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Nosé
SECOND EDITION
ii
Second Edition
Vania Nosé, MD, PhD

Associate Chief of Pathology
Director of Anatomic and Molecular Pathology
Massachusetts General Hospital
Professor of Pathology
Harvard Medical School
Boston, Massachusetts
iii
Elsevier
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
DIAGNOSTIC PATHOLOGY: FAMILIAL CANCER SYNDROMES, SECOND EDITION ISBN: 978-0-323-71204-0

Inkling: 978-0-323-71206-4
Copyright © 2020 by Elsevier. All rights reserved.
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This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).
Notices
Practitioners and researchers must always rely on their own experience and knowledge in
evaluating and using any information, methods, compounds or experiments described herein.
Because of rapid advances in the medical sciences, in particular, independent verification of
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assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or
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any methods, products, instructions, or ideas contained in the material herein.
Previous edition copyrighted 2013.
Library of Congress Control Number: 2019956687
Printed in Canada by Friesens, Altona, Manitoba, Canada
Last digit is the print number: 9 8 7 6 5 4 3 2 1
iv
Dedication
Developing a comprehensive book like this could only be accomplished with
high levels of amazing teamwork. I would like to acknowledge and thank so
many remarkable people for their support and contributions to this book. I will
start with my parents, Dalva and Antonio Nosé, for their support, invaluable
teaching and guidance, and for being my life examples. To my wonderful sons
and best friends, Gustave, Erick, and Phillip, and their wives, Carla, Suzana,
and Bianca, and to my grandsons, Nicolas, Leonardo, and Lucas Antonio, you
all make my life so lovely and complete. To my brothers, Dalton and Walton,
and their families for their love and continuous support. To the outstanding
and dedicated contributing authors of this book for their hard work and
contributions to this unique project. To the wonderful Elsevier team for their
extraordinary work in making this book a reality. My final thanks are to all my
family, friends, residents, fellows, colleagues, and everyone who shares our
love and commitment to a better understanding of familial cancer diseases.
VN
v
Contributing Authors
Ying-Hsia Chu, MD Jochen K. Lennerz, MD, PhD
Clinical Fellow Medical Director
Department of Pathology Center for Integrated Diagnostics
Massachusetts General Hospital Associate Chief, Department of Pathology
Boston, Massachusetts Massachusetts General Hospital
Associate Professor
Daniel C. Chung, MD Harvard Medical School
Medical Co-Director, Center for Cancer Risk Assessment Boston, Massachusetts
MGH Cancer Center and Division of Gastroenterology
Director, High-Risk GI Cancer Clinic Susan C. Lester, MD, PhD
Associate Professor of Medicine Associate Pathologist
Harvard Medical School Breast Pathology Services
Boston, Massachusetts Brigham and Women’s Hospital
Assistant Professor
Vikram Deshpande, MD Harvard Medical School
Pathologist Boston, Massachusetts
Department of Pathology
Massachusetts General Hospital Alexander Craig MacKinnon, MD, PhD
Professor of Pathology Director
Harvard Medical School Division of Genomics, Diagnostics, and Bioinformatics
Boston, Massachusetts Professor
Department of Pathology
Alexander J. Gallan, MD University of Alabama at Birmingham
Renal and Genitourinary Pathologist Birmingham, Alabama
Assistant Professor
Department of Pathology Fabiola Medeiros, MD
Medical College of Wisconsin Director of Gynecologic, Placental and
Milwaukee, Wisconsin Perinatal Pathology
Department of Pathology and Laboratory Medicine
David G. Hicks, MD Cedars-Sinai Medical Center
Professor and Director of IHC-ISH Laboratory and Los Angeles, California
Breast Subspecialty Service
University of Rochester Medical Center Mari Mino-Kenudson, MD
Rochester, New York Pathologist, Department of Pathology
Director, Pulmonary Pathology
Mai P. Hoang, MD Massachusetts General Hospital
Professor of Pathology Professor of Pathology
Harvard Medical School Harvard Medical School
Director, Dermatopathology Services Boston, Massachusetts
Boston, Massachusetts Michelle Menon Miyake, MD
Otolaryngologist
Yin Rex Hung, MD, PhD Research Fellow
Assistant in Pathology Department of Otolaryngology
Department of Pathology Massachusetts Eye and Ear Infirmary
Massachusetts General Hospital Harvard Medical School
Boston, Massachusetts Boston, Massachusetts
vi
Valentina Nardi, MD
Assistant Professor of Pathology
Additional Contributing
Assistant in Pathology
Authors
Carla Martins Alberti, MD
Lori A. Erickson, MD
G. Petur Nielsen, MD Larissa V. Furtado, MD
Harvard Medical School Joel K. Greenson, MD
Pathologist, Department of Pathology
Director of Bone & Soft Tissue Pathology
Julie Guilmette, MD
Director of Electron Microscopy Unit Gregory Y. Lauwers, MD
M. Beatriz S. Lopes, MD, PhD
Alexandros D. Polydorides, MD, PhD
Patricia Nogueira de Sa, MD Von Samedi, MD, PhD
Internal Medicine Residency Program
Rochester General Hospital Karen S. Thompson, MD
Rochester, New York
Arthur S. Tischler, MD
Gladell P. Paner, MD, (BS) MT
Associate Professor of Pathology and Surgery,
Section of Urology
Director of Genitourinary Pathology Fellowship
Director of Point of Care Testing
Associate Director UC Medlabs
The University of Chicago Medical Center
Chicago, Illinois
Fausto J. Rodríguez, MD
Associate Professor of Pathology, Oncology and
Ophthalmology
Johns Hopkins University School of Medicine
Baltimore, Maryland
Amitabh Srivastava, MD
Associate Professor of Pathology
Chief, GI Pathology
Associate Director, Surgical Pathology
Director, Surgical Pathology Fellowship Program
Brigham and Women’s Hospital
vii
viii
Preface
Welcome to the second edition of Diagnostic Pathology: Familial Cancer Syndromes!
The expanding use of gene sequencing (as NGS) technologies and our insight in neoplasm-
predisposing genes has greatly impacted our understanding of cancer initiation and progression.
Neoplasms that were formerly considered sporadic have been now redefined as part of novel
hereditary cancer predisposition syndromes. The proportion of tumors with a hereditary background,
and the list of hereditary cancer syndromes and cancer-predisposing genes, has been steadily
increasing. Presently, at least 10% of all tumors develop in the setting of germline predispositions.
Diagnostic Pathology: Familial Cancer Syndromes, second edition, features a comprehensive review
of the top inherited tumor syndromes. It is becoming increasingly well recognized that a given
familial tumor syndrome may be very heterogeneous in clinical appearance, where patients may
present initially with an apparently isolated tumor. It is crucial for clinicians, oncologists, and
surgical pathologists to be aware of the specific clinical and morphological findings that suggest a
possible syndromic association. A significant number of the hereditary neoplasms have distinct and
reproducible morphological and immunophenotypic, as well as molecular, findings.
Written by clinicians, molecular pathologists, and subspecialty pathology experts focused on familial
diseases, this book’s 166 chapters will help clinicians, oncologists, surgical pathologists, fellows, and
residents understand the critical aspects of diagnosing familial tumors and differentiating these
from their sporadic counterparts.
The book is organized into three parts. The first part, “Diagnoses Associated With Syndromes
by Organ,” discusses in detail the diseases encompassing the syndromes, highlighting the
characteristics of the tumors in each organ across the different syndromes. The book points out
some of the distinct characteristics of tumors found in inherited tumor syndromes that distinguish
these tumors from tumors in a sporadic setting. This part also contains tables that can be used as
a quick tumor classification reference.
The second part, “Overview of Syndromes,” has detailed descriptions of the major syndromes,
including genes involved, associated tumors, and diagnostic criteria. We have also included several
newly defined cancer syndromes.
Finally, the third part, “Reference,” offers a detailed index of each gene referenced in the book and
in which chapters each gene appears.
We hope that this second edition of Diagnostic Pathology: Familial Cancer Syndromes will guide you
to master diagnostic criteria when diagnosing tumors associated with inherited tumor syndromes.

Associate Chief of Pathology
Director of Anatomic and Molecular Pathology
ix
x
Acknowledgments
LEAD EDITOR
Arthur G. Gelsinger, MA
TEXT EDITORS
Nina I. Bennett, BA
Rebecca L. Bluth, BA
Terry W. Ferrell, MS
Megg Morin, BA
Kathryn Watkins, BA
IMAGE EDITORS
Jeffrey J. Marmorstone, BS
Lisa A. M. Steadman, BS
MEDICAL EDITORS
Daniel C. Chung, MD
Jochen K. Lennerz, MD, PhD
Alexander Craig MacKinnon, MD, PhD
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
xi
xii
Sections
PART I: Diagnoses Associated With Syndromes by Organ
SECTION 1: Blood and Bone Marrow
SECTION 2: Bone and Soft Tissue
SECTION 3: Breast
SECTION 4: Endocrine
SECTION 5: Gastrointestinal
SECTION 6: Genitourinary
SECTION 7: Gynecology
SECTION 8: Head and Neck
SECTION 9: Nervous System
SECTION 10: Pulmonary
SECTION 11: Skin
PART II: Overview of Syndromes

SECTION 1: Introduction
SECTION 2: Syndromes
PART III: Reference

SECTION 1: Molecular Factors
xiii
TABLE OF CONTENTS
Part I: Diagnoses Associated With ADRENAL MEDULLA AND PARAGANGLIA

Syndromes by Organ 88 Adrenal Medullary Hyperplasia
92 Neuroblastic Tumors of Adrenal Gland
SECTION 1: BLOOD AND BONE MARROW
4 Acute Lymphoblastic Leukemia and Non-Hodgkin 104 Pheochromocytoma and Paraganglioma
Lymphoma Vania Nosé, MD, PhD and Arthur S. Tischler, MD
Valentina Nardi, MD 114 Adrenal Medulla and Paraganglia Table
6 Blood and Bone Marrow Table Vania Nosé, MD, PhD
Valentina Nardi, MD
PANCREAS
SECTION 2: BONE AND SOFT TISSUE 118 Pancreatic Neuroendocrine Neoplasms
10 Chondrosarcoma Vania Nosé, MD, PhD
G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD 128 Endocrine Pancreas Table
14 Chordoma Vania Nosé, MD, PhD
G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD
18 Malignant Peripheral Nerve Sheath Tumor PARATHYROID
G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD 130 Parathyroid Adenoma
22 Osteosarcoma Vania Nosé, MD, PhD and Lori A. Erickson, MD
G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD 136 Parathyroid Carcinoma
28 Rhabdomyosarcoma Vania Nosé, MD, PhD and Lori A. Erickson, MD
G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD 142 Primary Parathyroid Hyperplasia
32 Schwannoma Lori A. Erickson, MD and Vania Nosé, MD, PhD
G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD 152 Parathyroid Table
36 Bone and Soft Tissue Table Vania Nosé, MD, PhD
G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD
PITUITARY
SECTION 3: BREAST
158 Pituitary Adenoma
46 Breast Carcinoma M. Beatriz S. Lopes, MD, PhD and Vania Nosé, MD, PhD
Susan C. Lester, MD, PhD and David G. Hicks, MD 164 Pituitary Hyperplasia
54 Breast Table M. Beatriz S. Lopes, MD, PhD
David G. Hicks, MD and Susan C. Lester, MD, PhD 166 Pituitary Table
SECTION 4: ENDOCRINE
ADRENAL CORTEX THYROID, MEDULLARY
170 C-Cell Hyperplasia
58 Adrenal Cortical Adenoma
176 Medullary Thyroid Carcinoma
62 Adrenal Cortical Carcinoma
Vania Nosé, MD, PhD and Julie Guilmette, MD
186 Thyroid, Medullary Carcinoma Table
70 Adrenal Cortical Neoplasms in Children
78 Primary Pigmented Nodular Adrenocortical Disease THYROID, NONMEDULLARY
84 Adrenal Cortex Table 188 Familial Thyroid Carcinoma
Vania Nosé, MD, PhD Vania Nosé, MD, PhD
200 Follicular Thyroid Carcinoma
xiv
TABLE OF CONTENTS
208 Thyroid, Nonmedullary Carcinoma Table 308 Succinate Dehydrogenase-Deficient Renal Cell
Vania Nosé, MD, PhD Carcinoma
Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS)
SECTION 5: GASTROINTESTINAL MT
312 Wilms Tumor
HEPATOBILIARY AND PANCREAS
212 Hepatoblastoma MT
Larissa V. Furtado, MD and Karen S. Thompson, MD 320 Kidney Table
218 Hepatocellular Carcinoma Gladell P. Paner, MD, (BS) MT
222 Pancreatic Adenocarcinoma PROSTATE
Amitabh Srivastava, MD and Von Samedi, MD, PhD 326 Prostate Carcinoma
226 Biliary Tract/Liver/Pancreas Table Gladell P. Paner, MD, (BS) MT
Amitabh Srivastava, MD 338 Prostate Table
TUBULAR GUT
228 Colonic Adenomas RENAL PELVIS AND URETER
Ying-Hsia Chu, MD and Vikram Deshpande, MD 344 Renal Urothelial Carcinoma
234 Esophageal Adenocarcinoma Gladell P. Paner, MD, (BS) MT
Ying-Hsia Chu, MD and Vikram Deshpande, MD 348 Ureter Urothelial Carcinoma
236 Esophageal Squamous Cell Carcinoma Gladell P. Paner, MD, (BS) MT
Ying-Hsia Chu, MD and Vikram Deshpande, MD 350 Renal Pelvis and Ureter Table
238 Gastric Adenocarcinoma Gladell P. Paner, MD, (BS) MT
Ying-Hsia Chu, MD and Vikram Deshpande, MD
244 Gastrointestinal Stromal Tumor TESTICLE
352 Germ Cell Tumor
252 Hamartomatous Polyposis Syndromes
Vania Nosé, MD, PhD and Amitabh Srivastava, MD
358 Sertoli Cell Neoplasms
262 Small Bowel Adenocarcinoma
362 Testicle Table
268 Colon/Rectum Table
Joel K. Greenson, MD and Amitabh Srivastava, MD
270 Esophagus/Stomach/Small Bowel Table SECTION 7: GYNECOLOGY
370 Cervical Carcinoma
SECTION 6: GENITOURINARY Fabiola Medeiros, MD
372 Fallopian Tube Carcinoma
BLADDER Fabiola Medeiros, MD
274 Bladder Urothelial Carcinoma 374 Ovarian Tumors
Gladell P. Paner, MD, (BS) MT Fabiola Medeiros, MD
282 Bladder Table 380 Endometrial Carcinoma
Gladell P. Paner, MD, (BS) MT Fabiola Medeiros, MD
384 Gynecologic Tumors
KIDNEY Fabiola Medeiros, MD
286 Angiomyolipoma SECTION 8: HEAD AND NECK
290 Clear Cell Renal Cell Carcinoma 390 Endolymphatic Sac Tumor
Gladell P. Paner, MD, (BS) MT Vania Nosé, MD, PhD
294 Cystic Nephroma 394 Head and Neck Squamous Cell Carcinoma
Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS) Vania Nosé, MD, PhD
MT 400 Head and Neck Table
296 HLRCC Syndrome-Associated Renal Cell Carcinoma Vania Nosé, MD, PhD
Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS) 404 Salivary Glands Table
MT Vania Nosé, MD, PhD
300 Papillary Renal Cell Carcinoma
SECTION 9: NERVOUS SYSTEM
304 Renal Oncocytoma, Chromophobe, and Hybrid 412 Central Nervous System
Tumors Fausto J. Rodríguez, MD
xv
TABLE OF CONTENTS
416 Eye 522 Bloom Syndrome
Fausto J. Rodríguez, MD Valentina Nardi, MD
420 Peripheral Nervous System 524 Brooke-Spiegler Syndrome
Fausto J. Rodríguez, MD Mai P. Hoang, MD
528 Carney Complex
SECTION 10: PULMONARY Vania Nosé, MD, PhD
426 Adenocarcinoma, Lung 536 Colonic Carcinoma Syndromes
Mari Mino-Kenudson, MD Joel K. Greenson, MD and Amitabh Srivastava, MD
432 Adenocarcinoma With Lepidic (Bronchioloalveolar) 540 Costello Syndrome
Predominant Pattern Mai P. Hoang, MD
Mari Mino-Kenudson, MD 542 Denys-Drash Syndrome
434 Lymphangioleiomyomatosis Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS)
Mari Mino-Kenudson, MD MT
438 Neuroendocrine Tumor, Lung 546 Diamond-Blackfan Anemia
Mari Mino-Kenudson, MD and Yin Rex Hung, MD, PhD Valentina Nardi, MD
442 Pleuropulmonary Blastoma 548 DICER1 Syndrome
Mari Mino-Kenudson, MD and Yin Rex Hung, MD, PhD Vania Nosé, MD, PhD and Michelle Menon Miyake, MD
444 Lung Table 556 Down Syndrome
Mari Mino-Kenudson, MD Valentina Nardi, MD
560 Dyskeratosis Congenita
SECTION 11: SKIN Mai P. Hoang, MD
564 Familial Acute Myeloid Leukemia and
448 BAP1-Inactivated Melanocytic Tumor
Mai P. Hoang, MD Myelodysplastic Syndrome
450 Basal Cell Carcinoma Valentina Nardi, MD
Mai P. Hoang, MD 568 Familial Adenomatous Polyposis
456 Cutaneous Melanoma Alexandros D. Polydorides, MD, PhD and Vania Nosé, MD,
Mai P. Hoang, MD PhD
460 Cutaneous Squamous Cell Carcinoma 576 Familial Chordoma
Mai P. Hoang, MD G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD
466 Sebaceous Carcinoma 578 Familial Gastrointestinal Stromal Tumor
Mai P. Hoang, MD Vania Nosé, MD, PhD and Daniel C. Chung, MD
472 Skin Table 584 Familial Infantile Myofibromatosis
Mai P. Hoang, MD G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD
586 Familial Isolated Hyperparathyroidism
Part II: Overview of Syndromes 590 Familial Nonmedullary Thyroid Carcinoma
SECTION 1: INTRODUCTION 596 Familial Paraganglioma Pheochromocytoma
476 Pathology of Familial Tumor Syndromes Syndrome
Vania Nosé, MD, PhD Vania Nosé, MD, PhD and Arthur S. Tischler, MD
484 Clinical Diagnosis and Management of 600 Familial Testicular Tumor
Familial/Hereditary Tumor Syndromes
602 Familial Uveal Melanoma
Vania Nosé, MD, PhD and Daniel C. Chung, MD
494 Molecular Aspects of Familial/Hereditary Tumor
604 Familial Wilms Tumor
Syndromes
Alexander Craig Mackinnon, MD, PhD
MT
SECTION 2: SYNDROMES 606 Fanconi Anemia
Valentina Nardi, MD
502 Ataxia Telangiectasia 608 Glucagon Cell Hyperplasia and Neoplasia
Fausto J. Rodríguez, MD Vania Nosé, MD, PhD
504 BAP1 Tumor Predisposition Syndrome 610 Breast/Ovarian Cancer Syndrome: BRCA1
Mai P. Hoang, MD Susan C. Lester, MD, PhD and David G. Hicks, MD
506 Basal Cell Nevus Syndrome/Gorlin Syndrome 616 Breast/Ovarian Cancer Syndrome: BRCA2
Mai P. Hoang, MD David G. Hicks, MD and Susan C. Lester, MD, PhD
510 Beckwith-Wiedemann Syndrome 620 Hereditary Diffuse Gastric Cancer
Vania Nosé, MD, PhD and Patricia Nogueira de Sa, MD Joel K. Greenson, MD and Daniel C. Chung, MD
518 Birt-Hogg-Dubé Syndrome
Mai P. Hoang, MD
xvi
TABLE OF CONTENTS
624 Hereditary Leiomyomatosis and Renal Cell 744 Hamartomatous Polyps, Peutz-Jeghers
Carcinoma Syndrome Gregory Y. Lauwers, MD and Amitabh Srivastava, MD
Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS) 750 PTEN-Hamartoma Tumor Syndromes
MT Vania Nosé, MD, PhD
628 Hereditary Mixed Polyposis Syndrome 758 RASopathies: Noonan Syndrome
Joel K. Greenson, MD Valentina Nardi, MD
630 Multiple Osteochondromas 762 Rhabdoid Predisposition Syndrome
G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD Fausto J. Rodríguez, MD
632 Hereditary Neuroblastoma 766 Schwannomatosis
Vania Nosé, MD, PhD Fausto J. Rodríguez, MD
636 Hereditary Pancreatic Cancer Syndrome 770 Shwachman-Diamond Syndrome
Daniel C. Chung, MD and Vania Nosé, MD, PhD Valentina Nardi, MD
640 Hereditary Papillary Renal Cell Carcinoma 772 Steatocystoma Multiplex
Gladell P. Paner, MD, (BS) MT Mai P. Hoang, MD
642 Hereditary Paraganglioma/Pheochromocytoma 774 Tuberous Sclerosis Complex
Syndromes Fausto J. Rodríguez, MD
Vania Nosé, MD, PhD 780 Tumor Syndromes Predisposing to Osteosarcoma
650 Hereditary Prostate Cancer G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD
Gladell P. Paner, MD, (BS) MT 782 von Hippel-Lindau Syndrome
652 Hereditary Renal Epithelial Tumors, Others Vania Nosé, MD, PhD and Carla Martins Alberti, MD
Gladell P. Paner, MD, (BS) MT 790 Werner Syndrome/Progeria
656 Hereditary Retinoblastoma Mai P. Hoang, MD
Fausto J. Rodríguez, MD 794 Wilms Tumor-Associated Syndromes
658 Hereditary SWI/SNF Complex Deficiency Syndromes Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS)
Fausto J. Rodríguez, MD MT
660 Howel-Evans Syndrome/Keratosis Palmares and 796 Wiskott-Aldrich Syndrome
Plantares With Esophageal Cancer Valentina Nardi, MD
Mai P. Hoang, MD 798 Xeroderma Pigmentosum
662 Hyperparathyroidism-Jaw Tumor Syndrome Mai P. Hoang, MD
668 Juvenile Polyposis Syndrome
Daniel C. Chung, MD, Gregory Y. Lauwers, MD, and
Part III: Reference
674 Li-Fraumeni Syndrome
SECTION 1: MOLECULAR FACTORS
David G. Hicks, MD and Susan C. Lester, MD, PhD 804 Molecular Factors Index
680 Lynch Syndrome Vania Nosé, MD, PhD
Joel K. Greenson, MD, Daniel C. Chung, MD, and Vania
Nosé, MD, PhD
686 McCune-Albright Syndrome
692 Melanoma/Pancreatic Carcinoma Syndrome
Mai P. Hoang, MD
696 Multiple Endocrine Neoplasia Type 1 (MEN1)
Vania Nosé, MD, PhD and Michelle Menon Miyake, MD
718 MUTYH-Associated Polyposis
720 Neurofibromatosis Type 1
728 Neurofibromatosis Type 2
734 Nijmegen Breakage Syndrome
Valentina Nardi, MD
736 Pancreatic Neuroendocrine Tumor Syndromes
xvii
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Nosé
SECOND EDITION
PART I
SECTION 1
Blood and Bone Marrow
Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma 4

Blood and Bone Marrow Table 6
Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma
KEY FACTS
Diagnoses Associated With Syndromes by Organ:
CLINICAL ISSUES ○ Germline IKZF1 mutations

• Acute lymphoblastic leukemia (ALL) • ALL as manifestations of genetic syndromes
○ Not exclusively sporadic disease ○ Li-Fraumeni syndrome
○ Risk of developing B-acute lymphoblastic leukemia (B- ○ Down syndrome
ALL) is 2-4x increased among siblings of affected children ○ Wiskott-Aldrich syndrome
• Number of genetic alterations that predispose individuals ○ Bloom syndrome
to development of ALL is growing ○ Ataxia telangiectasia syndrome
• Children with ALL should have thorough history and ○ Constitutional mismatch repair syndrome
focused physical exam or be referred to screen for ○ Nijmegen breakage syndrome
potential familial syndrome ○ Familial platelet disorder due to RUNX1 mutations
• Implications for preimplantation genetic diagnosis, ○ Fanconi anemia
management of patient and relatives, screening of related ○ Neurofibromatosis type 1
stem cell donors ○ Noonan syndrome
DIAGNOSTIC CHECKLIST • Genetic predisposition to lymphoma
○ No known syndromes predisposing exclusively to
• Familial B-ALL due to
lymphomas
○ Germline PAX5 mutations
○ Syndromes leading to immunodeficiency can predispose
○ Germline ETV6 mutations or deletions
to NHL
○ Germline SH2B3 mutations
B-ALL/Lymphoma in Bone Marrow B-ALL/Lymphoma Morphology

(Left) Bone marrow is 100%
cellular. Hematopoietic
marrow is replaced by blasts
with high nuclear:cytoplasmic
ratio conferring the blue
appearance at low power.
(Right) Lymphoid blasts can
have irregular nuclear
contours mimicking myeloid
blasts. The chromatin is
vesicular, and distinct nucleoli
can be seen.
B-ALL/Lymphoma in Bone Marrow Aspirate B-ALL/Lymphoma in Lymph Node

(Left) High-power view shows
bone marrow involved by B-
ALL. The cellularity consists of
sheets of small- to medium-
sized blasts, with scant
cytoplasm, slightly indented,
irregular nuclei, fine
chromatin, and occasional
distinct nucleoli. (Right) Sheets
of immature cells with open
chromatin and distinct nucleoli
consistent with blasts are
filling the sinuses and
replacing the parenchyma.
4
Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma

• 25-30% of patients with germline ETV6 mutations will
TERMINOLOGY develop B-ALL; in addition some may develop solid tumors
Abbreviations &/or myeloid malignancies
• Acute lymphoblastic leukemia (ALL) Familial B-ALL Due to Germline SH2B3 Mutations
• Non-Hodgkin lymphoma (NHL)
• SH2B adaptor protein 3 (SH2B3) gene (a.k.a. LNK) encodes
negative regulator of cytokine signaling and tyrosine
ETIOLOGY/PATHOGENESIS kinases
ALL as Manifestation of Genetic Syndromes • SH2B3 plays critical role in development and function of
• Li-Fraumeni (pediatric hypodiploid B-ALL) hematopoietic stem cells and lymphoid progenitors
• Down syndrome (often characterized by somatic CRLF2 • Biallelic germline loss of function mutations in SH2B3 are
rearrangements) associated with familial developmental delay,
• Wiskott-Aldrich syndrome autoimmunity, and B-ALL
• Bloom syndrome • ALL with sporadic or germline SH2B3 mutations, may be
• Ataxia telangiectasia: T-ALL > B-ALL sensitive to kinase inhibitors or agents inhibiting activated
JAK-STAT pathway
• Constitutional mismatch repair syndrome
• Nijmegen breakage syndrome: T-ALL > B-ALL Familial B-ALL Due to Germline IKZF1 Mutations
• Familial platelet disorder with predisposition to myeloid • IKZF1 encodes zinc finger transcription factor IKAROS,
malignancy due to RUNX1 mutations (T-ALL) critical regulator of lymphoid development
• Fanconi anemia • ~ 0.9% of presumed sporadic pediatric B-ALL will have
• Neurofibromatosis type I germline IKZF1 variants
• Noonan syndrome • Germline IKZF1 variants tend to cluster outside known
annotated functional domains
Familial B-ALL Secondary to Germline Mutations in
• Germline IKZF1 alterations predispose to ALL, with variable
Genes Somatically Mutated in ALL
penetrance, and potentially reduce response to
• PAX5 chemotherapy and kinase inhibitors
• ETV6 • Some patients with germline IKZF1 variants have B
• SH2B3 lymphopenia
• IKZF1
Genetic Predisposition to Lymphoma MICROSCOPIC
• Currently no known syndromes predisposing exclusively to Histologic Features
lymphomas (mostly NHL) • Histologically indistinguishable from pediatric sporadic
• Syndromes leading to immunodeficiency can predispose to acute lymphoblastic leukemia/lymphoma and from
NHL sporadic Hodgkin and non-Hodgkin lymphomas
○ Ataxia telangiectasia (also at risk for Hodgkin lymphoma)
○ Bloom syndrome ANCILLARY TESTS
○ Nijmegen breakage syndrome Genetic Testing
○ Wiskott Aldrich syndrome
• Targeted gene sequencing to detect point mutations,
○ Constitutional mismatch repair syndrome insertions and deletions
• Microarrays, multiplex ligation-dependent probe
CLINICAL ISSUES amplification-based (MLPA), or next-generation sequencing
Familial B-ALL Due to Germline PAX5 Mutations assays to detect large-scale genomic
• B-cell transcription factor paired box protein PAX5 is rearrangements &/or deletions
essential for normal B-cell development • Preferred tissue for germline genetic testing in patients
• PAX5 is somatically deleted, rearranged, or otherwise with hematologic malignancy are cultured skin fibroblasts
mutated in ~ 30% of sporadic B-ALL
• Heterozygous hypomorph germline mutations (i.e., SELECTED REFERENCES
p.Gly183Ser) need somatic loss of wild-type PAX5 allele to 1. Pui CH et al: Somatic and germline genomics in paediatric acute
be leukemogenic lymphoblastic leukaemia. Nat Rev Clin Oncol. 16(4):227-40, 2019
2. Rampersaud E et al: Germline deletion of ETV6 in familial acute
Familial B-ALL Due to Germline ETV6 Mutations or lymphoblastic leukemia. Blood Adv. 3(7):1039-46, 2019
3. Churchman ML et al: Germline genetic IKZF1 variation and predisposition to
Deletions childhood acute lymphoblastic leukemia. Cancer Cell. 33(5):937-48.e8, 2018
• ETV6 is ETS family transcriptional repressor essential for 4. Auer F et al: Inherited susceptibility to pre B-ALL caused by germline
bone marrow haematopoiesis transmission of PAX5 c.547G>A. Leukemia. 28(5):1136-8, 2014
5. Perez-Garcia A et al: Genetic loss of SH2B3 in acute lymphoblastic leukemia.
• Many germline ETV6 variants have dominant negative Blood. 122(14):2425-32, 2013
effect on transcriptional repression mediated by wild-type
protein
• Heterozygous germline mutations in ETV6 are associated
with thrombocytopenia and predisposition to B-ALL with
hyperdiploid karyotype
5
Diagnoses Associated With Syndromes by Organ: Blood and Bone Marrow Table
Germline Mutations and Conditions Associated With Increased Risk of Hematological

Malignancies
Disorder Genes Inheritance Hematologic Nonhematological Additional Clinical
Malignancy Malignancies Findings
Fanconi anemia FANCA, FANCB*, AR MDS, AML, [ALL Squamous cell Short stature, skin
FANCC, FANCD1 * X-linked with FANCD1 carcinomas of head and pigmentation, skeletal and
(BRCA2), FANCD2, ** AD (BRCA2)] neck, vulva, GI tract; liver thumb abnormalities,
FANCE, FANCF, tumors; brain tumors facial dysmorphisms,
FANCG, FANCI, FANCJ and Wilms tumor renal, gonadal, cardiac, GI,
(BRIP1/BACH1), [FANCD1 (BRCA2)] and CNS abnormalities
FANCL, FANCM,
FANCN (PALB2),
FANCO (RAD51C),
FANCP (SLX4), FANCQ
(ERCC4), FANCR
(RAD51)**, FANCS
(BRCA1), FANCT
(UBE2T), FANCU
(XRCC2), FANCV
(MAD2L2/REV7)
Diamond-Blackfan anemia RPL5, RPL11, RPL15, AD MDS, AML Osteosarcoma, soft Macrocytic anemia, short
RPL23, RPL 26, RPL27, tissue sarcomas stature, thumb
RPL31, RPL35A, abnormalities, facial
RPL36, RPS7, RPS10, dysmorphisms, cleft
RPS15, RPS17, RPS19, lip/palate, Pierre Robin
RPS24, RPS26, RPS27, syndrome, cardiac and
RPS27A, RPS28, genitourinary
RPS29, abnormalities
GATA1
TSR2
X-linked
X-linked
Dyskeratosis congenita DKC1 X-linked MDS, AML, AA Squamous cell Nail dystrophy, rash,
TERC AD carcinomas of head and leukoplakia, short stature,
TERT AD, AR neck, GI tract pulmonary fibrosis,
NOLA3/NOP10 AR vascular anomalies, early
NOLA2/NHP2 AR graying of hair, hair loss;
TINF2 AD dental, CNS, GI and GU
WRAP53/TCAB1 AR abnormalities
CTC1 AR
RTEL1 AD, AR
ACD/TPP1 AD, AR
PARN AD, AR
NAF1 AD
STN1 AD
Shwachman-Diamond syndrome SBDS AR MDS, AML - Short stature, steatorrhea,
metaphyseal dysostosis
Severe congenital neutropenia ELANE AD MDS, AML - Neurological
HAX1 AR abnormalities
Familial MDS/AML with mutated GATA2 AD MDS, AML, - Warts, atypical
GATA2 CMML mycobacteria,
lymphedema, deafness,
pulmonary alveolar
proteinosis, arteriovenous
malformations
MIRAGE syndrome SAMD9 AD MDS, AML - Short stature, adrenal
hypoplasia, infections;
CNS, GI, GU, and skeletal
abnormalities
Ataxia-pancytopenia syndrome SAMD9L AD MDS, AML - Ataxia (variable)
Myeloid neoplasm with mutated SRP72 AD MDS - Sensorineural hearing loss
6
Blood and Bone Marrow Table

Germline Mutations and Conditions Associated With Increased Risk of Hematological
Malignancies (Continued)
Disorder Genes Inheritance Hematologic Nonhematological Additional Clinical
Malignancy Malignancies Findings
SRP72
Familial MDS/AML with mutated DDX41 AD MDS, AML - -
DDX41
Familial platelet disorder RUNX1 AD MDS, AML, ALL - Thrombocytopenia and
with propensity to abnormal platelet
myeloid malignancy function
Thrombocytopenia 2 ANKRD26 AD MDS, AML - Thrombocytopenia and
abnormal platelet
function
Thrombocytopenia 5 ETV6 AD ALL, MDS, AML - Thrombocytopenia and
abnormal platelet
function
Familial AML with CEBPA CEBPA AD AML - -
mutation
Li-Fraumeni TP53 AD ALL, MDS, AML Breast, soft tissue -
sarcomas, brain,
adrenocortical
carcinoma, lung, colon,
pancreas, Wilms,
prostate
Susceptibility to ALL3 PAX5 AD ALL - -
Constitutional mismatch MLH1 AR Lymphoma, CNS, GI tract, other Café au lait spots, axillary
repair deficiency PMS2 AR ALL, AML freckling, Lisch nodules,
syndrome MSH2 AR neurofibromas, intestinal
MSH6 AR adenomas
Wiskott Aldrich WAS X-linked Lymphoma, Thrombocytopenia,
leukemia neutropenia, eczema,
infections, autoimmune
disorders
Nijmegen breakage syndrome NBN AR Lymphoma Gliomas, Severe microcephaly,
rhabdomyosarcoma, abnormal facies, other
medulloblastoma malformations
Bloom syndrome BLM AR Lymphoma, Colon, skin cancer, Facial rash with butterfly
MDS, ALL squamous cell distribution, other
carcinomas of head and dermatologic
neck, Wilms tumor, and manifestations, chronic
others, at early age obstructive lung disease,
endocrine abnormalities
Ataxia telangiectasia ATM AR Lymphoma, Solid tumors -
leukemia
Noonan syndrome PTPN11, SOS1, RAF1, AD JMML Rhabdomyosarcoma, Short stature,
KRAS, NRAS, BRAF, neuroblastoma macrocephaly, feeding
MAP2K1 difficulty, cardiac defects,
other
AD = autosomal dominant; AR = autosomal recessive; A<L = acute myeloid leukemia: ALL = acute lymphoblastic leukemia; JMML = juvenile
myelomonocytic leukemia; MDS = myelodysplasic syndrome.
Godley LA et al: Genetic predisposition to hematologic malignancies: management and surveillance. Blood, 130(4):424-432), 2017.
7
PART I
SECTION 2
Bone and Soft Tissue
Chondrosarcoma 10
Chordoma 14
Malignant Peripheral Nerve Sheath Tumor 18
Osteosarcoma 22
Rhabdomyosarcoma 28
Schwannoma 32
Bone and Soft Tissue Table 36
Chondrosarcoma
KEY FACTS
TERMINOLOGY – Ollier disease and Maffucci syndrome: Somatic

• Malignant cartilaginous matrix-producing tumor postzygotic mutation in IDH1/IDH2
• Secondary chondrosarcoma arises in association with – Metachondromatosis: Germline mutation in PTPN11
preexisting benign tumor or diseased bone ○ Hereditary multiple exostoses/osteochondromatosis:
• Atypical cartilaginous tumor is used for tumor arising in Germline mutation in EXT1/EXT2
appendicular skeleton with microscopic appearance CLINICAL ISSUES
identical to grade 1 chondrosarcoma
• Conventional central chondrosarcoma accounts for > 90%
• Dedifferentiated chondrosarcoma contains high-grade of all chondrosarcomas
nonchondrogenic sarcoma juxtaposed to low-grade
• Atypical cartilaginous tumor can be treated conservatively
cartilaginous tumor
with curettage
ETIOLOGY/PATHOGENESIS MACROSCOPIC
• > 90% of cases sporadic
• Permeation of medullary cavity, scalloping of endosteal
○ Somatic mutations in IDH1/IDH2 in 50-60% and COL2A1 surface, cortical thickening
in 20-40% of tumors
• Secondary cases associated with MICROSCOPIC
enchondromatosis/osteochondromatosis • Infiltration of preexisting trabecular bone is single most
○ Enchondromatosis important histologic criterion
• Histologic grading (grades 1, 2, and 3) is prognostic
Pelvic Chondrosarcoma Pelvic Chondrosarcoma

(Left) Axial CT shows a large
chondrosarcoma ﬊ arising
from the left iliac wing with
scattered ring and arc
mineralization ﬆ. (Right)
Gross photograph shows pelvic
chondrosarcoma in the same
patient. The tumor is
lobulated with a blue-gray cut
surface ﬅ; adjacent residual
normal bone can be seen ﬇.
Conventional Chondrosarcoma in Proximal

Chondrosarcoma Tibia
(Left) Radiograph shows a
chondrosarcoma in the
proximal tibia with ill-defined
border and characteristic ring
and arc mineralization ﬉.
(Right) Gross photograph
shows conventional
chondrosarcoma with a blue-
gray cut surface in the same
patient.
10
Chondrosarcoma

• Most commonly pelvis (especially ilium), followed by
TERMINOLOGY proximal/distal femur, proximal humerus, and ribs
Definitions ○ In long bones, chondrosarcoma usually involves
• Malignant cartilaginous matrix-producing tumor of bone metaphysis or diaphysis
○ Primary chondrosarcoma: Arises in medullary cavity • Rarely (< 1%) develops in small bones of hands and feet
(conventional type) or on bone surface • Chondrosarcomas of cranium usually involve skull base
(periosteal/juxtacortical type) • Secondary chondrosarcomas: Arise in association with
○ Secondary chondrosarcoma: Arises from preexisting preexisting osteochondromas/enchondromas
benign tumor (e.g., enchondroma, osteochondroma) or
Presentation
diseased bone (e.g., radiation, Paget disease)
○ Atypical cartilaginous tumor: Low-grade cartilaginous • Pain, enlarging mass, &/or pathologic fracture
tumor in appendicular skeleton with microscopic • Skull-based tumors: Headache, cranial nerve palsies
appearance identical to grade 1 chondrosarcoma • Abrupt mass enlargement and worsening of clinical
○ Dedifferentiated chondrosarcoma: High-grade symptoms in preexisting osteochondromas/enchondromas
nonchondrogenic sarcoma juxtaposed to areas of low- Treatment
grade cartilaginous tumor
• Curettage for atypical cartilaginous tumor
• Wide surgical resection for grade 1 chondrosarcomas
ETIOLOGY/PATHOGENESIS
arising in axial skeleton and high-grade chondrosarcoma
Sporadic • Adjuvant chemotherapy considered in dedifferentiated
• > 90% of cases chondrosarcomas
• Rarely arise associated with solitary sporadic/nonsyndromic • Radiation considered in surgically unresectable tumors
osteochondroma Prognosis
• 50-60% of cases harbor somatic mutations in isocitrate
dehydrogenase IDH1 or IDH2 • Histologic grade is single most important prognostic factor
• 20-40% of cases harbor somatic mutations in major • Atypical cartilaginous tumors show excellent prognosis
cartilage collagen gene COL2A1 with conservative surgical curettage treatment
• Grade 1 chondrosarcomas are locally aggressive
Hereditary Multiple Exostosis/Osteochondromatosis ○ 5-year survival ~ 80-85%
• Autosomal dominant • Grades 2-3 chondrosarcomas show worse prognosis
○ Mutations in EXT1 (8q24) or EXT2 (11p11) ○ 5-year survival ~ 50%
○ As part of trichorhinophalangeal syndrome type 2 • Dismal prognosis in dedifferentiated chondrosarcomas
(Langer-Giedion syndrome) ○ Median survival < 1-2 years, frequent metastases
– Disruption/microdeletion of genes including EXT1
○ As part of Potocki-Schaffer syndrome IMAGING
– Disruption/microdeletion of genes including EXT2 Radiographic Findings
• Develop multiple exostoses/osteochondromas often by
• Lytic with irregular spiculations and radiodensities caused
2nd decade of life
by matrix calcification
• Risk of malignant transformation 2-25%
• Densities often in "rings and arcs" configuration indicative
Enchondromatosis of endochondral ossification and reactive bone formation
• Sporadic (Ollier disease, Maffucci syndrome) or familial • Low-grade tumors often show mineralization, bone
(metachondromatosis) expansion, endosteal scalloping, and thickening of cortex
○ Ollier disease and Maffucci syndrome • High-grade tumors often show large radiolucency, cortical
– Somatic postzygotic mutation in isocitrate destruction/permeation, frequently accompanied by soft
dehydrogenase genes IDH1 or IDH2 tissue extension
– Maffucci syndrome differs from Ollier disease with MR Findings
additional development of vascular tumors (spindle
• Helpful in visualizing tumor extent, particularly in soft tissue
cell hemangiomas)
• Dark on T1WI
– Risk of malignant transformation up to 35-40%
• Bright on T2WI
○ Metachondromatosis
• Cartilage cap of > 2 cm in osteochondroma may raise
– Autosomal dominant
concern for malignant transformation but not entirely
– Develops multiple enchondromas and
sufficient
osteochondromas
• Contrast enhancement may aid in distinguishing secondary
– Germline PTPN11 loss-of-function mutation
chondrosarcoma from preexisting
– Risk of malignant transformation unclear osteochondroma/enchondroma
CLINICAL ISSUES CT Findings

Site • Unmineralized and mineralized components of tumor
delineated in medullary or cortical lesion
• Arise in bone derived from endochondral ossification
11
Diagnoses Associated With Syndromes by Organ: Chondrosarcoma
• Recurrent GRM1 gene rearrangement in subset of tumors

MACROSCOPIC
General Features Chondroid Chordoma
• Usually arises in skull base
• Low-grade tumors permeate medullary cavity, scallop
endosteal surface, and produce cortical thickening • Can be difficult to differentiate from low-grade
chondrosarcoma
• High-grade tumors destroy cortex and extend into soft
tissue, frequently associated with elevated periosteum • Expresses both keratin and T-brachyury (not expressed by
chondrosarcoma)
• Neoplastic hyaline cartilage appears gray-blue and
glistening Chondroblastic Osteosarcoma
• Mineralized matrix appears as punctate, chalk-like deposits • Osteoid deposition
• Myxoid matrix appears translucent, gray, mucoid-to-watery • Chondrogenic component is typically high grade
• Chondrosarcoma arising in osteochondroma shows thick • Lacks mutations in IDH1/IDH2 (whereas 50-60% of
cartilage cap and frequent cystic changes chondrosarcomas harbor IDH1/IDH2 mutations)
• Areas of dedifferentiation appear firm and fleshy
Fracture Callus
MICROSCOPIC • Small nodules of cartilages often with pronounced
endochondral ossification
Histologic Features
• May simulate malignancy based on histologic appearance
• Infiltrative growth pattern encasing preexisting trabecular • Correlation with radiologic features aids recognition
bone is single most important diagnostic criterion
• Diverse histologic subtypes: Conventional (hyaline or SELECTED REFERENCES
myxoid), clear cell, dedifferentiated, mesenchymal
1. de Andrea CE et al: Integrating morphology and genetics in the diagnosis of
• Conventional hyaline type cartilage tumors. Surg Pathol Clin. 10(3):537-52, 2017
○ Hyaline cartilaginous matrix: Homogeneous, pink 2. Andreou D et al: Metastatic potential of grade I chondrosarcoma of bone:
○ Neoplastic chondrocytes vary in size with moderate results of a multi-institutional study. Ann Surg Oncol. 23(1):120-5, 2016
eosinophilic-to-vacuolated cytoplasm in lacunar spaces 3. DeLaney TF et al: Long-term results of Phase II study of high dose
photon/proton radiotherapy in the management of spine chordomas,
• Conventional myxoid type chondrosarcomas, and other sarcomas. J Surg Oncol. 110(2):115-22, 2014
○ Myxoid cartilaginous matrix frothy, bubbly, basophilic 4. Nord KH et al: GRM1 is upregulated through gene fusion and promoter
swapping in chondromyxoid fibroma. Nat Genet. 46(5):474-7, 2014
○ Bipolar-to-stellate cells singly or in cords and strands
5. Kerr DA et al: Molecular distinction of chondrosarcoma from chondroblastic
• Clear cell osteosarcoma through IDH1/2 mutations. Am J Surg Pathol. 37(6):787-95,
○ Low-grade subtype, abundant clear cytoplasm 2013
6. Tarpey PS et al: Frequent mutation of the major cartilage collagen gene
• Mesenchymal COL2A1 in chondrosarcoma. Nat Genet. 45(8):923-6, 2013
○ Sheets of round to spindled cells with scant cytoplasm 7. Vanel D et al: Enchondroma vs. chondrosarcoma: a simple, easy-to-use, new
admixed with nodules of hyaline cartilage magnetic resonance sign. Eur J Radiol. 82(12):2154-60, 2013
○ Recurrent HEY1-NCOA2 fusion 8. Yang W et al: Ptpn11 deletion in a novel progenitor causes
metachondromatosis by inducing hedgehog signalling. Nature.
• Dedifferentiated 499(7459):491-5, 2013
○ Transition from typically low-grade cartilaginous tumor 9. de Andrea CE et al: Interobserver reliability in the histopathological diagnosis
to high-grade nonchondrogenic sarcoma of cartilaginous tumors in patients with multiple osteochondromas. Mod
Pathol. 25(9):1275-83, 2012
• Infiltration of preexisting bony trabeculae most helpful clue 10. Amary MF et al: IDH1 and IDH2 mutations are frequent events in central
in recognizing malignant transformation chondrosarcoma and central and periosteal chondromas but not in other
• Histologic grading (grades 1, 2, and 3) important prognostic mesenchymal tumours. J Pathol. 224(3):334-43, 2011
11. Amary MF et al: Ollier disease and Maffucci syndrome are caused by somatic
factor mosaic mutations of IDH1 and IDH2. Nat Genet. 43(12):1262-5, 2011
○ Based on cellularity and degree of cytologic atypia 12. Pansuriya TC et al: Somatic mosaic IDH1 and IDH2 mutations are associated
with enchondroma and spindle cell hemangioma in Ollier disease and
Maffucci syndrome. Nat Genet. 43(12):1256-61, 2011
DIFFERENTIAL DIAGNOSIS 13. Verdegaal SH et al: Incidence, predictive factors, and prognosis of
Enchondroma chondrosarcoma in patients with Ollier disease and Maffucci syndrome: an
international multicenter study of 161 patients. Oncologist. 16(12):1771-9,
• No infiltrative pattern or extension into soft tissue 2011
• Relatively paucicellular and lacks significant cytologic atypia 14. Lin PP et al: Secondary chondrosarcoma. J Am Acad Orthop Surg.
18(10):608-15, 2010
Osteochondroma 15. Eefting D et al: Assessment of interobserver variability and histologic
parameters to improve reliability in classification and grading of central
• No infiltrative pattern or extension into soft tissue cartilaginous tumors. Am J Surg Pathol. 33(1):50-7, 2009
• Characteristic stalk with cortical and medullary continuity 16. Porter DE et al: Severity of disease and risk of malignant change in hereditary
multiple exostoses. A genotype-phenotype study. J Bone Joint Surg Br.
• Thin cartilaginous cap, typically < 2 cm 86(7):1041-6, 2004
Chondromyxoid Fibroma 17. Bovée JV et al: Chondrosarcoma of the phalanx: a locally aggressive lesion
with minimal metastatic potential: a report of 35 cases and a review of the
• Radiographically and histologically nonaggressive and well- literature. Cancer. 86(9):1724-32, 1999
circumscribed 18. Rosenberg AE et al: Chondrosarcoma of the base of the skull: a
clinicopathologic study of 200 cases with emphasis on its distinction from
• Fibromyxoid stroma with conspicuous small staghorn blood chordoma. Am J Surg Pathol. 23:1370-8, 1999
vessels
• Spindled-shaped cells and frequent osteoclast-type giant
cells
12
Chondrosarcoma

Chondrosarcoma Arising in Association
Chondrosarcoma With Enchondromatosis With Enchondromatosis
(Left) Radiograph shows the
proximal femur in a patient
with Ollier disease, with
multiple intramedullary
cartilaginous lesions in the
form of ring and arc
mineralization ﬅ, associated
with an adjacent large
chondrosarcoma ﬇. (Right)
Gross photograph of proximal
femur in the same patient
shows multiple blue-gray
intramedullary nodules ﬆ,
consistent with Ollier disease.
An expansile, fleshy
chondrosarcoma ﬊ is also
present.
Chondrosarcoma With Permeative Pattern Clear Cell Chondrosarcoma

(Left) A helpful histologic clue
to the diagnosis of
chondrosarcoma is the
presence of permeation.
Chondrosarcoma shows
infiltration of normal
trabecular bone ﬊. (Right)
Clear cell chondrosarcoma is a
histologic subtype with
prominent clear-cell changes
with abundant clear
cytoplasm and variably
hyperchromatic nuclei.
Dedifferentiated Chondrosarcoma Mesenchymal Chondrosarcoma

(Left) Dedifferentiated
chondrosarcoma comprises a
high-grade sarcoma ﬊
juxtaposed to a low-grade
cartilaginous tumor ﬆ. Here,
both components infiltrate
among preexisting bony
trabeculae ﬈. (Right)
Mesenchymal chondrosarcoma
characteristically shows
sheets-to-nodules of small
blue cells ﬅ intermixed with
small aggregates of
cartilaginous nodules ﬊.
13
Chordoma
KEY FACTS
TERMINOLOGY IMAGING
• Primary malignant tumor of bone that shows notochordal • Destructive lytic lesion
differentiation and usually arises within axial skeleton • Invariably extends into soft tissues
ETIOLOGY/PATHOGENESIS MACROSCOPIC
• Benign notochordal cell tumor (BNCT) thought to be • Gelatinous, lobulated, and well delineated
precursor lesion to chordoma • Solid and fish flesh-like in dedifferentiated chordomas
• Mutation in TBXT implicated in both somatic and familial
chordomas MICROSCOPIC
• Histologically classified into 4 groups: Conventional,
CLINICAL ISSUES chondroid, dedifferentiated, and poorly differentiated
• Accounts for ~ 1-3% of primary malignant bone tumors • Conventional chordomas show epithelioid cells with
• Usually diagnosed in patients 30-70 years old, rarely vacuolated bubbly "physaliferous" cells in myxoid stroma
children or infants • Chondroid chordomas have areas that mimic hyaline-type
• Primarily involves axial skeleton with soft tissue extension chondrosarcomas
• Treated by surgery &/or radiotherapy, generally with • Dedifferentiated chordomas contain areas of high-grade
limited role for chemotherapy sarcoma and portend worst prognosis
• Median overall survival 5-7 years for most chordomas but < • Poorly differentiated chordomas defined by loss of
1 year for dedifferentiated chordomas SMARCB1/INI1 expression
Sacrococcygeal Chordoma Sacrococcygeal Chordoma

(Left) Chordomas most
commonly involve the
sacrococcygeal region ﬇ in
the distal coccyx with
considerable soft tissue
extension. (Right) Sagittal
section of the same tumor in
the distal coccyx demonstrates
a well-circumscribed,
gelatinous mass with
multinodular architecture and
a patchy red-brown area,
consistent with hemorrhage.
Conventional Chordoma With

Physaliferous Cells T-Brachyury Expression in Chordoma
(Left) Tumor cells in
conventional chordoma often
show prominent
intracytoplasmic, pale to clear
vacuoles, which give rise to a
bubbly appearance (so-called
physaliferous cells). (Right)
Chordomas express T-
brachyury, a transcription
factor involved in notochord
development and regulation.
While nuclear staining ﬈ is
seen in chordoma cells,
background inflammatory and
endothelial cells are negative
﬊.
14
Chordoma

○ Mobile spine: Pain, neurologic symptoms, compression
TERMINOLOGY fracture
Definitions ○ Sacrum: Pain, constipation, incontinence, bladder
• Chordoma: Primary malignant tumor of bone showing dysfunction
notochordal differentiation and arising usually in axial Treatment
skeleton
• Surgery and preoperative/postoperative radiotherapy
• Chondroid chordoma: Showing areas of hyaline matrix,
resembling low-grade hyaline-type chondrosarcoma • No established role for chemotherapy in conventional or
chondroid chordomas
• Dedifferentiated chordoma: Showing areas of high-grade
sarcoma juxtaposed to conventional chordoma ○ Chemotherapy may be used in managing
dedifferentiated or poorly differentiated chordomas
• Poorly differentiated chordoma: Showing loss of
SMARCB1/INI1 expression Prognosis
• Depends on histology
ETIOLOGY/PATHOGENESIS ○ Best prognosis in conventional and chondroid
Sporadic chordomas
• Thought to arise from notochordal remnants – Median overall survival 5-7 years
• Benign notochordal cell tumor (BNCT) may be precursor ○ Poorly differentiated chordomas show median survival
lesion to chordoma of 4.4 years
• Associated with somatic TBXT duplication &/or mutations in ○ Worst prognosis in dedifferentiated chordoma
growth factor signaling pathways – Median overall survival < 1 year, usually rapidly fatal
• Poorly differentiated chordoma with SMARCB1 deletion with disseminated disease
&/or mutation • Depends on tumor location, size, and resectability
○ Best prognosis seen in sacral chordomas with complete
Familial resection and negative margin
• Associated with germline TBXT duplication • Metastatic chordoma seen in < 5-40% of patients
• Chordoma of childhood/infancy reported in tuberous ○ Commonly to lung, skin, and bone
sclerosis complex (germline mutations in TSC1/TSC2)
• Germline mutations in DNA repair machinery BRCA2, NBN, IMAGING
or CHEK2
Radiographic Findings
CLINICAL ISSUES • Lytic and destructive
• Extends into adjacent soft tissue
Epidemiology
• Calcifications may be seen
• Incidence • In sacrococcygeal chordomas, soft tissue component is
○ < 1 per 1 million usually anterior
○ 1-3% of primary malignant bone tumors ○ May displace rectum and extend along sacral nerve roots
• Age into sciatic notch
○ Median 60 years, range usually 30-70 years
MR Findings
○ Earlier in familial chordomas (30-50 years)
○ 5% of chordomas seen in patients < 20 years • Bright, lobulated-appearing on T2WI
○ Chordomas in children/infancy often in skull base, • Foci of calcification are frequent
occasionally in setting of tuberous sclerosis complex • Soft tissue extension is better delineated
• Sex CT Findings
○ Slight male predominance for sacral chordoma
• Destructive and radiolucent bone lesion
○ Slight female predominance for skull base chordoma
• Calcifications may be seen
Site
• Primarily arises within axial skeleton MACROSCOPIC
○ ~ 60% in sacrococcygeal region General Features
○ ~ 30% in skull base • Soft, lobulated, tan-gray, gelatinous to mucoid
○ ~ 10% in cervical, lumbar, or thoracic spine • Well delineated from surrounding tissues
○ Rarely reported outside axial skeleton • Dedifferentiated chordoma appears variegated with solid,
• Chondroid chordoma predominantly in skull base fish flesh-like appearance similar to soft tissue sarcomas
• Dedifferentiated chordoma usually in sacrococcygeal • Poorly differentiated chordoma lacks mucoid areas but
region instead often shows hemorrhage and necrosis
• Poorly differentiated chordoma most often in skull base
Size
Presentation • Skull-base tumors typically small (< 5 cm)
• Depends on tumor site • Sacrococcygeal tumors often large (up to > 20 cm)
○ Skull base: Headache, diplopia, cranial nerve defects
15
Diagnoses Associated With Syndromes by Organ: Chordoma
○ T-brachyury expression absent in high-grade component

MICROSCOPIC of dedifferentiated chordoma
Histologic Features • Poorly differentiated chordoma shows loss of
• 4 histologic types: Conventional, chondroid, SMARCB1/INI1 expression in addition
dedifferentiated, and poorly differentiated
○ Similar histologic appearance in familial and sporadic DIFFERENTIAL DIAGNOSIS
chordomas Metastatic Adenocarcinoma
• Conventional chordoma shows lobular pattern, infiltrates
• Mucinous adenocarcinoma mimic chordoma on small
marrow space, encases preexisting bony trabeculae, and
biopsy sample
usually breaches cortex, forming demarcated soft tissue
• Mucinous adenocarcinoma is negative for T-brachyury and
mass
S100 protein; these markers are positive in chordoma
○ Composed of large epithelioid cells arranged in cohesive
nests and cords Chondrosarcoma
○ Nuclei are of moderate size and may contain small • Distinction between chordoma and chondrosarcoma can
nucleolus or pseudoinclusions be difficult on small biopsies, especially from skull base
○ Moderate eosinophilic to clear cytoplasm • Chondrosarcoma is negative for T-brachyury and
○ Physaliferous cells with numerous small, cytokeratins; these markers are positive in chordoma
intracytoplasmic vacuoles that impart bubbly
appearance Benign Notochordal Cell Tumor
– Physaliferous cells not pathognomonic of chordoma, • Generally confined to bone with no soft tissue involvement
as other tumor types may have similar-appearing cells • Radiographically sclerotic with no contrast enhancement;
and some chordomas lack them whereas chordoma appears lytic
○ One tumor cell may wrap or "hug" another • Lacks extracellular myxoid matrix, which is present in
○ Pleomorphism and spindling of tumor cells may be conventional chordoma
present • Cells with abundant clear (adipocyte-like) to eosinophilic
○ Basophilic and myxoid extracellular matrix cytoplasm
○ Mitotic activity usually limited • Identical immunohistochemical profile as chordoma
○ Foci of necrosis common, especially in large tumors Ecchordosis Physaliphora
• Chondroid chordoma contains chondroid component and
• Proliferation of fetal notochordal remnants
areas of conventional chordoma
• Circumscribed, generally < 3 cm, mostly in retroclival region
○ Chondroid component composed of hyaline matrix, with
• Shows epithelioid vacuolated cells and myxoid stroma,
similar appearance to hyaline cartilage, containing
microscopically almost identical to chordoma
neoplastic cells in lacunar-like spaces
• Identical immunohistochemical profile as chordoma
○ Chondroid component abruptly abuts or merges with
conventional component • Distinction relies on radiologic correlation
○ Quantity of chondroid component variable
– Chondroid areas may predominate in some
SELECTED REFERENCES
chordomas, thus difficult to distinguish from 1. Gröschel S et al: Defective homologous recombination DNA repair as
therapeutic target in advanced chordoma. Nat Commun. 10(1):1635, 2019
chondrosarcomas
2. Shih AR et al: Clinicopathologic characteristics of poorly differentiated
• Dedifferentiated chordoma shows biphasic appearance chordoma. Mod Pathol. 31(8):1237-45, 2018
with high-grade sarcoma juxtaposed to conventional 3. Tarpey PS et al: The driver landscape of sporadic chordoma. Nat Commun.
chordoma 8(1):890, 2017
4. Rotondo RL et al: High-dose proton-based radiation therapy in the
○ High-grade sarcoma may show diverse histology: management of spine chordomas: outcomes and clinicopathological
Pleomorphic, osteosarcomatous, prognostic factors. J Neurosurg Spine. 23(6):788-97, 2015
rhabdomyosarcomatous, or fibrosarcoma-like 5. Choy E et al: Genotyping cancer-associated genes in chordoma identifies
• Poorly differentiated chordoma shows epithelioid tumor mutations in oncogenes and areas of chromosomal loss involving CDKN2A,
PTEN, and SMARCB1. PLoS One. 9(7):e101283, 2014
cells with eccentric nuclei 6. Le LP et al: Recurrent chromosomal copy number alterations in sporadic
○ Myxoid matrix is absent chordomas. PLoS One. 6(5):e18846, 2011
○ Lack of SMARCB1/INI1 expression with presence of 7. Yang XR et al: T (brachyury) gene duplication confers major susceptibility to
familial chordoma. Nat Genet. 41(11):1176-8, 2009
brachyury expression is diagnostic
8. Deshpande V et al: Intraosseous benign notochord cell tumors (BNCT):
• BNCT may be seen adjacent to chordoma, suggesting further evidence supporting a relationship to chordoma. Am J Surg Pathol.
malignant transformation 31(10):1573-7, 2007
9. Vujovic S et al: Brachyury, a crucial regulator of notochordal development, is
a novel biomarker for chordomas. J Pathol. 209(2):157-65, 2006
ANCILLARY TESTS 10. Rosenberg AE et al: Chondrosarcoma of the base of the skull: a
clinicopathologic study of 200 cases with emphasis on its distinction from
Immunohistochemistry chordoma. Am J Surg Pathol. 23:1370-8, 1999
• Consistent expression of cytokeratins and epithelial 11. O'Connell JX et al: Base of skull chordoma. A correlative study of histologic
membrane antigen and clinical features of 62 cases. Cancer. 74(8):2261-7, 1994
12. Coffin CM et al: Chordoma in childhood and adolescence. A clinicopathologic
• Variable expression of S100 protein analysis of 12 cases. Arch Pathol Lab Med. 117(9):927-33, 1993
• Consistent expression of T-brachyury 13. Meis JM et al: "Dedifferentiated" chordoma. A clinicopathologic and
immunohistochemical study of three cases. Am J Surg Pathol. 11(7):516-25,
1987
16
Chordoma

Skull Base Chordoma Conventional Chordoma
(Left) Chordomas generally
involve midline bony
structures. A typical location
for chordoma (~ 30% of cases)
is at the base of skull in the
region of clivus ﬊. (Right) On
low power, conventional
chordoma shows a lobulated
growth pattern, with fibrous
band ﬊ and epithelioid tumor
cells amidst prominent myxoid
stroma ﬊.
Chondroid Chordoma Dedifferentiated Chordoma

(Left) Chondroid chordoma
most often arises in the skull
base and shows areas of
hyaline-type chondroid matrix,
which can be a histologic
mimic of chondrosarcoma.
(Right) Dedifferentiated
chordoma, characterized by a
high-grade sarcoma ﬊
juxtaposed to areas of
conventional chordoma ﬊, is
highly aggressive.
Loss of INI1 Expression in Poorly

Poorly Differentiated Chordoma Differentiated Chordoma
(Left) Poorly differentiated
chordoma shows sheets of
epithelioid cells with abundant
cytoplasm. Necrosis is often
present ﬈. Unlike
conventional chordoma,
myxoid stroma is not a
feature. Poorly differentiated
chordoma expresses T-
brachyury (not shown). (Right)
Poorly differentiated
chordoma characteristically
shows loss of INI1 expression
with lack of nuclear staining in
the tumor cells ﬊, whereas
intact expression can be seen
in the control stromal and
inflammatory cells ﬈.
17
Malignant Peripheral Nerve Sheath Tumor
KEY FACTS
TERMINOLOGY ○ Alternating hypercellular/hypocellular areas ("marbled")

• Sarcoma arising from nerve or benign nerve sheath tumor ○ Fascicles of spindle cells, variable pleomorphism
or showing nerve sheath cellular differentiation ○ Perivascular accentuation of tumor cells around vessels
• Heterologous differentiation (15%)
ETIOLOGY/PATHOGENESIS • Epithelioid MPNST (5%)
• 50% associated with neurofibromatosis type 1 (NF1)
• 10% associated with radiation ANCILLARY TESTS
• Mutations in polycomb complex (EED, SUZ12) or tumor • Immunohistochemistry: Focal S100, SOX10, GFAP
suppressors (CDKN2A, TP53) • Loss of H3K27Me3 in ~ 50% of conventional MPNST
• Loss of SMARCB1 in ~ 70% of epithelioid MPNST
CLINICAL ISSUES
• Mostly adults, younger in NF1-associated cases TOP DIFFERENTIAL DIAGNOSES
• Most arise in major nerve trunks • Synovial sarcoma
• 5-year survival 15-40% • Malignant melanoma
• Local recurrence > 40% • Clear cell sarcoma
• Metastasis 30-60%, commonly to lungs and bones • Cellular schwannoma
• Atypical neurofibroma
MICROSCOPIC
• Atypical neurofibromatous neoplasm of uncertain biologic
• Spindle-cell MPNST (80%) potential
MPNST Arising in Plexiform Neurofibroma Radiation-Associated MPNST

(Left) Grossly, malignant
peripheral nerve sheath tumor
(MPNST) shows a yellow-tan,
fleshy cut surface, often with
necrosis and hemorrhage ﬉.
This MPNST arises in a
plexiform neurofibroma ﬅ in
a patient with
neurofibromatosis type 1
(NF1). (Right) About 10% of
MPNST arises in patients with
history of prior therapeutic
radiation. This radiation-
associated MPNST involves
the sciatic nerve ﬇.
MPNST With "Marbled" Pattern Spindle Cells in Conventional MPNST

(Left) MPNST often shows
fascicles of spindle cells in
alternating hypercellular and
hypocellular areas within the
tumor, giving a "marbled"
histologic appearance. (Right)
MPNST typically shows
fascicles of spindle cells with
variably hyperchromatic nuclei
in a myxoid-to-collagenous
stromal background.
Conspicuous mitoses may be
seen.
18

TERMINOLOGY Treatment
• Surgical approaches
Abbreviations ○ Wide excision/resection or amputation
• Malignant peripheral nerve sheath tumor (MPNST) • Adjuvant therapy
Synonyms ○ Radiation
• Neurofibrosarcoma, neurogenic sarcoma, malignant ○ Chemotherapy, though generally less effective
schwannoma Prognosis
Definitions • Depends on age, tumor location, size, and histologic grade
• Diagnostic criteria (1 of following) ○ Superior survival in pediatric and intracranial MPNST
○ Sarcoma arising from nerve or benign nerve sheath ○ Worse survival in central and head/neck MPNST (more
tumor (e.g., neurofibroma) common in NF1 patients)
○ Sarcoma with histologic features of nerve sheath • 5-year overall survival 15-40%
differentiation in patients with neurofibromatosis type 1 • Local recurrence > 40%
(NF1) • Metastasis 30-60%
○ Sarcoma with histologic and immunophenotypic or ○ Most commonly to lungs, bones, &/or pleura
ultrastructural evidence of nerve sheath differentiation
in patients without NF1 IMAGING
General Features
ETIOLOGY/PATHOGENESIS
• Large, heterogeneous, fusiform mass associated with major
Genetic Predisposition nerve trunk
• 50% of tumors associated with NF1 • Tumor necrosis seen on MR suggests MPNST rather than
○ Lifetime incidence of MPNST in NF1 patients: 8-15% neurofibroma in NF1 patients
• 40% of tumors sporadic
MACROSCOPIC
Environmental Exposure
General Features
• 10% of tumors associated with radiation exposure
• Fusiform or eccentric mass associated with major nerve or
Molecular Pathogenesis nerve trunk
• NF1 characterized by germline mutation in NF1 • Color/consistency similar to other soft tissue sarcomas
○ MPNST tumorigenesis accelerated by somatic loss of ○ Gray-tan, firm to fleshy
2nd NF1 allele ○ Necrosis and hemorrhage common
• Recurrent mutations in polycomb repressive complex 2
(PRC2) components: EED or SUZ12
Size
○ Subsequent loss of histone 3 lysine 27 trimethylation • Usually > 5 cm, sometimes massive > 20 cm
marks (H3K27Me3)
• Recurrent mutations in tumor suppressors CDKN2A (p16) MICROSCOPIC
&/or TP53 (p53) Histologic Features
• Inactivating mutation in SMARCB1 in ~ 70% of epithelioid • Mostly high grade, < 20% low grade
MPNST
• Some arising from preexisting benign nerve sheath tumor
○ Most commonly from neurofibroma (usually NF1
CLINICAL ISSUES patients), rarely schwannoma, ganglioneuroma, and
Epidemiology others
• Rare, 3-10% of soft tissue sarcomas • Histologic types: Conventional/spindle cell (80%),
• Mostly adults heterologous differentiation (15%), and epithelioid (5%)
○ Wide age range: ~ 10-70 years ○ Conventional/spindle-cell MPNST
○ Average age in NF1 patients: ~ 30 years (vs. ~ 40 years in – Alternating hypercellular and hypocellular areas
sporadic cases) ("marbled" pattern)
• No sex predilection – Fascicles of spindle cells, variable pleomorphism
– Perivascular accentuation of tumor cells around small
Site vessels
• Most commonly deep-seated soft tissue: Thigh, buttock, – Extensive necrosis common, mitoses frequent
trunk, upper extremities, followed by retroperitoneum, ○ MPNST with heterologous differentiation
head and neck – Rhabdomyosarcomatous (malignant triton tumor)
• Most arise in major nerves: Sciatic nerve, followed by – Osteosarcomatous, chondrosarcomatous,
brachial plexus, sacral plexus, and paraspinal nerves angiosarcomatous, etc.
Presentation ○ Epithelioid MPNST
• Painful mass – Lobules of large epithelioid cells with eosinophilic
cytoplasm, vesicular nuclei, prominent nucleoli
• Neurological deficit
19
Diagnoses Associated With Syndromes by Organ: Malignant Peripheral Nerve Sheath Tumor
– Associated with schwannomatosis and germline Atypical Neurofibromatous Neoplasm of Uncertain

SMARCB1 mutation Biologic Potential
• Schwann cell neoplasm with at least 2 of following
ANCILLARY TESTS ○ Cytologic atypia
Immunohistochemistry ○ Loss of neurofibroma architecture
• Conventional MPNST ○ Hypercellularity
○ Positive for S100, typically focal, in 20-60% of cases ○ Mitotic activity > 1/50 HPF to < 3/10 HPF
○ Positive for SOX10 &/or GFAP in 20-60% of cases
○ Complete loss of H3K27Me3 in ~ 50% of cases SELECTED REFERENCES
• Epithelioid MPNST 1. Martin E et al: Treatment and survival differences across tumor sites in
○ Diffusely positive for S100 in all cases malignant peripheral nerve sheath tumors: a SEER database analysis and
review of the literature. Neurooncol Pract. 6(2):134-43, 2019
○ Complete loss of SMARCB1/INI1 nuclear staining in ~ 2. Schwabe M et al: How effective are noninvasive tests for diagnosing
70% of cases malignant peripheral nerve sheath tumors in patients with
neurofibromatosis type 1? Diagnosing MPNST in NF1 patients. Sarcoma.
2019:4627521, 2019
DIFFERENTIAL DIAGNOSIS 3. Yan P et al: Nomograms for predicting the overall and cause-specific survival
in patients with malignant peripheral nerve sheath tumor: a population-
Synovial Sarcoma based study. J Neurooncol. 143(3):495-503, 2019
• Usually uniformly hypercellular (rather than "marbled" 4. Makise N et al: Clarifying the distinction between malignant peripheral nerve
pattern with alternations of cellularity in MPNST) sheath tumor and dedifferentiated liposarcoma: a critical reappraisal of the
diagnostic utility of MDM2 and H3K27me3 Status. Am J Surg Pathol.
• Immunohistochemistry 42(5):656-64, 2018
○ Usually positive for cytokeratin, EMA, and TLE1 5. Le Guellec S et al: Loss of H3K27 trimethylation is not suitable for
distinguishing malignant peripheral nerve sheath tumor from melanoma: a
○ Generally negative for S100 and SOX10 study of 387 cases including mimicking lesions. Mod Pathol. 30(12):1677-87,
• Gene fusion between SS18 (formerly SYT) and SSX1, SSX2, 2017
or SSX4 in nearly all cases 6. Miettinen MM et al: Histopathologic evaluation of atypical
neurofibromatous tumors and their transformation into malignant
Malignant Melanoma peripheral nerve sheath tumor in neurofibromatosis 1 patients - a consensus
overview. Hum Pathol. 67:1-10, 2017
• Typically superficial dermal tumors 7. Pekmezci M et al: Significance of H3K27me3 loss in the diagnosis of
○ Sometimes metastasize/involve deep-seated locations malignant peripheral nerve sheath tumors. Mod Pathol. 30(12):1710-9, 2017
• Presence of melanoma in situ component or melanin 8. Cleven AH et al: Loss of H3K27 tri-methylation is a diagnostic marker for
malignant peripheral nerve sheath tumors and an indicator for an inferior
pigments can be helpful clues survival. Mod Pathol. 29(6):582-90, 2016
• Immunohistochemistry 9. Le Guellec S et al: Malignant peripheral nerve sheath tumor is a challenging
○ Diffusely positive for S100 diagnosis: a systematic pathology review, immunohistochemistry, and
molecular analysis in 160 patients from the French Sarcoma Group
○ Positive for melanocytic markers HMB45, Melan-A, and Database. Am J Surg Pathol. 40(7):896-908, 2016
MiTF 10. Prieto-Granada CN et al: Loss of H3K27me3 expression is a highly sensitive
marker for sporadic and radiation-induced MPNST. Am J Surg Pathol.
• BRAF V600E mutation in some cases 40(4):479-89, 2016
Clear Cell Sarcoma 11. Röhrich M et al: Methylation-based classification of benign and malignant
peripheral nerve sheath tumors. Acta Neuropathol. 131(6):877-87, 2016
• Predilection for acral sites 12. Schaefer IM et al: Loss of H3K27 trimethylation distinguishes malignant
• Nests of uniform epithelioid-to-spindly cells, prominent peripheral nerve sheath tumors from histologic mimics. Mod Pathol. 29(1):4-
13, 2016
nucleoli, rare scattered multinucleated giant cells
13. Jo VY et al: Epithelioid malignant peripheral nerve sheath tumor:
• Immunohistochemistry clinicopathologic analysis of 63 cases. Am J Surg Pathol. 39(5):673-82, 2015
○ Diffusely positive for S100 14. Lee W et al: PRC2 is recurrently inactivated through EED or SUZ12 loss in
malignant peripheral nerve sheath tumors. Nat Genet. 46(11):1227-32, 2014
○ Positive for HMB45
15. Zhang M et al: Somatic mutations of SUZ12 in malignant peripheral nerve
• EWSR1-ATF1 or EWSR1-CREB1 gene fusion in most cases sheath tumors. Nat Genet. 46(11):1170-2, 2014
16. Rahrmann EP et al: Forward genetic screen for malignant peripheral nerve
Cellular Schwannoma sheath tumor formation identifies new genes and pathways driving
• Common locations: Retroperitoneum, pelvis, posterior tumorigenesis. Nat Genet. 45(7):756-66, 2013
17. Carter JM et al: Epithelioid malignant peripheral nerve sheath tumor arising
mediastinum, or gastrointestinal tract in a schwannoma, in a patient with "neuroblastoma-like" schwannomatosis
• Dominated by Antoni A (cellular) areas and a novel germline SMARCB1 mutation. Am J Surg Pathol. 36(1):154-60,
• May show focal necrosis, mitosis, &/or degenerative atypia 2012
18. Terry J et al: TLE1 as a Diagnostic immunohistochemical marker for synovial
with smudgy nuclei sarcoma emerging from gene expression profiling studies. Am J Surg Pathol.
• Immunohistochemistry 31(2):240-6, 2007
○ Diffusely positive for S100 and SOX10 19. Birindelli S et al: Rb and TP53 pathway alterations in sporadic and NF1-
related malignant peripheral nerve sheath tumors. Lab Invest. 81(6):833-44,
Atypical Neurofibroma 2001
20. Perry A et al: NF1 deletions in S-100 protein-positive and negative cells of
• Cytologic atypia ("ancient neurofibroma") or sporadic and neurofibromatosis 1 (NF1)-associated plexiform neurofibromas
hypercellularity and malignant peripheral nerve sheath tumors. Am J Pathol. 159(1):57-61,
2001
• Retain neurofibroma architecture with characteristic
collagen bundles ("shredded carrots" pattern)
20

Focal S100 Expression in Conventional
Spindle Cells in Conventional MPNST MPNST
(Left) The tumor cells in
conventional MPNST show
spindle morphology and
tapered nuclei, suggestive of
neural differentiation. (Right)
S100 expression is often focal
in conventional MPNST and is
only seen in 20-60% of cases.
This is in contrast to
schwannoma, which shows
strong, diffuse nuclear
staining for S100 in all cases.
Rhabdomyoblasts in Malignant Triton

MPNST With Heterologous Differentiation Tumor
(Left) MPNST can show
heterologous elements, such
as this example with
osteosarcomatous and
chondrosarcomatous
differentiation. (Right) A
subset of MPNSTs harbors
heterologous elements such as
rhabdomyoblasts, which are
tumor cells with abundant
eosinophilic cytoplasm
showing skeletal muscle
differentiation; these are
known as malignant triton
tumors.
Epithelioid MPNST Loss of INI1 in Epithelioid MPNST

(Left) Epithelioid MPNST
shows nodules to sheets of
epithelioid tumor cells with
prominent nucleoli. Diffuse
S100 expression (not shown) is
seen in epithelioid MPNST but
not in most conventional
MPNST. (Right) Epithelioid
MPNST shows loss of
SMARCB1/INI1 expression in
70% of cases. This example
shows loss of INI1 nuclear
staining in the tumor cells,
whereas the stromal and
inflammatory cells retain INI1
expression.
21
Osteosarcoma
KEY FACTS
TERMINOLOGY CLINICAL ISSUES

• High-grade malignant tumor in which neoplastic cells • Most patients are young, between 10 and 20 years
produce bone • Distal femur > proximal tibia > proximal humerus
ETIOLOGY/PATHOGENESIS MICROSCOPIC
• Primary osteosarcomas arise de novo without known • Admixture of 2 elements in varying proportions
predisposing condition ○ High-grade sarcoma with epithelioid, plasmacytoid,
• Secondary osteosarcomas arise within diseased bone fusiform, ovoid, small-round, spindle, or clear cells;
○ Paget disease of bone sometimes with multinucleated giant cells
○ Radiation exposure ○ Bone produced directly by tumor cells
○ Chemotherapy • Conventional osteosarcoma
○ Trauma ○ Histologic variants: Osteoblastic, chondroblastic,
○ Foreign body fibroblastic, telangiectatic, giant cell, small cell,
• Hereditary syndromes osteoblastoma-like, chondroblastoma-like,
○ Hereditary retinoblastoma: RB1 mutation chondromyxoid fibroma-like
○ Li-Fraumeni syndrome: TP53 mutation • Other variants with distinct biological/clinical behavior
○ Rothmund-Thomson syndrome: RECQL4 mutation ○ Parosteal osteosarcoma, periosteal osteosarcoma, well-
○ Bloom syndrome: BLM mutation differentiated intramedullary osteosarcoma,
○ Werner syndrome: WRN mutation osteosarcoma of craniofacial bones
Osteosarcoma in Distal Femur Osteosarcoma in Distal Femur
Osteosarcoma commonly arises in the region of the knee. Gross photograph of the same patient shows a tan-yellow,
Radiograph of an osteosarcoma in the distal femur fleshy mass involving the distal femur and adjacent soft
demonstrates a destructive, bone-forming tumor ﬇ tissue. A pathologic fracture is apparent ﬅ.
associated with pathologic fracture ﬅ.
22
Osteosarcoma

TERMINOLOGY Presentation
• Progressively enlarging, painful mass
Synonyms ○ Pain deep-seated and frequently noted months prior
• Osteogenic sarcoma ○ Pain intensity increases over time, eventually unremitting
Definitions • May appear as visible and palpable mass
• High-grade malignant tumor in which tumor cells produce • Overlying skin may be warm, erythematous, edematous,
bone and cartographed by prominent, engorged veins
○ Skin ulceration secondary to pressure ischemia can occur
ETIOLOGY/PATHOGENESIS • Restricted range of motion in those with large tumors
• Joint effusions when tumor involves epiphysis or
Neoplastic Process periarticular structures
• Primary osteosarcomas arise de novo without known • Weight loss and cachexia in patients with advanced disease
predisposing condition • Pathologic fracture as heralding event in 5-10% of cases
• Secondary osteosarcomas arise within diseased bone
○ Paget disease of bone
Laboratory Tests
○ Radiation exposure • Elevated serum alkaline phosphatase
○ Chemotherapy Treatment
○ Trauma • Surgical approaches
○ Foreign body (e.g., orthopedic implants) ○ Limb salvage; complete excision with wide negative
Genetic Susceptibility margins is optimal
• Hereditary retinoblastoma: Germline mutation in RB1 – Biopsy tract often removed with tumor
• Li-Fraumeni syndrome: Germline mutation in TP53 ○ Amputation necessary if major vessels and nerves
• Rothmund-Thomson syndrome: Germline mutation in compromised, if tumor involves region that cannot be
RECQL4 reconstructed, or if large volumes of tissue
contaminated by fracture or prior surgical intervention
• Bloom syndrome: Germline mutation in BLM
• Adjuvant therapy
• Werner syndrome: Germline mutation in WRN
○ Neoadjuvant &/or adjuvant chemotherapy often
Molecular Pathogenesis administered
• Frequent TP53 mutations – Tumor may diminish in size
• Subsets harbor amplification of PDGFRA, KDR, or VEGFA – Tumor often undergoes extensive mineralization and
• Subsets harbor mutations in cell cycle/DNA repair develops pseudocapsule facilitating excision
regulators: RB1, BRCA2, or BAP1 – Chemotherapeutic efficacy determined by histologic
• Genomic instability signature reminiscent of BRCA1/BRCA2- assessment of amount of induced tumor necrosis
deficient tumors □ Induced tumor necrosis of ≥ 90% considered good
response, important prognostic indicator
CLINICAL ISSUES • Drugs
○ High-dose methotrexate, doxorubicin, and cisplatin, &/or
Epidemiology
others
• Incidence • Radiation
○ Most common primary malignant tumor of bone, ○ Used for unresectable tumors because of size &/or site
exclusive of hematopoietic malignancies ○ Used in patients considered incurable with widely
– Accounts for ~ 20% of primary bone sarcomas metastatic disease
○ ~ 800 cases each year in USA ○ Adjuvant radiation if excision associated with positive
• Age margins
○ Most patients are young, between 10 and 20 years
– Females usually younger than males, probably due to Prognosis
earlier skeletal development • Relapse-free survival rates 50-80% (median ~ 70%)
○ 2nd peak occurs in patients > 50 years (often secondary • May vary by subtypes of conventional osteosarcoma
osteosarcoma) ○ Chondroblastic variant associated with poor response to
• Sex chemotherapy
○ M:F = 1.3:1.0
IMAGING
Site
Radiographic Findings
• Most commonly arises in long tubular bones
○ Distal femur > proximal tibia > proximal humerus • Permeative and destructive
– 50% of cases located in knee region • Centered around metaphysis of long bones
• In older individuals, pelvis and axial skeleton are most ○ < 10% diaphyseal
common locations ○ Rarely epiphyseal
• < 10% occur in mandible and craniofacial bones • Poorly defined, lack of sclerotic rim
• Mixed lytic and blastic mass transgressing cortex and
forming large soft tissue components
23
Diagnoses Associated With Syndromes by Organ: Osteosarcoma
○ 90% extend into soft issue • Skip metastases appear as intramedullary firm, ovoid, tan-
• Matrix visible in 90% of cases white nodules located adjacent to or far from main mass
○ Periphery usually less mineralized than central area • Variants of osteosarcoma confined to surface of bone
• Soft tissue components may have fine "cloud-like" pattern uncommon
of radiodensity
• Entirely lytic or sclerotic in some instances MICROSCOPIC
○ Entirely lytic appearance characteristic of telangiectatic Histologic Features
variant
• Admixture of 2 elements in varying proportions
• Lower grade lesions tend to be more mineralized
○ High-grade sarcoma with epithelioid, plasmacytoid,
• Periosteal reaction fusiform, ovoid, small-round, spindle, or clear cells;
○ Appears as multiple layers (onion skin) or radiating sometimes with multinucleated giant cells
(sunburst) appearance ○ Bone matrix produced directly by tumor
○ Codman triangle: Periosteal reaction at diaphyseal end • Nuclei hyperchromatic, central or eccentric in position
of tumor at angle created by cortex and elevated
○ Brisk mitotic activity, prominent nucleoli
periosteum
○ Degree of atypia variable but frequently severe
• Rarely, imaging appears deceptively benign
○ Numerous mitoses, including atypical forms
MR Findings • Eosinophilic cytoplasm, variable in volume
• Heterogeneous metaphyseal mass • Tumor cells intimately related to surface of neoplastic bone
• Osteoid shows low signal on all sequences ○ Tumor cells diminish in size and appear less atypical as
• Helpful in detecting skip lesions in same or adjacent bone they are surrounded and imprisoned by matrix
• T1WI: Nonosteoid portions of tumor near isointense to – In heavily mineralized portions, tumor cells lack atypia
skeletal muscle – This phenomenon is referred to as normalization
• Fluid-sensitive sequences: Appears heterogeneous • Neoplastic bone varies in quantity
○ Deposited as primitive disorganized trabeculae
CT Findings
producing coarse lace-like pattern, or broad large sheets
• Useful in defining bone matrix ○ Frequently mineralized
• Useful in delineating tumor extent and surgical planning ○ Neoplastic lamellar bone is very rare
Bone Scan ○ Preexisting bony trabeculae function as scaffold for
tumor growth in some cases
• Increased activity in primary tumor and metastasis
• Bone is eosinophilic or basophilic and may have pagetoid
appearance caused by haphazardly deposited cement lines
MACROSCOPIC
• Histologic variants
General Features ○ Osteoblastic osteosarcoma
• Intramedullary ○ Chondroblastic osteosarcoma
• Usually centered in metaphysis, but can involve any portion – Neoplastic cartilage is usually hyaline, but may be
of bone myxoid, particularly in tumors arising in jaw bones
• Tumors with abundant mineralized bone are tan-white and – Malignant chondrocytes demonstrate severe
hard cytologic atypia
• Nonmineralized components are glistening and gray ○ Fibroblastic osteosarcoma
○ May be mucinous if matrix is myxoid, or more rubbery if ○ Telangiectatic osteosarcoma
hyaline in nature ○ Giant cell-rich osteosarcoma
• Areas of hemorrhage and cystic change ○ Small-cell osteosarcoma
○ Can be extensive and produce friable, bloody, and ○ Osteoblastoma-like osteosarcoma
spongy mass (telangiectatic osteosarcoma) ○ Chondroblastoma-like osteosarcoma
• Usually destroys overlying cortex and forms eccentric or ○ Chondromyxoid fibroma-like osteosarcoma
circumferential soft tissue component displacing
periosteum peripherally DIFFERENTIAL DIAGNOSIS
• Dislodged periosteum becomes sharp interface between
mass and bordering skeletal muscle and fat Fracture Callus
• Layer of reactive bone at proximal and distal regions where • Bone rimmed by osteoblasts
periosteum lifted from cortex • Distribution zonal rather than haphazard
• May grow into joint space • Fracture site shows fibrocartilage, finding not seen in either
○ Growth may occur through synovium, via extension osteosarcoma or chondrosarcoma
along cortical surface, or through tendoligamentous and • Atypical mitotic figures not seen
joint capsule insertion sites • Radiographic correlation essential
• Open growth plates often function as effective barriers to
Osteoblastoma
advancing tumors
○ Penetration of physis and invasion through epiphysis to • Shows interconnecting trabeculae of tumor bone lined by
base of articular surface occurs in some cases plump osteoblasts
24
Osteosarcoma

• Distinction between osteoblastoma-like osteosarcoma and
aggressive osteoblastoma can be challenging
DIAGNOSTIC CHECKLIST
○ Radiographic correlation essential Pathologic Interpretation Pearls
○ Features supporting diagnosis of osteosarcoma • Delicate lace-like deposition of unmineralized eosinophilic
– Infiltration of preexisting bony trabeculae matrix (osteoid)
– Large size (> 5 cm) • At least focal bone production by malignant cells is
– Atypical mitotic figures necessary to render diagnosis of osteosarcoma
– Prominent abundant lace-like bone deposition • Ancillary tests do not help in identifying bone
Myositis Ossificans Assessment of Chemotherapy Effect
• Both soft tissue and parosteal myositis ossificans may be • Complete or near-complete response (> 90% necrosis)
mistaken for osteosarcoma associated with better survival
• Distinct zonal pattern characteristic of myositis ossificans • Assessment of necrosis should be performed by
and not seen in osteosarcoma histologically evaluating central slice of tumor and sampling
○ Radiologically and grossly, center lacks mineralization, remaining halves
whereas periphery is mineralized • Extent of necrosis on preoperative chemotherapy may be
○ Microscopically, center shows granulation tissue/nodular used to alter postoperative regimen
fasciitis-like appearance, whereas periphery shows
woven bone lined by osteoblasts with outermost layer of SELECTED REFERENCES
lamellar bone in mature lesions 1. Baumhoer D et al: An update of molecular pathology of bone tumors.
• Recently described to harbor USP6 rearrangement Lessons learned from investigating samples by next generation sequencing.
Genes Chromosomes Cancer. 58(2):88-99, 2019
Aneurysmal Bone Cyst 2. Suehara Y et al: Clinical genomic sequencing of pediatric and adult
osteosarcoma reveals distinct molecular subsets with potentially targetable
• May mimic telangiectatic osteosarcoma alterations. Clin Cancer Res. ePub, 2019
• Cells in cyst wall not severely atypical 3. Švajdler M et al: Fibro-osseous pseudotumor of digits and myositis ossificans
• Presence of USP6 rearrangements may support aneurysmal show consistent COL1A1-USP6 rearrangement: a clinicopathological and
genetic study of 27 cases. Hum Pathol. 88:39-47, 2019
bone cyst 4. Hameed M et al: Tumor syndromes predisposing to osteosarcoma. Adv Anat
Pathol. 25(4):217-22, 2018
Giant Cell Tumor of Bone
5. Kovac M et al: Exome sequencing of osteosarcoma reveals mutation
• May show reactive woven bone formation in periphery signatures reminiscent of BRCA deficiency. Nat Commun. 6:8940, 2015
• Bone lined by osteoblasts and not atypical tumor cells as in 6. Behjati S et al: Distinct H3F3A and H3F3B driver mutations define
chondroblastoma and giant cell tumor of bone. Nat Genet. 2013
osteosarcoma Dec;45(12):1479-82. Epub 2013 Oct 27. Erratum in: Nat Genet. 46(3):316,
• Most harbor histone H3F3A/H3F3B G34W mutation 2014
7. Perry JA et al: Complementary genomic approaches highlight the
Chondrosarcoma PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc Natl
Acad Sci U S A. 111(51):E5564-73, 2014
• Distinction from chondroblastic osteosarcoma can be 8. Kerr DA et al: Molecular distinction of chondrosarcoma from chondroblastic
challenging osteosarcoma through IDH1/2 mutations. Am J Surg Pathol. 37(6):787-95,
○ Bone may be scarce in chondroblastic osteosarcomas 2013
and some gnathic osteosarcomas 9. Deyrup AT et al: Sarcomas arising in Paget disease of bone: a
clinicopathologic analysis of 70 cases. Arch Pathol Lab Med. 131(6):942-6,
○ Extensive sampling may reveal diagnostic foci of osteoid 2007
deposition or immature bone for osteosarcoma 10. Mankin HJ et al: Survival data for 648 patients with osteosarcoma treated at
one institution. Clin Orthop Relat Res. (429):286-91, 2004
○ Cartilaginous tumor with marked atypia, particularly in
11. Ozaki T et al: Genetic imbalances revealed by comparative genomic
2nd-3rd decades of life, is suspicious for osteosarcoma hybridization in osteosarcomas. Int J Cancer. 102(4):355-65, 2002
• Presence of IDH1 or IDH2 mutations favors 12. Bridge JA et al: Cytogenetic findings in 73 osteosarcoma specimens and a
chondrosarcoma rather than osteosarcoma review of the literature. Cancer Genet Cytogenet. 95(1):74-87, 1997
13. Chow LT et al: Chondromyxoid fibroma-like osteosarcoma: a distinct variant
Dedifferentiated Chondrosarcoma of low-grade osteosarcoma. Histopathology. 29(5):429-36, 1996
14. Glasser DB et al: Survival, prognosis, and therapeutic response in osteogenic
• Characterized by low-grade cartilage juxtaposed to high- sarcoma. The Memorial Hospital experience. Cancer. 69(3):698-708, 1992
grade sarcoma (dedifferentiated component) 15. Unni KK et al: Osteosarcoma: pathology and classification. Semin
○ Dedifferentiated component may be osteosarcoma Roentgenol. 24(3):143-52, 1989
• Presence of IDH1 or IDH2 mutations favors 16. Rosen G et al: Primary osteogenic sarcoma: eight-year experience with
adjuvant chemotherapy. J Cancer Res Clin Oncol. 106 Suppl:55-67, 1983
chondrosarcoma rather than osteosarcoma 17. Dahlin DC et al: Osteosarcoma of bone and its important recognizable
varieties. Am J Surg Pathol. 1(1):61-72, 1977
Ewing Sarcoma
• Small cell variant of osteosarcoma mimic Ewing sarcoma
• Presence of EWSR1 rearrangements (present in ~ 95% of
cases) supports Ewing sarcoma
Metastatic Carcinoma
• Metastatic carcinoma from breast or prostate may evoke
robust osteoblastic reaction, mimicking osteosarcoma
25
Diagnoses Associated With Syndromes by Organ: Osteosarcoma
Osteosarcoma in Proximal Humerus Osteosarcoma

(Left) Radiograph of an
osteosarcoma in the proximal
humerus illustrates ill-defined
central densities ﬅ
corresponding to the
calcifications present in this
tumor. Codman triangle ﬇
indicative of a prominent
periosteal reaction and soft
tissue extension by tumor is
present. (Right) Axial STIR MR
in the same osteosarcoma in
the proximal humerus
illustrates a tumor forming a
circumferential soft tissue
mass.
Osteosarcoma in Proximal Humerus Treated Osteosarcoma With Necrosis

(Left) Gross photograph shows
osteosarcoma involving the
proximal humerus in the same
patient. The raised periosteum
﬇ corresponds to the
radiographic findings of the
Codman triangle. (Right) After
treatment, this osteosarcoma
in the proximal femur shows
residual bone ﬊. The tumor
demonstrates an infiltrative
growth pattern, encasing
preexisting bony trabeculae
ﬅ. Treatment effect is
present, with extensive tumor
necrosis ﬉.
Sclerotic Osteosarcoma With Permeative

Osteosarcoma Encasing Preexisting Bone Growth Pattern
(Left) In osteosarcoma, tumor
cells occasionally grow in
sheets ﬆ, infiltrating among
preexisting trabecular bone
﬊. (Right) In osteosarcoma,
neoplastic bone ﬆ can
sometimes be seen being built
along preexisting native
trabecular bone ﬊ as
scaffolds, giving rise to the
permeative pattern.
26
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Fig. 246.—Sepia officinalis L.,
with mantle cut away to show
position of internal shell, × ½.
(The ends of the tentacular
arms are cut off.)
The Belemnitidae are believed to have been gregarious, and to
have lived in shallow water on a muddy bottom. Specimens are
sometimes found in which even the ink-sac can be recognised in
situ. The relative proportions of rostrum and phragmocone vary
greatly in different groups, the rostrum being in some cases two feet
long, in others only just enclosing the phragmocone. As a rule the
rostrum is the only portion which has been preserved.
Fam. 3. Belosepiidae.—Phragmocone short, slightly curved,
chambers small, placed at the posterior end of a sepion, rostrum
solid, obtuse.—Eocene (Paris, Bracklesham, etc.).
Fam. 4. Belopteridae.—Sepion not known; phragmocone curved,
siphuncle on the ventral margin, rostrum well developed, pointed.
Principal genus, Spirulirostra.—Miocene of Turin.
These two families, with their small, curved phragmocone and (in
the case of the Belosepiidae) large sepion, are clearly intermediate
between the Phragmophora and Sepiophora. Some authorities place
them with the latter group.
Fig. 247.—Shell of Spirula Peronii Lam. A,

Cutside view; B, showing last chamber and
position of siphuncle; C, in section, showing
the septa and course of siphuncle; D, shell
broken to show the convexity of the inner
side of the septa; E, portion of a septal neck.
Fig. 248.—Spirula Peronii Lam.:
d, terminal sucker; f, funnel;
s1, s2, projecting portions of
shell, the internal part of
which is dotted in. (From
Owen and A. Adams
combined.)
B. Sepiophora.—Shell internal, consisting usually of (a) an
anterior cancellated portion, (b) a posterior laminated portion, the
laminae enclosing air. It terminates in a very rudimentary
phragmocone and a rostrum, but there is no siphuncle.
Fam. Sepiidae.—Eyes with cornea complete, body oval, fins
narrow, lateral, as long as the body, generally united behind; sessile
arms short, tentacular arms long, acetabula generally in four rows,
fourth left arm in the male hectocotylised near the base (Fig. 249).—
World-wide.
The sepion or ‘cuttle-bone’ runs the whole length and width of the
body. In Sepia it is very thick in front, while the posterior ventral end
is concave and terminated by a prominent spine, the rostrum or
mucro which points downwards. The whole shell is surrounded by a
thin chitinous margin, which forms a lateral expansion. Other genera
are Sepiella, Hemisepius, and Trachyteuthis (fossil only).
C. Chondrophora.—Shell (gladius or pen) long, chitinous.
(a) Myopsidae:[400] cornea entire, species mostly sub-littoral.
Fam. 1. Sepiolidae.—Fins large, dorso-lateral; tentacular arms
retractile; two first dorsal arms in the male hectocotylised; gladius
narrow, half as long as the body.—World-wide.
Principal genera: Sepiola, dorsal mantle connected with the head
by a broad cervical band, ventral mantle with the funnel by a ridge
fitting into a groove; Rossia, dorsal mantle supported by a ridge,
arms with never more than four rows of acetabula; Inioteuthis,
Stoloteuthis, Nectoteuthis, and Promachoteuthis.
Fam. 2. Sepiadariidae.—Fins not as long as the body, mantle
united to the head on the dorsal side, fourth left arm in the male
hectocotylised; no gladius. Principal genera, Sepiadarium,
Sepioloidea.—Chiefly Pacific Ocean.
Fig. 249.—Hectocotylised arm (h.a.) of Sepia

officinalis L., shown in contrast to one of
the ordinary sessile arms; m, mouth; p,
pocket into which the tentacular arm is
retracted.
Fam. 3. Idiosepiidae.—Fins very small, terminal; fourth pair of
arms in the male hectocotylised, bare of suckers.
The only genus, Idiosepion, with a single species (I. pygmaeum
Stp.) is from the Indian Ocean, and is the smallest known
Cephalopod, measuring only about 15 mm. in length.
Fam. 4. Loliginidae.—Body rather long, fins varying in size,
tentacular arms partially retractile, gladius as long as the back,
pointed in front, shaft keeled on the ventral side.—World-wide.
Loligo proper has a pointed body with triangular posterior fins
united behind; sessile arms with two rows of acetabula, tentacular
arms with four; fourth left arm hectocotylised at the tip; funnel
attached to the head. Other genera are Loliguncula, Sepioteuthis,
and Loliolus. Belemnosepia, Beloteuthis, Leptoteuthis, and
Phylloteuthis are fossil genera only, differing in the shape of the
gladius.
(b) Oigopsidae: cornea more or less open; species pelagic.
Fam. 5. Ommastrephidae.—Body cylindrical, fins generally
terminal, united together, regularly rhomboidal, sessile arms with
varying number of rows of acetabula, mantle connexions elaborate;
gladius horny, narrow lanceolate, with a hollow cone at the posterior
end.—World-wide.
Fig. 250.—Architeuthis princeps, Verr., E. America: f, Right

fin; fu, funnel; f.c, fixing cushions and acetabula on the
tentacular arms (t, t). (After Verrill, × 1/60.)
Ommastrephes proper has a natatory web on the sessile arms;

the wrist of each club has a series of acetabula with corresponding
cushions on the other wrist. In Thysanoteuthis (often made a
separate family) the sessile arms have two rows of cirrhi, with lateral
expansions of the skin; fins as long as the body. In Architeuthis, to
which belong the largest Cephalopoda known, the fins together are
shaped like a broad arrow-head; acetabula of sessile arms strongly
denticulate; tentacular arms very long, with equidistant pairs of
acetabula and fixing cushions throughout their entire length, and a
group of the same at the base of the club. The acetabula and
cushions correspond on the opposing tentacles, and enable them to
pull together. Other genera are Dosidicus, Todarodes, Illex,
Bathyteuthis and Mastigoteuthis.
Fam. 6. Onychoteuthidae.—Body cylindrical, fins terminal or
lateral, mantle-locking apparatus elaborate, tentacular arms very
long, sessile or tentacular arms furnished with retractile hooks,
gladius lanceolate, with a terminal cone.—World-wide.
The prehensile apparatus of Cephalopoda reaches its maximum
of power and singularity in this family. In Onychia, Onychoteuthis and
Ancistroteuthis, the sessile arms have acetabula only, in Gonatus
and Abralia they have hooks as well, while in Verania, Ancistrochirus
and Enoploteuthis, the sessile arms have hooks only. The number of
rows of hooks or acetabula varies with the different genera.
Fam. 7. Chiroteuthidae.—Head nearly as large as the body; fins
terminal, tentacular arms very long, sessile arms slightly webbed,
acetabula denticulated; mantle-supports consisting of cartilaginous
ridges on the mantle, which fit into corresponding depressions on the
funnel, gladius expanded at each end.—Atlantic Ocean.
The six dorsal arms in Histioteuthis are united by a broad web,
while in Histiopsis the web only reaches half way up the arm. In
Chiroteuthis the tentacular arms have scattered sessile suckers
throughout their whole length, and four rows of very long
pedunculate suckers on the clubs.
Fam. 8. Cranchiidae.—Head small, body rounded, barrel-shaped,
fins terminal, eyes often very large, sessile arms short, tentacular
arms long, thread-like.—World-wide.
Cranchia proper has the tentacular clubs finned, with eight rows of
suckers, body sometimes covered with warty tubercles. Loligopsis
has a very attenuated body, with fins terminally united; some species
are spotted with colour, or have rows of tubercles on the ventral side.
Taonius (Fig. 251) is doubtfully distinct from Loligopsis.
Fig. 251.—Taonius hyperboreus

Stp., N. Atlantic: e, e, eyes; f,
f, fins; t, t, tentacular arms.
(After Hoyle, × ¼.)
Order Tetrabranchiata
Cephalopoda with four branchiae and four kidneys; animal
inhabiting the last chamber of an external multilocular shell; funnel
consisting of two separate lobes; tentacles numerous, without
suckers or hooks; no ink-sac.
The shell consists of two layers, the outer being porcellanous, and
the inner, as well as the walls of the chambers or septa, nacreous.
The septa vary greatly in shape. In most of the Nautiloidea they are
regularly curved, as in Nautilus, or straight, as in Orthoceras, but in
the Ammonoidea they are often exceedingly complex. The edge of
the septum, where it unites with the shell-wall, is called the suture,
and the sutural line, which is not seen until the porcellanous layer is
removed, varies in shape with the septum.
Fig. 252.—Nautilus pompilius L., in section, showing

the septa (s, s), the septal necks (s.n, s.n), the
siphuncle dotted in (si), and the large body
chamber (ch).
The septa are traversed by a membranous tube known as the
siphuncle, which in Nautilus is said by Owen to connect ultimately
with the pericardium. The septal necks, or short tubular
prolongations of the septa where they are perforated by the
siphuncle, are in the great majority of the Nautiloidea directed
backwards (Fig. 252), i.e., they project from the front wall of each
chamber, while in nearly all Ammonoidea they are directed forwards.
When the siphuncle is narrow, as in the Ammonoidea, it is simple,
but when wide, as in many of the Nautiloidea, its walls are often
thickened by the deposition of masses of calcareous matter, or by
rings and radiating lamellae of the same material. In position, the
siphuncle is sometimes central, sometimes sub-central, sometimes
(Ammonoidea) marginal. In some cases its position is believed to
change during the growth of the individual. The precise object served
by the siphuncle is at present unknown. Some hold that it preserves
the vitality of the unoccupied chambers, by connecting them with the
soft parts of the animal; others have regarded it as a means for
lightening the shell by the passage of some gas into the chambers.
Fig. 253.—Ammonites
(Cadoceras) sublaevis
Sowb., Kellaway’s Rock,
showing the marginal
position of the siphuncle (si).
The initial chamber in Nautiloidea consists of an obtuse incurved
cone, marked on the outer surface of its posterior wall by a small
scar known as the cicatrix, which may be slit-like, round, oval, or
cruciform in shape. It has been held that the cicatrix originally
communicated with the protoconch or larval shell, which probably
dropped off as development proceeded. In the Ammonoidea, on the
other hand, there is no cicatrix, and the initial chamber probably
represents the protoconch, as seen in the nucleus of many
Gasteropoda.
Sub-order 1. Nautiloidea.—Shell straight, bent, or coiled,
aperture simple or contracted; siphuncle often narrowed by internal
deposits, position variable; septal necks short, usually directed
backwards; septa concave towards the aperture; initial chamber
conical, with a cicatrix on the posterior wall.
The Nautiloidea, of which Nautilus is the sole living
representative, date back to the Cambrian epoch, and attain their
maximum in the Silurian and Devonian. At the close of the
Palaeozoic era, every family, with the sole exceptions of the
Orthoceratidae and Nautilidae, appears to have become extinct. The
former disappear with the Trias, and after the lapse of the whole
Secondary era, Aturia, a form closely related to Nautilus, makes its
appearance.
(a) Retrosiphonata: septal necks directed backwards.
Fam. 1. Orthoceratidae.[401]—Shell straight or slightly curved,
aperture simple, body-chamber large; siphuncle cylindrical, position
variable. Single genus, Orthoceras (Fig. 254). Cambrian to Trias.
Fam. 2. Endoceratidae.—Shell straight, siphuncle wide, marginal,
septal necks produced into tubes fitting into one another. Principal
genera: Endoceras (specimens of which occur six feet long), and
Piloceras—Ordovician.
Fam. 3. Actinoceratidae.—Shell straight or slightly curved,
siphuncle wide, contracted at the septa by obstruction-rings.
Principal genera: Actinoceras, Discosorus, Huronia, Sactoceras.—
Ordovician to Carboniferous.
Fam. 4. Gomphoceratidae.—Shell globular, straight or
considerably curved, aperture narrowed, T-shaped, body-chamber
large, siphuncle variable in position. The aperture is in some cases
so narrow that probably only the arms could be protruded. Principal
genus, Gomphoceras (Fig. 255).—Silurian.
Fam. 5. Ascoceratidae.—Shell sac-like or flask-shaped, apex
truncated, unknown, body-chamber occupying nearly the whole of
the shell on the ventral side, contracting at the aperture, last few
septa coalescing on the dorsal side and encroaching upon the body-
chamber. The young form has a symmetrical shell like Orthoceras,
attached to the sac-like shell above described; as growth proceeds
the former portion is thrown off. Principal genera: Ascoceras,
Glossoceras.—Ordovician and Silurian.
Fig. 254.—A, Section of
Orthoceras, showing the
septa (s, s), and siphuncle
(si, si); B, portion of the
exterior of Orthoceras
annulatum Sowb., × ½.
(Woodwardian Museum,
Cambridge.)
Fam. 6. Poterioceratidae.—Shell fusiform, contracted at both
ends, aperture simple, siphuncle variable in position, inflated
between the septa. The form generally resembles Gomphoceras,
except for the simple aperture and fusiform shape.—Ordovician to
Carboniferous.
Fam. 7. Cyrtoceratidae.—Shell conical or sub-cylindrical, slightly
curved, body-chamber large, siphuncle variable in position. Single
genus, Cyrtoceras.—Cambrian to Carboniferous.
Fam. 8. Lituitidae.—Shell coiled in a flat, sometimes loose spiral,
last whorl straight, containing the body-chamber, often greatly
prolonged. Principal genera: Lituites, Ophidioceras.—Ordovician and
Silurian.
Fam. 9. Trochoceratidae.—Shell helicoid, with seldom more than
two whorls, dextral or sinistral, last whorl sometimes partly uncoiled.
Principal genera: Trochoceras, Adelphoceras.—Ordovician to
Devonian.
Fam. 10. Nautilidae.—Shell with few whorls, more or less
overlapping, septa simple, siphuncle central or sub-central, aperture
not contracted.
The ‘tentacles’ are about 90 in number, and consist of four groups
each of 12 or 13 labial tentacles surrounding the mouth, two groups
each of 17 larger (brachial) tentacles on each side of the head, two
thicker tentacles which combine to form the ‘hood,’ and two small
tentacles on each side of the eye. When the animal swims, the
tentacles are extended radially from the head, somewhat like those
of a sea-anemone. The direction of the many pairs of tentacles at
constant but different angles from the head, is the most striking
feature in the living Nautilus, and accounts for its being described,
when seen on the surface, as ‘a shell with something like a
cauliflower sticking out of it.’[402] The funnel is not a complete tube,
but is formed by the overlapping of the margins of two thin fleshy
lobes (which are probably morphologically epipodia), so that when
the two lobes are parted, a broad canal appears, leading to the
branchial cavity. The head is conical, and the mouth and its
appendages can be retracted into a sort of sheath, over which fits
the ‘hood.’
Fig. 255.—A, Gomphoceras
ellipticum M’Coy, Silurian: B,
aperture (ap) of same; s, s,
septa; si, position of
siphuncle. (After Blake.)
Other genera are Trocholites, Gyroceras, Hercoceras, Discites,
Aturia.—Ordovician to present time.
Fam. 11. Bactritidae.—Shell straight, conical, siphuncle small,
marginal, septal necks long, funnel-shaped, sutures undulating, with
a sinus corresponding to the siphuncle. This family, from the form of
its sutures, appears to constitute a passage to the Ammonoidea.
Single genus, Bactrites.—Silurian and Devonian.
(b) Prosiphonata.—Septal necks directed forwards.
The two genera are Bathmoceras (Ordovician), shell straight,
conical always truncated, siphon marginal; and Nothoceras
(Silurian), shell nautiloid with simple sutures.
Sub-order 2. Ammonoidea.—Shell multiform, straight, curved, flat
spiral, or turreted, sutural line more or less complex, siphuncle
simple.
Some authorities hold that the members of this great sub-order,
now totally extinct, belong to the Dibranchiata, on the ground that the
protoconch resembles that of Spirula rather than that of the
Nautiloidea. Others again regard the Ammonoidea as a third, and
distinct Order of Cephalopoda. Their distribution extends from the
Silurian to (possibly) the early Tertiary. No trace has ever been found
of an ink-sac, mandible, or hooks on the arms; the shell was
undoubtedly external.
Fig. 256.—Diagram of the sutures of Ammonites: A,

an elaborate suture (Phylloceras); B, a simple
suture (Ceratites); s.s, siphonal, s.v, ventral, s.l,
first lateral, s.l´, second lateral saddles; s.a, s.a,
auxiliary saddles; l.v, ventral, l, first lateral, l´,
second lateral lobe; l.a, l.a, auxiliary lobes. The
arrow points towards the aperture. (From
Woodward.) Compare Fig. 258.
The sutural line, which indicates the septa, and is generally
concealed beneath the outer layer of shell, consists of a number of
lobes or depressions, the concave part of which is directed towards
the aperture. Between these lobes lie corresponding elevations, or
saddles, the convex part of which is directed towards the aperture.
There are six principal lobes (Fig. 256): the siphonal or ventral,
which is traversed by the siphuncle, the dorsal, and a superior and
inferior lateral on each side; smaller auxiliary lobes may succeed
these latter. The adjacent saddles have received corresponding
names. As a rule the sutural line is very complex, but in some cases
(Goniatites, Lobites) it is simple (Fig. 258, A). The first saddle of a
large number of genera serves as a means of classification,
according as it is broad or narrow. Some authorities reverse the
terms ventral and dorsal, as applied above. It is probable, however,
that the position of the animal of Ammonites in its shell resembled
that of Nautilus. The siphuncle is dorsal (internal) in Clymenia only,
ventral (external) in all other genera.
The aptychus of Ammonoidea is a corneous or calcareous valve-
like body, generally formed of two symmetrical parts (Fig. 257). It has
been regarded by some as the covering of the nidamental gland, and
hence as occurring only in the female, by others, with more
probability, as an operculum, covering or imbedded in a hood
formed, as in Nautilus, of modified arms. Sometimes the Aptychus is
in a single piece (Anaptychus), sometimes the two pieces are united
on the median line (Synaptychus).
Fig. 257.—Aptychus of Ammonite

(Trigonellites latus). Kimmeridge
Clay, Ely. × ½.
The Ammonoidea are thus classified by Dr. P. Fischer:—
(a) Goniatitidae.
Retrosiphonata
(b) Prosiphonata No Aptychus First Arcestidae, Tropitidae,
or saddle, Ceratitidae, Clydonitidae.
Anaptychus wide
corneous, First Pinacoceratidae,
single saddle, Amaltheidae,
narrow Ammonitidae,
Lytoceratidae.
Aptychus calcareous, Harpoceratidae,
valves Stephanoceratidae.
double or united
(a) Retrosiphonata. Fam. 1. Goniatitidae.—Shell nautiloid, whorls
sometimes disjoined, siphuncle ventral or dorsal, sutures simple.
Principal genera: Clymenia, Goniatites (Fig. 258, A).—Devonian to
Carboniferous.
(b) Prosiphonata. Fam. 2. Arcestidae.—Shell globular, smooth or
striated and rayed, body-chamber very long, aperture often with a
projecting hood, umbilicus closed by a callosity, lobes numerous,
foliaceous, aptychus present. Principal genera: Arcestes, Lobites.—
Principally Trias.
Fam. 3. Tropitidae.—Differs from Arcestidae mainly in the more
highly ornamented surface, which is decorated with ribs which
become granular at the periphery. Principal genus, Tropites.—Trias
and Lias.
Fam. 4. Ceratitidae.—Shell ribbed and tuberculated, body-
chamber short, lobes denticulated, saddles simple. Principal genera:
Ceratites (Fig. 258, B), Trachyceras.—Principally Trias.
Fam. 5. Clydonitidae.—Shell variable in form, body-chamber short,
sutural line undulated, simple. Principal genera: Clydonites,
Choristoceras, Rhabdoceras, Cochloceras.—Trias.
Fam. 6. Pinacoceratidae.—Shell discoidal, usually smooth, body-
chamber short, sutural line very complex, lobes numerous. Principal
genera: Pinacoceras, Sageceras.—Carboniferous to Trias.
Fam. 7. Amaltheidae.—Shell broad, keeled, last whorl concealing
most of the spire, sutures with auxiliary lobes, incised.—Principal
genera: Amaltheus, Schloenbacia, Sphenodiscus.—Trias,
Cretaceous.
Fig. 258.—Various forms of Ammonoidea: A, Goniatites

crenistria J. Phil., Carb. Limestone; B, Ceratites
nodosus de Hann., Muschelkalk; C, Ammonites
(Parkinsonia) Parkinsoni Sowb., Inf. Oolite; D,
Phylloceras helerophyllum Sowb., Upper Lias; s, s,
sutural lines.
Fam. 8. Ammonitidae.—Body-chamber long, whorls narrow,
uncovered, more or less ribbed, aperture simple, sutural line normal,
aptychus single, corneous. Principal genera: Ammonites, Aegoceras.
—Principally Lias.
Fam. 9. Lytoceratidae.—Shell discoidal, body-chamber short,
aperture simple, no aptychus. Principal genera: Lytoceras,
Phylloceras (Fig. 258, D).—Trias to Cretaceous.
Fam. 10. Harpoceratidae.—Shell discoidal, compressed, margin
keeled, surface with straight or arched ribs, aperture with lateral
projections, suture with accessory lobes, aptychus in two pieces.
Principal genera: Harpoceras, Oppelia, Lissoceras.—Jurassic to
Cretaceous.
Fig. 259.—A, Turrilites

catenulatus d’Orb, Gault; B,
Macroscaphites Iranii d’Orb,
Upper Neocomian. (From
Zittel.)
Fam. 11. Stephanoceratidae.—Shell discoidal, helicoid or straight,
whorls sometimes disunited, surface often with bifurcating ribs,
which are tubercled, aperture often with lateral projections, sutural
line incised, aptychus in two pieces, sometimes united.
In the discoidal group, Stephanoceras is strongly ribbed, tubercled
at the point of bifurcation, Cosmoceras has long lateral projections of
the aperture when young, Perisphinctes has a large body-chamber
and numerous smooth ribs. Other genera are Acanthoceras,
Peltoceras, Aspidoceras, and Hoplites. Among the loosely whorled
genera, Scaphites (Fig. 260, A) has the last whorl produced and bent
back again in horse-shoe form, while the early whorls are concealed;
Hamites, Hamulina, and Ptychoceras have a shell shaped like a
single or double hook, the sides of which may or may not be united;
Crioceras (Fig. 260, B) in form of whorls resembles a Spirula,
Ancyloceras a Scaphites with the first whorls disunited.
Macroscaphites (Fig. 259, B) is similar, but with the first whorls
united and not concealed. Turrilites (Fig. 259, A) is turreted and
sinistral, while Baculites is quite straight, with a long body-chamber.
Fig. 260.—A, Scaphites aequalis Sowb.,

Cretaceous; B, Crioceras bifurcatum Quenst.,
Cretaceous. (From Zittel.)
CHAPTER XIV
CLASS GASTEROPODA—AMPHINEURA AND PROSOBRANCHIATA
Order I. Amphineura
Bilaterally symmetrical Mollusca, anus at the terminal end of the
body, dorsal tegument more or less furnished with spicules.
Sub-order 1. Polyplacophora (Chitons).—Foot co-extensive with
ventral surface of the body, dorsum with eight transverse plates,
articulated (except in Chitonellus), a row of ctenidia on each side
between the mantle and the foot. Silurian ——.
The Chitons are found in all parts of the world, ranging in size
from a length of about half an inch to six inches or more in the giant
Cryptochiton. Although in the main sub-littoral, they occur at very
great depths; the Challenger dredged Leptochiton benthus Hadd. at
2300 fathoms. Chiton Polii exceptionally occurs at Malta—teste
MacAndrew—above sea margin, but within reach of the ripple. As a
rule, the Chitons live in concealment, on the under surface of stones
or in deep and narrow fissures in the rocks. When the stone to which
they are attached is turned over, they crawl slowly to the side which
is not exposed, as if disliking the light. An undescribed species,
however, which I took at Panama, crawled quite as fast as an
ordinary snail. Chiton fulvus Wood, apparently is accustomed to
crawl with some rapidity. MacAndrew took it in abundance on his
anchor chain in Vigo Bay every time his yacht was got under weigh.
He also found it crawling in sand on the shore, to which habit is no
doubt due its extreme cleanness and freedom from the foreign
growths which are so characteristic of many of the species. When
detached a Chiton contracts the muscles of the whole body, and rolls
up into a ball like a wood-louse.

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Diagnostic Pathology Familial Cancer Syndromes 2Nd Edition Uk Full Chapter

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Diagnostic Pathology: Familial Cancer

Syndromes 2nd Edition Uk

Vania Nosé, MD, PhD

DIAGNOSTIC PATHOLOGY: FAMILIAL CANCER SYNDROMES, SECOND EDITION ISBN: 978-0-323-71204-0

Previous edition copyrighted 2013.

Library of Congress Control Number: 2019956687

Printed in Canada by Friesens, Altona, Manitoba, Canada

Last digit is the print number: 9 8 7 6 5 4 3 2 1

Vania Nosé, MD, PhD

ART DIRECTION AND DESIGN

PART II: Overview of Syndromes

PART III: Reference

Part I: Diagnoses Associated With ADRENAL MEDULLA AND PARAGANGLIA

Blood and Bone Marrow

Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma 4

CLINICAL ISSUES ○ Germline IKZF1 mutations

B-ALL/Lymphoma in Bone Marrow B-ALL/Lymphoma Morphology

B-ALL/Lymphoma in Bone Marrow Aspirate B-ALL/Lymphoma in Lymph Node

Blood and Bone Marrow

Germline Mutations and Conditions Associated With Increased Risk of Hematological

Blood and Bone Marrow

Bone and Soft Tissue

TERMINOLOGY – Ollier disease and Maffucci syndrome: Somatic

Pelvic Chondrosarcoma Pelvic Chondrosarcoma

Conventional Chondrosarcoma in Proximal

Bone and Soft Tissue

CLINICAL ISSUES CT Findings

• Recurrent GRM1 gene rearrangement in subset of tumors

Bone and Soft Tissue

Chondrosarcoma With Permeative Pattern Clear Cell Chondrosarcoma

Dedifferentiated Chondrosarcoma Mesenchymal Chondrosarcoma

Sacrococcygeal Chordoma Sacrococcygeal Chordoma

Conventional Chordoma With

Bone and Soft Tissue

○ T-brachyury expression absent in high-grade component

Bone and Soft Tissue

Chondroid Chordoma Dedifferentiated Chordoma

Loss of INI1 Expression in Poorly

TERMINOLOGY ○ Alternating hypercellular/hypocellular areas ("marbled")

MPNST Arising in Plexiform Neurofibroma Radiation-Associated MPNST

MPNST With "Marbled" Pattern Spindle Cells in Conventional MPNST

Bone and Soft Tissue

– Associated with schwannomatosis and germline Atypical Neurofibromatous Neoplasm of Uncertain

Bone and Soft Tissue

Rhabdomyoblasts in Malignant Triton

Epithelioid MPNST Loss of INI1 in Epithelioid MPNST

TERMINOLOGY CLINICAL ISSUES

Osteosarcoma in Distal Femur Osteosarcoma in Distal Femur

Bone and Soft Tissue

Bone and Soft Tissue

Osteosarcoma in Proximal Humerus Osteosarcoma

Osteosarcoma in Proximal Humerus Treated Osteosarcoma With Necrosis

Sclerotic Osteosarcoma With Permeative

Fig. 247.—Shell of Spirula Peronii Lam. A,

Fig. 249.—Hectocotylised arm (h.a.) of Sepia

Fig. 250.—Architeuthis princeps, Verr., E. America: f, Right

Ommastrephes proper has a natatory web on the sessile arms;

Fig. 251.—Taonius hyperboreus

Fig. 252.—Nautilus pompilius L., in section, showing

Fig. 256.—Diagram of the sutures of Ammonites: A,

Fig. 257.—Aptychus of Ammonite

Fig. 258.—Various forms of Ammonoidea: A, Goniatites

Fig. 259.—A, Turrilites