Immunohistochemistry
○ Chemotherapy is typically initial treatment of choice • CD99(+), characteristically strong, diffuse, and membranous
○ Surgical resection of residual tumor ○ Weak, patchy, or focal expression should lead to
○ Radiation therapy or combined radiation and surgical consideration of other diagnoses
resection for select cases • Nuclear FLI-1(+)
Prognosis • NKX2.2(+)
• Aggressive with propensity for early metastases • Focal expression of keratin, CD117, or S100 protein in 25-
○ Lungs, bone, and bone marrow are most frequent sites 30% of cases
of metastasis • Very rare focal desmin expression reported
○ Most predictive prognostic factor • Myogenin, MYOD1, BCOR, TdT, CD56, WT1, CD45, TLE1,
– 10-year survival for localized disease at presentation: SMA (-)
67%

707
 Extraskeletal Ewing Sarcoma
Tumors of Uncertain Differentiation
Molecular Genetics
• Multiple balanced translocations and fusions involving
EWSR1 gene on chromosome 22
○ EWSR1 rearrangements detectable by RT-PCR and break-
apart FISH probes
• Most common translocation: t(11;22)(q24;q12), EWSR1-FLI1
fusion
○ Type 1 fusion: Exons 1-7 of EWSR1 to exons 6-9 of FLI1
– Most common (60-65% of cases)
○ Type 2 fusion: Exons 1-7 of EWSR1 fuse to exons 6-9 of
FLI1
• 2nd most common translocation: t(21;22)(q12;q12),
EWSR1-ERG fusion (5-10%)
• Less common EWSR1 variant translocations (< 1%)
○ ETS family
– t(2;22)(q33;q12), EWSR1-FEV fusion
– t(7;22)(p22;q12), EWSR1-ETV1 fusion
– t(17;22)(q12;q12), EWSR1-ETV4 (E1AF) fusion
○ Non-ETS family
– t(2;22)(q31;q12), EWSR1-SP3 fusion
– t(6;22)(p21;q12), EWSR1-POU5F1 fusion
– t(20;22)(q13;q12), EWSR1-NFATC2 fusion
– t(4;22)(q31;q12), EWSR1-SMARCA5 fusion
• Genetic changes do not correlate with site or morphology
DIFFERENTIAL DIAGNOSIS
Alveolar Rhabdomyosarcoma
• Nests of small cells separated by variable-sized fibrous
septa
• Multinucleated "wreath" cells
• Diffuse desmin (+)
• Nuclear myogenin (+)
• FOXO1 gene fusions with PAX3 or PAX7
Poorly Differentiated Synovial Sarcoma
• Nuclei less regular, appear to overlap
• May be spindled or have spindled component
• Strong, diffuse nuclear TLE1(+)
• SS18 gene fusions
Desmoplastic Small Round Cell Tumor
• Usually intraabdominal, rarely other sites
• Nests of cells in cellular fibrous or desmoplastic stroma
• Polyphenotypic
○ Expresses keratin, desmin, and neural markers
• CD99(-) in most cases
• WT1(+) (carboxy-terminus only)
• EWSR1-WT1 gene fusion
Undifferentiated Sarcoma With CIC-DUX4
Translocation
• Nuclear WT1(+)
• Variable CD99(+)
• Lacks EWSR1 rearrangements
BCOR-CCNB3 Fusion-Positive Sarcoma
• Heterogeneous morphology (round to spindled cells)
• Myxoid matrix common
• CCNB3(+) by IHC
• Lacks EWSR1 rearrangements
708
Neuroblastoma
• Usually < 4 years of age
• Associated with sympathetic ganglia
• Sheets of neuroblasts, variable ganglionic differentiation
• NB84(+); CD99(-)
• Lacks specific translocations of ES
Lymphoma
• Involvement of lymphoid tissue
○ Lymph node, spleen
• Immunoreactivity with lymphoid markers
• Pitfall: Strong CD99(+) common in lymphoblastic
lymphomas
Extraskeletal Mesenchymal Chondrosarcoma
• Often prominent pericytomatous growth pattern
• Focal chondroid formation (can be sparse)
• Recurrent HEY1-NCOA2 fusion
Small Cell Carcinoma
• Usually older adults
• Nuclear molding, scanty cytoplasm
• Diffuse keratin (+), often dot-like
• CD56(+), nuclear TTF-1(+)
• CD99(-) in majority of cases
• Lacks specific fusion genes
SELECTED REFERENCES
1. Kao YC et al: BCOR-CCNB3 fusion positive sarcomas: a clinicopathologic and
molecular analysis of 36 cases with comparison to morphologic spectrum
and clinical behavior of other round cell sarcomas. Am J Surg Pathol.
42(5):604-15, 2018
2. Antonescu CR et al: Sarcomas with CIC-rearrangements are a distinct
pathologic entity with aggressive outcome: a clinicopathologic and
molecular study of 115 cases. Am J Surg Pathol. 41(7):941-9, 2017
3. Hamilton SN et al: Long-term outcomes and complications in pediatric Ewing
sarcoma. Am J Clin Oncol. 40(4):423-28, 2017
4. Yoshida A et al: CIC-rearranged sarcomas: a study of 20 cases and
comparisons with Ewing sarcomas. Am J Surg Pathol. 40(3):313-23, 2016
5. Duchman KR et al: Prognostic factors for survival in patients with Ewing's
sarcoma using the surveillance, epidemiology, and end results (SEER)
program database. Cancer Epidemiol. 39(2):189-95, 2015
6. Pan HY et al: Prognostic factors and patterns of relapse in Ewing sarcoma
patients treated with chemotherapy and R0 resection. Int J Radiat Oncol
Biol Phys. 92(2):349-57, 2015
7. Tomazou EM et al: Epigenome mapping reveals distinct modes of gene
regulation and widespread enhancer reprogramming by the oncogenic
fusion protein EWS-FLI1. Cell Rep. 10(7):1082-95, 2015
8. Brasme JF et al: Time to diagnosis of Ewing tumors in children and
adolescents is not associated with metastasis or survival: a prospective
multicenter study of 436 patients. J Clin Oncol. 32(18):1935-40, 2014
9. Crompton BD et al: The genomic landscape of pediatric Ewing sarcoma.
Cancer Discov. 4(11):1326-41, 2014
10. Fisher C: The diversity of soft tissue tumours with EWSR1 gene
rearrangements: a review. Histopathology. 64(1):134-50, 2014
11. Warren M et al: Integrated multimodal genetic testing of Ewing sarcoma--a
single-institution experience. Hum Pathol. 44(10):2010-9, 2013
12. Llombart-Bosch A et al: Histological heterogeneity of Ewing's
sarcoma/PNET: an immunohistochemical analysis of 415 genetically
confirmed cases with clinical support. Virchows Arch. 455(5):397-411, 2009
13. Machado I et al: Molecular diagnosis of Ewing sarcoma family of tumors: a
comparative analysis of 560 cases with FISH and RT-PCR. Diagn Mol Pathol.
18(4):189-99, 2009
14. Jambhekar NA et al: Comparative analysis of routine histology,
immunohistochemistry, reverse transcriptase polymerase chain reaction,
and fluorescence in situ hybridization in diagnosis of Ewing family of tumors.
Arch Pathol Lab Med. 130(12):1813-8, 2006
15. Lucas DR et al: Ewing sarcoma vs lymphoblastic lymphoma. A comparative
immunohistochemical study. Am J Clin Pathol. 115(1):11-7, 2001
 Extraskeletal Ewing Sarcoma
Cytologic Features
"Dark" Cells
Vague Lobular Growth
Tumors of Uncertain Differentiation
Admixed Clear Cells
(Left) Nuclei in ES are
generally small, round, and
relatively uniform. Nucleoli
are small, if present.
Occasional cases show
scattered cells with more
prominent nucleoli. (Right)
Clear tumor cells ﬉ are
admixed with more
conventional small cells in this
case of ES. Hemosiderin
pigment ﬈ is also present and
associated with stromal
vessels.
Degenerating Cells
(Left) An admixed population
of degenerating tumor cells
with smaller, hyperchromatic,
and angulated nuclei ﬊ may
be seen in many cases of ES
and have been referred to as
"dark" cells. Note the contrast
with the more conventional
tumor cells st. (Right) This
case of ES is beginning to
undergo degeneration with a
number of apoptotic bodies
and cells with smaller,
angulated hyperchromatic
nuclei ("dark" cells). Note the
distinct population of more
viable tumor cells ﬈ in this
H&E.
Prominent Lobulated Growth
(Left) A vaguely lobular
appearance with focal, thin
fibrovascular septa can be
appreciated in this case of ES.
Note the monotonous cell
population and small, round,
uniform nuclei. (Right) This
case of ES features a more
prominent lobulated pattern
of growth with large nests and
sheets of clear tumor cells
separated by thickened
fibrocollagenous septa ﬈.
709
 Extraskeletal Ewing Sarcoma
Tumors of Uncertain Differentiation

Neuroectodermal Differentiation True Rosette Formation

(Left) Some cases of ES
feature conspicuous
morphologic evidence of
neuroectodermal
differentiation in the form of
scattered true rosettes ﬈.
These tumors have also been
described as primitive
neuroectodermal tumors
(PNETs). (Right) The true
rosettes of ES (PNET) are
formed by tumor cells
arranged around a core of
fibrillary material ﬈ without
formation of a central lumen.
Cell boundaries are indistinct.
These structures are also
known as Homer Wright
rosettes.

Large Cell (Atypical) Variant Coagulative Necrosis

(Left) Occasional cases of ES
contain tumor cells that are
larger, show greater nuclear
irregularity, and often feature
prominent nucleoli ﬈. This
variant is known as atypical or
large cell ES. (Right)
Coagulative necrosis ﬈ is
common in ES and is often
geographic in distribution. A
common finding is the
presence of perivascular ﬉
tumor cell preservation
("peritheliomatous growth")
with degeneration and death
of surrounding cells.

Focal Spindled Cytomorphology Focal Keratin Expression

(Left) Focal spindle cell
morphology is a rare finding in
ES. In this H&E, spindled tumor
cells within an area of myxoid
stromal changes (also rare)
merge with more typical round
cells ﬉. Spindling is more
frequently seen in the large
cell (atypical) variant. (Right)
Focal keratin expression can
be seen in up to 25-30% of
cases of ES, often in a dot-like
pattern ﬊. Other
morphologically similar
entities, such as desmoplastic
small round cell tumor and
poorly differentiated synovial
sarcoma, should be carefully
excluded.

710
 Extraskeletal Ewing Sarcoma
Treated Ewing Sarcoma
Cytoplasmic Glycogen
Characteristic Translocation
Tumors of Uncertain Differentiation
Superficial Ewing Sarcoma
(Left) After chemotherapy,
there is often shrinkage and
loss of tumor cells with
prominent edema ﬈ &/or
fibrosis of the stroma. Large
areas of necrosis are also
common after therapy. (Right)
Rare cases of ES arise
superficially in the dermis.
Most are well demarcated and
many appear encapsulated.
Rosette formation is also
common. This group of ES
shows an overall better
prognosis than conventional
deep tumors.
Absence of Reticulin Staining
(Left) Intracytoplasmic
glycogen in ES can be
demonstrated by a periodic
acid-Schiff (PAS) stain and is
removed by pretreatment with
diastase. Glycogen appears
granular and brightly pink or
magenta. (Right) Reticulin
fibers are seen around blood
vessels ﬈ and between tumor
lobules in ES; however, these
fibers are absent between
neoplastic cells. By contrast,
reticulin often surrounds small
groups of cells in the
morphologically similar, poorly
differentiated synovial
sarcoma.
FISH Analysis for EWSR1
(Left) This graphic depicts the
t(11;22)(q24;q12)
translocation between the
carboxy-terminal domain of
FLI1 (11q24) and the EWSR1
gene aminoterminal domain
(22q12), resulting in an
EWSR1-FLI1 fusion gene.
(Right) In this fluorescence in
situ hybridization (FISH)
preparation, dual color break-
apart probes are used for the
EWSR1 gene on chromosome
22. In the nucleus of a tumor
cell, split red st and green ﬇
signals, instead of a fused
yellow one ſt, indicate a
translocation involving
EWSR1.
711
 Extraskeletal Myxoid Chondrosarcoma

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY MICROSCOPIC
• Soft tissue or bone sarcoma of uncertain differentiation • Abundant myxoid matrix; hyaline cartilage absent
with abundant myxoid matrix, multilobular architecture, • Cells interconnect to form cords, clusters, or fine networks
uniform cells in cords, clusters and fine networks, and • Cellular variant with minimal myxoid matrix and epithelioid
NR4A3 rearrangement &/or rhabdoid cells
CLINICAL ISSUES ANCILLARY TESTS
• Median age: 50 years • S100(+) but variable and inconsistent
• 2:1 male predominance • Cytogenetics, t(9;22)(q22;q12.2) most common
• Lower extremity most common • Break-apart FISH for EWSR1 or NR4A3
• Often prolonged clinical course
TOP DIFFERENTIAL DIAGNOSES
• High rate of local and distant recurrence
• Poor response to chemotherapy • Chordoma
• Tumors with variant NR4A3 translocations higher grade, • Myoepithelioma/myoepithelial carcinoma
more aggressive • Soft tissue chondroma
• Myxofibrosarcoma (epithelioid variant)
MACROSCOPIC • Epithelioid gastrointestinal stromal tumor
• Gelatinous lobules separated by thick, fibrous septa • Myxoid mesothelioma
• Cystic areas, hemorrhage, and necrosis common • Chordoid meningioma

Extraskeletal Myxoid Chondrosarcoma Lobular Architecture and Hemorrhage

(Left) Grossly, EMC usually
forms a large, well-
demarcated mass as
illustrated by this thigh tumor.
The cut surface has a well-
defined, lobular architecture
with fibrous septa ﬈ and
gelatinous lobules ﬉. This
tumor also has extensive
intralesional hemorrhage.
(Right) This low-power H&E
highlights the lobular growth
pattern of EMC, defined by
thick, fibrous septa ﬈. Areas
of acute hemorrhage ﬊,
hemosiderosis ſt, and scar ﬉
are common, as are necrosis
and cyst formation (not
shown).

Uniform Interconnecting Cells EWSR1 Break-Apart FISH

(Left) Conventional EMC is
typically composed of uniform
cells with round to oval nuclei
and wisps of eosinophilic
cytoplasm that interconnect
﬈ with each other. (Right)
Break-apart FISH for EWSR1 is
a useful diagnostic test for
EMC. This
immunofluorescence image
depicts a normal allele with
fused red and green signals ﬇
and a broken apart allele ſt.
Although sensitive, it will miss
tumors with variant NR4A3
fusions.

712
 Extraskeletal Myxoid Chondrosarcoma
TERMINOLOGY
Abbreviations
• Extraskeletal myxoid chondrosarcoma (EMC)
Synonyms
• Chordoid sarcoma
Definitions
• Soft tissue or bone sarcoma of uncertain differentiation
with abundant myxoid matrix, multilobular architecture,
uniform cells in cords, clusters and fine networks, and
NR4A3 rearrangement
CLINICAL ISSUES
Epidemiology
• Rare: < 3% of soft tissue sarcomas
• Median age: 50 years (range: 5-90 years); rare in
children; M:F = 2:1
Site
• Extremities; lower extremity most common
• Rare in abdomen, pelvis, head and neck, cranium, pleura
• Rare primary bone tumors
Presentation
• Deep soft tissue mass
• Pulmonary metastases at presentation in 13%
Treatment
• Wide local excision; poor response to chemotherapy
Prognosis
• Local recurrence rate (30-50%)
• Metastases (35-45%), usually pulmonary
• Often prolonged clinical course
• Tumors with variant NR4A3 translocations more aggressive
MACROSCOPIC
General Features
• Well demarcated; contained by pseudocapsule
• Gelatinous lobules separated by fibrous septa
• Cystic areas, hemorrhage, and necrosis common
Size
• Usually large; median: 7 cm; range: 1-30 cm
MICROSCOPIC
Histologic Features
• Conventional EMC
○ Multilobular architecture, fibrous septa, abundant
myxoid matrix
○ Uniform cells with eosinophilic cytoplasm and round to
spindle-shaped nuclei arranged in cords, clusters, or fine
networks and low mitotic rate
○ Necrosis, hemorrhage, and hemosiderosis common
• Cellular/poorly differentiated EMC
○ Densely cellular, often with little myxoid matrix
○ Large epithelioid &/or rhabdoid cells
○ Nonmyxoid spindle cell areas (dedifferentiation)
Tumors of Uncertain Differentiation
ANCILLARY TESTS
Immunohistochemistry
• S100(+) but variable and inconsistent
• Minority of cases cytokeratin &/or EMA (+)
• Loss of INI1 (SNF5) in tumors with rhabdoid features
• Neuroendocrine marker expression in some
In Situ Hybridization
• Break-apart FISH for NR4A3 rearrangement
Genetic Testing
• t(9;22)(q22;q12.2) most common; t(9;17)(q22;q11.2) and
other variants
• EWSR1-NR4A3 fusion in majority; variant NR4A3 fusions
(TFG, TCF12, TAF15, FUS) in high-grade and rhabdoid EMCs
Electron Microscopy
• Intracisternal bundles of parallel microtubules
DIFFERENTIAL DIAGNOSIS
Chordoma
• Larger cells with more abundant cytoplasm and
physaliferous cells
• Cytokeratin (+), EMA(+), S100(+), brachyury (+)
• Affects sacrum, clivus, vertebral bodies
Myoepithelioma/Myoepithelial Carcinoma
• Cords of cells in myxoid matrix, benign or malignant
• Variable expression of cytokeratin, S100, p63, SMA
• Can show EWSR1 rearrangement
Soft Tissue Chondroma
• Lobular myxoid architecture and interconnecting cells
• True hyaline cartilage, often heavily calcified
• Predilection for hands and feet
Myxofibrosarcoma (Epithelioid Variant)
• High-grade pleomorphic cells
• Prominent curvilinear blood vessels
• Usually admixed with conventional myxofibrosarcoma
Epithelioid Gastrointestinal Stromal Tumor
• May have abundant myxoid matrix and cell cords
• CD117(+) and DOG1(+)
Myxoid Mesothelioma
• Epithelioid mesothelioma with abundant myxoid matrix
• Cytokeratin (+), calretinin (+), WT1(+)
• Pleural/peritoneal tumor
Chordoid Meningioma
• Usually admixed with conventional meningioma
• EMA(+)
SELECTED REFERENCES
1. Agaram NP et al: Extraskeletal myxoid chondrosarcoma with non-EWSR1-
NR4A3 variant fusions correlate with rhabdoid phenotype and high-grade
morphology. Hum Pathol. 45(5):1084-91, 2014
2. Meis-Kindblom JM et al: Extraskeletal myxoid chondrosarcoma: a reappraisal
of its morphologic spectrum and prognostic factors based on 117 cases. Am
J Surg Pathol. 23(6):636-50, 1999
713
 Extraskeletal Myxoid Chondrosarcoma
Tumors of Uncertain Differentiation

Spindle Cells Lobular Pattern on MR

(Left) Spindle cell
differentiation is common in
EMC, and the amount varies
from case to case. Note the
interconnecting pattern of
spindle cells with abundant
eosinophilic cytoplasm and
low-grade, elongated nuclei
forming cords and fine
networks. (Right) Axial T2-
weighted MR discloses a large,
deep-seated EMC of the thigh
with heterogeneous,
hyperintense signal and well-
defined, lobular architecture.

Lobular Architecture and Hemorrhage Lobular Architecture

(Left) Grossly, EMC has a very
well-defined, lobular
architecture consisting of
gelatinous, yellow lobules ﬈
separated by fibrous septa.
Intralesional hemorrhage ﬉ is
common. (Right) This
scanning-power H&E
highlights the well-defined,
lobular architecture and
abundant pale blue myxoid
matrix in EMC.

Fibrous Septum Cystic Areas, Necrosis, and Hemorrhage

(Left) EMC has a lobular
architecture defined by thick,
fibrous septa ﬈ that divide it
into myxoid lobules containing
cords of interconnecting
uniform cells. (Right) Grossly,
most EMCs form large,
demarcated tumors with a
well-defined, lobular pattern
created by thick, fibrous septa
﬈ that divide it into
gelatinous lobules ﬉.
Necrosis ﬊, intratumoral
hemorrhage, and cyst
formation are often present,
as shown.

714
 Extraskeletal Myxoid Chondrosarcoma

Tumors of Uncertain Differentiation

Cell Clusters Complex Cohesive Structures
(Left) The neoplastic cells in
EMC can form rounded,
cohesive clusters. Note the
epithelioid cytology with
densely eosinophilic cytoplasm
and abundant pale blue
myxoid matrix. (Right) The
neoplastic cells in EMC
interconnect to form cords,
clusters, and more complex
structures ﬈, as shown within
a background of myxoid
matrix ﬉. True hyaline
cartilage is virtually never
seen. Note the thick, fibrous
band ﬊.

Cellular Extraskeletal Myxoid

Chondrosarcoma With Large Epithelioid
Complex Reticular Pattern
Cells
(Left) This EMC has a complex
reticular architecture
characterized by cohesive
arrays of epithelioid and
spindle cells forming
cribriform and whorling ﬉
patterns. Note the acute
hemorrhage ﬈. (Right)
Cellular EMC is characterized
by sheets of cells with little or
no intervening matrix. These
tumors often have large,
epithelioid cells with vesicular
nuclei, prominent nucleoli, and
brisk mitotic activity.
Histologic grade is regarded as
a prognostic variable in EMC.

Rhabdoid Cells Ultrastructure

(Left) Rhabdoid cells with
eccentric, eosinophilic
cytoplasm and perinuclear
hyalin globules ﬈ can be
found in EMC. As in rhabdoid
tumor, these cells are negative
for SNF5 (INI1). Rhabdoid
EMCs often have variant
NR4A3 fusions. (Right)
Electron micrograph depicts
parallel bundles of
microtubules ﬈ within the
cisternal compartment of an
EMC, a highly characteristic
feature found only in a
minority of cases. Rhabdoid
cells in EMC (not shown) have
perinuclear whorls of
intermediate filaments.

715
 Extrarenal Rhabdoid Tumor

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY ○ Frequent local recurrence and metastasis

• Highly malignant neoplasm composed of cells with
rhabdoid morphology and characterized by alterations in
SMARCB1/INI1 gene
○ No other line of cellular differentiation can be present
ETIOLOGY/PATHOGENESIS
• Familial cases are often associated with germline mutations
of SMARCB1/INI1 gene
CLINICAL ISSUES
• Affects infants and young children
• Deep soft tissues in axial locations
○ Paraspinal, retroperitoneum, perineum, others
• Rapidly growing mass
• Treatment: Chemotherapy/radiation followed by resection
○ Genetic testing is recommended to evaluate for
germline SMARCB1 alterations
• Dismal prognosis
MICROSCOPIC
• Sheets of characteristic polygonal rhabdoid cells
• MItotic figures and necrosis common
• Some cases show predominant component of
undifferentiated small round cells
ANCILLARY TESTS
• Keratin (+), EMA(+), vimentin (+)
• Loss of nuclear INI1 expression characteristic
• CD99(+) in 50% of cases
• Molecular: Chromosome 22q11.2 monosomy or deletions
(involving SMARCB1/hSN5/INI1 gene)
TOP DIFFERENTIAL DIAGNOSES
• Epithelioid sarcoma
• Carcinoma or melanoma
• Rhabdomyosarcoma

Extrarenal Rhabdoid Tumor Rhabdoid Cells

(Left) Extrarenal rhabdoid
tumor (ERT) of soft tissue is a
highly aggressive malignancy
that usually affects infants
and young children and has a
uniformly dismal prognosis. It
is composed of variably
cohesive sheets of polygonal
cells with a rhabdoid
morphology. (Right) Rhabdoid
cells are characteristic of ERT
but can be seen in a variety of
other, unrelated tumors.
Cytologically, they feature
large, eccentric vesicular
nuclei with prominent nucleoli
and a glassy, eosinophilic
cytoplasmic inclusion ﬊.

Keratin Expression Loss of Nuclear INI1 Expression

(Left) Keratin (especially CK8
and CK18) and vimentin are
commonly expressed in ERT
and show cytoplasmic staining
with accentuation in the
paranuclear inclusion ﬊
(contains aggregates of
intermediate filaments).
(Right) Loss of nuclear
expression of INI1 is a
characteristic feature of ERT;
however, other tumors (such
as epithelioid sarcoma) are
known to show loss as well.
Note the negative tumor cell
nuclei ﬉ amidst the positive
stromal and endothelial cell
nuclei ﬊.

716
 Extrarenal Rhabdoid Tumor

Tumors of Uncertain Differentiation

TERMINOLOGY Treatment
• Multiagent chemotherapy regimen and radiotherapy
Abbreviations followed by complete surgical resection, if feasible
• Extrarenal rhabdoid tumor (ERT) • Genetic testing is recommended to evaluate for germline
Synonyms SMARCB1 alterations
• Malignant rhabdoid tumor Prognosis
• Atypical teratoid/rhabdoid tumor (term for similar • Very poor
neoplasm occurring in central nervous system) ○ 5-year survival rate: 15-20%
Definitions • Frequent local recurrence and metastasis
• Highly malignant neoplasm composed of cells with
rhabdoid morphology and characterized by alterations in
MACROSCOPIC
SMARCB1/INI1 gene General Features
• No other line of cellular differentiation can be present (i.e., • Multinodular, nonencapsulated, poorly circumscribed
diagnosis of exclusion) • Pale or tan, with hemorrhage and necrosis
○ Specific tumor types that are known to occasionally
exhibit rhabdoid cytomorphology Size
– Carcinoma, melanoma • Often > 5 cm
– Epithelioid sarcoma, desmoplastic small round cell
tumor, epithelioid malignant peripheral nerve sheath MICROSCOPIC
tumor Histologic Features
– Mesothelioma, extraskeletal myxoid chondrosarcoma,
• Infiltrative peripheral borders
rhabdomyosarcoma
• Characteristic polygonal rhabdoid cells of varying sizes
– Myoepithelial tumors, gastrointestinal stromal tumor,
synovial sarcoma ○ Large eccentric, vesicular nuclei with prominent nucleoli
○ Variably abundant eosinophilic cytoplasm
ETIOLOGY/PATHOGENESIS – Often contains glassy paranuclear intracytoplasmic
inclusion (aggregates of intermediate filaments)
Genetic Factors ○ Mitotic figures are frequent
• Most are sporadic • Growth patterns: Cellular sheets or solid trabeculae
• Familial cases are often associated with germline mutations ○ Cellular dyscohesion common
of SMARCB1/INI1 gene – Pseudopapillary pattern may be seen
○ May present with multiple rhabdoid tumors • Necrosis common
○ Increased incidence of schwannomatosis in this group • Some cases show predominant component of
• Genetic testing is recommended for all patients who undifferentiated small round cells
develop ERT to evaluate for germline SMARCB1 alterations ○ Characteristic rhabdoid cells may be focal or
• Rare cases show retained SMARCB1 expression but inconspicuous
mutation &/or loss of SMARCA4 (BRG1) gene • Other findings: Epithelioid change, spindled morphology,
myxoid stroma, osteoclast-like giant cells
CLINICAL ISSUES
Epidemiology ANCILLARY TESTS
• Incidence Histochemistry
○ Very rare • Cytoplasmic inclusions are PAS(+), diastase resistant
• Age
Immunohistochemistry
○ Infants and young children
– May be congenital • Keratin (+), EMA(+), vimentin (+)
○ Very rarely in adults ○ Most often low molecular weight keratins (CK8, CK18)
– Often localized to paranuclear inclusions
Site • CD99(+) or synaptophysin (+) in 50% of cases, often patchy
• Deep soft tissues in axial locations • Loss of nuclear INI1 expression (negative nuclear staining)
○ Paravertebral, neck, retroperitoneum, perineum, ○ Highly characteristic but not specific
abdominopelvic cavities • Also SALL4(+)
• Also extremities, particularly thigh • May show focal expression of S100 protein or actins
• Viscera • Negative for desmin, HMB-45, MART-1, CD31, CD34,
○ Liver, GI tract, bladder, thymus, heart myogenin
• Cutaneous lesions also described
Molecular Genetics
Presentation • Chromosome 22q11.2 monosomy or deletions
• Rapidly growing mass ○ Site of SMARCB1/hSN5/INI1 tumor suppressor gene,
• Large tumors may ulcerate overlying skin which often shows homozygous deletion or mutation
• May present with multiple cutaneous nodules – Gene product is INI1 (BAF47)
717
 Extrarenal Rhabdoid Tumor
Tumors of Uncertain Differentiation
○ Translocations with 1p, 6p, 11p, or 18q
• 46,X,t(X;22;11)(q13;q11.2;q14.2) reported in one case
• Rare cases show retained SMARCB1 expression but
mutation &/or loss of SMARCA4 (BRG1) gene
DIFFERENTIAL DIAGNOSIS
Epithelioid Sarcoma
• Affects older age group than ERT
• Multinodular growth pattern
• Proximal variant can show marked morphologic overlap
with ERT
○ Prominent rhabdoid cells
• Keratin (+); CD34(+) in 50% of cases
• Loss of nuclear INI1 in 80-93% of cases
Metastatic Melanoma
• History of melanoma may be present
• Cells may show rhabdoid morphology
• S100 protein (+) in almost all cases
• HMB-45, Melan-A positivity in many cases (may be focal)
• Retention of nuclear INI1
Carcinoma
• Some high-grade carcinomas may show focal or
predominant rhabdoid morphology
• Usually organ based
○ Can be metastatic in soft issue, but primary site is usually
evident
• More conventional, nonrhabdoid morphology usually
present
○ Expression of specific site markers (TTF-1, PSA, pax-8,
etc.)
• Retention of nuclear INI1
○ Some GI tract carcinomas with rhabdoid morphology
may lose INI1 expression
Rhabdomyosarcoma
• Desmin (+), myogenin (+), myoD1(+)
• Focal keratin (+) may be seen in alveolar
rhabdomyosarcoma
• Retention of nuclear INI1
Ewing Sarcoma
• Can be morphologically similar to small cell variant of ERT
• Strong, membranous CD99(+)
• May be keratin (+)
• Retention of nuclear INI1
• EWSR1 gene translocations in most cases
Myoepithelioma
• Can have rhabdoid cytoplasmic morphology
○ Often prominent nucleoli in myoepithelial carcinoma
• Myoepithelial marker expression
○ S100 protein, SMA, GFAP, calponin
• Retention of nuclear INI1
○ Loss of INI1 may be seen in myoepithelial carcinoma
Epithelioid Malignant Peripheral Nerve Sheath
Tumor
• Prominent nucleoli; may show rhabdoid morphology
• Diffuse S100 protein (+); keratin (-)
• Loss of nuclear INI1 in 50% of cases
718
Extraskeletal Myxoid Chondrosarcoma
• Affects older age group than ERT
• Most common in extremities
• May show focal rhabdoid morphology in cellular or poorly
differentiated cases
• Often prominent myxoid stroma
• Keratin (-)
• Retention of nuclear INI1
• NR4A3 gene translocations characteristic
Desmoplastic Small Round Cell Tumor
• Characteristic abundant desmoplastic fibrous stroma
• May show focal rhabdoid morphology
• Keratin (+), desmin (+)
• Retention of nuclear INI1
SELECTED REFERENCES
1. Ginat DT et al: Disseminated malignant rhabdoid tumor of the head and
neck. Head Neck Pathol. 11(2):224-7, 2017
2. Huang SC et al: Secondary EWSR1 gene abnormalities in SMARCB1-deficient
tumors with 22q11-12 regional deletions: potential pitfalls in interpreting
EWSR1 FISH results. Genes Chromosomes Cancer. 55(10):767-76, 2016
3. Agaimy A et al: SMARCB1 (INI1)-negative rhabdoid carcinomas of the
gastrointestinal tract: clinicopathologic and molecular study of a highly
aggressive variant with literature review. Am J Surg Pathol. 38(7):910-20,
2014
4. Bahrami A et al: SMARCB1 deletion by a complex three-way chromosomal
translocation in an extrarenal malignant rhabdoid tumor. Cancer Genet.
207(9):437-40, 2014
5. Margol AS et al: Pathology and diagnosis of SMARCB1-deficient tumors.
Cancer Genet. 207(9):358-64, 2014
6. Chakrapani AL et al: Congenital extrarenal malignant rhabdoid tumor in an
infant with distal 22q11.2 deletion syndrome: the importance of SMARCB1.
Am J Dermatopathol. 34(6):e77-80, 2012
7. Rizzo D et al: SMARCB1 deficiency in tumors from the peripheral nervous
system: a link between schwannomas and rhabdoid tumors? Am J Surg
Pathol. 36(7):964-72, 2012
8. Eaton KW et al: Spectrum of SMARCB1/INI1 mutations in familial and
sporadic rhabdoid tumors. Pediatr Blood Cancer. 56(1):7-15, 2011
9. Schneppenheim R et al: Germline nonsense mutation and somatic
inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor
predisposition syndrome. Am J Hum Genet. 86(2):279-84, 2010
10. Argenta PA et al: Proximal-type epithelioid sarcoma vs. malignant rhabdoid
tumor of the vulva: a case report, review of the literature, and an argument
for consolidation. Gynecol Oncol. 107(1):130-5, 2007
11. Kohashi K et al: Highly aggressive behavior of malignant rhabdoid tumor: a
special reference to SMARCB1/INI1 gene alterations using molecular genetic
analysis including quantitative real-time PCR. J Cancer Res Clin Oncol.
133(11):817-24, 2007
12. Biegel JA: Molecular genetics of atypical teratoid/rhabdoid tumor.
Neurosurg Focus. 20(1):E11, 2006
13. Izumi 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. 19(6):820-31, 2006
14. Oda Y et al: Extrarenal rhabdoid tumors of soft tissue: clinicopathological
and molecular genetic review and distinction from other soft-tissue
sarcomas with rhabdoid features. Pathol Int. 56(6):287-95, 2006
15. Tekkök IH et al: Primary malignant rhabdoid tumor of the central nervous
system--a comprehensive review. J Neurooncol. 73(3):241-52, 2005
16. Higashino K et al: Malignant rhabdoid tumor shows a unique neural
differentiation as distinct from neuroblastoma. Cancer Sci. 94(1):37-42, 2003
17. Duvdevani M et al: Pure rhabdoid tumor of the bladder. J Urol. 166(6):2337,
2001
18. Ogino S et al: Malignant rhabdoid tumor: a phenotype? An entity?--A
controversy revisited. Adv Anat Pathol. 7(3):181-90, 2000
19. White FV et al: Congenital disseminated malignant rhabdoid tumor: a
distinct clinicopathologic entity demonstrating abnormalities of
chromosome 22q11. Am J Surg Pathol. 23(3):249-56, 1999
20. Fanburg-Smith JC et al: Extrarenal rhabdoid tumors of soft tissue: a
clinicopathologic and immunohistochemical study of 18 cases. Ann Diagn
Pathol. 2(6):351-62, 1998
21. Wick MR et al: Malignant rhabdoid tumors: a clinicopathologic review and
conceptual discussion. Semin Diagn Pathol. 12(3):233-48, 1995
 Extrarenal Rhabdoid Tumor
Cellular Dyscohesion
Large Epithelioid Cell Morphology
Stromal Hyalinization
Tumors of Uncertain Differentiation
Small Rhabdoid Cell Morphology
(Left) Loss of cellular cohesion
is common in ERT and may
impart a pseudopapillary ﬊
pattern around blood vessels.
Other areas show solid, dense
sheets or trabeculae of
rhabdoid cells. (Right) In some
cases of ERT, the rhabdoid
cells are smaller and less
plump; however, they still
show eccentric nuclei with
prominent nucleoli and
intracytoplasmic eosinophilic
inclusions ﬈. Confusion with
a hematopoietic neoplasm is
possible with this morphology.
Myxoid Stromal Change
(Left) A large, epithelioid cell
morphology may be present in
ERT and mimic a poorly
differentiated carcinoma.
Intracytoplasmic inclusions are
also more difficult to identify.
However, prominent nucleoli
are easily identified. (Right)
Myxoid stromal changes are
uncommonly seen in ERT and
are generally focal, if present.
Undifferentiated Small Round Cells
(Left) Stromal hyalinization
may be seen in ERT, imparting
a sclerotic/nested appearance
to the tumor and potentially
leading to confusion with
other sclerosing tumors. Areas
of typical morphology are
often present elsewhere.
(Right) Some cases of ERT
show a predominant
component of small
undifferentiated cells and few
classic rhabdoid cells.
Awareness of this morphology
is important to avoid
confusion with a variety of
other small round blue cell
tumors, such as Ewing
sarcoma.
719
 Intimal Sarcoma

KEY FACTS
Tumors of Uncertain Differentiation

TERMINOLOGY MICROSCOPIC
• Malignant mesenchymal neoplasm arising within lumina of • Usually poorly differentiated spindle cells, but wide range
large blood vessels of features
○ May be epithelioid
CLINICAL ISSUES
• Cellularity, atypia/pleomorphism, and mitotic activity vary
• Pulmonary trunk or pulmonary artery
• Myxoid background common
• Descending thoracic or lower abdominal aorta
• Specific differentiation sometimes present
• Variety of symptoms due to vascular occlusion by tumor
○ Rhabdomyosarcoma
○ Pulmonic tumors: Recurrent pulmonary embolism
○ Osteosarcoma
○ Aortic tumors: Systemic embolic symptoms
○ Angiosarcoma
– Claudication of legs
– Abdominal pain (superior mesenteric artery occlusion) TOP DIFFERENTIAL DIAGNOSES
– Ruptured aortic aneurysm at site of tumor • Cardiac (atrial) myxoma
• Often not discovered until autopsy • Primary cardiac sarcomas
• Poor prognosis; 80% mortality at 12 months • Leiomyosarcoma
• Epithelioid hemangioendothelioma
MACROSCOPIC
• Metastatic carcinoma
• Intravascular mass adherent to vessel wall, often polypoid
• Metastatic melanoma
• May grossly mimic thrombus

Intimal Sarcoma of Pulmonary Artery Plaque-Like Intravascular Growth

(Left) This pulmonary artery
intimal sarcoma adheres to
the vessel wall ﬇ and extends
along a large part of its
circumference filling much of
the arterial lumen st. The
tumor has a gelatinous cut
surface. (Right) Intimal
sarcoma often forms an
intravascular plaque that
adheres to and conforms to
the vessel wall (not present in
this image) similar to
atherosclerosis (side adherent
to vessel wall ﬈ and lumen
﬊). There are alternating
areas of cellularity, and foci of
myxoid background change
are apparent ﬈.

Myxoid and Hypocellular Atypical Epithelioid Cells

(Left) Some areas of intimal
sarcoma are relatively
hypocellular with
hyperchromatic atypical
spindle cells set in a myxoid
background. The appearance
in these areas is somewhat
similar to myxofibrosarcoma.
(Right) Other foci are more
cellular and display strikingly
atypical epithelioid cells.

720
 Intimal Sarcoma

Tumors of Uncertain Differentiation

• Cellularity, atypia/pleomorphism, and mitotic activity vary
TERMINOLOGY
• Myxoid background common
Definitions • May have fascicular pattern resembling leiomyosarcoma
• Malignant mesenchymal neoplasm arising within lumina of • Specific differentiation sometimes present
large blood vessels ○ Rhabdomyosarcoma
○ Osteosarcoma
ETIOLOGY/PATHOGENESIS ○ Angiosarcoma
Environmental Exposure
ANCILLARY TESTS
• Rare association with Dacron prosthetic graft
Immunohistochemistry
CLINICAL ISSUES • Variable SMA(+); may show focal desmin (+)
Epidemiology • Endothelial markers usually negative (unless
angiosarcomatous differentiation is present)
• Incidence
• Nuclear MDM2(+) in up to 70% of cases
○ Rare
• Age Genetic Testing
○ Older adults • Amplification/gains of MDM2, PDGFRA, EGFR common
Site
DIFFERENTIAL DIAGNOSIS
• Pulmonary trunk or pulmonary artery
○ Can extend to pulmonary valve or right ventricle Cardiac (Atrial) Myxoma
○ Direct invasion or metastasis to lung parenchyma • Pedunculated lesion mostly in left atrium
○ Extrathoracic metastasis less common: Skin, brain, lymph • Arises from interatrial septum
nodes, kidneys • Bland spindle cells
• Descending thoracic or lower abdominal aorta • Myxoid stroma
○ Distant metastasis common: Bone, liver, peritoneum,
Primary Cardiac Sarcomas
mesenteric nodes
• Similar histologic features as intimal sarcoma
Presentation • Arising within heart rather than great vessels
• Variety of symptoms due to vascular occlusion by tumor ○ Debatable if undifferentiated cardiac sarcoma should be
○ Pulmonic tumors: Recurrent pulmonary embolism classified as intimal sarcoma
– Rarely, acute myocardial infarction
Leiomyosarcoma
○ Aortic tumors: Systemic embolic symptoms
– Claudication of legs • Arise from media of large veins rather than within lumina
– Abdominal pain (superior mesenteric artery occlusion) • Fascicles of spindle cells with stringy eosinophilic cytoplasm
– Ruptured aortic aneurysm at site of tumor • Usually stronger and more diffuse SMA and desmin
expression
• Often not discovered until autopsy
Treatment Epithelioid Hemangioendothelioma
• Often angiocentric: Fills lumen, expanding vessel (usually
• Surgical removal when possible
vein), and infiltrates adjacent tissue
• Chemotherapy for inoperable or disseminated disease
• Aorta or pulmonary artery uncommon sites
Prognosis • Cords of epithelioid cells with intracytoplasmic vacuoles
• Poor; 80% mortality at 12 months containing erythrocytes ("blister" cells)
○ Survival shorter for aortic (5-9 months) vs. pulmonary • Expresses endothelial markers (CD31, CD34, ERG)
(13-18 months) tumors • Often keratin (+)
Metastatic Carcinoma or Melanoma
MACROSCOPIC
• Primary site elsewhere
General Features • Express markers for carcinoma (keratins, EMA, p63/p40,
• Intravascular mass adherent to vessel wall, often polypoid TTF-1, etc.) or melanoma (S100, SOX10, MART-1, HMB-45)
○ Extends along vessel
○ May grossly mimic thrombus SELECTED REFERENCES
○ In aorta, may resemble aneurysm or atherosclerosis 1. Maleszewski JJ et al: Do "intimal" sarcomas of the heart exist? Am J Surg
• Myxoid, hemorrhagic, fibrous, or ossified areas Pathol. 38(8):1158-9, 2014
2. Neuville A et al: Intimal sarcoma is the most frequent primary cardiac
sarcoma: clinicopathologic and molecular retrospective analysis of 100
MICROSCOPIC primary cardiac sarcomas. Am J Surg Pathol. 38(4):461-9, 2014
3. Dewaele B et al: Coactivated platelet-derived growth factor receptor {alpha}
Histologic Features and epidermal growth factor receptor are potential therapeutic targets in
• Usually poorly differentiated spindle cells, but wide range intimal sarcoma. Cancer Res. 70(18):7304-14, 2010
4. Sebenik M et al: Undifferentiated intimal sarcoma of large systemic blood
of features vessels: report of 14 cases with immunohistochemical profile and review of
○ May be epithelioid the literature. Am J Surg Pathol. 29(9):1184-93, 2005

721
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 SECTION 17

Undifferentiated/Unclassified Sarcomas

Undifferentiated Pleomorphic Sarcoma 724

Undifferentiated Round Cell Sarcoma With CIC-DUX4 Translocation 728
BCOR-CCNB3 Fusion-Positive Sarcoma 734
 Undifferentiated Pleomorphic Sarcoma

KEY FACTS
Undifferentiated/Unclassified Sarcomas

TERMINOLOGY
• High-grade sarcoma composed of pleomorphic spindle and
polygonal cells and showing no other identifiable line of
differentiation
○ Essentially diagnosis of exclusion
• Synonym: Malignant fibrous histiocytoma
CLINICAL ISSUES
• Usually older and elderly adults (50-70 years)
• Most arise in deep soft tissues of extremities (thigh
common)
• Treatment: Complete surgical resection with margins
• Fully malignant; usually high grade
○ Local recurrence in up to 30%; distant metastasis in up to
50%
MACROSCOPIC
• Usually large (most 5-15 cm)
MICROSCOPIC
• Storiform, fascicular, or patternless arrangement of highly
atypical spindled &/or polygonal cells
○ Marked nuclear pleomorphism in most cases
○ Abundant mitoses, often abnormal, and necrosis
• May contain chronic inflammatory infiltrate or osteoclast-
like giant cells
• No discernible microscopic evidence of any specific form of
differentiation (e.g., lipoblasts, bone formation)
ANCILLARY TESTS
• Immunohistochemistry used to exclude other diagnoses
• Molecular: Complex and nonspecific cytogenetic
abnormalities
TOP DIFFERENTIAL DIAGNOSES
• Dedifferentiated liposarcoma
• Other high-grade pleomorphic sarcomas
• Carcinoma, melanoma, lymphoma

Undifferentiated Pleomorphic Sarcoma Undifferentiated Pleomorphic Sarcoma

(Left) Gross photograph of
undifferentiated pleomorphic
sarcoma (UPS) shows a
lobulated, tan-white mass
within skeletal muscle and
focally abutting the subcutis
﬉. Necrosis is a prominent
feature ﬇. (Right) Most cases
of UPS show markedly atypical
cytologic features with
marked nuclear enlargement,
hyperchromasia, and
pleomorphism. Mitotic figures
are also easily identified, and
tumor necrosis is common.

Extreme Atypia Variable Growth Patterns

(Left) Extreme nuclear and
cytologic atypia are not
uncommon in UPS. The bizarre
cells are often significantly
enlarged and show anaplastic
nuclear configurations and
extremely deranged mitotic
figures. (Right) The patterns of
growth in UPS vary from case
to case, but most show a
mixture of storiform and short,
fascicular architectures. The
stroma is generally
collagenous but is often
difficult to appreciate due to
the high cellularity of the
tumor.

724
 Undifferentiated Pleomorphic Sarcoma

Undifferentiated/Unclassified Sarcomas
○ Marked nuclear pleomorphism in most cases
TERMINOLOGY
– Bizarre nuclei &/or multinucleation common
Abbreviations – Abundant mitoses, often with abnormal forms
• Undifferentiated pleomorphic sarcoma (UPS) • Coagulative necrosis is common and may be abundant
• Collagenous stroma that may be focally myxoid or sclerotic
Synonyms
• Chronic inflammatory cells common, including lymphocytes
• Malignant fibrous histiocytoma and histiocytes
Definitions ○ May rarely show prominent neutrophilic infiltrate
• High-grade sarcoma composed of pleomorphic spindle and • May contain osteoclast-like giant cells 
polygonal cells and showing no other identifiable line of • No discernible microscopic evidence of any specific form of
differentiation differentiation (e.g., lipoblasts, bone formation, epithelial
○ Essentially diagnosis of exclusion structures)

CLINICAL ISSUES ANCILLARY TESTS

Epidemiology Immunohistochemistry
• Age • No diffuse expression of keratins, S100 protein, CD31,
○ Most occur in older and elderly adults (50-70 years) CD34, CD68, CD163, desmin, SMA, CD45, CD30
– Very rare in adolescents and young adults ○ Focal SMA, CD34, keratin, EMA (+) may occur and is likely
nonspecific
• Sex
– SMA expression is usually wispy (myofibroblastic
○ 2:1 male predominance
staining pattern)
Site ○ CD68, CD163, CD31, MiTF highlight intratumoral
• Most arise in deep soft tissues of extremities (subfascial) histiocytes
○ Lower limb (thigh) most common • Myogenin, MYOD1, p63, ERG (-)
○ Minority arise in subcutaneous tissue (superficially) • Main purpose of immunohistochemistry is to exclude other
• May also arise on trunk diagnoses

Presentation Molecular Genetics

• Enlarging, painless mass • Complex and nonspecific cytogenetic abnormalities
○ Patient may have history of radiation to area
DIFFERENTIAL DIAGNOSIS
Treatment
Dedifferentiated Liposarcoma
• Complete surgical resection with margins
• Relatively common in extremities and retroperitoneum
• Adjuvant radiation therapy
○ True UPS very rare in retroperitoneum
Prognosis • May have component of well-differentiated liposarcoma
• Fully malignant; usually high grade • MDM2 amplification by FISH
○ ~ 50% 5-year survival • MDM2(+), CDK4(+) by immunohistochemistry
• Local recurrence in up to 30% of cases
Other High-Grade Pleomorphic Sarcomas
• Distant metastasis in up to 50% of cases
• Often contain areas indistinguishable from UPS
○ Minority of patients have metastases at time of
presentation • Mainly myxofibrosarcoma, leiomyosarcoma,
rhabdomyosarcoma, pleomorphic liposarcoma,
• Superficial tumors have better prognosis than deep ones
extraskeletal osteosarcoma, angiosarcoma, malignant
peripheral nerve sheath tumor
MACROSCOPIC
○ Thorough sampling and careful scrutiny is necessary to
General Features identify characteristic histologic findings that support
• Generally circumscribed; multilobulated these other diagnoses
• Heterogeneous cut surface with gray-tan firm and fleshy • Immunohistochemistry often necessary in pleomorphic
areas leiomyosarcoma, rhabdomyosarcoma, and angiosarcoma
• Necrosis and hemorrhage are common and may be Carcinoma, Melanoma, Lymphoma
extensive
• Can be excluded through immunohistochemistry and often
Size clinical history
• Usually large (most 5-15 cm)
SELECTED REFERENCES
MICROSCOPIC 1. Le Guellec S et al: Are peripheral purely undifferentiated pleomorphic
sarcomas with MDM2 amplification dedifferentiated liposarcomas? Am J
Histologic Features Surg Pathol. 38(3):293-304, 2014
• Storiform, fascicular, or patternless arrangement of highly 2. Fletcher CD et al: Clinicopathologic re-evaluation of 100 malignant fibrous
histiocytomas: prognostic relevance of subclassification. J Clin Oncol.
atypical spindled &/or polygonal cells 19(12):3045-50, 2001
○ Eosinophilic or amphophilic cytoplasm

725
 Undifferentiated Pleomorphic Sarcoma
Undifferentiated/Unclassified Sarcomas

Storiform Growth Fascicular Growth

(Left) A loose or vague
storiform growth pattern is
common in UPS and is seen in
the majority of cases, at least
focally. (Right) Formation of
short, irregular fascicles by
tumor cells is common in UPS;
however, long fascicles are
less frequent and should at
least raise the possibility of
other entities, such as
malignant peripheral nerve
sheath tumor, synovial
sarcoma, or adult-type
fibrosarcoma.

Stromal Sclerosis Coagulative Necrosis

(Left) Some cases of UPS may
show focal or extensive
stromal collagen and sclerosis.
This finding is more common
following neoadjuvant
therapy but may be seen in
untreated tumors as well.
(Right) Coagulative tumor
necrosis is very common in
UPS and ranges from multiple
small pockets to large zones.
In some cases, nearly the
entire tumor may be necrotic.

Chronic Inflammation Neutrophils and Foamy Histiocytes

(Left) A chronic inflammatory
infiltrate is not uncommon in
UPS and often consists of
lymphocytes. This infiltrate is
usually mild or inconspicuous,
but in occasional cases, it can
be marked (shown). (Right) A
prominent neutrophilic
infiltrate associated with
foamy histiocytes ﬈ is a
feature of rare cases of UPS,
particularly of the
retroperitoneum. However, in
this location, a
dedifferentiated liposarcoma
is far more likely and should
always be thoroughly
excluded first.

726
 Undifferentiated Pleomorphic Sarcoma
Osteoclast-Like Giant Cells
Skeletal Muscle Infiltration
CD31 Expression in Histiocytes
Undifferentiated/Unclassified Sarcomas
Focal Myxoid Stroma
(Left) Osteoclast-like
multinucleated giant cells ﬉
may be seen in UPS and are
occasionally numerous. These
cells are often also a feature
of extraskeletal
osteosarcoma, which should
always be excluded. (Right)
Focal myxoid stromal change
may be seen in UPS and is not
immediately diagnostic of
myxofibrosarcoma. However,
if the myxoid change is diffuse
or shows more typical features
of myxofibrosarcoma, the
latter diagnosis is more
appropriate.
Epithelioid Cells
(Left) Given that UPS shows a
predilection for subfascial
sites, it is not uncommon to
see infiltrated skeletal
myocytes ﬈ at or near the
periphery of the tumor. These
otherwise mature-appearing
cells should not be used as
evidence for diagnosing
pleomorphic
rhabdomyosarcoma. (Right)
An epithelioid cytomorphology
may be seen in UPS; however,
it is often focal. Rare cases
may show prominent
epithelioid change and
warrant consideration of
carcinoma and melanoma.
Postradiation Sarcoma
(Left) CD31 often shows a
faint, granular expression
pattern in histiocytes ﬊ and is
not indicative of endothelial
differentiation in a
pleomorphic sarcoma
(angiosarcoma). In contrast,
note the strong, sharp CD31
expression by endothelial cells
﬈ of intratumoral vessels.
(Right) Bizarre atypia is not a
specific feature of UPS and
may be seen in just about any
high-grade sarcoma treated
with neoadjuvant therapy.
Note the hypocellular,
microcystic, and sclerotic
stroma, further evidence of
treatment effect.
727
 Undifferentiated Round Cell Sarcoma With CIC-DUX4 Translocation

KEY FACTS
Undifferentiated/Unclassified Sarcomas

TERMINOLOGY • Geographic necrosis

• Highly aggressive translocation-associated round cell ○ Perivascular preservation in necrotic areas
sarcoma • Focal myxoid matrix
• Oncogenic fusion of CIC and DUX4 • Focal cord-like arrangement of cells

CLINICAL ISSUES ANCILLARY TESTS

• Age: children and young adults; range: 6-62 years • Cytogenetics/molecular
• Rapidly enlarging, deep or superficial soft tissue mass ○ t(4;19)(q35;q13.1) or t(10;19)(q26.3;q13) translocation
• High metastatic rate ○ CIC rearrangement (FISH)
• Most patients die of disease within 2 years ○ CIC-DUX4 fusion (FISH or RT-PCR)

MACROSCOPIC TOP DIFFERENTIAL DIAGNOSES

• Large, bulky, necrotizing mass • Extraskeletal Ewing sarcoma
• Malignant peripheral nerve sheath tumor
MICROSCOPIC • Synovial sarcoma (poorly differentiated)
• Sheets of closely spaced small round cells • Alveolar rhabdomyosarcoma
○ Coarse chromatin with prominent nucleoli • Other undifferentiated round cell sarcomas
○ Brisk mitotic activity
○ Focal cytoplasmic clearing

CIC-DUX4 Sarcoma Cytologic Features

(Left) CIC-DUX4 sarcoma is a
necrotizing round cell tumor
with distinctive histological
features. Most tumors have
extensive areas of geographic
necrosis ﬈ and sheets of
closely spaced small round
cells ﬉, as depicted in this
low-power micrograph. (Right)
Although often referred to as
Ewing-like, the cells of CIC-
DUX4 sarcoma are more
pleomorphic and
hyperchromatic than those of
Ewing sarcoma, containing
coarse chromatin, prominent
nucleoli, and ill-defined,
eosinophilic, or clear
cytoplasm.

Myxoid Matrix Simple Karyotype: t(4;19) and Trisomy 8

(Left) Although often sparse,
extracellular myxoid matrix is
present in most tumors. It
usually presents as a small
area of pale blue, hyalinized or
fine fibrillary material ﬈.
(Right) CIC-DUX4 sarcoma is a
translocation-associated
sarcoma that often has a
simple karyotype. The only
cytogenetic aberrations in this
tumor are its pathognomonic
t(4;19) ﬈ and trisomy 8 ﬊,
which is frequently present, as
depicted.

728
 Undifferentiated Round Cell Sarcoma With CIC-DUX4 Translocation

Undifferentiated/Unclassified Sarcomas
TERMINOLOGY MACROSCOPIC
Synonyms General Features
• CIC-rearranged sarcoma, Ewing-like sarcoma • Large, bulky mass
• Fleshy cut surface
Definitions
• Geographic necrosis and hemorrhage
• Highly aggressive, translocation-associated round cell
sarcoma MICROSCOPIC
• No specific line of differentiation
• Oncogenic fusion of CIC and DUX4 Histologic Features
• Sheets of closely spaced small round cells
ETIOLOGY/PATHOGENESIS ○ Moderate nuclear pleomorphism
CIC-DUX4 Functions as Transcription Factor ○ Coarse chromatin with prominent nucleoli
○ Indistinct cytoplasm
• Upregulates expression of ETV1, ETV4, and ETV5
– Focal cytoplasmic clearing
MYC Amplification □ With sharp cell borders
• Majority of cases ○ High mitotic rate
○ Spindle-shaped, epithelioid &/or rhabdoid cells in some
CLINICAL ISSUES • Geographic necrosis common
Epidemiology ○ Perivascular preservation in necrotic areas
• Myxoid matrix in most
• Incidence
○ Variable amount, usually focal
○ Rare; < 150 reported cases
• Focal cord-like arrangement of cells
– ~ 2/3 of EWSR1-negative small blue round cell
sarcomas
ANCILLARY TESTS
• Age
○ Children and young adults mostly Immunohistochemistry
– Range: 6-62 years • Mostly useful for ruling out other neoplasms
• WT1(+) and ETV4(+)
Site
○ Useful for distinguishing CIC-rearranged from Ewing
• Extremities and trunk most common sarcoma
• Other sites: Pelvis, retroperitoneum, head and neck, pleura,
bone, brain, visceral organs Cytogenetics
• t(4;19)(q35;q13.1)
Presentation
○ t(10;19)(q26.3;q13) variant translocation
• Rapidly enlarging mass • Simple karyotype in most tumors
• Deep or superficial soft tissue ○ Complex karyotype post treatment
• Metastatic disease often present at presentation • Trisomy 8 frequent
Treatment Molecular Genetics
• Wide surgical excision or amputation • CIC rearrangement by FISH
• May show initial response to chemotherapy • CIC-DUX4 fusion by RT-PCR or FISH
○ Often acquires chemoresistance • Array-based DNA-methylation analysis
• Radiation for local control and palliation
• Best therapeutic strategy poorly defined DIFFERENTIAL DIAGNOSIS
Prognosis Extraskeletal Ewing Sarcoma
• Very poor • More uniform nuclear size
○ 43% 5-year overall survival • Softer chromatin
– Most die of disease within 2 years • Smaller nucleoli
• High metastatic rate • Cytoplasmic clearing common
○ Lungs most common • CD99 diffuse membrane positivity
– Other sites: Brain, soft tissue, bone • EWSR1 translocation

IMAGING Malignant Peripheral Nerve Sheath Tumor

• Can mimic round cell sarcoma
General Features
• Geographic necrosis common
• Large, lobulated, heterogeneous soft tissue mass • Spindle cells common
○ Usually deep seated • Often associated with nerve or neurofibromatosis type 1
○ Secondary bone invasion in some cases (NF1) syndrome
• S100(+) in 60% but often focal

729
 Undifferentiated Round Cell Sarcoma With CIC-DUX4 Translocation
Undifferentiated/Unclassified Sarcomas

Immunohistochemistry Table
Antibody Reactivity Staining Pattern Comment
CD99 Positive Cell membrane & Focal in most, sometimes diffuse
cytoplasm
WT1 Positive Nuclear > 90%
ETV4 Positive Nuclear > 90%
FLI-1 Positive Nuclear Usually strong, diffuse
ERG Positive Nuclear Variable expression
CK-PAN Equivocal Cytoplasmic Rarely focally positive
S100 Equivocal Nuclear & cytoplasmic Rarely focally positive
Desmin Equivocal Cytoplasmic Rarely focally positive
Myogenin Negative Nuclear
TLE1 Negative Nuclear
INI1 Positive Nuclear Retained expression

Synovial Sarcoma (Poorly Differentiated) SELECTED REFERENCES

• Can mimic round cell sarcoma
1. Koelsche C et al: Array-based DNA-methylation profiling in sarcomas with
• Softer ("blastoid") chromatin small blue round cell histology provides valuable diagnostic information.
• Strong, diffuse nuclear TLE1(+) Mod Pathol. 31(8):1246-56, 2018
2. Renzi S et al: Ewing-like sarcoma: an emerging family of round cell sarcomas.
• Usually cytokeratin (+), EMA(+), CD99(+) J Cell Physiol. ePub, 2018
• SS18-SSX1, SS18-SSX2, or SS18-SSX4 fusion 3. Antonescu CR et al: Sarcomas With CIC-rearrangements are a distinct
pathologic entity with aggressive outcome: a clinicopathologic and
Alveolar Rhabdomyosarcoma molecular study of 115 cases. Am J Surg Pathol. 41(7):941-9, 2017
• Small round cell sarcoma 4. Maghrebi H et al: Round cell sarcoma of the colon with CIC rearrangement.
BMC Res Notes. 10(1):582, 2017
• Alveolar growth pattern in most cases 5. Hung YP et al: Evaluation of ETV4 and WT1 expression in CIC-rearranged
• Rhabdomyoblasts can be scarce sarcomas and histologic mimics. Mod Pathol. 29(11):1324-34, 2016
• Multinucleated cells often present 6. Le Guellec S et al: ETV4 is a useful marker for the diagnosis of CIC-rearranged
undifferentiated round-cell sarcomas: a study of 127 cases including
• Diffuse desmin (+) and nuclear myogenin (+) mimicking lesions. Mod Pathol. 29(12):1523-31, 2016
• PAX3-FOXO1 or PAX7-FOXO1 fusion 7. Bielle F et al: Unusual primary cerebral localization of a CIC-DUX4
translocation tumor of the Ewing sarcoma family. Acta Neuropathol.
Other Undifferentiated Round Cell Sarcomas 128(2):309-11, 2014
8. Puls F et al: BCOR-CCNB3 (Ewing-like) sarcoma: a clinicopathologic analysis
• BCOR-CCNB3 sarcoma of 10 cases, in comparison with conventional Ewing sarcoma. Am J Surg
○ Involves bone > soft tissue Pathol. 38(10):1307-18, 2014
○ Either round cell or spindle cell morphology 9. Smith SC et al: CIC-DUX sarcomas demonstrate frequent MYC amplification
and ETS-family transcription factor expression. Mod Pathol. 28(1):57-68,
○ BCOR-CCNB3 fusion transcript 2014
• CIC-FOXO4 sarcoma 10. Solomon DA et al: Clinicopathologic features of a second patient with Ewing-
○ Very rare round cell soft tissue sarcoma like sarcoma harboring CIC-FOXO4 gene fusion. Am J Surg Pathol.
38(12):1724-5, 2014
○ Abundant desmoplastic stroma 11. Specht K et al: Distinct transcriptional signature and immunoprofile of CIC-
○ CD99(+) DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged
Ewing sarcomas: further evidence toward distinct pathologic entities. Genes
Chromosomes Cancer. 53(7):622-33, 2014
DIAGNOSTIC CHECKLIST 12. Sugita S et al: A novel CIC-FOXO4 gene fusion in undifferentiated small
round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma. Am J
Clinically Relevant Pathologic Features Surg Pathol. 38(11):1571-6, 2014
• Rapidly enlarging soft tissue mass 13. Choi EY et al: Undifferentiated small round cell sarcoma with
t(4;19)(q35;q13.1) CIC-DUX4 fusion: a novel highly aggressive soft tissue
• Affects both children and adults tumor with distinctive histopathology. Am J Surg Pathol. 37(9):1379-86,
• High metastatic potential 2013
○ Often present at time of diagnosis 14. Graham C et al: The CIC-DUX4 fusion transcript is present in a subgroup of
pediatric primitive round cell sarcomas. Hum Pathol. 43(2):180-9, 2012
• Poor or unsustained response to chemotherapy 15. Italiano A et al: High prevalence of CIC fusion with double-homeobox (DUX4)
transcription factors in EWSR1-negative undifferentiated small blue round
Pathologic Interpretation Pearls cell sarcomas. Genes Chromosomes Cancer. 51(3):207-18, 2012
• Closely spaced small round cells 16. Kawamura-Saito M et al: Fusion between CIC and DUX4 up-regulates PEA3
family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation.
• Geographic zones of necrosis Hum Mol Genet. 15(13):2125-37, 2006
• Coarse chromatin, prominent nucleoli, moderate 17. Richkind KE et al: t(4;19)(q35;q13.1): a recurrent change in primitive
pleomorphism mesenchymal tumors? Cancer Genet Cytogenet. 87(1):71-4, 1996
• Clear cell areas; focal myxoid matrix
• WT1(+) and ETV4(+) by IHC
• Molecular confirmation required for diagnosis

730
Undifferentiated Round Cell Sarcoma With CIC-DUX4 Translocation

Undifferentiated/Unclassified Sarcomas
MR Calf Mass
(Left) On MR, CIC-DUX4
sarcoma usually presents as a
large, heterogeneous,
lobulated, deep-seated soft
tissue mass, as depicted by this
11-cm calf mass ﬈ in a 29-
year-old woman. (Right) In the
amputation specimen, the
tumor has been bivalved to
display the cut surface, which
shows a multinodular mass
containing fleshy ſt, necrotic
st, and hemorrhagic ﬇ areas.
Note the entrapped sciatic
nerve ﬈.

Gross Appearance Gross Appearance

(Left) This gross specimen is
from an inguinal soft tissue
metastasis from a primary
popliteal CIC-DUX4 sarcoma in
a 40-year-old man. The cut
surface depicts a bulky, white,
fleshy soft tissue tumor with
geographic areas of
hemorrhagic necrosis ﬈.
(Right) This gross photograph
shows an irregular zone of
hemorrhagic necrosis ﬈. Note
the tan, gelatinous area ﬉
that corresponds to
extracellular myxoid matrix of
the tumor.

Amputation Specimen Shoulder Mass

(Left) This patient had an
above-elbow amputation for a
painful, locally aggressive CIC-
DUX4 sarcoma ſt of the wrist.
The tumor ulcerated the skin,
invaded and destroyed the
underling bones, and spread
proximally throughout the
forearm (not shown). (Right)
This bulky shoulder mass,
initially misdiagnosed as a
poorly differentiated synovial
sarcoma, was treated with
neoadjuvant chemotherapy. It
showed no histologic response
to therapy, which is noted
grossly by an extensive white,
fleshy viable tumor ﬈.

731
 Undifferentiated Round Cell Sarcoma With CIC-DUX4 Translocation
Undifferentiated/Unclassified Sarcomas

Cytologic Features Clear Cells

(Left) The cells in CIC-DUX4
sarcoma are uniform in size
and shape with coarse
chromatin, irregular nuclear
membranes, prominent
nucleoli, and pale, eosinophilic
to clear cytoplasm. The mitotic
rate is high ﬈. (Right) Areas
containing cells with clear
cytoplasm and sharply defined
cell membranes are found in
most tumors. The clearing is
due to glycogen accumulation.
Such areas mimic Ewing
sarcoma. However, the
nuclear chromatin in CIC-
DUX4 sarcoma is coarser than
in Ewing sarcoma.

CIC-DUX4 Sarcoma Geographic Necrosis

(Left) Scanning-power view
shows large geographic zones
of necrosis ﬈ in between
nodules ﬉ and garlands ﬇ of
viable tumor, a typical pattern
in CIC-DUX4 sarcoma. (Right)
Large geographic areas of
necrosis ſt and hemorrhagic
necrosis st alternating with
viable neoplasm ﬇ is a typical
low-power pattern in CIC-
DUX4 sarcoma, as depicted.
Note the areas of perivascular
preservation ﬈.

Necrosis Perivascular Preservation

(Left) This medium-power
micrograph illustrates the
interface between viable
neoplasm ſt and coagulation
tumor necrosis ﬉. In the
necrotic area, one can still
make out individual necrotic
cells. (Right) Although
nonspecific, perivascular
preservation of viable
neoplastic cells is a common
finding in CIC-DUX4 sarcoma.
This H&E depicts a medium-
sized blood vessel ſt
surrounded by a cuff of viable
round cells ﬉ within an area
of necrosis ﬊.

732
 Undifferentiated Round Cell Sarcoma With CIC-DUX4 Translocation

Myxoid Matrix and Nuclear Pleomorphism
Undifferentiated/Unclassified Sarcomas
Multinodular Architecture
(Left) This high-power H&E
illustrates malignant round
cells with moderate nuclear
pleomorphism admixed with
pale blue myxoid matrix ﬉ in
a CIC-DUX4 sarcoma. The
nuclei are generally more
pleomorphic than those of
Ewing sarcoma. (Right) This
low-power H&E highlights the
nodular architecture of a CIC-
DUX4 sarcoma consisting of
sheets of closely spaced round
cells ſt divided by fibrous
septa st.

Cell Cords CD99 Expression

(Left) Cords of round cells
arranged in parallel, single-file
rows are present focally in
many CIC-DUX4 sarcomas, as
illustrated. (Right) CIC-DUX4
sarcoma is undifferentiated
and has no specific
immunohistochemical marker.
CD99 is frequently positive
and usually shows only focal
staining, as illustrated.
However, it can sometimes be
diffuse. Note the cytoplasmic
membrane pattern ﬈.

WT1 Expression CIC Rearrangement

(Left) CIC-DUX4 sarcoma
shows diffuse nuclear staining
for WT1 in most tumors (95%),
which is useful for
distinguishing it from Ewing
sarcoma (0%). Similar results
for ETV4 staining have also
been reported. (Right) CIC
gene rearrangement can be
detected by FISH. The green
probe, which marks the
centromere of chromosome
19, shows the normal 2
homologs. The red probe that
spans the CIC gene indicates
an extra (3rd) signal,
indicating gene
rearrangement.

733
 BCOR-CCNB3 Fusion-Positive Sarcoma

KEY FACTS
Undifferentiated/Unclassified Sarcomas

TERMINOLOGY • Uniform, monomorphic small round cells

• Translocation-associated, undifferentiated round to spindle • Hyperchromatic or finely dispersed chromatin
cell sarcoma arising in bone or soft tissue with BCOR-CCNB3 • Mitotic activity highly variable
gene fusion ANCILLARY TESTS
CLINICAL ISSUES • CCNB3(+) in almost all tumors
• Median age in 2nd decade (range: 0-44 years) • BCOR(+) in almost all tumors (less specific than CCNB3)
• Male predominance (75%) • CD99(+) in 60-90%
• Various bone and soft tissue locations • SATB2(+) in 80%
• Favorable clinical response to chemotherapy • TLE1(+) in 75%
• 77% 5-year survival rate • BCOR-CCNB3 fusion created by X-chromosomal paracentric
inversion
MICROSCOPIC • Dual-fusion FISH required due to X-chromosomal inversion
• Solid sheets of closely spaced, small, round to plump
spindle cells TOP DIFFERENTIAL DIAGNOSES
• Fascicles of elongated spindle cells in some tumors • Ewing sarcoma
• Variable amounts of myxoid matrix (50% of tumors) • CIC-DUX4 sarcoma
• Dense collagenous matrix in some • Poorly differentiated synovial sarcoma
• Small concentric whorls in some • Small cell osteosarcoma

BCOR-CCNB3 Sarcoma CT Scan

(Left) Scanning-power view of
BCOR-CCNB3 sarcoma depicts
sheets of closely spaced small
round cells and an area of
geographic necrosis ﬈.
(Right) CT scan taken from a 5-
year-old boy shows a large
(9.8-cm) soft tissue tumor ﬈
involving the left chest with
heterogeneous signal due to
tumor necrosis. BCOR-CCNB3
more often presents as a
primary bone tumor than a
soft tissue tumor.

Soft Chromatin Mimicking Synovial

Small Round Cells Sarcoma
(Left) High-power H&E
highlights the cytologic
features of BCOR-CCNB3
sarcoma, consisting of sheets
of closely spaced small cells
with round to oval nuclei with
dispersed nuclear chromatin,
smooth nuclear membranes,
and pinpoint nucleoli and
scant, ill-defined cytoplasm.
(Right) In some BCOR-CCNB3
sarcomas, the nuclei have fine
"powdery" nuclear chromatin
and well-defined nuclear
membranes mimicking poorly
differentiated synovial
sarcoma. (Courtesy W.-S. Li,
MD.)

734
 BCOR-CCNB3 Fusion-Positive Sarcoma

Undifferentiated/Unclassified Sarcomas
• Fascicles of elongated spindle cells (20% of tumors)
TERMINOLOGY
○ Long fascicles with slit-like spaces and hemorrhage in
Abbreviations some
• BCOR-CCNB3 sarcoma • Variable amounts of myxoid matrix (50% of tumors)
• Rich capillary vascular stroma
Synonyms
○ May have gaping or thin-walled, branching
• BCOR-rearranged sarcoma, undifferentiated round/spindle (pericytomatous) vessels
cell sarcoma, Ewing-like sarcoma • Necrosis present to varying degrees in ~ 1/2 of tumors
Definitions • Dense collagenous matrix in some
• Translocation-associated, undifferentiated round to spindle ○ Hypocellular fibrotic areas some tumors
cell sarcoma arising in bone or soft tissue with BCOR-CCNB3 • Small concentric whorls in some tumors
gene fusion • Focal osteoid in rare tumors
○ Alternate BCOR-rearrangements: BCOR-MAML3 and Cytologic Features
ZC3H7B-BCOR
• Uniform, monomorphic small round cells
CLINICAL ISSUES ○ Scant, ill-defined eosinophilic cytoplasm
○ Round, oval or angulated nuclei
Epidemiology ○ Hyperchromatic or finely dispersed chromatin
• Incidence ○ Inconspicuous nucleoli
○ Rare ○ Smooth nuclear contours
– ~ 120 reported cases ○ Round cells may be admixed with minor population of
– Represents ~ 15% of undifferentiated unclassified spindle cells
sarcomas • Spindle cells
• Age ○ Plump spindle cells in short fascicles
○ Adolescents and young adults ○ Elongated spindle cells in some tumors
– Median age in 2nd decade (range: 0-44 years) ○ Most often mixed with round cells
– Rare congenital tumors – Pure spindle cell population in some tumors
• Sex • Mitotic activity highly variable
○ Male predominance (75%) ○ Average number: 6-8 mitotic figures per 10 HPF (range:
1-25)
Site
• Various bone and soft tissue locations ANCILLARY TESTS
○ 60% are primary bone tumors
Immunohistochemistry
Presentation
• CCNB3(+) in almost all tumors
• Pain and swelling • BCOR(+) in almost all tumors
Treatment ○ Less specific than CCNB3
• Wide local excision • CD99(+) in 60-90%
• Chemotherapy ○ More heterogeneous staining distribution compared to
Ewing sarcoma
○ Favorable clinical response
○ Can stain with membranous; cytoplasmic; or perinuclear,
• Radiotherapy
dot-like patterns
Prognosis • SATB2(+) in 80%
• Most tumors are localized at time of diagnosis • TLE1(+) in 75%
• 77% 5-year survival; 68% disease-free survival • pax-8(+) 50%
• NKX2.2(+) in 25%
MACROSCOPIC • EMA rarely (+)
General Features • Negative markers include: ETV4, WT1, SMA, desmin,
cytokeratin, S100 protein, and BCL-2
• Destructive osteolytic bone tumors
• Circumscribed or ill-defined soft tissue tumors Cytogenetics
○ Multinodular architecture • BCOR-CCNB3 fusion created by X-chromosomal paracentric
○ Necrosis and hemorrhage in 1/2 of tumors inversion
Size In Situ Hybridization
• Average size: 10 cm (range: 2-25 cm) • Dual-fusion FISH required due to X-chromosomal inversion
PCR
MICROSCOPIC
• Useful when fusion transcript is known
Histologic Features
• Solid sheets of closely spaced, small, round to plump
spindle cells (80% of tumors)

735
 BCOR-CCNB3 Fusion-Positive Sarcoma
Undifferentiated/Unclassified Sarcomas

• Relatively favorable prognosis (77% 5-year survival rate)

DIFFERENTIAL DIAGNOSIS
Ewing Sarcoma Pathologic Interpretation Pearls
• Heterogeneous morphology with round &/or spindle cells
• Spindle cells very uncommon
and variable myxoid stroma
• Myxoid matrix not present
• CCNB3(+) by immunohistochemistry
• More often CD99(+) and NKX2.2(+)
• Molecular confirmation for definitive diagnosis
• EWSR1 rearrangement by FISH
• EWSR1-FLI1, EWSR1-ERG, EWSR1-FEV, EWSR1-ETV1, EWSR1-
SELECTED REFERENCES
ETV4, and rare fusions involving FUS
1. Miettinen M et al: New fusion sarcomas histopathology and clinical
Undifferentiated Sarcoma With CIC-DUX4 significance of selected entities. Hum Pathol. ePub, 2019
Translocation 2. Anderson WJ et al: Immunohistochemical correlates of recurrent genetic
alterations in sarcomas. Genes Chromosomes Cancer. 58(2):111-23, 2018
• Overlapping morphologic features with BCOR-CCNB3 3. Machado I et al: Review with novel markers facilitates precise categorization
sarcoma of 41 cases of diagnostically challenging, "undifferentiated small round cell
tumors". A clinicopathologic, immunophenotypic and molecular analysis.
• ETV4(+), WT1(+), BCOR(-), and CCNB3(-) by Ann Diagn Pathol. 34:1-12, 2018
immunohistochemistry 4. Alfaro-Cervello C et al: Congenital undifferentiated sarcoma associated to
• CIC rearrangement by FISH BCOR-CCNB3 gene fusion. Pathol Res Pract. 213(11):1435-9, 2017
• CIC-DUX4 or CIC-DUX4L1 fusions 5. Argani P 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
Undifferentiated Round or Spindle Cell Sarcomas kidney and soft tissues. Am J Surg Pathol. 41(12):1702-12, 2017
• All diagnoses of exclusion 6. Creytens D: SATB2 and TLE1 expression in BCOR-CCNB3 (Ewing-like)
sarcoma, mimicking small cell osteosarcoma and poorly differentiated
• No specific immunohistochemical or molecular signature synovial sarcoma. Appl Immunohistochem Mol Morphol. ePub, 2017
Poorly Differentiated Synovial Sarcoma 7. Le Loarer F et al: Update on families of round cell sarcomas other than
classical Ewing sarcomas. Surg Pathol Clin. 10(3):587-620, 2017
• Soft or "powdery" chromatin mimics BCOR-CCNB3 sarcoma 8. Ludwig K et al: BCOR-CCNB3 undifferentiated sarcoma-does
• Immunohistochemical overlap with BCOR-CCNB3 sarcoma immunohistochemistry help in the identification? Pediatr Dev Pathol.
20(4):321-9, 2017
○ BCOR(+), TLE1(+), EMA(+), CD99(+), SATB2(+) 9. Ludwig K et al: BCOR-CCNB3 undifferentiated sarcoma-does
• SS18 (SYT) rearrangement by FISH immunohistochemistry help in the identification? Pediatr Dev Pathol.
• SS18-SSX fusions 20(4):321-9, 2017
10. Matsuyama A et al: Clinicopathologic diversity of undifferentiated sarcoma
Malignant Peripheral Nerve Sheath Tumor with BCOR-CCNB3 fusion: analysis of 11 cases with a reappraisal of the utility
of immunohistochemistry for BCOR and CCNB3. Am J Surg Pathol.
• Alternating hyper-/hypocellular marbled architecture 41(12):1713-21, 2017
sometimes seen in BCOR-CCNB3 sarcoma 11. Yamada Y et al: Histological and immunohistochemical characteristics of
undifferentiated small round cell sarcomas associated with CIC-DUX4 and
• S100 protein (+) &/or SOX10(+) in most, though often BCOR-CCNB3 fusion genes. Virchows Arch. 470(4):373-80, 2017
patchy/focal 12. Hung YP et al: Evaluation of ETV4 and WT1 expression in CIC-rearranged
• Diffuse loss of nuclear H3K27me3 by sarcomas and histologic mimics. Mod Pathol. 29(11):1324-34, 2016
immunohistochemistry 13. Kao YC et al: BCOR overexpression is a highly sensitive marker in round cell
sarcomas with BCOR genetic abnormalities. Am J Surg Pathol. 40(12):1670-
Solitary Fibrous Tumor 8, 2016
14. Li WS et al: BCOR-CCNB3-positive soft tissue sarcoma with round-cell and
• Can show morphologic overlap with BCOR-CCNB3 sarcoma spindle-cell histology: a series of four cases highlighting the pitfall of
○ Areas of stromal fibrosis mimicking poorly differentiated synovial sarcoma. Histopathology.
69(5):792-801, 2016
○ Pericytomatous vascular pattern 15. Machado I et al: Defining Ewing and Ewing-like small round cell tumors
• STAT6(+) (SRCT): the need for molecular techniques in their categorization and
differential diagnosis. A study of 200 cases. Ann Diagn Pathol. 22:25-32,
Vascular Neoplasms 2016
16. Specht K et al: Novel BCOR-MAML3 and ZC3H7B-BCOR gene fusions in
• Spindle cell-rich morphology with blood-filled, slit-like undifferentiated small blue round cell sarcomas. Am J Surg Pathol.
spaces can mimic BCOR-CCNB3 40(4):433-42, 2016
• CD31(+), CD34(+), ERG(+) 17. Peters TL et al: BCOR-CCNB3 fusions are frequent in undifferentiated
sarcomas of male children. Mod Pathol. 28(4):575-86, 2015
• HHV-8(+) in Kaposi sarcoma
18. Cohen-Gogo S et al: Ewing-like sarcomas with BCOR-CCNB3 fusion
transcript: a clinical, radiological and pathological retrospective study from
Small Cell Osteosarcoma the Société Française des Cancers de L'Enfant. Pediatr Blood Cancer.
• BCOR-CCNB3 sarcoma can rarely produce osteoid and is 61(12):2191-8, 2014
often SATB2(+) 19. Puls F et al: BCOR-CCNB3 (Ewing-like) sarcoma: a clinicopathologic analysis
of 10 cases, in comparison with conventional Ewing sarcoma. Am J Surg
• Lacks BCOR-CCNB3 fusion Pathol. 38(10):1307-18, 2014

DIAGNOSTIC CHECKLIST
Clinically Relevant Pathologic Features
• Primary bone or soft tissue round or spindle cell sarcoma in
adolescent or young adult patient
• Usually localized at time of diagnosis
• Responsive to chemotherapy

736
 BCOR-CCNB3 Fusion-Positive Sarcoma

Undifferentiated/Unclassified Sarcomas
Spindle Cells Pericytomatous Vessels and Myxoid Matrix
(Left) The microscopic features
of BCOR-CCNB3 sarcoma are
heterogeneous. In some
tumors, prominent areas
composed of spindle cells
arranged in fascicles are
present, as depicted in this
medium-power micrograph.
(Courtesy A. Matsuyama, MD.)
(Right) Some BCOR-CCNB3
sarcomas display a prominent
pericytomatous vascular
pattern consisting of thin-
walled, branching vessels ﬈.
This micrograph also depicts
cellular dyscohesion and pale
blue myxoid matrix in an area
of necrosis st.

Spindle Cells and Myxoid Stroma Whorling Pattern

(Left) The heterogeneous
morphologic spectrum of
BCOR-CCNB3 sarcomas
includes tumors with
prominent pale blue myxoid
stroma and spindle cells with
eosinophilic cytoplasm
arranged in a reticulated
fascicular pattern, as depicted.
(Courtesy W.-S. Li, MD.) (Right)
Small foci of cellular whorling
can be found in some tumors,
as highlighted in this high-
power micrograph that shows
spindle cells arranged in a
concentric spiral pattern ﬈.
(Courtesy A. Matsuyama, MD.)

Lobular Configuration CCNB3 Immunohistochemistry

(Left) BCOR-CCNB3 sarcomas
often have a lobular
architecture highlighted by
solid cellular areas surrounded
by fibrous septa ﬈. (Courtesy
A. Matsuyama, MD.) (Right)
Immunohistochemistry for
CCNB3 is highly sensitive and
specific for BCOR-CCNB3
sarcoma, as depicted by strong
nuclear staining in this case.

737
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 SECTION 18

Mesenchymal Tumors of
Gastrointestinal Tract
Benign Neural Gastrointestinal Polyps 740
Gastrointestinal Stromal Tumor 744
Gastrointestinal Schwannoma 760
Gastrointestinal Smooth Muscle Neoplasms 762
Inflammatory Fibroid Polyp 766
Gangliocytic Paraganglioma 770
Plexiform Fibromyxoma 772
Malignant Gastrointestinal Neuroectodermal Tumor 776
 Benign Neural Gastrointestinal Polyps

KEY FACTS
Mesenchymal Tumors of Gastrointestinal Tract

TERMINOLOGY MICROSCOPIC
• Benign neural proliferations that present as polypoid • Schwann cell hamartoma, ganglioneuroma, and
growths in GI tract perineurioma all show uniform, bland spindled cells
○ Schwann cell hamartoma, ganglioneuroma, proliferating between and around crypts of colonic lamina
perineurioma, granular cell tumor propria
○ Ganglioneuroma also has ganglion cells
CLINICAL ISSUES
• Granular cell tumor shows large, polygonal cells with
• Wide age range (most common in adults) abundant granular, eosinophilic cytoplasm and small nuclei
• Most arise in colon
○ Esophagus most common GI site for granular cell tumor ANCILLARY TESTS
• Small, asymptomatic polyps or nodules discovered • S100 protein (+) in Schwann cell hamartoma,
endoscopically ganglioneuroma, granular cell tumor
• Most are solitary and sporadic • EMA(+), claudin-1 (+), GLUT1(+) in perineurioma
○ Multiple ganglioneuromas often associated with various • All keratin (-), SMA(-), desmin (-), CD117(-), CD34(-)
syndromes TOP DIFFERENTIAL DIAGNOSES
• Treatment: Polypectomy
• Submucosal leiomyoma
• Benign
• Inflammatory fibroid polyp
• Neurofibroma

Schwann Cell Hamartoma Schwann Cells

(Left) Schwann cell
hamartoma is a benign neural
proliferation that usually
arises in the lamina propria of
the colon or rectum. It can be
nodular and well demarcated
or irregular and poorly
circumscribed. (Right)
Schwann cell hamartoma is
composed of a variably
cellular proliferation of
spindled Schwann cells. Nuclei
are usually small, elongated,
and bland, but occasionally
larger nuclei are evident.
Small areas lacking nuclei are
common, but true Verocay
body formation is not seen.

S100 Expression in Schwann Cell

Subtle Proliferation Hamartoma
(Left) Schwann cell
hamartoma may lack
nodularity and appear to
subtly infiltrate the lamina
propria as small, elongated
groups ﬈ of eosinophilic
spindle cells. This morphology
may be easily overlooked as
fibrosis. (Right) All Schwann
cell hamartomas strongly
express S100 protein,
consistent with their cellular
origin. This image highlights a
more irregular and subtly
infiltrative example.

740
 Benign Neural Gastrointestinal Polyps

Mesenchymal Tumors of Gastrointestinal Tract

– Some cases extend into superficial submucosa
TERMINOLOGY
○ Entrapped crypts often have serrated architecture
Definitions – May show features of hyperplastic polyp or sessile
• Benign neural proliferations that present as polypoid serrated polyp/adenoma
growths in GI tract • Granular cell tumor
○ Schwann cell hamartoma ○ Usually based in submucosa (colon) or lamina propria
○ Ganglioneuroma (esophagus)
○ Perineurioma ○ Large, polygonal cells with abundant granular,
○ Granular cell tumor eosinophilic cytoplasm and small, bland nuclei
○ Small nests and sheets separated by fibrous septa
CLINICAL ISSUES ○ May incite overlying reactive pseudoepitheliomatous
hyperplasia in esophagus
Epidemiology
• Incidence ANCILLARY TESTS
○ Uncommon
• Age
Immunohistochemistry
○ Wide range (most common in adults) • S100 protein (+) and SOX10(+) in Schwann cell hamartoma,
ganglioneuroma, granular cell tumor
Site • EMA(+), claudin-1 (+), GLUT1(+) in perineurioma
• Most arise in large bowel • All keratin (-), SMA(-), desmin (-), CD117(-), CD34(-)
• Esophagus most common GI site for granular cell tumor
Presentation DIFFERENTIAL DIAGNOSIS
• Small asymptomatic polyps or nodules discovered Submucosal Leiomyoma
endoscopically • Based in submucosa (arise from muscularis mucosa)
• Most are solitary and sporadic • Bundles and fascicles of plump, eosinophilic spindled cells
○ Multiple ganglioneuromas may indicate presence of with blunted nuclei
genetic syndrome, such as multiple endocrine neoplasia • SMA(+), desmin (+), S100 protein (-)
type 2B (MEN 2B), neurofibromatosis type 1, familial
adenomatous polyposis, or Cowden syndrome
Gastrointestinal Stromal Tumor
• Arises only in muscularis propria
Treatment • CD117(+), DOG1(+), S100 protein (-)
• Polypectomy
Inflammatory Fibroid Polyp
Prognosis • Often based in submucosa
• Benign • CD34(+), S100 protein (-)
• Solitary polyps do not recur if completely removed • Bland, hypocellular spindle cell proliferation with chronic
inflammatory infiltrate, particularly eosinophils
MICROSCOPIC
Neurofibroma
Histologic Features • Very rare in GI tract
• Schwann cell hamartoma • Not composed entirely of Schwann cells
○ Poorly delineated or nodular; most confined to mucosa • Usually plexiform and associated with neurofibromatosis
○ Cellular proliferation of relatively uniform spindle cells type 1
with bland nuclei
– Cells proliferate between and around crypts of colonic Mucosal Neuroma
lamina propria, pushing them apart • Most arise on tongue or lips (rare in GI tract)
– Generally no palisading or whorling architectures • Highly associated with MEN 2B
• Ganglioneuroma • Hyperplastic bundles of nerve fibers; axons common
○ Uniform, bland spindled cells proliferating between
crypts of lamina propria SELECTED REFERENCES
– Essentially indistinguishable from Schwann cell 1. van Wyk AC et al: Colonic perineurioma (benign fibroblastic polyp): case
hamartoma report and review of the literature. Diagn Pathol. 13(1):16, 2018
○ Presence of ganglion cells necessary for diagnosis 2. An S et al: Granular cell tumor of the gastrointestinal tract: histologic and
immunohistochemical analysis of 98 cases. Hum Pathol. 46(6):813-9, 2015
– May be sparse or numerous and clustered 3. Rittershaus AC et al: Benign gastrointestinal mesenchymal BUMPS: a brief
○ May rarely have diffuse growth pattern and arise deeper review of some spindle cell polyps with published names. Arch Pathol Lab
Med. 135(10):1311-9, 2011
than mucosa (associated with genetic syndromes)
4. Singhi AD et al: Colorectal granular cell tumor: a clinicopathologic study of 26
• Perineurioma cases. Am J Surg Pathol. 34(8):1186-92, 2010
○ Uniform, pale spindle cells with indistinct cell borders 5. Gibson JA et al: Mucosal Schwann cell "hamartoma": clinicopathologic study
and bland, often pale nuclei of 26 neural colorectal polyps distinct from neurofibromas and mucosal
neuromas. Am J Surg Pathol. 33(5):781-7, 2009
○ Cells proliferate between and around crypts of colonic 6. Hornick JL et al: Intestinal perineuriomas: clinicopathologic definition of a
lamina propria, splaying them apart new anatomic subset in a series of 10 cases. Am J Surg Pathol. 29(7):859-65,
– May show circumferential whorling around crypts 2005

741
 Benign Neural Gastrointestinal Polyps
Mesenchymal Tumors of Gastrointestinal Tract

Ganglioneuroma Schwann Cell Component

(Left) Polypoid
ganglioneuroma of the colon
may occur in both children and
adults and is histologically
similar to Schwann cell
hamartoma except for the
presence of admixed ganglion
cells ﬈, which vary in number.
(Right) Ganglion cells may be
difficult to find in some cases
of ganglioneuroma, and the
overall morphology of the
lesion may be
indistinguishable from
Schwann cell hamartoma.
Careful searching and cutting
of deeper levels often reveals
at least 1 ganglion cell in a
true ganglioneuroma.

Ganglion Cells Perineurioma

(Left) In some cases of
ganglioneuroma, the ganglion
cells are quite numerous and
form clusters and loose
aggregates. They are easily
identified by their large nuclei
with prominent nucleoli ﬈.
(Right) Intestinal perineurioma
﬈ is a small neural
proliferation that may bear
some resemblance to Schwann
cell hamartoma; however,
there are several key
histologic differences. For one,
they are commonly identified
along with serrated lesions,
particularly a hyperplastic
polyp ﬊ or sessile serrated
adenoma/polyp.

Perineurioma Perineurioma
(Left) Perineurioma often
proliferates between and
around the colonic crypts,
splaying them apart. Many
cases also characteristically
show a concentric "onion-skin"
pattern of growth around the
crypts. (Right) The cells of
perineurioma are palely
eosinophilic and have very
indistinct cell borders, often
leading to the appearance of
small pale nuclei "floating in a
sea" of pink stroma. Note the
compressed, but normal
overlying lamina propria ﬈.

742
 Benign Neural Gastrointestinal Polyps

Mesenchymal Tumors of Gastrointestinal Tract

Nuclear Vacuoles Perineurial Markers
(Left) The nuclei of
perineurioma are often small,
irregular, and pale and usually
show conspicuous nuclear
vacuoles ﬈ or
pseudoinclusions. Note the
absence of distinct
cytoplasmic borders. (Right)
Similar to their cutaneous and
soft tissue counterparts,
intestinal perineuriomas
express markers such as EMA,
claudin-1 (shown), and GLUT-
1. They are negative for S100
protein, helping to distinguish
them from Schwann cell
hamartoma and
ganglioneuroma.

Granular Cell Tumor Nests and Sheets

(Left) Granular cell tumor of
the GI tract is histologically
similar to its counterparts
found elsewhere. Although
many are small, some may be
> 1 cm in size. Peripheral
lymphoid aggregates ﬈ and
focal calcifications may also
be seen at low power. (Right)
Granular cell tumor is
composed of nests and sheets
of polygonal to spindled cells
with abundant granular,
eosinophilic cytoplasm. Nuclei
are often small and bland but
may be mildly enlarged.
Mitoses are absent.

Esophageal Granular Cell Tumor Smooth Muscle Resemblance

(Left) The esophagus is the
most common site for granular
cell tumor within the tubular
GI tract. It often presents as a
small nodule endoscopically
and may be easily overlooked
on a superficial biopsy. Note
the prominent eosinophilia ﬈
of the subepithelial region,
indicating the presence of a
granular cell tumor. (Right)
The cells ﬊ of an esophageal
granular cell tumor may
resemble small bundles of
smooth muscle fibers ﬉ from
the muscularis mucosa cut in
cross section; however, the
former are often larger and
granular.

743
 Gastrointestinal Stromal Tumor

KEY FACTS
Mesenchymal Tumors of Gastrointestinal Tract

TERMINOLOGY MICROSCOPIC
• Histologically versatile, spindled or epithelioid • Extremely broad and variable morphologic spectrum
mesenchymal neoplasm thought to arise from or • Tumors are spindled, epithelioid, or mixed type
differentiate toward interstitial cells of Cajal (ICC) • Succinate dehydrogenase (SDH)-deficient GIST is distinctive
ETIOLOGY/PATHOGENESIS subtype
• Most are sporadic ANCILLARY TESTS
• Some associated with clinical syndromes • Characteristic CD117 and DOG1 (+)
○ Carney triad, Carney-Stratakis, NF1, GIST • CD34(+) in majority (75%)
CLINICAL ISSUES • Loss of SDHB in SDH-deficient GIST
• Molecular: KIT or PDGFRA mutations in majority (85-90%)
• Most common primary mesenchymal neoplasm of GI tract
• Usually older adults (median age: 60 years) TOP DIFFERENTIAL DIAGNOSES
• Stomach and small bowel most common sites • GI smooth muscle neoplasms
• Treatment: Complete surgical resection, regardless of site • GI schwannoma
○ Chemotherapy (imatinib, others) for advanced GIST • Solitary fibrous tumor
• Risk of malignant behavior currently assessed by observing • Carcinoma or melanoma
anatomic site, size, and mitotic rate • Malignant GI neuroectodermal tumor
○ Also, molecular prognostication for GISTs

Gastrointestinal Stromal Tumor Spindle Cell Morphology

(Left) Gastrointestinal stromal
tumor (GIST) is the most
common primary
mesenchymal neoplasm of the
GI tract. As shown in this low-
power H&E, GIST ﬈ arises
from within the muscularis
propria. It can arise at any
location in the GI tract but is
most commonly seen in the
stomach (shown) or small
bowel. (Right) Most GISTs
contain spindled cells, which
are generally cytologically low
grade and uniform. Cellularity
varies.

Epithelioid Morphology Immunophenotype

(Left) A minority of GISTs
demonstrate an epithelioid,
rather than spindled,
morphology, as shown.
Nuclear pleomorphism is
uncommon in GIST, overall,
but is more frequent in tumors
with an epithelioid
morphology. Occasional
tumors feature a mixture of
spindled and epithelioid cells.
(Right) CD117 (C-kit) and
DOG1 are highly sensitive and
specific markers for GIST,
particularly when diffusely
expressed. CD34 (shown) is
also positive in up to 75% of
cases and is also diffusely
expressed.

744
 Gastrointestinal Stromal Tumor

Mesenchymal Tumors of Gastrointestinal Tract

○ Preferred site of origin for NF1-associated GIST
TERMINOLOGY
• Colorectum (< 5%)
Abbreviations • Esophagus and appendix (rare)
• Gastrointestinal stromal tumor (GIST) • Primary extraintestinal (mesentery, omentum) is rare
○ Possibility of metastases/direct spread from GI tract
Synonyms
must be excluded
• GI stromal sarcoma • Retroperitoneal tumors most commonly arise around or
• Leiomyoblastoma near pancreas
• GI autonomic nerve tumor ○ Vast majority arise from stomach or small bowel,
Definitions however
• Histologically versatile, spindled or epithelioid Presentation
mesenchymal neoplasm thought to arise from or • GI bleeding (most common)
differentiate toward interstitial cells of Cajal (ICC) • Abdominal pain, obstructive symptoms
• May be incidentally discovered
ETIOLOGY/PATHOGENESIS ○ During surgery, imaging studies, or endoscopy
Subset Associated With Various Clinical Syndromes • Can present with other signs/features of clinical syndrome
• Carney triad (e.g., NF1)
○ Gastric GIST, paraganglioma, and pulmonary chondroma Treatment
○ Noninherited • Complete surgical resection, regardless of site, if possible
○ Lacks mutations in KIT, PDGFRA, and succinate • Chemotherapy [tyrosine kinase inhibitors (TKIs)] for
dehydrogenase (SDH) complex advanced GIST (unresectable or metastatic)
• Carney-Stratakis syndrome ○ 1st-line therapy: Imatinib mesylate (Gleevec)
○ Familial paraganglioma and GIST ○ Additional approved therapies for use within setting of
○ Autosomal dominant with incomplete penetrance imatinib resistance (primary or secondary)
○ Germline inactivating mutations in SDH complex – Approved 2nd (sunitinib) and 3rd lines (regorafenib)
• Familial GIST syndrome ○ Additional drugs in development
○ Autosomal dominant ○ SDH-deficient GIST often resistant to imatinib
○ Multiple GISTs, often throughout GI tract (most – May show better response to 2nd- and 3rd-line drugs
commonly small bowel) – Reports of IGF1R overexpression suggest potential
○ Hyperpigmentation of skin; mast cell disorders role for IGF1R and VEGFR inhibitor therapy
○ Germline KIT or PDGFRA mutations • Genetic testing and long-term clinical follow-up for all
• Neurofibromatosis type 1 (NF1) patients with SDH-deficient GIST
○ Increased risk of GIST (particularly in small bowel)
○ May have multiple primary tumors; often associated with Prognosis
ICC hyperplasia • Risk of malignant behavior currently assessed by observing
○ Somatic inactivating NF1 mutations of wild-type allele anatomic site, size, and mitotic rate of tumor
○ Lacks KIT and PDGFRA mutations ○ Site is important factor
– Small intestinal, colorectal, and esophageal GIST more
CLINICAL ISSUES likely to be clinically aggressive than gastric GIST
○ Size < 2 cm always associated with very low risk
Epidemiology
– Micro-GISTs (< 1 cm) are essentially invariably benign
• Incidence ○ This system does not predict behavior of SDH-deficient
○ Most common primary mesenchymal neoplasm of GI GISTs
tract – Overall indolent clinical course despite metastatic
○ Minute (< 1 cm), clinically silent lesions ("micro-GIST") are potential and poor imatinib response
seemingly common • Molecular prognostication for GISTs
– Potentially present in up to 35% of general population ○ Can assist in predicting tumor response to TKI therapy
• Age ○ Molecular analysis not indicated in all cases
○ Usually older adults (median: 60 years); tumors rare in – Best reserved for patients with advanced
children and young adults (unresectable &/or metastatic) disease or disease
– Syndromic tumors often affect young age groups, refractory to treatment
including children • Metastases to liver (most common) or other
• Sex intraabdominal sites (e.g., ovary)
○ Female predominance in SDH-deficient GIST ○ Very rarely to extraabdominal sites (e.g., lung)
Site ○ Lymph node metastases characteristic of SDH-deficient
GIST
• Stomach most common site (60%)
• Dedifferentiated GIST follows highly aggressive clinical
○ Site of all SDH-deficient GIST
course
• Small bowel (30-35%)
• Up to 1/3 of patients with GIST may develop subsequent,
○ Particularly jejunum and ileum
non-GIST tumor
745
 Gastrointestinal Stromal Tumor
Mesenchymal Tumors of Gastrointestinal Tract
○ Includes carcinomas, hematologic malignancies
MACROSCOPIC
General Features
• Usually well-marginated lesions with their epicenter in
muscularis propria
○ May lead to overlying surface ulceration
• Often fleshy cut surface
• Variable cystic change, hemorrhage, necrosis
• Rarely multinodular peritoneal growth
Size
• Wide range (millimeters to > 30 cm)
○ Median: 5 cm
○ Subcentimeter tumors known as GIST tumorlets or
micro-GISTs
MICROSCOPIC
Histologic Features
• Extremely broad and variable morphologic spectrum
• Site, size, and mitotic rate of each tumor should be noted
for purposes of risk assessment
○ Mitotic rate traditionally expressed in terms of 50 HPF
• Tumors show spindled, epithelioid, or mixed-type
morphology
○ Spindle cell GIST (most common; 70% of cases)
– Uniform fusiform cells arranged in sheets, fascicles,
bundles, or whorls
□ Relatively monomorphic nuclei; marked
pleomorphism is very rare
□ Fine chromatin with inconspicuous nucleoli
□ Pale fibrillary eosinophilic cytoplasm
□ Paranuclear vacuoles common in gastric tumors
– Occasional nuclear palisading
– Fibrocollagenous to myxoid stroma
□ May show diffuse myxoid change or prominent
stromal hyalinization/sclerosis
– Skeinoid fibers common in small bowel GIST
□ Coarse, wire-like, haphazardly arranged collagen
bundles
– Aggressive tumors are often hypercellular
○ Epithelioid GIST (20% of cases)
– Uniform, rounded cells arranged in sheets, nests, or
clusters
□ Cells may appear epithelioid, plasmacytoid,
rhabdoid
□ Variable eosinophilic to clear cytoplasm
– Relatively monomorphic nuclei in many cases
– Subset of tumors show prominent nuclear
pleomorphism and multinucleation
□ Mitoses often sparse or absent, however
– Cytoplasmic vacuolization in some cases; may be
prominent (signet ring cell-like or lipoblast-like)
– Fibrous to myxoid stroma
□ Myxoid, epithelioid GIST more likely to harbor
PDGFRA mutation or be associated with SDH-
deficiency
– Aggressive tumors often hypercellular
• Stromal lymphocytic infiltrate may be present; occasionally
brisk
746
• Inconspicuous stromal vasculature
○ Occasional larger, ectatic "staghorn" vessels
• Calcification or chondroosseous metaplasia in occasional
tumors
• Coagulative tumor necrosis uncommon
○ Most common in aggressive tumors
○ Perivascular tumor cell preservation in background of
geographic necrosis (peritheliomatous growth)
• Posttherapy GIST
○ Hypo- or paucicellularity
○ Stromal fibrosis, hyalinization, myxoid change, necrosis
○ Occasional increased nuclear pleomorphism
○ Can lose CD117 expression
○ Histologic response does not appear to correlate well
with clinical response
• Rare rhabdomyoblastic differentiation reported in
progressive tumors, often following years of therapy
Dedifferentiated Gastrointestinal Stromal Tumor
• Rare
• Defined as conventional GIST (usually spindled type) with
abrupt transition to high-grade pleomorphic
(dedifferentiated) areas
○ Dedifferentiated areas lose CD117 and DOG1 (and often
CD34) and feature abundant mitoses and necrosis
– Anomalous keratin &/or desmin expression may be
seen
• May occur in de novo or following chronic imatinib therapy
Succinate Dehydrogenase-Deficient Gastrointestinal
Stromal Tumor
• Characteristic multinodular and plexiform growth within
muscularis propria of stomach
• Epithelioid morphology predominates
• Regional lymph node metastases in up to 30% of cases
• Strong CD117(+) and DOG1(+) despite absence of
KIT and PDGFRA mutations
• SDHB IHC useful in morphologically suggestive cases
ANCILLARY TESTS
Immunohistochemistry
• Characteristic CD117(+), often diffuse
○ a.k.a. KIT or C-kit
○ Cytoplasmic or membranous expression (occasionally
dot-like)
○ Negative in 5% of cases (usually epithelioid gastric GIST
with PDGFRA mutations)
• DOG1(+), often diffuse, cytoplasmic, membranous
○ Similar sensitivity and specificity as CD117
○ Expressed in ~ 30-60% of CD117(-) GIST
– Therefore, useful 2nd-line diagnostic marker
• Very rare cases (< 3%) are CD117 and DOG1 (-)
• CD34(+) in majority (75%)
• Minor subset are SMA(+) &/or caldesmon (+); can be diffuse
○ Often small bowel GIST
• Markers for SDH-deficient GIST
○ Loss of cytoplasmic SDHB expression in tumors with
mutations in SDHA, SDHB, SDHC, or SDHD
○ Loss of both SDHB and SDHA expression seen only in
tumors with SDHA mutations
 Gastrointestinal Stromal Tumor

Mesenchymal Tumors of Gastrointestinal Tract

○ Also, recent reports indicate overexpression of IGFR1 in Solitary Fibrous Tumor
this subtype • Usually extrinsic to GI tract
• Generally keratin, S100 protein, desmin, HMB-45, melan-A, • Prominent ectatic, "staghorn" vasculature
STAT5, MDM2 (-)
• CD34 and STAT6 (+)
○ Rare focal positivity for these markers in sporadic GIST
• CD117 and DOG1 (-)
○ S100 protein (+) reported in up to 35% of NF1-associated
• NAB2-STAT6 fusion
GISTs
Desmoid Fibromatosis
Molecular Genetics
• Epicenter in mesentery with extension into muscularis
• Most tumors (85-90%) harbor KIT or PDGFRA oncogenic
propria
activating mutations
○ Some mesenteric tumors associated with Gardner
○ KIT mutations in majority (80-85%)
syndrome
– Exon 11 (most common), 9, 13, 17, or 8
• More common in younger adults
○ PDGFRA mutations
• Poorly marginated with highly infiltrative growth pattern
– Most common in stomach or omentum
• Abundant stromal collagen with characteristic thin-walled
– Exon 8 (most common), 12, or 14 blood vessels
– D842V associated with resistance to imatinib • SMA(+), often wispy/patchy expression
○ KIT and PDGFRA mutations are mutually exclusive • Usually CD117, CD34, and DOG1 (-)
• Wild-type GIST (10-15% of tumors) • No KIT or PDGFRA mutations
○ Defined as GIST that lacks KIT and PDGFRA mutations
○ Most cases (90%) of pediatric GIST Poorly Differentiated Carcinoma
○ SDH-deficient GIST • Morphologic overlap with pleomorphic epithelioid GIST
– Harbor mutations in 25% of cases ○ Particularly epithelioid GIST with vacuoles (signet ring-
□ SDHA > SDHB > > SDHC and SDHD like)
○ Also those associated with NF1 or BRAF (V600E) • Mitotic figures common
mutations • Keratin and EMA(+)
• CD117 and CD34 (-)
DIFFERENTIAL DIAGNOSIS • DOG1 expression seen in gastric carcinomas; rare in
colorectal carcinoma
Gastrointestinal Smooth Muscle Neoplasms
• Leiomyoma Melanoma
○ Most common in esophagus (mural mass) or colorectum • Morphologic overlap with pleomorphic epithelioid GIST
(polyp) ○ However, melanoma often shows greater atypia and
○ Low cellularity; brightly eosinophilic spindled cells with mitotic activity
blunt-ended nuclei • May have prior history of melanoma
○ Strongly SMA(+), desmin (+) ○ Metastases to GI tract tend to affect small bowel
○ CD117 and DOG1 (-) – Can involve mucosal lymphatics
• Leiomyosarcoma • Strong S100 protein (+)
○ Nuclear pleomorphism and mitotic activity common • Variable expression of melanocytic markers
○ Perpendicularly oriented fascicles of brightly eosinophilic • Variable CD117(+)
spindled cells ○ Usually CD34 and DOG1 (-)
○ Subset contains myxoid stroma
Malignant Gastrointestinal Neuroectodermal Tumor
○ SMA(+); variable desmin (+)
○ CD117 and DOG1 (-) • Very rare but most frequently arise in small bowel
• Scattered osteoclast-like multinucleated giant cells
Gastrointestinal Schwannoma common
• Microtrabecular architecture common • Strong S100 protein (+)
• Characteristic patchy peripheral lymphoid cuff • Usually CD117 and DOG1 (-)
• Strong, diffuse S100 protein (+) • EWSR1 rearrangements
• CD117 and DOG1 (-)
Plexiform Fibromyxoma
Inflammatory Fibroid Polyp • Essentially always involves gastric antrum
• Originates in submucosa (usually gastric antrum or • Characteristic multinodular, plexiform growth with myxoid
intestines) stroma
• Bland spindled cells, often with at least focal "whorling" • SMA(+)
growth around blood vessels • CD117, DOG1, CD34 (-)
• Conspicuous inflammatory component, particularly
eosinophils SELECTED REFERENCES
• CD34(+) 1. Miettinen M et al: GIST manifesting as a retroperitoneal tumor:
• CD117 and DOG1 (-) clinicopathologic immunohistochemical, and molecular genetic study of 112
• Harbors PDGFRA mutations but no KIT mutations cases. Am J Surg Pathol. 41(5):577-85, 2017

747
 Gastrointestinal Stromal Tumor
Mesenchymal Tumors of Gastrointestinal Tract

Risk Stratification for GISTs (Untreated With Imatinib)

Size Mitoses/50 HPF Risk of Aggressive Behavior
Gastric GISTs
≤ 2 cm ≤5 Very low
> 2 and ≤ 5 cm ≤5 Low
> 5 and ≤ 10 cm ≤5 Intermediate
> 10 cm ≤5 Intermediate
≤ 2 cm >5 Low
> 2 and ≤ 5 cm >5 Intermediate
> 5 and ≤ 10 cm >5 High
> 10 cm >5 High
Any size > 10 High
Small Bowel GISTs
≤ 2 cm ≤5 Very low
> 2 and ≤ 5 cm ≤5 Low
> 5 and ≤ 10 cm ≤5 Intermediate
≤ 2 cm >5 Intermediate
> 2 and ≤ 10 cm >5 High
> 10 cm Any mitotic rate High
Any size > 10 High

Note: Small bowel schematic can be applied to other nongastric sites (e.g., esophagus, colorectum); GIST = gastrointestinal stromal tumor.

Molecular Prognostication for GISTs

Mutation Most Common Site Response to Imatinib Comment
Therapy
KIT exon 11 mutation All sites Excellent Deletions associated with worse outcome
(vs. insertions and substitutions)
KIT exon 9 mutation Small and large intestines Limited unless higher dosage Sunitinib shows efficacy in setting of
is used imatinib resistance
KIT exon 13 or 17 mutation Small bowel Partial Rare
PDGFRA exon 18 Stomach Poor D842V (most common exon 18 mutation)
results in total imatinib resistance
PDGFRA exon 12 or 14 mutation Stomach Variable Most respond to imatinib
SDHA, SDHB, SDHC, SDHD Stomach Poor or resistant Most follow indolent clinical course
mutations
BRAF V600E mutant Small bowel Poor or resistant
NF1-associated GIST Small bowel Poor or resistant Better overall outcome

GIST = gastrointestinal stromal tumor.

2. Mason EF et al: Conventional risk stratification fails to predict progression of 7. Joensuu H: Risk stratification of patients diagnosed with gastrointestinal
succinate dehydrogenase-deficient gastrointestinal stromal tumors: a stromal tumor. Hum Pathol. 39(10):1411-9, 2008
clinicopathologic study of 76 cases. Am J Surg Pathol. 40(12):1616-21, 2016 8. Miettinen M et al: Gastrointestinal stromal tumors of the jejunum and ileum:
3. Patil DT et al: Utility of BRAF V600E mutation-specific a clinicopathologic, immunohistochemical, and molecular genetic study of
immunohistochemistry in detecting BRAF V600E-mutated gastrointestinal 906 cases before imatinib with long-term follow-up. Am J Surg Pathol.
stromal tumors. Am J Clin Pathol. 144(5):782-9, 2015 30(4):477-89, 2006
4. Miettinen M et al: Succinate dehydrogenase deficient gastrointestinal 9. Miettinen M et al: Gastrointestinal stromal tumors of the stomach: a
stromal tumors (GISTs) - a review. Int J Biochem Cell Biol. 53:514-9, 2014 clinicopathologic, immunohistochemical, and molecular genetic study of
5. Antonescu CR et al: Dedifferentiation in gastrointestinal stromal tumor to an 1765 cases with long-term follow-up. Am J Surg Pathol. 29(1):52-68, 2005
anaplastic KIT-negative phenotype: a diagnostic pitfall: morphologic and
molecular characterization of 8 cases occurring either de novo or after
imatinib therapy. Am J Surg Pathol. 37(3):385-92, 2013
6. Doyle LA 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 genotype-phenotype
correlation study. Histopathology. 61(5):801-9, 2012

748
 Gastrointestinal Stromal Tumor

Mesenchymal Tumors of Gastrointestinal Tract

Radiologic Imaging of Gastrointestinal
Gross Appearance Stromal Tumor
(Left) This gross photograph
shows a small intestinal GIST.
The bulk of the tumor is in the
muscularis propria, but the
lesion has extended into the
submucosa and was diagnosed
by mucosal biopsy. Note the
overlying mucosa ﬇, which is
eroded in places. (Right) This
axial radiologic image shows a
large GIST arising in
association with the gastric
wall ﬈ and showing local
compression of the liver ﬊.

Origin From Muscularis Propria Microgastrointestinal Stromal Tumor

(Left) GIST arises from within
the muscularis propria ﬈.
Smaller tumors may be
completely confined, as
depicted, but larger tumors
often grow outward into the
submucosa &/or the serosa.
(Right) Several tiny micro-
GISTs or "seedling" GISTs can
be seen ﬉ near the
gastroesophageal junction in
this resection specimen. These
were found incidentally in a
resection performed for a
separate gastric carcinoma.
These tiny lesions are not
uncommon and do not imply
familial GIST syndrome.

CD34 in Microgastrointestinal Stromal

Tumor Liver Metastasis
(Left) CD34 shows prominent
staining in micro-GISTs ﬉
similar to what is seen in the
larger, more clinically
significant versions. These
micro-GISTs are relatively
common in all populations,
particularly if sought out in
resection or autopsy
specimens. (Right) The liver ﬉
is the most common site of
metastasis for malignant GIST
﬊. Intraabdominal spread
may also be seen. Metastatic
disease outside of the
abdomen is extremely rare.

749
 Gastrointestinal Stromal Tumor
Mesenchymal Tumors of Gastrointestinal Tract

DOG1 Expression CD117 and Mast Cells

(Left) DOG1 is a newer marker
for GIST and can be used as a
2nd-line marker to support a
diagnosis of GIST in which
CD117 is negative. The
sensitivity, specificity, and
expression pattern are all
similar to CD117. (Right)
CD117 expression is typically
diffuse ﬉ in GIST. Normal
mast cells ﬈ in adjacent
tissue serve as a nice internal
positive control. Of note, it is
important to recognize that
some non-GIST tumors, such as
leiomyoma, can contain
scattered mast cells. These
tumors lack diffuse CD117
positivity, however.

Spindled Gastrointestinal Stromal Tumor Uniform Spindle Cells

(Left) GISTs most frequently
demonstrate a spindled tumor
cell morphology. Cellularity
varies from case to case and
sometimes from field to field.
The morphologic spectrum of
these tumors is quite broad.
(Right) Spindled tumor cells in
GIST are arranged in sheets,
fascicles, or bundles and
generally show monomorphic
cytologic features. Prominent
nuclear pleomorphism is very
rare in spindled GIST.

Myxoid Stroma Lymphocytes

(Left) Myxoid foci are common
in GIST and may be prominent
in occasional cases. (Right) A
subtle intratumoral
lymphocytic infiltrate ﬉ is
common in GIST and may
occasionally be brisk.
Lymphocytes can sometime be
difficult to distinguish from
mitotic figures. Note also the
bland, uniform, elongated
nuclei characteristic of most
low-grade spindled tumors.

750
 Gastrointestinal Stromal Tumor
Paranuclear Vacuoles
Rare Prominently Myxoid Gastrointestinal
Stromal Tumor
Hyalinizing Gastrointestinal Stromal
Tumor
Mesenchymal Tumors of Gastrointestinal Tract
Abundant Vacuoles
(Left) Tumor cells in GIST may
contain paranuclear vacuoles
﬉, similar to what is seen in
some smooth muscle
neoplasms. This finding is
particularly common in GIST
arising in the stomach. (Right)
This gastric GIST featured
numerous spindled tumor cells
with paranuclear vacuoles
diffusely present throughout
the tumor.
Stromal Hyalinization
(Left) Myxoid stroma is not
uncommon in GIST but is
usually focal or patchy. Rare
cases show diffuse, prominent
myxoid change, as depicted.
(Right) Stromal hyalinization is
seen in many GISTs but varies
widely in extent. Not
uncommonly, hyalinization
appears to form septa dividing
sheets and nests of spindled
tumor cells and imparting a
lobular appearance.
Sclerosis
(Left) The morphologic
appearance of nests and
bundles of spindled cells
within a hyalinized stroma
raises the possibility of a
smooth muscle tumor or
PEComa. IHC often makes this
distinction easy. (Right)
Diffuse stromal hyalinization
or sclerosis with concomitant
paucicellularity is uncommon
in untreated GIST and may
lead to consideration of
leiomyoma.
751
 Gastrointestinal Stromal Tumor
Mesenchymal Tumors of Gastrointestinal Tract

Stromal Collagen Degenerative Changes

(Left) Increased stromal
collagen without overt
hyalinization, as depicted, is
seen in some GISTs and can
impart an appearance
suggestive of smooth muscle.
(Right) Degenerative changes
in GIST include mainly fibrosis,
hemorrhage, hemosiderin
deposition, and architectural
disruptions. As seen in this
H&E, the tissue can appear to
tear apart and is associated
with myxoedematous stroma
and hemorrhage.

Intratumoral Hemorrhage Calcifications

(Left) Hemorrhage may be
seen in GIST and may even be
evident at the time of gross
examination. Cellular spindled
tumors with hemorrhage can
mimic Kaposi sarcoma, which
can also express CD34 and
CD117. (Right) This H&E shows
a focus of chunky calcification
﬈. Calcification is uncommon
in GIST and, in the stomach, is
more likely to be seen in mural
leiomyomas.

Hyalinized Blood Vessels Ectatic Blood Vessels

(Left) Perivascular
hyalinization ﬉ is seen in
some cases of GIST and is
often associated with other
degenerative features, such as
myxoedematous stroma and
architectural disruption. Rare
cases can show striking,
diffusely hyalinized vessels.
(Right) Stromal blood vessels
are generally small and
inconspicuous in GIST;
however, occasional tumors
feature larger, ectatic vessels,
as depicted. Some may even
show irregular shapes
(staghorn) similar to solitary
fibrous tumor.

752
 Gastrointestinal Stromal Tumor

Mesenchymal Tumors of Gastrointestinal Tract

Small Bowel Gastrointestinal Stromal
Nuclear Palisading Tumor
(Left) Nuclear palisading ﬈
may be seen in spindled GIST.
Interestingly, palisading is
more common in GIST than in
other primary spindle cell
neoplasms of the GI tract,
including schwannoma. (Right)
After the stomach, the small
bowel is the 2nd most
common site for GIST. The
jejunum and ileum are
preferentially affected. This
site is also the most common
site for GIST arising within the
context of NF1.

Discrete Vascular Network Skeinoid Fibers

(Left) This neurofibromatosis
type 1 (NF1)-associated GIST
arose within the small bowel
and showed in areas a
distinctive compartmentalized
pattern demarcated by thin
capillary channels ﬈.
Occasional GISTs can feature a
prominent nested growth
pattern. (Right) Skeinoid fibers
﬉ are well described in GIST
and consist of thick ropy
matrix deposited between
tumor cells. They are most
commonly seen in small bowel
tumors but have been
described in other GI sites.

Prominent Skeinoid Fibers Fascicular Growth

(Left) This GIST features
prominent skeinoid fibers ﬊.
These fibers are principally
found in small bowel GISTs,
where they are associated
with a favorable outcome.
(Right) This more cellular area
of an NF1-associated small
bowel GIST shows fascicular
growth, resembling a smooth
muscle neoplasm. Note the
focal skeinoid fibers ﬈.

753
 Gastrointestinal Stromal Tumor
Mesenchymal Tumors of Gastrointestinal Tract

Malignant Gastrointestinal Stromal Tumor Hypercellularity

(Left) Risk of aggressive
behavior in GIST is assessed
primarily by evaluating the
combination of site, size, and
mitotic activity of a given
tumor. Although cellularity is
not a defined factor in
stratifying GIST, most
malignant cases show a
marked increased in overall
cellularity, as depicted. (Right)
Hypercellularity is a common
finding in high-risk GIST and
portends a strong likelihood of
identifying a high mitotic
count in a tumor.

Myxoid Change in Malignant

Prominent Fascicular Growth Gastrointestinal Stromal Tumor
(Left) Fascicular growth is
often more pronounced in
malignant GIST and may even
show a herringbone
architectural pattern, as
depicted. (Right) Myxoid
change can also be seen in
malignant GIST and may be
extensive in rare cases, as
shown in this example. This
tumor contained abundant
mitoses and showed diffuse
CD117 and DOG1 expression.

Nuclear Palisading in Malignant Nuclear Pleomorphism in Spindled

Gastrointestinal Stromal Tumor Gastrointestinal Stromal Tumor
(Left) This malignant GIST
showed prominent nuclear
palisading. Note the overall
high cellularity and mitotic
activity ſt. (Right) Significant
nuclear pleomorphism is very
uncommon in an untreated
spindle cell GIST; however, this
finding may be present in
resection specimens following
imatinib therapy. As a general
rule, any spindle cell neoplasm
with pleomorphism in the GI
tract should lead to
consideration of many other
entities (e.g., leiomyosarcoma)
before GIST.

754
 Gastrointestinal Stromal Tumor

Mesenchymal Tumors of Gastrointestinal Tract

Necrosis Geographic Necrosis
(Left) Necrosis ﬉ is generally
uncommon in GIST and may be
associated with a poorer
prognosis in high-risk tumors.
Necrosis can also be seen in
the setting of
ischemia/degeneration or
following imatinib therapy.
(Right) Geographic necrosis in
GIST is often associated with
retained viability ﬊ of
perivascular tumor cells
(peritheliomatous pattern).
This morphology is also
classically associated with
Ewing sarcoma and malignant
peripheral nerve sheath
tumor.

Highly Cystic Gastrointestinal Stromal

Unusual Pseudopapillary Appearance Tumor
(Left) This unusual GIST
showed areas of cellular
degeneration and dyscohesion
around hyalinized stromal
vessels ﬈, creating a
pseudopapillary appearance.
(Right) This case of GIST
showed abundant cystic and
microcystic changes ﬈,
resembling schwannoma as
well as other neoplasms.

Posttherapy Gastrointestinal Stromal

Tumor Rare Rhabdomyoblastic Differentiation
(Left) Following therapy with
imatinib, GIST may show a
variety of changes, including
fibrosis, myxoid change, or
necrosis. Areas of residual
viable tumor ﬈ are almost
always seen in resection
specimens, however. (Right)
Rare progressive GISTs, often
after years of therapy, have
been reported to show areas
of rhabdomyoblastic
differentiation ﬉, which can
be highlighted with desmin
&/or myogenin immunostains.
These areas may also closely
resemble pleomorphic
rhabdomyosarcoma.

755
 Gastrointestinal Stromal Tumor
Mesenchymal Tumors of Gastrointestinal Tract

Epithelioid Gastrointestinal Stromal Tumor Eosinophilic to Clear Cytoplasm

(Left) An epithelioid
morphology is less common
than a spindled morphology in
GIST, but awareness is very
important due to the potential
for confusion with carcinoma
and melanoma. Cells may
form nests, clusters, or sheets.
(Right) Epithelioid tumor cells
in GIST feature variable
eosinophilic ﬈ to clear ﬉
cytoplasm. Cytoplasmic
borders are distinct in some
tumors, but inapparent in
others, and can appear
syncytial.

Prominent Epithelioid Morphology Myxoid Stroma

(Left) GIST may feature
distinctly epithelioid cells with
sharp, prominent cytoplasmic
borders and peripheral
cytoplasmic retraction,
creating a halo-like ﬉ effect
around nuclei. (Right) Myxoid
stromal changes are more
common in epithelioid than
spindled GIST. In the stomach,
myxoid epithelioid tumors are
more likely to harbor PDGFRA
than KIT mutations.

Signet Ring-Like Vacuolizations Pseudolipoblastic Appearance

(Left) Paranuclear vacuoles
may be seen in epithelioid
GIST as with spindled GIST.
Notably, vacuoles in
epithelioid cells tend to
produce a signet ring-like
appearance, which can lead to
a significant misdiagnosis of
adenocarcinoma. (Right)
Larger, more prominent
vacuolizations in epithelioid
GIST can impart a morphologic
appearance reminiscent of
lipoblastic differentiation, as
depicted.

756
 Gastrointestinal Stromal Tumor
Sclerosing Epithelioid Gastrointestinal
Stromal Tumor
Pleomorphic Epithelioid Gastrointestinal
Stromal Tumor
Rhabdoid Morphology
Mesenchymal Tumors of Gastrointestinal Tract
Multinucleated Tumor Cells
(Left) Prominent hyalinized or
sclerotic stroma may be seen
in epithelioid GIST. Individual
tumor cells ﬈ and small
clusters of cells may resemble
plasma cells or even
osteoblasts. (Right) Scattered
bi- or multinucleated tumor
cells ﬈ are relatively common
in epithelioid GIST.
Retraction Artifact
(Left) Nuclear pleomorphism
and multinucleation may be
quite prominent in some cases
of epithelioid GIST.
Interestingly, mitotic figures in
these tumors are often rare to
absent. On a small biopsy,
there is significant risk of
confusion with melanoma or
carcinoma. (Right) This
particularly unfriendly case of
pleomorphic epithelioid GIST
showed areas with significant
retraction space artifact,
simulating lymphatic space
invasion. Note, however, the
lack of an endothelial lining to
the spaces.
Plasmacytoid Morphology
(Left) Occasional tumor cells
in epithelioid GIST may feature
a rhabdoid morphology ﬉
characterized by glassy
eosinophilic cytoplasm
associated with eccentric
enlarged nuclei. (Right) This
case of malignant epithelioid
GIST featured dense sheets of
tumor cells with a decidedly
plasmacytoid morphology.
757
 Gastrointestinal Stromal Tumor
Mesenchymal Tumors of Gastrointestinal Tract

Malignant Epithelioid Gastrointestinal

Distinct Nodular Growth Stromal Tumor
(Left) This case of GIST arose
from the muscularis propria of
the esophagus and initially
presented as a large
mediastinal mass. It shows a
distinctive growth pattern
composed of variably sized
nodules of tumor cells within a
hypocellular myxocollagenous
stroma. Some areas also
showed dense stromal
hyalinization. (Right) Similar
to spindled forms, epithelioid
GISTs with a high risk for
malignant behavior often
show a marked increased in
cellularity with a concomitant
marked increased in mitotic
activity.

Hypercellularity Abundant Mitoses

(Left) Malignant epithelioid
GIST can show a variety of
growth patterns similar to
low-risk GIST; however,
hypercellularity is often a
feature. (Right) As suggested
by the markedly increased
cellularity, the high mitotic
rate ﬉ of this epithelioid GIST
assists in classifying it as
having a high risk of
aggressive/malignant
behavior. Size and anatomic
location are also usually
important in this endeavor.

Mixed-Type Gastrointestinal Stromal

Corded Growth Tumor
(Left) This case of malignant
epithelioid GIST showed focal
areas of corded growth within
a fibrous stroma, mimicking an
infiltrating lobular carcinoma
or a variety of sclerosing
sarcomas. (Right) Some GISTs
show a mixture of spindled ﬈
and epithelioid ﬊
morphologies. This clinically
malignant tumor shows an
abrupt transition between the
2 components.

758
 Gastrointestinal Stromal Tumor
Dedifferentiated Gastrointestinal Stromal
Tumor
Succinate Dehydrogenase-Deficient
Gastrointestinal Stromal Tumor
SDHB Immunohistochemistry
Mesenchymal Tumors of Gastrointestinal Tract
Dedifferentiated Gastrointestinal Stromal
Tumor
(Left) Dedifferentiated GIST is
rare and is defined as
morphologically conventional
GIST with abrupt transition to
high-grade pleomorphic areas
﬈ lacking CD117 &/or DOG1
expression. The
dedifferentiated areas usually
show abundant mitoses and
necrosis. (Right) The
sarcomatous areas of
dedifferentiated GIST often
show a nonspecific high-grade
morphology; however,
prominent nucleoli, mitotic
figures ﬉, and inflammatory
infiltrates ﬈ are all common.
Epithelioid Predominant
(Left) Succinate
dehydrogenase (SDH)-
deficient GIST is a distinctive
clinicopathologic subtype that
shows several unique features,
including a characteristic
multinodular and plexiform
growth pattern within the
muscularis propria of the
stomach. (Right) An epithelioid
tumor cell morphology
predominates in SDH-deficient
GIST, although a mixture of
spindled and epithelioid cells
can also be seen. Myxoid
stroma can also be seen.
Lymph Node Metastases
(Left) Loss of granular
cytoplasmic SDHB expression
is highly useful in the diagnosis
of SDH-deficient GIST. Note
the positive internal control
(endothelial cells ﬈), which
should always be present
when evaluating this stain.
(Right) SDH-deficient GIST
shows a notable tendency for
lymph node metastases ﬈,
which may be identified and
removed along with the
resected tumor. Despite this
apparent aggressive behavior,
these tumors are often
relatively clinically indolent.
759
 Gastrointestinal Schwannoma

KEY FACTS
Mesenchymal Tumors of Gastrointestinal Tract

TERMINOLOGY MICROSCOPIC
• Benign peripheral nerve sheath tumor composed • Well circumscribed but encapsulated
predominantly of Schwann cells and arising directly within • Characteristic patchy peripheral lymphoid cuff in 90%
tubular gastrointestinal tract • Predominantly interlacing bundles, fascicles, and
CLINICAL ISSUES microtrabeculae of banal spindled cells
○ Mild nuclear atypia with scattered, degenerative,
• Affects predominantly middle-aged and older adults
"ancient" nuclei may be seen
• Overall female predominance
○ Mitotic rate low to absent
• Majority arise in stomach
• Nuclear palisading, hyalinized vessels, Verocay body
• Often incidentally discovered formation all rare to absent
• Treatment: Simple surgical excision is curative
• Excellent prognosis ANCILLARY TESTS
• S100 protein (+), SOX10 (+), GFAP(+)
MACROSCOPIC
• SMA(-), desmin (-), CD117(-), DOG1(-)
• Tumor is centered in muscularis propria but can grow to fill
submucosa TOP DIFFERENTIAL DIAGNOSES
• Usually < 10 cm (median: 4.5) • Gastrointestinal stromal tumor
• Leiomyoma
• Neurofibroma

Gastrointestinal Schwannoma Patchy, Peripheral Lymphoid Cuff

(Left) Although it bears
similarities to cellular
schwannoma of the soft
tissues, gastrointestinal (GI)
schwannoma is distinctive in
that it is unencapsulated and
generally shows an absence of
hyalinized vessels and well-
formed Verocay bodies.
(Right) A diagnostically useful
(though not completely
pathognomonic) feature of GI
schwannoma is the presence
of a patchy lymphoid cuff ﬉
around the periphery of the
tumor. Lymphoid aggregates
can also be seen within the
lesion.

Microtrabecular Growth Pattern S100 Protein Expression

(Left) An interesting feature of
many cases of GI schwannoma
is a microtrabecular growth
pattern identified by distinct,
small linear clusters and cords
of tumor cells ﬉. This
architecture is often seen in
addition to more typical
fascicular and whorled growth
patterns. Note also the
lymphocytic infiltrate ﬈,
another common finding in
this tumor. (Right) Like
conventional schwannoma of
soft tissue, GI schwannoma
classically shows strong and
diffuse expression of S100
protein.

760
 Gastrointestinal Schwannoma

Mesenchymal Tumors of Gastrointestinal Tract

• Predominantly interlacing bundles, fascicles, and
TERMINOLOGY microtrabeculae of banal spindled cells
Definitions ○ Moderate cellularity
• Benign peripheral nerve sheath tumor composed ○ Mild nuclear atypia with scattered, degenerative,
predominantly of Schwann cells and arising directly within "ancient" nuclei may be seen
tubular gastrointestinal (GI) tract ○ Mitotic rate low to absent
• Stromal lymphocytic infiltrate (± plasma cells) common
ETIOLOGY/PATHOGENESIS • In contrast to conventional soft tissue schwannoma, some
Genetics features of GI schwannoma are rare to absent
○ Nuclear palisading, hyalinized vessels, foamy histiocytes,
• Most analyzed cases lack alteration of NF2 gene well-formed Verocay bodies
○ In contrast to conventional, non-GI schwannoma • Finely collagenous to myxoid stroma
• Occasional tumors (usually intestinal) can show
CLINICAL ISSUES morphologic patterns of conventional non-GI schwannoma
Epidemiology ○ Epithelioid, plexiform, pseudoglandular,
• Incidence microcystic/reticular
○ Rare
– Greatly outnumbered by gastrointestinal stromal ANCILLARY TESTS
tumor (GIST) in GI tract Immunohistochemistry
• Age • Strong, diffuse S100 protein (+), SOX10(+)
○ Predominantly middle-aged and older adults • Variable GFAP(+)
• Sex • May rarely express cytokeratin AE1/AE3
○ Overall female predominance • Usually SMA(-), desmin (-), CD117(-), DOG1(-), HMB-45(-)
– 4:1 in stomach (largest series)
Site DIFFERENTIAL DIAGNOSIS
• Majority arise in stomach Gastrointestinal Stromal Tumor
• Less frequent in small intestine, colorectum, and esophagus • Much more common than GI schwannoma
Presentation • Generally lacks peripheral lymphoid cuff
• CD117(+), DOG1(+), CD34(+), S100 protein (-)
• Often incidentally discovered
• KIT or PDGFRA mutations in most cases
• Can cause bleeding, discomfort, &/or obstructive symptoms
• Association with neurofibromatosis exceptionally rare Leiomyoma
Treatment • Prominent cytologic eosinophilia
• Generally lacks peripheral lymphoid cuff
• Simple surgical excision is curative
• SMA(+), desmin (+), S100 protein (-)
Prognosis
Neurofibroma
• Excellent
• Usually plexiform type in GI tract
• No recurrences or metastases reported
• Lacks fascicular and microtrabecular growth patterns
MACROSCOPIC • Less cellular than GI schwannoma

General Features Hybrid Nerve Sheath Tumor

• Well-circumscribed, firm mass • Can arise within GI tract but very rare
○ Overlying ulceration of mucosa in 1/2 of cases • Few reported cases have been schwannoma/perineurioma
• Tan/gray to yellow/white cut surface ○ Lacks peripheral lymphoid cuff and microtrabecular
• Tumor is centered in muscularis propria but can grow to fill architecture of GI schwannoma
submucosa ○ Expression of S100 protein and perineurial cell markers
(EMA, claudin-1)
Size
• Usually < 10 cm (median: 4.5) SELECTED REFERENCES
1. Hu BG et al: Gastric schwannoma: a tumor must be included in differential
MICROSCOPIC diagnoses of gastric submucosal tumors. Case Rep Gastrointest Med.
2017:9615359, 2017
Histologic Features 2. Mohanty SK et al: Gastric GIST or gastric schwannoma-a diagnostic dilemma
in a young female. Int J Surg Case Rep. 28:60-64, 2016
• Well circumscribed but encapsulated
3. Tao K et al: Clinicopathologic features of gastric schwannoma: 8-year
○ Tumor cells can appear to infiltrate between fibers of experience at a single institution in china. Medicine (Baltimore).
muscularis propria 94(45):e1970, 2015
○ Characteristic patchy peripheral lymphoid cuff in most 4. Voltaggio L et al: Gastrointestinal tract spindle cell lesions-just like real
estate, it's all about location. Mod Pathol. 28 Suppl 1:S47-66, 2015
cases (90%) 5. Voltaggio L et al: Gastric schwannoma: a clinicopathologic study of 51 cases
– May contain reactive germinal centers and critical review of the literature. Hum Pathol. 43(5):650-9, 2012

761
 Gastrointestinal Smooth Muscle Neoplasms

KEY FACTS
Mesenchymal Tumors of Gastrointestinal Tract

TERMINOLOGY • Mural LM several cm or larger

• Leiomyoma (LM)
• Leiomyosarcoma (LMS)
• Mesenchymal tumors in GI tract composed of smooth
muscle cells
○ Benign (LM) or malignant (LMS)
○ May arise as small polyp from muscularis mucosa
(superficial LM) or as mural mass from muscularis propria
CLINICAL ISSUES
• General male predominance (~ 2.5:1)
• Superficial LM presents as asymptomatic polyp, usually in
colorectum
• Mural LM most common in esophagus; also, stomach
• Excellent prognosis in superficial and mural LMs
• Generally poor prognosis for LMS at any GI site
MACROSCOPIC
• Superficial LM is usually 1-5 mm
MICROSCOPIC
• All show smooth muscle cytologic features (prominent
cytoplasmic eosinophilia, oval blunted nuclei)
○ Nuclear pleomorphism, mitoses, necrosis in LMS
ANCILLARY TESTS
• SMA(+), desmin (+) in all types of LM
• Desmin may be focal or negative in LMS
• Negative for CD117, DOG1, CD34, S100 protein
TOP DIFFERENTIAL DIAGNOSES
• Gastrointestinal stromal tumor
• Gastrointestinal schwannoma
• Inflammatory fibroid polyp
• LMS (extrinsic to GI tract)

Superficial (Polypoid) Leiomyoma Superficial Leiomyoma

(Left) Leiomyoma (LM) of the
GI tract most commonly arises
from the muscularis mucosa
and appears as a small polyp,
most frequently in the sigmoid
or rectum. All show a well-
circumscribed contour and
appear as an eosinophilic
nodule at low power. (Right)
Superficial LM usually shows a
sharp demarcation from the
overlying mucosa; however, it
is not uncommon to see small
strands or fascicles of tumor
cells extending into the base
of the mucosa.

Smooth Muscle Cytology Smooth Muscle Actin (SMA) Expression

(Left) As is the case in sites
throughout the body, LM
(both superficial and mural
types) is composed of spindled
cells with mature smooth
muscle differentiation
(prominent eosinophilic
cytoplasm and oval cigar-
shaped nuclei ﬊). The overall
cellularity is generally low.
(Right) Expression of diffuse
SMA (shown) and desmin is
characteristic of LM. Note,
however, that desmin
expression may be focal or
absent in leiomyosarcoma
(LMS).

762
 Gastrointestinal Smooth Muscle Neoplasms
TERMINOLOGY
Abbreviations
• Leiomyoma (LM)
• Leiomyosarcoma (LMS)
Synonyms
• Mural leiomyoma (deep leiomyoma)
Definitions
• Mesenchymal tumors in GI tract composed of smooth
muscle cells
○ Benign (LM) or malignant (LMS)
○ May arise as small polyp from muscularis mucosa
(superficial LM) or as mural mass from muscularis propria
CLINICAL ISSUES
Epidemiology
• Incidence
○ Generally uncommon overall
– Superficial LM is more common than mural LM
○ Varies depending on site in GI tract
– Mural LM is most common mesenchymal tumor in
esophagus
– Superficial LM most frequent in sigmoid colon and
rectum
– LMS very rare, regardless of GI tract site
□ Secondary GI tract involvement by LMS from other
primary site (e.g., retroperitoneum, uterus) must
always be excluded
• Age
○ Median of 62 years in superficial LM
○ 30-50 years most common in mural LM
○ Most patients with LMS over age 50
• Sex
○ General male predominance (~ 2.5:1)
Site
• Superficial LM usually arises in colorectum
• Mural LM most common in esophagus (particularly distal,
near gastroesophageal junction)
○ Also arise in stomach
○ Rarely anorectum, duodenum
• LMS may arise in colon (particularly right side), esophagus,
stomach, duodenum
Presentation
• Superficial LM is usually asymptomatic (detected on
screening endoscopy)
○ Small, nonspecific polyp
• Mural esophageal LM may present with dysphagia or be
incidental discovery on imaging
○ Small, microscopic ("seedling") mural LM may be
discovered incidentally on resection for unrelated tumor
• GI bleeding, abdominal pain, obstruction in rare deep
colonic tumors (mural LM/LMS)
Treatment
• Polypectomy for small, superficial lesions
• Simple excision (enucleation) for mural LM
• Complete surgical resection for LMS
Mesenchymal Tumors of Gastrointestinal Tract
Prognosis
• Excellent prognosis in superficial and mural LM
○ All benign with no risk of malignant degeneration
• Generally poor prognosis for LMS at any GI site
○ Polypoid intraluminal LMS may have better prognosis
IMAGING
General Features
• Mural LM is often misconstrued as gastrointestinal stromal
tumor on imaging
• Large esophageal LM may bulge externally and be
confused clinically for primary tumor of posterior
mediastinum
MACROSCOPIC
General Features
• Firm, fibrous, tan-white cut surface
○ LMS additionally often features necrosis, hemorrhage,
&/or surface ulceration
• LM is generally a well-circumscribed mass
○ Esophageal LM may show lobulations or serpiginous
contours
Size
• Superficial LM is usually 1-5 mm
• Esophageal mural LM has median of 5 cm
○ Microscopic "seedling" mural LM
○ Some cases > 10 cm
• LMS tends to be much larger on average than mural LM
MICROSCOPIC
Histologic Features
• Superficial (polypoid) LM
○ Arises from muscularis mucosa
– Cells often peripherally merge with adjacent normal
smooth muscle
○ Small, well circumscribed, nodular
○ Usually of low cellularity
○ Composed of uniform spindled smooth muscle cells
– Prominent eosinophilic cytoplasm, bland oval (cigar-
shaped) nuclei
– Very rare cases with isolated bizarre nuclear atypia
("symplastic LM")
– Eosinophilic intracytoplasmic globules common
– Mitoses and necrosis absent
○ Scattered intratumoral mast cells may be present
• Mural (deep) LM
○ Arises from muscularis propria
○ Well circumscribed or rounded
– Esophageal tumors may be more lobular or show
serpentine borders
○ Composed of uniform, bland, spindled smooth muscle
cells
○ Calcification and other degenerative changes (e.g.,
edema) may be seen
○ Intratumoral mast cells &/or interstitial cells of Cajal (ICC)
may be present
– May lead to diagnostic confusion when using
immunohistochemistry
763
 Gastrointestinal Smooth Muscle Neoplasms
Mesenchymal Tumors of Gastrointestinal Tract

• LMS Mucosal Perineurioma

○ Usually large, invasive, destructive tumors
– Surface ulceration common
○ Morphologically similar to LMS elsewhere
– Nuclear pleomorphism and necrosis common
– Mitoses often numerous and include atypical forms
ANCILLARY TESTS
Immunohistochemistry
• Diffuse cytoplasmic SMA(+), desmin (+), h-caldesmon (+) in
all types of LM
○ Desmin (+) less frequent in LMS (40-50% of cases)
• Negative for CD117 (KIT), DOG1, CD34, S100 protein,
keratin
○ Pitfalls
– Intratumoral mast cells express CD117
– Intratumoral ICCs, if present, may express CD117 and
DOG1
□ Seen in mural (deep) LM, not superficial LM
DIFFERENTIAL DIAGNOSIS
Gastrointestinal Stromal Tumor
• Arises from muscularis propria, not muscularis mucosa
• Most common in stomach; rare in esophagus and
colorectum
• May show spindled &/or epithelioid morphologies
○ Often much more cellular than LM
• Strong, diffuse CD117(+) &/or DOG1(+)
• Majority are CD34(+)
• Occasional tumors express SMA or H-caldesmon
• Generally negative for S100 protein, keratin, and desmin
• Majority show KIT or PDGFRA mutation
Gastrointestinal Schwannoma
• Most common in stomach
• Arises in muscularis propria but often grows into
submucosa
• Lacks prominent cytoplasmic eosinophilia of LM
• Patchy, peripheral lymphoid cuff common
• Strong S100 protein (+)
• Generally negative for SMA and desmin
Mucosal Schwann Cell Hamartoma
• Small, bland spindle cell proliferation within superficial
mucosa
• Strong S100 protein (+)
• Negative for SMA and desmin
Inflammatory Fibroid Polyp
• Arise in submucosa
• Most common in stomach (particularly antrum) and small
intestine
• Lacks prominent cytoplasmic eosinophilia of LM
• Prominent chronic inflammatory infiltrate (particularly
eosinophils)
• CD34(+)
• Negative for SMA and desmin
• PDGFRA mutations
• Presents as small mucosal polyp
• Often associated with serrated lesion (hyperplastic polyp,
serrated adenoma)
• Grows in between and around crypts in mucosa
• Lacks prominent cytoplasmic eosinophilia of LM
• EMA(+), claudin-1 (+)
• Negative for SMA and desmin
Leiomyosarcoma (Extrinsic to GI Tract)
• Must always be excluded before diagnosing primary GI
tract LMS
• Most often from retroperitoneum or gynecologic tract
(e.g., uterus)
• Histologic and immunohistochemical features are identical
Granular Cell Tumor
• Polygonal to spindled cells with prominent granular
cytoplasm
• Strong S100 protein (+)
• Negative for SMA and desmin
SELECTED REFERENCES
1. Lopes CV et al: Differential diagnosis of mesenchymal neoplasms of the
digestive tract by cell block and immunohistochemistry. Cytopathology.
ePub, 2018
2. Voltaggio L et al: Gastrointestinal tract spindle cell lesions-just like real
estate, it's all about location. Mod Pathol. 28 Suppl 1:S47-66, 2015
3. Deshpande A et al: Leiomyoma of the gastrointestinal tract with interstitial
cells of Cajal: a mimic of gastrointestinal stromal tumor. Am J Surg Pathol.
38(1):72-7, 2014
4. Hechtman JF et al: Corpora amylacea in gastrointestinal leiomyomas: a
clinical, light microscopic, ultrastructural and immunohistochemical study
with comparison to hyaline globules. J Clin Pathol. 66(11):951-5, 2013
5. Rittershaus AC et al: Benign gastrointestinal mesenchymal BUMPS: a brief
review of some spindle cell polyps with published names. Arch Pathol Lab
Med. 135(10):1311-9, 2011
6. Abraham SC: Distinguishing gastrointestinal stromal tumors from their
mimics: an update. Adv Anat Pathol. 14(3):178-88, 2007
7. Abraham SC et al: "Seedling" mesenchymal tumors (gastrointestinal stromal
tumors and leiomyomas) are common incidental tumors of the
esophagogastric junction. Am J Surg Pathol. 31(11):1629-35, 2007
8. Agaimy A et al: True smooth muscle neoplasms of the gastrointestinal tract:
morphological spectrum and classification in a series of 85 cases from a
single institute. Langenbecks Arch Surg. 392(1):75-81, 2007
9. Matsukuma S et al: Endoscopically resected colorectal leiomyomas often
containing eosinophilic globules. Histopathology. 45(3):302-3, 2004
10. Miettinen M et al: Gastrointestinal stromal tumors, intramural leiomyomas,
and leiomyosarcomas in the duodenum: a clinicopathologic,
immunohistochemical, and molecular genetic study of 167 cases. Am J Surg
Pathol. 27(5):625-41, 2003
11. Miettinen 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. 25(9):1121-33, 2001
12. Miettinen M et al: Gastrointestinal stromal tumors and leiomyosarcomas in
the colon: a clinicopathologic, immunohistochemical, and molecular genetic
study of 44 cases. Am J Surg Pathol. 24(10):1339-52, 2000
13. Miettinen M 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. 24(2):211-22, 2000

764
 Gastrointestinal Smooth Muscle Neoplasms

Mesenchymal Tumors of Gastrointestinal Tract

Mural Leiomyoma Calcifications
(Left) Mural LM is
histologically identical to
superficial LM; however, it
arises from the muscularis
propria rather than the
muscularis mucosa and
therefore is often much larger.
It most commonly arises in the
esophagus (shown), and the
overlying epithelium can show
features suggestive of reflux
esophagitis. (Right)
Calcifications are common in
mural leiomyoma.

Hyaline Globules Leiomyosarcoma of GI Tract

(Left) Hyaline globules ﬊ are
relatively common in all forms
of GI leiomyoma and can be
focal or abundant. They are
likely a form of cellular
degeneration. (Right) Primary
LMS of the GI tract is very rare,
and secondary involvement
from an external primary (such
as from the retroperitoneum
or uterus) should always be
excluded. Histologically, GI
LMS is indistinguishable from
LMS at other sites and usually
features overt nuclear
pleomorphism and atypia, at
least focally.

Leiomyosarcoma of GI Tract Leiomyosarcoma of GI Tract

(Left) As can be seen in tumors
from other sites/organs,
myxoid change is a feature in
some cases of GI LMS and may
lead to consideration of a
gastrointestinal stromal tumor
(GIST). Note, however, that
nuclear pleomorphism is rare
in spindled GISTs. (Right) Some
cases of GI LMS are well
differentiated and show only
mild or focal nuclear
pleomorphism ﬈.
Identification of mitoses ﬊
and observation of aggressive,
infiltrative growth is helpful.

765
 Inflammatory Fibroid Polyp

KEY FACTS
Mesenchymal Tumors of Gastrointestinal Tract

TERMINOLOGY
• Distinctive benign fibroblastic neoplasm of gastrointestinal
tract characterized by bland, spindled to stellate cells and
admixed chronic inflammatory cells within prominent
vascularized stroma
CLINICAL ISSUES
• Most common in older adults (mean: 60 years)
• Stomach (particularly antrum) is most common site overall
○ Also arises in small intestine and colorectum
• Nonspecific abdominal pain or asymptomatic
• Small intestinal tumors often cause intussusception
• Treatment: Simple excision
• Excellent prognosis
MACROSCOPIC
• Solitary sessile or polypoid submucosal growth
• Most 1-5 cm in size
MICROSCOPIC
• Loose, haphazard proliferation of bland, spindled to stellate
cells within prominent vascularized stroma
○ Perivascular or periglandular orientation of tumor cells
("onion-skin") in most cases
• Loose collagenous to myxoid stroma
• Multinucleated stromal giant cells in minority of cases
• Mixed chronic inflammatory infiltrate in all cases
○ Eosinophils typically prominent but may be sparse
ANCILLARY TESTS
• CD34(+)
• CD117, DOG1, S100, EMA, keratin, ALK1 (-)
• Molecular: PDGFRA mutations in majority of cases
TOP DIFFERENTIAL DIAGNOSES
• Gastrointestinal stromal tumor
• Inflammatory myofibroblastic tumor
• Perineurioma

Inflammatory Fibroid Polyp Inflammatory Fibroid Polyp

(Left) Inflammatory fibroid
polyp (IFP) is a distinctive
benign mesenchymal
neoplasm of the
gastrointestinal tract that
occurs predominantly in the
stomach, large bowel, and
small intestine. As shown in
this H&E, IFP arises in the
submucosa but often extends
into the overlying mucosa.
(Right) The typical case of IFP
is composed of a haphazard
arrangement of cytologically
bland, spindled and stellate
fibroblastic cells within a
variable fibromyxoid and
vascularized stroma.

Onion-Skin Pattern Eosinophils

(Left) A characteristic finding
seen in most cases of IFP is a
concentric onion-skin
arrangement ﬈ of tumor cells
around stromal blood vessels
&/or mucosal glands; however,
this finding may be subtle or
entirely absent in some cases.
(Right) A mixed chronic
inflammatory infiltrate is
present in all cases of IFP but
varies in prominence.
Eosinophils are often the most
noticeable type of cell and can
be numerous; however,
lymphocytes, plasma cells, and
mast cells are also often seen.

766
 Inflammatory Fibroid Polyp

Mesenchymal Tumors of Gastrointestinal Tract

○ Variable cellularity
TERMINOLOGY
○ Perivascular or periglandular orientation of tumor cells
Abbreviations ("onion-skin") in most cases
• Inflammatory fibroid polyp (IFP) ○ Short fascicular growth seen in some cases
• Multinucleated stromal giant cells in minority of cases
Synonyms
• Loose collagenous to myxoid stroma
• Vanek tumor ○ Can be hyalinized
Definitions • Mixed chronic inflammatory infiltrate in all cases
• Distinctive benign fibroblastic proliferation of ○ Eosinophils typically prominent but may be sparse
gastrointestinal tract characterized by bland, spindled to ○ Lymphoid aggregates common
stellate cells and admixed chronic inflammatory cells within • Mitoses rare to absent; no necrosis
prominent vascularized stroma • Background gastric mucosa often shows features of
chronic gastritis
CLINICAL ISSUES ○ Concomitant Helicobacter pylori infection not uncommon
(up to 1/2 of cases in one large series)
Epidemiology
• Incidence ANCILLARY TESTS
○ Rare
• Age
Immunohistochemistry
○ Most common in older adults (mean: 60 years) • CD34(+) in majority
• Sex • Occasional cases show focal SMA(+), desmin (+)
○ Female predominance • CD117, DOG1, S100, EMA, keratin, ALK1 (-)

Site Molecular Genetics

• Stomach is most common site overall • Activating PDGFRA mutations in majority of cases
○ Particularly gastric antrum ○ Exon 18 mutations most common in stomach
• Also arises in small intestine and colorectum ○ Exon 12 mutations most common in small intestine
• Very rare cases reported in esophagus, appendix, anus
DIFFERENTIAL DIAGNOSIS
Presentation
Gastrointestinal Stromal Tumor
• Nonspecific abdominal pain or asymptomatic
• Can be incidental finding discovered on endoscopy • CD117(+), DOG1(+), CD34(+)
○ For routine screening or for other diseases (e.g., • Most contain KIT mutations
inflammatory bowel disease) • PDGFRA-mutant gastrointestinal stromal tumor much less
• May present with obstructive symptoms related to common than KIT mutants and often shows epithelioid
intussusception morphology
○ Particularly small bowel tumors Inflammatory Myofibroblastic Tumor
Treatment • Most common in children, adolescents, and young adults
• Simple excision or polypectomy • Arises externally to gastrointestinal tract (i.e., mesentery)
• ALK1(+) in majority of cases
Prognosis
Perineurioma
• Excellent
• No significant risk of recurrence • Lamellar, storiform, and whorled growth common
• No malignant potential • EMA(+), claudin-1 (+), variable CD34(+)
• Lacks PDGFRA mutations
MACROSCOPIC
SELECTED REFERENCES
General Features
1. Voltaggio L et al: Polypoid stromal lesions of the intestines. Histopathology.
• Solitary sessile or polypoid growth 66(1):88-101, 2015
○ Overlying surface ulceration in 1/3 of cases 2. Albuquerque A et al: Evaluation of clinico-pathological features and
Helicobacter pylori infection in gastric inflammatory fibroid polyps. Virchows
• Arises from submucosa Arch. 465(6):643-7, 2014
3. Liu TC et al: Inflammatory fibroid polyps of the gastrointestinal tract:
Size spectrum of clinical, morphologic, and immunohistochemistry features. Am
• Most 1-5 cm J Surg Pathol. 37(4):586-92, 2013
4. Daum O et al: Comparison of morphological, immunohistochemical, and
molecular genetic features of inflammatory fibroid polyps (Vanek's tumors).
MICROSCOPIC Virchows Arch. 456(5):491-7, 2010
5. Lasota J et al: Gain-of-function PDGFRA mutations, earlier reported in
Histologic Features gastrointestinal stromal tumors, are common in small intestinal
• Well marginated and submucosal based but can involve inflammatory fibroid polyps. A study of 60 cases. Mod Pathol. 22(8):1049-56,
2009
overlying mucosa
• Loose, haphazard proliferation of bland, spindled to stellate
cells within prominent vascularized stroma

767
 Inflammatory Fibroid Polyp
Mesenchymal Tumors of Gastrointestinal Tract

Mucosal Extension Entrapped Muscularis Mucosa

(Left) Although IFP arises in
the submucosa and is
relatively well marginated,
variable extension into the
overlying mucosa is not
uncommon. Tumor cells often
grow around clusters of
mucosal glands ﬈, as shown
here. (Right) Fragments or
strips of overrun smooth
muscle fibers ﬈ of the
muscularis mucosa may be
seen in cases of IFP with
mucosal extension. Note the
entrapped mucosal glands ﬊.

Colonic Inflammatory Fibroid Polyp Lymphoid Aggregates

(Left) The most common
gastrointestinal tract location
for IFP to arise in is the
stomach (particularly the
antrum); however, it also
occurs in the small intestine
and large intestine (shown).
Note how the tumor cells
grow through and around
mucosal crypts. Although not
obvious at low power,
eosinophils were abundant in
this case. (Right) Stromal
lymphocytes are a common
finding in IFP, as are large
mucosal and submucosal
lymphoid aggregates ﬊.

Multinucleated Giant Cells Stromal Collagen

(Left) Multinucleated stromal
giant cells ﬈ are seen in ~ 1/3
of cases of IFP. Note the
perivascular "onion-skin"
growth ﬉ in this H&E. (Right)
The stroma in IFP varies from
loose and collagenous to
myxoid or edematous. Thin
collagen bundles may be
prominent in some cases, as
depicted in this H&E.

768
 Inflammatory Fibroid Polyp

Mesenchymal Tumors of Gastrointestinal Tract

Hypocellular Tumors Mast Cells
(Left) Some cases of IFP are
paucicellular and can be
prominently hyalinized. The
vascularized stroma is often
better appreciated in these
examples. Of note, eosinophils
may be less conspicuous in
cases of IFP with stromal
hyalinization. (Right) Although
the eosinophil is the most
recognized type of
inflammatory cell associated
with IFP, other types of cells
are commonly present,
including lymphocytes, plasma
cells, and mast cells ﬈.
Neutrophils are not generally
a feature of IFP.

Short Fascicular Growth Vascularized Stroma

(Left) A more organized, short,
fascicular or bundled pattern
of growth can be seen in some
cases of IFP and may lead to
morphologic confusion with
gastrointestinal stromal tumor
(GIST) or neural tumors.
Expression of CD34 in IFP can
also lead to confusion with
GIST; however, IFP is CD117
and DOG1 negative. (Right) A
vascularized stroma is a
typical feature of IFP but
varies in prominence. Vessels
range from small capillaries to
larger, thin-walled vessels.

Myxoid Stroma Myxoid Stroma

(Left) H&E shows an IFP with
areas of loose collagenous
stroma (left) admixed with
areas of prominent myxoid
stroma (right). Some cases are
entirely myxoid. Note the
prominent stromal vasculature
in this H&E. (Right) Even in
areas of myxoid stroma, other
classic features of IFP,
including "onion-skin" growth
(shown) and a mixed
inflammatory cell infiltrate,
can be identified.

769
 Gangliocytic Paraganglioma

KEY FACTS
Mesenchymal Tumors of Gastrointestinal Tract

TERMINOLOGY • 3 main cellular components in varying proportions

• Rare, usually benign, neoplasm composed of 3 distinct
cellular components (neuroendocrine, schwannian, and
ganglion cell) showing marked predilection for duodenum
CLINICAL ISSUES
• Wide age range (median: 50-55 years)
• Arises in duodenum almost exclusively
• Obstructive biliary symptoms common
• Treatment: Complete surgical excision
• Usually benign with great prognosis
• Rare cases may spread to local lymph nodes
MACROSCOPIC
• Pedunculated or sessile mass
• Often small (1-3 cm)
MICROSCOPIC
• Expansile or infiltrative
○ Epithelial (neuroendocrine), schwannian, ganglion cells
– Epithelial component may resemble carcinoid tumor
• Low mitotic activity
ANCILLARY TESTS
• Keratin (+), synaptophysin (+), chromogranin (+) in epithelial
component
• S100 protein (+) in spindled Schwann cell component
• Synaptophysin (+), NSE(+) in ganglion cells
TOP DIFFERENTIAL DIAGNOSES
• Carcinoid tumor
• Gastrointestinal stromal tumor (spindled)
• Paraganglioma (conventional)

Gangliocytic Paraganglioma Neuroendocrine Cell Component

(Left) Gangliocytic
paraganglioma (GPG) is an
unusual neoplasm that shows
a striking predilection for the
duodenum, particularly in the
2nd part near the ampulla of
Vater. Tumors arise in the
submucosa but may extend to
involve the mucosa or
muscular propria. (Right) The
epithelial component of GPG is
composed of nests and
trabeculae of neuroendocrine
cells and is often the most
prominent of the 3
components. The morphology
may closely resemble a
carcinoid tumor.

Spindled Schwann Cell Component Ganglion Cells

(Left) The stromal component
﬈ of GPG is composed of
bland spindled cells with
abundant eosinophilic
cytoplasm that show evidence
of schwannian differentiation,
particularly strong S100
protein expression. (Right)
Ganglion cells ﬊ may be seen
within GPG either singly or in
aggregates, and they
characteristically show
prominent nucleoli. Although
they are well developed in
many cases, in some tumors,
they can be difficult to
visualize.

770
 Gangliocytic Paraganglioma

Mesenchymal Tumors of Gastrointestinal Tract

– Often most prevalent of 3 components
TERMINOLOGY
– Epithelioid to spindled cells with eosinophilic to
Abbreviations amphophilic cytoplasm
• Gangliocytic paraganglioma (GPG) □ Uniform ovoid nuclei
– Arranged in nests ("zellballen" configuration),
Synonyms trabeculae/ribbons, or pseudoglandular structures
• Duodenal ganglioneuroma (often focal)
Definitions □ May closely resemble carcinoid tumor
○ Schwannian
• Rare, usually benign neoplasm composed of 3 distinct
cellular components (neuroendocrine, schwannian, and – Short fascicles and sheets of spindled cells
ganglion cell) showing marked predilection for duodenum – May surround epithelial nests, similar to sustentacular
cells
CLINICAL ISSUES ○ Ganglion cells
– Singly or in clusters; uni- or multinucleated
Epidemiology • Rare psammoma bodies
• Incidence • Mitotic activity low to absent
○ Rare • No necrosis
– Comprise up to 25% of ampullary/periampullary
neuroendocrine neoplasms ANCILLARY TESTS
• Age
Immunohistochemistry
○ Wide range (median: 50-55 years)
• Keratin (+), synaptophysin (+), chromogranin (+) in epithelial
Site component
• Arises in duodenum almost exclusively • S100 protein (+) in spindled Schwann cell component
○ Usually 2nd portion, around ampulla of Vater ○ Also highlights sustentacular cells, if present
• Very rarely in other sites such as jejunum, stomach, • Synaptophysin (+), NSE(+) in ganglion cells
appendix, lung
○ Of note, paraganglioma of cauda equina often shows DIFFERENTIAL DIAGNOSIS
histologic similarities to GPG
Carcinoid Tumor
Presentation • Keratin (+), synaptophysin (+), chromogranin (+)
• Obstructive biliary symptoms common • Lacks spindled S100 protein (+) schwannian component
• May be asymptomatic • Lacks ganglion cells
Treatment Gastrointestinal Stromal Tumor (Spindled)
• Complete surgical excision • Originates in muscularis propria
• Local lymph node dissection may be warranted • Diffuse CD117(+), DOG1(+) in lesional cells
Prognosis • Lacks spindled S100 protein (+) schwannian component
• Lacks ganglion cells
• Usually benign with great prognosis
• Some cases may spread to local lymph nodes Paraganglioma (Conventional)
○ Mostly tumors > 2 cm • Commonly arise along sympathetic nerve trunk
○ Generally does not affect prognosis • Synaptophysin (+), chromogranin (+)
• Lacks spindled S100 protein (+) schwannian component
MACROSCOPIC • Negative for keratins
General Features
SELECTED REFERENCES
• Pedunculated or sessile mass
• May show ulceration of overlying mucosa 1. Cathcart SJ et al: Duodenal gangliocytic paraganglioma with lymph node
metastases: a case report and comparative review of 31 cases. World J Clin
Size Cases. 5(6):222-233, 2017
2. Park HK et al: Duodenal aangliocytic paraganglioma with lymph node
• Often small (1-3 cm) metastasis. Arch Pathol Lab Med. 140(1):94-8, 2016
• Very rare cases > 10 cm 3. Loftus TJ et al: Duodenal gangliocytic paraganglioma: a case report and
literature review. Int J Surg Case Rep. 8C:5-8, 2015
4. Rowsell C et al: Gangliocytic paraganglioma: a rare case with metastases of
MICROSCOPIC all 3 elements to liver and lymph nodes. Ann Diagn Pathol. 15(6):467-71,
2011
Histologic Features 5. Witkiewicz A et al: Gangliocytic paraganglioma: case report and review of the
• Expansile or infiltrative appearance literature. J Gastrointest Surg. 11(10):1351-4, 2007
6. Plaza JA et al: Duodenal gangliocytic paraganglioma: a radiological-
○ Arises in submucosa and may involve muscularis propria pathological correlation. Ann Diagn Pathol. 9(3):143-7, 2005
○ Admixed smooth muscle fibers of muscularis may be 7. Hironaka M et al: Pulmonary gangliocytic paraganglioma: case report and
seen within tumor comparative immunohistochemical study of related neuroendocrine
neoplasms. Am J Surg Pathol. 25(5):688-93, 2001
• 3 main components in varying proportions
○ Epithelial (neuroendocrine)

771
 Plexiform Fibromyxoma

KEY FACTS
Mesenchymal Tumors of Gastrointestinal Tract

TERMINOLOGY MICROSCOPIC
• Distinctive, presumably benign mesenchymal spindle cell • Characteristic infiltrative, multinodular, plexiform growth
neoplasm of stomach that exhibits multinodular and pattern
plexiform growth and abundant myxoid to fibromyxoid • Small, bland spindled cells within abundant myxoid,
matrix fibromyxoid, or collagenous matrix
• Synonym: Plexiform angiomyxoid myofibroblastic tumor • Prominent arborizing capillary vascular network
CLINICAL ISSUES • Mitoses sparse to absent
• Very rare disease ANCILLARY TESTS
• Age range: 7-75 years (mean: 43 years) • SMA(+), often diffuse
• Arises in stomach (specifically antrum) • Occasional focal expression of desmin, caldesmon, CD10
• Treatment: Complete surgical excision • Negative for CD117, DOG1, S100 protein, CD34, keratin
• No recurrences or metastases reported
TOP DIFFERENTIAL DIAGNOSES
MACROSCOPIC • Gastrointestinal stromal tumor
• Arises in submucosa &/or muscularis propria • Leiomyoma
• Overlying mucosal ulceration often present • Inflammatory fibroid polyp
• Size range: 1.9-15.0 cm (mean: 6.3 cm) • Plexiform neurofibroma

Plexiform Fibromyxoma Multinodular, Plexiform Growth

(Left) Plexiform fibromyxoma
(PFM) is a very rare but
distinctive gastric
mesenchymal neoplasm. As its
name implies, the growth
pattern of the tumor is
characteristically plexiform
and multinodular, and
involvement of the muscularis
propria and submucosa is
common. (Right) In most cases
of PFM, the irregular nodules
of the tumor often show a
more pronounced plexiform
growth pattern within the
muscularis propria than in the
submucosa or serosa (if
involved).

Prominent Stromal Vasculature SMA Expression

(Left) The matrix of PFM is
typically myxoid or
fibromyxoid, and the lesional
spindle cells are cytologically
bland. The stromal vasculature
is often prominent and is
composed of mostly small,
thin-walled capillary channels
﬊; however, larger ectatic
vessels can also be seen.
(Right) Although still a matter
of discussion, the lesional cells
of PFM appear to be either
myofibroblasts or modified
smooth muscle cells.
Accordingly, SMA expression is
routinely expressed by tumor
cells ﬈ to a variable degree.

772
 Plexiform Fibromyxoma

Mesenchymal Tumors of Gastrointestinal Tract

○ Pale eosinophilic cytoplasm with indistinct cytoplasmic
TERMINOLOGY borders
Abbreviations ○ Mitoses sparse to absent
• Plexiform fibromyxoma (PFM) • Prominent arborizing capillary vascular network
○ Larger, dilated, thin-walled vessels can be seen
Synonyms
• Mast cell infiltrate common
• Plexiform angiomyxoid myofibroblastic tumor • Coagulative tumor necrosis absent
• Plexiform angiomyxoid tumor
Definitions ANCILLARY TESTS
• Distinctive, presumably benign mesenchymal spindle cell Immunohistochemistry
neoplasm of stomach that exhibits multinodular and • SMA(+), often diffuse but can be patchy
plexiform growth and abundant myxoid to fibromyxoid • Occasional focal expression of desmin, caldesmon, CD10
matrix • Negative for CD117, DOG1, S100 protein, CD34, keratin
CLINICAL ISSUES Molecular Genetics
Epidemiology • Subset with MALAT1-GLI1 fusion
• No KIT or PDGFRA mutations reported
• Incidence
○ Very rare
DIFFERENTIAL DIAGNOSIS
• Age
○ Range: 7-75 years (mean: 43 years) Gastrointestinal Stromal Tumor
• Significantly higher incidence than PFM
Site
• Generally lacks plexiform growth
• Arises in stomach ○ Exceptions: Pediatric and SDH-deficient gastrointestinal
○ Specifically, gastric antrum in all reported case series stromal tumors
– May involve pylorus and can extend to duodenal bulb • CD117(+), DOG1(+)
Presentation • Detectable KIT or PDGFRA mutations
• Variable: Abdominal pain, nausea/vomiting, weight loss, Leiomyoma
obstructive symptoms • Generally lack plexiform growth pattern
• Hematemesis &/or anemia in ulcerated tumors • Cytologic features of smooth muscle differentiation are
Treatment conspicuous
• Complete surgical excision • Prominent myxoid matrix uncommon
• Strong diffuse SMA(+), desmin (+)
Prognosis
Inflammatory Fibroid Polyp
• No recurrences or metastases reported
• Arises in submucosa (very rarely involves muscularis
MACROSCOPIC propria)
• Plexiform growth absent
General Features • CD34(+); SMA(-)
• Arises in muscularis propria and often extends into
submucosa (and mucosa) Plexiform Neurofibroma
○ Larger tumors may show extragastric (serosal) extension • S100 protein (+) and SMA(-)
• Overlying mucosal ulceration often present and may be • Most patients show evidence of neurofibromatosis
extensive • Most common in intestines
• Multinodular, firm or gelatinous, white to brown-red cut Inflammatory Myofibroblastic Tumor
surface
• Prominent chronic inflammatory cell infiltrate, particularly
Size plasma cells
• Range: 1.9-15.0 cm (mean: 6.3 cm) • Most common in children and young adults
• ALK(+) in most cases
MICROSCOPIC
Histologic Features SELECTED REFERENCES
1. Spans L et al: Recurrent MALAT1-GLI1 oncogenic fusion and GLI1 up-
• Characteristic infiltrative, multinodular, plexiform growth regulation define a subset of plexiform fibromyxoma. J Pathol. 239(3):335-
pattern 43, 2016
• Small spindled cells within abundant myxoid, fibromyxoid, 2. Kang Y et al: Plexiform angiomyxoid myofibroblastic tumor of the stomach:
report of two cases and review of the literature. Korean J Pathol. 46(3):292-
or collagenous matrix 6, 2012
○ Variable cellularity but often low 3. Miettinen M et al: Plexiform fibromyxoma: a distinctive benign gastric antral
– More cellular nodules can show focal fascicular neoplasm not to be confused with a myxoid GIST. Am J Surg Pathol.
33(11):1624-32, 2009
growth
4. Takahashi Y et al: Plexiform angiomyxoid myofibroblastic tumor of the
○ Oval, bland nuclei with inconspicuous nucleoli stomach. Am J Surg Pathol. 31(5):724-8, 2007

773
 Plexiform Fibromyxoma
Mesenchymal Tumors of Gastrointestinal Tract

Classic Appearance Muscularis Propria Involvement

(Left) This intermediate-power
image shows the classic
myxoid nodules of PFM
containing bland spindle cells
and conspicuous thin-walled
vascular channels. (Right)
Similar to a gastrointestinal
stromal tumor (GIST), PFM
often arises within the
muscularis propria, at least in
part. However, plexiform
growth is generally
uncommon in GIST, and this
pattern should always raise
the possibility of PFM.

Serosal Involvement Prominent Myxoid Matrix

(Left) Serosal fat involvement
by PFM is generally
uncommon; however, it can be
seen in larger lesions. This
image shows the tumor ﬉
pushing into adipose tissue.
Muscularis propria can be seen
to the left. (Right) Myxoid
matrix is common in PFM and,
in hypocellular areas, may
appear quite prominent.

Focal Clear Cell Appearance Inflammation

(Left) A small zone of clearing
﬈ may form around some
tumor cells in PFM,
reminiscent of lacunae, and,
when focally prominent, can
impart a clear cell appearance.
(Right) Some cases of PFM can
ulcerate the overlying mucosa,
introducing a mixed
inflammatory infiltrate to the
tumor. Granulation tissue can
also be present.

774
 Plexiform Fibromyxoma
Fibrocollagenous Matrix
Increased Cellularity
Vascular Involvement
Mesenchymal Tumors of Gastrointestinal Tract
Fibrocollagenous Matrix
(Left) Although the matrix in
PFM is often myxoid, in some
cases it may be fibromyxoid or
fibrocollagenous, as depicted.
(Right) This higher power
image of PFM shows a nodule
with collagenous matrix. The
cells are overall bland with at
most mild nuclear
enlargement ﬈. Note also the
lacuna-like small zone ﬊ of
clear spacing around some of
the tumor cells.
Rare Fascicular Growth
(Left) Most cases of PFM are
relatively hypocellular or
paucicellular; however, it is
not uncommon for some
nodules to show increased
cellularity. Note, though, the
retention of bland nuclear
features and an absence of
mitotic activity. (Right) Areas
of increased cellularity may be
seen in PFM, and fascicular
growth may be a focal finding,
as depicted. Note the banal
nature of the tumor cells.
SMA Expression
(Left) Occasional cases of PFM
may show focal luminal
involvement ﬈ of capillaries,
lymphatics, or larger muscular-
walled veins. This finding does
not appear to alter the benign
nature of this tumor. (Right)
Expression of SMA is a
relatively consistent finding in
PFM, though variable in
degree. Note the less
prominent staining of the
tumor cells ﬊ as compared to
the smooth muscle cells of the
muscularis propria ﬈. CD117
and DOG1 are negative in
PFM.
775
 Malignant Gastrointestinal Neuroectodermal Tumor

KEY FACTS
Mesenchymal Tumors of Gastrointestinal Tract

TERMINOLOGY
• Synonym: Clear cell sarcoma-like tumor of gastrointestinal
(GI) tract
• Rare, malignant neoplasm of GI tract showing evidence of
primitive neural or neuroectodermal differentiation
○ Melanocytic differentiation absent
CLINICAL ISSUES
• Very rare
• Median age: 36 years
• Most common in small intestine (particularly ileum)
○ Also occurs in stomach and large bowel
• Treatment: Complete surgical resection
• Aggressive clinical course with high mortality rate
○ High rate of local recurrence and metastases (usually to
lymph nodes, liver)
MACROSCOPIC
• Mean: 5.5 cm
MICROSCOPIC
• Cellular proliferation of epithelioid, ovoid, or spindled cells
forming sheets and nests
○ Pale eosinophilic to amphophilic cytoplasm
○ Relatively uniform, vesicular nuclei with small nucleoli
• Other patterns: Pseudopapillary, pseudoalveolar, fascicular
• Osteoclast-like multinucleated giant cells common
ANCILLARY TESTS
• Diffuse S100 protein (+), SOX10(+)
• Keratin, CD117, SMA, melanocytic markers (-)
• Molecular: EWSR1 rearrangements with CREB1 or ATF1
TOP DIFFERENTIAL DIAGNOSES
• Gastrointestinal stromal tumor
• Clear cell sarcoma
• Metastatic melanoma
• Malignant peripheral nerve sheath tumor
• Synovial sarcoma (monophasic or poorly differentiated)

Malignant Gastrointestinal
Neuroectodermal Tumor Sheets and Nests
(Left) Malignant
gastrointestinal
neuroectodermal tumor
(GNET) is a very rare but
distinctive neoplasm of the
gastrointestinal tract that is
usually characterized by an
aggressive clinical course. The
tumor ﬈ primarily involves
the submucosa and muscularis
propria; however, mucosal
involvement is noted in some
cases. (Right) Most cases of
GNET are composed of nests
and sheets of relatively
uniform epithelioid tumor cells
with predominantly pale
eosinophilic cytoplasm.

Cytologic Features S100 Protein Expression

(Left) Nuclei in GNET are
typically round to oval with
somewhat irregular contours
and often contain small
nucleoli; however, in some
areas, nucleoli are prominent.
Nuclear pseudoinclusions ﬈
can also be seen. (Right)
Similar to clear cell sarcoma
(CCS) of soft tissue, most cases
of GNET display strong, diffuse
expression of S100 protein
(shown). In contrast to CCS,
melanocytic antigens (e.g.,
HMB-45, Melan-A) are not
expressed. Note the
osteoclast-like giant cell ﬈,
which is negative for S100 but
can be highlighted with CD68.

776
 Malignant Gastrointestinal Neuroectodermal Tumor

Mesenchymal Tumors of Gastrointestinal Tract

TERMINOLOGY MICROSCOPIC
Abbreviations Histologic Features
• Gastrointestinal neuroectodermal tumor (GNET) • Tumor generally involves submucosa and muscularis
propria
Synonyms
○ May extend into mucosa
• Clear cell sarcoma-like tumor of GI tract (CCSLTGT) • Cellular proliferation of epithelioid, ovoid, or spindled cells
• Clear cell sarcoma-like tumor with osteoclast-like giant cells forming sheets and nests
of GI tract ○ Pale eosinophilic to amphophilic cytoplasm
Definitions – Variable clear cell morphology (often minor)
• Rare, malignant neoplasm of GI tract showing evidence of ○ Relatively uniform, vesicular nuclei with small nucleoli
primitive neural or neuroectodermal differentiation – Nuclear pseudoinclusions may be seen
○ Melanocytic differentiation absent – Cells with prominent nucleoli or nuclear
pleomorphism can be seen
ETIOLOGY/PATHOGENESIS □ Nuclear pleomorphism more common in
recurrent/metastatic lesions
Unknown • Variety of other architectural growth patterns described
• Several reports of GNET/CCSLTGT arising in patients with ○ Pseudoalveolar
prior history of neuroblastoma, acute leukemia, ○ Pseudopapillary
hepatoblastoma ○ Trabecular/corded
○ Potential link to previous radiation therapy ○ Fascicular
○ Microcystic
CLINICAL ISSUES ○ Formation of rosette-like structures
Epidemiology • Osteoclast-like multinucleated giant cells common
• Incidence ○ Vary widely in number; may be absent
○ Very rare • Variable mitotic rate (mean: 6 mitoses per 10 HPF)
• Age • Tumor necrosis common
○ Wide range: 10-81 years ○ May be extensive
○ Median: 36 years • Rare findings: Oncocytic cytomorphology, stromal myxoid
• Sex change
○ M=F
ANCILLARY TESTS
Site
Immunohistochemistry
• Can arise at any location in GI tract
○ Most common in small intestine (particularly ileum) • Diffuse S100 protein (+), SOX10(+)
• All melanocytic markers (-)
Presentation
Molecular Genetics
• Abdominal pain, distention, weight loss, occasional systemic
symptoms • EWSR1 gene (22q12) rearrangement in most cases
• Metastatic disease frequent at initial presentation ○ Fusion partners: CREB1 (2q34) or ATF1 (12q13)
– Identical to true clear cell sarcoma of soft tissue
Treatment
• Complete surgical resection DIFFERENTIAL DIAGNOSIS
Prognosis Gastrointestinal Stromal Tumor
• Aggressive clinical course with high mortality rate • Much more common than GNET
• High rate of local recurrence and metastases • Osteoclast-like giant cells rare
○ Metastases most frequently go to regional lymph nodes • CD117(+), DOG1(+)
and liver • Also CD34(+)
• KIT or PDGFRA mutations
MACROSCOPIC • Lacks EWSR1 rearrangement
General Features Clear Cell Sarcoma
• Transmural, often ulcerating mass • May be primary to GI tract (rare) or metastasis from soft
○ Can also be exophytic/polypoid or circumferential tissue site
• Firm, solid, tan to gray-brown cut surface • Can be morphologically indistinguishable from GNET
○ May show foci of hemorrhage or necrosis • Macronucleoli common
Size • Expression of melanocytic markers (HMB-45, Melan-A, etc.)
○ Key distinguishing feature from GNET
• Range: 2.4-15.0 cm
• Identical EWSR1 rearrangements as seen in GNET
• Mean: 5.5 cm

777
 Malignant Gastrointestinal Neuroectodermal Tumor
Mesenchymal Tumors of Gastrointestinal Tract

Immunohistochemistry
Antibody Reactivity Staining Pattern Comment
S100 Positive Nuclear & cytoplasmic Strong, diffuse expression
SOX10 Positive Nuclear Strong, diffuse expression
HMB-45 Negative
Melan-A Negative Also MART-1 negative
Tyrosinase Negative
MITF Negative
CD68 Negative Highlights osteoclast-like giant cells only
CK-PAN Negative
CD99 Negative
GFAP Negative
CD117 Negative
DOG1 Negative
CD34 Negative
Desmin Negative
Myogenin Negative
Actin-sm Negative
CD56 Equivocal Cell membrane Variable expression (70% of cases)
Synaptophysin Equivocal Cytoplasmic Variable expression (50% of cases)
NB84 Equivocal Cytoplasmic Variable (50% of cases)

• Ultrastructural examination (electron microscopy) may be Synovial Sarcoma (Monophasic or Poorly

helpful
○ True melanosomes present in clear cell sarcoma
Metastatic Melanoma
• Clinical history of previous melanoma may be present
○ Intestinal metastases can present as multiple nodules
• Can show close morphologic overlap with GNET
○ However, nuclear atypia is usually more prominent in
melanoma
• Evidence of melanocytic differentiation
○ Melanin pigment, expression of melanocytic markers by
IHC
• Lacks EWSR1 rearrangement
Alveolar Rhabdomyosarcoma
• May show some morphologic overlap (nests,
pseudoalveolar growth) with GNET
• Desmin (+), myogenin (+)
• S100 protein (-)
• Characteristic t(2;13) or t(1;13)
• Lacks EWSR1 rearrangement
Malignant Peripheral Nerve Sheath Tumor
• Alternating cellularity (marbled pattern) with perivascular
cellularity in classic cases
• Diffuse S100 protein (+) in epithelioid malignant peripheral
nerve sheath tumor (MPNST)
○ Can be challenging to distinguish from GNET
○ Lacks osteoclast-like giant cells
• S100 protein (+) in 60% of spindle cell MPNST
○ Characteristically focal/patchy rather than diffuse
• Lacks EWSR1 rearrangement
Differentiated)
• Very rare in GI tract
• Keratin (+) &/or EMA(+), often focal or patchy
• Strong, diffuse nuclear TLE1
• Minority show focal S100 protein (+)
○ Diffuse expression is not feature
• Characteristic t(X;18) involving SS18 (SYT)
• Lacks EWSR1 rearrangements
SELECTED REFERENCES
1. Green C et al: Clear cell sarcoma of the gastrointestinal tract and malignant
gastrointestinal neuroectodermal tumour: distinct or related entities? A
review. Pathology. 50(5):490-8, 2018
2. Libertini M et al: Clear cell sarcoma-like tumor of the gastrointestinal tract:
clinical outcome and pathologic features of a molecularly characterized
tertiary center case series. Anticancer Res. 38(3):1479-83, 2018
3. Boland JM et al: Oncocytic variant of malignant gastrointestinal
neuroectodermal tumor: a potential diagnostic pitfall. Hum Pathol. 57:13-6,
2016
4. Wang J et al: Clear cell sarcoma-like tumor of the gastrointestinal tract: an
evolving entity. Arch Pathol Lab Med. 139(3):407-12, 2015
5. Kong J et al: Malignant gastrointestinal neuroectodermal tumor: a case
report and review of the literature. Oncol Lett. 8(6):2687-290, 2014
6. Thway K et al: Clear cell sarcoma-like tumor of the gastrointestinal tract,
presenting as a second malignancy after childhood hepatoblastoma. Case
Rep Med. 2014:984369, 2014
7. Stockman DL et al: Malignant gastrointestinal neuroectodermal tumor:
clinicopathologic, immunohistochemical, ultrastructural, and molecular
analysis of 16 cases with a reappraisal of clear cell sarcoma-like tumors of the
gastrointestinal tract. Am J Surg Pathol. 36(6):857-68, 2012
8. Kosemehmetoglu K et al: Clear cell sarcoma of tendons and aponeuroses,
and osteoclast-rich tumour of the gastrointestinal tract with features
resembling clear cell sarcoma of soft parts: a review and update. J Clin
Pathol. 63(5):416-23, 2010
9. Friedrichs N et al: Clear cell sarcoma-like tumor with osteoclast-like giant cells
in the small bowel: further evidence for a new tumor entity. Int J Surg
Pathol. 13(4):313-8, 2005

778
 Malignant Gastrointestinal Neuroectodermal Tumor
Osteoclast-Like Giant Cells
Pseudoalveolar Growth
Trabecular/Corded Growth
Mesenchymal Tumors of Gastrointestinal Tract
Clear Cell Change
(Left) Osteoclast-like giant
cells ﬈ are seen in ~ 50% of
cases of GNET and are a
helpful clue to the diagnosis
when present. Metastatic
clear cell sarcoma and
melanoma, however, may
feature these giant cells as
well and therefore must
always be considered and
excluded. (Right) Cytoplasmic
clearing may be seen in GNET
but is generally not a
prominent finding.
Pseudopapillary Growth
(Left) A pseudoalveolar
pattern ﬊ may manifest in
GNET, created by nests of
tumor cells with central loss of
cellular cohesion. This
appearance is similar to what
is seen in alveolar
rhabdomyosarcoma. (Right)
This H&E shows an area of
GNET with prominent cellular
dyscohesion, rendering the
vasculature ﬉ more
prominent and imparting a
vague pseudopapillary
pattern. Note the larger
osteoclast-like giant cell ﬈.
Fascicular Spindle Cell Morphology
(Left) A compressed trabecular
or corded growth pattern may
also be seen in GNET, as
depicted. Although not shown
here, microcystic foci and
rosette-like structures have
also been reported in this
tumor. (Right) Although most
tumor cells in GNET are
epithelioid, spindled cells can
also often be identified, at
least focally. In some tumors,
areas of fascicular growth can
be appreciated, as depicted.
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 SECTION 19

Other Entities

Benign
Amyloidoma 782
Ganglion Cyst 784
Tumoral Calcinosis 786
Idiopathic Tumefactive Fibroinflammatory Lesions 788
Cardiac Myxoma 792
Cardiac Fibroma 796
Congenital Granular Cell Epulis 798
Nasopharyngeal Angiofibroma 800
Sinonasal Glomangiopericytoma 804
Ectopic Meningioma 810
Glial Heterotopia 812

Intermediate
Paraganglioma 814
Peripheral Hemangioblastoma 822
Melanotic Neuroectodermal Tumor of Infancy 824
Ependymoma of Soft Tissue 826

Malignant
Metastatic Tumors to Soft Tissue Sites 828
Neuroblastoma and Ganglioneuroblastoma 832
Extraaxial Soft Tissue Chordoma 842
Undifferentiated Embryonal Sarcoma of Liver 844
Primary Pulmonary Myxoid Sarcoma 846
Biphenotypic Sinonasal Sarcoma 850
Spindle Epithelial Tumor With Thymus-Like Differentiation 854
Low-Grade Endometrial Stromal Sarcoma 856
 Amyloidoma

KEY FACTS
Other Entities

TERMINOLOGY MICROSCOPIC
• Solitary, localized, tumor-like deposit of amyloid • Amorphous acellular eosinophilic material in lobules and
sheets
ETIOLOGY/PATHOGENESIS
• Adjacent lymphoplasmacytic infiltrate
• Idiopathic • Multinucleated foreign body-type giant cells
• Related to underlying hematologic disease (myeloma, • Vessel walls often involved
lymphoplasmacytic lymphoma)
• Long-term hemodialysis ANCILLARY TESTS
• Chronic inflammatory or infectious disease • Congo red (+)
○ Apple green birefringent areas in polarized light
CLINICAL ISSUES
• May occur in essentially any site TOP DIFFERENTIAL DIAGNOSES
• Treated by excision • Elastofibroma
• Prognosis related to underlying disease, if present • Collagen
• Tophaceous gout
MACROSCOPIC
• Fibrin deposits
• Pale waxy cut surface
• Tumoral calcinosis

Amyloidoma Amyloid
(Left) Amyloid appears
histologically as acellular,
amorphous eosinophilic
material in well-delineated
lobules and sheets. A patchy
lymphoplasmacytic infiltrate
ſt is often present, and a
peripheral multinucleated
foreign body giant cell
reaction ﬇ may also be seen.
(Right) Amyloid deposits are
essentially acellular and may
involve vessel walls,
surrounding connective tissue,
or both.

Congo Red Stain Polarized Congo Red

(Left) A Congo red stain
highlights amyloid deposits
with a prominent red-orange
coloration. Care must be
taken, however, as Congo red
can also stain collagen, albeit
somewhat less intensely.
(Right) Under polarized light,
amyloid deposits stained with
Congo red show a
characteristic apple green
birefringence ſt. Other colors,
such as yellow and orange,
may be seen as well but are
nonspecific.

782
 Amyloidoma

Other Entities
TERMINOLOGY MICROSCOPIC
Synonyms Histologic Features
• Tumoral amyloidosis • Amorphous, acellular, eosinophilic material in lobules and
sheets
Definitions
• Vessel walls often involved
• Solitary, localized tumor-like deposit of amyloid • Plasma cell and lymphocytic infiltrate
• Multinucleated foreign body-type giant cells
ETIOLOGY/PATHOGENESIS • Calcification or metaplastic bone/cartilage may be present
Idiopathic
• No associated disease ANCILLARY TESTS
Immunocytic Dyscrasias Histochemistry
• Plasma cell myeloma, lymphoplasmacytic lymphoma • Congo red (+)
• Usually AL (light chain) type of amyloid ○ Prominent red-orange staining
○ Overall most common type of amyloid in localized • PAS-diastase (+)
tumors • Crystal violet (+)

Long-Term Hemodialysis Electron Microscopy

• β2-microglobulin type of amyloid • Nonbranching fibrils 7-10 nm in diameter

Chronic Inflammatory or Infectious Disease DIFFERENTIAL DIAGNOSIS

• Rheumatoid arthritis
Elastofibroma
• Osteomyelitis
• Tuberculosis • Scapular location
• AA type of amyloid (associated with serum amyloid A • Elastic stain shows fragmented and globular fibers
protein) • Congo red (-)
Collagen
CLINICAL ISSUES • Appears Congo red (+)
Epidemiology ○ Less intense staining than amyloid
• Incidence ○ Difficult cases can be evaluated for amyloid by mass
○ Rare spectrometry
• Age • Associated with fibroblasts
○ Usually older adults • Parallel orientation
• Sex Tophaceous Gout
○ Male or female
• Amorphous eosinophilic material associated with
Site multinucleated giant cells
• Extremities, trunk, head and neck region • Congo red (-)
• Mediastinum, retroperitoneum • Contains needle-shaped crystals that polarize
• Bone, lung, bladder, gastrointestinal tract, and nervous Tumoral Calcinosis
system also reported
• Associated with fibroblastic proliferation
Presentation • Prominent basophilic calcification
• Solitary, painless mass Fibrin
○ Rarely multifocal
• Fibrillary &/or grainy appearance
• May have symptoms related to underlying hematologic,
• Associated red cells and neutrophils
inflammatory, or infectious disease
• Congo red (-)
Treatment
• Surgical excision SELECTED REFERENCES
1. Clark TC et al: Bilateral multifocal lower extremity localized soft tissue
Prognosis amyloidomas: case report with ultrasonographic characterization. Skeletal
• Relates to prognosis of underlying condition (myeloma, Radiol. 46(12):1783-1789, 2017
etc.) 2. Pasternak S et al: Soft tissue amyloidoma of the extremities: report of a case
and review of the literature. Am J Dermatopathol. 29(2):152-5, 2007
3. Bardin RL et al: Soft tissue amyloidoma of the extremities: a case report and
MACROSCOPIC review of the literature. Arch Pathol Lab Med. 128(11):1270-3, 2004
4. Sidoni A et al: Amyloid tumours in the soft tissues of the legs. Case report
General Features and review of the literature. Virchows Arch. 432(6):563-6, 1998
• Lobulated firm mass 5. Krishnan J et al: Tumoral presentation of amyloidosis (amyloidomas) in soft
tissues. A report of 14 cases. Am J Clin Pathol. 100(2):135-44, 1993
• Pale, waxy cut surface

783
 Ganglion Cyst

KEY FACTS
Other Entities

TERMINOLOGY MACROSCOPIC
• Presumably nonneoplastic cystic formation often • Usually attached to tendon sheath or joint capsule
associated with tendon sheath or joint capsule • Soft, cystic, superficial mass
ETIOLOGY/PATHOGENESIS • Often fragmented when surgically excised
• Formation may be related to degeneration of MICROSCOPIC
fibroconnective and meniscal tissue • Uni- or multiloculated cystic areas lined by dense
CLINICAL ISSUES collagenous rind
○ Cysts often filled with mucoid fluid
• Most common tumor of hand and wrist
– No epithelial lining
• Usually 25-45 years of age
• Myxoid stromal changes
• More common in women
• No significant nuclear atypia or mitoses
• Dorsal surface of wrist is most common site
• History of trauma may be present TOP DIFFERENTIAL DIAGNOSES
• Treated by aspiration or surgical excision • Myxoma
• Benign; excellent prognosis • Myxofibrosarcoma (low grade)
○ Rare recurrences • Neurofibroma

Uni- and Multiloculated Cysts Nonepithelial Lining

(Left) Ganglion cysts are uni-
or multiloculated cystic
growths that classically arise
in the dorsal wrist. Note the
cyst walls ﬈. These cysts are
often surrounded by a thick
fibrous lining or capsule ﬊.
(Right) The cystic spaces are
not true cysts as they lack an
epithelial lining ﬈. The
adjacent connective tissue
contains bland fibroblasts and
generally appears
histologically innocuous.

Reactive Changes Myxoid Material

(Left) The connective tissue
between the cysts often shows
a variable degree of reactive
change, and foci of subtle
myxoid change, resembling
myxoma ﬈, are common.
(Right) The material within the
cysts is usually clear and
gelatinous grossly but appears
myxoid histologically. In some
cases it can also spill into the
surrounding connective tissue
(shown), occasionally inciting
a reactive myofibroblastic or
vascular proliferation.

784
 Ganglion Cyst

Other Entities
○ No true epithelial lining
TERMINOLOGY
○ Cysts are uni- or multiloculated and may be filled with
Synonyms mucoid fluid
• Ganglion • Myxoid stromal changes adjacent to cysts
○ Extension of mucoid fluid into surrounding tissue may
Definitions incite reactive myofibroblastic or vascular proliferation
• Presumably nonneoplastic cystic formation often • No significant nuclear atypia
associated with tendon sheath or joint capsule • No significant mitotic activity

ETIOLOGY/PATHOGENESIS DIFFERENTIAL DIAGNOSIS

Nonneoplastic Myxoma
• Exact etiology uncertain • Absence of thick-walled cystic structures
• Formation may be related to degeneration of • Not common in dorsal wrist
fibroconnective and meniscal tissue
Myxofibrosarcoma (Low Grade)
CLINICAL ISSUES • Multinodular, subcutaneous neoplasm
Epidemiology ○ Evidence of infiltrative growth
• Often extensively myxoid with at least focal nuclear atypia
• Incidence
• Patient age often > 50 years
○ Common
• Usually > 3 cm
– Most common tumor of hand and wrist
• Age Neurofibroma
○ Usually 25-45 years • Generally lacks cystic spaces with mucoid material
– Can be seen in pediatric population • S100(+)
• Sex
○ More common in women DIAGNOSTIC CHECKLIST
Site Clinically Relevant Pathologic Features
• Dorsal surface of wrist (most common) • Small, superficial fluctuant mass
• Less likely foot, toes, knee, hip, and volar surface of wrist • Most common in dorsal wrist
• May arise in bone (intraosseous ganglion) or rarely involve • May also arise in bone (intraosseous ganglion)
nerve (intraneural ganglion)
Pathologic Interpretation Pearls
Presentation • Thick-walled cystic structures containing mucoid material
• Soft, cystic, superficial mass • Often fragmented when surgically excised
• Main be painful or tender (50% of cases) • No nuclear hyperchromasia or pleomorphism
• History of trauma may be present
Treatment
SELECTED REFERENCES
1. Meyerson J et al: Pediatric ganglion cysts: a retrospective review. Hand (N Y).
• Surgical approaches 1558944717751195, 2018
○ Surgical excision 2. Crawford C et al: Arthroscopic versus open excision of dorsal ganglion cysts:
○ Nonoperative approach by aspiration of fluid a systematic review. J Hand Surg Eur Vol. 1753193417734428, 2017
3. Wilson TJ et al: Intraneural ganglion cysts: a predictable method to their
Prognosis madness. Ann Phys Rehabil Med. 60(6):414-415, 2017
4. Kim JP et al: Arthroscopic excision of dorsal wrist ganglion: factors related to
• Excellent recurrence and postoperative residual pain. Arthroscopy. 29(6):1019-24,
• Benign 2013
• Higher risk of recurrence reported in pediatric population 5. Sakamoto A et al: Intraosseous Ganglia: a series of 17 treated cases. Biomed
Res Int. 2013:462730, 2013
6. Simon Cypel TK et al: Ganglion cyst in children: reviewing treatment and
MACROSCOPIC recurrence rates. Can J Plast Surg. 19(2):53-5, 2011
7. Casal D et al: Paresthesia and hypesthesia in the dorsum of the foot as the
General Features presenting complaints of a ganglion cyst of the foot. Clin Anat. 23(5):606-10,
• Usually attached to tendon sheath or joint capsule 2010
8. Schajowicz F et al: Juxta-articular bone cysts (intra-osseous ganglia): a
• No communication with joint space clinicopathological study of eighty-eight cases. J Bone Joint Surg Br.
• Small cysts often contain clear, sticky fluid 61(1):107-16, 1979
• Often excised in fragments
Size
• Usually < 3 cm

MICROSCOPIC
Histologic Features
• Cystic areas lined by dense collagenous rind
785
 Tumoral Calcinosis

KEY FACTS
Other Entities

TERMINOLOGY MACROSCOPIC
• Tumor-like deposits of calcium hydroxyapatite in • Firm, rubbery, multiloculated cystic mass containing milky
periarticular soft tissues fluid or semisolid gritty material
ETIOLOGY/PATHOGENESIS MICROSCOPIC
• 3 forms: Sporadic/idiopathic, familial, and secondary • Morphology is same regardless of form (sporadic, familial,
secondary)
CLINICAL ISSUES
• Variably calcified amorphous granular material
• Usually < 20 years of age (hydroxyapatite crystals) within cystic spaces
• Firm, painless subcutaneous mass • Cystic spaces separated by thick fibrous septa
• Subcutis around large joints ○ Lined by histiocytes and variable number of
○ Hip, elbow, and shoulder most common multinucleated giant cells
• Attached to underlying fascia or tendons
• Treatment: Surgical excision for sporadic/idiopathic and
TOP DIFFERENTIAL DIAGNOSES
familial forms • Calcified soft tissue chondroma
○ Treatment of underlying systemic condition is often • Milk alkali syndrome
necessary in secondary forms • Tophaceous gout
• Tophaceous pseudogout

Multiloculated Cystic Pattern Calcification

(Left) Tumoral calcinosis is
characterized by multiple
variably sized cystic spaces
containing amorphous
granular material and divided
by thick fibrous septa. The
overall degree of calcification
varies based upon the duration
of the lesion. (Right) The
calcium apatite crystals of
tumoral calcinosis appear as
amorphous eosinophilic
granular material ﬈ within
the cystic spaces.
Superimposed basophilic
calcification ﬊ often varies
from cyst to cyst and ranges
from heavy involvement to
absent.

Multinucleated Giant Cells Psammoma Body-Like Calcification

(Left) Histiocytes and
multinucleated giant cells are
commonly identified in
association with calcium
apatite crystals in active
tumoral calcinosis. (Right) In
more longstanding cases of
tumoral calcinosis, cystic
spaces may be absent and only
calcified aggregates remain
within hyalinized fibrous
tissue. Occasionally, the
calcium deposits are rounded
and lamellated (shown),
resembling psammoma bodies
or possibly even parasitic ova.

786
 Tumoral Calcinosis

Other Entities
• Radiolucent septations
TERMINOLOGY
• May see fluid levels in some nodules
Synonyms
• Lipid calcinosis, tumoral lipocalcinosis MACROSCOPIC
• Calcifying collagenolysis, calcifying bursitis General Features
• Hip stone disease
• Firm, rubbery, multiloculated cystic mass
Definitions • Cystic spaces contain milky white-yellow fluid or semisolid,
• Tumor-like deposits of calcium hydroxyapatite in gritty material
periarticular soft tissues Size
• Ranges from several mm up to 30 cm
ETIOLOGY/PATHOGENESIS
Three Forms MICROSCOPIC
• Sporadic/idiopathic (most common) Histologic Features
• Familial
• Morphology is same regardless of form (sporadic, familial,
○ Autosomal recessive secondary)
○ Hyperphosphatemic type: Mutations in GALNT3, FGF23, • Amorphous granular material (hydroxyapatite crystals)
or KL genes within cystic spaces
○ Normophosphatemic type: Mutations in SAMD9 gene ○ Variable degrees of chunky basophilic calcification
• Secondary • Cystic spaces separated by thick fibrous septa
○ Presence of underlying disorder (e.g., chronic renal ○ Lined by histiocytes and variable number of
failure) that promotes ectopic calcification multinucleated giant cells
• May have psammoma body-like calcospherites
CLINICAL ISSUES • Early lesions may show fibrohistiocytic proliferation without
Epidemiology calcification, and late lesions may be entirely calcified
• Age
○ Most cases < 20 years (rarely over 50 years) DIFFERENTIAL DIAGNOSIS
• Ethnicity Calcified Soft Tissue Chondroma
○ Familial form more common in African Americans • Usually distal extremities (hands and feet)
Site • Component of hyaline cartilage
• Subcutis around large joints Milk Alkali Syndrome
○ Hip, elbow, and shoulder most common • Clinical history
• May be multiple • Hypercalcemia
• Subset of similar lesions in acral extremities (tumoral
calcinosis-like lesions) Tophaceous Gout
○ Some associated with trauma or scleroderma • Polarizable, negatively birefringent needle-shaped crystals
• Usually lack degree of calcification seen in tumoral
Presentation
calcinosis
• Firm, painless, subcutaneous mass • Deposits appear amorphous and eosinophilic
○ Attached to underlying fascia and tendons
○ Unrelated to bone and joint Tophaceous Pseudogout
○ Rarely ulcerates overlying skin • Polarizable, positively birefringent, rhomboid-shaped
• In secondary forms, may show symptoms related to calcium pyrophosphate crystals
underlying disease • Deposits appear basophilic (calcium)
• Incites fibroblastic rather than histocytic response
Treatment
• Surgical excision for sporadic/idiopathic and familial forms SELECTED REFERENCES
• Medical treatment of underlying systemic condition is often
1. Banshelkikar SN et al: Idiopathic tumoral calcinosis with unusual
necessary in secondary forms presentation-case report with review of literature. J Orthop Case Rep.
4(3):59-62, 2014
Prognosis 2. Fathi I et al: Review of tumoral calcinosis: a rare clinico-pathological entity.
• Benign World J Clin Cases. 2(9):409-14, 2014
3. Chaabane S et al: Idiopathic tumoral calcinosis. Acta Orthop Belg. 74(6):837-
• Familial forms may recur 45, 2008
• Secondary forms depend upon treatment of underlying 4. Laskin WB et al: Calcareous lesions of the distal extremities resembling
systemic condition tumoral calcinosis (tumoral calcinosislike lesions): clinicopathologic study of
43 cases emphasizing a pathogenesis-based approach to classification. Am J
Surg Pathol. 31(1):15-25, 2007
IMAGING 5. Möckel G et al: Tumoral calcinosis revisited: pathophysiology and treatment.
Rheumatol Int. 25(1):55-9, 2005
General Features
• Rounded nodules of dense periarticular calcification

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 Idiopathic Tumefactive Fibroinflammatory Lesions

KEY FACTS
Other Entities

TERMINOLOGY • Benign, nonneoplastic; good overall prognosis

• Group of mass-forming inflammatory disorders of
uncertain etiology characterized by fibrosclerosis and
variable chronic inflammatory infiltrate
○ Sclerosing mesenteritis, idiopathic retroperitoneal
fibrosis (IRF), and IgG4-related sclerosing disease (IgG4-
SD)
ETIOLOGY/PATHOGENESIS
• Uncertain/unknown
CLINICAL ISSUES
• Middle-aged to elderly adults
○ Male predominance in IRF and IgG4-SD
• IgG4-SD commonly shows visceral organ involvement
• Urinary obstructive symptoms common in IRF
• Serum IgG4 levels often elevated in IgG4-SD
• Treatment: Surgical excision for sclerosing mediastinitis
○ Long-term corticosteroid therapy for IRF and IgG4-SD
MICROSCOPIC
• Sclerosing mesenteritis and IRF
○ Abundant fibrosis with chronic inflammatory infiltrate
○ Fat necrosis common in sclerosing mesenteritis
• IgG4-SD
○ Storiform fibrosis, prominent lymphoplasmacytic
infiltrate, obliterative phlebitis, native tissue atrophy
ANCILLARY TESTS
• Elevated numbers of IgG4(+) plasma cells or increased
IgG4:IgG ratio can support diagnosis of IgG4-SD
TOP DIFFERENTIAL DIAGNOSES
• Inflammatory myofibroblastic tumor
• Lymphoma
• Well-differentiated liposarcoma (sclerosing type)

Fibroinflammatory Process Chronic Inflammatory Infiltrate

(Left) Sclerosing mesenteritis
and idiopathic retroperitoneal
fibrosis (IRF) are histologically
similar. Both are characterized
by fibrosclerosis of region
adipose and connective tissue
with a variable prominent
chronic inflammatory
infiltrate ſt. (Right) Chronic
inflammatory cells are typical
of the tumoral
fibroinflammatory diseases
and usually consist of mainly
lymphocytes and plasma cells;
the latter is usually more
prominent in a true IgG4-
related disease. Eosinophils ﬈
may also be seen.

Fat Necrosis Germinal Centers

(Left) Fat necrosis is a common
finding in sclerosing
mesenteritis but may be seen
in other disorders. It is
identified by eosinophilic to
clear/foamy histiocytes
associated with adipocytes ﬈.
(Right) A few germinal centers
﬈ may be seen in sclerosing
mesenteritis and IRF; however,
they are often much more
numerous in an IgG4-related
process.

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 Idiopathic Tumefactive Fibroinflammatory Lesions

Other Entities
• IRF
TERMINOLOGY
○ Abdominal or back pain
Abbreviations ○ Urinary obstructive symptoms; possible acute renal
• IgG4-related sclerosing disease (IgG4-SD) failure
• Idiopathic retroperitoneal fibrosis (IRF) ○ Elevated C-reactive protein level and erythrocyte
sedimentation rate common
Synonyms ○ Cases with coexistence of visceral organ involvement
• Idiopathic tumoral fibroinflammatory disorders suggests IgG4-SD
• Mesenteric lipodystrophy, mesenteric panniculitis, or • IgG4-SD
retractile mesenteritis (sclerosing mesenteritis) ○ Symptoms depend upon sites involved
• Ormond disease (IRF) – Organ involvement common and characteristic
Definitions ○ Fever, constitutional symptoms uncommon
• Group of mass-forming inflammatory disorders of ○ Serum IgG4 levels often elevated
uncertain etiology characterized by fibrosclerosis and – May be low or normal following resection of tumoral
variable chronic inflammatory infiltrate mass
○ Sclerosing mesenteritis Treatment
○ IRF • Sclerosing mesenteritis
○ IgG4-SD ○ Simple surgical excision
– Systemic fibrosing disorder + visceral involvement and • IRF
variably elevated serum IgG4 ○ Long-term corticosteroid therapy
○ Ureteral stenting
ETIOLOGY/PATHOGENESIS
• IgG4-SD
Uncertain Etiology ○ Long-term corticosteroid therapy
• IgG4-SD may be related to autoimmune, infection (e.g., Prognosis
Helicobacter pylori), or allergy/hypersensitivity
• Benign, nonneoplastic
○ Specific trigger unknown
• Good overall; treatments generally effective
• Subset of cases of sclerosing mesenteritis and primary IRF
are related to IgG4-SD • Rare reported cases complicated by development of
lymphoma
○ Secondary retroperitoneal fibrosis can occur from
radiotherapy, certain drugs (e.g., methysergide), and
certain tumors (e.g., lymphoma) MACROSCOPIC
General Features
CLINICAL ISSUES • Hard, tan-white tissue + gritty cut surface
Epidemiology Size
• Incidence • Wide range (nodules/masses can be > 10 cm)
○ Sclerosing mesenteritis is most common of idiopathic
fibroinflammatory disorders MICROSCOPIC
• Age
○ Middle-aged to elderly adults Histologic Features
• Sex • Sclerosing mesenteritis
○ Male predominance in IRF and IgG4-SD ○ Hypocellular + abundant fibrosis
○ Chronic inflammatory infiltrate
Site
– Mainly lymphocytes and histiocytes
• Mesentery or retroperitoneum (sclerosing mesenteritis and – Occasional lymphoid aggregates
IRF, respectively) ○ Fat necrosis may be prominent
• IgG4-SD ○ May show calcification
○ Pancreas, liver/biliary tract, orbit, salivary gland, lung, • IRF
other visceral organs
○ Similar to sclerosing mesenteritis
○ Skin, central nervous system, lymph nodes,
– Abundant fibrosis or sclerosis + chronic inflammatory
retroperitoneum
infiltrate
Presentation • IgG4-SD
• Usually slow-growing masses ○ Storiform fibrosis characteristic
• Sclerosing mesenteritis – Extraparenchymal extension common
○ Abdominal pain ○ Prominent lymphoplasmacytic infiltrate
○ May be detected incidentally – Often abundant lymphoid aggregates
– Solitary or multiple mesenteric masses or diffuse – May show increased eosinophils
thickening of mesentery ○ May show inflammation and destructive of large veins
○ Cases with coexistence of visceral organ involvement and venules (obliterative phlebitis)
suggests IgG4-SD (rare) ○ Atrophy &/or destruction of native tissue
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 Idiopathic Tumefactive Fibroinflammatory Lesions
Other Entities
ANCILLARY TESTS
Immunohistochemistry
• IgG4-SD
○ In general, elevated numbers of IgG4(+) plasma cells can
support diagnosis
– Minimum of 30-40 IgG4(+) plasma cells per HPF
– IgG4 plasma cells comprise > 40% of total IgG plasma
cells (> 0.4:1.0 ratio)
• Sclerosing mesenteritis and IRF
○ Immunohistochemistry best used to exclude other
diagnoses (e.g., carcinoma, lymphoma)
○ Subset may be related to IgG4-SD [show elevated IgG4(+)
plasma cells or increased IgG4:total IgG ratio]
DIFFERENTIAL DIAGNOSIS
Inflammatory Myofibroblastic Tumor
• Most common in children, adolescents, and young adults
• Generally well circumscribed
• More cellular with fascicles of plump myofibroblasts
• Absence of obliterative phlebitis and lack of abundant
lymphoid aggregates
• Most cases have few IgG4(+) plasma cells
• ALK(+) in 50-60% of cases
Lymphoma
• Clonal B-cell lymphoid population
○ Immunohistochemistry can be very helpful
• Stromal sclerosis uncommon in lymphoma
○ Exception: Rare cases of follicular lymphoma
• Most lymphomas lack plasma cell population
Well-Differentiated Liposarcoma (Sclerosing Type)
• Can show histologic overlap with IRF
• Atypical, pleomorphic stromal "smudge" cells are
characteristic of well-differentiated liposarcoma
Reactive Nonlesional Fibroblastic Proliferation
• Different clinical presentation from sclerosing mesenteritis,
IRF, and IgG4-SD
• Mixed acute and chronic inflammation ± granulation tissue
formation
• May be related to prior surgical procedure or secondary to
unsampled carcinoma
Fibrosing (Sclerosing) Mediastinitis
• Related to chronic Histoplasma infection
• May show histologic overlap with IgG4-SD
○ Occasional cases show increased numbers of IgG4(+)
plasma cells
Desmoid Fibromatosis
• Generally young adults
• Usually more cellular with long, "sweeping" fascicles of
myofibroblastic cells
• Negligible inflammatory infiltrate
• Nuclear β-catenin (+) in 70% of cases
Gastrointestinal Stromal Tumor
• More cellular but variety of architectures and morphologies
• Stromal sclerosis uncommon
• CD117(+), DOG1(+), CD34(+)
790
Extranodal Rosai-Dorfman Disease
• Most cases lack diffuse sclerosis
• Large histiocytes with emperipolesis
○ S100 protein (+)
SELECTED REFERENCES
1. Martorana D et al: A large-scale genetic analysis reveals an autoimmune
origin of idiopathic retroperitoneal fibrosis. J Allergy Clin Immunol.
142(5):1662-65, 2018
2. Sulieman I et al: IgG4-related disease mimicking pancreatic cancer: case
report and review of the literature. Int J Surg Case Rep. 50:100-5, 2018
3. Tzou M et al: Retroperitoneal fibrosis. Vasc Med. 19(5):407-14, 2014
4. Khosroshahi A et al: Rethinking Ormond's disease: "idiopathic"
retroperitoneal fibrosis in the era of IgG4-related disease. Medicine
(Baltimore). 92(2):82-91, 2013
5. Cheuk W et al: Lymphadenopathy of IgG4-related disease: an
underdiagnosed and overdiagnosed entity. Semin Diagn Pathol. 29(4):226-
34, 2012
6. Divatia M et al: IgG4-related sclerosing disease, an emerging entity: a review
of a multi-system disease. Yonsei Med J. 53(1):15-34, 2012
7. Grimm KE et al: Histopathological findings in 29 lymph node biopsies with
increased IgG4 plasma cells. Mod Pathol. 25(3):480-91, 2012
8. Saab ST et al: IgG4 plasma cells in inflammatory myofibroblastic tumor:
inflammatory marker or pathogenic link? Mod Pathol. 24(4):606-12, 2011
9. Cheuk W et al: IgG4-related sclerosing disease: a critical appraisal of an
evolving clinicopathologic entity. Adv Anat Pathol. 17(5):303-32, 2010
10. Geyer JT et al: Chronic sclerosing sialadenitis (Küttner tumor) is an IgG4-
associated disease. Am J Surg Pathol. 34(2):202-10, 2010
11. Inoue D et al: Immunoglobulin G4-related lung disease: CT findings with
pathologic correlations. Radiology. 251(1):260-70, 2009
12. Vega J et al: Treatment of idiopathic retroperitoneal fibrosis with colchicine
and steroids: a case series. Am J Kidney Dis. 53(4):628-37, 2009
13. Yamamoto H et al: Inflammatory myofibroblastic tumor versus IgG4-related
sclerosing disease and inflammatory pseudotumor: a comparative
clinicopathologic study. Am J Surg Pathol 33: 1330-40, 2009
14. Zen Y et al: Retroperitoneal fibrosis: a clinicopathologic study with respect to
immunoglobulin G4. Am J Surg Pathol. 33(12):1833-9, 2009
15. Chen TS et al: Are tumefactive lesions classified as sclerosing mesenteritis a
subset of IgG4-related sclerosing disorders? J Clin Pathol. 61(10):1093-7,
2008
16. Cheuk W et al: Lymphadenopathy of IgG4-related sclerosing disease. Am J
Surg Pathol. 32(5):671-81, 2008
17. Akram S et al: Sclerosing mesenteritis: clinical features, treatment, and
outcome in ninety-two patients. Clin Gastroenterol Hepatol. 5(5):589-96;
quiz 523-4, 2007
18. Björnsson E et al: Immunoglobulin G4 associated cholangitis: description of
an emerging clinical entity based on review of the literature. Hepatology.
45(6):1547-54, 2007
19. Zhang L et al: IgG4-positive plasma cell infiltration in the diagnosis of
autoimmune pancreatitis. Mod Pathol. 20(1):23-8, 2007
20. Kitagawa S et al: Abundant IgG4-positive plasma cell infiltration characterizes
chronic sclerosing sialadenitis (Küttner's tumor). Am J Surg Pathol.
29(6):783-91, 2005
21. Zen Y et al: IgG4-positive plasma cells in inflammatory pseudotumor (plasma
cell granuloma) of the lung. Hum Pathol. 36(7):710-7, 2005
22. Abraham SC et al: Pancreaticoduodenectomy (Whipple resections) in
patients without malignancy: are they all 'chronic pancreatitis'? Am J Surg
Pathol. 27(1):110-20, 2003
23. Montgomery E et al: Beta-catenin immunohistochemistry separates
mesenteric fibromatosis from gastrointestinal stromal tumor and sclerosing
mesenteritis. Am J Surg Pathol. 26(10):1296-301, 2002
24. Emory TS et al: Sclerosing mesenteritis, mesenteric panniculitis and
mesenteric lipodystrophy: a single entity? Am J Surg Pathol. 21(4):392-8,
1997
 Idiopathic Tumefactive Fibroinflammatory Lesions

Other Entities
Dense Collagen Calcification
(Left) Dense or sclerotic
collagen is a consistent finding
in the tumoral
fibroinflammatory diseases
and may be patchy or
extensive. (Right) Calcification
ſt may be seen in some cases
of sclerosing mesenteritis or
IRF, particularly in
longstanding lesions. The
presence of this feature is
often readily noticed during
gross sectioning of the
specimen.

IgG4-Related Sclerosing Disease IgG4-Related Sclerosing Disease

(Left) Fibrosis with a storiform
or loose-swirling pattern is
characteristic of IgG4-related
sclerosing disease. This image
is of the disease affecting the
lung in a 52-year-old man.
(Right) A lymphoplasmacytic
infiltrate is often prominent in
IgG4-related sclerosing
disease, and plasma cells are
usually plentiful. Eosinophils
may also be increased.

Phlebitis IgG4(+) Plasma Cells

(Left) This H&E shows
inflammation and destruction
of a vein ﬈ (lymphocytic or
obliterative phlebitis) within
the setting of IgG4-related
sclerosing disease. Note the
normal artery ﬈. A mild form
of this finding may be seen
focally in rare cases of
sclerosing mesenteritis and
IRF. (Right) Quantification of
IgG4(+) plasma cells or the
ratio of IgG4(+):IgG(+) plasma
cells is often a helpful method
for supporting a diagnosis of
IgG4-related sclerosing
disease.

791
 Cardiac Myxoma

KEY FACTS
Other Entities

TERMINOLOGY • Cells are spindled or stellate and often associated with

• Benign myxoid neoplasm that occurs specifically in heart capillaries in concentric onion-skin or sheath-like
and is of uncertain etiology arrangement
• Hemorrhage and degenerative changes are common
CLINICAL ISSUES • Mitoses uncommon
• Most common tumor of heart overall
ANCILLARY TESTS
• Most cases are sporadic; rarely familial
• Usually left atrium (most common) or right atrium • Immunophenotype
• Symptoms at presentation depend upon site of origin ○ CD34(+), CD31(+), vimentin (+)
○ Often valvular obstruction ○ Variably positive for calretinin, desmin, SMA, S100
• Surgical excision is generally curative; recurrences rare ○ Negative for keratin, CD117
• Systemic or pulmonary embolization may occur, depending • Molecular
on site of origin ○ Rearrangements of 12p1 and 17p1
○ PRKAR1A gene (17q24) mutations occur in cases
MACROSCOPIC associated with Carney complex
• Soft, gelatinous mass
TOP DIFFERENTIAL DIAGNOSES
MICROSCOPIC • Myxofibrosarcoma
• Generally hypocellular with abundant myxoid stroma

Cardiac Myxoma Myxoid Stroma

(Left) Cardiac myxoma ſt is
the most common tumor of
the heart and frequently arises
from the interatrial wall of the
left atrium. Cardiac muscle ﬊
is usually identified in
histologic sections near the
base of the myxoma. (Right)
Cardiac myxoma classically
shows an abundant
eosinophilic myxoid matrix
containing small spindled,
polygonal, or stellate cells in
various architectures,
including singly and in cords.

Myxoma Cells Perivascular Organization

(Left) The constituent cells of
cardiac myxoma generally
show small hyperchromatic
nuclei, which may number
from 1 to several. Significant
nuclear atypia is not a feature
of this tumor. Mitoses are
generally rare but may be
more prominent in cellular
foci. (Right) Among other
growth patterns, a distinct
perivascular orientation of
tumor cells is common in
cardiac myxoma. In this image,
the cells adopt a loose,
concentric arrangement.

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 Cardiac Myxoma

Other Entities
TERMINOLOGY MICROSCOPIC
Definitions Histologic Features
• Benign myxoid neoplasm that occurs specifically in heart • Luminal surface may be smooth or
and is of uncertain etiology irregular/papillary/villous
• Generally hypocellular with abundant myxoid stroma
CLINICAL ISSUES ○ Luminal and subluminal cellularity may be seen
Epidemiology • Cells have eosinophilic cytoplasm and are spindled, stellate,
or polygonal
• Incidence
○ 1 or more small hyperchromatic nuclei
○ Most common tumor of heart
○ Often associated with capillaries in concentric onion-skin
○ Most cases are sporadic
or sheath-like arrangement
– Rare cases are familial and may present as part of
• Hemorrhage and degenerative changes are common
syndrome (including Carney complex)
○ Hemosiderin deposition, fibrosis, chronic inflammation,
• Age
macrophages
○ All ages (most common: 30-60 years)
○ Calcification, extramedullary hematopoiesis, and
• Sex metaplastic bone formation are less common
○ 2:1 female predominance • Mitoses uncommon
Site ○ Both normal and atypical figures may be seen in cellular
• Usually left atrium (70% of cases) or right atrium regions
○ Often at or near foramen ovale • Very rare findings
○ Usually attached by narrow pedicle ○ Mucinous glandular differentiation, thymic rests
• Rare locations: Left ventricle, right ventricle, and valves
• Syndromic examples are more likely to be multiple and
ANCILLARY TESTS
occur in unusual intracardiac locations Immunohistochemistry
Presentation • CD34(+), CD31(+), vimentin (+)
• Negative for keratin, CD117
• Up to 20% of cases are asymptomatic at time of diagnosis
• Loss of PRKAR1-α protein expression
• Symptomatic cases depend upon site of origin
• Variable expression of calretinin, desmin, SMA, S100
○ Left atrium
• Rare epithelial elements express keratins, EMA, CK7, and
– Symptoms of mitral valve obstruction
CEA and may also show neuroendocrine differentiation
– May also send tumor emboli into systemic circulation,
which may result in myocardial infarction, stroke, or Molecular Genetics
peripheral infarction • Rearrangements of 12p1 and 17p1
○ Right atrium • PRKAR1A gene (17q24) mutations occur in cases associated
– Symptoms related to tricuspid valve obstruction with Carney complex
– May send tumor emboli to lungs
Treatment DIFFERENTIAL DIAGNOSIS
• Surgical excision of myxoma with portion of interatrial Myxofibrosarcoma
septum or surrounding tissue • Much rarer in heart than cardiac myxoma
Prognosis • Often prominent nuclear atypia and often numerous
mitotic figures
• Recurrences are rare
• Invasive growth with involvement of pedicle/cardiac muscle
○ Higher risk in familial and syndromic cases
• Systemic or pulmonary embolization may occur SELECTED REFERENCES
○ Tumors with irregular/papillary/villous outer contour
1. Wang JG et al: Clinicopathologic features and outcomes of primary cardiac
have increased risk tumors: a 16-year-experience with 212 patients at a Chinese medical center.
Cardiovasc Pathol. 33:45-54, 2018
IMAGING 2. Nath D et al: Immunohistochemical characterization of glandular elements in
glandular cardiac myxoma: study of six cases. Indian J Pathol Microbiol.
Ultrasonographic Findings 60(3):319-23, 2017
3. Maleszewski JJ et al: PRKAR1A in the development of cardiac myxoma: a
• Usually detected on echocardiography study of 110 cases including isolated and syndromic tumors. Am J Surg
Pathol. 38(8):1079-87, 2014
MACROSCOPIC 4. Zhang M et al: Cardiac myxoma with glandular elements: a
clinicopathological and immunohistochemical study of five new cases with
General Features an emphasis on differential diagnosis. Pathol Res Pract. 210(1):55-8, 2014
5. Swartz MF et al: Atrial myxomas: pathologic types, tumor location, and
• Soft, gelatinous mass presenting symptoms. J Card Surg. 21(4):435-40, 2006
• Smooth or irregular/papillary/villous outer contour 6. Pucci A et al: Histopathologic and clinical characterization of cardiac
myxoma: review of 53 cases from a single institution. Am Heart J.
Size 140(1):134-8, 2000
• 0.1-10.0 cm (average: 5 cm)

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 Cardiac Myxoma
Other Entities

Perivascular Organization Corded Growth

(Left) A tight perivascular
growth pattern ﬈ with
increased cellularity (often
referred to as "cuffing") is
commonly seen in cardiac
myxoma. The degree of
cellularity may be striking in
some cases. (Right) Although
tumor cells in cardiac myxoma
most often occur singly or in
small groups, a relatively
delicate anastomosing corded
growth pattern may also be
seen.

Hemorrhage and Hemosiderin Thrombus Formation

(Left) Hemorrhage is common
in cardiac myxoma and is
hardly surprising given the
vascularity of this tumor.
Hemosiderin deposition ﬈ is
also easily identified in most
cases, even away from areas
of hemorrhage. (Right) In
many cases of cardiac
myxoma, thrombus formation
can be identified grossly on
the surface of the tumor.
Thrombi ﬈ may also be
identified within the tumor in
dilated vessels.

Thick-Walled Vessels Inflammatory Infiltrate

(Left) In some cases of cardiac
myxoma, a collection of thick-
walled and often tortuous
blood vessels can be identified,
particularly near the
base/pedicle of the tumor.
(Right) A chronic inflammatory
infiltrate is quite common in
cardiac myxoma and usually
consists of lymphocytes,
plasma cells, and histiocytes.
Neutrophils may also be
identified and in some cases
might possibly represent an
overlying, coexisting infection.

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 Cardiac Myxoma

Other Entities
Calcification Smooth Luminal Contour
(Left) Stromal calcification ﬈
may be seen in some cases of
cardiac myxoma, particularly
tumors localized to the right
atrium. Foci of calcification
superimposed upon elastic
fibers have been referred to as
Gamna-Gandy bodies. (Right)
In most cases of cardiac
myxoma, the outer/luminal
surface is smooth and regular,
both macro- and
microscopically. This surface is
often lined by tumor cells,
which may show focal
increases in cellularity ﬈,
reminiscent of synovial lining.

Papillary/Villous Configuration Increased Surface Cellularity

(Left) Less commonly, a
cardiac myxoma may show an
irregular papillary or villous
luminal configuration, which
can also be appreciated
grossly. This variant has a
higher risk of shedding tumor
emboli due to its relative
friability. (Right) Increased
surface cellularity may be seen
in papillary/villous forms of
cardiac myxoma and can be
alarming. The tumor cells are
also often more rounded and
plump, as depicted.

Mitotic Figures Glandular Myxoma

(Left) In areas of increased
cellularity, mitotic figures ﬈
(including atypical forms) may
be identified in cardiac
myxoma. (Right) Rare cases of
cardiac myxoma contain
glandular elements, as
depicted. Note that no cellular
anaplasia, mitotic activity, or
necrosis is present. Most
reported cases have shown
CK7 expression in these
elements, while markers such
as CK20 and TTF-1 are
negative.

795
 Cardiac Fibroma

KEY FACTS
Other Entities

TERMINOLOGY MACROSCOPIC
• Benign cardiac neoplasm composed of fibroblasts and • Usually 3-8 cm
occurring predominantly in childhood
MICROSCOPIC
ETIOLOGY/PATHOGENESIS • Often mildly infiltrative border with normal cardiac tissue
• Most are sporadic • Spindle cells in irregular, loose fascicles
• May occur as feature of Gorlin (nevoid basal cell carcinoma) • Edematous or myxoid matrix containing collagen and
syndrome elastic fibers
CLINICAL ISSUES • Bland nuclear cytology and rare-to-no mitotic figures
• May show foci of extramedullary hematopoiesis, chronic
• 2nd most common primary pediatric heart tumor
inflammation, or calcification
• Most cases (80%) occur in children
• Primarily ventricular septum or free wall of left ventricle ANCILLARY TESTS
• May be asymptomatic or present with heart murmur, • Immunophenotype: SMA(+), desmin (-), S100 protein (-)
arrhythmia, symptoms of congestive heart failure, or as • PTCH1 gene (9q22) abnormalities (deletion/translocations)
sudden death
TOP DIFFERENTIAL DIAGNOSES
• Treatment: Surgical excision
• Inflammatory myofibroblastic tumor
IMAGING • Atrial myxoma
• Often detected on echocardiogram or MR

Cardiac Fibroma Infiltrative Border

(Left) Cardiac fibroma is the
2nd most common primary
pediatric heart tumor and is
most frequently encountered
in the ventricular wall or
septum during the 1st year of
life. Histologically, it is
characterized by loose
fascicles of fibroblastic
spindled cells. (Right) In
cardiac fibroma, there is often
evidence of focal infiltration
at the peripheral interface
with the normal heart. Note
the irregular clusters of
cardiac myocytes ﬈ between
tumor cells.

Bland Cytology Extramedullary Hematopoiesis

(Left) The cytologic features of
cardiac fibroma are uniformly
bland, and there is often a
conspicuous component of
stromal collagen ﬈ and small,
irregular elastic fibers. Mitotic
figures are rare to absent in
most cases. (Right) In some
cases of cardiac fibroma,
particularly in patients
younger than 5 months, foci of
extramedullary hematopoiesis
are seen. Calcification and
chronic inflammation may also
be seen in rare cases.

796
 Cardiac Fibroma

Other Entities
TERMINOLOGY MICROSCOPIC
Definitions Histologic Features
• Benign cardiac neoplasm composed of fibroblasts • Often mildly infiltrative border with normal cardiac tissue
○ Unencapsulated
ETIOLOGY/PATHOGENESIS • Spindle cells in irregular, loose fascicles
Genetics • Edematous or myxoid matrix containing collagen and
elastic fibers
• Most are sporadic
• Bland nuclear cytology
• May occur as feature of Gorlin (nevoid basal cell carcinoma)
• Mitotic figures rare
syndrome
• May show foci of extramedullary hematopoiesis or chronic
○ Autosomal dominant inheritance
inflammation
○ Other features: Basal cell carcinoma, skeletal
• Focal calcification in 25% of cases
abnormalities, jaw cysts, ovarian fibromas,
medulloblastoma, cataracts
• PTCH1 (tumor suppressor) gene on 9q22 appears to play
ANCILLARY TESTS
role in pathogenesis Immunohistochemistry
○ Identified in both syndromic and sporadic cases • SMA(+)
• Desmin (-), CD34(-), S100 protein (-)
CLINICAL ISSUES
Genetic Testing
Epidemiology
• PTCH1 gene (9q22) abnormalities
• Incidence ○ Loss/deletion
○ 2nd most common primary pediatric heart tumor ○ Translocations reported include t(1;9)(q32;q22) and
• Age t(1;9;5)(q24;q22;q22)
○ Most cases (80%) occur in children
– Particularly 1st year of life DIFFERENTIAL DIAGNOSIS
○ Rare cases in young adults
Inflammatory Myofibroblastic Tumor
Site • Very rare in heart
• Primarily ventricular septum or free wall of left ventricle • Usually endocardial or polypoid growth
• Less commonly free wall of right ventricle • Inflammatory cells (both acute and chronic) are usually
abundant
Presentation
• May be asymptomatic or present with heart murmur, Atrial Myxoma
arrhythmia, or symptoms of congestive heart failure • Rarely occur in cardiac ventricles
○ Also sudden death • Very different morphologic appearance
• Usually solitary lesions
Papillary Fibroelastoma
Treatment • Most commonly arise from cardiac valves
• Surgical excision • Prominent papillary fronds with collagen- and elastin-rich
• Reports of heart transplant being performed for large, cores
unresectable tumors • Fronds lined by plump endothelial cells
Prognosis
SELECTED REFERENCES
• Benign
1. Humez S et al: [Cardiac fibroma: a rare cause of sudden child death.] Ann
• Surgical removal often relieves symptoms Pathol. 35(5):445-8, 2015
2. Zhang Q et al: Somatic copy number losses on chromosome 9q21.33q22.33
IMAGING encompassing the PTCH1 loci associated with cardiac fibroma. Cancer
Genet. 208(12):615-20, 2015
General Features 3. Chu ZG et al: Cardiac fibromas in the adult. J Card Surg. 29(2):159-62, 2014
• Intramural growth 4. Cronin B et al: Cardiac fibroma presenting as sudden unexpected death in an
adolescent. Forensic Sci Med Pathol. 10(4):647-50, 2014
• Often detected on echocardiogram or MR 5. Kumar N et al: Primary cardiac tumours in a paediatric population: an
experience from a tertiary centre with a review of literature. Afr J Paediatr
MACROSCOPIC Surg. 11(1):44-7, 2014
6. Tao TY et al: Pediatric cardiac tumors: clinical and imaging features.
General Features Radiographics. 34(4):1031-46, 2014
7. Piazza N et al: Primary cardiac tumours: eighteen years of surgical
• Well demarcated experience on 21 patients. Can J Cardiol. 20(14):1443-8, 2004
• Firm, tan/gray/white cut surface 8. Ferguson HL et al: Infant cardiac fibroma with clonal t(1;9)(q32;q22) and
review of benign fibrous tissue cytogenetics. Cancer Genet Cytogenet.
Size 87(1):34-7, 1996
• Usually 3-8 cm

797
 Congenital Granular Cell Epulis

KEY FACTS
Other Entities

TERMINOLOGY MICROSCOPIC
• Rare, benign lesion of uncertain histogenesis that most • Overlying squamous mucosa is thinned/attenuated or
commonly arises in newborn girls and is composed of large, ulcerated
granular cells • Nests, sheets, and cords of polygonal to ovoid cells with
abundant granular cytoplasm and distinct cell membranes
CLINICAL ISSUES
• Small nuclei with vesicular to stippled chromatin and often
• Exclusively newborn infants small nucleoli
• Marked female predominance (10:1) • Prominent stromal capillary network
• Maxillary alveolar ridge most common site
• Enlarging gingival growth while in utero ANCILLARY TESTS
• Most cases are solitary and polypoid • Negative for S100 protein, CD68, keratins, CD34, SMA,
• No reported associations with syndromes or genetic desmin, calponin
anomalies TOP DIFFERENTIAL DIAGNOSES
• Treatment: Conservative excision
• Granular cell tumor
• Benign
• Adult-type rhabdomyoma
MACROSCOPIC • Alveolar soft part sarcoma
• Well circumscribed • Lobular capillary hemangioma (pyogenic granuloma)
• Usually 1-2 cm

Congenital Granular Cell Epulis Nests and Sheets

(Left) Congenital granular cell
epulis (CGCE) is a rare but
distinctive lesion that arises
along the maxillary or
mandibular alveolar ridges in
newborns, particularly girls.
These lesions are well
circumscribed and commonly
show thinning of the overlying
squamous epithelium ﬈.
(Right) CGCE is composed of
nests and sheets of polygonal
to ovoid cells with granular
cytoplasm. Stromal vessels are
prominent ﬈, and a chronic
inflammatory infiltrate ﬊
may be seen.

Granular Cells Fibrosis

(Left) The lesional cells of
CGCE demonstrate prominent
granular cytoplasm and sharp
cytoplasmic borders. Nuclei
are often slightly irregular in
contour with vesicular to
stippled chromatin and small
nucleoli. (Right) Some cases of
CGCE show zones of fibrosis or
other uncommon findings,
such as spindled cells and
odontogenic epithelial rests.
Note the ectatic (sometimes
"staghorn") stromal vessels
﬈, a relatively common
finding in CGCE, at least
focally.

798
 Congenital Granular Cell Epulis

Other Entities
• Small nuclei with vesicular to stippled chromatin and often
TERMINOLOGY small nucleoli
Synonyms • Mitoses absent
• Congenital epulis of newborn • Prominent stromal capillary network
• Congenital granular cell tumor ○ May be associated with lymphocytic infiltrate
• Granular cell fibroblastoma ○ Some vessels may be large and ectatic with staghorn
appearance
Definitions • Uncommon findings: Spindle cell morphology, fibrotic
• Rare, benign lesion of uncertain histogenesis that most zones, odontogenic epithelial rests
commonly arises in newborn girls and is composed of large,
granular cells ANCILLARY TESTS
CLINICAL ISSUES Immunohistochemistry
• Negative for S100 protein, CD68, keratins, CD34, SMA,
Epidemiology desmin, calponin
• Incidence
○ Rare DIFFERENTIAL DIAGNOSIS
• Age
Granular Cell Tumor
○ Exclusively newborn infants
• Sex • Occurs mainly in adults
○ Marked female predominance (10:1) • Wide distribution but common in tongue
• Overlying squamous epithelium often shows
Site pseudoepitheliomatous hyperplasia
• Dental alveolar ridge • Large nest and sheet-like growth patterns typical
○ Maxilla more common than mandible • Small nerve involvement is commonly identified
• Diffuse S100 protein expression (schwannian)
Presentation
• Can be diagnosed prenatally by ultrasound Adult-Type Rhabdomyoma
• Enlarging growth while in utero • Most common in older adults, particularly men
○ Growth is rapid during 3rd trimester and ceases after • Large polygonal cells with prominent eosinophilic
birth cytoplasm
• Most cases are solitary and polypoid • Desmin (+), myogenin (+)
○ Up to 10% may be multiple
Alveolar Soft Part Sarcoma
• Bone and teeth are not involved
• Rare < 3 years of age
• No reported associations with syndromes or genetic
anomalies • Large, deeply situated tumors
• Prominent lobularity
Treatment • PAS-D(+) intracytoplasmic crystals in most cases
• Conservative excision
Lobular Capillary Hemangioma (Pyogenic
• Rare cases may regress spontaneously
Granuloma)
Prognosis • Prominent lobulated vascular component (hemangioma)
• Benign • Lacks granular cells
• Local recurrence very rare; no malignant transformation • Surface ulceration common

MACROSCOPIC SELECTED REFERENCES

General Features 1. Kumar RM et al: Congenital epulis of the newborn. J Oral Maxillofac Pathol.
19(3):407, 2015
• Well circumscribed 2. Conrad R et al: Congenital granular cell epulis. Arch Pathol Lab Med.
• Overlying mucosa intact or ulcerated 138(1):128-31, 2014
3. Garg S et al: Congenital epulis: from birth to childhood. Turk J Pediatr.
Size 56(1):97-9, 2014
• Usually 1-2 cm 4. Saki N et al: Multiple congenital epulis in alveolar ridges of maxilla and
mandible in a newborn: a rare case report. Case Rep Otolaryngol.
○ Rare, larger examples reported 2014:606985, 2014
5. Yee J: Congenital epulis in a newborn. Minn Med. 97(5):39, 2014
MICROSCOPIC 6. Bhatia SK et al: Spontaneous regression of a congenital epulis in a newborn.
J Clin Pediatr Dent. 37(3):297-9, 2013
Histologic Features 7. Prigkos AC et al: Spindle cell epulis in an 8-month-old child: a histologic
variant of congenital granular cell epulis? Head Neck Pathol. 6(4):467-70,
• Overlying squamous mucosa is thinned/attenuated or 2012
ulcerated 8. Childers EL et al: Congenital epulis of the newborn: 10 new cases of a rare
• Nests, sheets, and cords of polygonal to ovoid cells with oral tumor. Ann Diagn Pathol. 15(3):157-61, 2011
abundant granular cytoplasm and distinct cell membranes
○ Cytoplasmic hyaline globules usually absent

799
 Nasopharyngeal Angiofibroma

KEY FACTS
Other Entities

TERMINOLOGY ○ Tumor blush is characteristic

• Benign, highly cellular, and richly vascularized mesenchymal MICROSCOPIC
neoplasm arising in nasopharynx in male patients
• Scattered, variably sized vessels within prominent
• Associated with familial adenomatous polyposis fibrocollagenous stroma
CLINICAL ISSUES ○ Stroma composed of plump spindle, angular, or stellate-
• Most arise in patients < 25 years shaped cells
• Occurs exclusively in male patients • Mitotic figures rare
• Arises in nasopharynx ANCILLARY TESTS
• Recurrent, spontaneous epistaxis is common presentation • Stromal cells are androgen receptor (+) and nuclear β-
• Often shows locally aggressive growth catenin (+)
• Overall good prognosis ○ SMA, desmin, and CD34 (-)
IMAGING TOP DIFFERENTIAL DIAGNOSES
• Anterior bowing of posterior wall of maxillary sinus with • Lobular capillary hemangioma (pyogenic granuloma)
posterior displacement of pterygoid plates (Holman-Miller • Solitary fibrous tumor
sign) • Sinonasal glomangiopericytoma
• Angiography identifies feeding vessel(s) and allows for • Desmoid fibromatosis
presurgical embolization
• Antrochoanal polyp

Nasopharyngeal Angiofibroma Characteristic Vasculature

(Left) Nasopharyngeal
angiofibroma (NPA) is a rare
mesenchymal neoplasm of the
male nasopharynx that is
classically composed of
irregularly scattered, variably
sized blood vessels within a
fibrocollagenous stroma.
(Right) NPA contains
numerous vessels of various
calibers, some with smooth
muscle ﬊, set in a heavily
collagenized stroma. The
stroma varies in cellularity but
is often relatively hypocellular.

Cytologic Features Increased Stromal Collagen

(Left) The lesional cells of NPA
have plump, ovoid nuclei ﬈
and indistinct cell margins.
The cells are randomly
oriented within a fibrous
stroma that contains
scattered mast cells ﬊ and
lymphocytes. (Right) Increased
collagen deposition is often
seen in NPAs of a long
duration. Note how the vessels
are compressed and narrowed
in this image. In some cases,
they appear slit-like.

800
 Nasopharyngeal Angiofibroma

Other Entities
TERMINOLOGY Natural History
• Often shows locally aggressive growth
Abbreviations • Potential for facial deformity if allowed to grow
• Nasopharyngeal angiofibroma (NPA)
Treatment
Synonyms • Surgical resection is treatment of choice
• Juvenile NPA ○ Definitive resection is frequently associated with
• Angiofibroma significant morbidity
Definitions • Biopsy is contraindicated due to potential fatal
exsanguination
• Benign, richly vascularized mesenchymal neoplasm arising
• Selective angiography preoperatively allows embolization
in nasopharynx in male patients
with sclerosing agent or cryotherapy
• Nonsurgical medical management (preoperative hormone
ETIOLOGY/PATHOGENESIS
therapy) is option
Hormonal ○ Not as popular as other modalities
• Testosterone-dependent growth – Giving estrogen to pubertal male patients is
undesirable
Genetic
• Radiation may be used to manage large, intracranial, or
• Association with familial adenomatous polyposis recurrent tumors

CLINICAL ISSUES Prognosis

• Overall good prognosis
Epidemiology
○ Very low mortality rate (1%)
• Incidence • Benign, but locally aggressive neoplasm
○ Rare ○ Recurrences in ~ 20% of patients
• Age – Often related to incomplete excision
○ Most arise in patients < 25 years – Usually develop within 2 years of diagnosis
– Peak incidence: 10-20 years – Commonly extend intracranially
○ Rare cases in older adults
– Supports notion of avoiding term juvenile NPA IMAGING
• Sex
○ Occurs exclusively in male patients General Features
– If diagnosed in female patients, studies of sex • Best diagnostic clue
chromosomes required to confirm gender ○ Anterior bowing of posterior wall of maxillary sinus with
posterior displacement of pterygoid plates (Holman-
Site Miller sign)
• Arises in nasopharynx • Location
○ Usually affects posterolateral region ○ Nasopharynx with extension into surrounding structures
• May expand to involve surrounding structures (30% of • Angiography identifies feeding vessel(s) and allows for
cases) presurgical embolization
○ Anterior: Nasal cavity and maxillary sinus via roof of ○ Tumor blush is characteristic
nasopharynx
○ Lateral: Temporal and infratemporal fossae via CT Findings
pterygomaxillary fissure, resulting in cheek or intraoral • Allows for accurate determination of size and extent
buccal mass • Enhancement is different from adjacent muscle,
○ Posterior: Middle cranial fossa accentuated with contrast
○ Superior: Pterygopalatine fossa and orbit via inferior and • Bony margins may be eroded
superior orbital fissures resulting in proptosis
○ Medial: Contralateral side MACROSCOPIC
Presentation General Features
• Symptoms often present for 12-24 months (nonspecific • Sessile or lobulated
presentation) • Can be polypoid or pedunculated
• Recurrent, spontaneous epistaxis • Red, gray-tan cut surface
• Nasal obstruction Size
• Nasal discharge
• Most are 3-5 cm (mean: 4 cm)
• Facial deformity (proptosis), exophthalmia, diplopia
• Rare cases are much larger
• Rhinolalia, sinusitis
• Otitis media, tinnitus, deafness
MICROSCOPIC
• Headaches
• Rarely, anosmia or pain Histologic Features
• Unencapsulated
801
 Nasopharyngeal Angiofibroma
Other Entities

• Submucosal proliferation of vascular channels within • Hyalinized vessels frequently present

fibrocollagenous stroma • SMA(+)
○ Many variably sized, disorganized vessels • Nuclear β-catenin (+)
– Varying thickness of vessel wall with patchy muscle
Desmoid Fibromatosis
content
□ Focal, pad-like smooth muscle thickenings within • Usually contain long, "streaming" fascicles of tumor cells
vessel walls • Does not express androgen/testosterone receptors
– Vessels are mostly thin walled, slit-like ("staghorn") • Nuclear β-catenin (+) in 70%
– Range from capillary size to large, dilated vessels Antrochoanal Polyp
– Endothelial cells may be plump but are usually
• Arise in maxillary sinus
attenuated
• Heavy stromal fibrosis but usually lacks characteristic
○ Fibrocollagenous stroma consists of plump spindle or
vascular pattern of NPA
stellate-shaped cells
– Stromal cells may be angulated, multinucleated, and
SELECTED REFERENCES
pleomorphic
– Variable amounts of fine and coarse collagen fibers 1. Jones JW et al: Differential gene expression and pathway analysis in juvenile
nasopharyngeal angiofibroma using RNA sequencing. Otolaryngol Head
– Myxoid degeneration is common (especially in Neck Surg. 194599818769879, 2018
embolized specimens) 2. Sánchez-Romero C et al: Nasopharyngeal angiofibroma: a clinical,
histopathological and immunohistochemical study of 42 cases with
□ Embolization material may be present within vessel emphasis on stromal features. Head Neck Pathol. 12(1):52-61, 2018
– As stroma increases, vascular compression results in 3. Agaimy A et al: CTNNB1 (β-catenin)-altered neoplasia: a review focusing on
virtually nonexistent lumina soft tissue neoplasms and parenchymal lesions of uncertain histogenesis.
Adv Anat Pathol. 23(1):1-12, 2016
□ Central areas may lack vessels
4. Renkonen S et al: Tenascin-C, GLUT-1, and syndecan-2 expression in juvenile
– Elastic tissue is not identified within stroma nasopharyngeal angiofibroma: correlations to vessel density and tumor
– Hormone-treated cases show increased stage. Head Neck. 35(7):1036-42, 2013
collagenization of stroma with fewer but thicker 5. Wang JJ et al: Endoglin (CD105) expression on microvessel endothelial cells
in juvenile nasopharyngeal angiofibroma: tissue microarray analysis and
walled vessels association with prognostic significance. Head Neck. 35(12):1719-25, 2013
• Mitotic figures are sparse 6. Yi Z et al: Nasopharyngeal angiofibroma: a concise classification system and
• Mast cells are common appropriate treatment options. Am J Otolaryngol. 34(2):133-41, 2013
7. Silveira SM et al: Tumor microenvironmental genomic alterations in juvenile
• Sarcomatous transformation is exceedingly uncommon nasopharyngeal angiofibroma. Head Neck. 34(4):485-92, 2012
event 8. Blount A et al: Juvenile nasopharyngeal angiofibroma. Otolaryngol Clin
○ Develops following massive doses of radiation North Am. 44(4):989-1004, ix, 2011
9. Renkonen S et al: Stem cell-related proteins C-KIT, C-MYC and BMI-1 in
juvenile nasopharyngeal angiofibroma--do they have a role? Virchows Arch.
ANCILLARY TESTS 458(2):189-95, 2011
10. Zhang M et al: Biological distinctions between juvenile nasopharyngeal
Histochemistry angiofibroma and vascular malformation: an immunohistochemical study.
• Reticulin shows positive black staining around stromal cells Acta Histochem. 113(6):626-30, 2011
and blood vessels 11. Sun XC et al: Analysis of risk factors associated with recurrence of
nasopharyngeal angiofibroma. J Otolaryngol Head Neck Surg. 39(1):56-61,
• Elastic van Gieson highlights elastic tissue within vessel 2010
walls 12. Bleier BS et al: Current management of juvenile nasopharyngeal
angiofibroma: a tertiary center experience 1999-2007. Am J Rhinol Allergy.
Immunohistochemistry 23(3):328-30, 2009
13. Carrillo JF et al: Juvenile nasopharyngeal angiofibroma: clinical factors
• Stromal cells associated with recurrence, and proposal of a staging system. J Surg Oncol.
○ Androgen receptor (+) 98(2):75-80, 2008
○ Nuclear β-catenin (+) 14. Coutinho-Camillo CM et al: Genetic alterations in juvenile nasopharyngeal
angiofibromas. Head Neck. 30(3):390-400, 2008
○ SMA, desmin, and CD34 (-) 15. Glad H et al: Juvenile nasopharyngeal angiofibromas in Denmark 1981-2003:
diagnosis, incidence, and treatment. Acta Otolaryngol. 127(3):292-9, 2007
DIFFERENTIAL DIAGNOSIS 16. Tyagi I et al: Staging and surgical approaches in large juvenile angiofibroma--
study of 95 cases. Int J Pediatr Otorhinolaryngol. 70(9):1619-27, 2006
Lobular Capillary Hemangioma (Pyogenic 17. Thompson LDR et al: Tumours of the nasopharynx: nasopharyngeal
Granuloma) angiofibroma. In Barnes EL et al: Pathology and Genetics of Head and Neck
Tumours. World Health Organization Classification of Tumours. Lyon: IARC
• Usually in nasal cavity (vs. nasopharynx) Press. 102-3, 2005
• Blood vessels are more organized 18. Fletcher CD: Distinctive soft tissue tumors of the head and neck. Mod Pathol.
15(3):324-30, 2002
○ Lobular growth with central "feeder" vessels 19. Lee JT et al: The role of radiation in the treatment of advanced juvenile
• Often ulcerated and inflamed angiofibroma. Laryngoscope. 112(7 Pt 1):1213-20, 2002
20. Coffin CM et al: Fibroblastic-myofibroblastic tumors in children and
Solitary Fibrous Tumor adolescents: a clinicopathologic study of 108 examples in 103 patients.
Pediatr Pathol. 11(4):569-88, 1991
• Striking ectatic "staghorn" vasculature
21. Makek MS et al: Malignant transformation of a nasopharyngeal
• CD34(+), STAT6(+) angiofibroma. Laryngoscope. 99(10 Pt 1):1088-92, 1989

Sinonasal Glomangiopericytoma
• Affects older adults
• Ovoid to spindled tumor cells

802
 Nasopharyngeal Angiofibroma
Embolization Material
Scattered Atypical Cells
Nuclear β-Catenin Expression
Other Entities
Marked Stromal Collagen
(Left) Cases of NPA
preoperatively treated by
embolization prior to surgical
resection show embolization
material ﬊ within blood
vessels. (Right) Longstanding
cases of NPA and those
treated with hormonal
therapy often show increased
stromal collagen and fewer
vessels, as depicted.
Perivascular Smooth Muscle
(Left) Occasional cases of NPA
contain scattered cells with
nuclear atypia ﬊ or
multinucleation. This finding
does not affect the prognosis.
(Right) Muscle specific actin
(shown) and smooth muscle
actin (SMA) highlight the
smooth muscle walls around
vessels ﬊ in NPA. The
variable intensity of the
reaction helps to demonstrate
the variable amounts of
smooth muscle associated
with the vessels. Note that the
stromal cells are negative.
Nasopharyngeal Angiofibroma
(Left) Immunohistochemistry
for β-catenin shows strong,
diffuse positivity in nuclei ﬊
in the majority of the lesional
cells of NPA. The nonfascicular
architecture, nuclear features,
vascular pattern, and absence
of SMA in lesional cells allow
distinction from desmoid
fibromatosis. (Right) MR of
NPA shows intracranial
extension of a large,
destructive, hyperintense mass
in the nasopharynx. The bone
has been remodeled and
pushed aside.
803
 Sinonasal Glomangiopericytoma

KEY FACTS
Other Entities

TERMINOLOGY MICROSCOPIC
• Distinctive mesenchymal neoplasm of sinonasal cavity • Composed of uniform, syncytial sheets and fascicles of
demonstrating pericytic (perivascular) myoid phenotype round to spindle-shaped cells intimately associated with
• Synonym: Sinonasal-type hemangiopericytoma vascular component
○ Perivascular hyalinization common
ETIOLOGY/PATHOGENESIS
• Stroma often scant but may be myxoid or loose and
• Mutational activation of β-catenin involved in pathogenesis edematous 
CLINICAL ISSUES • Chronic inflammatory cells common
• 75% of cases occur in 6th-8th decades ANCILLARY TESTS
• Slight female predilection • Smooth muscle actin (+), nuclear β-catenin (+)
• Most frequently arises in nasal cavity • Desmin, CD34, S100 protein, keratin (-)
• Unilateral polypoid intranasal mass
• Complete surgical excision TOP DIFFERENTIAL DIAGNOSES
• Benign; ~ 1/3 will recur/persist • Phosphaturic mesenchymal tumor
• Solitary fibrous tumor
MACROSCOPIC
• Nasopharyngeal angiofibroma
• Mean size: 3.5 cm (range: 1.5-8.0 cm) • Lobular capillary hemangioma
• Myoepithelioma

Sinonasal Glomangiopericytoma Characteristic Vasculature

(Left) Low-power H&E of
sinonasal
glomangiopericytoma (GPC)
shows an intact surface ﬈
and a subepithelial
mesenchymal neoplastic
proliferation with prominent
vascularity st and
extravasated blood ﬊.
Normal regional subepithelial
structures are also effaced.
(Right) A characteristic feature
of sinonasal GPC is the
presence of prominent
perivascular hyalinization ﬉.
This histologic feature is seen
in up to 90% of tumors. Note
the overlying intact surface
(schneiderian) epithelium ﬊.

Cytologic Features Smooth Muscle Actin Expression

(Left) Sinonasal GPC is
composed of cytologically
bland to ovoid spindle cells
with oval nuclei containing
even chromatin and small
nucleoli. The cytoplasm is
eosinophilic and finely
vacuolated with indistinct cell
borders imparting a syncytial
appearance. (Right) The cells
of sinonasal GPC are true
pericytic cells, and they
demonstrate a myoid
phenotype both
ultrastructurally and
immunophenotypically.
Diffuse SMA expression
(shown) is characteristic.

804
 Sinonasal Glomangiopericytoma

Other Entities
• If resected intact, appears as polypoid solid mass with tan
TERMINOLOGY hemorrhagic cut surface
Abbreviations • Surface mucosa typically intact
• Glomangiopericytoma (GPC) Size
Synonyms • Mean: 3.5 cm (range: 1.5-8.0 cm)
• Sinonasal-type hemangiopericytoma
• Hemangiopericytoma-like tumor of sinonasal cavity MICROSCOPIC
Definitions Histologic Features
• Distinctive mesenchymal neoplasm of sinonasal cavity • Subepithelial, well-demarcated but unencapsulated,
demonstrating pericytic (perivascular) myoid phenotype cellular mesenchymal proliferation
○ Surface (schneiderian) mucosa usually intact but may be
ETIOLOGY/PATHOGENESIS eroded or show squamous metaplasia
○ Usually efface but may surround submucosal minor
Genetics salivary glands
• Mutational activation of β-catenin involved in pathogenesis • Composed of uniform, closely packed sheets of round to
spindle-shaped cells intimately associated with vascular
CLINICAL ISSUES component
Epidemiology ○ Vascular channels are variable in size, ranging from
capillaries to patulous "staghorn" vessels
• Incidence
– Prominent perivascular hyalinization is characteristic
○ Rare
and seen in up to 90% of cases
– Accounts for < 0.5% of sinonasal neoplasms
○ Neoplastic cells have uniform, oval to round nuclei
• Age
– Nuclear chromatin is typically homogeneous or
○ Wide range (5-86 years) vesicular with 1 or more small nucleoli
– 75% of cases occur in 6th-8th decades – Cytoplasm is lightly eosinophilic and indiscrete,
• Sex resulting in syncytial appearance
○ Slight female predilection □ Focal areas composed of clear cells may be seen
Site – Rare mitoses and mild nuclear pleomorphism may be
identified
• Most frequently arises in nasal cavity
• Stroma is typically scant but may be myxoid or loose and
○ Often have concomitant paranasal sinus involvement
edematous 
○ Right and left side equally affected
○ Stromal edema may result in hypocellular zones with
• Rarely arise primarily in paranasal sinuses
residual smaller cellular lobules
Presentation • Most tumors have solid or fascicular growth, but mixed
• Unilateral polypoid intranasal mass growth patterns are common
• Nasal obstruction, epistaxis ○ Whorled growth patterns can be seen in up to 10% of
• Congestion, sinusitis, &/or difficulty breathing cases
○ Also occasional nuclear palisading
Treatment • Chronic inflammatory cells are invariably present
• Complete surgical excision ○ Particularly eosinophils and mast cells
• Radiation therapy is of unproven value • Extravasated red blood cells are usually present
Prognosis • Scattered tumor giant cells (~ 5%) may be present
○ Likely represent degenerative phenomenon
• Excellent overall 5-year survival (> 90%)
○ Consist of agglomerated tumor cells
• ~ 1/3 will recur/persist (range: 18-44%)
○ Recurrences can occur after many years
ANCILLARY TESTS
– Mean interval to 1st recurrence is ~ 6.5 years (range:
1.0-17.5 years) Immunohistochemistry
– Long-term follow-up warranted • Vast majority demonstrate myoid phenotype with actin
positivity
IMAGING ○ Smooth muscle actin (+) (80-100%)
Radiographic Findings ○ Muscle specific actin (+) (77-100%)
• Nuclear β-catenin (+)
• Opacification filling nasal cavity ± adjacent sinuses
• Desmin, keratin, and C-kit (CD117) (-)
• Bone erosion or sclerosis can be seen
• Usually CD34 and S100 protein (-)
• Concomitant sinusitis not uncommon

MACROSCOPIC
General Features
• Often removed piecemeal
805
 Sinonasal Glomangiopericytoma
Other Entities

DIFFERENTIAL DIAGNOSIS DIAGNOSTIC CHECKLIST

Phosphaturic Mesenchymal Tumor
• Sinonasal examples can show significant morphologic
overlap with sinonasal GPC
• Often associated with clinical evidence of osteomalacia
• Overexpression of fibroblast growth factor 23 (FGF23)
Solitary Fibrous Tumor
• Also previously known as hemangiopericytoma
• Prominent ectatic "staghorn" vasculature
• Stromal collagen often prominent
• Uniform CD34(+)
• SMA and MSA (-)
Nasopharyngeal Angiofibroma
• Majority occur in adolescent males
• Arise in posterior nasal cavity with extension into
nasopharynx
○ Often involve nasal cavity, sinuses, and skull base when
they enlarge
• Evenly spaced spindled and stellate tumor cells
• Stromal collagen prominent
• Nuclear β-catenin (+) in stromal cells
○ Some cases occur in patients with familial adenomatosis
polyposis (FAP)
Lobular Capillary Hemangioma (Pyogenic
Granuloma)
• Composed of vascular lobules arranged in fibrovascular
stroma
• Lobules contain small, slit-like vascular channels emanating
from larger central "feeder" vessels
• Absence of sheet-like growth
• Surface erosion is frequent
Myoepithelioma
• Myxoid stroma common
• Keratin (+) &/or S100 protein (+) common
• Can also expression SMA, GFAP, calponin, desmin, p63
Sinonasal Smooth Muscle Neoplasms
• Rare
• Tumor cells arranged in bundled fascicles
• Abundant fibrillary eosinophilic cytoplasm
• Blunt-ended, cigar-shaped, oval nuclei
• SMA(+), desmin (+)
Schwannoma
• Nuclear palisading much more frequent than in sinonasal
GPC
• Diffuse S100 protein (+)
• SMA(-)
Glomus Tumor
• Extremely rare in sinonasal sites
• Rounded tumor cells with central round nucleus,
eosinophilic cytoplasm, and prominent cell borders
• Spindled morphology uncommon and usually focal, if
present
• SMA(+)
Clinically Relevant Pathologic Features
• Localization to sinonasal cavity
• Bland spindle and rounded cells associated with prominent
vascular component
• Low mitotic rate
• Myoid immunophenotype (SMA and MSA)
Pathologic Interpretation Pearls
• Features that can lead to misdiagnosis
○ Lack of awareness of this unique sinonasal tumor
○ Multinodularity secondary to edema or degenerative
changes
○ Multinucleated tumor giant cells
○ Whorled growth pattern &/or nuclear palisading
SELECTED REFERENCES
1. Suzuki Y et al: β-catenin (CTNNB1) mutation and LEF1 expression in
sinonasal glomangiopericytoma (sinonasal-type hemangiopericytoma).
Virchows Arch. ePub, 2018
2. Park ES et al: Characteristics and prognosis of glomangiopericytomas: a
systematic review. Head Neck. 39(9):1897-1909, 2017
3. Asimakopoulos P et al: Sinonasal glomangiopericytoma: Is anything new? Ear
Nose Throat J. 95(2):E1-5, 2016
4. Lasota J et al: Nuclear expression and gain-of-function β-catenin mutation in
glomangiopericytoma (sinonasal-type hemangiopericytoma): insight into
pathogenesis and a diagnostic marker. Mod Pathol. 28(5):715-20, 2014
5. Duval M et al: Systematic review of treatment and prognosis of sinonasal
hemangiopericytoma. Head Neck. 35(8):1205-10, 2013
6. Brandwein-Gensler M et al: Striking pathology gold: a singular experience
with daily reverberations: sinonasal hemangiopericytoma
(glomangiopericytoma) and oncogenic osteomalacia. Head Neck Pathol.
6(1):64-74, 2012
7. Dandekar M et al: Sinonasal glomangiopericytoma: case report with
emphasis on the differential diagnosis. Arch Pathol Lab Med. 134(10):1444-
9, 2010
8. Hofmann V et al: Sinonasal hemangiopericytoma. Rev Laryngol Otol Rhinol
(Bord). 131(4-5):313-5, 2010
9. Lin SH et al: Diagnosis and treatment of sinonasal hemangiopericytoma:
three case reports and review of the literature. J Otolaryngol. 35(2):141-3,
2006
10. Kuo FY et al: Sinonasal hemangiopericytoma-like tumor with true pericytic
myoid differentiation: a clinicopathologic and immunohistochemical study
of five cases. Head Neck. 27(2):124-9, 2005
11. Li XQ et al: Intranasal pericytic tumors (glomus tumor and sinonasal
hemangiopericytoma-like tumor): report of two cases with review of the
literature. Pathol Int. 53(5):303-8, 2003
12. Thompson LD et al: Sinonasal-type hemangiopericytoma: a clinicopathologic
and immunophenotypic analysis of 104 cases showing perivascular myoid
differentiation. Am J Surg Pathol. 27(6):737-49, 2003
13. Tse LL et al: Sinonasal haemangiopericytoma-like tumour: a sinonasal glomus
tumour or a haemangiopericytoma? Histopathology. 40(6):510-7, 2002
14. Watanabe K et al: True hemangiopericytoma of the nasal cavity. Arch Pathol
Lab Med. 125(5):686-90, 2001
15. Catalano PJ et al: Sinonasal hemangiopericytomas: a clinicopathologic and
immunohistochemical study of seven cases. Head Neck. 18(1):42-53, 1996
16. Thiringer JK et al: Sinonasal hemangiopericytoma: case report and literature
review. Skull Base Surg. 5(3):185-90, 1995
17. el-Naggar AK et al: Sinonasal hemangiopericytomas. A clinicopathologic and
DNA content study. Arch Otolaryngol Head Neck Surg. 118(2):134-7, 1992
18. Eichhorn JH et al: Sinonasal hemangiopericytoma. A reassessment with
electron microscopy, immunohistochemistry, and long-term follow-up. Am J
Surg Pathol. 14(9):856-66, 1990
19. Batsakis JG et al: Hemangiopericytoma of the nasal cavity: electron-optic
study and clinical correlations. J Laryngol Otol. 97(4):361-8, 1983
20. Compagno J: Hemangiopericytoma-like tumors of the nasal cavity: a
comparison with hemangiopericytoma of soft tissues. Laryngoscope.
88(3):460-9, 1978
21. Compagno J et al: Hemangiopericytoma-like intranasal tumors. A
clinicopathologic study of 23 cases. Am J Clin Pathol. 66(4):672-83, 1976

806
 Sinonasal Glomangiopericytoma
Prominent Vasculature
Nonhyalinized Blood Vessels
Fascicular Growth
Other Entities
Perivascular Hyalinization
(Left) The stromal vasculature
of sinonasal GPC is
characteristic of the tumor.
The vessels range from small
capillaries to larger, dilated
and "staghorn" vessels similar
to what is seen in solitary
fibrous tumor. (Right) H&E
shows the characteristic
perivascular hyalinization ﬊
seen in most cases of sinonasal
GPC. It manifests as a sharply
demarcated zone of
homogeneous and
paucicellular eosinophilic
collagen surrounding
capillaries.
Hypovascular Areas
(Left) In the minority of cases
of sinonasal GPC, perivascular
hyalinization is focal or
absent. Therefore, the absence
of this otherwise
characteristic finding does not
exclude the diagnosis. (Right)
Although the vasculature of
sinonasal GPC is a
characteristic feature of the
tumor, blood vessels may be
absent in some fields, as
shown. This absence may
potentially lead to diagnostic
problems on small biopsy.
Inflammatory Infiltrate
(Left) The most common
growth patterns in sinonasal
GPC are sheet-like and
fascicular (shown), and a
mixture of patterns in a given
tumor is common. The latter
may naturally raise concerns
for sarcoma if the pathologist
is unaware of this entity.
(Right) A chronic inflammatory
infiltrate is invariably present
in sinonasal GPC and usually
consists of a mixture of
eosinophils ﬈ and mast cells,
but neutrophils, plasma cells
ſt, and lymphocytes ﬉ may
also be seen.
807
 Sinonasal Glomangiopericytoma
Other Entities

Rounded Cellular Morphology Rounded Cellular Morphology

(Left) In addition to a spindled
morphology, tumor cells in
sinonasal GPC may show a
round or oval cytomorphology,
similar to glomus tumor. This
morphology varies in extent
but is often not prominent.
(Right) The round cell areas in
sinonasal GPC may resemble
glomus tumors but lack the
prominent cell borders seen in
the latter entity.

Stromal Changes Stromal Edema

(Left) Sinonasal GPC usually
contains minimal stroma,
predominantly consisting of
only mesenchymal cells and
vessels. Focal areas of stromal
edema ﬈ or myxoid change
can often be seen, however.
(Right) Extensive stromal
edema may be seen in
sinonasal GPC and is usually
more prominent at the
periphery. The stromal edema
in this example imparts a
reticular appearance in the
paucicellular region and
multinodularity ﬊ in the
preserved cellular zones.

Extensive Stromal Edema Myxoid Stroma

(Left) Some cases of sinonasal
GPC show large zones of
loose, edematous matrix and
can suggest an inflammatory
or allergic polyp. Residual
islands ﬊ of tumor cells
within these paucicellular
areas are diagnostic. (Right)
Although focal myxoid stromal
change is not uncommon in
sinonasal GPC, rare cases
show prominent myxoid
stroma, as depicted.

808
 Sinonasal Glomangiopericytoma
Architectural Whorling
Focal Clear Cell Change
Desmin, S100, CD34 Negativity
Other Entities
Rare Nuclear Palisading
(Left) This case of a sinonasal
GPC shows a prominent
whorled or meningothelial-like
growth pattern ﬈. This
pattern can be seen in up to
10% of cases and is usually
limited in extent when
present. (Right) Nuclear
palisading is a rare finding in
sinonasal GPC but can lead to
diagnostic confusion with
other tumors (particularly
those of nerve sheath origin).
Multinucleated Cells
(Left) H&E shows a focus of
rounded tumor cells with clear
cytoplasm ﬈. Clear cytoplasm
can be seen in many sinonasal
GPCs, but it is usually only
focal and rarely is extensive.
(Right) Multinucleated tumor
giant cells ﬉ can be seen in
up to 5% of cases of sinonasal
GPC and likely represent a
degenerative change. Note the
extravasated blood, which is
typical of sinonasal GPC and
seen in almost all tumors.
Imaging Features
(Left) While SMA and MSA
expression is present in most
cases of sinonasal GPC, desmin
(shown), keratin, CD34, and
S100 protein are negative. The
latter 2 antigens, however,
may be weakly and focally
expressed in some tumors.
(Right) Coronal CT scan shows
a sinonasal GPC filling the
right nasal cavity ﬇ with
bone erosion and extension
into the adjacent ethmoid
sinus ﬉. The right maxillary
sinus has associated sinusitis
﬈.
809
 Ectopic Meningioma

KEY FACTS
Other Entities

TERMINOLOGY MICROSCOPIC
• Meningothelial neoplasm occurring outside of cranial vault • Often infiltrative into surrounding tissues
and spinal column • Morphologic spectrum similar to CNS tumors 
○ Soft tissue extension from intracranial or intraspinal ○ Meningothelial, fibrous, psammomatous, transitional
tumor are excluded from definition morphologies
CLINICAL ISSUES • Meningothelial hamartoma variant: Slit-like pseudovascular
spaces lined by meningothelial cells; variable
• Rare meningothelial nodules
• Most common in children and young adults
• Usually occurs in head and neck region ANCILLARY TESTS
○ Skin and subcutis of scalp • Positive: EMA, progesterone receptor
○ Sinonasal tract • Variable: Claudin-1, S100 protein, p63
• Treatment: Complete surgical excision, if possible • Negative: Chromogranin, synaptophysin, CD31, SMA
• Overall prognosis depends upon grade of tumor and TOP DIFFERENTIAL DIAGNOSES
completeness of resection
• Primary meningioma of CNS
○ Similar to CNS meningiomas
• Cellular neurothekeoma
• Meningothelial hamartoma is benign; recurrences rare
• Plexiform fibrohistiocytic tumor

Ectopic Meningioma Whorls and Nodules

(Left) Ectopic meningioma
shows a similar morphologic
spectrum to
intracranial/intraspinal
tumors. The meningothelial or
transitional form is most
common. Architectural
whorling and small
nest/nodule formation are
characteristic. (Right)
Extensive nested or nodular
growth may mimic a cellular
neurothekeoma or even
paraganglioma, depending on
the site.
Immunohistochemistry is
valuable in the distinction.

Infiltrative Growth Meningothelial Hamartoma

(Left) Ectopic meningioma ﬊
typically shows infiltrative
growth within the surrounding
soft tissues, as evidence in this
H&E by the admixed collagen
bundles and mature adipose
tissue. (Right) Meningothelial
hamartoma is a variant of
ectopic meningioma that
classically occurs in infants
around the posterior scalp.
Histologically, it shows
collagenous stroma with slit-
like vascular spaces lined by
meningothelial cells ﬊.

810
 Ectopic Meningioma

Other Entities
TERMINOLOGY MACROSCOPIC
Synonyms General Features
• Cutaneous meningioma, meningothelial choristoma, • Usually tan-white-gray, rubbery mass
extracranial meningioma • May infiltrate bone
Definitions Size
• Meningothelial proliferation or neoplasm occurring outside • Range: 1-8 cm (mean: 3.5 cm)
of cranial vault and spinal column
○ Soft tissue extension from intracranial or intraspinal MICROSCOPIC
tumor are not included in definition
Histologic Features
○ Meningothelial hamartoma is distinctive, benign clinical
variant • Often infiltrative into surrounding tissues
• Morphologic spectrum similar to CNS tumors 
ETIOLOGY/PATHOGENESIS ○ Meningothelial (most common)
– Syncytial lobules of neoplastic cells without distinct
Unknown borders
• Various hypotheses, including ectopic arachnoid cap cells, – Whorled architecture
displaced meningothelial cells, others – Round, regular nuclei with even nuclear chromatin
and small nucleoli
CLINICAL ISSUES – Pale intranuclear cytoplasmic inclusions
Epidemiology ○ Variant morphologies: Transitional, fibroblastic,
• Incidence psammomatoid, atypical, others
○ Rare • Meningothelial hamartoma variant
• Age ○ Slit-like pseudovascular spaces lined by meningothelial
○ Wide range reported (most common in children and cells
young adults) ○ Small to large clusters of meningothelial cells
– Meningothelial hamartoma usually in
neonates/infants ANCILLARY TESTS
Site Immunohistochemistry
• Most common in head and neck region • Positive: EMA, progesterone receptor
○ Skin and subcutis of scalp, paravertebral areas • Variable: Claudin-1, S100 protein, p63
– Meningothelial hamartoma most common in • Negative: Chromogranin, synaptophysin, CD31, SMA
posterior scalp
○ Sinonasal tract
DIFFERENTIAL DIAGNOSIS
○ Rarely in other sites, including orbit (unassociated with Primary Meningioma of Central Nervous System
optic nerve dural sheath), skull, facial bones, oropharynx • May grow out into (or metastasize to)
Presentation extracranial/extraspinal soft tissues
○ Must always be excluded through imaging
• Varies widely depending upon site of origin
○ Skin/subcutis Cellular Neurothekeoma
– Often painless, slow-growing mass • May show morphological overlap with meningioma
– May be mistaken for skin tag or epidermal cyst • Head, neck, upper extremity of young adults
○ Sinonasal tract • Prominent micronodular growth
– Nasal obstruction, discharge, epistaxis • NKI/C3(+); MITF(+); EMA(-); S100 protein (-)
Treatment Plexiform Fibrohistiocytic Tumor
• Complete surgical excision • Usually mixture of spindled fibroblastic cells and
Prognosis histiocytoid nodules
○ Multinucleated giant cells common
• Similar to CNS tumors
• Plexiform growth pattern
○ Overall prognosis depends upon grade of tumor and
• SMA(+), EMA(-)
completeness of resection
– Recurrences not uncommon
SELECTED REFERENCES
– Distant metastases in rare malignant (anaplastic)
meningiomas 1. Jaiswal P et al: Primary type I cutaneous meningioma of the scalp:
cytohistological and immunohistochemical features of a rare neoplasm.
• Meningothelial hamartoma is benign, and recurrences are Asian J Neurosurg. 13(1):110-112, 2018
rare 2. Lee DH et al: Extracranial meningioma presenting as an eyebrow mass. J
Craniofac Surg. 28(4):e305-e307, 2017
3. Miedema JR et al: Cutaneous meningioma. Arch Pathol Lab Med.
136(2):208-11, 2012

811
 Glial Heterotopia

KEY FACTS
Other Entities

TERMINOLOGY MACROSCOPIC
• Mature, heterotopic neuroglial tissue arising as mass • Firm, smooth, well-circumscribed mass
outside of cranial cavity • Usually 1-3 cm (can reach 7 cm)
• Synonyms: Nasal glial heterotopia, nasal glioma
MICROSCOPIC
ETIOLOGY/PATHOGENESIS • Nonencapsulated
• Congenital, nonhereditary malformation • Variably sized nests of mature glial tissue within
vascularized connective tissue
CLINICAL ISSUES
○ Evenly distributed astrocytes within fine neurofibrillary
• Very rare matrix
• Most common in newborns • Lacks mitoses
• Occurs most frequently in nasal area
○ Dorsum of nose, nasal cavity ANCILLARY TESTS
– Nasal cavity lesions may present with obstructive • GFAP(+), S100 protein (+)
symptoms
TOP DIFFERENTIAL DIAGNOSES
• Treatment: Simple surgical excision
• True encephalocele
• Benign, nonneoplastic
• Neurofibroma
• Meningothelial hamartoma

Glial Heterotopia Mature Glial Tissue

(Left) Heterotopic glial tissue
﬊ is most commonly seen in
the region of the nose and
nasal cavity and is
characterized by nests of
mature glial tissue within a
vascularized connective tissue
stroma. (Right) The glial tissue
resembles that of the central
nervous system; however,
neurons are often rare. The
size of the nests varies from
small and well formed to large
and confluent.

Fine Fibrillary Matrix Rare Eccrine Hyperplasia

(Left) Mature glial tissue is
evidenced by the presence of
astrocytes and other cells
lightly distributed within a fine
fibrillary matrix. Thin or thick
bundles of collagen are not
present. (Right) Rare cases of
cutaneous glial heterotopia of
the nose may show an
associated hyperplasia of
eccrine sweat glands ﬈. Note
the focus of mature glial tissue
﬊.

812
 Glial Heterotopia

Other Entities
TERMINOLOGY Size
• Usually 1-3 cm (can reach 7 cm)
Synonyms
• Nasal glial heterotopia MICROSCOPIC
• Heterotopic glial tissue
Histologic Features
• Nasal glioma
• Nonencapsulated; often poorly defined borders
Definitions • Variably sized nests of mature glial tissue within
• Mature, heterotopic neuroglial tissue arising as mass vascularized connective tissue
outside of cranial cavity ○ Evenly distributed astrocytes within fine, neurofibrillary
matrix
ETIOLOGY/PATHOGENESIS – Larger gemistocytes may be seen
Developmental Anomaly – Neurons are often absent
○ May contain choroid plexus, ependyma, or retinal
• Congenital, nonhereditary malformation
epithelium
• Anterior displacement of mature neuroglial tissue without
• Lacks mitoses
intracranial connection
• Focal calcification may be seen
CLINICAL ISSUES • Rarely may be associated with proliferation of eccrine ducts
• In older patients, lesions may be more fibrotic or
Epidemiology collagenous
• Incidence • Isolated case report of tumor showing combined glial and
○ Very rare meningothelial features ("gliomeningeal heterotopia")
– Rarely associated with other brain or systemic
anomalies ANCILLARY TESTS
• Age Immunohistochemistry
○ Most common in newborns
• GFAP(+), S100 protein (+)
– Usually identified at birth or within first 2 years of life
• Negative for EMA, CD34, SMA, desmin
○ Very rare cases reported in adults
• Sex
DIFFERENTIAL DIAGNOSIS
○ M=F
True Encephalocele
Site
• Histologically indistinguishable
• Nasal area • Shows connection with brain
○ Bridge of nose is most common site (60% of cases) ○ Requires imaging studies
○ Nasal cavity (30%)
– Can be attached to septum Neurofibroma
• May rarely occur in other sites such as tongue, pharynx, • Wide distribution
tonsil, orbit, palate • Spindled cells with wavy, buckled, tapered nuclei
• Collagenous rather than fibrillary stroma
Presentation
• Extranasal Meningothelial Hamartoma
○ Smooth, subcutaneous mass on dorsum of nose • Most common in posterior scalp
• Intranasal • Meningothelial-lined, slit-like spaces and small
○ Nasal obstruction or deformity meningothelial clusters
○ No intracranial component or bony defect • Fibrocollagenous stroma
– If present, encephalocoele is more likely • EMA(+), S100 protein (-)
• Rare parapharyngeal lesions may present with airway
obstruction SELECTED REFERENCES
Treatment 1. Schauer A et al: Unusual case of combined gliomeningeal heterotopia on the
nose of an infant. Am J Dermatopathol. 40(7): 515-8, 2018
• Simple surgical excision 2. Riffaud L et al: Glial heterotopia of the face. J Pediatr Surg. 43(12):e1-3, 2008
3. Ma KH et al: Nasal glioma. Hong Kong Med J. 12(6):477-9, 2006
Prognosis 4. Chen CY et al: Parapharyngeal neuroglial heterotopia presenting as a
• Benign; nonneoplastic growing single locular cyst: MR imaging findings. AJNR Am J Neuroradiol.
26(1):96-9, 2005
• Local recurrence (up to 30%) with incomplete excision 5. Penner CR et al: Nasal glial heterotopia: a clinicopathologic and
immunophenotypic analysis of 10 cases with a review of the literature. Ann
MACROSCOPIC Diagn Pathol. 7(6):354-9, 2003
6. Cerdá-Nicolás M et al: Nasal glioma or nasal glial heterotopia? Morphological,
General Features immunohistochemical and ultrastructural study of two cases. Clin
Neuropathol. 21(2):66-71, 2002
• Firm, smooth, well-circumscribed mass 7. Jartti PH et al: MR of a nasal glioma in a young infant. Acta Radiol. 43(2):141-
• Intranasal lesions are smooth and polypoid 3, 2002

813
 Paraganglioma

KEY FACTS
Other Entities

TERMINOLOGY
• Distinctive tumor of neural crest origin that arises from
paraganglia at specified locations
• Pheochromocytoma is paraganglioma (PG) arising
exclusively within medulla of adrenal gland
ETIOLOGY/PATHOGENESIS
• May be sporadic or arise within setting of various hereditary
tumor syndromes
CLINICAL ISSUES
• Usually affects adults (but overall wide age range)
• Head and neck (particularly carotid body), mediastinum,
retroperitoneum, bladder, other sites
• May be solitary, bilateral, or multicentric
• Treatment: Complete surgical excision
• Most are clinically benign but may recur
• Malignant behavior in specific subset
○ Associated with germline SDHB mutations
MICROSCOPIC
• Characteristic zellballen growth of tumor cells within highly
vascularized fibrous stroma
• Epithelioid or polygonal tumor cells with eosinophilic,
basophilic, or amphophilic, finely granular cytoplasm
• Sustentacular cells often present (but not always)
• Sinusoidal vascular pattern common, often prominent
• Variant: Sclerosing PG
ANCILLARY TESTS
• Synaptophysin (+), chromogranin (+), CD56(+)
• Sustentacular cells are S100 protein (+), SOX10(+)
• Keratin (-), SMA(-), desmin (-), TFE3(-)
• Molecular: Significant subset harbors SDH mutations
TOP DIFFERENTIAL DIAGNOSES
• Alveolar soft part sarcoma
• Carcinoid tumor
• Carcinoma or melanoma

Paraganglioma Characteristic Zellballen Pattern

(Left) Paraganglioma (PG) is a
well-circumscribed
neuroendocrine neoplasm that
arises from parasympathetic
paraganglia in the neck
(particularly carotid body) and
within thoracoabdominal sites
along the sympathetic chain.
PG arising in the adrenal gland
is usually referred to as a
pheochromocytoma. (Right)
The zellballen pattern of PG
features rounded nests of
tumor cells within a
vascularized fibrous stroma.
This growth pattern is not well
developed in all tumors,
however, and may be absent.

Cytologic Features Prominent Vasculature

(Left) The tumor cells of PG
often contain finely granular,
eosinophilic cytoplasm and
regular, centralized nuclei that
may or may not show nucleoli.
Intranuclear pseudoinclusions
﬊ are common, as are
scattered nuclei with
enlargement and
pleomorphism. (Right) PG
characteristically contains a
conspicuous stromal
vasculature. The vessels are
often compressed and
sinusoidal, but larger ectatic
or "staghorn" vessels ﬈ can
also be seen, as depicted in
this H&E.

814
 Paraganglioma

Other Entities
TERMINOLOGY Site
• Head and neck (most common extraadrenal location)
Abbreviations ○ Majority arise in carotid body
• Paraganglioma (PG) – More common in high-altitude habitat
Synonyms ○ Also jugular bulb, middle ear, vagus nerve
• Chemodectoma • Mediastinum (aorticopulmonary)
• Glomus tympanicum (middle ear) and glomus jugulare • Retroperitoneum (from aorticosympathetic paraganglia or
(jugular foramen of temporal bone) organ of Zuckerkandl)
○ These tumors are PGs and are not related to soft tissue • May also arise in bladder, heart, other organs
glomus tumor Presentation
• Extraadrenal PG • Often painless mass
Definitions • May be solitary, bilateral, or multicentric
• Distinctive tumor of neural crest origin that arises from • Head and neck PG may be associated with features of
paraganglia at specified locations and often demonstrates cranial nerve palsies
characteristic nested zellballen growth pattern • Thoracoabdominal PG often associated with
○ Parasympathetic paraganglia in head and neck symptoms/signs attributable to catecholamine production
– Usually nonfunctional ○ Hypertension, palpitations, headache, tachycardia,
○ Sympathetic paraganglia of abdomen, pelvis, and thorax sweating
– Usually functional Treatment
• Pheochromocytoma is PG that arises from within medulla • Complete surgical excision
of adrenal gland ○ Preoperative embolization may be utilized
• Radiotherapy may be utilized in larger, unresectable tumors
ETIOLOGY/PATHOGENESIS • Recommendation: All patients with PG should be evaluated
Genetics for possible hereditary syndromes (particularly those found
• May be sporadic or arise within setting of various hereditary to be SDH deficient)
tumor syndromes Prognosis
○ Hereditary PG-pheochromocytoma syndrome • Most are clinically benign but may recur
– Germline mutations in SDH (succinate dehydrogenase) • Malignant behavior in specific subset
gene subunits
○ Metastasize to lymph nodes, lung, bone
○ Multiple endocrine neoplasia type 2 (MEN2) syndrome
○ Significantly increased risk in PG with germline SDHB
– Germline mutations in RET gene mutations
○ von Hippel-Lindau syndrome
– Germline mutations in VHL gene MACROSCOPIC
○ Neurofibromatosis type 1
– Germline mutations in NF1 gene General Features
○ Carney-Stratakis syndrome • Well-demarcated mass
– Germline mutations in SDH gene subunits • Pink-tan to pink and dark red cut surface
– Features gastric gastrointestinal stromal tumor (GIST) Size
and multicentric PG
• Usually < 5 cm
○ Carney triad
– Features GIST, PG, and pulmonary chondroma
MICROSCOPIC
– Exact genetic mechanism unclear
Histologic Features
CLINICAL ISSUES • Well circumscribed
Epidemiology • Characteristic rounded, nested, or compartmentalized
growth pattern of tumor cells within highly vascularized
• Incidence fibrous stroma
○ Rare ○ Termed zellballen
• Age ○ Often best developed in carotid body tumors
○ Usually adults (but overall wide age range) ○ Tumor cells may also grow in sheets, trabeculae, or
– Tumors associated with hereditary syndromes often pseudopapillary arrangements
affect younger age group • Epithelioid or polygonal tumor cells with eosinophilic,
• Sex basophilic, or amphophilic, finely granular cytoplasm
○ M = F overall ○ Centralized nuclei ± nucleoli
– Female predominance reported in sclerosing PG and – May contain nuclear pseudoinclusions
in PG arising in patients who live in high-altitude – Nuclear pleomorphism not uncommon and often
habitats focal
○ Clear cell change may be present

815
 Paraganglioma
Other Entities
– May be prominent and resemble lipoblastic
differentiation
○ Intracytoplasmic pigment (lipofuscin, neuromelanin) or
eosinophilic globules in occasional cases
○ Tumor cells may show spindled morphology
○ Mitotic figures rare
• Spindled to stellate sustentacular cells at periphery of nests
○ Can be absent
• Sinusoidal vascular pattern common, often prominent
○ May show extensive hemorrhage or vascular congestion
• Variably prominent fibrous stroma/septa
• Clinically malignant tumors generally histologically
indistinguishable from clinically benign tumors
○ However, malignant PG is more likely to show overall
worrisome features (marked nuclear pleomorphism,
mitotic activity, necrosis, and vascular invasion)
• Rare retroperitoneal extraadrenal PG can contain
component of ganglioneuroma
Morphologic Variant
• Sclerosing PG
○ Prominent, diffuse stromal fibrosis
○ Most common in head and neck
ANCILLARY TESTS
Immunohistochemistry
• Synaptophysin (+), chromogranin (+), CD56(+)
• Sustentacular cells (if present) are S100 protein (+) and
SOX10(+)
• Keratin (-), SMA (-), desmin (-), TFE3(-)
• Loss of SDHB protein expression (if PG contains germline
SDH mutations)
○ Specific mutation (SDHA, SDHB, SDHC, SDHD) should be
confirmed by mutation analysis
Genetic Testing
• Significant subset of PG harbors SDH mutations (SDHA,
SDHB, SDHC, or SDHD)
○ SDHD mutation most common in head/neck PG
○ SDHB mutation most common in thoracoabdominal PG
• Very rare SDHAF2 gene mutations in head/neck PG
DIFFERENTIAL DIAGNOSIS
Alveolar Soft Part Sarcoma
• Usually located in deep soft tissues
• Large polygonal cells with abundant eosinophilic cytoplasm
• Synaptophysin (-), chromogranin (-), S100 protein (-)
• Nuclear TFE3(+)
• t(X;17)(p11;q25), with ASPSCR1-TFE3 fusion
Carcinoid Tumor
• Speckled salt and pepper chromatin pattern
• Keratin (+), synaptophysin (+)
• Sustentacular cells absent
Primary or Metastatic Carcinoma
• Particularly renal cell or adrenocortical in abdomen
• Keratin (+)
• Coexisting or prior renal/adrenal mass
816
Metastatic Melanoma
• Previous clinical history may or may not be present
• S100 protein (+)
• Expression of melanocytic markers (HMB-45, MART-1, etc.)
Gastrointestinal Stromal Tumor (SDH-Deficient Type)
• Arises in muscular wall of stomach
• Loss of SDHB by immunohistochemistry
• CD117(+), DOG1(+)
• Synaptophysin (-), chromogranin (-)
SELECTED REFERENCES
1. Cho YY et al: A clinical prediction model to estimate the metastatic potential
of pheochromocytoma/paraganglioma: ASES score. Surgery. ePub, 2018
2. Fite JJ et al: Paraganglioma: Cytomorphologic features, radiologic and
clinical findings in 12 cases. Diagn Cytopathol. 46(6):473-81, 2018
3. Turchini J et al: Pathology and genetics of phaeochromocytoma and
paraganglioma. Histopathology. 72(1):97-105, 2018
4. Udager AM et al: The utility of SDHB and FH immunohistochemistry in
patients evaluated for hereditary paraganglioma-pheochromocytoma
syndromes. Hum Pathol. 71:47-54, 2017
5. Amato B et al: Surgical resection of carotid body paragangliomas: 10 years of
experience. Am J Surg. 207(2):293-8, 2014
6. Santi R et al: Sclerosing paraganglioma of the carotid body: a potential pitfall
of malignancy. Head Neck Pathol. 9(2):300-4, 2014
7. Fishbein L et al: Inherited mutations in pheochromocytoma and
paraganglioma: why all patients should be offered genetic testing. Ann Surg
Oncol. 20(5):1444-50, 2013
8. Galan SR et al: Genetics and molecular pathogenesis of pheochromocytoma
and paraganglioma. Clin Endocrinol (Oxf). 78(2):165-75, 2013
9. Jimenez C et al: Current and future treatments for malignant
pheochromocytoma and sympathetic paraganglioma. Curr Oncol Rep.
15(4):356-71, 2013
10. Letouzé E et al: SDH mutations establish a hypermethylator phenotype in
paraganglioma. Cancer Cell. 23(6):739-52, 2013
11. Mason EF et al: Identification of succinate dehydrogenase-deficient bladder
paragangliomas. Am J Surg Pathol. 37(10):1612-8, 2013
12. Rattenberry E et al: A comprehensive next generation sequencing-based
genetic testing strategy to improve diagnosis of inherited
pheochromocytoma and paraganglioma. J Clin Endocrinol Metab.
98(7):E1248-56, 2013
13. Barletta JA et al: Succinate dehydrogenase-deficient tumors: diagnostic
advances and clinical implications. Adv Anat Pathol. 19(4):193-203, 2012
14. Castelblanco E et al: Thyroid paraganglioma. Report of 3 cases and
description of an immunohistochemical profile useful in the differential
diagnosis with medullary thyroid carcinoma, based on complementary DNA
array results. Hum Pathol. 43(7):1103-12, 2012
15. Mazzaglia PJ: Hereditary pheochromocytoma and paraganglioma. J Surg
Oncol. 106(5):580-5, 2012
16. van Hulsteijn LT et al: Risk of malignant paraganglioma in SDHB-mutation
and SDHD-mutation carriers: a systematic review and meta-analysis. J Med
Genet. 49(12):768-76, 2012
17. King KS et al: Metastatic pheochromocytoma/paraganglioma related to
primary tumor development in childhood or adolescence: significant link to
SDHB mutations. J Clin Oncol. 29(31):4137-42, 2011
18. Singhi AD et al: Peripancreatic paraganglioma: a potential diagnostic
challenge in cytopathology and surgical pathology. Am J Surg Pathol.
35(10):1498-504, 2011
19. Gill AJ et al: Immunohistochemistry for SDHB triages genetic testing of
SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes.
Hum Pathol. 41(6):805-14, 2010
20. Sangoi AR et al: A tissue microarray-based comparative analysis of novel and
traditional immunohistochemical markers in the distinction between adrenal
cortical lesions and pheochromocytoma. Am J Surg Pathol. 34(3):423-32,
2010
21. Petri BJ et al: Phaeochromocytomas and sympathetic paragangliomas. Br J
Surg. 96(12):1381-92, 2009
22. Plaza JA et al: Sclerosing paraganglioma: report of 19 cases of an unusual
variant of neuroendocrine tumor that may be mistaken for an aggressive
malignant neoplasm. Am J Surg Pathol. 30(1):7-12, 2006
23. Wasserman PG et al: Paragangliomas: classification, pathology, and
differential diagnosis. Otolaryngol Clin North Am. 34(5):845-62, v-vi, 2001
 Paraganglioma

Other Entities
Paraganglia Paraganglia
(Left) Graphic shows the
location of paraganglia in the
head, neck, and upper thorax
associated with arteries or
cranial nerves. They include
aortic st and carotid ﬇
bodies, jugulotympanic ſt,
and laryngeal ﬈ paraganglia.
(Right) Graphic shows
aorticosympathetic
paraganglia in thorax and
abdomen. These are
associated with the
sympathetic chain ﬇ and
arterial plexuses and include
the adrenal medulla and organ
of Zuckerkandl ſt.
Paraganglia in the bladder st
can be the site of PG.

Carotid Body Carotid Body

(Left) Low-power H&E shows a
normal carotid body ﬈ in
connective tissue at the
bifurcation of the carotid
artery ﬊ in the neck. This
structure represents an
aggregate of chemoreceptor
tissue that is not
encapsulated. (Right) Higher
magnification of a carotid
body shows nested or
organoid appearance with
small nests of chief cells ﬊
intimately admixed with thin-
walled blood vessels. Note the
absence of nuclear
pleomorphism.

Variable Nested Growth Trabecular Growth

(Left) The small, nested,
organoid or zellballen growth
that is characteristic of PG
varies somewhat from case to
case. The pattern is often well
developed in head/neck PG
but may be less noticeable or
even absent in other sites.
Note the larger and less
rounded nests in the lower
right as compared to the
smaller, rounder nests in the
upper left. (Right) Trabecular
growth may be seen in PG, as
shown in this H&E.

817
 Paraganglioma
Other Entities

Focal Carcinoid-Like Morphology Pseudorosette Pattern

(Left) The combination of
artifactual clefting and a
sinusoidal vasculature can
impart a focal morphologic
appearance that mimics
carcinoid tumor, as depicted.
Unlike the latter tumor,
however, PG is negative for
keratins. (Right) Occasional
cases of PG may show
formation of pseudorosettes
with tumor cells oriented
around small blood vessels ﬈.
This morphology is more
frequently seen in PG of the
cauda equina, where it can
resemble myxopapillary
ependymoma.

Nuclear Pleomorphism Nuclear Pleomorphism

(Left) Nuclear pleomorphism
&/or multinucleation ﬈ is
common as a focal finding in
PG, but it may be more
extensive and prominent in
some tumors. This finding has
no prognostic significance in
isolation. Note the nested
zellballen pattern in this H&E.
(Right) Nuclear pleomorphism
may be striking in some cases
of PG; however, its presence
does not appear to directly
predict behavior.

Nuclear Pseudoinclusions Basophilic Cytoplasm

(Left) Nuclear
pseudoinclusions ﬈ are
frequently identified in PG and
are formed by projections of
eosinophilic cytoplasm into
the nucleus. (Right) Although
many examples of PG are
composed of tumor cells with
eosinophilic cytoplasm, some
tumors show prominent
basophilic cytoplasm, as
depicted. This finding is most
characteristic of
pheochromocytoma (adrenal
PG) but can also be seen in
extraadrenal sites.

818
 Paraganglioma

Other Entities
Basophilic Cytoplasm Basophilia and Nuclear Pleomorphism
(Left) Basophilic tumor cells in
PG often show a more
prominent granular quality to
the cytoplasm than
eosinophilic tumor cells.
(Right) Similar to their
predominantly eosinophilic
counterparts, PG with
basophilic tumor cells can also
show nuclear pleomorphism
&/or multinucleation.

Granular Cytoplasm Vacuolated Cells

(Left) Granular eosinophilic
cytoplasm is an occasional
finding in PG and may
somewhat resemble a soft
tissue granular cell tumor. This
tumor arose in the
mediastinum. (Right) Clear cell
change due to cytoplasmic
vacuolization ﬊ is a common
finding in PG and may be focal,
patchy, or, rarely, diffuse.

Clear Cell Change Sheet-Like Growth

(Left) Intracytoplasmic
vacuolizations may be quite
prominent in some cases of PG
and can lend a bubbly
appearance to the cell,
sometimes suggesting
lipoblastic differentiation.
(Right) Although nested or
organoid growth is more
common in PG, some tumors
can show areas with sheet-like
growth, as depicted. Note the
vacuolated tumor cells.

819
 Paraganglioma
Other Entities

Intracytoplasmic Pigment Spindle Cell Morphology

(Left) Tumor cells in PG may
show an accumulation of dark
intracytoplasmic pigment
(often neuromelanin). Rarely,
it can be diffuse and
prominent and obscure the
underlying tumor. Lipofuscin
and hemosiderin can also be
seen in PG. (Right) Most tumor
cells in PG are polygonal or
epithelioid; however, a
spindled morphology can also
be seen focally, as depicted.

Hemorrhage Vascular Congestion

(Left) Given the vascular
nature of PG, hemorrhage is
not an uncommon histologic
finding. In the setting of
extensive intratumoral
hemorrhage, a vascular
neoplasm may even be
considered. (Right) Vascular
congestion is common in PG
and may lead to the formation
of large dilated spaces ﬈
filled with proteinaceous fluid
and blood.

Stromal Edema Hemangiopericytoma-Like Vasculature

(Left) Centralized areas with
loose, edematous stroma ﬉
can be seen within otherwise
typical PG. Note the
micronodular appearance that
results. (Right) Scattered
dilated, irregular ("staghorn")
blood vessels are not
uncommon in PG. In some
cases, they can be numerous
and prominent in areas,
closely resembling solitary
fibrous tumor at low power, as
depicted.

820
 Paraganglioma

Other Entities
Lobular Growth Sclerosing Paraganglioma
(Left) Some cases of PG show
a lobulated growth pattern
with thick fibrous septa, as
depicted, particularly near the
tumor periphery. This
morphology can lead to
consideration of alveolar soft
part sarcoma. (Right) The
sclerosing variant of PG is
characterized by irregularly
compressed nests of tumor
cells within a prominent
fibrocollagenous stroma, as
shown. This variant appears to
be most common in the head
and neck region. Smaller foci
of stromal fibrosis may also be
seen in otherwise
conventional PG.

Composite Paraganglioma-
Ganglioneuroma Neuroendocrine Marker Expression
(Left) Rare cases of
pheochromocytoma ﬊
(adrenal PG) arise in
association with
ganglioneuroma ﬈. This
event is even rarer in
extraadrenal PG but has been
reported in the
retroperitoneum. (Right)
Tumor cells in PG typically
show diffuse expression of
neuroendocrine markers,
including synaptophysin
(shown), chromogranin, and
CD56. Unlike carcinoid tumors,
keratins are negative in PG.

Sustentacular Cells Sustentacular Cells

(Left) Sustentacular cells, or
modified Schwann cells that
surround nests and aggregates
of tumor cells in PG, are best
visualized on an S100 protein
immunostain. Note the
characteristic thin, delicate
cytoplasmic processes ﬉ and
nuclei ﬈ of these cells. These
cells are not present in all
cases, however. (Right)
SOX10, a nuclear marker of
neural crest origin, is
expressed by sustentacular
cells in PG and may be used as
an alternative to S100 protein.

821
 Peripheral Hemangioblastoma

KEY FACTS
Other Entities

TERMINOLOGY MICROSCOPIC
• True hemangioblastoma (HB) arising in locations outside • Morphologically very similar to CNS HB
CNS ○ However, peripheral HB lacks prominent cystic growth
○ Uncertain cellular origin • Well-circumscribed, often lobular growth pattern
ETIOLOGY/PATHOGENESIS • Mixture of spindled cells and larger, polygonal cells
± prominent cytoplasmic vacuolization
• Associated with von Hippel-Lindau (VHL) syndrome
• Rich, delicate, ramifying capillary vascular network between
CLINICAL ISSUES cells
• Very rare ANCILLARY TESTS
• Median age: 56.5 years • Inhibin (+); variable S100 protein (+)
• Most frequently arise in spinal nerve roots (extradural) • Keratin (-), SMA(-), CD34(-), CD31(-), synaptophysin (-)
○ Also visceral organs (rare)
• Patients may show other features or tumors of VHL TOP DIFFERENTIAL DIAGNOSES
• Treatment: Complete surgical excision • Solitary fibrous tumor
• True local recurrence or distant metastasis has yet to be • Metastatic renal cell carcinoma
documented • Well-differentiated liposarcoma
• Genetic testing for VHL should be performed for all • PEComa
patients • Paraganglioma

Peripheral Hemangioblastoma 2 Cell Populations

(Left) Peripheral
hemangioblastoma (HB) is a
very rare form of HB that
occurs outside of the CNS. It is
a highly vascularized
neoplasm and features vessels
ranging from interconnecting,
thin-walled capillary channels
to larger, ectatic vessels ﬈.
(Right) A mixture of spindled
and polygonal cells comprise
most cases of HB. A
prominent, blood-filled
capillary vascular network ﬉
is often easily appreciated, as
depicted.

Vacuolated Cells Focal Nuclear Pleomorphism

(Left) Some of the larger
polygonal cells in HB may
show numerous cytoplasmic
vacuolizations ﬊ and closely
resemble multivacuolated
lipoblasts; however, the
vacuoles in HB generally do
not indent or scallop the
nucleus. This finding is
characteristic of HB and helps
establish the diagnosis. (Right)
Scattered tumor cell nuclei
showing hyperchromasia and
pleomorphism are not
uncommon in HB and in some
cases may be focally
prominent.

822
 Peripheral Hemangioblastoma

Other Entities
TERMINOLOGY MICROSCOPIC
Abbreviations Histologic Features
• Hemangioblastoma (HB) • Well-circumscribed, often lobular growth pattern
• Morphologically very similar to CNS HB
Synonyms
○ However, peripheral HB (PHB) lacks prominent cystic
• Capillary HB growth
• Extraneuraxial HB • Mixture of 2 cell populations
Definitions ○ Spindle cells with scant pale eosinophilic cytoplasm
• True HB arising in locations outside CNS – Irregular, vesicular, or hyperchromatic nuclei with
○ Uncertain cellular origin small nucleoli
○ Large polygonal cells with hypervacuolated eosinophilic
ETIOLOGY/PATHOGENESIS or clear cytoplasm
– These cells may be focal or absent in areas
Genetics • Nuclear pleomorphism may be present
• Associated with von Hippel-Lindau (VHL) syndrome • Rich, delicate, capillary vascular network between cells
○ Similar to CNS HB ○ Larger, ectatic, or "staghorn" vessels not uncommon
• Loose-to-dense collagenous stroma, may be focally myxoid
CLINICAL ISSUES • Mitotic activity low to absent
Epidemiology • Necrosis absent
• Incidence
○ Very rare
ANCILLARY TESTS
• Age Immunohistochemistry
○ Median: 56.5 years • Spindled and polygonal cells
Site ○ Inhibin (+) in nearly all cases
○ Variable S100 protein (+)
• Most frequently arise in spinal nerve roots (extradural)
• Only vascular endothelial cells are CD31(+), CD34(+)
○ Cervical, thoracic, lumbosacral
• Variable GLUT1(+) in endothelial cells
– Can present as mediastinal, retroperitoneal, or pelvic
• Keratin (-), EMA(-), SMA(-), desmin (-), synaptophysin (-),
mass
chromogranin (-), GFAP(-), HMB-45(-)
• Visceral organs (rare)
○ Kidney, intestines, liver, adrenal gland
DIFFERENTIAL DIAGNOSIS
• Extremities (very rare)
Solitary Fibrous Tumor
Presentation
• Lacks vacuolated cells
• Usually solitary mass
• Diffuse CD34(+)
○ Rare multifocality, mainly within setting of VHL
• Site-specific symptoms Metastatic Renal Cell Carcinoma
○ Extremity weakness or numbness, hematuria, etc. • History of current or prior renal mass
• Patients may show other features or tumors of VHL • Keratin (+), EMA(+)
Treatment Well-Differentiated Liposarcoma
• Complete surgical excision • True lipoblasts are often less vacuolated than cells of HB
• Genetic testing for VHL should be performed for all and more commonly show nuclear scalloping
patients with peripheral (and CNS) HB • MDM2 gene amplification
Prognosis PEComa
• True local recurrence or distant metastasis has yet to be • Lacks prominent cytoplasmic vacuolization
documented • SMA(+), HMB-45(+), MART-1(+)
○ Persistent local disease in cases with incomplete excision
Paraganglioma
MACROSCOPIC • May show morphologic overlap with PHB
• Synaptophysin (+), chromogranin (+)
General Features • S100 protein (+) but only in sustentacular cells
• Well-circumscribed, solid mass
• Yellow, tan-gray, or red-brown cut surface SELECTED REFERENCES
Size 1. Bisceglia M et al: Extraneuraxial hemangioblastoma: clinicopathologic
features and review of the literature. Adv Anat Pathol. ePub, 2017
• Median: 4 cm (range: 1.3-15.0 cm) 2. Doyle LA et al: Peripheral hemangioblastoma: clinicopathologic
characterization in a series of 22 cases. Am J Surg Pathol. 38(1):119-27, 2014
3. Nonaka D et al: Extraneural hemangioblastoma: a report of 5 cases. Am J
Surg Pathol. 31(10):1545-51, 2007

823
 Melanotic Neuroectodermal Tumor of Infancy

KEY FACTS
Other Entities

TERMINOLOGY MICROSCOPIC
• Rare, fast-growing, pigmented neoplasm, likely of neural • Irregular nests, cords, and alveolar spaces within
crest origin fibrocollagenous stroma
○ Nests/spaces are lined by large epithelioid cells
CLINICAL ISSUES
containing melanin granules
• Most present in 1st year of life (> 90%) ○ Clusters of small round neuroblastic cells often located
• Most involve craniofacial sites, particularly maxilla centrally within nests/spaces
• Rapidly enlarging, painless, expansile mass • Mitoses are rare
• Treatment: Complete local excision
• Benign to intermediate clinical course ANCILLARY TESTS
○ Recurrence rate: 10-15% • Large epithelioid cells: Keratin (+), HMB-45(+),
○ Metastatic spread in < 5% synaptophysin (variable), S100 protein (-)
• Age at diagnosis is prognostic factor • Neuroblastic cells: Synaptophysin (+), keratin (-), S100(-)
○ Shorter disease-free survival in patients < 2 months • All cells desmin (-)

MACROSCOPIC TOP DIFFERENTIAL DIAGNOSES

• Usually 2-6 cm • Desmoplastic small round cell tumor
• Alveolar rhabdomyosarcoma
• Neuroblastoma

Melanotic Neuroectodermal Tumor of

Infancy Biphasic Morphology
(Left) Melanotic
neuroectodermal tumor of
infancy (MNTI) is a rare,
rapidly growing
neuroectodermal neoplasm
that usually affects infants
and most commonly involves
the jaw. The classic case
shows irregular nests, cords,
and alveolar spaces within a
prominent fibrocollagenous
stroma. (Right) A biphasic
morphology is observed in
MNTI, composed of larger
eosinophilic cells ﬈ and
smaller, more primitive cells
﬊. Melanin pigment is often
conspicuous in the larger cells.

Melanin Pigment Primitive Neuroblastic Cells

(Left) The larger eosinophilic
cells characteristically contain
melanin pigment ﬈, which
may be abundant. They
routinely express keratin and
HMB-45, but S100 protein is
negative. Synaptophysin is
variably positive. (Right) The
smaller, more primitive
neuroblastic cells resemble
the constituent cells of other
small round blue cell tumors,
such as neuroblastoma. These
cells express synaptophysin
and are negative for keratin,
S100 protein, and desmin.

824
 Melanotic Neuroectodermal Tumor of Infancy

Other Entities
TERMINOLOGY MICROSCOPIC
Abbreviations Histologic Features
• Melanotic neuroectodermal tumor of infancy(MNTI) • Irregular nests, cords, and alveolar spaces within
fibrocollagenous stroma
Synonyms
○ Nests/spaces are lined by large epithelioid cells with
• Retinal anlage tumor round vesicular nuclei
• Melanotic progonoma – Abundant pale eosinophilic cytoplasm containing
• Melanotic ameloblastoma melanin granules
Definitions ○ Clusters of small round neuroblastic cells often located
centrally within nests/spaces
• Rare, fast-growing, pigmented neoplasm, likely of neural
– Small round hyperchromatic nuclei and scant
crest origin
cytoplasm
– May be present without larger epithelioid cells
CLINICAL ISSUES
– Rarely, may be associated with glial tissue
Epidemiology ○ Thick-walled capillaries within stroma
• Incidence ○ Mitoses are rare
○ Rare
• Age ANCILLARY TESTS
○ Most present in 1st year of life (> 90%) Immunohistochemistry
Site • Large epithelioid cells: Keratin (+), HMB-45(+),
• Most involve craniofacial sites synaptophysin (variable), S100 (-)
○ Upper and lower jaw • Neuroblastic cells: Synaptophysin (+), keratin (-), S100(-)
– Maxilla (69%) • All cells desmin (-)
– Mandible (6%)
○ Skull (11%) DIFFERENTIAL DIAGNOSIS
• Unusual sites reported Desmoplastic Small Round Cell Tumor
○ Epididymis, mediastinum, brain, skin, soft tissue • Rare in jaw and in infants
Presentation • Nests of small cells within prominent desmoplastic stroma
• Rapidly enlarging, painless, expansile mass • Keratin (+), desmin (+)
○ Intact overlying mucosa, often with bluish discoloration • EWSR1-WT1 gene fusion
• Erosion into adjacent bone Alveolar Rhabdomyosarcoma
Laboratory Tests • Nests of poorly differentiated small hyperchromatic cells
• Elevated urinary vanillylmandelic acid may be present separated by fibrous septa
• Desmin (+), myogenin (+), keratin (-), HMB-45(-)
Treatment • FOXO1 gene rearrangements
• Complete local excision
Neuroblastoma
Prognosis • Sheets and lobules of small round hyperchromatic cells
• Benign to intermediate clinical course • Absence of large cell component with intracytoplasmic
○ Recurrence rate: 10-15% melanin pigment
○ Metastatic spread reported in < 5% • NB84(+), keratin (-), HMB-45(-)
• Age at diagnosis is prognostic factor Malignant Melanoma
○ Shorter disease-free survival in patients < 2 months of
age • S100 protein (+), HMB-45(+), MART-1(+), keratin (-)
○ Minimal risk of recurrence in patients > 4.5 months • Usually overtly malignant cytology with numerous mitoses
• No morphologic features predict aggressive behavior
SELECTED REFERENCES
MACROSCOPIC 1. Moreau A et al: Melanotic neuroectodermal tumor of infancy (MNTI) of the
head and neck: a French multicenter study. J Craniomaxillofac Surg.
General Features 46(2):201-206, 2018
2. Rachidi S et al: Melanotic neuroectodermal tumor of infancy: a systematic
• Firm, well circumscribed review. J Oral Maxillofac Surg. 73(10):1946-56, 2015
• Gray to blue-black cut surface 3. Camuzard O et al: Melanotic neuroectodermal tumor of infancy: case report
and review of the literature. Rev Laryngol Otol Rhinol (Bord). 132(3):173-6,
Size 2011
4. Chaudhary A et al: Melanotic neuroectodermal tumor of infancy: 2 decades
• Usually 2-6 cm (median: 3.5 cm) of clinical experience with 18 patients. J Oral Maxillofac Surg. 67(1):47-51,
2009
5. Kruse-Losler B et al: Melanotic neuroectodermal tumor of infancy:
systematic review of the literature and presentation of a case. Oral Surg Oral
Med Oral Pathol Oral Radiol Endod. 102:204-16, 2006

825
 Ependymoma of Soft Tissue

KEY FACTS
Other Entities

TERMINOLOGY
• Ependymal neoplasm arising outside of CNS
CLINICAL ISSUES
• Wide age range (most common in children and young
adults)
• Most commonly arises in subcutaneous tissue dorsal to
sacrum and coccyx
• Slow-growing, longstanding masses
• Treatment: Complete surgical excision
○ Long-term clinical follow-up recommended
• Protracted clinical course
○ Local recurrences common
○ Up to 25% metastasize to regional lymph nodes or lung
MACROSCOPIC
• Lobulated, myxoid masses ± hemorrhage
MICROSCOPIC
• Most are well-marginated lesions
• Usually resemble myxopapillary ependymoma
○ Pseudopapillary architecture
○ Abundant perivascular and intercellular myxoid matrix
○ Perivascular pseudorosettes may be present
• May also form cellular sheets of epithelioid cells
ANCILLARY TESTS
• GFAP, S100, CD99, and CD56 (+)
• Keratin (+) in most cases, at least focally
• EMA, synaptophysin, and PLAP (-)
TOP DIFFERENTIAL DIAGNOSES
• Chordoma
• Schwannoma

Soft Tissue Ependymoma Myxopapillary Pattern

(Left) Ependymoma of soft
tissue is very rare compared to
its counterpart in the CNS.
Most cases arise in the dorsal
subcutaneous tissue overlying
the sacrum and coccyx and
demonstrate the morphologic
appearance of a myxopapillary
ependymoma. A microcystic
pattern (shown) is common.
(Right) These tumors are often
heavily myxoid and show
formation of pseudopapillae
around a centralized
fibrovascular core ﬈
secondary to degenerative
changes.

Hyalinization Cytologic Features

(Left) In addition to extensive
myxoid changes, ependymoma
of soft tissue may show
stromal hyalinization. Note
the prominent microcystic
morphology. (Right)
Cytologically, the cells of
ependymoma usually contain
ovoid or elongated nuclei with
a finely granular, evenly
distributed chromatin pattern
and inconspicuous nucleoli.
Mitotic activity is often low.

826
 Ependymoma of Soft Tissue

Other Entities
TERMINOLOGY MICROSCOPIC
Synonyms Histologic Features
• Extraspinal ependymoma, sacrococcygeal ependymoma • Most are well-marginated lesions
• Usually resemble myxopapillary ependymoma
Definitions
○ Pseudopapillary architecture
• Ependymal neoplasm arising outside of CNS
○ Abundant perivascular and intercellular myxoid matrix
– Microcystic change common
ETIOLOGY/PATHOGENESIS
○ Ovoid to elongated nuclei with evenly distributed, finely
Subcutaneous Sacrococcygeal Ependymomas granular chromatin
• Believed to arise from coccygeal medullary vestige ○ Perivascular pseudorosettes may be present in more
cellular, compact areas
Presacral Ependymomas ○ Hemorrhage common
• Believed to arise from extradural remnants of filum • May also form cellular sheets of epithelioid cells
terminale • Low mitotic rate
• Anterior soft tissue extension from cauda equina primary ○ Rare atypical mitotic figures
tumor
Ependymomas of Ovary and Mediastinum ANCILLARY TESTS
• Germ cell origin postulated Immunohistochemistry
• GFAP, S100, CD99, and CD56 (+)
CLINICAL ISSUES • Keratin (+) in most cases, at least focally
Epidemiology • EMA, synaptophysin, TTF-1, PLAP, and brachyury (-)
• Incidence
○ Rare DIFFERENTIAL DIAGNOSIS
• Age Chordoma
○ Wide range; most common in children and young adults • Sacrococcygeal
Site • Usually arises in bone with soft tissue extension
• Contains uni- and multivacuolated (physaliferous) cells
• Subcutaneous tissue dorsal to sacrum and coccyx (most
common) • Inconspicuous vascularity
○ Can be mistaken clinically for teratoma, pilonidal cyst, or • CK(+), EMA(+), brachyury (+), S100 protein (+), GFAP(-)
sweat gland tumors Schwannoma
• Anterior to sacrum and posterior to rectum (presacral • Wide anatomic distribution
region)
• Spindle cell lesions with variable hypercellular (Antoni A)
○ May be soft tissue extension of cauda equina primary and hypocellular myxoid (Antoni B) zones
tumor
○ Also often hyalinized vessels, hemosiderin deposition,
Presentation foam cells, and lymphocytes
• Slow-growing, longstanding masses • Pseudorosettes generally absent
• Dorsal subcutaneous tumors may be associated with spina • Diffuse, strong S100(+)
bifida
SELECTED REFERENCES
Treatment
1. Shelekhova KV et al: Myxopapillary ependymoma of lumbar soft tissue: a
• Complete surgical excision case report with gene expression evaluation. Int J Surg Pathol.
• Radiation may be indicated for residual or inoperable 1066896917748195, 2017
2. Lamzabi I et al: Immunophenotype of myxopapillary ependymomas. Appl
disease Immunohistochem Mol Morphol. 21(6):485-9, 2013
• Long-term clinical follow-up recommended 3. Lee KJ et al: Subcutaneous sacrococcygeal myxopapillary ependymoma in
asian female: a case report. J Clin Med Res. 4(1):61-3, 2012
Prognosis 4. Hussein SA et al: Cytokeratin positivity in myxopapillary ependymoma--a
• Protracted clinical course potential diagnostic pitfall. Diagn Pathol. 3:40, 2008
5. Ma YT et al: Case report: primary subcutaneous sacrococcygeal
○ Local recurrences common ependymoma: a case report and review of the literature. Br J Radiol.
○ Up to 25% metastasize to regional lymph nodes or lung 79(941):445-7, 2006
– Distant metastases usually occur late in clinical course 6. Takano T et al: Primary ependymoma of the ovary: a case report and
literature review. Int J Gynecol Cancer. 15(6):1138-41, 2005
7. King P et al: Soft tissue ependymoma: a report of three cases.
MACROSCOPIC Histopathology. 22(4):394-6, 1993
8. Helwig EB et al: Subcutaneous sacrococcygeal myxopapillary ependymoma.
General Features A clinicopathologic study of 32 cases. Am J Clin Pathol. 81(2):156-61, 1984
• Lobulated, myxoid masses ± hemorrhage 9. Estrozi B et al: Myxopapillary ependymoma of the posterior mediastinum.
Ann Diagn Pathol. 10(5):283-7, 2006
Size
• Wide range (usually < 10 cm)

827
 Metastatic Tumors to Soft Tissue Sites

KEY FACTS
Other Entities

TERMINOLOGY
• Nonnodal somatic soft tissue deposits of nonmesenchymal
visceral, extrasomatic, or cutaneous primary tumors
CLINICAL ISSUES
• Sites: Extremity, back, abdominal wall, others
• Localized soft tissue mass; may be painful
○ Often clinical or radiologic evidence of primary disease
elsewhere (e.g., lung, colon)
○ Soft tissue mass can be initial manifestation of disease
(up to 25% of cases)
○ In up to 15% of cases, no known primary tumor can be
detected
• Treatment individualized according to primary neoplasm
and clinical stage
• Generally poor prognosis due to high clinical stage of
disease
MICROSCOPIC
• Histologic features vary according to primary tumor
○ Adenocarcinoma, squamous cell carcinoma,
neuroendocrine carcinoma, sarcomatoid carcinoma
○ Metastatic melanoma
○ Metastatic sarcoma
ANCILLARY TESTS
• Diffuse cytokeratin (+) in most cases of carcinoma
○ Lineage markers often helpful (e.g., TTF-1, CDX2, pax-8)
• S100 protein (+), SOX10(+) in melanoma
TOP DIFFERENTIAL DIAGNOSES
• Undifferentiated pleomorphic sarcoma
• Malignant peripheral nerve sheath tumor
• Myoepithelial carcinoma
• Clear cell sarcoma

Metastatic Carcinoma Sarcomatoid Carcinoma

(Left) Carcinoma metastatic to
soft tissue sites is most easily
recognized when tumor cells
form clear epithelial
structures, such as cohesive
nests, glands, or tubules.
However, in poorly
differentiated metastases,
histologic confusion with
sarcoma is possible. (Right)
Sarcomatoid (or spindle cell)
carcinoma often lacks
formation of cohesive
epithelial structures and can
closely mimic a spindle cell
sarcoma. Sheets of highly
pleomorphic cells can likewise
mimic a high-grade
pleomorphic sarcoma.

Metastatic Melanoma Rhabdoid Melanoma

(Left) Metastatic melanoma
must always be considered
when evaluating a soft tissue
mass. Most cases are
epithelioid with prominent
nucleoli, as depicted, but some
cases can show a spindled
morphology. Sarcomas with
similar morphology include
clear cells sarcoma, epithelioid
sarcoma, and epithelioid
angiosarcoma. (Right)
Rhabdoid cytologic change in
metastatic melanoma can lead
to confusion with extrarenal
rhabdoid tumor, epithelioid
rhabdomyosarcoma,
epithelioid MPNST, malignant
myoepithelioma, and others.

828
 Metastatic Tumors to Soft Tissue Sites

Other Entities
• Metastatic melanoma
TERMINOLOGY
○ Sheets of epithelioid cells most common
Definitions ○ Marked nuclear atypia common, including macronucleoli
• Nonnodal somatic soft tissue deposits of nonmesenchymal ○ Melanin pigment, if present, is helpful feature
visceral, extrasomatic, or cutaneous primary tumors ○ Variants: Spindle cell, balloon cell, others
○ Hematopoietic neoplasms not included • Metastatic sarcoma
○ Highly variable; depends on type of sarcoma
CLINICAL ISSUES • Other primaries reported
Epidemiology ○ Seminoma, carcinosarcoma, neuroblastoma, teratoma,
malignant gastrointestinal stromal tumor
• Rare
Site ANCILLARY TESTS
• Extremity Immunohistochemistry
• Back, abdominal wall, chest wall • Diffuse cytokeratin (+) in most cases of carcinoma
• Occasionally other sites ○ Expression may be focal or even absent in poorly
Presentation differentiated or undifferentiated tumors
• Localized soft tissue mass; may be painful ○ Squamous cell carcinoma usually p63(+) and p40(+)
○ Often clinical or radiologic evidence of primary disease • Synaptophysin, chromogranin, CD56 in neuroendocrine
elsewhere (e.g., lung, colon) carcinomas
– Previous or concurrent nodal or bony metastases may • Lineage markers often helpful (e.g., TTF-1, CDX2, pax-8)
also be present • S100 protein (+), SOX10(+) in melanoma
○ Soft tissue mass can be initial manifestation of disease ○ Variable expression of melanocytic markers
(up to 25% of cases)
○ In up to 15% of cases, no known primary tumor can be DIFFERENTIAL DIAGNOSIS
detected Undifferentiated Pleomorphic Sarcoma
Treatment • Keratin, S100 protein, and almost all other markers (-)
• Individualized according to primary neoplasm and clinical • Usually severe nuclear pleomorphism, including bizarre
stage atypia
• Lesion may be resected de novo if easily accessible Malignant Peripheral Nerve Sheath Tumor
○ Often due to clinical misdiagnosis as mesenchymal • Highly atypical spindled cells in sheets and fascicles;
neoplasm necrosis common
Prognosis • Heterologous epithelial elements very rare
• Generally poor, due to high clinical stage of disease • Keratins (-); limited S100 protein expression (focal to
negative)
MICROSCOPIC ○ Caveat: Epithelioid MPNST shows diffuse S100 protein
– Can closely mimic melanoma
Histologic Features
• Metastatic carcinoma Myoepithelial Carcinoma
○ Lung, skin, kidney, breast, uterus/ovary, GI tract, others • Can be difficult to distinguish from metastatic carcinoma
○ Specific morphology depends on specific type of ○ Presence of primary tumor elsewhere favors carcinoma
carcinoma • Variable expression of keratins, S100, SMA, GFAP, calponin,
– Adenocarcinoma others
□ Nests, sheets, or cords of malignant epithelioid cells Clear Cell Sarcoma
□ May show gland formation, mucin production, or
• Often challenging to distinguish from metastatic
cribriform architecture
melanoma
– Squamous cell
• Deep mass; lacks overlying junctional component
□ Nests and sheets of eosinophilic cells ± keratin
• Characteristic EWSR1 translocations (usually EWSR1-ATF1)
production
– Neuroendocrine
SELECTED REFERENCES
□ Usually nests and sheets of epithelioid cells with
limited cytoplasm 1. Sammon J et al: Magnetic resonance imaging appearance of soft-tissue
metastases: our experience at an orthopedic oncology center. Skeletal
□ Also acinar, trabecular, micronodular patterns Radiol. 46(4):513-521, 2017
□ Small cell carcinoma often shows nuclear molding, 2. Plaza JA et al: Metastases to soft tissue: a review of 118 cases over a 30-year
prominent apoptosis period. Cancer. 112(1):193-203, 2008
3. Damron TA et al: Distant soft tissue metastases: a series of 30 new patients
– Sarcomatoid and 91 cases from the literature. Ann Surg Oncol. 7(7):526-34, 2000
□ Atypical spindled cells in sheets or vague fascicles 4. Lodding P et al: Metastases of malignant melanoma simulating soft tissue
□ Myxoid zones in some cases sarcoma. A clinico-pathological, light- and electron microscopic and
immunohistochemical study of 21 cases. Virchows Arch A Pathol Anat
○ Desmoplastic, inflammatory, or sclerosing stromal Histopathol. 417(5):377-88, 1990
response can be present
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 Metastatic Tumors to Soft Tissue Sites
Other Entities

Sarcomatoid Squamous Cell Carcinoma Neuroendocrine Carcinoma

(Left) This case of metastatic
sarcomatoid squamous cell
carcinoma of the lung features
a prominent myxoid and
spindle cell morphology,
leading to consideration of
MPNST. Note the focal tumor
cell nest with clear cell change
﬉. (Right) Metastatic
neuroendocrine carcinoma can
closely mimic a variety of
mesenchymal tumors,
including myoepithelioma,
ossifying fibromyxoid tumor,
desmoplastic small round cell
tumor, and Ewing sarcoma.
Immunohistochemistry is often
required in these cases.

Hepatocellular Carcinoma Metastatic Breast Carcinoma

(Left) Metastatic
hepatocellular carcinoma to
soft tissue locations is very
rare but can morphologically
resemble mesenchymal
tumors, such as alveolar soft
part sarcoma and granular cell
tumor. (Right) This case of
metastatic ductal breast
carcinoma to the proximal
thigh features well-developed
epithelial structures ﬉ but
also contains a population of
osteoclast-like multinucleated
giant cells ﬊. The latter
finding is more common in
bony metastases.

Sarcomatoid Carcinoma Spindled Eosinophilic Tumor Cells

(Left) Low-power H&E of
sarcomatoid squamous cell
sarcoma shows a diffuse
spindle cell proliferation,
indistinguishable from a
spindle cell sarcoma, such as
MPNST. Immunostains
revealed diffuse keratin and
P63 expression by the lesional
cells. (Right) Tumor cells in
sarcomatoid carcinoma may
show more abundant
eosinophilic cytoplasm,
mimicking a smooth muscle
neoplasm, particularly
leiomyosarcoma.

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 Metastatic Tumors to Soft Tissue Sites
Edematous Zones With Necrosis
Balloon Cell Melanoma
Metastatic Seminoma
Other Entities
Large Epithelioid Cells in Melanoma
(Left) This sarcomatoid
carcinoma contains zones of
small pleomorphic cells
arranged around small vessels.
A focus of coagulative can be
seen in the lower left. (Right)
The combination of
voluminous eosinophilic
cytoplasm and macronucleoli
in metastatic melanoma can
lead to confusion with solid-
type alveolar soft part
sarcoma.
Spindled Melanoma With Giant Cells
(Left) Some cases of
melanoma show focal to
diffuse granular cell change,
mimicking a granular cell
tumor. Note the presence of
melanin pigment ﬉, a helpful
diagnostic clue. (Right) Rare
cases of melanoma can
feature a component of
osteoclast-like multinucleated
giant cells. This example also
showed a conspicuous
spindled morphology.
CD117 Expression in Seminoma
(Left) Metastatic germ cell
tumors, particularly
seminoma, can be easily
misdiagnosed if not considered
in the differential diagnosis.
Seminoma, pictured here,
generally shows epithelioid
tumor cells with prominent
nucleoli and a fibrovascular
stroma containing
lymphocytes ﬉. (Right) Most
cases of seminoma are
negative for keratins, but they
do express markers, such as
CD117 (shown), OCT 3/4, D2-
40, SALL4, and PLAP.
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 Neuroblastoma and Ganglioneuroblastoma

KEY FACTS
Other Entities

TERMINOLOGY ○ Poorly differentiated NB

• Malignant tumor derived from pluripotent sympathetic ○ Differentiating NB
cells ○ Nodular GNB and intermixed GNB
• Mitotic-karyorrhectic index (MKI)
ETIOLOGY/PATHOGENESIS
• Majority of cases sporadic ANCILLARY TESTS
• Autosomal dominant familial cases have been reported • Immunoreactive for neural markers: NB84, NSE,
synaptophysin, chromogranin
CLINICAL ISSUES • Strong nuclear GATA3(+)
• Most common malignancy in infants < 12 months of age • S100(+) in schwannian stroma
• 90% diagnosed by 5 years of age • Molecular aberrations (MYCN, ALK, ATRX) well described
• Follows distribution of sympathetic ganglia
TOP DIFFERENTIAL DIAGNOSES
• ~ 2/3 have metastases at presentation
• Elevated urine catecholamines in 95% • Alveolar rhabdomyosarcoma (ARMS)
• Ewing sarcoma/primitive neuroectodermal tumor (PNET)
MICROSCOPIC • Translocation-associated undifferentiated sarcomas
• International Neuroblastoma Pathology Committee ○ CIC-DUX4 and BCOR-CCNB3
Classification • Lymphoma
○ Undifferentiated neuroblastoma (NB) • Ganglioneuroma

Neuroblastoma Poorly Differentiated Neuroblastoma

(Left) The typical appearance
of an undifferentiated
neuroblastoma (NB) is a small
round cell tumor without
histologic differentiation. IHC
is generally required to make
the diagnosis and to exclude
other neoplasms. (Right) This
low-power view of a poorly
differentiated NB shows thin
septa of schwannian stroma
﬉. Pale, eosinophilic neuropil
﬈ is seen in places between
the nodules or nests of NB
cells.

Intermixed Ganglioneuroblastoma NB84 Expression

(Left) A typical intermixed
ganglioneuroblastoma (GNB)
is seen in this H&E. The tumor
is composed of a mixture of
maturing ganglion cells ﬈,
neuroblasts ﬉, and abundant
schwannian stroma ﬊. (Right)
In this bone marrow trephine
specimen, there is diffuse
immunoreactivity for NB
antigen (NB84) in metastatic
deposits of NB ﬊ that extend
between bony trabeculae ﬈.
This marker is not entirely
specific, however, and may be
seen focally in other small
round blue cell tumors.

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 Neuroblastoma and Ganglioneuroblastoma

Other Entities
• Fetuses may have hydrops
TERMINOLOGY
• Palpable mass in ~ 1/2
Abbreviations • ~ 2/3 have metastases at presentation
• Neuroblastoma (NB) • "Blueberry muffin" baby
• Ganglioneuroblastoma (GNB) ○ Blue-red, cutaneous masses in infants
• Paraneoplastic myoclonus-opsoclonus-ataxia syndrome
Synonyms
○ Rapid, alternating eye movements and myoclonic
• Schwannian stroma-poor neuroblastic tumor (NB) movements of extremities
• Schwannian stroma-rich neuroblastic tumor (GNB) ○ Associated with more favorable prognosis
Definitions ○ Resolves with tumor eradication but many will have
• Malignant tumor derived from pluripotent sympathetic permanent neurologic deficits
cells • Other associated syndromes
• Maturational spectrum of neuroblastic tumors ○ Myasthenia gravis, Beckwith-Wiedemann syndrome,
○ NB is least differentiated Cushing syndrome, neurofibromatosis, fetal hydantoin
syndrome, Hirschsprung disease
○ GNB is moderately differentiated
○ Ganglioneuroma (GN) is well differentiated, benign Laboratory Tests
• Urine catecholamines (elevated in 95% of patients with NB)
ETIOLOGY/PATHOGENESIS ○ Epinephrine, norepinephrine
Developmental Anomaly ○ Homovanillic acid (HVA), vanillylmandelic acid (VMA)
• Derived from primordial neural crest cells – VMA:HVA ratio > 1.5 associated with better prognosis
○ During fetal development, these cells migrate along ○ May not be elevated in undifferentiated tumors
neuraxis to adrenal medulla and sympathetic ganglia • Associated with worse clinical outcome
• Majority of cases sporadic ○ Lactate dehydrogenase > 1,500 IU/L
○ Some autosomal dominant familial cases have been ○ Ferritin > 142 ng/mL
reported ○ Neuron-specific enolase (NSE) > 100 ng/mL
Natural History
CLINICAL ISSUES
• 1-2% will spontaneously regress
Epidemiology ○ Most in children < age 1 year
• Incidence • NB can metastasize widely via lymphatics and vessels
○ ~ 650 new cases per year in USA
Treatment
○ 3rd most common malignant tumor in children
• Low risk
○ Most common extracranial solid tumor in first 2 years of
life ○ Surgery or observation alone
○ Most common malignancy in infants < 12 months of age • Intermediate risk
• Age ○ Surgery and adjuvant chemotherapy
○ 40% of patients diagnosed by 2 years (median age: 17 • High risk
months) ○ Chemotherapy
○ 90% diagnosed by 5 years ○ Delayed tumor resection
○ ~ 25% are congenital with some detected prenatally on ○ Radiation of primary site
ultrasound ○ Myeloablative chemotherapy with stem cell recovery
• Sex Prognosis
○ Slight male predominance
• Favorable prognostic factors
• Ethnicity
○ Age < 1.5 years at diagnosis
○ More common in white infants
○ Favorable histology
Site ○ Stage 1, 2, or 4S
• Follows distribution of sympathetic ganglia – Related to location of tumor
○ Paramidline from base of skull to pelvis ○ No MYCN amplification
○ Most common sites: Abdomen, retroperitoneum, and ○ Hyperdiploidy
posterior mediastinum ○ No loss of 1p or 11q
• Adrenal medulla ○ High expression of TrKA and TrKC
• Dorsal root ganglia ○ Normal serum ferritin, NSE, and LDH
• Sites of metastasis: Bone, lymph nodes, liver, and skin ○ Urinary VMA:HVA ratio > 1.5
Presentation IMAGING
• Depends on age of patient, location of tumor, and
associated clinical syndromes General Features
• Most have nonspecific symptoms • Extensive radiographic evaluation is required to determine
○ Fever, weight loss, diarrhea, anemia, hypertension extent of disease and identify metastatic foci
• Calcifications often seen in central portion of tumor
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 Neuroblastoma and Ganglioneuroblastoma
Other Entities

Bone Scan ○ Neuropil background

• Radiolabeled metaiodobenzylguanidine (MIBG) ○ No or minimal schwannian stroma
incorporates into catecholamine-secreting cells and can • Differentiating NB
detect NB ○ > 5% of tumor cells showing ganglionic differentiation
○ Usually more abundant neuropil
MACROSCOPIC ○ Usually more prominent schwannian stroma (must be <
50%)
General Features
• Nodular GNB
• NB ○ Grossly identifiable nodules will be NB
○ Fine, membranous capsules ○ Abrupt demarcation between stroma-poor NB and
○ Cut surface is soft, fleshy, often with hemorrhage and stroma-rich component
necrosis ○ Fibrous pseudocapsule often seen surrounding NB
• GNB component
○ Cut surface is firm, gray-white ○ > 50% schwannian stroma
○ Nodular GNB must have grossly visible, usually • Intermixed GNB
hemorrhagic nodules ○ Microscopic nests of NB within schwannian stroma
○ Intermixed GNB can look like NB or GN depending on ○ > 50% schwannian stroma
extent of differentiation
Size ANCILLARY TESTS
• Average: 6- to 8-cm diameter Immunohistochemistry
• NB84(+) in almost all NBs
MICROSCOPIC ○ Not entirely specific; occasionally positive in other small
Histologic Features round cell tumors (often focally)
• Variable tumor composition depending on degree of • Strong nuclear GATA3(+)
differentiation/maturation • NSE
○ Neuroblasts: Small round blue cells with minimal ○ Most sensitive but least specific
cytoplasm ○ Found at least focally even in very undifferentiated NBs
○ Homer Wright pseudorosettes: Neuroblasts forming ring • S100 protein (+) in schwannian stroma
around central core of fibrillary cytoplasmic processes • Also, frequently synaptophysin, chromogranin, CD56 (+)
○ Ganglionic differentiation • Newer markers: PHOX2B(+) and HuC/D(+)
– Cells enlarge
Genetic Testing
– Increased eosinophilic or amphophilic cytoplasm
• MYCN
– Nuclear chromatin pattern becomes vesicular
○ Amplification is associated with worse prognosis
– Must have synchronous differentiation of cytoplasm
and nucleus ○ Usually seen in advanced disease
○ Neuropil characterized by fibrillar eosinophilic matrix • ALK mutation &/or gene amplification
○ Schwannian stroma appears as thin septa composed of ○ Associated with advanced disease
bland spindle cells ○ Alterations seen in both sporadic and hereditary cases
• Mitotic-karyorrhectic index (MKI) calculated in neuroblastic • ATRX inactivating mutations
component ○ More frequent in children > 12 years of age
○ Count of number of cells undergoing mitosis or ○ Worse prognosis
karyorrhexis, per 5,000 cells
– Can be estimated DIFFERENTIAL DIAGNOSIS
– Cannot use bone marrow to calculate MKI Alveolar Rhabdomyosarcoma
○ Low: < 100 cells per 5,000 • More marked alveolar pattern except in solid variant
○ Intermediate: 100-200 cells per 5,000 • More pleomorphism
○ High: > 200 cells per 5,000 • Cells have more abundant cytoplasm than NB
International Neuroblastoma Pathology Committee • Diffuse desmin (+) and myogenin (+)
Classification • Characteristic t(1;13) or t(2;13) with FOXO1 fusions
• Note: Do not classify posttreatment resections Ewing Sarcoma/Primitive Neuroectodermal Tumor
○ "NB with treatment effect" is sufficient • Usually in older patients than those with NB
○ May classify metastatic disease if resection/biopsy is • CD99(+) with diffuse membranous immunoreactivity
pretreatment • Specific gene fusions, most commonly EWSR1-FLI1
• Undifferentiated NB
○ No ganglionic differentiation Translocation-Associated Undifferentiated Sarcomas
○ No neuropil and no or minimal schwannian stroma • Molecular testing required for definitive diagnosis
○ Often requires IHC for accurate diagnosis ○ CIC-DUX4 sarcoma
• Poorly differentiated NB ○ BCOR-CCNB3 sarcoma
○ < 5% of tumor cells showing ganglionic differentiation – CCNB3(+) by IHC also helpful
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 Neuroblastoma and Ganglioneuroblastoma

Other Entities
Favorable vs. Unfavorable Histology in Neuroblastic Tumors
Classification Subclass MKI Age at Diagnosis Histologic Category
Neuroblastoma (NB) Undifferentiated Any Any Unfavorable
Poorly differentiated High Any Unfavorable
Low or intermediate > 1.5 years Unfavorable
< 1.5 years Favorable
Differentiating High Any Unfavorable
Intermediate > 1.5 years Unfavorable
< 1.5 years Favorable
Low > 5.0 years Unfavorable
< 5.0 years Favorable
Ganglioneuroblastoma (GNB) Nodular ** ** Unfavorable or favorable
Intermixed N/A Any Favorable
Ganglioneuroma (GN) Mature or maturing N/A Any Favorable

**The determination of favorable vs. unfavorable histology in nodular GNB is based on the NB component. MKI = mitotic-karyorrhectic index; N/A = not
applicable.

Prognosis Based on MYCN Amplification and Histology

MYCN Amplification Favorable Histology Unfavorable Histology
Nonamplified Excellent prognosis Poor prognosis
Amplified Rare Extremely poor prognosis

Neuroblastoma Staging System

Stage Definition
1 Localized tumor; complete gross resection; ipsilateral nodes negative
2A Localized tumor; incomplete gross resection; nonadherent ipsilateral nodes negative
2B Localized tumor ± complete gross resection; nonadherent ipsilateral nodes negative
3 Unresectable tumor that crosses midline ± positive nodes; or localized tumor with positive contralateral nodes; or midline tumor
with bilateral extension (includes nodal involvement)
4 Distant metastases to nodes, bone, bone marrow, liver, skin, &/or other organs (except as defined for stage 4S)
4S Localized primary tumor (stage 1 or 2) with metastases limited to skin, liver, &/or bone marrow (infants < 1 year old)

Lymphoma 4. Wiles AB et al: GATA3 is a reliable marker for neuroblastoma in limited

samples, including FNA cell blocks, core biopsies, and touch imprints. Cancer
• NSE, synaptophysin, and chromogranin (-) Cytopathol. 125(12):940-6, 2017
• Has confirmatory lymphoid markers 5. Bresler SC et al: ALK mutations confer differential oncogenic activation and
sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell.
○ CD45, CD3, CD20 26(5):682-94, 2014
○ TdT in lymphoblastic lymphoma 6. Vo KT et al: Clinical, biologic, and prognostic differences on the basis of
primary tumor site in neuroblastoma: a report from the international
Maturing Ganglioneuroma neuroblastoma risk group project. J Clin Oncol. 32(28):3169-76, 2014
7. Wang LL et al: Neuroblastoma of undifferentiated subtype, prognostic
• Differs from intermixed GNB in having single ganglion cells significance of prominent nucleolar formation, and MYC/MYCN protein
instead of nests of cells within schwannian stroma expression: a report from the Children's Oncology Group. Cancer.
119(20):3718-26, 2013
SELECTED REFERENCES
1. Machado I 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. 34:1-12, 2018
2. Takemoto J et al: HuC/D expression in small round cell tumors and
neuroendocrine tumors: a useful tool for distinguishing neuroblastoma from
childhood small round cell tumors. Hum Pathol. ePub, 2018
3. Hung YP et al: PHOX2B reliably distinguishes neuroblastoma among small
round blue cell tumors. Histopathology. 71(5):786-94, 2017

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Sympathetic Chain MR of Ganglioneuroblastoma

(Left) Graphic shows the
anatomic extent of the
sympathetic chain ſt
(including adrenal gland) from
the cervical region through the
mediastinum and abdomen to
the inferior pelvis. NB can
arise anywhere along the
sympathetic chain. (Right)
Coronal T2-weighted MR in a
patient with GNB shows a
mildly hyperintense posterior
mediastinal mass ſt with no
abnormality in the adjacent
osseous marrow signal.

Adrenal Neuroblastoma MR of Adrenal Neuroblastoma

(Left) Gross photograph of NB
shows a large, circumscribed
mass ﬇ arising from the
adrenal gland and
compressing the upper pole of
the subjacent kidney ſt. NB is
often grossly hemorrhagic
with areas of necrosis and
calcification seen on
sectioning the specimen.
(Right) Coronal T2-weighted
MR shows an NB ﬈ of the left
adrenal gland with an area of
central necrosis st.

Metastatic Neuroblastoma MR of Metastatic Neuroblastoma

(Left) This whole liver
specimen shows diffuse
involvement and extensive
replacement by multiple
deposits of metastatic NB.
There are several foci of
hemorrhage. (Right) Axial T2-
weighted MR shows a left
adrenal mass ﬊, which
proved to be an NB. It was
widely metastatic; the liver
was filled with multiple high-
signal nodular lesions ſt with
little normal remaining
hepatic parenchyma.

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 Neuroblastoma and Ganglioneuroblastoma
Undifferentiated Neuroblastoma
Apoptosis and Necrosis Poorly Differentiated Neuroblastoma
Neuropil
Other Entities
Cytologic Features
(Left) In undifferentiated NB,
the cells have scant cytoplasm
and rounded, deeply staining
nuclei. On H&E, this
morphology could be easily
mistaken for Ewing sarcoma,
alveolar rhabdomyosarcoma,
or lymphoma. (Right) Tumor
cells in undifferentiated NB
show scant cytoplasm and
feature relatively
monomorphic nuclei. Areas of
nuclear molding may be seen.
Mitoses ﬈ and apoptotic cells
are common.
(Left) Apoptotic and necrotic
cells are common in
undifferentiated NB. Necrosis
often varies from focal and
patchy to diffuse and
geographic. (Right) H&E shows
the typical low-power
appearance of a poorly
differentiated NB. Small strips
of schwannian stroma ſt
separate the neuroblasts and
neuropil, imparting a nested or
multinodular appearance.
True Rosette Formation
(Left) This poorly
differentiated NB shows
sheets of small round cells ﬈
in aggregates within a
background of neuropil ﬇.
The neuropil is composed of a
dense tangle of fibrillary,
eosinophilic cytoplasmic
processes. (Right) This poorly
differentiated NB shows
scattered rosettes st, an early
sign of differentiation. Also
seen are thin bands of
schwannian stroma ﬈.
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Homer Wright Rosettes Subtle Schwannian Stroma

(Left) Homer Wright rosettes
st are composed of
neuroblasts surrounding a
central core of neurites
(cytoplasmic processes)
without a central lumen.
These can be found in varying
numbers in poorly
differentiated NB but are not
wholly specific. (Right)
Schwannian stroma in an NB is
often present as thin septa
composed of spindled cells,
sometimes with wavy nuclei
﬈. The Schwann cell
component can be
demonstrated by IHC for S100
protein.

Hemorrhage and Necrosis Differentiating Neuroblastoma

(Left) NBs are commonly
hemorrhagic with areas of
necrosis ﬊. These changes
can also be seen after
treatment. NBs that have
undergone treatment should
not be classified in the
International Neuroblastoma
Pathology Committee system.
(Right) This is an example of
differentiating NB, in which >
5% of the neuroblasts show
differentiation with increased
cytoplasm and vesicular nuclei
﬊.

Differentiating Neuroblasts Mitotic-Karyorrhectic Index

(Left) Differentiating
neuroblasts st are
characterized by an increased
amount of eosinophilic
cytoplasm, an eccentrically
placed nucleus, and vesicular
chromatin. (Right) The mitotic-
karyorrhectic index (MKI) is
determined by counting the
number of mitoses ﬉ and
karyorrhectic cells ﬈ per
5,000 tumor cells. An
estimated result is usually
considered acceptable, as
counting 5,000 cells can be
tedious. MKI counts should be
averaged over the entire
tumor and not assessed in only
the worst-looking areas.

838
 Neuroblastoma and Ganglioneuroblastoma
Intermediate Mitotic-Karyorrhectic Index
Tumor
Focus of Metastatic Neuroblastoma
Neurofilament Protein
Other Entities
Bony Metastasis in Neuroblastoma
(Left) This is an example of a
poorly differentiated NB,
which has an intermediate
MKI. (Right) This core biopsy
specimen of bone marrow
shows normal marrow in the
lower part of the field ﬉ and
a focus of metastatic NB in the
upper part ﬈. Notice how the
architecture changes in the
focus of metastatic tumor.
NSE Expression
(Left) This is a focus of
metastatic NB in a core biopsy
specimen of bone. The marrow
has been extensively replaced
by sheets of metastatic small
round cell tumor ﬇ and
shows no areas with normal
trilineage hematopoiesis.
(Right) Immunohistochemical
staining for NSE shows strong,
diffuse cytoplasmic staining in
NB. NSE is a sensitive marker
for NB, and although very
nonspecific, it can usefully be
included in a panel of
antibodies in the differential
diagnosis with other small
round cell tumors.
Amplification of MYCN
(Left) Neurofilament protein is
demonstrable, diffusely or
focally, in cytoplasm of 70% of
NBs. It is negative in most
Ewing sarcomas. (Right)
Fluorescence in situ
hybridization (FISH) of this NB
shows marked amplification of
MYCN demonstrated by
numerous red dots ﬇. This
finding predicts poor
prognosis, although the
amount of amplification does
not relate to outcome.
(Courtesy L. McGavran, PhD,
and K. Swisshelm, PhD.)
839
 Neuroblastoma and Ganglioneuroblastoma
Other Entities

Ganglioneuroblastoma Nodular Ganglioneuroblastoma

(Left) Gross photograph of
GNB from the mediastinum
depicts a tumor with a tan,
firm cut surface, but the gross
appearance of GNB depends
on how much of the tumor is
neuroblastic. (Right) This is the
typical look of a nodular GNB
on cut surface. The
hemorrhagic nodule in the
center ﬉ is stroma-poor NB,
whereas the tan, fleshy rim ﬊
is either ganglioneuroma (GN)
or intermixed GNB. The
diagnosis of nodular GNB
requires grossly visible
nodules.

Nodular Ganglioneuroblastoma Intermixed Ganglioneuroblastoma

(Left) This nodular GNB shows
the pushing border between
the stroma-poor NB
component ﬉ and the GN
component ﬈. There is often
a fibrous pseudocapsule
between the 2 components.
Even with this histologic
picture, a grossly visible
nodule is required to diagnose
nodular GNB. (Right) In
intermixed GNB, the nests of
NB can vary in size and
maturation of neuroblasts.
Here, a larger nest of
immature neuroblasts is seen
﬈.

Schwannian Stroma in Intermixed

Ganglioneuroblastoma Nested Growth
(Left) To diagnose intermixed
GNB, at least 50% of the
tumor must be composed of
schwannian stroma. This is
characterized by spindled,
wavy cells in bundles of
varying cellularity. The
Schwann cells lack nuclear
atypia and demonstrate
nuclear immunoreactivity for
S100 protein. (Right) This
intermixed GNB shows well-
defined nests ﬉ of maturing
neuroblasts, ganglion cells,
and neuropil within a
schwannian stroma ﬈.

840
 Neuroblastoma and Ganglioneuroblastoma
Clusters of Ganglion Cells
Intermixed Ganglioneuroblastoma
Prominent Schwannian Stroma
Other Entities
Mature Ganglion Cells
(Left) The neuroblastomatous
component of this intermixed
GNB is predominantly mature
(or nearly mature) ganglion
cells ﬊. The ganglion cells are
present in clusters in this
tumor, differing from the
pattern in maturing GN in
which they are present as
single cells. (Right) Mature
ganglion cells ﬈ are
characterized by abundant
eosinophilic to amphophilic
cytoplasm, eccentric nuclei,
and prominent nucleoli. Nissl
substance may or may not be
present.
Neuroblasts and Ganglion Cells
(Left) This low-magnification
field of intermixed GNB shows
clusters of maturing
neuroblasts and ganglion cells
﬊, foci of neuropil ﬉, and
areas of schwannian stroma
﬈. (Right) Higher
magnification of intermixed
GNB shows details of
neuroblasts ſt, maturing
neuroblasts ﬈, and ganglion
cells ﬉ blending into the
schwannian stroma ﬊.
Neurofibroma-Like Areas
(Left) This section from an
intermixed GNB could be
mistaken for a maturing GN. In
maturing GN, the tumor is
predominantly composed of
schwannian stroma, and
individual neuroblastic cells
merge into the schwannian
stroma instead of forming
distinct nests. (Right) This field
of an intermixed GNB could be
mistaken for neurofibroma
(spindled wavy cells in a
myxoid background) or mature
GN. Adequate sampling,
generally 1 section per cm of
tumor, is required to make an
accurate diagnosis.
841
 Extraaxial Soft Tissue Chordoma

KEY FACTS
Other Entities

TERMINOLOGY MICROSCOPIC
• True chordoma arising in soft tissue without evidence of • Histologic features identical to skeletal (axial) chordoma
skeletal origin • Multinodular with fibrous septa
CLINICAL ISSUES • Epithelioid or spindle cells in cords/nests set in myxoid
background
• Very rare (< 30 cases in literature)
• Pale eosinophilic or clear cytoplasm with vacuoles
• Usually adults
• Characteristic physaliferous cells may be present
• Acral sites (~ 50%)
○ Remainder in proximal extremity or trunk ANCILLARY TESTS
• Subcutaneous or deep mass, usually slowly growing • Strong nuclear brachyury (+)
• Majority behave indolently ○ Present in essentially 100% of cases (defining criterion
○ Local recurrence &/or distant metastasis (lung or for diagnosis)
intraabdominal) in subset (20-30%) • Usually also keratin (+), EMA(+), S100 protein (+)
MACROSCOPIC TOP DIFFERENTIAL DIAGNOSES
• Multilobulated, circumscribed mass • Myoepithelioma of soft tissue
• Gelatinous cut surface • Extraskeletal myxoid chondrosarcoma
• Metastatic or primary cutaneous mucinous carcinoma
• Soft tissue metastasis from axial chordoma

Multinodular Growth Cords Within Myxoid Matrix

(Left) Similar to its primary
skeletal counterpart,
extraaxial soft tissue
chordoma typically shows a
multinodular growth pattern
with intervening fibrous septa
similar to conventional
chordoma. This case gave rise
to a lung metastasis that had
a strikingly similar
architecture. (Right)
Epithelioid tumor cells with
pale vacuolated cytoplasm
form cords, chains, and nests
set within a blue myxoid
matrix in chordoma.

Physaliferous Cells Nuclear Atypia

(Left) Tumor cells with bubbly
vacuolated cytoplasm
(physaliferous cells) ﬈ are a
characteristic finding in
chordoma; however, they are
not always present and are
not required for the diagnosis.
(Right) High-power H&E shows
physaliferous cells ﬈ with
multiple cytoplasmic vacuoles
set within an abundant blue
myxoid matrix ﬇. Nuclear
atypia and pleomorphism ﬉
may be present.

842
 Extraaxial Soft Tissue Chordoma

Other Entities
• Usually low cellularity but can be hypercellular
TERMINOLOGY
• Tumor cells may wrap around each other
Definitions • May have rhabdoid cytology
• True chordoma arising in soft tissue without evidence of • Cartilaginous matrix may be present focally
skeletal origin
ANCILLARY TESTS
CLINICAL ISSUES Immunohistochemistry
Epidemiology • Strong nuclear brachyury (+)
• Incidence ○ Present in essentially 100% of cases (defining criterion
○ Very rare (< 30 cases in literature) for diagnosis)
• Age ○ Only marker that can reliably distinguish chordoma from
○ Usually adults myoepithelioma
• Sex • Usually also keratin (+), EMA(+), and S100 protein (+)
○ M>F • Nuclear SMARCB1/INI1 retained in few cases tested to date
(subset of pediatric axial chordomas show SMARCB1/INI1
Site loss)
• Most cases occur in soft tissue near bone or joints
○ Acral sites (~ 50%) DIFFERENTIAL DIAGNOSIS
○ Remainder in proximal extremity or trunk
Myoepithelioma of Soft Tissue
Presentation • May show morphologic overlap with chordoma
• Subcutaneous or deep mass, usually slowly growing • Usually keratin (+), EMA(+), and S100 protein (+); other
○ Clinically resemble benign cyst (when small, myoepithelial markers variable
subcutaneous, distal) or sarcoma (when large, deep, • Brachyury (-) (key distinguishing feature)
proximal) • Obsolete synonyms for myoepithelioma: Parachordoma,
chordoma periphericum, peripheral chordoma, chordoid
Treatment
tumor
• Complete excision with free margins ○ Older literature often incorrectly equated these with
• Chemotherapy has been attempted for metastatic lesions true soft tissue chordomas
Prognosis Extraskeletal Myxoid Chondrosarcoma
• Majority behave indolently • May have similar histologic features to chordoma
• Local recurrence &/or distant metastasis (lung or • EMA(+) in subset; S100 protein and keratins usually (-) or
intraabdominal) in subset (20-30%)  only focally (+)
○ Larger proximally located tumors may have higher risk of • Brachyury (-)
aggressive behavior • Characteristic translocations usually detectable, including
t(9;22) and variants
IMAGING
Metastatic or Primary Cutaneous Mucinous
Radiographic Findings
Carcinoma
• Small tumors: Circumscribed nodules
• Known primary site elsewhere in some cases
• Large tumors: Circumscribed, multilobulated masses with
• Usually has larger nests of tumor cells floating in mucin
heterogeneous enhancement
pools
• Keratin (+); may coexpress other more specific lineage
MACROSCOPIC markers
General Features • Brachyury (-)
• Multilobulated, circumscribed mass Soft Tissue Metastasis From Axial Chordoma
• Gelatinous cut surface
• Uncommon scenario that can be excluded by clinical history
• May have hemorrhage or necrosis
&/or imaging studies
MICROSCOPIC SELECTED REFERENCES
Histologic Features 1. Righi A et al: Extra-axial chordoma: a clinicopathologic analysis of six cases.
• Histologically identical to skeletal (axial) chordoma Virchows Arch. 472(6):1015-1020, 2018
2. Lauer SR et al: Soft tissue chordomas: a clinicopathologic analysis of 11 cases.
• Multinodular with fibrous septa Am J Surg Pathol. 37(5):719-26, 2013
• Epithelioid or spindle cells in cords/nests set in myxoid 3. Suzuki H et al: Extra-axial soft tissue chordoma of wrist. Pathol Res Pract.
background 207(5):327-31, 2011
• Pale eosinophilic or clear cytoplasm with vacuoles 4. Tirabosco R et al: Brachyury expression in extra-axial skeletal and soft tissue
chordomas: a marker that distinguishes chordoma from mixed
○ Characteristic physaliferous cells may be present tumor/myoepithelioma/parachordoma in soft tissue. Am J Surg Pathol.
• Nuclear atypia usually mild but can be focally moderate to 32(4):572-80, 2008
severe

843
 Undifferentiated Embryonal Sarcoma of Liver

KEY FACTS
Other Entities

TERMINOLOGY MICROSCOPIC
• Malignant, primitive neoplasm of liver, often with evidence • Spindled, ovoid, and stellate cells with granular or bubbly
of partial divergent differentiation eosinophilic cytoplasm
○ Cellularity varies from loose to compact
CLINICAL ISSUES
○ Marked nuclear pleomorphism and hyperchromasia
• Usually < 20 years (most common: 6-10 years)
○ Multinucleation and bizarre atypia
• Occurs in liver
• Usually prominent myxoid stroma
• Abdominal swelling and pain
• Clusters of variably sized eosinophilic globules common
• Treatment: Complete surgical resection, often with
• Mitoses usually numerous
chemotherapy
• Hemorrhage and coagulative necrosis common
○ Much improved 5-year survival rate with combination
therapy (surgery, neoadjuvant and adjuvant therapy) ANCILLARY TESTS
• Local recurrence is common; metastases rare • Globules are PAS(+), diastase resistant
MACROSCOPIC • CD31(-), CD34(-), myogenin (-), S100 protein (-), CD117(-),
HMB-45(-)
• Well-demarcated mass; variegated cut surface with solid,
cystic, and gelatinous areas TOP DIFFERENTIAL DIAGNOSES
• Often large (> 10 cm) • Embryonal rhabdomyosarcoma

Undifferentiated Embryonal Sarcoma Marked Nuclear Atypia

(Left) Undifferentiated
embryonal sarcoma of the
liver (UESL) is a primitive
malignant neoplasm that most
commonly occurs in childhood.
Most cases show a prominent
myxoid stroma, and cellularity
varies from low and dispersed
﬈ to highly compact ﬉.
Hemorrhage and necrosis are
common. (Right) Nuclear
pleomorphism and
hyperchromasia are consistent
features of UESL, at least
focally. In many tumors,
multinucleated forms and
bizarre atypia are present, as
depicted.

Eosinophilic Globules Entrapment of Hepatobiliary Elements

(Left) Eosinophilic globules ﬉
of varying shapes and sizes are
common in UESL. They may be
intracytoplasmic or found
extracellularly, and they are
PAS(+), diastase resistant.
(Right) Entrapment of residual
normal biliary ductules ﬈ or
hepatic parenchyma ﬊ can be
seen in UESL, particularly near
the periphery of the tumor.

844
 Undifferentiated Embryonal Sarcoma of Liver

Other Entities
TERMINOLOGY MICROSCOPIC
Abbreviations Histologic Features
• Undifferentiated embryonal sarcoma of liver (UESL) • May show partial pseudocapsule formation
○ Entrapped biliary ductules and hepatocytes often
Synonyms
entrapped near tumor periphery
• Embryonal sarcoma – Tumor cells may involve sinusoids
Definitions • Spindled, ovoid, and stellate cells with granular or bubbly
• Malignant, primitive neoplasm of liver, often with evidence eosinophilic cytoplasm
of partial divergent differentiation ○ Cellularity varies from loose to compact
– May rarely show formation of cellular fascicles or
ETIOLOGY/PATHOGENESIS storiform arrays
○ Marked nuclear pleomorphism and hyperchromasia
Unknown ○ Multinucleation and bizarre atypia
• May rarely occur in association with mesenchymal • Usually prominent myxoid stroma
hamartoma of liver ○ May be fibrous or focally hyalinized
○ Both contain chromosome 19 abnormalities • Clusters of variably sized eosinophilic globules common
○ Intracytoplasmic or extracellular
CLINICAL ISSUES • Mitoses usually numerous
Epidemiology • Hemorrhage and coagulative necrosis common
• Incidence • Extramedullary hematopoiesis may be present
○ Rare
• Age ANCILLARY TESTS
○ Usually < 20 years (most commonly 6-10 years) Histochemistry
– Very rare cases in adults • Globules are PAS(+), diastase resistant
Site Immunohistochemistry
• Exclusive to liver • Vimentin (+), α-1-antitrypsin (+)
○ More common in right lobe • Variable, focal expression of glypican-3, keratins, SMA,
Presentation desmin, CD68, and others
○ Evidence of partial divergent differentiation
• Abdominal swelling and pain
• CD31(-), CD34(-), myogenin (-), S100 protein (-), CD117(-),
• Large mass
HMB-45(-)
○ May or may not be palpable
• Possible fever &/or weight loss
DIFFERENTIAL DIAGNOSIS
• Normal serum α-fetoprotein levels
Embryonal Rhabdomyosarcoma
Treatment
• Usually biliary tree; rare in liver
• Multimodal therapy ideal
• Rhabdomyoblasts often present, at least focally
○ Complete surgical resection
• Desmin, myogenin, MYOD1 (+)
○ Chemotherapy &/or radiation
• Transplantation may be considered in unresectable cases Sarcomatoid Carcinoma
• Usually adults
Prognosis
• Often more extensive keratin (+)
• Markedly improved survival in recent years (> 70%) with
combination therapy (surgery, neoadjuvant and adjuvant Mesenchymal Hamartoma
chemotherapy, and radiation) • Most occur < 3 years of age
• Local recurrence is common • Absence of marked cytologic atypia
• Rare metastases • Rare reports of UESL arising in mesenchymal hamartoma

MACROSCOPIC SELECTED REFERENCES

General Features 1. Shi Y et al: Characteristics and outcomes in children with undifferentiated
embryonal sarcoma of the liver: a report from the National Cancer Database.
• Well demarcated, partially encapsulated Pediatr Blood Cancer. 64(4), 2017
• Variegated cut surface with solid, cystic, and gelatinous 2. Putra J et al: Undifferentiated embryonal sarcoma of the liver: a concise
areas review. Arch Pathol Lab Med. 139(2):269-73, 2015
3. Shehata BM et al: Undifferentiated embryonal sarcoma of the liver is
○ Hemorrhage, necrosis common associated with mesenchymal hamartoma and multiple chromosomal
abnormalities: a review of eleven cases. Pediatr Dev Pathol. 14(2):111-6,
Size 2011
• Wide range (often large, > 10 cm) 4. Zheng JM et al: Primary and recurrent embryonal sarcoma of the liver:
clinicopathological and immunohistochemical analysis. Histopathology.
51(2):195-203, 2007

845
 Primary Pulmonary Myxoid Sarcoma

KEY FACTS
Other Entities

TERMINOLOGY MICROSCOPIC
• Low-grade translocation-associated sarcoma, exclusively • Related to bronchus
occurring in lung, adjacent to or within bronchus, • Abundant myxoid matrix
composed of abundant myxoid matrix with reticulated • Epithelioid to spindle cells with low-level nuclear
cords, clusters, or sheets of epithelioid to spindle cells pleomorphism
CLINICAL ISSUES • Prominent reticulated cytoarchitecture
○ Interconnecting cord and strands of cells
• Rare: 23 reported cases
• Solid sheets of cells
• Mean age: 45 years
• Peripheral rind of fibrosis
• 2:1 female predominance
• Patchy chronic inflammation
• Most patients alive with no evidence of disease
• 3 reports of metastasis ANCILLARY TESTS
MACROSCOPIC • EWSR1 rearrangement by FISH
• EWSR1-CREB1 fusion by RT-PCR
• Well circumscribed
• Partially encapsulated TOP DIFFERENTIAL DIAGNOSES
• Frequently forms endobronchial mass • Angiomatoid fibrous histiocytoma
• Mean size: 4.9 cm • Extraskeletal myxoid chondrosarcoma
• Myoepithelioma

Primary Pulmonary Myxoid Sarcoma Architectural Features

(Left) Primary pulmonary
myxoid sarcoma (PPMS)
typically presents as a well-
circumscribed, lobular mass. It
is typically associated with a
bronchus ﬈ and often forms
an endobronchial mass. It is
often surrounded by a thick
rind of fibrosis ﬉. However,
focal pulmonary parenchymal
infiltration may be present.
(Right) The dominant
histological pattern in PPMS is
a reticulated or net-like
pattern formed by
interconnecting cords of cells
﬈ within abundant pale blue
myxoid matrix ﬉.

Reticulated Pattern EWSR1 Rearrangement

(Left) This medium-power
micrograph highlights the
reticulated pattern composed
of cords ﬈ and clusters ﬉ of
epithelioid cells with abundant
eosinophilic cytoplasm within
a myxoid stroma ﬊. (Right)
EWSR1 break-apart FISH can
confirm the diagnosis of PPMS
since EWSR1-CREB1
translocations can be detected
in most tumors. This FISH
assay shows 1 normal, intact
allele with fused red and
green signals ſt adjacent to 2
abnormal, separated, red and
green signals st within single
cells. (Courtesy S. Smith, MD.)

846
 Primary Pulmonary Myxoid Sarcoma

Other Entities
○ Focally infiltrates pulmonary parenchyma
TERMINOLOGY
• Lobular architecture
Abbreviations • Abundant myxoid matrix
• Primary pulmonary myxoid sarcoma (PPMS) • Epithelioid, spindled, and polygonal/stellate cells
○ Vesicular chromatin
Synonyms
○ Mild to moderate nuclear pleomorphism
• Malignant myxoid endobronchial tumor ○ Low mitotic rate in most tumors
Definitions • Prominent reticulated cytoarchitecture
• Low-grade translocation-associated sarcoma, exclusively ○ Interconnecting cord and strands of cells
occurring in lung, adjacent to or within bronchus, – Major component in most tumors
composed of abundant myxoid matrix with reticulated ○ Small clusters of cells
cords, clusters, or sheets of epithelioid to spindle cells ○ Individual cells
○ Characterized by EWSR1-CREB1 fusion ○ Solid sheets of cells
– Usually minor component
CLINICAL ISSUES – Pericytomatous vascular pattern in some tumors
Epidemiology • Fibrosis
○ Often forming peripheral rind
• Incidence
• Patchy chronic inflammation
○ Rare: 23 reported cases
○ Lymphoplasmacytic most common
• Age
○ Hemosiderophages, xanthoma cells, giant cells, &/or
○ Mean: 45 years (median: 30 years)
eosinophils common
○ Range: 27-80 years
• Necrosis common
• Sex
○ Usually focal when present
○ 2:1 female predominance
Presentation ANCILLARY TESTS
• Cough Immunohistochemistry
• Hemoptysis • No distinct immunophenotype
• Fever • Most helpful for excluding other entities
• Weight loss
In Situ Hybridization
Treatment
• EWSR1 rearrangement by FISH
• Complete surgical resection
PCR
Prognosis
• EWSR1-CREB1 fusion
• Very good
○ Most patients alive with no evidence of disease DIFFERENTIAL DIAGNOSIS
• 3 reports of metastasis
○ Brain
Angiomatoid Fibrous Histiocytoma
– May not be true PPMS • Endobronchial mass
○ Kidney • Sheets or short fascicles
○ Contralateral lung • Ovoid to spindle cells
• Less myxoid matrix, less reticulated cell pattern
MACROSCOPIC • Dense lymphoplasmacytic infiltrate and fibrous capsule
• Blood-filled spaces may be absent
General Features
• Desmin (+)
• Well circumscribed • EWSR1-ATF1 or EWSR1-CREB1
○ Partially encapsulated
○ Focally infiltrates pulmonary parenchyma Extraskeletal Myxoid Chondrosarcoma
• Most tumors associated with bronchus • Very rare as primary pulmonary tumor
○ Frequently forms endobronchial polypoid mass • Reticulated cell cords
• Lobular, gelatinous to firm cut surface • Epithelioid or spindle cells
• Rhabdoid cells in some tumors
Size
• Abundant myxoid matrix
• Mean: 4.9 cm ○ Alcian blue (+) but not abolished by hyaluronidase (unlike
• Range: 1.5-13.0 cm PPMS)
• Necrosis common
MICROSCOPIC • NR4A3-EWSR1 or alternate NR4A3 fusions
Histologic Features Myoepithelioma
• Related to bronchus
• Abundant myxoid matrix
○ Often endobronchial
• Reticulated cell cords

847
 Primary Pulmonary Myxoid Sarcoma
Other Entities

Immunohistochemistry
Antibody Reactivity Staining Pattern Comment
Vimentin Positive Cytoplasmic
EMA Positive Cell membrane and Focally &/or weakly positive in subset of tumors
cytoplasm
CK-PAN Negative
p63 Negative
Desmin Negative
S100 Negative
CD34 Negative
Synaptophysin Negative
HMB-45 Negative
Melan-A Negative
Actin-sm Equivocal Cytoplasmic Only 1 positive tumor reported
CD56 Equivocal Only 1 positive tumor reported
Chromogranin-A Equivocal Only 1 positive tumor reported

• Plasmacytoid cells
SELECTED REFERENCES
• Fascicles of spindle cells
• Variable expression of keratins, S100, SMA, p63 1. Agaimy A et al: EWSR1-fusion-negative, SMARCB1-deficient primary
pulmonary myxoid sarcoma. Pol J Pathol. 68(3):261-7, 2017
• EWSR1-ZNF444, EWSR1-PBX1, or EWSR1-POU5F1 fusions 2. Kim S et al: Primary pulmonary myxoid sarcoma located in interlobar fissure
without parenchymal invasion. Thorac Cancer. 8(5):535-8, 2017
Myxofibrosarcoma 3. Yanagida R et al: Primary pulmonary myxoid sarcoma, a potential mimic of
• Very rare as primary pulmonary tumor metastatic extraskeletal myxoid chondrosarcoma. Pathology. 49(7):792-94,
2017
• Abundant myxoid matrix 4. Fisher C: The diversity of soft tissue tumours with EWSR1 gene
• Lacks reticulated cell cords rearrangements: a review. Histopathology. 64(1):134-50, 2014
• Nuclear pleomorphism 5. Jeon YK et al: Primary pulmonary myxoid sarcomas with EWSR1-CREB1
translocation might originate from primitive peribronchial mesenchymal
• Curvilinear, thin-walled vascular pattern cells undergoing (myo)fibroblastic differentiation. Virchows Arch.
465(4):453-61, 2014
Myxoid Liposarcoma 6. Shen W et al: Primary pulmonary leiomyosarcoma. J Chin Med Assoc.
• Very rare as primary pulmonary tumor 77(1):49-51, 2014
• Abundant myxoid matrix 7. Smith SC et al: At the intersection of primary pulmonary myxoid sarcoma
and pulmonary angiomatoid fibrous histiocytoma: observations from three
• Ovoid to spindle cells new cases. Histopathology. 65(1):144-6, 2014
• Lipoblasts 8. Matsukuma S et al: Primary pulmonary myxoid sarcoma with EWSR1-CREB1
fusion, resembling extraskeletal myxoid chondrosarcoma: case report with a
• Chicken-wire vascular pattern review of Literature. Pathol Int. 62(12):817-22, 2012
• FUS-DDIT3 or EWSR1-DDIT3 fusion 9. Son C et al: Primary Pulmonary myxoid liposarcoma with translocation
t(12;16)(q13;p11) in a young female patient: a brief case report. Korean J
Myxoid Leiomyosarcoma Pathol. 46(4):392-4, 2012
• Very rare as primary pulmonary tumor 10. Thway K et al: Tumors with EWSR1-CREB1 and EWSR1-ATF1 fusions: the
current status. Am J Surg Pathol. 36(7):e1-e11, 2012
• Long fascicles of spindle cells 11. Thway K et al: Endobronchial pulmonary angiomatoid fibrous histiocytoma:
• Blunt-ended nuclei two cases with EWSR1-CREB1 and EWSR1-ATF1 fusions. Am J Surg Pathol.
36(6):883-8, 2012
• Eosinophilic fibrillary cytoplasm
12. Zhou Q et al: Extraskeletal myxoid chondrosarcoma in the lung:
• SMA(+); variable desmin (+) asymptomatic lung mass with severe anemia. Diagn Pathol. 7:112, 2012
13. Chen G et al: Angiomatoid fibrous histiocytoma: unusual sites and unusual
DIAGNOSTIC CHECKLIST morphology. Mod Pathol. 24(12):1560-70, 2011
14. Hasanoğlu HC et al: A mass of myxofibrosarcoma in the lung. Tuberk Toraks.
Clinically Relevant Pathologic Features 59(1):73-6, 2011
15. Thway K et al: Primary pulmonary myxoid sarcoma with EWSR1-CREB1
• Mean age: 45 years fusion: a new tumor entity. Am J Surg Pathol. 35(11):1722-32, 2011
Pathologic Interpretation Pearls 16. Kourda J et al: Benign myoepithelioma of the lung - a case report and review
of the literature. Cases J. 3(1):25, 2010
• Associated with bronchus 17. Inayama Y et al: Low-grade pulmonary myxoid sarcoma of uncertain
• Usually forms endobronchial mass histogenesis. Pathol Int. 51(3):204-10, 2001
18. Nicholson AG et al: Malignant myxoid endobronchial tumour: a report of two
• Abundant myxoid matrix cases with a unique histological pattern. Histopathology. 35(4):313-8, 1999
• Interconnecting cords of cell
• Chronic inflammation and fibrosis
• No distinct immunophenotype
• EWSR1-CREB1 fusion

848
 Primary Pulmonary Myxoid Sarcoma

Primary Pulmonary Myxoid Sarcoma
Other Entities
Fibrosis and Chronic Inflammation
(Left) This micrograph depicts
classic features of PPMS. The
neoplastic cells have round to
ovoid nuclei and eosinophilic
cytoplasm and are arranged in
cords ﬊, clusters ﬉, and
single cells. There is abundant
pale blue myxoid matrix and
bundles of collagen ﬈. (Right)
Fibrosis and chronic
inflammation are present in
most PPMSs. In this example, a
neoplastic area ﬈ is
surrounded by a peripheral
rind of dense collagen ﬉,
which is surrounded by a band
of chronic inflammatory cells
﬊. Note the sharp interface
with adjacent lung ﬈.

Epithelioid Cells Spindle Cells

(Left) The neoplastic cells in
PPMS typically have low-grade
cytological features and low
mitotic activity. They range
from epithelioid to spindle and
stellate cells. This high-power
micrograph depicts clusters of
epithelioid cells with round,
vesicular nuclei and abundant
eosinophilic cytoplasm. (Right)
The neoplastic cells in PPMS
are often spindle-shaped with
elongated nuclei ﬈ and
extended tails of eosinophilic
cytoplasm. This area has only
a small amount of myxoid
matrix ﬉.

Solid Area EMA

(Left) Solid areas consisting of
closely spaced neoplastic cells
with little intervening matrix
usually account for a minor
component in PPMS. In this
case, the cells are large
epithelioid cells with abundant
cytoplasm and vesicular, round
nuclei ﬈. (Right) There is no
specific immunohistochemical
marker for PPMS, which is
negative for most markers
other than vimentin. Focal
EMA staining ﬈, which is
often weakly positive, is
common. (Courtesy S. Smith,
MD.)

849
 Biphenotypic Sinonasal Sarcoma

KEY FACTS
Other Entities

TERMINOLOGY ○ Fascicular growth with "herringbone" architecture

• Synonym: Low-grade sinonasal sarcoma with neural and
myogenic features
• Definition: Rare, distinctive sarcoma of sinonasal tract that
shows neural and myogenic differentiation and is
characterized by unique t(2;4) chromosomal translocation
CLINICAL ISSUES
• Middle-aged women most commonly affected
• Most arise in nasal cavity &/or ethmoid sinus
• Present with obstructive symptoms
• Treatment: Complete surgical resection
• Prognosis
○ Local recurrence in 44%
○ No reported cases of metastases or death from disease
MICROSCOPIC
• Poorly circumscribed, unencapsulated, infiltrative
• Highly cellular proliferation of monomorphic spindle cells
common
○ Uniform, elongated nuclei, often overlapping
• Most cases associated with benign epithelial component
• Rhabdomyoblastic elements in subset
• Mitotic figures, necrosis, hemorrhage rare
ANCILLARY TESTS
• Variable S100 protein (+), SMA(+), MSA(+) in most cases
• Subset contain myogenin (+) cells
• Molecular: Recurrent t(2;4)(q35;q31) resulting in PAX3-
MAML3 fusion
TOP DIFFERENTIAL DIAGNOSES
• Synovial sarcoma
• Malignant peripheral nerve sheath tumor with
rhabdomyoblastic differentiation
• Solitary fibrous tumor
• Spindle cell rhabdomyosarcoma

Biphenotypic Sinonasal Sarcoma Cellular, Fascicular Growth

(Left) Biphenotypic sinonasal
sarcoma (SNS) is a distinctive
sinonasal tumor that most
commonly arises in middle-
aged women. The sarcomas
are infiltrative and poorly
circumscribed spindle cell
neoplasms and often contain
invaginations of benign
surface respiratory epithelium
(not shown). (Right) A
fascicular growth pattern is a
common feature of
biphenotypic SNS, as depicted.
A herringbone architecture
such as that seen in
fibrosarcomatous DFSP and
several other sarcomas is also
a frequent finding.

Uniform Cytologic Features S100 Protein Expression

(Left) The tumor cells of
biphenotypic SNS are uniform,
elongated, and lack nuclear
pleomorphism. A wavy or
neural-like cytologic
appearance may be evident in
some cases. Mitotic activity is
typically very low. (Right)
S100 protein expression is
characteristic of biphenotypic
SNS. Notably, SOX10
expression is absent, which
suggests that these tumors
may not actually feature
partial neural derivation.
Vascular elements ﬉ are
negative for S100 in this
image.

850
 Biphenotypic Sinonasal Sarcoma

Other Entities
• Mitotic figures rare
TERMINOLOGY
• Necrosis, hemorrhage, surface ulceration uncommon
Abbreviations
• Biphenotypic sinonasal sarcoma (SNS) ANCILLARY TESTS
Synonyms Immunohistochemistry
• Low-grade sinonasal sarcoma with neural and myogenic • S100 protein (+), SMA(+), calponin (+), desmin (+/-)
features ○ Expression may be focal, patchy, or diffuse
• Nuclear β-catenin (+)
Definitions
• Negative for keratin, SOX10, CD34, TLE1
• Rare, distinctive sarcoma of sinonasal tract that shows • Subset of cases feature desmin &/or myogenin (+) cells
evidence of neural and myogenic differentiation and is
characterized by PAX3 rearrangements Molecular Genetics
• Distinctive recurrent t(2;4)(q35;q31) resulting in PAX3-
CLINICAL ISSUES MAML3 fusion
Epidemiology • Also, PAX3-NCOA1 and PAX3-FOXO1 fusions reported
○ PAX3-NCOA1 tumors associated with rhabdomyoblastic
• Incidence
differentiation
○ Rare; incidence likely underestimated due to lack of
recognition
DIFFERENTIAL DIAGNOSIS
• Age
○ Mean: 52 years (range: 24-85 years) Synovial Sarcoma
• Sex • May show significant morphologic overlap with
○ 3:1 female predominance biphenotypic SNS
• Keratin (+); TLE1(+); negative for myogenic markers
Site
• Characteristic t(X;18) involving SS18 (SYT)
• Most arise in nasal cavity &/or ethmoid sinus
○ May extend to involve orbit, cribriform plate, or rarely Malignant Peripheral Nerve Sheath Tumor With
cranial vault Rhabdomyoblastic Differentiation
• Usually shows variations in cellularity and conspicuous
Presentation
nuclear pleomorphism, mitoses, and necrosis
• Obstructive symptoms • May arise from demonstrable nerve or in setting of
• Pain may or may not be present neurofibromatosis
• No reported associations with neurofibromatosis • Usually negative for SMA and MSA
Treatment • Lacks genetic features of biphenotypic SNS
• Complete surgical resection Solitary Fibrous Tumor
Prognosis • Characteristic ectatic, "staghorn" vasculature
• Limited data • Thick bands of stromal collagen common
○ Local recurrence in 44% • Diffuse CD34(+), STAT6(+)
○ No reported cases of metastases or death from disease Spindle Cell Rhabdomyosarcoma
• Can show significant morphologic overlap with
MACROSCOPIC biphenotypic SNS
Size • Negative for S100 protein
• Often 2-4 cm • Lacks genetic features of biphenotypic SNS

MICROSCOPIC SELECTED REFERENCES

Histologic Features
• Poorly circumscribed, unencapsulated
• Infiltrative growth
• Highly cellular proliferation of monomorphic spindle cells
○ Fascicular growth + herringbone architecture common
○ Uniform, elongated nuclei, often overlapping
– May appear wavy or buckled
• Delicate stromal collagen present but often inapparent
• Majority of reported cases associated with benign epithelial
component
○ Invaginations of surface-type respiratory epithelium
• Focal rhabdomyoblastic elements in subset of cases
• Stromal vasculature may be prominent and appear to be
like hemangiopericytoma
1. Kakkar A et al: Biphenotypic sinonasal sarcoma: a series of six cases with
evaluation of role of β-catenin immunohistochemistry in differential
diagnosis. Ann Diagn Pathol. 33:6-10, 2018
2. Cannon RB et al: Imaging and outcomes for a new entity: low-grade
sinonasal sarcoma with neural and myogenic features. J Neurol Surg Rep.
78(1):e15-e19, 2017
3. Huang SC et al: Novel PAX3-NCOA1 Fusions in biphenotypic sinonasal
sarcoma with focal rhabdomyoblastic differentiation. Am J Surg Pathol.
40(1):51-9, 2016
4. Rooper LM et al: Biphenotypic sinonasal sarcoma: an expanded
immunoprofile including consistent nuclear beta-catenin positivity and
absence of SOX10 expression. Hum Pathol. 55:44-50, 2016
5. Wang X et al: Recurrent PAX3-MAML3 fusion in biphenotypic sinonasal
sarcoma. Nat Genet. 46(7):666-8, 2014
6. Lewis JT et al: Low-grade sinonasal sarcoma with neural and myogenic
features: a clinicopathologic analysis of 28 cases. Am J Surg Pathol.
36(4):517-25, 2012
851
 Biphenotypic Sinonasal Sarcoma
Other Entities

Surface Epithelial Invaginations Prominent Sinonasal Epithelium

(Left) A common finding in
biphenotypic SNS is the
presence of invaginations of
surface epithelium within the
tumor, at least focally. The
appearance may lead to
confusion with a biphasic
synovial sarcoma. (Right)
Surface sinonasal epithelium
may be prominent in tissue
samples of biphenotypic
sinonasal sarcoma, somewhat
overshadowing the actual
neoplastic spindle cells ﬉.

Stromal Vasculature Infiltration of Bone

(Left) A prominent
hemangiopericytoma-like
vascular pattern, as shown in
this image, can be present in a
subset of cases of
biphenotypic SNS, lending
morphologic overlap with
solitary fibrous tumor. (Right)
Bone invasion by tumor cells
may be seen in up to 20% of
cases of biphenotypic SNS.
Extension into the orbit is one
of the more frequent events.

Stromal Collagen Hemorrhage

(Left) Similar to synovial
sarcoma, stromal collagen
may be difficult to appreciate
in cellular examples of
biphenotypic SNS. In less
cellular zones ﬈, however,
prominent collagen can
resemble a benign fibroblastic
neoplasm. (Right) Stromal
hemorrhage (shown) and
surface ulceration can be seen
in biphenotypic SNS, though
neither feature is common.
Necrosis is usually absent as
well.

852
 Biphenotypic Sinonasal Sarcoma

Other Entities
SMA Expression Desmin Expression
(Left) SMA expression is
characteristic of biphenotypic
SNS and is classically
coexpressed with S100
protein. This
immunophenotype gave rise to
the original name for this
tumor: Low-grade sinonasal
sarcoma with neural and
myogenic features. (Right)
Biphenotypic SNS can show
expression of desmin in a small
subset of cases; however, the
positivity is likely to be focal.

Cytokeratin Immunostain Rhabdomyoblasts

(Left) Keratin immunostains
are negative in the lesional
cells of biphenotypic SNS.
Entrapped epithelial elements
﬈ serve as a prominent
internal control. (Right) A
subset of cases of
biphenotypic SNS contain
rhabdomyoblastic elements
﬉. This finding may be
related to the presence of a
PAX3-NCOA1 gene fusion in
these variant tumors.

Rhabdomyoblasts Myogenin Expression

(Left) Rhabdomyoblastic
elements ﬉ may be focally
prominent in biphenotypic SNS
and, in conjunction with loose
stroma, may resemble
embryonal
rhabdomyosarcoma. (Right)
Nuclear expression ﬈ of
myogenin is seen in a subset of
cases of biphenotypic SNS and
is often focal. Morphologically
distinct rhabdomyoblastic
elements may or may not be
readily identifiable.

853
 Spindle Epithelial Tumor With Thymus-Like Differentiation

KEY FACTS
Other Entities

TERMINOLOGY MICROSCOPIC
• Spindle epithelial tumor with thymus-like differentiation • Moderately to highly cellular neoplasm, usually with
(SETTLE) biphasic morphology
• Low-grade, often biphasic malignant neoplasm showing ○ Fascicles, bands, and sheets of uniform spindled cells
evidence of primitive thymic differentiation ○ Glands, cysts, cords, nests, tubules, or papillary structures
CLINICAL ISSUES • Oval to round monomorphic nuclei with fine chromatin
• Stromal hyalinization very common
• Most common in children and young adults (mean: 19
• Mitoses &/or necrosis rare
years)
• Affects thyroid or perithyroidal soft tissues ANCILLARY TESTS
• Often presents as painless, slow-growing neck mass or • Keratin (+), EMA(+), CK7(+) in spindled and epithelial cells
enlarged thyroid • S100 protein (-), CD34(-), CK20(-), CD5(-), TTF-1(-)
• Treatment: Complete surgical resection
• Metastases occur in 25% of cases, often after many years TOP DIFFERENTIAL DIAGNOSES
○ Indefinite, long-term clinical follow-up recommended • Synovial sarcoma
• Overall reported survival rate 83% at 5 years • Solitary fibrous tumor
• Spindle cell carcinoma
MACROSCOPIC
• Range: 1-12 cm (mean: 3.6 cm)

Spindle Epithelial Tumor With Thymus-Like

Differentiation Stromal Sclerosis
(Left) Spindle epithelial tumor
with thymus-like
differentiation (SETTLE) is a
low-grade malignancy of the
thyroid that generally shows
moderate to high cellularity
and vague lobules of spindled
cells separated by hyalinized
fibrous stroma. (Right) The
morphologic appearance of
SETTLE is characterized by
cellular sheets and fascicles of
monomorphic spindle cells,
very similar to synovial
sarcoma. Of note, stromal
sclerosis ﬊ is more common
and more abundant in SETTLE.

Epithelial Structures Uniform Cytologic Features

(Left) The spindled component
of SETTLE often blends
imperceptibly into epithelial
structures ﬈, such as glands,
tubules, and papillary
structures. Ciliated or
mucinous epithelium may also
be seen. Squamous metaplasia
is rare. (Right) The tumor cells
in SETTLE are cytologically
uniform and show round to
elongated nuclei with fine
chromatin. Mitoses are
generally rare.

854
 Spindle Epithelial Tumor With Thymus-Like Differentiation

Other Entities
TERMINOLOGY Size
• Range: 1-12 cm (mean: 3.6 cm)
Abbreviations
• Spindle epithelial tumor with thymus-like differentiation MICROSCOPIC
(SETTLE)
Histologic Features
Definitions • Often peripherally infiltrative
• Low-grade, often biphasic malignant neoplasm showing • Moderately to highly cellular
evidence of primitive thymic differentiation • Most show biphasic morphology
○ Fascicles, bands, and sheets of uniform spindled cells
ETIOLOGY/PATHOGENESIS – May appear myxoid/reticular
Pathogenesis ○ Epithelial component
• Intrathyroidal ectopic thymic tissue – Glands, cysts, cords, nests, tubules, or papillary
• Remnants of branchial pouches that retained ability to structures
differentiate into thymic-type tumor □ May be ciliated, mucinous, or show focal squamous
metaplasia
CLINICAL ISSUES – Intraluminal necrotic debris rare
○ Rare cases are monophasic
Epidemiology
• Oval to round monomorphic nuclei with fine chromatin
• Incidence • Stromal hyalinization very common
○ Very rare • Mitoses &/or necrosis rare
• Age
○ Most common in children and young adults (mean: 19 ANCILLARY TESTS
years)
– May be congenital
Immunohistochemistry
– Rarely occurs in adults > 30 years • Keratin (+), EMA(+), CK7(+) in both spindled and epithelial
• Sex cells
○ Slight male predominance ○ Diffuse high-molecular-weight keratin and CK7
○ Often focal low-molecular-weight keratin and EMA
Site • Also CD117(+)
• Thyroid • S100 protein (-), CD34(-), CK20(-), CD5(-), TTF-1(-)
○ Right lobe more common (59%) • Usually TLE1(-) [may rarely be (+)]
• Very rarely in soft tissues of neck, adjacent to thyroid
Presentation DIFFERENTIAL DIAGNOSIS
• Often painless, slow-growing neck mass or enlarged thyroid Synovial Sarcoma
○ Mass may be present for many years before diagnosis is • Less elaborate array of epithelial structures than is seen in
sought SETTLE
• Usually unilateral; rarely bilateral • Usually less prominent stromal hyalinization than is seen in
• Metastases may be present at time of presentation SETTLE
• Characteristic t(X;18) with SS18 (SYT) gene arrangement
Treatment
• Complete surgical resection (partial or complete Solitary Fibrous Tumor
thyroidectomy) • Patternless growth pattern
• Long-term clinical follow-up recommended to monitor for • Prominent ectatic staghorn vascular pattern
metastatic disease • CD34(+), STAT6(+)
• Chemotherapy &/or radiotherapy may be utilized in setting
Spindle Cell Carcinoma
of metastatic disease
• Usually affects older age group than SETTLE
Prognosis • Malignant cytologic features, often with mitotic activity
• Overall reported survival rate: 83% at 5 years
• Metastases occur in 25% of cases, often after many years SELECTED REFERENCES
○ Rate appears higher with follow-up > 5 years 1. Ippolito S et al: Spindle epithelial tumor with thymus-like differentiation
○ Cervical lymph nodes, lung, mediastinum most common (SETTLE): clinical-pathological features, differential pathological diagnosis
sites and therapy. Endocrine. 51(3):402-12, 2016
2. Recondo G Jr et al: Spindle epithelial tumor with thymus-like differentiation:
a case report and comprehensive review of the literature and treatment
MACROSCOPIC options. Head Neck. 37(5):746-54, 2014
3. Folpe AL et al: Spindle epithelial tumor with thymus-like differentiation: a
General Features morphologic, immunohistochemical, and molecular genetic study of 11
cases. Am J Surg Pathol. 33(8):1179-86, 2009
• Vaguely lobulated, circumscribed, or infiltrative
4. Grushka JR et al: Spindle epithelial tumor with thymus-like elements of the
• Firm, usually solid, gray-white cut surface thyroid: a multi-institutional case series and review of the literature. J Pediatr
Surg. 44(5):944-8, 2009

855
 Low-Grade Endometrial Stromal Sarcoma

KEY FACTS
Other Entities

TERMINOLOGY • Plexiform vascular pattern

• Malignant tumor composed of cells that resemble those of • Associated endometriosis in some cases
proliferative endometrium • Focal smooth muscle differentiation in some

CLINICAL ISSUES ANCILLARY TESTS

• Peak incidence in 4th-5th decades • Diffuse CD10(+) in most
• Can present as intraabdominal soft tissue tumor • Diffuse ER(+) and PR(+)
○ Extends from uterus or arises in endometriosis • Desmin and SMA are typically focally positive with increased
• Mass or abdominal distension positivity in fibrous or mixed variants
• Wide differential diagnosis • Molecular: Rearrangements involving JAZF1, SUZ12, or
PHF1
MACROSCOPIC
TOP DIFFERENTIAL DIAGNOSES
• Often shows worm-like configuration of large vessel
involvement • Synovial sarcoma
• Ewing sarcoma
MICROSCOPIC • Desmoplastic small round cell tumor
• Sheets of uniform ovoid cells • Smooth muscle neoplasm
• Minimal nuclear atypia • Solitary fibrous tumor
• Minimal cytoplasm • Gastrointestinal stromal tumor

Endometrial Stromal Sarcoma Cytologic Features

(Left) At low power,
endometrial stromal sarcoma
(ESS) is a multilobulated,
highly cellular tumor
composed of islands of ovoid
cells with scant cytoplasm,
some in vessels ﬈. (Right) At
higher power, the cells of ESS
contain bland, vesicular nuclei
and small amounts of
amphophilic cytoplasm. The
mitotic index can be high,
although this is not thought to
alter prognosis. The stroma
here is fibrous, but it can also
be myxoid.

Characteristic Vasculature Lymphovascular Invasion

(Left) Medium-power view of
ESS shows the homogeneous
appearance of the small
spindled cells. Note the
numerous curvilinear
arterioles that are spread
evenly throughout the tumor
﬊. These thin vessels set ESS
apart from smooth muscle
tumors, which have thick-
walled vessels. (Right)
Lymphovascular space
invasion ﬊ can be found in
nearly every case of ESS and
can be a helpful feature in
differentiating ESS from
endometrial stromal nodule
and smooth muscle tumors.

856
 Low-Grade Endometrial Stromal Sarcoma

Other Entities
TERMINOLOGY ANCILLARY TESTS
Abbreviations Immunohistochemistry
• Endometrial stromal sarcoma (ESS) • Diffuse CD10(+) in majority
• Diffuse nuclear ER(+) and PR(+)
Synonyms
• Variable, focal desmin (+) and SMA(+)
• Endolymphatic stromal myosis
○ Often increased expression in fibrous or mixed variants
• Low-grade stromal sarcoma
• H-caldesmon and keratin (-)
Definitions Molecular Genetics
• Malignant mesenchymal tumor composed of cells that
• JAZF1-SUZ12 (formerly JAZF1-JJAZ1) fusions most
resemble those of proliferative endometrium
common in low-grade tumors
○ Rearrangements involving PHF1 less common
CLINICAL ISSUES
• YWHAE-NUTM2A/B fusion associated with higher grade
Epidemiology tumors
• Age
○ Peak incidence in 4th-5th decades DIFFERENTIAL DIAGNOSIS
Site Synovial Sarcoma
• Most tumors are intrauterine (arise from endometrium) • Can be biphasic
○ May extend to parametria or abdomen, especially • Short ovoid nuclei with overlapping nuclei
through vascular channels • CK(+), EMA(+), TLE1(+)
• Some arise in extrauterine sites, usually associated with • Characteristic t(X;18) involving SS18(SYT)
endometriosis Ewing Sarcoma
Presentation • Younger age group
• Painful or painless intraabdominal mass • Sheets of rounded cells
• Diffuse CD99(+) in membranous distribution
Prognosis
• Various rearrangements involving EWSR1 gene
• Although tumor is low grade, there may be recurrence in ~
1/3 of patients Desmoplastic Small Round Cell Tumor
• Distant metastases and death in smaller percentage • Adolescent age group
• Islands of small cells in desmoplastic stroma
MACROSCOPIC • CK(+), desmin (+), WT1(+)
General Features • Characteristic t(11;22) with EWSR1-WT1 gene fusion
• Solid, white to yellow cut surface that typically presents as Endometrial Stromal Nodule
polypoid mass, intramural nodules, or thickened • Histologically identical to ESS but lacks infiltrative borders
myometrium
• Occasional tumors contain cystic degeneration, Smooth Muscle Neoplasm
hemorrhage, and necrosis • Prominently eosinophilic spindle cells with blunt-ended
• Tumor often has worm-like configuration of tumor nuclei
processes in vessels • Diffuse desmin, H-caldesmon, and SMA expression
Solitary Fibrous Tumor
MICROSCOPIC
• Variable cellular and fibrous areas with
Histologic Features hemangiopericytomatous pattern
• Monotonous sheets of small cells with ovoid to round • Diffuse CD34(+)
nuclei, vesicular chromatin, and scant cytoplasm
Gastrointestinal Stromal Tumor
○ Cells have minimal nuclear atypia but are typically
mitotically active • Usually monomorphic spindled or epithelioid cells
• Characteristic vascular pattern that recapitulates • Diffuse CD117(+) &/or DOG1(+)
endometrial spiral arterioles
• Stroma can be focally fibrous or myxoid or may show SELECTED REFERENCES
smooth muscle differentiation 1. Lee CH et al: Endometrial stromal sarcoma-the new genetic paradigm.
• Small tubules or other sex cord-stromal tumor elements Histopathology. 67(1):1-19, 2015
2. Conklin CM et al: Endometrial stromal tumors: the new WHO classification.
may be present Adv Anat Pathol. 21(6):383-93, 2014
• Residual or associated endometriosis in some cases, 3. Lee CH et al: Cyclin D1 as a diagnostic immunomarker for endometrial
especially extrauterine sites stromal sarcoma with YWHAE-FAM22 rearrangement. Am J Surg Pathol.
36(10):1562-70, 2012
• Marked nuclear pleomorphism is seen in clinically
4. Chiang S et al: Frequency of known gene rearrangements in endometrial
aggressive, high-grade tumors stromal tumors. Am J Surg Pathol. 35(9):1364-72, 2011
5. Oliva E et al: Endometrial stromal tumors: an update on a group of tumors
with a protean phenotype. Adv Anat Pathol. 7(5):257-81, 2000

857
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 INDEX

A
lipoma vs., 48
prognosis, 67
- dedifferentiated liposarcoma, 94–99
differential diagnosis, 96
molecular genetics, 96
Abdominopelvic sarcoma of perivascular epithelioid cells. prognosis, 95
See Perivascular epithelioid cell tumor. - hibernoma, 74–77
Abrikossoff tumor. See Granular cell tumor. differential diagnosis, 75
Acquired smooth muscle "hamartoma" of scrotum, molecular genetics, 75
smooth muscle hamartoma vs., 333 prognosis, 75
Acquired tufted angioma, 436–437 - lipoblastoma, 80–83
- diagnostic checklist, 437 differential diagnosis, 81
- differential diagnosis, 437 molecular genetics, 81
- Kaposi sarcoma vs., 478 prognosis, 81
- kaposiform hemangioendothelioma vs., 455 - lipoma, 46–51
- prognosis, 437 diagnostic checklist, 48
Acquired tufted hemangioma, glomeruloid hemangioma differential diagnosis, 48
vs., 443 genetic testing, 48
Acral fibrokeratoma, storiform collagenoma vs., 161 prognosis, 47
Acral fibromyxoma, 624–625 spindle cell, lipoma vs., 48
- dermal nerve sheath myxoma vs., 547 - lipomatosis of nerve, 52–53
- differential diagnosis, 625 differential diagnosis, 53
- inclusion body fibromatosis vs., 251 prognosis, 53
- prognosis, 625 - myelolipoma, 78–79
Acral myxoinflammatory fibroblastic sarcoma. See differential diagnosis, 79
Myxoinflammatory fibroblastic sarcoma. molecular genetics, 79
Acroangiodermatitis, Kaposi sarcoma vs., 478 prognosis, 79
Adenocarcinoma - myolipoma, 70–73
- metastatic, adenomatoid tumor vs., 591 differential diagnosis, 71
- ovarian serous, malignant mesothelioma vs., 600 prognosis, 71
- pulmonary, malignant mesothelioma vs., 600 - myxoid liposarcoma, 100–105
Adenomatoid tumor, 590–591 differential diagnosis, 102
- differential diagnosis, 591 molecular genetics, 102
- genetic testing, 591 prognosis, 101
- multicystic peritoneal mesothelioma vs., 593 - pleomorphic liposarcoma, 106–111
- prognosis, 591 differential diagnosis, 107–108
Adipose tissue, tumors of molecular genetics, 107
- angiolipoma, 56–59 prognosis, 107
diagnostic checklist, 57 - spindle cell/pleomorphic lipoma, 60–65
differential diagnosis, 57 differential diagnosis, 62
prognosis, 57 molecular genetics, 61
- atypical lipomatous tumor/well-differentiated prognosis, 61
liposarcoma, 88–93 - synovial lipomatosis, 54–55
differential diagnosis, 90 differential diagnosis, 55
molecular genetics, 90 prognosis, 55
prognosis, 89 Adrenocortical adenoma, myelolipoma vs., 79
- atypical spindle cell lipomatous tumor, 84–87 Adult-type fibrosarcoma, 214–215
differential diagnosis, 85 - differential diagnosis, 215
molecular genetics, 85 - genetic testing, 215
prognosis, 85 - prognosis, 215
- chondroid lipoma, 66–69 - spindle cell rhabdomyosarcoma vs., 394
differential diagnosis, 67 Adult-type rhabdomyoma, 372–373
genetic testing, 67 - cardiac rhabdomyoma vs., 379
i
 INDEX
- congenital granular cell epulis vs., 799 deep (aggressive) angiomyxoma vs., 585
- differential diagnosis, 373 differential diagnosis, 581
- embryonal rhabdomyosarcoma vs., 382 fibroepithelial stromal polyp vs., 575
- granular cell tumor vs., 542 mammary-type myofibroblastoma vs., 149
- prognosis, 373 prognosis, 581
AFH. See Angiomatoid fibrous histiocytoma. solitary fibrous tumor vs., 186
AFX. See Atypical fibroxanthoma. spindle cell/pleomorphic lipoma vs., 62
Aggressive fibromatosis. See Desmoid-type fibromatosis. - giant cell. See Solitary fibrous tumor.
ALT/WDLPS. See Atypical lipomatous tumor/well- - nasopharyngeal, 800–803
differentiated liposarcoma. differential diagnosis, 802
Alveolar rhabdomyosarcoma, 386–391 genetics, 801
- desmoplastic small round cell tumor vs., 701 prognosis, 801
- differential diagnosis, 388 sinonasal glomangiopericytoma vs., 806
- embryonal rhabdomyosarcoma vs., 382 - pleomorphic fibroma vs., 157
- extraskeletal Ewing sarcoma vs., 708 - of soft tissue, 144–147
- malignant gastrointestinal neuroectodermal tumor vs., differential diagnosis of, 145
778 lobular capillary hemangioma vs., 421
- melanotic neuroectodermal tumor of infancy vs., 825 molecular genetics, 145
- neuroblastoma and ganglioneuroblastoma vs., 834 solitary fibrous tumor vs., 186
- pleomorphic rhabdomyosarcoma vs., 401 Angioleiomyoma, 366–367
- prognosis, 387 - differential diagnosis, 367
- sclerosing epithelioid fibrosarcoma vs., 234 - Epstein-Barr virus-associated smooth muscle tumor vs.,
- sclerosing rhabdomyosarcoma vs., 397 343
- undifferentiated round cell sarcoma with CIC-DUX4 - glomus tumors vs., 354
translocation vs., 729 - myopericytoma vs., 359
Alveolar soft part sarcoma, 684–687 - prognosis, 367
- adult rhabdomyoma vs., 373 - superficial leiomyoma vs., 335
- alveolar rhabdomyosarcoma vs., 388 Angiolipoma, 56–59
- congenital granular cell epulis vs., 799 - diagnostic checklist, 57
- differential diagnosis, 685 - differential diagnosis, 57
- granular cell tumor vs., 542 - infiltrating. See Angiomatosis.
- molecular genetics, 685 - intramuscular hemangioma vs., 431
- paraganglioma vs., 816 - prognosis, 57
- PEComa vs., 694 Angiolymphoid hyperplasia with eosinophilia. See
- prognosis, 685 Epithelioid hemangioma.
AMFB. See Angiomyofibroblastoma. Angioma
Amyloidoma, 782–783 - acquired tufted, 436–437
- differential diagnosis, 783 diagnostic checklist, 437
- prognosis, 783 differential diagnosis, 437
Anaplastic large cell lymphoma Kaposi sarcoma vs., 478
- inflammatory myofibroblastic tumor vs., 198 kaposiform hemangioendothelioma vs., 455
- pleomorphic rhabdomyosarcoma vs., 401 prognosis, 437
Ancient schwannoma, 510 - cherry, sinusoidal hemangioma vs., 441
Aneurysmal bone cyst of soft tissue, 630–631 - glomeruloid. See Glomeruloid hemangioma.
- differential diagnosis, 631 - microcapillary. See Microvenular hemangioma.
- molecular genetics, 631 - tufted
- myositis ossificans vs., 127 congenital hemangioma vs., 414
- prognosis, 631 infantile hemangioma vs., 418
Aneurysmal fibrous histiocytoma, angiomatoid fibrous Angiomatoid fibrous histiocytoma (AFH), 642–649
histiocytoma vs., 644 - differential diagnosis, 644
Angioblastoma - molecular genetics, 644
- glomeruloid hemangioma vs., 443 - nodular fasciitis vs., 116
- of Nakagawa. See Acquired tufted angioma. - primary pulmonary myxoid sarcoma vs., 847
Angioendothelioma, papillary intralymphatic, 456–457 - prognosis, 643
- diagnostic checklist, 457 Angiomatoid malignant fibrous histiocytoma. See
- differential diagnosis, 457 Angiomatoid fibrous histiocytoma.
- prognosis, 457 Angiomatosis, 444–445
- retiform hemangioendothelioma vs., 459 - bacillary, 410–411
Angiofibroma diagnostic checklist, 411
- cellular, 580–583 differential diagnosis, 411
angiomyofibroblastoma vs., 577 lobular capillary hemangioma vs., 421
ii
 INDEX
prognosis, 411 composite hemangioendothelioma vs., 461
- differential diagnosis, 445 Antrochoanal polyp, nasopharyngeal angiofibroma vs.,
- intramuscular hemangioma vs., 431 802
- prognosis, 445 Aponeurotic fibroma, calcifying, 244–247
- systemic. See Lymphangioma. - differential diagnosis, 245
Angiomyofibroblastoma (AMFB), 576–579 - inclusion body fibromatosis vs., 251
- cellular angiofibroma vs., 581 - prognosis, 245
- deep (aggressive) angiomyxoma vs., 585 - soft tissue chondroma vs., 488
- differential diagnosis, 577 Arteriovenous hemangioma, sinusoidal hemangioma vs.,
- fibroepithelial stromal polyp vs., 575 441
- prognosis, 577 Arteriovenous malformation
Angiomyofibroblastoma-like tumor, of male genital tract. - papillary endothelial hyperplasia vs., 409
See Cellular angiofibroma. - sinusoidal hemangioma vs., 441
Angiomyolipoma ASCLT. See Atypical spindle cell lipomatous tumor.
- angiolipoma vs., 57 Askin tumor. See Extraskeletal Ewing sarcoma.
- extrarenal epithelioid. See Perivascular epithelioid cell Atrial myxoma, cardiac fibroma vs., 797
tumor. Atypical decubital fibroplasia. See Ischemic fasciitis.
- myolipoma vs., 71 Atypical fibroxanthoma (AFX), 636–641
Angiomyoma. See Angioleiomyoma. - angiosarcoma vs., 472
Angiomyxoma - dermatofibroma vs., 272
- deep (aggressive), 584–587 - differential diagnosis, 637–638
angiomyofibroblastoma vs., 577 - immunohistochemistry, 638
cellular angiofibroma vs., 581 - pleomorphic fibroma vs., 157
desmoid-type fibromatosis vs., 170 - prognosis, 637
differential diagnosis, 585 - superficial CD34(+) fibroblastic tumor vs., 211
fibroepithelial stromal polyp vs., 575 Atypical intradermal smooth muscle neoplasm, smooth
genetic testing, 585 muscle hamartoma vs., 333
juxtaarticular myxoma vs., 619 Atypical lipomatous tumor/well-differentiated
prognosis, 585 liposarcoma (ALT/WDLPS), 88–93
superficial angiomyxoma vs., 621 - atypical spindle cell lipomatous tumor vs., 85
- superficial, 620–623 - chondroid lipoma vs., 67
acral fibromyxoma vs., 625 - differential diagnosis, 90
deep (aggressive) angiomyxoma vs., 585 - elastofibromas vs., 143
dermal nerve sheath myxoma vs., 547 - hibernoma vs., 75
differential diagnosis, 621 - massive localized lymphedema vs., 451
juxtaarticular myxoma vs., 619 - molecular genetics, 90
prognosis, 621 - myxoid liposarcoma vs., 102
Angiosarcoma, 470–475 - pleomorphic liposarcoma vs., 108
- atypical fibroxanthoma vs., 638 - prognosis, 89
- dermatofibroma vs., 272 - spindle cell/pleomorphic lipoma vs., 62
- differential diagnosis, 472 - synovial lipomatosis vs., 55
- epithelioid Atypical myxoinflammatory fibroblastic tumor. See
epithelioid hemangioendothelioma vs., 468 Myxoinflammatory fibroblastic sarcoma.
epithelioid hemangioma vs., 423 Atypical neurofibroma, malignant peripheral nerve sheath
epithelioid sarcoma vs., 680 tumor vs., 560
malignant mesothelioma vs., 600 Atypical spindle cell lipoma. See Atypical spindle cell
myeloid sarcoma vs., 609 lipomatous tumor.
- giant cell fibroblastoma vs., 261 Atypical spindle cell lipomatous tumor (ASCLT), 84–87
- intramuscular hemangioma vs., 431 - atypical lipomatous tumor/well-differentiated
- Kaposi sarcoma vs., 478 liposarcoma vs., 90
- lobular capillary hemangioma vs., 421 - dedifferentiated liposarcoma vs., 96
- lymphangioma vs., 448 - differential diagnosis, 85
- molecular genetics, 472 - molecular genetics, 85
- papillary endothelial hyperplasia vs., 409 - prognosis, 85
- papillary intralymphatic angioendothelioma vs., 457 Atypical teratoid/rhabdoid tumor. See Extrarenal rhabdoid
- prognosis, 471 tumor.
- retiform hemangioendothelioma vs., 459 Atypical vascular lesion, 452–453
- sclerosing rhabdomyosarcoma vs., 397 - angiosarcoma vs., 472
- undifferentiated pleomorphic sarcoma vs., 725 - diagnostic checklist, 453
- well-differentiated - differential diagnosis, 453
atypical vascular lesion vs., 453
iii
 INDEX
- prognosis, 453
Atypical vascular proliferation. See Atypical vascular lesion.
Atypical vascular proliferation, lymphangioma vs., 448
AVL. See Atypical vascular lesion.
Axial chordoma, soft tissue metastasis from, extraaxial
soft tissue chordoma vs., 843
B C
Bacillary angiomatosis (BA), 410–411
- diagnostic checklist, 411
- differential diagnosis, 411
- lobular capillary hemangioma vs., 421
- prognosis, 411
Basal cell carcinoma, dermatofibroma vs., 272
BCOR-CCNB3 (Ewing-like) sarcoma, synovial sarcoma vs.,
668
BCOR-CCNB3 fusion-positive sarcoma
- undifferentiated round cell sarcoma with CIC-DUX4
translocation vs., 730
BCOR-CCNB3 fusion-positive sarcoma, 734–737
- cytogenetics, 735
- differential diagnosis, 736
- extraskeletal Ewing sarcoma vs., 708
- prognosis, 735
BCOR-CCNB3 sarcoma. See BCOR-CCNB3 fusion-positive
sarcoma.
BCOR-rearranged sarcoma. See BCOR-CCNB3 fusion-
positive sarcoma.
Benign adnexal tumors, glomus tumors vs., 354
Benign cutaneous biphasic (or plexiform) hybrid tumor of
perineurioma, cellular neurothekeoma vs., 291
Benign cystic mesothelioma. See Multicystic peritoneal
mesothelioma.
Benign fibrous histiocytoma, fibroma of tendon sheath vs.,
136
Benign lymphangioendothelioma
- atypical vascular lesion vs., 453
- Kaposi sarcoma vs., 478
Benign mesothelioma. See Well-differentiated papillary
mesothelioma.
Benign neural gastrointestinal polyps, 740–743
- differential diagnosis, 741
- prognosis, 741
Biopsy, soft tissue tumors, 22–23
- specimens, 22–23
Biphasic sinonasal sarcoma, synovial sarcoma vs., 668
Biphasic synovial sarcoma, 668
Biphenotypic sinonasal sarcoma, 850–853
- differential diagnosis, 851
- prognosis, 851
Bizarre parosteal osteochondromatous proliferation,
fibroosseous pseudotumor of digit vs., 131
Blastoma, pleuropulmonary, embryonal
rhabdomyosarcoma vs., 382
Blue nevus
- cellular, clear cell sarcoma vs., 690
- combined, smooth muscle hamartoma vs., 333
iv
Botryoid-type embryonal rhabdomyosarcoma,
fibroepithelial stromal polyp vs., 575
Branchial anlage mixed tumor. See Ectopic
hamartomatous thymoma.
Brown fat, normal, hibernoma vs., 75
Calcifying aponeurotic fibroma, 244–247
- differential diagnosis, 245
- inclusion body fibromatosis vs., 251
- prognosis, 245
- soft tissue chondroma vs., 488
Calcifying bursitis. See Tumoral calcinosis.
Calcifying collagenolysis. See Tumoral calcinosis.
Calcifying fibroma. See Calcifying aponeurotic fibroma.
Calcifying fibrous pseudotumor. See also Calcifying fibrous
tumor.
- desmoplastic fibroblastoma vs., 141
Calcifying fibrous tumor (CFT), 248–249
- differential diagnosis, 249
- prognosis, 249
Calcinosis, tumoral, 786–787
- amyloidoma vs., 783
- differential diagnosis, 787
- prognosis, 787
- soft tissue chondroma vs., 488
Capillary hemangioblastoma. See Peripheral
hemangioblastoma.
Capillary hemangioma, lobular, 420–421
- acquired tufted angioma vs., 437
- angiofibroma of soft tissue vs., 145
- congenital granular cell epulis vs., 799
- differential diagnosis, 421
- glomeruloid hemangioma vs., 443
- infantile hemangioma vs., 418
- nasopharyngeal angiofibroma vs., 802
- prognosis, 421
- sinonasal glomangiopericytoma vs., 806
Carcinoid tumor
- gangliocytic paraganglioma vs., 771
- glomus tumors vs., 354
- paraganglioma vs., 816
Carcinoma
- extrarenal rhabdoid tumor vs., 718
- metastatic
angiosarcoma vs., 472
epithelioid hemangioendothelioma vs., 468
histiocytic sarcoma vs., 325
intimal sarcoma vs., 721
myoepithelioma of soft tissue vs., 656
myxofibrosarcoma vs., 218
paraganglioma vs., 816
pleomorphic rhabdomyosarcoma vs., 401
sclerosing epithelioid fibrosarcoma vs., 233
sclerosing rhabdomyosarcoma vs., 397
solitary extramedullary plasmacytoma vs., 607
- metastatic renal cell, alveolar soft part sarcoma vs., 685
 INDEX
- myoepithelial. See also Myoepithelioma, of soft tissue. Cellular digital fibroma. See Acral fibromyxoma.
epithelioid rhabdomyosarcoma vs., 405 Cellular fibrous histiocytoma
epithelioid sarcoma vs., 680 - epithelioid sarcoma vs., 680
extraskeletal myxoid chondrosarcoma vs., 713 - Kaposi sarcoma vs., 478
metastatic tumors to soft tissue sites vs., 829 - leiomyosarcoma vs., 346
- neuroendocrine, metastatic, desmoplastic small round - pseudomyogenic hemangioendothelioma vs., 463
cell tumor vs., 702 Cellular neurothekeoma, 290–293
- PEComa vs., 694 - differential diagnosis, 291
- poorly differentiated - ectopic meningioma vs., 811
epithelioid rhabdomyosarcoma vs., 405 - plexiform fibrohistiocytic tumor vs., 317
gastrointestinal stromal tumor vs., 747 - prognosis, 291
myeloid sarcoma vs., 609 Cellular pseudosarcomatous fibroepithelial stromal polyp.
pleomorphic liposarcoma vs., 108 See Fibroepithelial stromal polyp.
- sarcomatoid Cellular schwannoma, 510
atypical fibroxanthoma vs., 637 - deep leiomyoma vs., 339
ectopic hamartomatous thymoma vs., 633 - ganglioneuroma vs., 551
extraskeletal osteosarcoma vs., 498 - malignant peripheral nerve sheath tumor vs., 560
metastatic, follicular dendritic cell sarcoma vs., 327 - spindle cell rhabdomyosarcoma vs., 394
spindle cell rhabdomyosarcoma vs., 394 Central nervous system, primary meningioma of, ectopic
squamous cell, leiomyosarcoma vs., 346 meningioma vs., 811
undifferentiated embryonal sarcoma of liver vs., 845 Cerebrotendinous xanthomatosis, 295
- small cell, extraskeletal Ewing sarcoma vs., 708 CFT. See Calcifying fibrous tumor.
- spindle cell, spindle epithelial tumor with thymus-like Checkerboard skeletal muscle pattern, 30
differentiation vs., 855 Chemodectoma. See Paraganglioma.
- undifferentiated, pleomorphic rhabdomyosarcoma vs., Cherry angioma, sinusoidal hemangioma vs., 441
401 Chloroma. See Myeloid sarcoma.
- undifferentiated pleomorphic sarcoma vs., 725 Chondroblastoma, diffuse-type tenosynovial giant cell
Cardiac fibroma, 796–797 tumor vs., 286
- cardiac rhabdomyoma vs., 379 Chondroid lipoma, 66–69
- differential diagnosis, 797 - differential diagnosis, 67
- genetics, 797 - epithelioid hemangioendothelioma vs., 468
- prognosis, 797 - genetic testing, 67
Cardiac myxoma, 792–795 - lipoma vs., 48
- differential diagnosis, 793 - prognosis, 67
- intimal sarcoma vs., 721 Chondroid meningioma, extraskeletal myxoid
- molecular genetics, 793 chondrosarcoma vs., 713
- prognosis, 793 Chondroid metaplasia, cutaneous mixed tumor with, soft
Cardiac rhabdomyoma, 378–379 tissue chondroma vs., 488
- adult rhabdomyoma vs., 373 Chondroma
- differential diagnosis, 379 - extraskeletal myxoid chondrosarcoma vs., 713
- genetics, 379 - juxtaarticular, synovial chondromatosis vs., 493
- prognosis, 379 - soft tissue, 486–491
Cavernous hemangioma calcified, tumoral calcinosis vs., 787
- lobular capillary hemangioma vs., 421 calcifying aponeurotic fibroma vs., 245
- sinusoidal hemangioma vs., 441 chondroid lipoma vs., 67
- spindle cell hemangioma vs., 427 diagnostic checklist, 488
Cavernous lymphangioma. See Lymphangioma. differential diagnosis, 487–488
Cellular angiofibroma, 580–583 extraskeletal myxoid chondrosarcoma vs., 713
- angiomyofibroblastoma vs., 577 myoepithelioma of soft tissue vs., 656
- deep (aggressive) angiomyxoma vs., 585 phosphaturic mesenchymal tumor vs., 665
- differential diagnosis, 581 prognosis, 487
- fibroepithelial stromal polyp vs., 575 synovial chondromatosis vs., 493
- mammary-type myofibroblastoma vs., 149 Chondromatosis, synovial, 492–495
- prognosis, 581 - diagnostic checklist, 493
- solitary fibrous tumor vs., 186 - differential diagnosis, 493
- spindle cell/pleomorphic lipoma vs., 62 - prognosis, 493
Cellular blue nevus, clear cell sarcoma vs., 690 - soft tissue chondroma vs., 487–488
Cellular dermatofibroma Chondroosseous tumors
- adult-type fibrosarcoma vs., 215 - extraskeletal mesenchymal chondrosarcoma, 500–503
- dermatofibrosarcoma protuberans vs., 176 differential diagnosis, 502
- Kaposi sarcoma vs., 478 extraskeletal Ewing sarcoma vs., 708
v
 INDEX
extraskeletal osteosarcoma vs., 498
molecular genetics, 501
prognosis, 501
- extraskeletal osteosarcoma, 496–499
aneurysmal bone cyst of soft tissue vs., 631
diagnostic checklist, 498
differential diagnosis, 498
fibroosseous pseudotumor of digit vs., 131
myositis ossificans vs., 127
ossifying fibromyxoid tumor vs., 652
prognosis, 497
sclerosing epithelioid fibrosarcoma vs., 234
sclerosing rhabdomyosarcoma vs., 397
undifferentiated pleomorphic sarcoma vs., 725
- soft tissue chondroma, 486–491
calcified, tumoral calcinosis vs., 787
calcifying aponeurotic fibroma vs., 245
chondroid lipoma vs., 67
diagnostic checklist, 488
differential diagnosis, 487–488
extraskeletal myxoid chondrosarcoma vs., 713
myoepithelioma of soft tissue vs., 656
phosphaturic mesenchymal tumor vs., 665
prognosis, 487
synovial chondromatosis vs., 493
- synovial chondromatosis, 492–495
diagnostic checklist, 493
differential diagnosis, 493
prognosis, 493
soft tissue chondroma vs., 487–488
Chondrosarcoma
- extraskeletal mesenchymal, 500–503
differential diagnosis, 502
extraskeletal Ewing sarcoma vs., 708
extraskeletal osteosarcoma vs., 498
molecular genetics, 501
prognosis, 501
- extraskeletal myxoid, 712–715
chondroid lipoma vs., 67
differential diagnosis, 713
epithelioid hemangioendothelioma vs., 468
extraaxial soft tissue chordoma vs., 843
extrarenal rhabdoid tumor vs., 718
extraskeletal mesenchymal chondrosarcoma vs., 502
genetic testing, 713
myoepithelioma of soft tissue vs., 656
myxoid liposarcoma vs., 102
ossifying fibromyxoid tumor vs., 652
perineurioma vs., 532
primary pulmonary myxoid sarcoma vs., 847
prognosis, 713
soft tissue chondroma vs., 488
- mesenchymal, phosphaturic mesenchymal tumor vs.,
665
- synovial, synovial chondromatosis vs., 493
Chordoid sarcoma. See Extraskeletal myxoid
chondrosarcoma.
Chordoma
- axial, soft tissue metastasis from, extraaxial soft tissue
chordoma vs., 843
- ependymoma of soft tissue vs., 827
vi
- extraaxial soft tissue, 842–843
differential diagnosis, 843
prognosis, 843
- myoepithelioma of soft tissue vs., 656
Chrondroblastoma-like chondroma. See Soft tissue
chondroma.
CIC-FOXO4 sarcoma, undifferentiated round cell sarcoma
with CIC-DUX4 translocation vs., 730
CIC-rearranged sarcoma. See Undifferentiated round cell
sarcoma with CIC-DUX4 translocation.
Clear cell myomelanocytic tumor. See Perivascular
epithelioid cell tumor.
Clear cell sarcoma, 688–691
- diagnostic checklist, 690
- differential diagnosis, 690
- epithelioid malignant peripheral nerve sheath tumor
vs., 567
- malignant gastrointestinal neuroectodermal tumor vs.,
777–778
- melanotic schwannoma vs., 557
- metastatic tumors to soft tissue sites vs., 829
- molecular genetics, 689
- PEComa vs., 694
- prognosis, 689
- of tendon and aponeurosis, 689
Clear cell sarcoma-like tumor
- of gastrointestinal tract (CCSLTGT). See Malignant
gastrointestinal neuroectodermal tumor.
- with osteoclast-like giant cells, of gastrointestinal tract.
See Malignant gastrointestinal neuroectodermal
tumor.
Collagen, amyloidoma vs., 783
Collagenoma, storiform, 160–161
- diagnostic checklist, 161
- differential diagnosis, 161
- prognosis, 161
Collagenosis nuchae. See Nuchal-type fibroma.
Collagenous fibroma. See also Desmoplastic
fibroblastoma.
- Gardner fibroma vs., 257
- nodular fasciitis vs., 116
- storiform collagenoma vs., 161
Combined blue nevus, smooth muscle hamartoma vs., 333
Composite hemangioendothelioma, 460–461
- differential diagnosis, 461
- epithelioid hemangioendothelioma vs., 468
- papillary intralymphatic angioendothelioma vs., 457
- prognosis, 461
- retiform hemangioendothelioma vs., 459
Congenital epulis of newborn. See Congenital granular cell
epulis.
Congenital fibrosarcoma. See Infantile fibrosarcoma.
Congenital granular cell epulis, 798–799
- differential diagnosis, 799
- granular cell tumor vs., 542
- prognosis, 799
Congenital granular cell tumor. See Congenital granular
cell epulis.
Congenital hemangioma, 412–415
- differential diagnosis, 414
 INDEX
- genetics, 413
- infantile hemangioma vs., 418
- prognosis, 413
Congenital nonprogressive hemangioma. See Congenital
hemangioma.
Congenital smooth muscle hamartoma. See Smooth
muscle hamartoma.
Conventional lipoma, myelolipoma vs., 79
Cranial fasciitis, 115
Crystal-storing histiocytosis, 314–315
- adult rhabdomyoma vs., 373
- differential diagnosis, 315
- prognosis, 315
Cutaneous focal mucinosis, superficial angiomyxoma vs.,
621
Cutaneous leiomyoma. See also Superficial leiomyoma.
- smooth muscle hamartoma vs., 333
Cutaneous leiomyosarcoma, smooth muscle hamartoma
vs., 333
Cutaneous lymphangioma, superficial. See Lymphangioma.
Cutaneous meningioma. See Ectopic meningioma.
Cutaneous mixed tumor, with chondroid metaplasia, soft
tissue chondroma vs., 488
Cutaneous mucinous carcinoma, metastatic or primary
- extraaxial soft tissue chordoma vs., 843
Cutaneous myxoma. See also Superficial angiomyxoma.
- in Carney complex, dermal nerve sheath myxoma vs.,
547
Cutaneous reticulohistiocytosis, generalized,
reticulohistiocytoma vs., 301–302
Cutaneous syncytial myoepithelioma, 657
Cystic hygroma. See Lymphangioma.
Cystic lymphangioma. See also Lymphangioma.
- multicystic peritoneal mesothelioma vs., 593
D
D-TGCT. See Diffuse-type tenosynovial giant cell tumor.
Dabska tumor. See Papillary intralymphatic
angioendothelioma.
DDLPS. See Dedifferentiated liposarcoma.
Dedifferentiated liposarcoma (DDLPS), 94–99
- atypical lipomatous tumor/well-differentiated
liposarcoma vs., 90
- atypical spindle cell lipomatous tumor vs., 85
- differential diagnosis, 96
- extraskeletal osteosarcoma vs., 498
- histiocytic sarcoma vs., 325
- low-grade morphology, myolipoma vs., 71
- molecular genetics, 96
- pleomorphic liposarcoma vs., 107
- prognosis, 95
- undifferentiated pleomorphic sarcoma vs., 725
Deep (aggressive) angiomyxoma, 584–587
- angiomyofibroblastoma vs., 577
- cellular angiofibroma vs., 581
- desmoid-type fibromatosis vs., 170
- differential diagnosis, 585
- fibroepithelial stromal polyp vs., 575
- genetic testing, 585
- juxtaarticular myxoma vs., 619
- prognosis, 585
- superficial angiomyxoma vs., 621
Deep benign fibrous histiocytoma, 276–277
- angiofibroma of soft tissue vs., 145
- dermatofibrosarcoma protuberans vs., 176
- differential diagnosis, 277
- prognosis, 277
- solitary fibrous tumor vs., 186
Deep granuloma annulare, 304–305
- differential diagnosis, 305
- prognosis, 305
- rheumatoid nodule vs., 307
Deep leiomyoma, 338–341
- differential diagnosis, 339
- prognosis, 339
Deep lymphangioma. See Lymphangioma.
Dendritic cell sarcoma
- follicular, 326–327
angiomatoid fibrous histiocytoma vs., 644
differential diagnosis, 327
extranodal Rosai-Dorfman disease vs., 312
interdigitating dendritic cell sarcoma vs., 329
prognosis, 327
- interdigitating, 328–329
differential diagnosis, 329
follicular dendritic cell sarcoma vs., 327
prognosis, 329
Dermal melanocytic nevus, glomus tumors vs., 354
Dermal nerve sheath myxoma, 546–549
- cellular neurothekeoma vs., 291
- differential diagnosis of, 547
- prognosis, 547
- superficial angiomyxoma vs., 621
Dermatofibroma, 270–275
- acral fibromyxoma vs., 625
- cellular
adult-type fibrosarcoma vs., 215
dermatofibrosarcoma protuberans vs., 176
Kaposi sarcoma vs., 478
- dermatofibrosarcoma protuberans vs., 176
- dermatomyofibroma vs., 159
- diagnostic checklist, 272
- differential diagnosis, 272
- epithelioid sarcoma vs., 680
- giant cell fibroblastoma vs., 261
- lipidized-type, xanthomas vs., 296
- localized-type tenosynovial giant cell tumor vs., 280
- nodular fasciitis vs., 116
- pleomorphic fibroma vs., 157
- prognosis, 271
- solitary (juvenile) xanthogranuloma vs., 299
- storiform collagenoma vs., 161
Dermatofibrosarcoma protuberans, 174–183
- acral fibromyxoma vs., 625
- atypical spindle cell lipomatous tumor vs., 85
- deep benign fibrous histiocytoma vs., 277
- dermatofibroma vs., 272
- dermatomyofibroma vs., 159
vii
 INDEX
- differential diagnosis, 176
- fibrosarcomatous, 175
adult-type fibrosarcoma vs., 215
infantile fibrosarcoma vs., 265
spindle cell rhabdomyosarcoma vs., 394
synovial sarcoma vs., 668
- giant cell fibroblastoma vs., 261
- hemosiderotic fibrolipomatous tumor vs., 635
- molecular genetics, 176
- myxoid
dermal nerve sheath myxoma vs., 547
myxoid liposarcoma vs., 102
- neurofibroma vs., 524
- perineurioma vs., 532
- prognosis, 175
- solitary fibrous tumor vs., 186
- spindle cell/pleomorphic lipoma vs., 62
Dermatomyofibroma, 158–159
- dermatofibrosarcoma protuberans vs., 176
- differential diagnosis, 159
- prognosis, 159
- superficial leiomyoma vs., 335
Desmoid tumor. See Desmoid-type fibromatosis.
Desmoid-type fibromatosis, 168–173
- adult-type fibrosarcoma vs., 215
- deep (aggressive) angiomyxoma vs., 585
- differential diagnosis, 170
- elastofibromas vs., 143
- Gardner fibroma vs., 257
- gastrointestinal stromal tumor vs., 747
- idiopathic tumefactive fibroinflammatory lesions vs.,
790
- inclusion body fibromatosis vs., 251
- inflammatory myofibroblastic tumor vs., 198
- intranodal palisade myofibroblastoma vs., 153
- leiomyosarcoma vs., 346
- low-grade fibromyxoid sarcoma vs., 224
- low-grade myofibroblastic sarcoma vs., 193
- molecular genetics, 169
- nasopharyngeal angiofibroma vs., 802
- nodular fasciitis vs., 116
- palmar/plantar fibromatosis vs., 167
- perineurioma vs., 532
- primary, neuromuscular choristoma vs., 555
- prognosis, 169
- spindle cell rhabdomyosarcoma vs., 394
Desmoplastic fibroblastoma, 140–141
- differential diagnosis, 141
- fibroma of tendon sheath vs., 136
- Gardner fibroma vs., 257
- nodular fasciitis vs., 116
- prognosis, 141
Desmoplastic melanoma
- atypical fibroxanthoma vs., 637–638
- keloid vs., 163
- neurofibroma vs., 524
Desmoplastic small round cell tumor, 700–705
- alveolar rhabdomyosarcoma vs., 388
- differential diagnosis, 701–702
- extrarenal rhabdoid tumor vs., 718
- extraskeletal Ewing sarcoma vs., 708
viii
- immunohistochemistry, 702
- low-grade endometrial stromal sarcoma vs., 857
- melanotic neuroectodermal tumor of infancy vs., 825
- molecular genetics, 701
- prognosis, 701
Diffuse hemangioma. See Angiomatosis.
Diffuse mesothelioma. See Malignant mesothelioma.
Diffuse neurofibroma
- dermatofibrosarcoma protuberans vs., 176
- lipoma vs., 48
Diffuse-type tenosynovial giant cell tumor (D-TGCT),
284–289
- differential diagnosis, 286
- localized-type tenosynovial giant cell tumor vs., 280
- myxoinflammatory fibroblastic sarcoma vs., 204
- prognosis, 285
- synovial lipomatosis vs., 55
Digital fibromyxoma. See Acral fibromyxoma.
Digital fibrous tumor of childhood. See Inclusion body
fibromatosis.
Digital mucoid cyst
- dermal nerve sheath myxoma vs., 547
- superficial angiomyxoma vs., 621
Duodenal ganglioneuroma. See Gangliocytic
paraganglioma.
Dupuytren contracture. See Palmar/plantar fibromatosis.
E
Early scar, microvenular hemangioma vs., 439
Ectomesenchymal chondromyxoid tumor. See
Myoepithelioma, of soft tissue.
Ectomesenchymoma, 570–571
- differential diagnosis, 571
- embryonal rhabdomyosarcoma vs., 382
- genetic testing, 571
- prognosis, 571
Ectopic hamartomatous thymoma (EHT), 632–633
- differential diagnosis, 633
- prognosis, 633
Ectopic meningioma, 810–811
- differential diagnosis, 811
- perineurioma vs., 532
- prognosis, 811
EHE. See Epithelioid hemangioendothelioma.
EHT. See Ectopic hamartomatous thymoma.
Elastofibroma, 142–143
- amyloidoma vs., 783
- desmoplastic fibroblastoma vs., 141
- differential diagnosis, 143
- Gardner fibroma vs., 257
- nuchal-type fibroma vs., 165
- prognosis, 143
Elastofibroma dorsi. See Elastofibroma.
Elastofibromatous change, elastofibromas vs., 143
Embryonal rhabdomyosarcoma, 380–385
- alveolar rhabdomyosarcoma vs., 388
- botryoid-type, fibroepithelial stromal polyp vs., 575
 INDEX
- differential diagnosis, 382
- fetal rhabdomyoma vs., 375
- pleomorphic rhabdomyosarcoma vs., 401
- prognosis, 381
- proliferative fasciitis/myositis vs., 121
- spindle cell rhabdomyosarcoma vs., 394
- undifferentiated embryonal sarcoma of liver vs., 845
Embryonic fat, lipoma. See Hibernoma.
Embryonic lipoma. See Lipoblastoma.
EMC. See Extraskeletal mesenchymal chondrosarcoma;
Extraskeletal myxoid chondrosarcoma.
Encephalocele, true, glial heterotopia vs., 813
Endolymphatic stromal myosis. See Low-grade
Endometrial stromal sarcoma.
Endometrial stromal nodule, low-grade endometrial
stromal sarcoma vs., 857
Endometrial stromal sarcoma, low-grade, 856–857
- differential diagnosis, 857
- prognosis, 857
Endothelial hyperplasia, papillary
- angiosarcoma vs., 472
- diagnostic checklist, 409
- differential diagnosis, 409
- prognosis, 409
Endovascular papillary angioendothelioma. See Papillary
intralymphatic angioendothelioma.
Eosinophilic granuloma. See Langerhans cell histiocytosis.
Ependymoma, of soft tissue, 826–827
- differential diagnosis, 827
- prognosis, 827
Epithelioid angiomatosis. See Bacillary angiomatosis.
Epithelioid angiosarcoma
- epithelioid hemangioendothelioma vs., 468
- epithelioid hemangioma vs., 423
- epithelioid sarcoma vs., 680
- malignant mesothelioma vs., 600
- myeloid sarcoma vs., 609
Epithelioid cell patterns, 30
- abundant cytoplasm, 30
- arranged in cords or trabeculae, 30
- arranged in nests or lobules, 30
- associated with adipose tissue, 30
- associated with prominent stromal vasculature, 30
- within collagenous, hyalinized or sclerotic stroma, 30
- minimal/scant cytoplasm, 30
- within myxoid stroma, 30
Epithelioid fibrosarcoma, sclerosing, 232–237
- differential diagnosis, 233–234
- low-grade fibromyxoid sarcoma vs., 224
- ossifying fibromyxoid tumor vs., 652
- prognosis, 233
- sclerosing rhabdomyosarcoma vs., 397
Epithelioid fibrous histiocytoma, cellular neurothekeoma
vs., 291
Epithelioid gastrointestinal stromal tumor, extraskeletal
myxoid chondrosarcoma vs., 713
Epithelioid hemangioendothelioma (EHE), 466–469
- angiosarcoma vs., 472
- composite hemangioendothelioma vs., 461
- differential diagnosis, 468
- epithelioid hemangioma vs., 423
- intimal sarcoma vs., 721
- malignant mesothelioma vs., 600
- molecular genetics, 467
- prognosis, 467
- pseudomyogenic hemangioendothelioma, 463
- spindle cell hemangioma vs., 427
Epithelioid hemangioma, 422–425
- differential diagnosis, 423
- epithelioid hemangioendothelioma vs., 468
- molecular genetics, 423
- prognosis, 423
Epithelioid malignant peripheral nerve sheath tumor,
566–569
- differential diagnosis, 567
- extrarenal rhabdoid tumor vs., 718
- myoepithelioma of soft tissue vs., 656
- ossifying fibromyxoid tumor vs., 652
- prognosis, 567
Epithelioid rhabdomyosarcoma, 404–405
- differential diagnosis, 405
- molecular genetics, 405
- pleomorphic rhabdomyosarcoma vs., 401
- prognosis, 405
Epithelioid sarcoma (ES), 678–683
- angiosarcoma vs., 472
- classic, 679
- deep granuloma annulare vs., 305
- differential diagnosis, 680
- epithelioid hemangioendothelioma vs., 468
- epithelioid rhabdomyosarcoma vs., 405
- extrarenal rhabdoid tumor vs., 718
- inclusion body fibromatosis vs., 251
- ischemic fasciitis vs., 125
- molecular genetics, 680
- myoepithelioma of soft tissue vs., 656
- prognosis, 679
- proximal-type, 679–680
- pseudomyogenic hemangioendothelioma, 463
- rheumatoid nodule vs., 307
- solitary extramedullary plasmacytoma vs., 607
- superficial CD34(+) fibroblastic tumor vs., 211
Epithelioid sarcoma-like hemangioendothelioma. See
Pseudomyogenic hemangioendothelioma.
Epithelioid schwannoma, 510
- epithelioid malignant peripheral nerve sheath tumor
vs., 567
Epstein-Barr virus-associated smooth muscle tumor,
342–343
- differential diagnosis, 343
- prognosis, 343
Eruptive xanthoma, 295
Evans tumor. See Low-grade fibromyxoid sarcoma.
Ewing-like sarcoma. See BCOR-CCNB3 fusion-positive
sarcoma; Undifferentiated round cell sarcoma with CIC-
DUX4 translocation.
Ewing sarcoma
- alveolar rhabdomyosarcoma vs., 388
- BCOR-CCNB3 fusion-positive sarcoma vs., 736
- extrarenal rhabdoid tumor vs., 718
- extraskeletal, 706–711
desmoplastic small round cell tumor vs., 701
ix
 INDEX
differential diagnosis, 708
extraskeletal osteosarcoma vs., 498
molecular genetics, 708
prognosis, 707
undifferentiated round cell sarcoma with CIC-DUX4
translocation vs., 729
- extraskeletal mesenchymal chondrosarcoma vs., 502
- low-grade endometrial stromal sarcoma vs., 857
- lymphoma of soft tissue vs., 611
- myxoid liposarcoma vs., 102
- neuroblastoma and ganglioneuroblastoma vs., 834
- synovial sarcoma vs., 668
Extraadrenal paraganglioma. See Paraganglioma.
Extraaxial soft tissue chordoma, 842–843
- differential diagnosis, 843
- prognosis, 843
Extracranial meningioma. See Ectopic meningioma.
Extramedullary hemopoiesis, myelolipoma vs., 79
Extramedullary plasmacytoma, solitary, 606–607
- differential diagnosis, 607
- prognosis, 607
Extraneural soft tissue perineurioma. See Perineurioma.
Extraneuraxial hemangioblastoma. See Peripheral
hemangioblastoma.
Extranodal Rosai-Dorfman disease, 310–313
- differential diagnosis, 312
- histiocytic sarcoma vs., 325
- idiopathic tumefactive fibroinflammatory lesions vs.,
790
- Langerhans cell histiocytosis vs., 309
- prognosis, 311
Extraosseous plasmacytoma, solitary. See Solitary
extramedullary plasmacytoma.
Extrarenal epithelioid angiomyolipoma. See Perivascular
epithelioid cell tumor.
Extrarenal rhabdoid tumor, 716–719
- alveolar rhabdomyosarcoma vs., 388
- desmoplastic small round cell tumor vs., 702
- differential diagnosis, 718
- epithelioid rhabdomyosarcoma vs., 405
- epithelioid sarcoma vs., 680
- molecular genetics, 717–718
- prognosis, 717
Extraskeletal chondroma. See Soft tissue chondroma.
Extraskeletal Ewing sarcoma, 706–711. See also Ewing
sarcoma.
- desmoplastic small round cell tumor vs., 701
- differential diagnosis, 708
- extraskeletal osteosarcoma vs., 498
- molecular genetics, 708
- prognosis, 707
- undifferentiated round cell sarcoma with CIC-DUX4
translocation vs., 729
Extraskeletal mesenchymal chondrosarcoma, 500–503
- differential diagnosis, 502
- extraskeletal Ewing sarcoma vs., 708
- extraskeletal osteosarcoma vs., 498
- molecular genetics, 501
- prognosis, 501
x
Extraskeletal myxoid chondrosarcoma, 712–715
- chondroid lipoma vs., 67
- differential diagnosis, 713
- epithelioid hemangioendothelioma vs., 468
- extraaxial soft tissue chordoma vs., 843
- extrarenal rhabdoid tumor vs., 718
- extraskeletal mesenchymal chondrosarcoma vs., 502
- genetic testing, 713
- myoepithelioma of soft tissue vs., 656
- myxoid liposarcoma vs., 102
- ossifying fibromyxoid tumor vs., 652
- perineurioma vs., 532
- primary pulmonary myxoid sarcoma vs., 847
- prognosis, 713
- soft tissue chondroma vs., 488
Extraskeletal osteosarcoma, 496–499
- aneurysmal bone cyst of soft tissue vs., 631
- diagnostic checklist, 498
- differential diagnosis, 498
- fibroosseous pseudotumor of digit vs., 131
- myositis ossificans vs., 127
- ossifying fibromyxoid tumor vs., 652
- prognosis, 497
- sclerosing epithelioid fibrosarcoma vs., 234
- sclerosing rhabdomyosarcoma vs., 397
- undifferentiated pleomorphic sarcoma vs., 725
Extraskeletal recurrence of giant cell tumor of bone, giant
cell tumor of soft tissue vs., 321
Extraspinal ependymoma. See Ependymoma, of soft
tissue.
Extrauterine lipoleiomyoma. See Myolipoma.
F
Fasciitis
- ischemic, 124–125
differential diagnosis, 125
prognosis, 125
- nodular, 114–119
aneurysmal bone cyst of soft tissue vs., 631
angiomatoid fibrous histiocytoma vs., 644
desmoid-type fibromatosis vs., 170
desmoplastic fibroblastoma vs., 141
differential diagnosis, 116
fibroma of tendon sheath vs., 136
fibromatosis colli vs., 255
inflammatory myofibroblastic tumor vs., 198
ischemic fasciitis vs., 125
keloid vs., 163
molecular genetics, 116
myofibroma and myofibromatosis vs., 363
myositis ossificans vs., 127
prognosis, 115
proliferative fasciitis/myositis vs., 121
- proliferative fasciitis/myositis, 120–123
desmoid-type fibromatosis vs., 170
differential diagnosis, 121
ischemic fasciitis vs., 125
 INDEX
myxoinflammatory fibroblastic sarcoma vs., 204 - ischemic fasciitis, 124–125
nodular fasciitis vs., 116 differential diagnosis, 125
prognosis, 121 prognosis, 125
Fasciitis ossificans. See Fibroosseous pseudotumor of digit. - keloid, 162–163
Fatty infiltration of median nerve. See Lipomatosis. diagnostic checklist, 163
FDCS. See Follicular dendritic cell sarcoma. differential diagnosis, 163
Fédération Nationale des Centres de Lutte Contre le prognosis, 163
Cancer (FNCLCC), 6 - low-grade fibromyxoid sarcoma, 222–231
Fetal lipoma. See Hibernoma; Lipoblastoma. differential diagnosis, 224
Fetal rhabdomyoma, 374–375 prognosis, 223
- differential diagnosis, 375 - low-grade myofibroblastic sarcoma, 192–195
- embryonal rhabdomyosarcoma vs., 382 differential diagnosis, 193
- genetics, 375 prognosis, 193
- genital rhabdomyoma vs., 377 - mammary-type myofibroblastoma, 148–151
- prognosis, 375 differential diagnosis, 149
- spindle cell rhabdomyosarcoma vs., 394 molecular genetics, 149
FHI. See Fibrous hamartoma of infancy. prognosis, 149
Fibrin, amyloidoma vs., 783 - myositis ossificans, 126–129
Fibroblastic connective tissue nevus, lipofibromatosis vs., differential diagnosis, 127
259 prognosis, 127
Fibroblastic/myofibroblastic lesions - myxofibrosarcoma, 216–221
- adult-type fibrosarcoma, 214–215 differential diagnosis, 218
differential diagnosis, 215 prognosis, 217
genetic testing, 215 - myxoinflammatory fibroblastic sarcoma, 202–209
prognosis, 215 differential diagnosis, 204
- angiofibroma of soft tissue, 144–147 molecular genetics, 204
differential diagnosis of, 145 prognosis, 203
molecular genetics, 145 - nodular fasciitis, 114–119
- dermatofibrosarcoma protuberans, 174–183 differential diagnosis, 116
differential diagnosis, 176 molecular genetics, 116
fibrosarcomatous, 175 prognosis, 115
molecular genetics, 176 - nuchal fibrocartilaginous pseudotumor, nuchal-type
prognosis, 175 fibroma vs., 165
- dermatomyofibroma, 158–159 - nuchal-type fibroma, 164–165
differential diagnosis, 159 differential diagnosis, 165
prognosis, 159 prognosis, 165
- desmoid-type fibromatosis, 168–173 - palmar/plantar fibromatosis, 166–167
differential diagnosis, 170 differential diagnosis, 167
molecular genetics, 169 prognosis, 167
prognosis, 169 - pleomorphic fibroma, 156–157
- desmoplastic fibroblastoma, 140–141 diagnostic checklist, 157
differential diagnosis, 141 differential diagnosis, 157
prognosis, 141 prognosis, 157
- elastofibroma, 142–143 - proliferative fasciitis/myositis, 120–123
differential diagnosis, 143 differential diagnosis, 121
nuchal-type fibroma vs., 165 prognosis, 121
prognosis, 143 - sclerosing epithelioid fibrosarcoma, 232–237
- fibroma of tendon sheath, 134–139 differential diagnosis, 233–234
differential diagnosis, 136 prognosis, 233
prognosis, 135 - solitary fibrous tumor, 184–191
- fibroosseous pseudotumor of digit, 130–133 differential diagnosis, 186
differential diagnosis, 131 molecular genetics, 186
- inflammatory myofibroblastic tumor, 196–201 prognosis, 185
differential diagnosis, 198 - storiform collagenoma, 160–161
molecular genetics, 197–198 diagnostic checklist, 161
prognosis, 197 differential diagnosis, 161
- intranodal palisade myofibroblastoma, 152–155 prognosis, 161
differential diagnosis, 153 - superficial CD34(+) fibroblastic tumor, 210–213
molecular genetics, 153 differential diagnosis, 211
prognosis, 153 prognosis, 211

xi
 INDEX
Fibroblastic/myofibroblastic tumors, pediatric
- calcifying aponeurotic fibroma, 244–247
differential diagnosis, 245
prognosis, 245
- calcifying fibrous tumor, 248–249
differential diagnosis, 249
prognosis, 249
- fibromatosis colli, 254–255
differential diagnosis, 255
prognosis, 255
- fibrous hamartoma of infancy, 240–243
differential diagnosis, 241
prognosis, 241
- Gardner fibroma, 256–257
diagnostic checklist, 257
differential diagnosis, 257
prognosis, 257
- giant cell fibroblastoma, 260–263
differential diagnosis, 261
prognosis, 261
- hyaline fibromatosis syndrome, 252–253
differential diagnosis, 253
prognosis, 253
- inclusion body fibromatosis, 250–251
differential diagnosis, 251
prognosis, 251
- infantile fibrosarcoma, 264–267
differential diagnosis, 265
molecular genetics, 265
prognosis, 265
- lipofibromatosis, 258–259
calcifying aponeurotic fibroma vs., 245
differential diagnosis, 259
fibrous hamartoma of infancy vs., 241
genetics, 259
prognosis, 259
Fibroblastic sarcoma, myxoinflammatory, 202–209
- differential diagnosis, 204
- extranodal Rosai-Dorfman disease vs., 312
- hemosiderotic fibrolipomatous tumor vs., 635
- molecular genetics, 204
- myxofibrosarcoma vs., 218
- pleomorphic hyalinizing angiectatic tumor vs., 627
- prognosis, 203
- superficial CD34(+) fibroblastic tumor vs., 211
Fibroblastic tumor, superficial CD34(+), myxoinflammatory
fibroblastic sarcoma vs., 204
Fibroblastoma
- desmoplastic
differential diagnosis, 141
fibroma of tendon sheath vs., 136
Gardner fibroma vs., 257
nodular fasciitis vs., 116
prognosis, 141
- giant cell
angiosarcoma vs., 472
differential diagnosis, 261
fibrous hamartoma of infancy vs., 241
prognosis, 261
spindle cell/pleomorphic lipoma vs., 62
xii
Fibrocartilaginous pseudotumor, nuchal
- Gardner fibroma vs., 257
- nuchal-type fibroma vs., 165
Fibrochondroma. See Soft tissue chondroma.
Fibrodysplasia (myositis) ossificans progressiva, hyaline
fibromatosis syndrome vs., 253
Fibroepithelial stromal polyp (FSP), 574–575
- angiomyofibroblastoma vs., 577
- differential diagnosis, 575
- genital rhabdomyoma vs., 377
- prognosis, 575
Fibrohistiocytic, histiocytic, and dendritic cell tumors
- crystal-storing histiocytosis, 314–315
- deep granuloma annulare, 304–305
- extranodal Rosai-Dorfman disease, 310–313
- giant cell tumor of soft tissue, 320–323
- histiocytic sarcoma, 324–325
- Langerhans cell histiocytosis, 308–309
- plexiform fibrohistiocytic tumor, 316–319
- reticulohistiocytoma, 300–303
- rheumatoid nodule, 306–307
- solitary (juvenile) xanthogranuloma, 298–299
Fibrohistiocytic tumor, plexiform, 316–319
- cellular neurothekeoma vs., 291
- differential diagnosis, 317
- ectopic meningioma vs., 811
- localized-type tenosynovial giant cell tumor vs., 280
- prognosis, 317
- xanthomas vs., 296
Fibroid polyp, inflammatory, 766–769
- benign neural gastrointestinal polyps vs., 741
- differential diagnosis, 767
- gastrointestinal smooth muscle neoplasms vs., 764
- gastrointestinal stromal tumor vs., 747
- inflammatory myofibroblastic tumor vs., 198
- plexiform fibromyxoma vs., 773
Fibrokeratoma, acral, storiform collagenoma vs., 161
Fibrolipoma
- elastofibromas vs., 143
- Gardner fibroma vs., 257
- nuchal-type fibroma vs., 165
Fibrolipomatous hamartoma
- of nerve. See Lipomatosis.
- neuromuscular choristoma vs., 555
Fibrolipomatous tumor, hemosiderotic, 634–635
- differential diagnosis, 635
- molecular genetics, 635
- myxoinflammatory fibroblastic sarcoma vs., 204
- pleomorphic hyalinizing angiectatic tumor vs., 627
- prognosis, 635
Fibroma
- cardiac, 796–797
cardiac rhabdomyoma vs., 379
differential diagnosis, 797
genetics, 797
prognosis, 797
- collagenous, storiform collagenoma vs., 161
- Gardner, 256–257
diagnostic checklist, 257
differential diagnosis, 257
elastofibromas vs., 143
 INDEX
nuchal-type fibroma vs., 165 - superficial
prognosis, 257 dermatomyofibroma vs., 159
- nuchal-type, 164–165 fibroma of tendon sheath vs., 136
differential diagnosis, 165 inclusion body fibromatosis vs., 251
elastofibromas vs., 143 Fibromatosis colli, 254–255
Gardner fibroma vs., 257 - differential diagnosis, 255
prognosis, 165 - prognosis, 255
- plaque-like CD34(+) dermal, dermatofibrosarcoma Fibromyxoid sarcoma, low-grade
protuberans vs., 176 - angiofibroma of soft tissue vs., 145
- pleomorphic, 156–157 - desmoid-type fibromatosis vs., 170
diagnostic checklist, 157 - desmoplastic fibroblastoma vs., 141
differential diagnosis, 157 - differential diagnosis, 224
prognosis, 157 - intramuscular myxoma vs., 615
storiform collagenoma vs., 161 - juxtaarticular myxoma vs., 619
- subungual and periungual, storiform collagenoma vs., - myxofibrosarcoma vs., 218
161 - myxoid liposarcoma vs., 102
- tendon sheath, 134–139 - ossifying fibromyxoid tumor vs., 652
desmoplastic fibroblastoma vs., 141 - perineurioma vs., 532
differential diagnosis, 136 - prognosis, 223
localized-type tenosynovial giant cell tumor vs., 280 - sclerosing epithelioid fibrosarcoma vs., 233
nodular fasciitis vs., 116 - superficial angiomyxoma vs., 621
prognosis, 135 Fibromyxoid sarcoma, low-grade, 222–231
Fibromatosis Fibromyxoid tumor, ossifying, 650–655
- calcifying fibrous tumor vs., 249 - differential diagnosis, 652
- desmoid-type, 168–173 - extraskeletal osteosarcoma vs., 498
adult-type fibrosarcoma vs., 215 - fibroosseous pseudotumor vs., 131
deep (aggressive) angiomyxoma vs., 585 - malignant, 651
differential diagnosis, 170 - molecular genetics, 652
elastofibromas vs., 143 - myoepithelioma of soft tissue vs., 656
Gardner fibroma vs., 257 - myositis ossificans vs., 127
gastrointestinal stromal tumor vs., 747 - prognosis, 651
idiopathic tumefactive fibroinflammatory lesions vs., - sclerosing epithelioid fibrosarcoma vs., 234
790 Fibromyxoma
inclusion body fibromatosis vs., 251 - acral, 624–625
inflammatory myofibroblastic tumor vs., 198 differential diagnosis, 625
intranodal palisade myofibroblastoma vs., 153 inclusion body fibromatosis vs., 251
leiomyosarcoma vs., 346 prognosis, 625
low-grade fibromyxoid sarcoma vs., 224 - plexiform, 772–775
low-grade myofibroblastic sarcoma vs., 193 differential diagnosis, 773
molecular genetics, 169 gastrointestinal stromal tumor vs., 747
nasopharyngeal angiofibroma vs., 802 - superficial acral
nodular fasciitis vs., 116 dermal nerve sheath myxoma vs., 547
palmar/plantar fibromatosis vs., 167 superficial angiomyxoma vs., 621
perineurioma vs., 532 Fibroosseous pseudotumor of digit, 130–133
primary, neuromuscular choristoma vs., 555 - differential diagnosis, 131
prognosis, 169 - extraskeletal osteosarcoma vs., 498
spindle cell rhabdomyosarcoma vs., 394 Fibrosarcoma
- desmoplastic fibroblastoma vs., 141 - adult-type, 214–215
- fibromatosis colli vs., 255 differential diagnosis, 215
- fibrous hamartoma of infancy vs., 241 genetic testing, 215
- inclusion body, 250–251 prognosis, 215
differential diagnosis, 251 spindle cell rhabdomyosarcoma vs., 394
fibroma of tendon sheath vs., 136 - atypical fibroxanthoma vs., 638
prognosis, 251 - fibromyxoid type. See Low-grade fibromyxoid sarcoma.
- myofibroma and myofibromatosis vs., 363 - infantile, 264–267
- palmar/plantar, 166–167 differential diagnosis, 265
calcifying aponeurotic fibroma vs., 245 embryonal rhabdomyosarcoma vs., 382
differential diagnosis, 167 molecular genetics, 265
prognosis, 167 myofibroma and myofibromatosis vs., 363
- plexiform fibrohistiocytic tumor vs., 317 prognosis, 265
spindle cell rhabdomyosarcoma vs., 394
xiii
 INDEX
- sclerosing epithelioid, 232–237 cellular angiofibroma vs., 581
differential diagnosis, 233–234 cellular/malignant, extraskeletal mesenchymal
low-grade fibromyxoid sarcoma vs., 224 chondrosarcoma vs., 502
ossifying fibromyxoid tumor vs., 652 deep benign fibrous histiocytoma vs., 277
prognosis, 233 dermatofibrosarcoma protuberans vs., 176
sclerosing rhabdomyosarcoma vs., 397 differential diagnosis, 186
Fibrosarcoma-like lipomatous neoplasm. See Atypical ectopic hamartomatous thymoma vs., 633
spindle cell lipomatous tumor. gastrointestinal stromal tumor vs., 747
Fibrosarcomatous dermatofibrosarcoma protuberans, 175 low-grade endometrial stromal sarcoma vs., 857
- adult-type fibrosarcoma vs., 215 malignant mesothelioma vs., 600
- infantile fibrosarcoma vs., 265 mammary-type myofibroblastoma vs., 149
- spindle cell rhabdomyosarcoma vs., 394 molecular genetics, 186
- synovial sarcoma vs., 668 myopericytoma vs., 359
Fibrosing (sclerosing) mediastinitis, idiopathic tumefactive nasopharyngeal angiofibroma vs., 802
fibroinflammatory lesions vs., 790 nuchal-type fibroma vs., 165
Fibrous hamartoma of infancy (FHI), 240–243 perineurioma vs., 532
- differential diagnosis, 241 peripheral hemangioblastoma vs., 823
- lipofibromatosis vs., 259 phosphaturic mesenchymal tumor vs., 665
- prognosis, 241 prognosis, 185
Fibrous histiocytoma, 270–275 sinonasal glomangiopericytoma vs., 806
- acral fibromyxoma vs., 625 spindle cell/pleomorphic lipoma vs., 62
- angiomatoid, 642–649 spindle epithelial tumor with thymus-like
differential diagnosis, 644 differentiation vs., 855
molecular genetics, 644 synovial sarcoma vs., 668
nodular fasciitis vs., 116 Fibroxanthoma, atypical, 636–641
primary pulmonary myxoid sarcoma vs., 847 - angiosarcoma vs., 472
prognosis, 643 - dermatofibroma vs., 272
- cellular - differential diagnosis, 637–638
epithelioid sarcoma vs., 680 - immunohistochemistry, 638
Kaposi sarcoma vs., 478 - pleomorphic fibroma vs., 157
leiomyosarcoma vs., 346 - prognosis, 637
pseudomyogenic hemangioendothelioma vs., 463 - superficial CD34(+) fibroblastic tumor vs., 211
- deep benign, 276–277 Focal myositis, 370–371
angiofibroma of soft tissue vs., 145 - differential diagnosis, 371
dermatofibrosarcoma protuberans vs., 176 - fibromatosis colli vs., 255
differential diagnosis, 277 - prognosis, 371
prognosis, 277 Follicular dendritic cell sarcoma (FDCS), 326–327
solitary fibrous tumor vs., 186 - angiomatoid fibrous histiocytoma vs., 644
- diagnostic checklist, 272 - differential diagnosis, 327
- differential diagnosis, 272 - extranodal Rosai-Dorfman disease vs., 312
- epithelioid, cellular neurothekeoma vs., 291 - interdigitating dendritic cell sarcoma vs., 329
- giant cell fibroblastoma vs., 261 - prognosis, 327
- granular cell tumor vs., 542 Follicular dendritic reticulum cell sarcoma. See Follicular
- nodular fasciitis vs., 116 dendritic cell sarcoma.
- pleomorphic fibroma vs., 157 Fracture callus, fibroosseous pseudotumor of digit vs., 131
- prognosis, 271

G
- solitary (juvenile) xanthogranuloma vs., 299
- xanthomas vs., 296
Fibrous papule, pleomorphic fibroma vs., 157
Fibrous pleurisy, malignant mesothelioma vs., 600
Fibrous scar, desmoid-type fibromatosis vs., 170 Gangliocytic paraganglioma, 770–771
Fibrous tumor - differential diagnosis, 771
- calcifying, 248–249 Ganglion cyst, 784–785
differential diagnosis, 249 - differential diagnosis, 785
prognosis, 249 - prognosis, 785
- solitary, 184–191 Ganglioneuroblastoma, neuroblastoma and, 832–841
acral fibromyxoma vs., 625 - differential diagnosis, 834–835
angiofibroma of soft tissue vs., 145 - favorable vs. unfavorable histology in neuroblastic
BCOR-CCNB3 fusion-positive sarcoma vs., 736 tumors, 835
biphenotypic sinonasal sarcoma vs., 851 - ganglioneuroma vs., 551
calcifying fibrous tumor vs., 249
xiv
 INDEX
- genetic testing, 834
- intermixed, 834
- International Neuroblastoma Pathology Committee
(INPC) classification, 834
- neuroblastoma staging system, 835
- nodular, 834
- poorly differentiated, 834
- prognosis, 833
- prognosis based on MYCN amplification and histology,
835
- undifferentiated, 834
Ganglioneuroma, 550–553
- differential diagnosis, 551
- ectomesenchymoma vs., 571
- maturing, neuroblastoma and ganglioneuroblastoma
vs., 835
- prognosis, 551
Gangliorhabdomyosarcoma. See Ectomesenchymoma.
Gardner fibroma, 256–257
- diagnostic checklist, 257
- differential diagnosis, 257
- elastofibromas vs., 143
- nuchal-type fibroma vs., 165
- prognosis, 257
Gastrointestinal autonomic nerve tumor. See
Gastrointestinal stromal tumor.
Gastrointestinal mesenchymal tumors, by location, 27
Gastrointestinal neuroectodermal tumor, malignant,
776–779
- differential diagnosis, 777–778
- gastrointestinal stromal tumor vs., 747
- immunohistochemistry, 778
- molecular genetics, 777
Gastrointestinal schwannoma, 760–761
- differential diagnosis, 761
- gastrointestinal smooth muscle neoplasms vs., 764
- gastrointestinal stromal tumor vs., 747
- melanotic schwannoma vs., 557
- prognosis, 761
Gastrointestinal smooth muscle neoplasms, 762–765
- differential diagnosis, 764
- gastrointestinal stromal tumor vs., 747
- prognosis, 763
Gastrointestinal stromal sarcoma. See Gastrointestinal
stromal tumor.
Gastrointestinal stromal tumor
- malignant gastrointestinal neuroectodermal tumor vs.,
777
Gastrointestinal stromal tumor (GIST), 744–759
- benign neural gastrointestinal polyps vs., 741
- calcifying fibrous tumor vs., 249
- deep leiomyoma vs., 339
- desmoid-type fibromatosis vs., 170
- differential diagnosis, 747
- epithelioid, extraskeletal myxoid chondrosarcoma vs.,
713
- gastrointestinal schwannoma vs., 761
- gastrointestinal smooth muscle neoplasms vs., 764
- histiocytic sarcoma vs., 325
- idiopathic tumefactive fibroinflammatory lesions vs.,
790
- inflammatory fibroid polyp vs., 767
- inflammatory myofibroblastic tumor vs., 198
- leiomyosarcoma vs., 346
- low-grade endometrial stromal sarcoma vs., 857
- malignant gastrointestinal neuroectodermal tumor vs.,
777
- molecular prognostication, 748
- paraganglioma vs., 816
- plexiform fibromyxoma vs., 773
- prognosis, 745–746
- risk stratification, 748
- solitary fibrous tumor vs., 186
- spindled, gangliocytic paraganglioma vs., 771
GCFB. See Giant cell fibroblastoma.
Generalized lymphangioma. See Lymphangioma.
Genital rhabdomyoma, 376–377
- botryoid-type embryonal, fibroepithelial stromal polyp
vs., 575
- differential diagnosis, 377
- embryonal rhabdomyosarcoma vs., 382
- fetal rhabdomyoma vs., 375
- prognosis, 377
Genital stromal tumors
- angiomyofibroblastoma, 576–579
differential diagnosis, 577
prognosis, 577
- cellular angiofibroma, 580–583
differential diagnosis, 581
prognosis, 581
- deep (aggressive) angiomyxoma, 584–587
differential diagnosis, 585
genetic testing, 585
prognosis, 585
- fibroepithelial stromal polyp, 574–575
differential diagnosis, 575
prognosis, 575
GH. See Glomeruloid hemangioma.
Giant cell angiofibroma. See Solitary fibrous tumor.
Giant cell fibroblastoma (GCFB), 260–263
- angiosarcoma vs., 472
- differential diagnosis, 261
- fibrous hamartoma of infancy vs., 241
- prognosis, 261
- spindle cell/pleomorphic lipoma vs., 62
Giant cell reticulohistiocytoma. See Reticulohistiocytoma.
Giant cell tumor
- diffuse-type tenosynovial
differential diagnosis, 286
localized-type tenosynovial giant cell tumor vs., 280
myxoinflammatory fibroblastic sarcoma vs., 204
prognosis, 285
synovial lipomatosis vs., 55
- diffuse-type tenosynovial, 284–289
- localized-type tenosynovial, 278–283
deep benign fibrous histiocytoma vs., 277
differential diagnosis, 280
diffuse-type tenosynovial giant cell tumor vs., 286
fibroma of tendon sheath vs., 136
prognosis, 279
xv
 INDEX
xanthomas vs., 296 for retroperitoneum, 7
- tenosynovial for trunk and extremities, 7
fibroosseous pseudotumor vs., 131 Granular cell change, reactive, granular cell tumor vs., 542
giant cell tumor of soft tissue vs., 321 Granular cell dermatofibroma, granular cell tumor vs., 542
malignant, diffuse-type tenosynovial giant cell tumor Granular cell epulis, congenital, granular cell tumor vs.,
vs., 286 542
soft tissue chondroma vs., 488 Granular cell fibroblastoma. See Congenital granular cell
Giant cell tumor of bone epulis.
- extraskeletal recurrence of, giant cell tumor of soft Granular cell histiocytosis, crystal-storing histiocytosis vs.,
tissue vs., 321 315
- localized-type tenosynovial giant cell tumor vs., 280 Granular cell myoblastoma. See Granular cell tumor.
Giant cell tumor of soft tissue, 320–323 Granular cell schwannoma. See Granular cell tumor.
- aneurysmal bone cyst of soft tissue vs., 631 Granular cell tumor, 540–545
- differential diagnosis, 321 - adult rhabdomyoma vs., 373
- diffuse-type tenosynovial giant cell tumor vs., 286 - alveolar soft part sarcoma vs., 685
- extraskeletal osteosarcoma vs., 498 - congenital granular cell epulis vs., 799
- fibroosseous pseudotumor vs., 131 - crystal-storing histiocytosis vs., 315
- localized-type tenosynovial giant cell tumor vs., 280 - differential diagnosis, 542
- plexiform fibrohistiocytic tumor vs., 317 - gastrointestinal smooth muscle neoplasms vs., 764
- prognosis, 321 - hibernoma vs., 75
GIST. See Gastrointestinal stromal tumor. - nonneural, granular cell tumor vs., 542
Glial heterotopia, 812–813 - PEComa vs., 694
- differential diagnosis, 813 - prognosis, 541
- prognosis, 813 Granulocytic sarcoma. See Myeloid sarcoma.
Glomangiomatosis, angiomatosis vs., 445 Granuloma
Glomangiopericytoma, sinonasal, 804–809 - infectious
- diagnostic checklist, 806 deep granuloma annulare vs., 305
- differential diagnosis, 806 rheumatoid nodule vs., 307
- genetics, 805 - palisading subcutaneous. See Deep granuloma annulare.
- nasopharyngeal angiofibroma vs., 802 - pyogenic. See also Lobular capillary hemangioma.
- prognosis, 805 angiofibroma of soft tissue vs., 145
Glomeruloid angioma. See Glomeruloid hemangioma. antrochoanal, nasopharyngeal angiofibroma vs., 802
Glomeruloid hemangioma, 442–443 bacillary angiomatosis vs., 411
- acquired tufted angioma vs., 437 congenital granular cell epulis vs., 799
- diagnostic checklist, 443 glomeruloid hemangioma vs., 443
- differential diagnosis, 443 infantile hemangioma vs., 418
- prognosis, 443 nasopharyngeal angiofibroma vs., 802
- sinusoidal hemangioma vs., 441 sinonasal glomangiopericytoma vs., 806
Glomus jugulare. See Paraganglioma. Granuloma annulare, deep, 304–305
Glomus tumors (and variants), 352–357 - differential diagnosis, 305
- differential diagnosis, 354 - prognosis, 305
- myopericytoma vs., 359 Granulomatous inflammation, Langerhans cell
- ossifying fibromyxoid tumor vs., 652 histiocytosis vs., 309
- prognosis, 353 Granulomatous lesions, angiomatoid fibrous histiocytoma
- sinonasal glomangiopericytoma vs., 806 vs., 644
Glomus tympanicum. See Paraganglioma. Granulomatous processes, epithelioid sarcoma vs., 680
Gout, tophaceous Gross examination, 4–5
- amyloidoma vs., 783 - clinical findings, 4
- tumoral calcinosis vs., 787 - procedure, 4
Grading and staging, 6–11

H
- additional descriptors (pTNM system), 9
- anatomic stage/prognostic groups
retroperitoneum, 9
trunk and extremities, 7
- grading system of French FNCLCC system, 6 Hamartoma
- histologic features evaluated in grading (FNCLCC), 6 - fibrolipomatous
- soft tissue sarcoma staging (pTNM System), for head of nerve. See Lipomatosis.
and neck, 8 neuromuscular choristoma vs., 555
- soft tissue sarcoma staging (TNM System) - fibrous hamartoma of infancy, 240–243
for abdomen and thoracic organs, 8 differential diagnosis, 241
for orbit, 7
xvi
 INDEX
lipofibromatosis vs., 259 papillary intralymphatic angioendothelioma vs., 457
prognosis, 241 prognosis, 459
- meningothelial, glial heterotopia vs., 813 Hemangioma
- mucosal Schwann cell, gastrointestinal smooth muscle - acquired tufted, glomeruloid hemangioma vs., 443
neoplasms vs., 764 - angioleiomyoma vs., 367
- smooth muscle, 332–333 - angiosarcoma vs., 472
congenital, superficial leiomyoma vs., 335 - arteriovenous, sinusoidal hemangioma vs., 441
differential diagnosis, 333 - cavernous, sinusoidal hemangioma vs., 441
prognosis, 333 - congenital, 412–415
superficial leiomyoma vs., 335 differential diagnosis, 414
Hamartomatous thymoma, ectopic, 632–633 genetics, 413
- differential diagnosis, 633 infantile hemangioma vs., 418
- prognosis, 633 prognosis, 413
Hand-Schüller-Christian disease. See Langerhans cell - diffuse. See Angiomatosis.
histiocytosis. - epithelioid, 422–425
Hemangioblastoma, peripheral, 822–823 differential diagnosis, 423
- differential diagnosis, 823 epithelioid hemangioendothelioma vs., 468
- genetics, 823 molecular genetics, 423
- prognosis, 823 prognosis, 423
Hemangioendothelioma - glomeruloid, 442–443
- composite, 460–461 acquired tufted angioma vs., 437
differential diagnosis, 461 diagnostic checklist, 443
epithelioid hemangioendothelioma vs., 468 differential diagnosis, 443
papillary intralymphatic angioendothelioma vs., 457 prognosis, 443
prognosis, 461 sinusoidal hemangioma vs., 441
retiform hemangioendothelioma vs., 459 - hobnail, 434–435
- epithelioid, 466–469 atypical vascular lesion vs., 453
angiosarcoma vs., 472 diagnostic checklist, 435
composite hemangioendothelioma vs., 461 differential diagnosis, 435
differential diagnosis, 468 glomeruloid hemangioma vs., 443
epithelioid hemangioma vs., 423 Kaposi sarcoma vs., 478
intimal sarcoma vs., 721 microvenular hemangioma vs., 439
malignant mesothelioma vs., 600 prognosis, 435
molecular genetics, 467 - infantile, 416–419
prognosis, 467 acquired tufted angioma vs., 437
pseudomyogenic hemangioendothelioma, 463 angiomatosis vs., 445
spindle cell hemangioma vs., 427 congenital hemangioma vs., 414
- epithelioid sarcoma-like. See Pseudomyogenic differential diagnosis, 418
hemangioendothelioma. genetics, 417
- hobnail. See Retiform hemangioendothelioma. kaposiform hemangioendothelioma vs., 455
- Kaposiform, 454–455 prognosis, 417
acquired tufted angioma vs., 437 - intramuscular
congenital hemangioma vs., 414 angiolipoma vs., 57
diagnostic checklist, 455 angiomatosis vs., 445
differential diagnosis, 455 differential diagnosis, 431
infantile hemangioma vs., 418 lipoma vs., 48
Kaposi sarcoma vs., 478 prognosis, 431
prognosis, 455 - lobular capillary, 420–421
spindle cell hemangioma vs., 427 acquired tufted angioma vs., 437
- pseudomyogenic, 462–465 angiofibroma of soft tissue vs., 145
differential diagnosis, 463 congenital granular cell epulis vs., 799
epithelioid hemangioendothelioma vs., 468 differential diagnosis, 421
epithelioid sarcoma vs., 680 glomeruloid hemangioma vs., 443
molecular genetics, 463 infantile hemangioma vs., 418
prognosis, 463 nasopharyngeal angiofibroma vs., 802
- retiform, 458–459 prognosis, 421
angiosarcoma vs., 472 sinonasal glomangiopericytoma vs., 806
composite hemangioendothelioma vs., 461 - lymphangioma vs., 448
diagnostic checklist, 459 - microvenular, 438–439
differential diagnosis, 459 diagnostic checklist, 439
hobnail hemangioma vs., 435 differential diagnosis, 439
xvii
 INDEX
hobnail hemangioma vs., 435 - molecular genetics, 75
Kaposi sarcoma vs., 478 - prognosis, 75
prognosis, 439 Hip stone disease. See Tumoral calcinosis.
- papillary endothelial hyperplasia vs., 409 Histiocytic proliferations, extranodal Rosai-Dorfman
- sinusoidal, 440–441 disease vs., 312
diagnostic checklist, 441 Histiocytic proliferations, miscellaneous, extranodal Rosai-
differential diagnosis, 441 Dorfman disease vs., 312
prognosis, 441 Histiocytic sarcoma, 324–325
- spindle cell, 426–429 - differential diagnosis, 325
angiolipoma vs., 57 - extranodal Rosai-Dorfman disease vs., 312
angiomatoid fibrous histiocytoma vs., 644 - interdigitating dendritic cell sarcoma vs., 329
composite hemangioendothelioma vs., 461 - Langerhans cell histiocytosis vs., 309
diagnostic checklist, 427 - prognosis, 325
differential diagnosis, 427 Histiocytoma
Kaposi sarcoma vs., 478 - deep benign fibrous, angiofibroma of soft tissue vs.,
kaposiform hemangioendothelioma vs., 455 145
prognosis, 427 - fibrous. See Fibrous histiocytoma.
- targetoid hemosiderotic - myxoid malignant fibrous. See Myxofibrosarcoma.
glomeruloid hemangioma vs., 443 Histiocytosis
microvenular hemangioma vs., 439 - crystal-storing, 314–315
Hemangiopericytoma. See Solitary fibrous tumor. adult rhabdomyoma vs., 373
Hemangiopericytoma-like tumor of sinonasal cavity. See differential diagnosis, 315
Sinonasal glomangiopericytoma. prognosis, 315
Hemangiosarcoma. See Angiosarcoma. - granular cell, crystal-storing histiocytosis vs., 315
Hemarthrosis, diffuse-type tenosynovial giant cell tumor - Langerhans cell, 308–309
vs., 286 differential diagnosis, 309
Hematoma, papillary endothelial hyperplasia vs., 409 extranodal Rosai-Dorfman disease vs., 312
Hematopoietic tumors in soft tissue prognosis, 309
- lymphoma of soft tissue, 610–611 reticulohistiocytoma vs., 302
differential diagnosis, 611 solitary (juvenile) xanthogranuloma vs., 299
prognosis, 611 Histiocytosis X. See Langerhans cell histiocytosis.
- myeloid sarcoma, 608–609 HLRCC. See Hereditary leiomyomatosis and renal cell
differential diagnosis, 609 cancer syndrome.
molecular genetics, 609 Hobnail hemangioendothelioma. See Retiform
prognosis, 609 hemangioendothelioma.
- solitary extramedullary plasmacytoma, 606–607 Hobnail hemangioma, 434–435
differential diagnosis, 607 - atypical vascular lesion vs., 453
prognosis, 607 - diagnostic checklist, 435
Hemosiderotic fibrohistiocytic lipomatous lesion. See - differential diagnosis, 435
Hemosiderotic fibrolipomatous tumor. - glomeruloid hemangioma vs., 443
Hemosiderotic fibrolipomatous tumor (HFLT), 634–635 - Kaposi sarcoma vs., 478
- differential diagnosis, 635 - microvenular hemangioma vs., 439
- molecular genetics, 635 - prognosis, 435
- myxoinflammatory fibroblastic sarcoma vs., 204 Hodgkin disease, extranodal, myxoinflammatory
- pleomorphic hyalinizing angiectatic tumor vs., 627 fibroblastic sarcoma vs., 204
- prognosis, 635 Hoffa disease, synovial lipomatosis vs., 55
Hemosiderotic hemangioma, targetoid Hyaline fibromatosis syndrome, 252–253
- glomeruloid hemangioma vs., 443 - differential diagnosis, 253
- microvenular hemangioma vs., 439 - prognosis, 253
Hereditary leiomyomatosis and renal cell cancer syndrome Hyalinizing spindle cell tumor, with giant rosettes. See
(HLRCC), 335 Low-grade fibromyxoid sarcoma.
Heterotopic glial tissue. See Glial heterotopia. Hybrid nerve sheath tumor, 536–539
HFLT. See Hemosiderotic fibrolipomatous tumor. - differential diagnosis, 537
HH. See Hobnail hemangioma. - gastrointestinal schwannoma vs., 761
Hibernoma, 74–77 - low-grade fibromyxoid sarcoma vs., 224
- adult rhabdomyoma vs., 373 - perineurioma vs., 532
- atypical lipomatous tumor/well-differentiated - prognosis, 537
liposarcoma vs., 90 Hyperlipoproteinemia (Fredrickson) classification, 296
- differential diagnosis, 75 Hyperplasia, papillary endothelial, 408–409
- granular cell tumor vs., 542 - angiosarcoma vs., 472
- lipoma vs., 48
xviii
 INDEX
- diagnostic checklist, 409 - plexiform fibromyxoma vs., 773
- differential diagnosis, 409 Inflammatory fibrosarcoma. See Inflammatory
- prognosis, 409 myofibroblastic tumor.
Hypertrophic scar Inflammatory myofibroblastic sarcoma. See Inflammatory
- dermatomyofibroma vs., 159 myofibroblastic tumor.
- keloid vs., 163 Inflammatory myofibroblastic tumor, 196–201
- calcifying fibrous tumor vs., 249

I
- cardiac fibroma vs., 797
- desmoid-type fibromatosis vs., 170
- differential diagnosis, 198
- focal myositis vs., 371
IDCS. See Interdigitating dendritic cell sarcoma. - follicular dendritic cell sarcoma vs., 327
Idiopathic retroperitoneal fibrosis, 789 - idiopathic tumefactive fibroinflammatory lesions vs.,
- atypical lipomatous tumor/well-differentiated 790
liposarcoma vs., 90 - inflammatory fibroid polyp vs., 767
- desmoid-type fibromatosis vs., 170 - leiomyosarcoma vs., 346
Idiopathic tumefactive fibroinflammatory lesions, - low-grade myofibroblastic sarcoma vs., 193
788–791 - molecular genetics, 197–198
- differential diagnosis, 790 - myxoinflammatory fibroblastic sarcoma vs., 204
- prognosis, 789 - nodular fasciitis vs., 116
Idiopathic tumoral fibroinflammatory disorders. See - plexiform fibromyxoma vs., 773
Idiopathic tumefactive fibroinflammatory lesions. - prognosis, 197
IFS. See Infantile fibrosarcoma. - spindle cell rhabdomyosarcoma vs., 394
IgG4-related sclerosing disease, 789 - superficial CD34(+) fibroblastic tumor vs., 211
Inclusion body fibromatosis, 250–251 Inflammatory myxohyaline tumor of distal extremities
- differential diagnosis, 251 with virocyte or Reed-Sternberg-like cells. See
- fibroma of tendon sheath vs., 136 Myxoinflammatory fibroblastic sarcoma.
- prognosis, 251 Inflammatory pseudotumor. See Inflammatory
Infantile digital fibroma. See Inclusion body fibromatosis. myofibroblastic tumor.
Infantile digital fibromatosis. See Inclusion body Interdigitating dendritic cell sarcoma (IDCS), 328–329
fibromatosis. - differential diagnosis, 329
Infantile fibrosarcoma (IFS), 264–267 - follicular dendritic cell sarcoma vs., 327
- differential diagnosis, 265 - prognosis, 329
- embryonal rhabdomyosarcoma vs., 382 Interdigitating dendritic reticulum cell sarcoma. See
- molecular genetics, 265 Interdigitating dendritic cell sarcoma.
- myofibroma and myofibromatosis vs., 363 Internal evaluation, gross examination, 4
- prognosis, 265 Intimal sarcoma, 720–721
- spindle cell rhabdomyosarcoma vs., 394 - differential diagnosis, 721
Infantile hemangioma, 416–419 - genetic testing, 721
- acquired tufted angioma vs., 437 - prognosis, 721
- angiomatosis vs., 445 Intraabdominal DSRCT. See Desmoplastic small round cell
- congenital hemangioma vs., 414 tumor.
- differential diagnosis, 418 Intraarticular fibroma. See Fibroma, tendon sheath.
- genetics, 417 Intralymphatic angioendothelioma, papillary, retiform
- kaposiform hemangioendothelioma vs., 455 hemangioendothelioma vs., 459
- prognosis, 417 Intramuscular angioma. See Intramuscular hemangioma.
Infantile/juvenile fibromatosis, nondesmoid type. See Intramuscular hemangioma (IMH), 430–433
Fibromatosis. - angiolipoma vs., 57
Infectious granulomas - angiomatosis vs., 445
- deep granuloma annulare vs., 305 - differential diagnosis, 431
- rheumatoid nodule vs., 307 - lipoma vs., 48
Infiltrating angiolipoma. See Angiomatosis. - prognosis, 431
Infiltrating/intramuscular angiolipoma. See Intramuscular Intramuscular myxoma, 614–617
hemangioma. - differential diagnosis, 615
Inflammatory fibroid polyp, 766–769 - genetic testing, 615
- benign neural gastrointestinal polyps vs., 741 - juxtaarticular myxoma vs., 619
- differential diagnosis, 767 - low-grade fibromyxoid sarcoma vs., 224
- gastrointestinal smooth muscle neoplasms vs., 764 - myxofibrosarcoma vs., 218
- gastrointestinal stromal tumor vs., 747 - myxoid liposarcoma vs., 102
- inflammatory myofibroblastic tumor vs., 198 - prognosis, 615

xix
 INDEX
Intranodal palisade myofibroblastoma, 152–155 - nodular fasciitis vs., 116
- differential diagnosis, 153 - papillary intralymphatic angioendothelioma vs., 457
- molecular genetics, 153 - prognosis, 477
- prognosis, 153 - retiform hemangioendothelioma vs., 459
Intranodal palisaded myofibroblastoma, angiomatoid - spindle cell hemangioma vs., 427
fibrous histiocytoma vs., 644 Kaposiform hemangioendothelioma, 454–455
Intravascular angiomatosis. See Papillary endothelial - acquired tufted angioma vs., 437
hyperplasia. - congenital hemangioma vs., 414
Intravascular bronchioloalveolar tumor. See Epithelioid - diagnostic checklist, 455
hemangioendothelioma. - differential diagnosis, 455
Intravascular papillary endothelial hyperplasia, spindle cell - infantile hemangioma vs., 418
hemangioma vs., 427 - Kaposi sarcoma vs., 478
Ischemic fasciitis, 124–125 - prognosis, 455
- differential diagnosis, 125 - spindle cell hemangioma vs., 427
- prognosis, 125 Keloid, 162–163
- diagnostic checklist, 163

J
- differential diagnosis, 163
- prognosis, 163
Kimura disease, epithelioid hemangioma vs., 423

Juvenile aponeurotic fibroma. See Calcifying aponeurotic

fibroma.
Juvenile hemangioma. See Infantile hemangioma.
Juvenile nasopharyngeal angiofibroma. See
L
Langerhans cell histiocytosis (LCH), 308–309
Nasopharyngeal angiofibroma. - differential diagnosis, 309
Juvenile xanthogranuloma, 298–299 - extranodal Rosai-Dorfman disease vs., 312
- differential diagnosis, 299 - prognosis, 309
- extranodal Rosai-Dorfman disease vs., 312 - reticulohistiocytoma vs., 302
- prognosis, 299 - solitary (juvenile) xanthogranuloma vs., 299
- reticulohistiocytoma vs., 302 Langerhans cell sarcoma
- xanthomas vs., 296 - interdigitating dendritic cell sarcoma vs., 329
Juxtaarticular chondroma - Langerhans cell histiocytosis vs., 309
- synovial chondromatosis vs., 493 LCH. See Langerhans cell histiocytosis.
Juxtaarticular myxoma, 618–619 Ledderhose disease. See Palmar/plantar fibromatosis.
- differential diagnosis, 619 Leiomyoblastoma. See Gastrointestinal stromal tumor.
- genetic testing, 619 Leiomyoma
- myxofibrosarcoma vs., 218 - cutaneous
- perineurioma vs., 532 smooth muscle hamartoma vs., 333
- prognosis, 619 - cutis. See Superficial leiomyoma.
- deep, 338–341

K
Kaposi sarcoma, 476–483
- acquired tufted angioma vs., 437
- angiolipoma vs., 57
- angiomatoid fibrous histiocytoma vs., 644
- angiosarcoma vs., 472
- bacillary angiomatosis vs., 411
- composite hemangioendothelioma vs., 461
- dermatofibroma vs., 272
- differential diagnosis, 478
- glomeruloid hemangioma vs., 443
- hobnail hemangioma vs., 435
- intranodal palisade myofibroblastoma vs., 153
- kaposiform hemangioendothelioma vs., 455
- lymphangioma-like, lymphangioma vs., 448
- microvenular hemangioma vs., 439
xx
differential diagnosis, 339
prognosis, 339
- deep (aggressive) angiomyxoma vs., 585
- dermatomyofibroma vs., 159
- desmoid-type fibromatosis vs., 170
- Epstein-Barr virus-associated smooth muscle tumor vs.,
343
- with fatty metaplasia/degeneration, myolipoma vs., 71
- ganglioneuroma vs., 551
- gastrointestinal schwannoma vs., 761
- gastrointestinal stromal tumor vs., 747
- granular cell tumor vs., 542
- leiomyosarcoma vs., 346
- myofibroma and myofibromatosis vs., 363
- palmar/plantar fibromatosis vs., 167
- PEComa vs., 694
- pilar
inclusion body fibromatosis vs., 251
smooth muscle hamartoma vs., 333
- plexiform fibromyxoma vs., 773
 INDEX
- schwannoma vs., 511 - atypical lipomatous tumor/well-differentiated
- submucosal, benign neural gastrointestinal polyps vs., liposarcoma vs., 90
741 - chondroid, 66–69
- superficial, 334–337 differential diagnosis, 67
differential diagnosis, 335 epithelioid hemangioendothelioma vs., 468
prognosis, 335 genetic testing, 67
Leiomyosarcoma, 344–349 lipoma vs., 48
- adult-type fibrosarcoma vs., 215 prognosis, 67
- atypical fibroxanthoma vs., 638 - diagnostic checklist, 48
- cutaneous, smooth muscle hamartoma vs., 333 - differential diagnosis, 48
- dedifferentiated liposarcoma vs., 96 - of embryonic fat. See Hibernoma.
- deep leiomyoma vs., 339 - fetal. See Hibernoma.
- differential diagnosis, 346 - genetic testing, 48
- Epstein-Barr virus-associated smooth muscle tumor vs., - lipoblastoma vs., 81
343 - of nerve, lipomatosis of nerve vs., 53
- gastrointestinal smooth muscle neoplasms vs., 764 - pleomorphic, giant cell fibroblastoma vs., 261
- gastrointestinal stromal tumor vs., 747 - prognosis, 47
- inflammatory myofibroblastic tumor vs., 198 - spindle cell, 60–65
- intimal sarcoma vs., 721 cellular angiofibroma vs., 581
- Kaposi sarcoma vs., 478 differential diagnosis, 62
- low-grade myofibroblastic sarcoma vs., 193 hemosiderotic fibrolipomatous tumor vs., 635
- malignant peripheral nerve sheath tumor vs., 560 lipoma vs., 48
- myxoid, primary pulmonary myxoid sarcoma vs., 848 mammary-type myofibroblastoma vs., 149
- nodular fasciitis vs., 116 molecular genetics, 61
- PEComa vs., 694 myolipoma vs., 71
- prognosis, 345 prognosis, 61
- spindle cell rhabdomyosarcoma vs., 394 solitary fibrous tumor vs., 186
- superficial, superficial leiomyoma vs., 335 Lipoma arborescens. See Synovial lipomatosis.
- synovial sarcoma vs., 668 Lipomatosis
- undifferentiated pleomorphic sarcoma vs., 725 - of nerve, 52–53
Letterer-Siwe disease. See Langerhans cell histiocytosis. differential diagnosis, 53
Leukemia, alveolar rhabdomyosarcoma vs., 388 lipofibromatosis vs., 259
LGFMS. See Low-grade fibromyxoid sarcoma. lipoma vs., 48
LGMS. See Low-grade myofibroblastic sarcoma. neuromuscular choristoma vs., 555
Lipid calcinosis. See Tumoral calcinosis. prognosis, 53
Lipidized-type dermatofibroma, xanthomas vs., 296 - synovial, 54–55
Lipoblastoma, 80–83 differential diagnosis, 55
- differential diagnosis, 81 prognosis, 55
- fibrous hamartoma of infancy vs., 241 Lipomatous tumor/well-differentiated liposarcoma
- hibernoma vs., 75 - atypical, 88–93
- lipofibromatosis vs., 259 atypical spindle cell lipomatous tumor vs., 85
- molecular genetics, 81 chondroid lipoma vs., 67
- myxoid liposarcoma vs., 102 differential diagnosis, 90
- prognosis, 81 elastofibromas vs., 143
Lipoblastoma-like tumor of vulva hibernoma vs., 75
- lipoblastoma vs., 81 massive localized lymphedema vs., 451
- myxoid liposarcoma vs., 102 molecular genetics, 90
Lipofibromatosis, 258–259 myxoid liposarcoma vs., 102
- calcifying aponeurotic fibroma vs., 245 pleomorphic liposarcoma vs., 108
- differential diagnosis, 259 prognosis, 89
- genetics, 259 spindle cell/pleomorphic lipoma vs., 62
- infantile fibrosarcoma vs., 265 synovial lipomatosis vs., 55
- prognosis, 259 - lipoma vs., 48
Lipofibromatosis-like neural tumor - spindle cell, spindle cell/pleomorphic lipoma vs., 62
- fibrous hamartoma of infancy vs., 241 Liposarcoma
- infantile fibrosarcoma vs., 265 - dedifferentiated, 94–99
- lipofibromatosis vs., 259 desmoid-type fibromatosis vs., 170
Lipoid proteinosis, hyaline fibromatosis syndrome vs., 253 differential diagnosis, 96
Lipoleiomyoma, extrauterine. See Myolipoma. extraskeletal osteosarcoma vs., 498
Lipoma, 46–51 histiocytic sarcoma vs., 325
- angiolipoma vs., 57 inflammatory myofibroblastic tumor vs., 198
xxi
 INDEX
low-grade morphology, myolipoma vs., 71
malignant peripheral nerve sheath tumor vs., 560
molecular genetics, 96
myxofibrosarcoma vs., 218
prognosis, 95
solitary fibrous tumor vs., 186
undifferentiated pleomorphic sarcoma vs., 725
- myxoid, 100–105
angiofibroma of soft tissue vs., 145
atypical lipomatous tumor/well-differentiated
liposarcoma vs., 90
chondroid lipoma vs., 67
dedifferentiated liposarcoma vs., 96
differential diagnosis, 102
hibernoma vs., 75
intramuscular myxoma vs., 615
lipoblastoma vs., 81
lipoma vs., 48
low-grade fibromyxoid sarcoma vs., 224
massive localized lymphedema vs., 451
molecular genetics, 102
myxofibrosarcoma vs., 218
pleomorphic liposarcoma vs., 108
primary pulmonary myxoid sarcoma vs., 848
prognosis, 101
spindle cell/pleomorphic lipoma vs., 62
superficial angiomyxoma vs., 621
- pleomorphic, 106–111
dedifferentiated liposarcoma vs., 96
differential diagnosis, 107–108
molecular genetics, 107
myxofibrosarcoma vs., 218
prognosis, 107
undifferentiated pleomorphic sarcoma vs., 725
- well-differentiated, 88–93
dedifferentiated liposarcoma vs., 96
differential diagnosis, 90
elastofibromas vs., 143
idiopathic tumefactive fibroinflammatory lesions vs.,
790
inflammatory myofibroblastic tumor vs., 198
ischemic fasciitis vs., 125
massive localized lymphedema vs., 451
molecular genetics, 90
myelolipoma vs., 79
peripheral hemangioblastoma vs., 823
prognosis, 89
synovial lipomatosis vs., 55
Lobular capillary hemangioma, 420–421
- acquired tufted angioma vs., 437
- angiofibroma of soft tissue vs., 145
- congenital granular cell epulis vs., 799
- differential diagnosis, 421
- glomeruloid hemangioma vs., 443
- infantile hemangioma vs., 418
- nasopharyngeal angiofibroma vs., 802
- prognosis, 421
- sinonasal glomangiopericytoma vs., 806
Localized fibrous mesothelioma. See Solitary fibrous
tumor.
xxii
Localized hypertrophic neuropathy of limbs. See
Perineurioma.
Localized lymphedema, massive, 450–451
- atypical lipomatous tumor/well-differentiated
liposarcoma vs., 90
- differential diagnosis, 451
- prognosis, 451
Localized-type tenosynovial giant cell tumor, 278–283
- deep benign fibrous histiocytoma vs., 277
- differential diagnosis, 280
- diffuse-type tenosynovial giant cell tumor vs., 286
- fibroma of tendon sheath vs., 136
- prognosis, 279
- xanthomas vs., 296
Low-grade endometrial stromal sarcoma, 856–857
- differential diagnosis, 857
- prognosis, 857
Low-grade fibromyxoid sarcoma (LGFMS), 222–231
- angiofibroma of soft tissue vs., 145
- desmoid-type fibromatosis vs., 170
- desmoplastic fibroblastoma vs., 141
- differential diagnosis, 224
- intramuscular myxoma vs., 615
- juxtaarticular myxoma vs., 619
- myxofibrosarcoma vs., 218
- myxoid liposarcoma vs., 102
- ossifying fibromyxoid tumor vs., 652
- perineurioma vs., 532
- prognosis, 223
- sclerosing epithelioid fibrosarcoma vs., 233
- superficial angiomyxoma vs., 621
Low-grade myofibroblastic sarcoma, 192–195
- adult-type fibrosarcoma vs., 215
- desmoid-type fibromatosis vs., 170
- differential diagnosis, 193
- nodular fasciitis vs., 116
- plexiform fibrohistiocytic tumor vs., 317
- prognosis, 193
- spindle cell rhabdomyosarcoma vs., 394
Low-grade sinonasal sarcoma with neural and myogenic
features. See Biphenotypic sinonasal sarcoma.
Low-grade stromal sarcoma. See Low-grade Endometrial
stromal sarcoma.
Lymph node metastasis, intranodal palisade
myofibroblastoma vs., 153
Lymphangiectasia, secondary, lymphangioma vs., 448
Lymphangioendothelioma, benign
- atypical vascular lesion vs., 453
- Kaposi sarcoma vs., 478
Lymphangioma, 446–449
- adenomatoid tumor vs., 591
- cystic, multicystic peritoneal mesothelioma vs., 593
- diagnostic checklist, 448
- differential diagnosis, 448
- genetics, 447
- prognosis, 447
- progressive
atypical vascular lesion vs., 453
hobnail hemangioma vs., 435
Kaposi sarcoma vs., 478
lymphangioma vs., 448
 INDEX
Lymphangioma circumscriptum. See also Lymphangioma.
- atypical vascular lesion vs., 453
Lymphangioma-like Kaposi sarcoma, lymphangioma vs.,
448
Lymphangiomatosis. See Lymphangioma.
Lymphatic malformation. See Lymphangioma.
Lymphatic pseudotumor. See Massive localized
lymphedema.
Lymphedema, massive localized, 450–451
- atypical lipomatous tumor/well-differentiated
liposarcoma vs., 90
- differential diagnosis, 451
- prognosis, 451
Lymphoma
- alveolar rhabdomyosarcoma vs., 388
- anaplastic large cell
inflammatory myofibroblastic tumor vs., 198
pleomorphic rhabdomyosarcoma vs., 401
- extraskeletal Ewing sarcoma vs., 708
- focal myositis vs., 371
- idiopathic tumefactive fibroinflammatory lesions vs.,
790
- malignant, desmoplastic small round cell tumor vs., 702
- myeloid sarcoma vs., 609
- neuroblastoma and ganglioneuroblastoma vs., 835
- non-Hodgkin, histiocytic sarcoma vs., 325
- sclerosing, sclerosing epithelioid fibrosarcoma vs., 234
- undifferentiated pleomorphic sarcoma vs., 725
Lymphoma of soft tissue, 610–611
- differential diagnosis, 611
- prognosis, 611
M
Malakoplakia, crystal-storing histiocytosis vs., 315
Malignant ectomesenchymoma. See Ectomesenchymoma.
Malignant epithelioid schwannoma. See Epithelioid
malignant peripheral nerve sheath tumor.
Malignant fibrous histiocytoma. See Undifferentiated
pleomorphic sarcoma.
Malignant gastrointestinal neuroectodermal tumor,
776–779
- differential diagnosis, 777–778
- gastrointestinal stromal tumor vs., 747
- immunohistochemistry, 778
- molecular genetics, 777
Malignant hemangioendothelioma. See Angiosarcoma.
Malignant lymphoma, desmoplastic small round cell tumor
vs., 702
Malignant melanoma. See Melanoma, malignant.
Malignant melanotic schwannian tumor (proposed). See
Melanotic schwannoma.
Malignant mesothelioma, 598–603
- adenomatoid tumor vs., 591
- differential diagnosis, 600
- molecular genetics, 600
- multicystic peritoneal mesothelioma vs., 593
- prognosis, 599
- well-differentiated papillary mesothelioma vs., 595
Malignant myoepithelioma, 657. See also Myoepithelioma,
of soft tissue.
- epithelioid malignant peripheral nerve sheath tumor
vs., 567
Malignant myxoid endobronchial tumor. See Primary
pulmonary myxoid sarcoma.
Malignant ossifying fibromyxoid tumor, 651
Malignant peripheral nerve sheath tumor (MPNST),
558–565
- adult-type fibrosarcoma vs., 215
- atypical fibroxanthoma vs., 638
- BCOR-CCNB3 fusion-positive sarcoma vs., 736
- clear cell sarcoma vs., 690
- dedifferentiated liposarcoma vs., 96
- differential diagnosis, 560
- epithelioid, 566–569
differential diagnosis, 567
extrarenal rhabdoid tumor vs., 718
myoepithelioma of soft tissue vs., 656
ossifying fibromyxoid tumor vs., 652
prognosis, 567
- extraskeletal mesenchymal chondrosarcoma vs., 502
- extraskeletal osteosarcoma vs., 498
- genetic predisposition, 559
- hybrid nerve sheath tumor vs., 537
- leiomyosarcoma vs., 346
- malignant gastrointestinal neuroectodermal tumor vs.,
778
- metastatic tumors to soft tissue sites vs., 829
- myxofibrosarcoma vs., 218
- neurofibroma vs., 524
- palmar/plantar fibromatosis vs., 167
- prognosis, 559
- with rhabdomyoblastic differentiation
biphenotypic sinonasal sarcoma vs., 851
embryonal rhabdomyosarcoma vs., 382
- schwannoma vs., 511
- spindle cell rhabdomyosarcoma vs., 393
- synovial sarcoma vs., 668
- undifferentiated pleomorphic sarcoma vs., 725
- undifferentiated round cell sarcoma with CIC-DUX4
translocation vs., 729
Malignant rhabdoid tumor. See Extrarenal rhabdoid tumor.
Malignant schwannoma. See Malignant peripheral nerve
sheath tumor.
Malignant synovioma. See Synovial sarcoma.
Malignant tenosynovial giant cell tumor, diffuse-type
tenosynovial giant cell tumor vs., 286
Mammary-type myofibroblastoma, 148–151
- atypical spindle cell lipomatous tumor vs., 85
- cellular angiofibroma vs., 581
- differential diagnosis, 149
- molecular genetics, 149
- prognosis, 149
- spindle cell/pleomorphic lipoma vs., 62
Massive localized lymphedema, 450–451
- atypical lipomatous tumor/well-differentiated
liposarcoma vs., 90
- differential diagnosis, 451
xxiii
 INDEX
- prognosis, 451 Meningioma
Masson tumor. See Papillary endothelial hyperplasia. - chondroid, extraskeletal myxoid chondrosarcoma vs.,
Mature adipose tissue, ectopic hamartomatous thymoma, 713
633 - ectopic, 810–811
Melanocytic nevus, dermal, glomus tumors vs., 354 differential diagnosis, 811
Melanoma perineurioma vs., 532
- angiosarcoma vs., 472 prognosis, 811
- desmoplastic, keloid vs., 163 Meningothelial choristoma. See Ectopic meningioma.
- desmoplastic, neurofibroma vs., 524 Meningothelial hamartoma, glial heterotopia vs., 813
- epithelioid rhabdomyosarcoma vs., 405 Merkel cell carcinoma, lymphoma of soft tissue vs., 611
- epithelioid sarcoma vs., 680 Mesenchymal chondrosarcoma
- gastrointestinal stromal tumor vs., 747 - extraskeletal, 500–503
- malignant differential diagnosis, 502
alveolar soft part sarcoma vs., 685 extraskeletal Ewing sarcoma vs., 708
epithelioid malignant peripheral nerve sheath tumor extraskeletal osteosarcoma vs., 498
vs., 567 molecular genetics, 501
granular cell tumor vs., 542 prognosis, 501
lymphoma of soft tissue vs., 611 - phosphaturic mesenchymal tumor vs., 665
malignant peripheral nerve sheath tumor vs., 560 Mesenchymal hamartoma, undifferentiated embryonal
melanotic neuroectodermal tumor of infancy vs., 825 sarcoma of liver vs., 845
metastatic, pleomorphic liposarcoma vs., 108 Mesenchymal tumors
myeloid sarcoma vs., 609 - gastrointestinal, by location, 27
schwannoma vs., 511 - involving lymph nodes, 27
solitary extramedullary plasmacytoma vs., 607 Mesenteric lipodystrophy. See Idiopathic tumefactive
- metastatic fibroinflammatory lesions.
clear cell sarcoma vs., 690 Mesenteric panniculitis. See Idiopathic tumefactive
extrarenal rhabdoid tumor vs., 718 fibroinflammatory lesions.
histiocytic sarcoma vs., 325 Mesenteritis, sclerosing, desmoid-type fibromatosis vs.,
interdigitating dendritic cell sarcoma vs., 329 170
intimal sarcoma vs., 721 Mesodermal stromal polyp. See Fibroepithelial stromal
malignant gastrointestinal neuroectodermal tumor polyp.
vs., 778 Mesothelial cells, tumors of
melanotic schwannoma vs., 557 - adenomatoid tumor, 590–591
myoepithelioma of soft tissue vs., 656 differential diagnosis, 591
paraganglioma vs., 816 genetic testing, 591
schwannoma vs., 511 prognosis, 591
- myxofibrosarcoma vs., 218 - malignant mesothelioma, 598–603
- osteogenic, extraskeletal osteosarcoma vs., 498 differential diagnosis, 600
- PEComa vs., 694 molecular genetics, 600
- pleomorphic, atypical fibroxanthoma vs., 637–638 prognosis, 599
- pleomorphic rhabdomyosarcoma vs., 401 - multicystic peritoneal mesothelioma, 592–593
- of soft parts (formerly). See Clear cell sarcoma. adenomatoid tumor vs., 591
- spindle cell differential diagnosis, 593
atypical fibroxanthoma vs., 637–638 prognosis, 593
desmoplastic, dermatofibrosarcoma protuberans vs., - well-differentiated papillary mesothelioma, 594–597
176 differential diagnosis, 595
spindle cell rhabdomyosarcoma vs., 394 prognosis, 595
- undifferentiated pleomorphic sarcoma vs., 725 Mesothelial hyperplasia, well-differentiated papillary
Melanotic ameloblastoma. See Melanotic mesothelioma vs., 595
neuroectodermal tumor of infancy. Mesothelial proliferation, reactive, malignant
Melanotic neuroectodermal tumor of infancy (MNTI), mesothelioma vs., 600
824–825 Mesothelioma
- differential diagnosis, 825 - localized fibrous. See Solitary fibrous tumor.
- prognosis, 825 - of low malignant potential. See Well-differentiated
Melanotic progonoma. See Melanotic neuroectodermal papillary mesothelioma.
tumor of infancy. - malignant, 598–603
Melanotic schwannoma, 556–557 adenomatoid tumor vs., 591
- differential diagnosis, 557 differential diagnosis, 600
- prognosis, 557 molecular genetics, 600
multicystic peritoneal mesothelioma vs., 593

xxiv
 INDEX
prognosis, 599 - malignant peripheral nerve sheath tumor vs., 560
well-differentiated papillary mesothelioma vs., 595 - palmar/plantar fibromatosis vs., 167
- multicystic peritoneal, 592–593 - solitary fibrous tumor vs., 186
adenomatoid tumor vs., 591 - spindle cell rhabdomyosarcoma vs., 393
differential diagnosis, 593 Monoplastic synovial sarcoma, calcifying aponeurotic
prognosis, 593 fibroma vs., 245
- myxoid, extraskeletal myxoid chondrosarcoma vs., 713 Mucoid cyst, digital
- well-differentiated papillary, 594–597 - dermal nerve sheath myxoma vs., 547
adenomatoid tumor vs., 591 - superficial angiomyxoma vs., 621
differential diagnosis, 595 Mucosal neuroma
prognosis, 595 - benign neural gastrointestinal polyps vs., 741
Metastatic adenocarcinoma, adenomatoid tumor vs., 591 - solitary circumscribed neuroma vs., 507
Metastatic carcinoma Mucosal perineurioma, gastrointestinal smooth muscle
- angiosarcoma vs., 472 neoplasms vs., 764
- epithelioid hemangioendothelioma vs., 468 Mucosal Schwann cell hamartoma, gastrointestinal
- histiocytic sarcoma vs., 325 smooth muscle neoplasms vs., 764
- intimal sarcoma vs., 721 Multicentric cutaneous reticulohistiocytosis,
- myoepithelioma of soft tissue vs., 656 reticulohistiocytoma vs., 301–302
- myxofibrosarcoma vs., 218 Multicystic peritoneal mesothelioma, 592–593
- paraganglioma vs., 816 - adenomatoid tumor vs., 591
- pleomorphic rhabdomyosarcoma vs., 401 - differential diagnosis, 593
- sclerosing epithelioid fibrosarcoma vs., 233 - prognosis, 593
- sclerosing rhabdomyosarcoma vs., 397 Multilocular peritoneal inclusion cyst. See Multicystic
- solitary extramedullary plasmacytoma vs., 607 peritoneal mesothelioma.
Metastatic melanoma Multiple myeloma, solitary extramedullary plasmacytoma
- clear cell sarcoma vs., 690 vs., 607
- extrarenal rhabdoid tumor vs., 718 Mural leiomyoma. See Gastrointestinal smooth muscle
- histiocytic sarcoma vs., 325 neoplasms.
- interdigitating dendritic cell sarcoma vs., 329 Musculoaponeurotic fibromatosis. See Desmoid-type
- intimal sarcoma vs., 721 fibromatosis.
- malignant gastrointestinal neuroectodermal tumor vs., MVH. See Microvenular hemangioma.
778 Mycobacterial pseudotumor, crystal-storing histiocytosis
- melanotic schwannoma vs., 557 vs., 315
- myoepithelioma of soft tissue vs., 656 Myeloid sarcoma, 608–609
- paraganglioma vs., 816 - differential diagnosis, 609
- schwannoma vs., 511 - lymphoma of soft tissue vs., 611
Metastatic neuroendocrine carcinoma, desmoplastic small - molecular genetics, 609
round cell tumor vs., 702 - myelolipoma vs., 79
Metastatic or primary cutaneous mucinous carcinoma, - prognosis, 609
extraaxial soft tissue chordoma vs., 843 Myelolipoma, 78–79
Metastatic renal cell carcinoma, alveolar soft part sarcoma - differential diagnosis, 79
vs., 685 - molecular genetics, 79
Metastatic sarcomatoid carcinoma, follicular dendritic cell - prognosis, 79
sarcoma vs., 327 Myoepithelial carcinoma, 657. See also Myoepithelioma, of
Metastatic tumors, to soft tissue sites, 828–831 soft tissue.
- differential diagnosis, 829 - epithelioid rhabdomyosarcoma vs., 405
- prognosis, 829 - epithelioid sarcoma vs., 680
Microcapillary angioma. See Microvenular hemangioma. - extraskeletal myxoid chondrosarcoma vs., 713
Microcystic/reticular schwannoma, 510 - metastatic tumors to soft tissue sites vs., 829
Microvenular hemangioma (MVH), 438–439 Myoepithelioma
- diagnostic checklist, 439 - extrarenal rhabdoid tumor vs., 718
- differential diagnosis, 439 - extraskeletal myxoid chondrosarcoma vs., 713
- hobnail hemangioma vs., 435 - malignant, 657
- Kaposi sarcoma vs., 478 epithelioid malignant peripheral nerve sheath tumor
- prognosis, 439 vs., 567
Milk alkali syndrome, tumoral calcinosis vs., 787 - perineurioma vs., 532
Mixed tumor, 657. See also Myoepithelioma, of soft tissue. - primary pulmonary myxoid sarcoma vs., 847
Molecular features, soft tissue tumors, 18–19 - sinonasal glomangiopericytoma vs., 806
Monomorphic spindle cell patterns, 28 - of soft tissue, 656–663
Monophasic synovial sarcoma, 667 chondroid lipoma vs., 67
- clear cell sarcoma vs., 690
xxv
 INDEX
differential diagnosis, 658
epithelioid hemangioendothelioma vs., 468
extraaxial soft tissue chordoma vs., 843
immunohistochemistry, 658
molecular genetics, 657
ossifying fibromyxoid tumor vs., 652
prognosis, 657
solitary extramedullary plasmacytoma vs., 607
Myofibroblastic sarcoma, low-grade, 192–195
- adult-type fibrosarcoma vs., 215
- desmoid-type fibromatosis vs., 170
- differential diagnosis, 193
- nodular fasciitis vs., 116
- plexiform fibrohistiocytic tumor vs., 317
- prognosis, 193
- spindle cell rhabdomyosarcoma vs., 394
Myofibroblastic tumor, inflammatory, 196–201
- calcifying fibrous tumor vs., 249
- cardiac fibroma vs., 797
- desmoid-type fibromatosis vs., 170
- differential diagnosis, 198
- focal myositis vs., 371
- follicular dendritic cell sarcoma vs., 327
- idiopathic tumefactive fibroinflammatory lesions vs.,
790
- inflammatory fibroid polyp vs., 767
- leiomyosarcoma vs., 346
- low-grade myofibroblastic sarcoma vs., 193
- molecular genetics, 197–198
- myxoinflammatory fibroblastic sarcoma vs., 204
- nodular fasciitis vs., 116
- plexiform fibromyxoma vs., 773
- prognosis, 197
- spindle cell rhabdomyosarcoma vs., 394
- superficial CD34(+) fibroblastic tumor vs., 211
Myofibroblastoma, mammary-type
- atypical spindle cell lipomatous tumor vs., 85
- cellular angiofibroma vs., 581
- differential diagnosis, 149
- molecular genetics, 149
- prognosis, 149
- spindle cell/pleomorphic lipoma vs., 62
Myofibroblastoma, mammary-type, 148–151
Myofibroma, 362–365
- differential diagnosis, 363
- infantile fibrosarcoma vs., 265
- myopericytoma vs., 359
- nodular fasciitis vs., 116
- prognosis, 363
- spindle cell rhabdomyosarcoma vs., 394
Myofibromatosis, 362–365
- differential diagnosis, 363
- infantile, hyaline fibromatosis syndrome vs., 253
- infantile fibrosarcoma vs., 265
- prognosis, 363
Myofibrosarcoma. See also Low-grade myofibroblastic
sarcoma.
- low-grade, angiofibroma of soft tissue vs., 145
Myolipoma, 70–73
- differential diagnosis, 71
- prognosis, 71
xxvi
Myoma, juxtaarticular, perineurioma vs., 532
Myopericytoma, 358–361
- angioleiomyoma vs., 367
- differential diagnosis, 359
- Epstein-Barr virus-associated smooth muscle tumor vs.,
343
- glomus tumors vs., 354
- prognosis, 359
- solitary fibrous tumor vs., 186
Myositis, focal, 370–371
- differential diagnosis, 371
- fibromatosis colli vs., 255
- prognosis, 371
Myositis ossificans, 126–129
- aneurysmal bone cyst of soft tissue vs., 631
- differential diagnosis, 127
- extraskeletal osteosarcoma vs., 498
- fibroosseous pseudotumor of digit vs., 131
- focal myositis vs., 371
- nodular fasciitis vs., 116
- prognosis, 127
Myxochondroid metaplasia, of plantar foot, soft tissue
chondroma vs., 488
Myxochondroma. See Soft tissue chondroma.
Myxofibrosarcoma, 216–221
- cardiac myxoma vs., 793
- dedifferentiated liposarcoma vs., 96
- differential diagnosis, 218
- epithelial variant, extraskeletal myxoid chondrosarcoma
vs., 713
- giant cell fibroblastoma vs., 261
- ischemic fasciitis vs., 125
- low-grade
ganglion cyst vs., 785
massive localized lymphedema vs., 451
- low-grade
dermal nerve sheath myxoma vs., 547
intramuscular myxoma vs., 615
juxtaarticular myxoma vs., 619
superficial angiomyxoma vs., 621
- low-grade fibromyxoid sarcoma vs., 224
- myoepithelioma of soft tissue vs., 656
- myxoid liposarcoma vs., 102
- myxoinflammatory fibroblastic sarcoma vs., 204
- pleomorphic liposarcoma vs., 108
- primary pulmonary myxoid sarcoma vs., 848
- prognosis, 217
Myxoid chondrosarcoma, extraskeletal, 712–715
- chondroid lipoma vs., 67
- differential diagnosis, 713
- epithelioid hemangioendothelioma vs., 468
- extraaxial soft tissue chordoma vs., 843
- extrarenal rhabdoid tumor vs., 718
- extraskeletal mesenchymal chondrosarcoma vs., 502
- genetic testing, 713
- myoepithelioma of soft tissue vs., 656
- myxoid liposarcoma vs., 102
- ossifying fibromyxoid tumor vs., 652
- perineurioma vs., 532
- primary pulmonary myxoid sarcoma vs., 847
- prognosis, 713
 INDEX
- soft tissue chondroma vs., 488
Myxoid dermatofibrosarcoma protuberans
- dermal nerve sheath myxoma vs., 547
- myxoid liposarcoma vs., 102
Myxoid leiomyosarcoma, primary pulmonary myxoid
sarcoma vs., 848
Myxoid liposarcoma (MLPS), 100–105
- angiofibroma of soft tissue vs., 145
- atypical lipomatous tumor/well-differentiated
liposarcoma vs., 90
- chondroid lipoma vs., 67
- dedifferentiated liposarcoma vs., 96
- differential diagnosis, 102
- hibernoma vs., 75
- intramuscular myxoma vs., 615
- lipoblastoma vs., 81
- lipoma vs., 48
- low-grade fibromyxoid sarcoma vs., 224
- massive localized lymphedema vs., 451
- molecular genetics, 102
- myxofibrosarcoma vs., 218
- pleomorphic liposarcoma vs., 108
- primary pulmonary myxoid sarcoma vs., 848
- prognosis, 101
- spindle cell/pleomorphic lipoma vs., 62
- superficial angiomyxoma vs., 621
Myxoid malignant fibrous histiocytoma. See
Myxofibrosarcoma.
Myxoid mesothelioma, extraskeletal myxoid
chondrosarcoma vs., 713
Myxoid neurofibroma
- acral fibromyxoma vs., 625
- dermal nerve sheath myxoma vs., 547
- juxtaarticular myxoma vs., 619
- superficial angiomyxoma vs., 621
Myxoinflammatory fibroblastic sarcoma, 202–209
- differential diagnosis, 204
- extranodal Rosai-Dorfman disease vs., 312
- hemosiderotic fibrolipomatous tumor vs., 635
- molecular genetics, 204
- myxofibrosarcoma vs., 218
- pleomorphic hyalinizing angiectatic tumor vs., 627
- prognosis, 203
- superficial CD34(+) fibroblastic tumor vs., 211
Myxoma
- cardiac, 792–795
differential diagnosis, 793
intimal sarcoma vs., 721
molecular genetics, 793
prognosis, 793
- cellular, myxofibrosarcoma vs., 218
- cutaneous, in Carney complex, dermal nerve sheath
myxoma vs., 547
- dermal nerve sheath, 546–549
cellular neurothekeoma vs., 291
differential diagnosis of, 547
prognosis, 547
superficial angiomyxoma vs., 621
- ganglion cyst vs., 785
- intramuscular, 614–617
differential diagnosis, 615
genetic testing, 615
juxtaarticular myxoma vs., 619
low-grade fibromyxoid sarcoma vs., 224
myxofibrosarcoma vs., 218
myxoid liposarcoma vs., 102
prognosis, 615
- juxtaarticular, 618–619
differential diagnosis, 619
genetic testing, 619
myxofibrosarcoma vs., 218
perineurioma vs., 532
prognosis, 619
- superficial, myxofibrosarcoma vs., 218
N
Nasal glial heterotopia. See Glial heterotopia.
Nasal glioma. See Glial heterotopia.
Nasopharyngeal angiofibroma, 800–803
- differential diagnosis, 802
- genetics, 801
- prognosis, 801
- sinonasal glomangiopericytoma vs., 806
Necrobiosis lipoidica diabeticorum
- deep granuloma annulare vs., 305
- rheumatoid nodule vs., 307
Nerve sheath myxoma, dermal, 546–549
- cellular neurothekeoma vs., 291
- differential diagnosis of, 547
- prognosis, 547
- superficial angiomyxoma vs., 621
Nerve sheath tumor
- hybrid, 536–539
differential diagnosis, 537
gastrointestinal schwannoma vs., 761
low-grade fibromyxoid sarcoma vs., 224
perineurioma vs., 532
prognosis, 537
- malignant peripheral nerve sheath tumor. See
Peripheral nerve sheath tumor, malignant.
Neural fibrolipoma. See Lipomatosis.
Neural gastrointestinal polyps, benign, 740–743
- differential diagnosis, 741
- prognosis, 741
Neurilemmoma. See Schwannoma.
Neuroblastoma
- alveolar rhabdomyosarcoma vs., 388
- desmoplastic small round cell tumor vs., 702
- ectomesenchymoma vs., 571
- embryonal rhabdomyosarcoma vs., 382
- extraskeletal Ewing sarcoma vs., 708
- and ganglioneuroblastoma, 832–841
differential diagnosis, 834–835
favorable vs. unfavorable histology in neuroblastic
tumors, 835
genetic testing, 834
intermixed, 834
xxvii
 INDEX
International Neuroblastoma Pathology Committee solitary circumscribed neuroma vs., 507
(INPC) classification, 834 - solitary circumscribed, 506–507
neuroblastoma staging system, 835 differential diagnosis, 507
nodular, 834 prognosis, 507
poorly differentiated, 834 - traumatic, solitary circumscribed neuroma vs., 507
prognosis, 833 Neuromuscular choristoma, 554–555
prognosis based on MYCN amplification and - diagnostic checklist, 555
histology, 835 - differential diagnosis, 555
undifferentiated, 834 - prognosis, 555
- melanotic neuroectodermal tumor of infancy vs., 825 Neuromuscular hamartoma. See Neuromuscular
Neuroblastoma-like schwannoma, 510 choristoma.
Neuroectodermal tumor Neurothekeoma
- of infancy, melanotic, 824–825 - cellular, 290–293
differential diagnosis, 825 differential diagnosis, 291
prognosis, 825 ectopic meningioma vs., 811
- malignant gastrointestinal, 776–779 plexiform fibrohistiocytic tumor vs., 317
differential diagnosis, 777–778 prognosis, 291
gastrointestinal stromal tumor vs., 747 - cellular neurothekeoma vs., 291
immunohistochemistry, 778 - dermal nerve sheath myxoma vs., 547
molecular genetics, 777 Nodal metastasis, angiomatoid fibrous histiocytoma vs.,
Neuroendocrine carcinoma, metastatic, desmoplastic 644
small round cell tumor vs., 702 Nodular fasciitis, 114–119
Neurofibroma, 522–529 - aneurysmal bone cyst of soft tissue vs., 631
- atypical, malignant peripheral nerve sheath tumor vs., - angiomatoid fibrous histiocytoma vs., 644
560 - desmoid-type fibromatosis vs., 170
- benign neural gastrointestinal polyps vs., 741 - desmoplastic fibroblastoma vs., 141
- desmoplastic fibroblastoma vs., 141 - differential diagnosis, 116
- differential diagnosis, 524 - fibroma of tendon sheath vs., 136
- diffuse - fibromatosis colli vs., 255
dermatofibrosarcoma protuberans vs., 176 - inflammatory myofibroblastic tumor vs., 198
lipoma vs., 48 - ischemic fasciitis vs., 125
- ganglion cyst vs., 785 - keloid vs., 163
- ganglioneuroma vs., 551 - molecular genetics, 116
- gastrointestinal schwannoma vs., 761 - myofibroma and myofibromatosis vs., 363
- glial heterotopia vs., 813 - myositis ossificans vs., 127
- hybrid nerve sheath tumor vs., 537 - prognosis, 115
- myxofibrosarcoma vs., 218 - proliferative fasciitis/myositis vs., 121
- myxoid Non-Hodgkin lymphoma, histiocytic sarcoma vs., 325
acral fibromyxoma vs., 625 Noninvoluting congenital hemangioma (NICH). See
dermal nerve sheath myxoma vs., 547 Congenital hemangioma.
juxtaarticular myxoma vs., 619 Nuchal fibrocartilaginous pseudotumor
superficial angiomyxoma vs., 621 - Gardner fibroma vs., 257
- nodular fasciitis vs., 116 - nuchal-type fibroma vs., 165
- perineurioma vs., 532 Nuchal fibroma. See Nuchal-type fibroma.
- plexiform Nuchal-type fibroma, 164–165
plexiform fibromyxoma vs., 773 - differential diagnosis, 165
solitary circumscribed neuroma vs., 507 - elastofibromas vs., 143
- prognosis, 523 - Gardner fibroma vs., 257
- schwannoma vs., 510–511 - prognosis, 165
- spindle cell/pleomorphic lipoma vs., 62

O
Neurofibromatosis type 1, lipomatosis of nerve vs., 53
Neurofibromatosis type 2, 509
Neurofibrosarcoma. See Malignant peripheral nerve
sheath tumor.
Neurogenic sarcoma. See Malignant peripheral nerve Ormond disease. See Idiopathic tumefactive
sheath tumor. fibroinflammatory lesions.
Neurolipomatosis. See Lipomatosis. Ossifying fibromyxoid tumor (OFMT), 650–655
Neuroma - differential diagnosis, 652
- lipomatosis of nerve vs., 53 - extraskeletal osteosarcoma vs., 498
- mucosal - fibroosseous pseudotumor vs., 131
benign neural gastrointestinal polyps vs., 741
xxviii
 INDEX
- malignant, 651 Parachordoma, 657. See also Myoepithelioma, of soft
- molecular genetics, 652 tissue.
- myoepithelioma of soft tissue vs., 656 Paraganglioma, 814–821
- myositis ossificans vs., 127 - adult rhabdomyoma vs., 373
- prognosis, 651 - alveolar soft part sarcoma vs., 685
- sclerosing epithelioid fibrosarcoma vs., 234 - conventional, gangliocytic paraganglioma vs., 771
Osteocartilaginous loose bodies, synovial chondromatosis - differential diagnosis, 816
vs., 493 - gangliocytic, 770–771
Osteochondroma. See Soft tissue chondroma. differential diagnosis, 771
Osteogenic melanoma, extraskeletal osteosarcoma vs., - genetic testing, 816
498 - genetics, 815
Osteosarcoma - glomus tumors vs., 354
- extraskeletal, 496–499 - peripheral hemangioblastoma vs., 823
aneurysmal bone cyst of soft tissue vs., 631 - prognosis, 815
diagnostic checklist, 498 Paraganglioma-like dermal melanocytic tumor, clear cell
differential diagnosis, 498 sarcoma vs., 690
fibroosseous pseudotumor of digit vs., 131 Parosteal fasciitis. See Fibroosseous pseudotumor of digit.
myositis ossificans vs., 127 PEComa (perivascular epithelioid cell tumor), 692–699
ossifying fibromyxoid tumor vs., 652 - alveolar soft part sarcoma vs., 685
prognosis, 497 - angioleiomyoma vs., 367
sclerosing epithelioid fibrosarcoma vs., 234 - clear cell sarcoma vs., 690
sclerosing rhabdomyosarcoma vs., 397 - deep leiomyoma vs., 339
undifferentiated pleomorphic sarcoma vs., 725 - differential diagnosis, 694
- extraskeletal mesenchymal chondrosarcoma vs., 502 - genetics, 693
- undifferentiated pleomorphic sarcoma vs., 725 - intranodal palisade myofibroblastoma vs., 153
Ovarian serous adenocarcinoma, malignant mesothelioma - leiomyosarcoma vs., 346
vs., 600 - peripheral hemangioblastoma vs., 823
- prognosis, 693

P
Penile fibromatosis, 167
Pericytic (perivascular) tumors
- angioleiomyoma, 366–367
differential diagnosis, 367
Palisade myofibroblastoma, intranodal, 152–155 prognosis, 367
- differential diagnosis, 153 - glomus tumors, 352–357
- molecular genetics, 153 differential diagnosis, 354
- prognosis, 153 prognosis, 353
Palisaded encapsulated neuroma. See Solitary - myofibroma and myofibromatosis, 362–365
circumscribed neuroma. differential diagnosis, 363
Palisading subcutaneous granuloma. See Deep granuloma prognosis, 363
annulare. - myopericytoma, 358–361
Palmar/plantar fibromatosis, 166–167 differential diagnosis, 359
- calcifying aponeurotic fibroma vs., 245 prognosis, 359
- differential diagnosis, 167 Perineurioma, 530–535
- prognosis, 167 - acral fibromyxoma vs., 625
Papillary endothelial hyperplasia (PEH), 408–409 - deep benign fibrous histiocytoma vs., 277
- angiosarcoma vs., 472 - dermatofibrosarcoma protuberans vs., 176
- diagnostic checklist, 409 - differential diagnosis, 532
- differential diagnosis, 409 - hybrid nerve sheath tumor vs., 537
- prognosis, 409 - inclusion body fibromatosis vs., 251
Papillary fibroelastoma, cardiac fibroma vs., 797 - inflammatory fibroid polyp vs., 767
Papillary intralymphatic angioendothelioma, 456–457 - intraneural, 531
- diagnostic checklist, 457 - low-grade fibromyxoid sarcoma vs., 224
- differential diagnosis, 457 - molecular genetics, 531
- prognosis, 457 - mucosal, gastrointestinal smooth muscle neoplasms vs.,
- retiform hemangioendothelioma vs., 459 764
Papillary mesothelioma, well-differentiated, 594–597 - neurofibroma vs., 524
- adenomatoid tumor vs., 591 - plexiform, 531
- differential diagnosis, 595 - prognosis, 531
- prognosis, 595 - reticular, 531
- sclerosing, 531

xxix
 INDEX
Peripheral hemangioblastoma, 822–823 prognosis, 555
- differential diagnosis, 823 - perineurioma, 530–535
- genetics, 823 differential diagnosis, 532
- prognosis, 823 intraneural, 531
Peripheral nerve sheath tumor molecular genetics, 531
- benign, intramuscular myxoma vs., 615 plexiform, 531
- dermal nerve sheath myxoma, 546–549 prognosis, 531
differential diagnosis of, 547 reticular, 531
prognosis, 547 sclerosing, 531
- ectomesenchymoma, 570–571 - schwannoma, 508–521
differential diagnosis, 571 ancient, 510
genetic testing, 571 cellular, 510
prognosis, 571 differential diagnosis, 510–511
- ganglioneuroma, 550–553 epithelioid, 510
differential diagnosis, 551 microcystic/reticular, 510
prognosis, 551 neuroblastoma-like, 510
- granular cell tumor, 540–545 plexiform, 510
differential diagnosis, 542 prognosis, 509
nonneural, 542 pseudoglandular, 510
prognosis, 541 - solitary circumscribed neuroma, 506–507
- hybrid nerve sheath tumor, 536–539 differential diagnosis, 507
differential diagnosis, 537 prognosis, 507
prognosis, 537 Peritoneal mesothelioma, multicystic, 592–593
- malignant, 558–565 - adenomatoid tumor vs., 591
adult-type fibrosarcoma vs., 215 - differential diagnosis, 593
atypical fibroxanthoma vs., 638 - prognosis, 593
BCOR-CCNB3 fusion-positive sarcoma vs., 736 Peritoneal serous carcinoma, well-differentiated papillary
clear cell sarcoma vs., 690 mesothelioma vs., 595
dedifferentiated liposarcoma vs., 96 Periungual fibroma, storiform collagenoma vs., 161
differential diagnosis, 560 Perivascular epithelioid cell tumor (PEComa), 692–699
epithelioid, 566–569. See also Epithelioid malignant - alveolar soft part sarcoma vs., 685
peripheral nerve sheath tumor. - angioleiomyoma vs., 367
extraskeletal mesenchymal chondrosarcoma vs., 502 - clear cell sarcoma vs., 690
extraskeletal osteosarcoma vs., 498 - deep leiomyoma vs., 339
genetic predisposition, 559 - differential diagnosis, 694
hybrid nerve sheath tumor vs., 537 - genetics, 693
leiomyosarcoma vs., 346 - intranodal palisade myofibroblastoma vs., 153
malignant gastrointestinal neuroectodermal tumor - leiomyosarcoma vs., 346
vs., 778 - peripheral hemangioblastoma vs., 823
metastatic tumors to soft tissue sites vs., 829 - prognosis, 693
myxofibrosarcoma vs., 218 Peyronie disease, 167
neurofibroma vs., 524 PFHT. See Plexiform fibrohistiocytic tumor.
palmar/plantar fibromatosis vs., 167 PFM. See Plexiform fibromyxoma.
prognosis, 559 Pheochromocytoma, 815
schwannoma vs., 511 Phosphaturic mesenchymal tumor (PMT), 664–665
spindle cell rhabdomyosarcoma vs., 393 - differential diagnosis, 665
synovial sarcoma vs., 668 - molecular genetics, 665
undifferentiated pleomorphic sarcoma vs., 725 - prognosis, 665
undifferentiated round cell sarcoma with CIC-DUX4 - sinonasal glomangiopericytoma vs., 806
translocation vs., 729 Pigmented villonodular synovitis, myxoinflammatory
- melanotic schwannoma, 556–557 fibroblastic sarcoma vs., 204
differential diagnosis, 557 PILA. See Papillary intralymphatic angioendothelioma.
prognosis, 557 Pilar leiomyoma
- neurofibroma, 522–529 - inclusion body fibromatosis vs., 251
differential diagnosis, 524 - smooth muscle hamartoma vs., 333
diffuse-type, 523, 524 Planar xanthoma, 295
plexiform, 523, 524 Plantar foot, myxochondroid metaplasia of, soft tissue
prognosis, 523 chondroma vs., 488
- neuromuscular choristoma, 554–555 Plaque-like dermal fibromatosis. See Dermatomyofibroma.
diagnostic checklist, 555 Plasma cell granuloma. See Inflammatory myofibroblastic
differential diagnosis, 555 tumor.
xxx
 INDEX
Pleomorphic adenoma, ectopic hamartomatous thymoma Plexiform angiomyxoid myofibroblastic tumor. See
vs., 633 Plexiform fibromyxoma.
Pleomorphic dermal sarcoma Plexiform angiomyxoid tumor. See Plexiform
- atypical fibroxanthoma vs., 638 fibromyxoma.
- superficial CD34(+) fibroblastic tumor vs., 211 Plexiform fibrohistiocytic tumor, 316–319
Pleomorphic fibroma, 156–157 - cellular neurothekeoma vs., 291
- diagnostic checklist, 157 - differential diagnosis, 317
- differential diagnosis, 157 - ectopic meningioma vs., 811
- prognosis, 157 - localized-type tenosynovial giant cell tumor vs., 280
- storiform collagenoma vs., 161 - prognosis, 317
Pleomorphic hyalinizing angiectatic tumor, 626–629 - xanthomas vs., 296
- differential diagnosis, 627 Plexiform fibromyxoma, 772–775
- hemosiderotic fibrolipomatous tumor vs., 635 - differential diagnosis, 773
- molecular genetics, 627 - gastrointestinal stromal tumor vs., 747
- prognosis, 627 Plexiform neurofibroma
- schwannoma vs., 511 - plexiform fibromyxoma vs., 773
Pleomorphic lipoma, 60–65 - solitary circumscribed neuroma vs., 507
- atypical lipomatous tumor/well-differentiated Plexiform schwannoma, 510
liposarcoma vs., 90 - xanthomas vs., 296
- differential diagnosis, 62 Plexiform xanthoma, 295
- giant cell fibroblastoma vs., 261 Plexiform xanthomatous tumor. See Xanthomas.
- molecular genetics, 61 PMH. See Pseudomyogenic hemangioendothelioma.
- prognosis, 61 PMT. See Phosphaturic mesenchymal tumor.
Pleomorphic liposarcoma (PLPS), 106–111 Polyp
- dedifferentiated liposarcoma vs., 96 - antrochoanal, nasopharyngeal angiofibroma vs., 802
- differential diagnosis, 107–108 - inflammatory fibroid, 766–769
- molecular genetics, 107 benign neural gastrointestinal polyps vs., 741
- myxofibrosarcoma vs., 218 differential diagnosis, 767
- prognosis, 107 gastrointestinal smooth muscle neoplasms vs., 764
- undifferentiated pleomorphic sarcoma vs., 725 gastrointestinal stromal tumor vs., 747
Pleomorphic melanoma, atypical fibroxanthoma vs., inflammatory myofibroblastic tumor vs., 198
637–638 plexiform fibromyxoma vs., 773
Pleomorphic rhabdomyosarcoma, 400–403 Polyphenotypic small round cell tumor. See Desmoplastic
- differential diagnosis, 401 small round cell tumor.
- embryonal rhabdomyosarcoma vs., 382 Poorly differentiated carcinoma
- epithelioid rhabdomyosarcoma vs., 405 - epithelioid rhabdomyosarcoma vs., 405
- prognosis, 401 - gastrointestinal stromal tumor vs., 747
- proliferative fasciitis/myositis vs., 121 - myeloid sarcoma vs., 609
Pleomorphic sarcoma - pleomorphic liposarcoma vs., 108
- pleomorphic rhabdomyosarcoma vs., 401 Poorly differentiated synovial sarcoma
- undifferentiated, 724–727 - BCOR-CCNB3 fusion-positive sarcoma vs., 736
adult-type fibrosarcoma vs., 215 - extraskeletal Ewing sarcoma vs., 708
angiomatoid fibrous histiocytoma vs., 644 - lymphoma of soft tissue vs., 611
dedifferentiated liposarcoma vs., 96 - undifferentiated round cell sarcoma with CIC-DUX4
differential diagnosis, 725 translocation vs., 730
extranodal Rosai-Dorfman disease vs., 312 PPMS. See Primary pulmonary myxoid sarcoma.
extraskeletal osteosarcoma vs., 498 Primary carcinoma, paraganglioma vs., 816
with giant cells, giant cell tumor of soft tissue vs., 321 Primary cardiac sarcomas, intimal sarcoma vs., 721
leiomyosarcoma vs., 346 Primary desmoid fibromatosis, neuromuscular choristoma
metastatic tumors to soft tissue sites vs., 829 vs., 555
molecular genetics, 725 Primary extrapulmonary sugar tumor. See Perivascular
myxofibrosarcoma vs., 218 epithelioid cell tumor.
nodular fasciitis vs., 116 Primary meningioma of CNS, ectopic meningioma vs., 811
pleomorphic hyalinizing angiectatic tumor vs., 627 Primary pulmonary myxoid sarcoma (PPMS), 846–849
pleomorphic liposarcoma vs., 108 - diagnostic checklist, 848
prognosis, 725 - differential diagnosis, 847–848
proliferative fasciitis/myositis vs., 121 - immunohistochemistry, 848
Pleomorphic spindle cell patterns, 29–30 Primary synovial chondromatosis. See Synovial
Pleuropulmonary blastoma, embryonal chondromatosis.
rhabdomyosarcoma vs., 382

xxxi
 INDEX
Primitive neuroectodermal tumor. See Extraskeletal Ewing Renal cell carcinoma, metastatic, peripheral
sarcoma. hemangioblastoma vs., 823
Progonoma, melanotic. See Melanotic neuroectodermal Resection, soft tissue tumors, 22–25
tumor of infancy. - specimens, 23–24
Progressive lymphangioma Reticulohistiocytic granuloma. See Reticulohistiocytoma.
- atypical vascular lesion vs., 453 Reticulohistiocytoma, 300–303
- hobnail hemangioma vs., 435 - diagnostic checklist, 302
- Kaposi sarcoma vs., 478 - differential diagnosis, 301–302
- lymphangioma vs., 448 - prognosis, 301
Proliferative fasciitis/myositis, 120–123 - solitary (juvenile) xanthogranuloma vs., 299
- desmoid-type fibromatosis vs., 170 Reticulohistiocytosis
- differential diagnosis, 121 - generalized cutaneous, reticulohistiocytoma vs.,
- ischemic fasciitis vs., 125 301–302
- myxoinflammatory fibroblastic sarcoma vs., 204 - multicentric cutaneous, reticulohistiocytoma vs.,
- nodular fasciitis vs., 116 301–302
- prognosis, 121 Reticulum cell sarcoma, interdigitating dendritic. See
Proliferative myositis, focal myositis vs., 371 Interdigitating dendritic cell sarcoma.
Proteinosis, lipoid, hyaline fibromatosis syndrome vs., 253 Retiform hemangioendothelioma, 458–459
Psammomatous melanotic schwannoma. See Melanotic - angiosarcoma vs., 472
schwannoma. - composite hemangioendothelioma vs., 461
Pseudoglandular schwannoma, 510 - diagnostic checklist, 459
Pseudogout, tophaceous - differential diagnosis, 459
- soft tissue chondroma vs., 488 - hobnail hemangioma vs., 435
- tumoral calcinosis vs., 787 - papillary intralymphatic angioendothelioma vs., 457
Pseudomyogenic hemangioendothelioma (PMH), 462–465 - prognosis, 459
- differential diagnosis, 463 Retinal anlage tumor. See Melanotic neuroectodermal
- epithelioid hemangioendothelioma vs., 468 tumor of infancy.
- epithelioid sarcoma vs., 680 Retractile mesenteritis. See Idiopathic tumefactive
- molecular genetics, 463 fibroinflammatory lesions.
- prognosis, 463 Retroperitoneal fibrosis, idiopathic, 789
Pseudorheumatoid nodule. See Deep granuloma annulare. - atypical lipomatous tumor/well-differentiated
Pseudosarcoma. See Massive localized lymphedema. liposarcoma vs., 90
Pseudosarcoma botryoides. See Fibroepithelial stromal - desmoid-type fibromatosis vs., 170
polyp. Retroperitoneum
Pseudosarcomatous fasciitis. See Nodular fasciitis. - anatomic stage/prognostic groups, 9
Pseudosarcomatous myofibroblastic proliferation, nodular - soft tissue sarcoma staging (TNM System), 7
fasciitis vs., 116 Rhabdoid tumor
Pulmonary adenocarcinoma, malignant mesothelioma vs., - atypical teratoid, extraskeletal mesenchymal
600 chondrosarcoma vs., 502
Pyogenic granuloma. See also Lobular capillary - extrarenal, 716–719
hemangioma. alveolar rhabdomyosarcoma vs., 388
- angiofibroma of soft tissue vs., 145 desmoplastic small round cell tumor vs., 702
- antrochoanal, nasopharyngeal angiofibroma vs., 802 differential diagnosis, 718
- bacillary angiomatosis vs., 411 epithelioid rhabdomyosarcoma vs., 405
- congenital granular cell epulis vs., 799 epithelioid sarcoma vs., 680
- glomeruloid hemangioma vs., 443 molecular genetics, 717–718
- infantile hemangioma vs., 418 prognosis, 717
- nasopharyngeal angiofibroma vs., 802 Rhabdomyoma
- sinonasal glomangiopericytoma vs., 806 - adult-type, 372–373
cardiac rhabdomyoma vs., 379

R
congenital granular cell epulis vs., 799
differential diagnosis, 373
embryonal rhabdomyosarcoma vs., 382
granular cell tumor vs., 542
Rapidly involuting congenital hemangioma (RICH). See prognosis, 373
Congenital hemangioma. - alveolar soft part sarcoma vs., 685
RDD. See Rosai-Dorfman disease. - cardiac, 378–379
Reactive granular cell change, granular cell tumor vs., 542 differential diagnosis, 379
Reactive nonlesional fibroblastic proliferation, idiopathic genetics, 379
tumefactive fibroinflammatory lesions vs., 790 prognosis, 379

xxxii
 INDEX
- crystal-storing histiocytosis vs., 315 sclerosing epithelioid fibrosarcoma vs., 234
- embryonal rhabdomyosarcoma vs., 382 - spindle cell, 392–395
- fetal, 374–375 biphenotypic sinonasal sarcoma vs., 851
differential diagnosis, 375 differential diagnosis, 393–394
embryonal rhabdomyosarcoma vs., 382 embryonal rhabdomyosarcoma vs., 382
genetics, 375 fetal rhabdomyoma vs., 375
genital rhabdomyoma vs., 377 genital rhabdomyoma vs., 377
prognosis, 375 infantile fibrosarcoma vs., 265
spindle cell rhabdomyosarcoma vs., 394 low-grade myofibroblastic sarcoma vs., 193
- focal myositis vs., 371 malignant peripheral nerve sheath tumor vs., 560
- genital, 376–377 prognosis, 393
botryoid-type embryonal, fibroepithelial stromal - undifferentiated pleomorphic sarcoma vs., 725
polyp vs., 575 RHE. See Retiform hemangioendothelioma.
differential diagnosis, 377 Rheumatoid arthritis, synovial lipomatosis vs., 55
embryonal rhabdomyosarcoma vs., 382 Rheumatoid nodule, 306–307
fetal rhabdomyoma vs., 375 - deep granuloma annulare vs., 305
prognosis, 377 - differential diagnosis, 307
Rhabdomyosarcoma - prognosis, 307
- alveolar, 386–391 Rosai-Dorfman disease
desmoplastic small round cell tumor vs., 701 - extranodal, 310–313
differential diagnosis, 388 differential diagnosis, 312
embryonal rhabdomyosarcoma vs., 382 histiocytic sarcoma vs., 325
extraskeletal Ewing sarcoma vs., 708 idiopathic tumefactive fibroinflammatory lesions vs.,
malignant gastrointestinal neuroectodermal tumor 790
vs., 778 Langerhans cell histiocytosis vs., 309
neuroblastoma and ganglioneuroblastoma vs., 834 prognosis, 311
pleomorphic rhabdomyosarcoma vs., 401 - reticulohistiocytoma vs., 302
prognosis, 387 - solitary (juvenile) xanthogranuloma vs., 299
sclerosing epithelioid fibrosarcoma vs., 234 Round blue cell tumors, various small, myeloid sarcoma
sclerosing rhabdomyosarcoma vs., 397 vs., 609
undifferentiated round cell sarcoma with CIC-DUX4 Round cell liposarcoma. See Myxoid liposarcoma.
translocation vs., 729

S
- angiomatoid fibrous histiocytoma vs., 644
- botryoid-type embryonal, fibroepithelial stromal polyp
vs., 575
- embryonal, 380–385
alveolar rhabdomyosarcoma vs., 388 Sacrococcygeal ependymoma. See Ependymoma, of soft
differential diagnosis, 382 tissue.
ectomesenchymoma vs., 571 Sampling, gross examination, 4
fetal rhabdomyoma vs., 375 Sarcoidosis, extranodal Rosai-Dorfman disease vs., 312
genital rhabdomyoma vs., 377 Sarcoma
prognosis, 381 - alveolar soft part, 684–687
spindle cell rhabdomyosarcoma vs., 394 adult rhabdomyoma vs., 373
undifferentiated embryonal sarcoma of liver vs., 845 alveolar rhabdomyosarcoma vs., 388
- epithelioid, 404–405 congenital granular cell epulis vs., 799
differential diagnosis, 405 differential diagnosis, 685
molecular genetics, 405 granular cell tumor vs., 542
pleomorphic rhabdomyosarcoma vs., 401 molecular genetics, 685
prognosis, 405 paraganglioma vs., 816
- extrarenal rhabdoid tumor vs., 718 PEComa vs., 694
- pleomorphic, 400–403 prognosis, 685
differential diagnosis, 401 - atypical fibroxanthoma vs., 638
embryonal rhabdomyosarcoma vs., 382 - BCOR-CCNB3 fusion-positive
epithelioid rhabdomyosarcoma vs., 405 diagnostic checklist, 736
prognosis, 401 differential diagnosis, 736
proliferative fasciitis/myositis vs., 121 prognosis, 735
- sclerosing, 396–399 undifferentiated round cell sarcoma with CIC-DUX4
alveolar rhabdomyosarcoma vs., 388 translocation vs., 729
differential diagnosis, 397 - BCOR-CCNB3 fusion-positive, 734–737
extraskeletal mesenchymal chondrosarcoma vs., 502
prognosis, 397
xxxiii
 INDEX
- biphenotypic sinonasal, 850–853
differential diagnosis, 851
prognosis, 851
- CIC-FOXO4, undifferentiated round cell sarcoma with
CIC-DUX4 translocation vs., 729
- clear cell
diagnostic checklist, 690
differential diagnosis, 690
epithelioid malignant peripheral nerve sheath tumor
vs., 567
malignant gastrointestinal neuroectodermal tumor
vs., 777–778
melanotic schwannoma vs., 557
metastatic tumors to soft tissue sites vs., 829
molecular genetics, 689
PEComa vs., 694
prognosis, 689
of tendon and aponeurosis, 689
- epithelioid
angiosarcoma vs., 472
classic, 679
deep granuloma annulare vs., 305
epithelioid hemangioendothelioma vs., 468
epithelioid rhabdomyosarcoma vs., 405
extrarenal rhabdoid tumor vs., 718
inclusion body fibromatosis vs., 251
ischemic fasciitis vs., 125
molecular genetics, 680
myoepithelioma of soft tissue vs., 656
prognosis, 679
proximal-type, 679–680
pseudomyogenic hemangioendothelioma, 463
rheumatoid nodule vs., 307
solitary extramedullary plasmacytoma vs., 607
superficial CD34(+) fibroblastic tumor vs., 211
- Ewing
alveolar rhabdomyosarcoma vs., 388
BCOR-CCNB3 fusion-positive sarcoma vs., 736
extrarenal rhabdoid tumor vs., 718
extraskeletal, 706–711
extraskeletal mesenchymal chondrosarcoma vs., 502
low-grade endometrial stromal sarcoma vs., 857
lymphoma of soft tissue vs., 611
myxoid liposarcoma vs., 102
neuroblastoma and ganglioneuroblastoma vs., 834
synovial sarcoma vs., 668
- follicular dendritic cell, 326–327
angiomatoid fibrous histiocytoma vs., 644
differential diagnosis, 327
extranodal Rosai-Dorfman disease vs., 312
interdigitating dendritic cell sarcoma vs., 329
prognosis, 327
- histiocytic, 324–325
differential diagnosis, 325
extranodal Rosai-Dorfman disease vs., 312
interdigitating dendritic cell sarcoma vs., 329
Langerhans cell histiocytosis vs., 309
prognosis, 325
- intimal, 720–721
differential diagnosis, 721
genetic testing, 721
xxxiv
prognosis, 721
- Kaposi, 476–483
acquired tufted angioma vs., 437
angiolipoma vs., 57
angiomatoid fibrous histiocytoma vs., 644
angiosarcoma vs., 472
bacillary angiomatosis vs., 411
composite hemangioendothelioma vs., 461
dermatofibroma vs., 272
differential diagnosis, 478
glomeruloid hemangioma vs., 443
hobnail hemangioma vs., 435
intranodal palisade myofibroblastoma vs., 153
kaposiform hemangioendothelioma vs., 455
lymphangioma-like, lymphangioma vs., 448
microvenular hemangioma vs., 439
nodular fasciitis vs., 116
papillary intralymphatic angioendothelioma vs., 457
prognosis, 477
retiform hemangioendothelioma vs., 459
spindle cell hemangioma vs., 427
- Langerhans cell
interdigitating dendritic cell sarcoma vs., 329
Langerhans cell histiocytosis vs., 309
- low-grade endometrial stromal, 856–857
differential diagnosis, 857
prognosis, 857
- low-grade fibromyxoid, 222–231
angiofibroma of soft tissue vs., 145
desmoid-type fibromatosis vs., 170
desmoplastic fibroblastoma vs., 141
differential diagnosis, 224
intramuscular myxoma vs., 615
juxtaarticular myxoma vs., 619
myxofibrosarcoma vs., 218
myxoid liposarcoma vs., 102
ossifying fibromyxoid tumor vs., 652
perineurioma vs., 532
prognosis, 223
sclerosing epithelioid fibrosarcoma vs., 233
superficial angiomyxoma vs., 621
- low-grade myofibroblastic
adult-type fibrosarcoma vs., 215
desmoid-type fibromatosis vs., 170
differential diagnosis, 193
nodular fasciitis vs., 116
plexiform fibrohistiocytic tumor vs., 317
prognosis, 193
spindle cell rhabdomyosarcoma vs., 394
- low-grade myofibroblastic, 192–195
- myeloid, 608–609
differential diagnosis, 609
lymphoma of soft tissue vs., 611
molecular genetics, 609
myelolipoma vs., 79
prognosis, 609
- myxoinflammatory fibroblastic
extranodal Rosai-Dorfman disease vs., 312
pleomorphic hyalinizing angiectatic tumor vs., 627
superficial CD34(+) fibroblastic tumor vs., 211
 INDEX
- pleomorphic, high-grade, undifferentiated pleomorphic Schwann cell hamartoma, mucosal, gastrointestinal
sarcoma vs., 725 smooth muscle neoplasms vs., 764
- pleomorphic dermal Schwannian stroma-poor neuroblastic tumor
atypical fibroxanthoma vs., 638 (neuroblastoma), 833
superficial CD34(+) fibroblastic tumor vs., 211 Schwannian stroma-rich neuroblastic tumor
- primary cardiac, intimal sarcoma vs., 721 (ganglioneuroblastoma), 833
- synovial, 666–677 Schwannoma, 508–521
adult-type fibrosarcoma vs., 215 - ancient, 510
biphasic, 668 - cellular, 510
biphenotypic sinonasal sarcoma vs., 851 deep leiomyoma vs., 339
calcifying fibrous tumor vs., 249 ganglioneuroma vs., 551
differential diagnosis, 668 malignant peripheral nerve sheath tumor vs., 560
ectopic hamartomatous thymoma vs., 633 spindle cell rhabdomyosarcoma vs., 394
extraskeletal mesenchymal chondrosarcoma vs., 502 - conventional, melanotic schwannoma vs., 557
extraskeletal osteosarcoma vs., 498 - differential diagnosis, 510–511
infantile fibrosarcoma vs., 265 - ependymoma of soft tissue vs., 827
leiomyosarcoma vs., 346 - epithelioid, 510
low-grade endometrial stromal sarcoma vs., 857 epithelioid malignant peripheral nerve sheath tumor
malignant gastrointestinal neuroectodermal tumor vs., 567
vs., 778 - gastrointestinal, 760–761
malignant mesothelioma vs., 600 differential diagnosis, 761
molecular genetics, 668 gastrointestinal smooth muscle neoplasms vs., 764
monophasic, 667 gastrointestinal stromal tumor vs., 747
monoplastic, calcifying aponeurotic fibroma vs., 245 melanotic schwannoma vs., 557
myxoid liposarcoma vs., 102 prognosis, 761
prognosis, 667 - hybrid nerve sheath tumor vs., 537
spindle epithelial tumor with thymus-like - intranodal palisade myofibroblastoma vs., 153
differentiation vs., 855 - melanotic, 556–557
- undifferentiated pleomorphic, 724–727 differential diagnosis, 557
adult-type fibrosarcoma vs., 215 prognosis, 557
angiomatoid fibrous histiocytoma vs., 644 - microcystic/reticular, 510
dedifferentiated liposarcoma vs., 96 - myoepithelioma of soft tissue vs., 656
differential diagnosis, 725 - neuroblastoma-like, 510
extranodal Rosai-Dorfman disease vs., 312 - neurofibroma vs., 524
extraskeletal osteosarcoma vs., 498 - ossifying fibromyxoid tumor vs., 652
with giant cells, giant cell tumor of soft tissue vs., 321 - perineurioma vs., 532
leiomyosarcoma vs., 346 - pleomorphic hyalinizing angiectatic tumor vs., 627
metastatic tumors to soft tissue sites vs., 829 - plexiform, 510
molecular genetics, 725 xanthomas vs., 296
myxofibrosarcoma vs., 218 - prognosis, 509
nodular fasciitis vs., 116 - pseudoglandular, 510
pleomorphic hyalinizing angiectatic tumor vs., 627 - sinonasal glomangiopericytoma vs., 806
pleomorphic liposarcoma vs., 108 - solitary circumscribed neuroma vs., 507
prognosis, 725 Schwannomatosis, 509
proliferative fasciitis/myositis vs., 121 SCL. See Spindle cell lipoma.
Sarcomatoid carcinoma Sclerosing disease, IgG4-related, inflammatory
- atypical fibroxanthoma vs., 637 myofibroblastic tumor vs., 198
- ectopic hamartomatous thymoma vs., 633 Sclerosing epithelioid fibrosarcoma (SEF), 232–237
- extraskeletal osteosarcoma vs., 498 - differential diagnosis, 233–234
- metastatic, follicular dendritic cell sarcoma vs., 327 - low-grade fibromyxoid sarcoma vs., 224
- spindle cell rhabdomyosarcoma vs., 394 - ossifying fibromyxoid tumor vs., 652
- squamous cell, leiomyosarcoma vs., 346 - prognosis, 233
- undifferentiated embryonal sarcoma of liver vs., 845 - sclerosing rhabdomyosarcoma vs., 397
Scar Sclerosing mesenteritis. See Idiopathic tumefactive
- early, microvenular hemangioma vs., 439 fibroinflammatory lesions.
- fibrous, desmoid-type fibromatosis vs., 170 Sclerosing perineurioma, fibroma of tendon sheath vs.,
- hypertrophic 136
dermatomyofibroma vs., 159 Sclerosing pseudovascular rhabdomyosarcoma. See
keloid vs., 163 Sclerosing rhabdomyosarcoma.
- keloidal collagen. See Keloid.
SCH. See Spindle cell hemangioma.
xxxv
 INDEX
Sclerosing rhabdomyosarcoma, 396–399 prognosis, 401
- alveolar rhabdomyosarcoma vs., 388 - sclerosing rhabdomyosarcoma, 396–399
- differential diagnosis, 397 differential diagnosis, 397
- extraskeletal mesenchymal chondrosarcoma vs., 502 prognosis, 397
- prognosis, 397 - spindle cell rhabdomyosarcoma, 392–395
- sclerosing epithelioid fibrosarcoma vs., 234 differential diagnosis, 393–394
Sclerotic fibroma. See also Storiform collagenoma. prognosis, 393
- pleomorphic fibroma vs., 157 Skin, normal, from special sites, smooth muscle
SCN. See Solitary circumscribed neuroma. hamartoma vs., 333
Secondary lymphangiectasia, lymphangioma vs., 448 Small cell carcinoma, extraskeletal Ewing sarcoma vs., 708
Sectioning, gross examination, 4 Small cell osteosarcoma, BCOR-CCNB3 fusion-positive
Serous borderline tumor, implants of, well-differentiated sarcoma vs., 736
papillary mesothelioma vs., 595 Small round cell tumor, desmoplastic, alveolar
SETTLE. See Spindle epithelial tumor with thymus-like rhabdomyosarcoma vs., 388
differentiation. Smooth muscle hamartoma, 332–333
Silicone granuloma, pleomorphic liposarcoma vs., 108 - congenital, superficial leiomyoma vs., 335
Sinonasal glomangiopericytoma, 804–809 - differential diagnosis, 333
- diagnostic checklist, 806 - prognosis, 333
- differential diagnosis, 806 - superficial leiomyoma vs., 335
- genetics, 805 Smooth muscle neoplasms
- nasopharyngeal angiofibroma vs., 802 - gastrointestinal, 762–765
- prognosis, 805 differential diagnosis, 764
Sinonasal-type hemangiopericytoma. See Sinonasal gastrointestinal stromal tumor vs., 747
glomangiopericytoma. prognosis, 763
Sinus histiocytosis with massive lymphadenopathy. See - low-grade endometrial stromal sarcoma vs., 857
Extranodal Rosai-Dorfman disease; Rosai-Dorfman - sinonasal, sinonasal glomangiopericytoma vs., 806
disease. Smooth muscle tumors
Sinusoidal hemangioma, 440–441 - deep leiomyoma, 338–341
- diagnostic checklist, 441 differential diagnosis, 339
- differential diagnosis, 441 prognosis, 339
- prognosis, 441 - Epstein-Barr virus-associated smooth muscle tumor,
Skeletal muscle, tumors of 342–343
- adult rhabdomyoma, 372–373 differential diagnosis, 343
differential diagnosis, 373 prognosis, 343
prognosis, 373 - leiomyosarcoma, 344–349
- alveolar rhabdomyosarcoma, 386–391 differential diagnosis, 346
differential diagnosis, 388 prognosis, 345
prognosis, 387 - smooth muscle hamartoma, 332–333
- cardiac rhabdomyoma, 378–379 differential diagnosis, 333
differential diagnosis, 379 prognosis, 333
genetics, 379 - superficial leiomyoma, 334–337
prognosis, 379 differential diagnosis, 335
- embryonal rhabdomyosarcoma, 380–385 prognosis, 335
differential diagnosis, 382 Soft part sarcoma, alveolar, 684–687
prognosis, 381 - adult rhabdomyoma vs., 373
- epithelioid rhabdomyosarcoma, 404–405 - alveolar rhabdomyosarcoma vs., 388
differential diagnosis, 405 - congenital granular cell epulis vs., 799
molecular genetics, 405 - differential diagnosis, 685
prognosis, 405 - granular cell tumor vs., 542
- fetal rhabdomyoma, 374–375 - molecular genetics, 685
differential diagnosis, 375 - paraganglioma vs., 816
genetics, 375 - PEComa vs., 694
prognosis, 375 - prognosis, 685
- focal myositis, 370–371 Soft tissue aneurysmal bone cyst, nodular fasciitis vs., 116
differential diagnosis, 371 Soft tissue chondroma, 486–491
prognosis, 371 - calcified, tumoral calcinosis vs., 787
- genital rhabdomyoma, 376–377 - calcifying aponeurotic fibroma vs., 245
differential diagnosis, 377 - chondroid lipoma vs., 67
prognosis, 377 - diagnostic checklist, 488
- pleomorphic rhabdomyosarcoma, 400–403 - differential diagnosis, 487–488
differential diagnosis, 401 - extraskeletal myxoid chondrosarcoma vs., 713
xxxvi
 INDEX
- myoepithelioma of soft tissue vs., 656 - dermatofibrosarcoma protuberans vs., 176
- phosphaturic mesenchymal tumor vs., 665 - differential diagnosis, 186
- prognosis, 487 - ectopic hamartomatous thymoma vs., 633
- synovial chondromatosis vs., 493 - gastrointestinal stromal tumor vs., 747
Soft tissue giant cell tumor of low malignant potential. See - low-grade endometrial stromal sarcoma vs., 857
Giant cell tumor of soft tissue. - malignant mesothelioma vs., 600
Soft tissue immunohistochemistry, 12–17 - mammary-type myofibroblastoma vs., 149
- commonly used antibodies in soft tissue pathology, 12 - molecular genetics, 186
- epithelioid cell tumors - myopericytoma vs., 359
in GI tract, 16 - nasopharyngeal angiofibroma vs., 802
in soft tissue, 15 - nuchal-type fibroma vs., 165
- pattern-based diagnostic approach, with prominent - perineurioma vs., 532
CD34 expression, 17 - peripheral hemangioblastoma vs., 823
- pleomorphic soft tissue tumors, 14 - phosphaturic mesenchymal tumor vs., 665
- small round blue cell tumors, 15 - prognosis, 185
- spindle cell tumors - sinonasal glomangiopericytoma vs., 806
in GI tract, 16 - spindle cell/pleomorphic lipoma vs., 62
in soft tissue, 14 - spindle epithelial tumor with thymus-like differentiation
Soft tissue metastasis, from axial chordoma, extraaxial vs., 855
soft tissue chordoma vs., 843 - synovial sarcoma vs., 668
Soft tissue tumors Solitary (juvenile) xanthogranuloma, 298–299
- diagnostic approach - differential diagnosis, 299
age-based approach, 26 - extranodal Rosai-Dorfman disease vs., 312
biopsy and resection, 22–25 - prognosis, 299
gastrointestinal mesenchymal tumors, 27 - reticulohistiocytoma vs., 302
involving lymph nodes, 27 - xanthomas vs., 296
location-based, 27 Specimen inking, 4
- diagnostic molecular and cytogenetic findings, 18 Spindle cell carcinoma, spindle epithelial tumor with
- feature-based diagnostic approach, 36–43 thymus-like differentiation vs., 855
cytologic features, 36 Spindle cell hemangioendothelioma. See Spindle cell
inflammatory component, 37 hemangioma.
multinucleated cells, 37 Spindle cell hemangioma (SCH), 426–429
nuclear features, 37–38 - angiolipoma vs., 57
stromal findings, 38 - angiomatoid fibrous histiocytoma vs., 644
structures, 38 - composite hemangioendothelioma vs., 461
vasculature, 38 - diagnostic checklist, 427
- molecular features, 18–19 - differential diagnosis, 427
- pattern-based diagnostic approach, 28–35 - Kaposi sarcoma vs., 478
epithelioid cell patterns, 30 - kaposiform hemangioendothelioma vs., 455
monomorphic spindle cell patterns, 28 - prognosis, 427
pleomorphic spindle cell patterns, 29–30 Spindle cell lipoma (SCL), 60–65
Solitary circumscribed neuroma, 506–507 - cellular angiofibroma vs., 581
- differential diagnosis, 507 - differential diagnosis, 62
- prognosis, 507 - hemosiderotic fibrolipomatous tumor vs., 635
Solitary cutaneous reticulohistiocytoma. See - lipoma vs., 48
Reticulohistiocytoma. - mammary-type myofibroblastoma vs., 149
Solitary extramedullary plasmacytoma, 606–607 - molecular genetics, 61
- differential diagnosis, 607 - myolipoma vs., 71
- prognosis, 607 - prognosis, 61
Solitary extraosseous plasmacytoma. See Solitary - solitary fibrous tumor vs., 186
extramedullary plasmacytoma. Spindle cell lipomatous tumor, atypical, 84–87
Solitary fibrous tumor, 184–191 - differential diagnosis, 85
- acral fibromyxoma vs., 625 - molecular genetics, 85
- angiofibroma of soft tissue vs., 145 - prognosis, 85
- BCOR-CCNB3 fusion-positive sarcoma vs., 736 - spindle cell/pleomorphic lipoma vs., 62
- biphenotypic sinonasal sarcoma vs., 851 Spindle cell liposarcoma. See Atypical spindle cell
- calcifying fibrous tumor vs., 249 lipomatous tumor.
- cellular angiofibroma vs., 581 Spindle cell melanoma
- cellular/malignant, extraskeletal mesenchymal - atypical fibroxanthoma vs., 637–638
chondrosarcoma vs., 502 - desmoplastic, dermatofibrosarcoma protuberans vs.,
- deep benign fibrous histiocytoma vs., 277 176
xxxvii
 INDEX
- spindle cell rhabdomyosarcoma vs., 394
Spindle cell/pleomorphic lipoma, atypical spindle cell
lipomatous tumor vs., 85
Spindle cell rhabdomyosarcoma, 392–395
- biphenotypic sinonasal sarcoma vs., 851
- differential diagnosis, 393–394
- embryonal rhabdomyosarcoma vs., 382
- genital rhabdomyoma vs., 377
- infantile fibrosarcoma vs., 265
- low-grade myofibroblastic sarcoma vs., 193
- malignant peripheral nerve sheath tumor vs., 560
- prognosis, 393
Spindle epithelial tumor with thymus-like differentiation
(SETTLE), 854–855
- differential diagnosis, 855
- prognosis, 855
Spitz nevus, cellular neurothekeoma vs., 291
Spitzoid melanoma, cellular neurothekeoma vs., 291
Squamous cell carcinoma, epithelioid sarcoma vs., 680
Stasis changes, microvenular hemangioma vs., 439
Stasis dermatitis, microvenular hemangioma vs., 439
Sterno(cleido) mastoid (pseudo)tumor of infancy. See
Fibromatosis colli.
Storiform collagenoma, 160–161
- diagnostic checklist, 161
- differential diagnosis, 161
- prognosis, 161
Storiform perineural fibroma. See Perineurioma.
Stromal tumor, gastrointestinal, 744–759
- benign neural gastrointestinal polyps vs., 741
- calcifying fibrous tumor vs., 249
- deep leiomyoma vs., 339
- desmoid-type fibromatosis vs., 170
- differential diagnosis, 747
- epithelioid, extraskeletal myxoid chondrosarcoma vs.,
713
- gastrointestinal schwannoma vs., 761
- gastrointestinal smooth muscle neoplasms vs., 764
- histiocytic sarcoma vs., 325
- idiopathic tumefactive fibroinflammatory lesions vs.,
790
- inflammatory fibroid polyp vs., 767
- inflammatory myofibroblastic tumor vs., 198
- leiomyosarcoma vs., 346
- low-grade endometrial stromal sarcoma vs., 857
- malignant gastrointestinal neuroectodermal tumor vs.,
777
- molecular prognostication, 748
- paraganglioma vs., 816
- plexiform fibromyxoma vs., 773
- prognosis, 745–746
- risk stratification, 748
- solitary fibrous tumor vs., 186
- spindled, gangliocytic paraganglioma vs., 771
Submucosal leiomyoma, benign neural gastrointestinal
polyps vs., 741
Subungual fibroma, storiform collagenoma vs., 161
Superficial acral fibromyxoma
- dermal nerve sheath myxoma vs., 547
- superficial angiomyxoma vs., 621
xxxviii
Superficial angiomyxoma, 620–623
- acral fibromyxoma vs., 625
- deep (aggressive) angiomyxoma vs., 585
- dermal nerve sheath myxoma vs., 547
- differential diagnosis, 621
- juxtaarticular myxoma vs., 619
- prognosis, 621
Superficial CD34(+) fibroblastic tumor (SCD34FT),
210–213
- differential diagnosis, 211
- prognosis, 211
Superficial cutaneous lymphangioma. See Lymphangioma.
Superficial fibromatosis
- dermatomyofibroma vs., 159
- fibroma of tendon sheath vs., 136
- inclusion body fibromatosis vs., 251
Superficial leiomyoma, 334–337
- differential diagnosis, 335
- prognosis, 335
Superficial leiomyosarcoma, superficial leiomyoma vs., 335
Synovial cell sarcoma. See Synovial sarcoma.
Synovial chondroma. See Synovial chondromatosis.
Synovial chondromatosis, 492–495
- diagnostic checklist, 493
- differential diagnosis, 493
- prognosis, 493
- soft tissue chondroma vs., 487–488
Synovial chondrometaplasia. See Synovial chondromatosis.
Synovial chondrosarcoma, synovial chondromatosis vs.,
493
Synovial lipoma. See Synovial lipomatosis.
Synovial lipomatosis, 54–55
- differential diagnosis, 55
- prognosis, 55
Synovial osteochondromatosis. See Synovial
chondromatosis.
Synovial sarcoma, 666–677
- adult-type fibrosarcoma vs., 215
- biphasic, 668
- biphenotypic sinonasal sarcoma vs., 851
- calcifying fibrous tumor vs., 249
- differential diagnosis, 668
- ectopic hamartomatous thymoma vs., 633
- extraskeletal mesenchymal chondrosarcoma vs., 502
- extraskeletal osteosarcoma vs., 498
- infantile fibrosarcoma vs., 265
- leiomyosarcoma vs., 346
- low-grade endometrial stromal sarcoma vs., 857
- malignant gastrointestinal neuroectodermal tumor vs.,
778
- malignant mesothelioma vs., 600
- molecular genetics, 668
- monophasic, 667
clear cell sarcoma vs., 690
malignant peripheral nerve sheath tumor vs., 560
palmar/plantar fibromatosis vs., 167
solitary fibrous tumor vs., 186
spindle cell rhabdomyosarcoma vs., 393
- monoplastic, calcifying aponeurotic fibroma vs., 245
- myxoid liposarcoma vs., 102
 INDEX
- poorly differentiated Tumoral calcinosis, 786–787
BCOR-CCNB3 fusion-positive sarcoma vs., 736 - amyloidoma vs., 783
extraskeletal Ewing sarcoma vs., 708 - differential diagnosis, 787
lymphoma of soft tissue vs., 611 - prognosis, 787
undifferentiated round cell sarcoma with CIC-DUX4 - soft tissue chondroma vs., 488
translocation vs., 730 Tumoral lipocalcinosis. See Tumoral calcinosis.
- prognosis, 667 Tumors of uncertain differentiation
- spindle epithelial tumor with thymus-like differentiation - acral fibromyxoma, 624–625
vs., 855 differential diagnosis, 625
Systemic angiomatosis. See Lymphangioma. prognosis, 625
- alveolar soft part sarcoma, 684–687

T
differential diagnosis, 685
molecular genetics, 685
prognosis, 685
- aneurysmal bone cyst of soft tissue, 630–631
Targetoid hemosiderotic hemangioma differential diagnosis, 631
- glomeruloid hemangioma vs., 443 molecular genetics, 631
- microvenular hemangioma vs., 439 prognosis, 631
Tendinous xanthoma, 295 - angiomatoid fibrous histiocytoma, 642–649
Tendon sheath, fibroma, 134–139 differential diagnosis, 644
- differential diagnosis, 136 molecular genetics, 644
- prognosis, 135 prognosis, 643
Tenosynovial fibroma. See Fibroma, tendon sheath. - atypical fibroxanthoma, 636–641
Tenosynovial giant cell tumor differential diagnosis, 637–638
- diffuse-type, 284–289 immunohistochemistry, 638
differential diagnosis, 286 prognosis, 637
localized-type tenosynovial giant cell tumor vs., 280 - clear cell sarcoma, 688–691
myxoinflammatory fibroblastic sarcoma vs., 204 diagnostic checklist, 690
prognosis, 285 differential diagnosis, 690
synovial lipomatosis vs., 55 molecular genetics, 689
- fibroosseous pseudotumor vs., 131 prognosis, 689
- giant cell tumor of soft tissue vs., 321 of tendon and aponeurosis, 689
- localized-type, 278–283 - desmoplastic small round cell tumor, 700–705
deep benign fibrous histiocytoma vs., 277 differential diagnosis, 701–702
differential diagnosis, 280 immunohistochemistry, 702
diffuse-type tenosynovial giant cell tumor vs., 286 molecular genetics, 701
fibroma of tendon sheath vs., 136 prognosis, 701
prognosis, 279 - ectopic hamartomatous thymoma, 632–633
xanthomas vs., 296 differential diagnosis, 633
- malignant, diffuse-type tenosynovial giant cell tumor prognosis, 633
vs., 286 - epithelioid sarcoma, 678–683
- soft tissue chondroma vs., 488 classic, 679
Teratoma, genital rhabdomyoma vs., 377 differential diagnosis, 680
Thrombus, organizing, spindle cell hemangioma vs., 427 molecular genetics, 680
Tophaceous gout prognosis, 679
- amyloidoma vs., 783 proximal-type, 679–680
- tumoral calcinosis vs., 787 - extrarenal rhabdoid tumor, 716–719
Tophaceous pseudogout differential diagnosis, 718
- soft tissue chondroma vs., 488 genetic factors, 717
- tumoral calcinosis vs., 787 molecular genetics, 717–718
Translocation-associated undifferentiated sarcomas, prognosis, 717
neuroblastoma and ganglioneuroblastoma vs., 834 - extraskeletal Ewing sarcoma, 706–711
Traumatic neuroma, solitary circumscribed neuroma vs., differential diagnosis, 708
507 molecular genetics, 708
Triton tumor, malignant prognosis, 707
- ectomesenchymoma vs., 571 - extraskeletal myxoid chondrosarcoma, 712–715
- embryonal rhabdomyosarcoma vs., 382 differential diagnosis, 713
True inflammatory myopathies, focal myositis vs., 371 genetic testing, 713
Tuberous xanthoma, 295 prognosis, 713
Tumoral amyloidosis. See Amyloidoma. - hemosiderotic fibrolipomatous tumor, 634–635
differential diagnosis, 635
xxxix
 INDEX
molecular genetics, 635
prognosis, 635
- intimal sarcoma, 720–721
differential diagnosis, 721
genetic testing, 721
prognosis, 721
- intramuscular myxoma, 614–617
differential diagnosis, 615
genetic testing, 615
prognosis, 615
- juxtaarticular myxoma, 618–619
differential diagnosis, 619
genetic testing, 619
prognosis, 619
- myoepithelioma of soft tissue, 656–663
differential diagnosis, 658
immunohistochemistry, 658
molecular genetics, 657
prognosis, 657
- ossifying fibromyxoid tumor, 650–655
differential diagnosis, 652
malignant, 651
molecular genetics, 652
prognosis, 651
- perivascular epithelioid cell tumor, 692–699
differential diagnosis, 694
genetics, 693
prognosis, 693
- phosphaturic mesenchymal tumor, 664–665
differential diagnosis, 665
molecular genetics, 665
prognosis, 665
- pleomorphic hyalinizing angiectatic tumor, 626–629
differential diagnosis, 627
molecular genetics, 627
prognosis, 627
- superficial angiomyxoma, 620–623
differential diagnosis, 621
prognosis, 621
- synovial sarcoma, 666–677
biphasic, 668
differential diagnosis, 668
molecular genetics, 668
monophasic, 667
prognosis, 667
U
Undifferentiated carcinoma, pleomorphic
rhabdomyosarcoma vs., 401
Undifferentiated embryonal sarcoma of liver (UESL),
844–845
- differential diagnosis, 845
- prognosis, 845
Undifferentiated pleomorphic sarcoma, 724–727
- adult-type fibrosarcoma vs., 215
- angiomatoid fibrous histiocytoma vs., 644
- dedifferentiated liposarcoma vs., 96
xl
- differential diagnosis, 725
- extranodal Rosai-Dorfman disease vs., 312
- extraskeletal osteosarcoma vs., 498
- with giant cells, giant cell tumor of soft tissue vs., 321
- leiomyosarcoma vs., 346
- metastatic tumors to soft tissue sites vs., 829
- molecular genetics, 725
- myxofibrosarcoma vs., 218
- nodular fasciitis vs., 116
- pleomorphic hyalinizing angiectatic tumor vs., 627
- pleomorphic liposarcoma vs., 108
- prognosis, 725
- proliferative fasciitis/myositis vs., 121
Undifferentiated round cell sarcoma with CIC-DUX4
translocation, 728–733
- diagnostic checklist, 730
- differential diagnosis, 729–730
- immunohistochemistry, 730
- prognosis, 729
Undifferentiated round or spindle cell sarcomas, BCOR-
CCNB3 fusion-positive sarcoma vs., 736
Undifferentiated sarcoma with CIC-DUX4 translocation
- BCOR-CCNB3 fusion-positive sarcoma vs., 736
- extraskeletal Ewing sarcoma vs., 708
Undifferentiated/unclassified sarcomas
- BCOR-CCNB3 fusion-positive sarcoma
diagnostic checklist, 736
differential diagnosis, 736
prognosis, 735
- BCOR-CCNB3 fusion-positive sarcoma, 734–737
- undifferentiated pleomorphic sarcoma, 724–727
differential diagnosis, 725
molecular genetics, 725
prognosis, 725
- undifferentiated round cell sarcoma with CIC-DUX4
translocation, 728–733
diagnostic checklist, 730
differential diagnosis, 729–730
immunohistochemistry, 730
prognosis, 729
V
Vaginal rhabdomyoma. See Genital rhabdomyoma.
Vanek tumor. See Inflammatory fibroid polyp.
Vascular leiomyoma. See Angioleiomyoma.
Vascular lesion, atypical, 452–453
- angiosarcoma vs., 472
- diagnostic checklist, 453
- differential diagnosis, 453
- prognosis, 453
Vascular malformation. See also Angiomatosis.
- congenital hemangioma vs., 414
- infantile hemangioma vs., 418
Vascular neoplasms, BCOR-CCNB3 fusion-positive sarcoma
vs., 736
Vascular proliferation, atypical, lymphangioma vs., 448
Vascular stasis, severe, Kaposi sarcoma vs., 478
 INDEX
Vascular tumors (including lymphatics)
- acquired tufted angioma, 436–437
diagnostic checklist, 437
differential diagnosis, 437
prognosis, 437
- angiomatosis, 444–445
differential diagnosis, 445
prognosis, 445
- angiosarcoma
differential diagnosis, 472
molecular genetics, 472
prognosis, 471
- atypical vascular lesion, 452–453
diagnostic checklist, 453
differential diagnosis, 453
prognosis, 453
- bacillary angiomatosis, 410–411
diagnostic checklist, 411
differential diagnosis, 411
prognosis, 411
- composite hemangioendothelioma, 460–461
differential diagnosis, 461
prognosis, 461
- congenital hemangioma, 412–415
differential diagnosis, 414
genetics, 413
prognosis, 413
- epithelioid hemangioendothelioma
differential diagnosis, 468
molecular genetics, 467
prognosis, 467
- epithelioid hemangioma, 422–425
differential diagnosis, 423
molecular genetics, 423
prognosis, 423
- glomeruloid hemangioma, 442–443
diagnostic checklist, 443
differential diagnosis, 443
prognosis, 443
- hobnail hemangioma, 434–435
diagnostic checklist, 435
prognosis, 435
- infantile hemangioma, 416–419
differential diagnosis, 418
genetics, 417
prognosis, 417
- intramuscular hemangioma, 430–433
differential diagnosis, 431
prognosis, 431
- Kaposi sarcoma
differential diagnosis, 478
prognosis, 477
- kaposiform hemangioendothelioma, 454–455
diagnostic checklist, 455
differential diagnosis, 455
prognosis, 455
- lobular capillary hemangioma, 420–421
differential diagnosis, 421
prognosis, 421
- lymphangioma, 446–449
diagnostic checklist, 448
differential diagnosis, 448
genetics, 447
prognosis, 447
- massive localized lymphedema, 450–451
differential diagnosis, 451
prognosis, 451
- microvenular hemangioma, 438–439
diagnostic checklist, 439
differential diagnosis, 439
hobnail hemangioma vs., 435
Kaposi sarcoma vs., 478
prognosis, 439
- papillary endothelial hyperplasia, 408–409
diagnostic checklist, 409
differential diagnosis, 409
prognosis, 409
- pseudomyogenic hemangioendothelioma, 462–465
differential diagnosis, 463
molecular genetics, 463
prognosis, 463
- retiform hemangioendothelioma, 458–459
diagnostic checklist, 459
differential diagnosis, 459
prognosis, 459
- sinusoidal hemangioma, 440–441
diagnostic checklist, 441
differential diagnosis, 441
prognosis, 441
- spindle cell hemangioma, 426–429
diagnostic checklist, 427
differential diagnosis, 427
prognosis, 427
Venous malformation
- sinusoidal hemangioma vs., 441
- spindle cell hemangioma vs., 427
Verruciform xanthoma, xanthomas vs., 296
Villous lipomatous proliferation of synovial membrane. See
Synovial lipomatosis.
W
Well-differentiated angiosarcoma, atypical vascular lesion
vs., 453
Well-differentiated liposarcoma, 88–93
- dedifferentiated liposarcoma vs., 96
- differential diagnosis, 90
- elastofibromas vs., 143
- idiopathic tumefactive fibroinflammatory lesions vs.,
790
- inflammatory myofibroblastic tumor vs., 198
- ischemic fasciitis vs., 125
- massive localized lymphedema vs., 451
- molecular genetics, 90
- myelolipoma vs., 79
- peripheral hemangioblastoma vs., 823
- prognosis, 89
- synovial lipomatosis vs., 55
xli
 INDEX
Well-differentiated papillary mesothelioma, 594–597
- adenomatoid tumor vs., 591
- differential diagnosis, 595
- prognosis, 595

X
Xanthelasma, 295
Xanthogranuloma, solitary (juvenile), 298–299
- differential diagnosis, 299
- extranodal Rosai-Dorfman disease vs., 312
- prognosis, 299
- reticulohistiocytoma vs., 302
- xanthomas vs., 296
Xanthomas, 294–297
- clinical forms, 296
- differential diagnosis, 296
- eruptive, 295
- hyperlipoproteinemia (Fredrickson) classification, 296
- plexiform, 295
- prognosis, 295
- solitary (juvenile) xanthogranuloma vs., 299
- tuberous, 295
- verruciform, xanthomas vs., 296
Xanthomatosis, cerebrotendinous, 295
Xanthomatous tumor, plexiform. See Xanthomas.

xlii