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Diagnose tumors with confidence with Diagnostic Histopathology of Tumors, 4th Edition. Dr. Christopher Fletcher's renowned reference provides the advanced, expert guidance you need to evaluate and interpret even the most challenging histopathology specimens more quickly and accurately.

  • Consult this title on your favorite e-reader with intuitive search tools and adjustable font sizes. Elsevier eBooks provide instant portable access to your entire library, no matter what device you're using or where you're located.
  • Diagnose efficiently and effectively using diagnostic flow charts, correlations of gross appearances to microscopic findings, and differential diagnosis tables for better recognition and evaluation of similar-looking entities.
  • Employ immunohistochemistry, molecular and genetic diagnostic tests, and other modern techniques as well as the best morphologic diagnostic methods to effectively identify each tumor or tumor-like entity.
  • Utilize new, clinically important molecular genetic data and updated classification schemes to help guide treatment and targeted therapy.
  • Apply the latest techniques and diagnostic criteria with completely rewritten chapters on Small and Large Intestines, Heart, Larynx and Trachea, Ear, and Peritoneum.
  • Find critical information quickly thanks to more tables and bulleted lists throughout.


Hodgkin's lymphoma
Lobular carcinoma
Women's Hospital of Greensboro
Kaposi's sarcoma
Ductal carcinoma
Follicular thyroid cancer
Respiratory tract neoplasm
Medullary carcinoma
Adrenal tumor
Eye neoplasm
Islet cell carcinoma
Perforated eardrum
Neuroendocrine tumor
Mucoepidermoid carcinoma
Acute myeloid leukemia
Pyogenic granuloma
Prostatic intraepithelial neoplasia
Pleomorphic adenoma
Large cell
Follicular lymphoma
Upper respiratory tract
Bone marrow examination
Anal canal
Adenoid cystic carcinoma
Carcinoma in situ
Sebacic acid
Adrenocortical carcinoma
Glioblastoma multiforme
Pituitary adenoma
Cutaneous conditions
Basal cell carcinoma
Tuberous sclerosis
Female reproductive system (human)
Chronic myelogenous leukemia
Wilms' tumor
Ewing's sarcoma
Physician assistant
Polycythemia vera
B-cell chronic lymphocytic leukemia
Ovarian cancer
Oral cancer
Renal cell carcinoma
Squamous cell carcinoma
Pancreatic cancer
Bowel obstruction
Parathyroid gland
Soft tissue sarcoma
Stomach cancer
Otitis media
Myelodysplastic syndrome
Growth hormone
Autonomic nervous system
Cushing's syndrome
Skin neoplasm
Peptic ulcer
Coeliac disease
Large intestine
X-ray computed tomography
Melanocytic nevus
Hearing impairment
Diabetes mellitus
World Health Organization
Data storage device
Magnetic resonance imaging
Lung cancer
Réaction en chaîne par polymérase


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Histopathology of
Christopher D.M. Fletcher, MD, FRCPath
Vice Chair, Anatomic Pathology
Brigham and Women's Hospital
Chief of Onco-Pathology
Dana-Farber Cancer Institute
Professor of Pathology
Harvard Medical School
Boston, MassachusettsTable of Contents
Cover image
Title Page
Volume 1
Chapter 1 Introduction
Chapter 2 Tumors of the Heart and Pericardium
General Clinical Features
Benign Tumors of the Heart and Pericardium
Malignant Tumors of the Heart and Pericardium
Chapter 3 Vascular Tumors
Benign Tumors
Vascular Tumors of Intermediate Malignancy
Malignant Vascular Tumors
Tumors of Lymph Vessels
Tumors of Perivascular Cells
Chapter 4 Tumors of the Upper Respiratory Tract
Benign Epithelial and Neuroectodermal NeoplasmsBenign Mesenchymal Neoplasms
Osseous, Fibroosseous, and Cartilaginous Lesions
Tumors of Indeterminant Malignant Potential
Malignant Epithelial and Neuroectodermal Neoplasms
Nonepithelial Malignant Neoplasms
Pseudoneoplastic Lesions
Normal Anatomy
Benign Neoplasms
Intraepithelial Precursor or Premalignant Lesions
Microinvasive, Superficial, or “early” Invasive Squamous Cell Carcinoma
Invasive Squamous Cell Carcinoma
Salivary Gland Malignant Neoplasms
Neuroendocrine Carcinomas
Cartilaginous Tumors
Other Malignant Neoplasms
Secondary Tumors
Nonneoplastic Mass Lesions
Chapter 5 Tumors of the Lung and Pleura
Bronchogenic-Alveolar Carcinomas
Neuroendocrine Carcinomas
Salivary Gland–Type Tumors
Biphasic Epithelial-Mesenchymal Neoplasms
Pulmonary Mesenchymal Neoplasms
Lymphoproliferative Disorders
Tumors Derived From Embryologically Displaced or Ectopic Tissues
Tumors of Uncertain Histogenesis
Miscellaneous Benign TumorsMetastases to the Lungs
Tumors of the Pleura
Chapter 6 Tumors of the Oral Cavity
Tumors of Oral Epithelium
Mesenchymal Neoplasms and Tumor-like Lesions
Odontogenic Cysts and Tumors
Tumors of Odontogenic Epithelium Without Odontogenic Ectomesenchyme
Tumors of Odontogenic Epithelium with Odontogenic Ectomesenchyme
Tumors of Odontogenic Ectomesenchyme with or Without Included Odontogenic
Malignant Odontogenic Neoplasms
Odontogenic Cysts
Chapter 7 Tumors of the Salivary Glands
The Normal Salivary Glands
Salivary Gland Neoplasms
Epithelial Tumors and Tumor-Like Lesions
Mesenchymal Neoplasms and Tumor-Like Lesions
Hematolymphoid Tumors and Tumor-Like Lesions
Analytic Approach to Diagnosis of Epithelial Tumors of the Salivary Gland
Chapter 8 Tumors of the Esophagus and Stomach
Chapter 9 Tumors of the Small and Large Intestines, Including Anal Canal
Small Intestine
AppendixLarge Intestine
Anal Canal
Anal Margin
Chapter 10 Tumors of the Liver, Biliary Tree, and Gallbladder
Biliary Tree
Chapter 11 Tumors of the Exocrine Pancreas
Classification and General Features
Ductal Adenocarcinoma
Intraductal Papillary Mucinous Neoplasms
Intraductal Tubulopapillary Neoplasm
Mucinous Cystic Neoplasms
Serous Cystic Neoplasms
Acinar Cell Carcinoma
Acinar Cell Cystadenoma
Solid Pseudopapillary Neoplasm
Tumors in Infants and Children
Nonepithelial Tumors and Secondary Tumors
Tumor-like Lesions
Chapter 12 Tumors of the Urinary Tract
Epithelial Tumors of the Kidney
Neuroendocrine and Neuroectodermal Neoplasms of the Kidney
Mesenchymal Tumors of the Kidney
Secondary Neoplasms of the KidneyRenal Tumors in Children
Benign Tumors and Tumor-like Lesions
Urothelial Carcinoma
Squamous Cell Carcinoma
Small Cell Carcinoma
Other Tumors
Chapter 13 Tumors of the Female Genital Tract
Tumors of the Ovary
Tumors of the Fallopian Tube
Tumors of the Broad and Round Ligaments
Endometrial Glandular Neoplasia
Endometrial Intraepithelial Neoplasia: A Precursor to Endometrioid (Type I)
Endometrial Adenocarcinoma
Precursors to Papillary Serous Adenocarcinoma
Endometrial Adenocarcinomas
Endometrioid AdenocarcinomaS
Papillary Serous and Clear Cell Carcinomas
Tumors Showing Mixed Differentiation
Endometrial Stromal Tumors
Non-Müllerian Neoplasms
Placental Chorangioma
Other Rare, Benign Placental Tumors
Fetal Malignancies Identified in the PlacentaMaternal Metastatic Tumors in the Placenta
Gestational Trophoblastic Disease
Benign Smooth Muscle Neoplasms
Malignant Smooth Muscle Neoplasms
Smooth Muscle Tumors of Uncertain Malignant Potential
Smooth Muscle Proliferations with Unusual Features
Rare and Unusual Neoplasms
Precancerous Disease
Early Invasive Squamous Cell Carcinoma
Invasive Squamous Cell Carcinoma
Early Invasive Adenocarcinoma
Invasive Adenocarcinoma
Mixed-Type Carcinomas
Neuroendocrine Carcinoma
Mixed Epithelial and Mesenchymal Tumors
Mesenchymal Tumors
Melanocytic Tumors
Miscellaneous Rare Tumors
Epithelial Tumors
Mesenchymal Neoplasia and Tumor-Like Conditions
Mixed Epithelial–mesenchymal Neoplasia
Melanocytic Lesions
Lymphoid and Hematopoietic Tumors
Other Rare Tumors
Metastatic Tumors
Squamous Neoplasia
Glandular NeoplasiaMelanocytic Lesions
mesenchymal Lesions
Other Rare Neoplasms
Chapter 14 Tumors and Tumor-like Conditions of the Male Genital Tract
Tumors and Tumor-Like Conditions of theSeminal Vesicles
Tumors and Tumor-like Conditions of the Testes
Tumors and Tumor-like Conditions of Paratesticular Tissues
Chapter 15 Tumors of the Peritoneum
Tumor-like Lesions
Mesothelial Neoplasms
Miscellaneous Primary Tumors
Metastatic Tumors
Tumors and Tumor-like Lesions of the Secondary Müllerian System
Volume 2
Chapter 16 Tumors of the Breast
Classification of Breast Disease
Fibrocystic Change and Associated Conditions
Inflammatory Disorders
Fibroadenoma, Variants, and Related Conditions
Sclerosing Lesions
Duct Papilloma and Related ConditionsColumnar Cell Lesions
Proliferative Breast Disease–epithelial Hyperplasia
Lobular Neoplasia
Myoepithelial Neoplasms
Stromal Tumors
Nonintrinsic Tumors
Chapter 17 Tumors of the Pituitary Gland
Introduction and Scope of the Problem
Tumors of the Anterior Pituitary Gland
Tumors of the Posterior Pituitary Gland
Other Tumors and Inflammatory Lesions
Chapter 18 Tumors of the Thyroid and Parathyroid Glands
The Normal Thyroid Gland
Thyroid Tumors: an Overview
Diagnosis of Thyroid Tumors
Tumors of Follicular or Metaplastic Epithelium
Tumors Showing C-Cell Differentiation
Tumors Showing Both Follicular and C-Cell Differentiation
Thymic and Related Branchial Pouch Tumors of the Thyroid
Tumors of Hematolymphoid Cells
Mesenchymal Tumors and Other Tumors
Unusual and Uncommon Tumors and Tumor-Like Lesions of the Thyroid
Metastatic Malignant Neoplasm in Thyroid
Practical Issues in Diagnosis of Thyroid Tumors
Fine-Needle Aspiration Cytology of Thyroid Lesions
Intraoperative Frozen Section Diagnosis of Thyroid Tumors
ReferencesThe Normal Parathyroid Glands
Parathyroid Adenoma
Parathyroid Carcinoma
Atypical Parathyroid Adenoma
Other Tumors
Intraoperative Diagnosis for Hyperparathyroidism
Chapter 19 Tumors of the Adrenal Gland
The Normal Adrenal Gland
The Nodular Adrenal Gland
Adrenal Cortical Adenoma
Adrenal Cortical Neoplasms Associated with Virilization or Feminization
Adrenal Cortical Carcinoma
Malignant Lymphoma and Plasmacytoma
Malignant Melanoma
Other Unusual Primary Adrenal Tumors
Tumors Metastatic to the Adrenal Gland
Chapter 20 Tumors of the Endocrine Pancreas
Terminology and Classification
Etiology, Pathogenesis, and Genetics
Malignant Potential and Biologic Behavior
Morphologic Features of Pannets
Morphologic Features of Pannecs
Specific Tumor Types
Differential DiagnosisReferences
Chapter 21 Tumors of the Lymphoreticular System, Including Spleen and Thymus
Lymph Node and Organized Lymphoid Tissues
Diagnosis of Lymphomas
Hodgkin Lymphoma
Non-Hodgkin Lymphomas
Precursor Lymphoblastic Lymphoma
Peripheral B-Cell Lymphomas
Peripheral T- and Putative NK-Cell Neoplasms
Lymphoproliferative Disorders Associated with Immunodeficiency
Tumors of Histiocytes and Dendritic Cells
Leukemia and Related Conditions
Metastatic Tumor in Lymph Node
Nonhematolymphoid Tumors and Tumor-Like Lesions of Lymph Node
Practical Issues in Diagnosis of Lymphoproliferative Lesions
The Normal Spleen
Patterns of Splenic Involvement in Lymphomas and Leukemias: Approach to
Primary Lymphoma of the Spleen
Lymphomas and Leukemias with Splenic Involvement as a Dominant Feature
Histiocytic and Dendritic Cell Proliferations in the Spleen
Mesenchymal Tumors and Tumor-Like Lesions of the Spleen
Rare Lesions of the Spleen
Metastatic Tumor in the Spleen
The Normal Thymus
Tumors of the Thymus
Thymic Epithelial Tumors
Neuroendocrine Tumors of the Thymus
Germ Cell Tumors of the Thymus and MediastinumLymphoid, Histiocytic, and Dendritic Cell Tumors
Mesenchymal Tumors of the Thymus and Anterior Mediastinum
Ectopic Tumors Occurring in the Thymus
Tumor-Like Lesions of the Thymus
Rare Tumors and Tumor-Like Lesions of the Thymus and Mediastinum
Metastatic Tumors in the Thymus or Anterior Mediastinum
Mediastinal Tumors: Diagnostic Approach and Pitfalls
Chapter 22 Tumors of the Hematopoietic System
Myelodysplastic Syndromes
Acute Myeloid Leukemia
B-Lymphoblastic Leukemia/Lymphoma
T-Lymphoblastic Leukemia/Lymphoma
Myeloproliferative Neoplasms
Chronic Myelogenous Leukemia, B C R – A B L - 1 Positive
Chronic Eosinophilic Leukemia (CEL), Not Otherwise Specified, and Idiopathic
Hypereosinophilic Syndrome
Polycythemia Vera
Essential Thrombocythemia
Primary Myelofibrosis
Myeloid and Lymphoid Neoplasms Associated with P D G F R A Rearrangement
Myeloid Neoplasms Associated with P D G F R B Rearrangement
Myeloid and Lymphoid Neoplasms Associated with F G F R - 1 Rearrangement
Plasma Cell Myeloma
Adult T-Cell Leukemia/Lymphoma
Hairy Cell Leukemia
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
B-Cell Prolymphocytic Leukemia
T-Cell Prolymphocytic Leukemia
T-Cell Large Granular Lymphocytic LeukemiaChronic Natural Killer Cell Lymphoproliferative Disorder
Aggressive Natural Killer Cell Leukemia
Mast Cell Disease
Chapter 23 Tumors of the Skin
Tumors of the Epidermis
Adnexal Tumors
Cutaneous Cysts
Merkel Cell (Neuroendocrine) Carcinoma
Melanocytic Tumors
Mesenchymal Tumors
Lymphoid Tumors
Chapter 24 Tumors of Soft Tissue
Adipocytic Tumors
Fibrous Tumors
Fibrohistiocytic Tumors (So-Called)
Smooth Muscle Tumors
Skeletal Muscle Tumors
Chondro-Osseous Tumors
Miscellaneous Benign Lesions
Miscellaneous Lesions of Intermediate Biologic Potential
Miscellaneous Malignant Lesions
Chapter 25 Tumors of the Osteoarticular System
Grading and Staging
Methods of Biopsy
Small Round Cell TumorsChondroid Tumors
Osteogenic Tumors
Osteoclast-Type Giant Cell–rich Tumors
Vascular Tumors
Fibrohistiocytic Tumors
Fibrogenic Tumors
Notochordal Tumors
Neural Tumors
Cystic Lesions of Bone
Benign Fibro-Osseous Tumors
Lesions with Reactive New Bone Formation
Miscellaneous Lesions
Tumors of Joints
Chapter 26 Tumors of the Central Nervous System
Tumors of Neuroepithelial Tissue
Tumors of the Meninges
Primary Lymphomas of the Central Nervous System
Germ Cell Tumors
Nonneuroepithelial Neoplasms and Cysts
Chapter 27 Peripheral Neuroectodermal Tumors
Reactive Lesions
Hamartomatous Lesions
Benign nerve sheath Tumors
Malignant Tumors
Miscellaneous Neuroectodermal Tumors Presenting in Soft Tissue
Chapter 28 Tumors of the Autonomic Nervous System, Including ParagangliaExtra-adrenal Paraganglia
Paragangliomas of the Head and Neck Region
Extra-adrenal Paraganglia of the Sympathoadrenal Neuroendocrine System
Extra-adrenal Paragangliomas of the Sympathoadrenal Neuroendocrine System
Gangliocytic Paraganglioma
Neuroblastoma and Related Tumors
Chapter 29 Tumors of the Eye and Ocular Adnexa
Tumors of the Eyelid and Periocular Skin
Tumors of the Conjunctiva
Tumors of the Lacrimal Drainage System
Tumors of the Orbit
Primary Tumors of the Optic Nerve
Intraocular Tumors
Chapter 30 Tumors of the Ear
Mass-Forming Lesions of the External Ear and Auditory Canal
Mass-Forming Lesions of the Middle and Inner Ear
Chapter 31 Molecular Genetic Techniques in Diagnosis and Prognosis
Somatic Mutations as Markers for the Diagnosis or Classification of Neoplasms
Antigen Receptor Rearrangements
Special Applications of Molecular Biologic Markers in Diagnosis and Prognosis
Pharmacogenomics of Cancer Therapy

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Library of Congress Cataloging-in-Publication Data
Diagnostic histopathology of tumors / [edited by] Christopher D.M. Fletcher.—4th ed.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-4377-1534-7 (2 v. set : alk. paper)
I. Fletcher, Christopher D.M.
[DNLM: 1. Neoplasms—pathology. QZ 241]
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Publishing Services Manager: Anne Altepeter
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Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1Contributors
Mahul B. Amin MD, Professor and Chairman, Department of Pathology and
Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
Tumors and Tumor-like Conditions of the Male Genital Tract
Alberto G. Ayala MD, Deputy Chief of Pathology, Department of Pathology and
Genomic Medicine, The Methodist Hospital; Professor of Pathology, Weill Medical
College of Cornell University, Houston, Texas
Tumors and Tumor-like Conditions of the Male Genital Tract
J. Eduardo Calonje MD, DipRCPath, Director of Dermatopathology, St. John's
Institute of Dermatology, St. Thomas Hospital, London, United Kingdom
Vascular Tumors
Fiona Campbell BSc, MD, FRCPath, Honorary Professor of Pathology, University of
Liverpool; Consultant Gastrointestinal Pathologist, Department of Pathology, Royal
Liverpool University Hospital, Liverpool, United Kingdom
Tumors of the Esophagus and Stomach
John K.C. Chan MD, Consultant Pathologist, Department of Pathology, Queen
Elizabeth Hospital, Hong Kong, China
Tumors of the Salivary Glands; Tumors of the Thyroid and Parathyroid Glands;
Tumors of the Lymphoreticular System, Including Spleen and Thymus
Wah Cheuk MD, Consultant Pathologist, Department of Pathology, Queen
Elizabeth Hospital, Hong Kong, China
Tumors of the Salivary Glands
Philip B. Clement MD, Professor Emeritus, Department of Pathology and
Laboratory Medicine, Faculty of Medicine, University of British Columbia; Consultant
Pathologist, Department of Pathology and Laboratory Medicine, Vancouver General
Hospital, Vancouver, British Columbia, Canada
Tumors of the Peritoneum
Christopher P. Crum MD, Professor of Pathology, Harvard Medical School;
Director, Division of Women's and Perinatal Pathology, Department of Pathology,
Brigham and Women's Hospital, Boston, Massachusetts
Tumors of the Female Genital Tract (Part C: Tumors of the Placenta and Gestational
Trophoblastic Disease, Part E: Cervix)
John N. Eble MD, FRCA, Nordschow Professor of Laboratory Medicine, Chairman,
Department of Pathology and Laboratory Medicine, Indiana University School of
Medicine, Indianapolis, Indiana
Tumors of the Urinary TractIan O. Ellis BM, BS, FRCPath, Professor of Cancer Pathology, Molecular Medical
Sciences, University of Nottingham, Nottingham, United Kingdom
Tumors of the Breast
Linda Ferrell MD, Professor, Vice Chairperson, and Director of Surgical Pathology,
Department of Pathology, University of California, San Francisco, San Francisco,
Tumors of the Liver, Biliary Tree, and Gallbladder
Christopher D.M. Fletcher MD, FRCPath, Vice Chair, Anatomic Pathology,
Brigham and Women's Hospital; Chief of Onco-Pathology, Dana-Farber Cancer
Institute; Professor of Pathology, Harvard Medical School, Boston, Massachusetts
Introduction; Vascular Tumors; Tumors of Soft Tissue; Peripheral Neuroectodermal
Jonathan A. Fletcher MD, Associate Professor of Pathology, Associate Professor of
Pediatrics, Harvard Medical School; Director, Solid Tumor Cytogenetics, Department
of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
Molecular Genetic Techniques in Diagnosis and Prognosis
Robert Folberg MD
Founding Dean, Oakland University William Beaumont School of Medicine,
Rochester, Michigan
Chief Academic Officer, Beaumont Health System, Royal Oak, Michigan
Tumors of the Eye and Ocular Adnexa
Karuna Garg MBBS, Assistant Professor, Department of Pathology, University of
California, San Francisco, San Francisco, California
Tumors of the Female Genital Tract (Part A: Ovary, Fallopian Tube, and Broad and
Round Ligaments)
David J. Grignon MD, FRCP(C), Centennial Professor and Vice Chair for Clinical
Programs, Department of Pathology, Indiana University School of Medicine,
Indianapolis, Indiana
Tumors of the Urinary Tract
Philipp U. Heitz MD, Emeritus Professor of Pathology, Chairman Emeritus,
Department of Pathology, University of Zurich, Zurich, Switzerland
Tumors of the Endocrine Pancreas
Jason L. Hornick MD, PhD, Director of Surgical Pathology, Director,
Immunohistochemistry Laboratory, Brigham and Women's Hospital; Associate
Professor of Pathology, Harvard Medical School, Boston, Massachusetts
Tumors of the Small and Large Intestines, Including Anal Canal
Carrie Y. Inwards MD, Associate Professor of Pathology, Mayo Clinic College of
Medicine; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester,
Tumors of the Osteoarticular System
Julie A. Irving MD, Clinical Associate Professor, Department of Pathology and
Laboratory Medicine, Faculty of Medicine, University of British Columbia;
Department of Laboratory Medicine, Pathology, and Medical Genetics, Royal JubileeHospital, Victoria, British Columbia, Canada
Tumors of the Peritoneum
Sanjay Kakar MD
Professor, Department of Anatomic Pathology, University of California, San Francisco
Chief of Pathology, Department of Anatomic Pathology, Veterans Affairs Medical
Center, San Francisco, California
Tumors of the Liver, Biliary Tree, and Gallbladder
Kyu-Rae Kim MD, PhD, Professor, Department of Pathology, Asan Medical Center,
University of Ulsan College of Medicine, Seoul, Korea
Tumors and Tumor-like Conditions of the Male Genital Tract
David S. Klimstra MD, James Ewing Alumni Chair of Pathology, Department of
Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
Tumors of the Exocrine Pancreas
Gunter Klöppel MD, Professor Emeritus, Department of Pathology, Technical
University of Munich, Munich, Germany
Tumors of the Exocrine Pancreas; Tumors of the Endocrine Pancreas
Jeffery L. Kutok MD, PhD, Senior Director, Molecular Pathology, Infinity
Pharmaceuticals, Inc., Cambridge, Massachusetts
Tumors of the Hematopoietic System
Ernest E. Lack MD, Senior Pathologist, Endocrine and Otorhinolaryngic-Head and
Neck Pathology, Joint Pathology Center, Silver Spring, Maryland
Tumors of the Adrenal Gland; Tumors of the Autonomic Nervous System, Including
Gregory Y. Lauwers MD, Professor of Pathology, Harvard Medical School; Vice
Chairman, Department of Pathology, Massachusetts General Hospital, Boston,
Tumors of the Esophagus and Stomach
Andrew H.S. Lee MD, MRCP, FRCPath, Consultant Histopathologist, Nottingham
University Hospitals, City Hospital Campus, Nottingham, United Kingdom
Tumors of the Breast
Kenneth R. Lee MD, Associate Professor, Department of Pathology, Harvard
Medical School; Staff Pathologist, Department of Pathology, Brigham and Women's
Hospital, Boston, Massachusetts
Tumors of the Female Genital Tract (Part E: Cervix)
Yonghee Lee MD, Professor of Pathology, Department of Pathology, Ajou
University School of Medicine, Suwon, Korea
Tumors of the Female Genital Tract (Part C: Tumors of the Placenta and Gestational
Trophoblastic Disease)
Neal I. Lindeman MD, Director of Molecular Diagnostics, Brigham and Women's
Hospital; Associate Professor of Pathology, Harvard Medical School, Boston,
Molecular Genetic Techniques in Diagnosis and PrognosisJanina A. Longtine MD, Vice Chairperson, Molecular Pathology and Genetics,
Department of Pathology, The Mount Sinai Medical Center, New York, New York
Molecular Genetic Techniques in Diagnosis and Prognosis
M. Beatriz S. Lopes MD, PhD, Director of Neuropathology, Professor of Pathology
and Neurological Surgery, Department of Pathology, Division of Neuropathology,
University of Virginia Health System, Charlottesville, Virginia
Tumors of the Pituitary Gland; Tumors of the Central Nervous System
Joseph J. Maleszewski MD, Assistant Professor of Pathology, Mayo Clinic College
of Medicine; Senior Associate Consultant Pathologist, Department of Laboratory
Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
Tumors of the Heart and Pericardium
Cesar A. Moran MD, Professor of Pathology, Section Chief, Thoracic Pathology,
Department of Pathology, The University of Texas MD Anderson Cancer Center,
Houston, Texas
Tumors of the Lung and Pleura
George L. Mutter MD, Professor of Pathology, Department of Pathology, Harvard
Medical School; Pathologist, Division of Women's and Perinatal Pathology,
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
Tumors of the Female Genital Tract (Part B: Endometrial Tumors)
Marisa R. Nucci MD, Associate Professor of Pathology, Harvard Medical School;
Associate Pathologist, Division of Women's and Perinatal Pathology, Department of
Pathology, Brigham and Women's Hospital, Boston, Massachusetts
Tumors of the Female Genital Tract (Part D: Myometrium, Part E: Cervix, Part F:
Vagina, Part G: Vulva)
André M. Oliveira MD, PhD, Associate Professor of Pathology, Department of
Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
Tumors of the Osteoarticular System
Mana M. Parast MD, PhD, Assistant Professor of Pathology, Department of
Pathology, University of California, San Diego, La Jolla, California
Tumors of the Female Genital Tract (Part C: Tumors of the Placenta and Gestational
Trophoblastic Disease)
Aurel Perren MD, Professor of Pathology, Institute of Pathology, University of
Bern, Bern, Switzerland
Tumors of the Endocrine Pancreas
Sarah E. Pinder MD, Professor of Breast Pathology, Department of Cancer Studies,
Research Oncology, King's College London; Consultant Breast Pathologist,
Department of Histopathology, Guy's and St. Thomas Hospitals, London, United
Tumors of the Breast
Emad A. Rakha MD, Department of Cellular Pathology, University of Nottingham
and Nottingham University Hospitals NHS Trust, City Hospital Campus,
Nottingham, United Kingdom
Tumors of the BreastJae Y. Ro MD, PhD, Director of Surgical Pathology, Department of Pathology and
Genomic Medicine, The Methodist Hospital; Professor of Pathology, Weill Medical
College of Cornell University; Adjunct Professor of Pathology, The University of Texas
MD Anderson Cancer Center, Houston, Texas
Tumors and Tumor-like Conditions of the Male Genital Tract
Scott Rodig MD, PhD, Associate Professor, Department of Pathology, Harvard
Medical School; Associate Pathologist, Department of Pathology, Brigham and
Women's Hospital, Boston, Massachusetts
Tumors of the Lymphoreticular System (Part A: Lymph Node; Part B: Spleen)
Daniel J. Santa Cruz, MD, Dermatopathologist, Cutaneous Pathology, WCP
Laboratories, Inc., St. Louis, Missouri
Tumors of the Skin
Steven S. Shen MD, PhD, Associate Director of Surgical Pathology, Department of
Pathology and Genomic Medicine, The Methodist Hospital; Associate Professor of
Pathology, Weill Medical College of Cornell University, Houston, Texas
Tumors and Tumor-like Conditions of the Male Genital Tract
Paul M. Speight BDS, PhD, FRSRCPS, FRCPath, Dean and Professor in Oral
Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, United
Tumors of the Oral Cavity
Saul Suster MD, Professor and Chairman, Department of Pathology and
Laboratory Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
Tumors of the Lung and Pleura
Henry D. Tazelaar MD
Professor of Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota
Chairperson, Department of Laboratory Medicine and Pathology, Mayo Clinic,
Scottsdale, Arizona
Tumors of the Heart and Pericardium
Lester D.R. Thompson MD, Consultant Pathologist, Department of Pathology,
Southern California Permanente Medical Group, Woodland Hills, California
Tumors of the Ear
Scott R. VandenBerg MD, PhD
Professor, Department of Pathology, Division of Neuropathology, University of
California, San Diego
Director of Neuropathology, Department of Pathology, University of California, San
Diego Medical Center, La Jolla, California
Tumors of the Central Nervous System
Sarah N. Walsh MD, Dermatopathologist, Cutaneous Pathology, WCP
Laboratories, Inc., St. Louis, Missouri
Tumors of the Skin
Bruce M. Wenig MD
Chairman, Department of Diagnostic Pathology and Laboratory Medicine, Beth Israel
Medical Center, St. Luke's and Roosevelt Hospitals, New York, New YorkProfessor of Pathology, Albert Einstein College of Medicine, Bronx, New York
Adjunct Professor of Pathology, Columbia University College of Medicine, New York,
New York
Tumors of the Upper Respiratory Tract
Jacqueline Wieneke MD, Medical Officer, Pathologist, U.S. Food and Drug
Administration, Silver Spring, Maryland
Tumors of the Adrenal Gland; Tumors of the Autonomic Nervous System, Including
Robert H. Young MD, FRCPath, Robert E. Scully Professor of Pathology,
Department of Pathology, Harvard Medical School; Pathologist, James Homer Wright
Pathology Laboratories, Massachusetts General Hospital, Boston, Massachusetts
Tumors of the Urinary Tract
Charles J. Zaloudek MD, Professor, Department of Pathology, University of
California, San Francisco, San Francisco, California
Tumors of the Female Genital Tract (Part A: Ovary, Fallopian Tube, and Broad and
Round Ligaments)Preface
I n the five-year interval since publication of D iagnostic H istopathology of Tumors, Third
Edition, conventional morphologic and immunohistochemical assessment has
continued to hold sway as the pre-eminent, most reliable, and most cost-effective
means to provide a diagnosis, prognostic assessment, and in most cases,
determination of the adequacy of excision for human tumors. S uch interpretation also
helps to guide therapy in many se ings. The continued utility of such “traditional”
technologies and interpretive skills is somewhat reassuring in the se ing of the
everwidening disparities in the availability of more expensive modern technologies, such
as molecular genetic diagnosis, gene expression profiling, and genomics, not only (to
a depressing degree) between the developed and still developing (or underdeveloped)
areas of the world, but even among different developed countries or regions.
The role of molecular diagnosis is now very well established and firmly integrated
in the practice of modern surgical pathology, and is especially valuable in confirming
the presence of diagnostically important gene fusions or mutations, in helping with
therapeutic target identification and, not least, in enhancing diagnostic
reproducibility and tumor classification schemes. Whereas some targets can be
identified immunohistochemically, mutational analysis may be er enable treatment
selection in some contexts, especially in the se ing of treatment resistance. A more
complex issue, however, in some of the developed countries (with dangerously
expanding health care expenditure) is the interface between pathology and genomic
medicine. Expression profiling as well as whole genome sequencing are increasingly
being promulgated as providing additional information of critical clinical importance
—yet, at this point in time, the value of such testing has only rarely been
demonstrated and validated, for example in prognostication for invasive carcinoma of
the breast (Oncotype D x and Mammaprint assays)—while most other such testing
remains unvalidated, analytically or clinically, and of unproven clinical value. I n
particular, there are no good data confirming that identification of a potentially
targetable mutation in a tumor type in which the role of that specific gene has never
been demonstrated represents anything more than a sophisticated (and expensive)
shot in the dark. S imilarly, gene expression profiling as a means of identifying the
primary site in metastatic carcinomas is rarely more effective than high-quality
immunohistochemistry combined with morphologic expertise, is more expensive and,
in any event, does not very often lead to clinically significant change in treatment or
outcome (as many of the more treatable metastases are easily recognized by
conventional means). I t is troubling that many such commercial tests are being
marketed directly to clinicians and patients, who are often completely unable to
distinguish snake oil from clinically worthwhile testing. A lthough it is likely that
genomic data will ultimately prove their (progressively more affordable) value, until
then pathologists have a responsibility to ensure (a) that often limited patient tissue
is used judiciously, and (b) that, in the routine (non-trial) se ing, testing of any kind
has proven clinical value that might merit action by the treating physician.Remarkably, and seemingly with no evident slowing of the pace, morphologic
tumor classifications and methods of prognostication continue to evolve and be ever
more refined, constantly enhancing the value of high-quality anatomic pathology.
Many of these advances have been codified in the new WHO classifications, which are
currently being updated in a fourth edition of the “blue books.” Furthermore, “new”
(newly recognized) tumor types or subtypes of clinical or therapeutic relevance
continue to be characterized, both morphologically and genetically, in a seemingly
limitless fashion. The fourth edition of this text has been substantially revised and
updated to incorporate this broad range of new information. S ome chapters have
been entirely rewri en, notably those dealing with tumors of the small and large
intestines, the heart, and the ear.
A s always, any and all errors or omissions are entirely the responsibility of the
editor, and I remain deeply indebted to the contributors for the unfailingly high
quality of the material that they provide, as well as the enthusiasm with which they do
so. Finally, I should like to warmly acknowledge, with considerable gratitude, the
hard work and unfailing support of my outstanding secretary, Kathleen Radzikowski,
and also of the “key players” at Elsevier—Bill S chmi , Katie D eFrancesco, and Louise
Christopher D.M. Fletcher
Boston, 2012Volume 1
Chapter 1 Introduction
Chapter 2 Tumors of the Heart and Pericardium
Chapter 3 Vascular Tumors
Chapter 4 Tumors of the Upper Respiratory Tract
Chapter 5 Tumors of the Lung and Pleura
Chapter 6 Tumors of the Oral Cavity
Chapter 7 Tumors of the Salivary Glands
Chapter 8 Tumors of the Esophagus and Stomach
Chapter 9 Tumors of the Small and Large Intestines, Including Anal Canal
Chapter 10 Tumors of the Liver, Biliary Tree, and Gallbladder
Chapter 11 Tumors of the Exocrine Pancreas
Chapter 12 Tumors of the Urinary Tract
Chapter 13 Tumors of the Female Genital Tract
Chapter 14 Tumors and Tumor-like Conditions of the Male Genital Tract
Chapter 15 Tumors of the PeritoneumC H A P T E R 1
I n t r o d u c t i o n
Christopher D.M. Fletcher
I n no area of surgical pathology, possibly even in all diagnostic histopathology, does
the pathologist play a more important and crucial role than in the diagnosis of
tumors. A lthough patients or laypersons are often entirely ignorant of this role and
fondly imagine that their surgeon, other clinician, or oncologist is the true
diagnostician—a misapprehension that some of our colleagues do not always dispel!
—the reality is that the histology report is the principal determinant of diagnosis,
likely clinical course, and therapy in any patient found to have a swelling or mass that
proves to be neoplastic.
The need for timely, accurate, and detailed reports has never been greater,
especially in our increasingly subspecialized profession and litigious society. This
need comes at a time when the fields of tumor pathology and surgical pathology in
general are expanding at an unprecedented rate, as reflected in the constant
characterization of previously unrecognized tumor types or variants and the
advancing delineation and application of new technologies that provide objective
aids, not only to diagnosis but also to prognostication and to the understanding of
pathogenetic mechanisms. This almost daily expansion in the surgical pathologist's
“database” is manifest in the perceived need for ever more numerous journals and
textbooks, which of themselves become more and more subspecialized. I t is against
this background that we have a' empted to put together a book dealing solely with
the diagnostic histopathology of tumors in all organ systems, employing contributors
who are all recognized specialists in their own areas of this field. I use the term “we”
to underline the close nature of the collaboration among editor, contributor, and
publisher in a project of this scale, but all errors and omissions, as in prior editions,
are the sole responsibility of the editor. I t should also be admi' ed that the rate at
which surgical pathology is progressing will be reflected in the fact that some small
parts of this book will inevitably be outdated or superseded by the time of
The philosophy of this book has been to use the word “tumor” in its traditionally
descriptive sense, in other words, to encompass neoplastic and, in some cases,
nonneoplastic swellings. In this regard, it is commonly impossible, or at least a source
of unresolved argument, to know whether certain lesions should be classified as
hamartomatous, hyperplastic, or neoplastic, and, most often, this text has adopted a
pragmatically neutral role. I t is of interest to note that currently no generally accepted
definition of a neoplasm exists, because clonality alone is undoubtedly insufficient in
this regard: some processes traditionally regarded as reactive, for example in
lymphoid tissue and synovium, have been shown to be clonal or oligoclonal. The
capacity for growth in a transplanted (xenograft) model is perhaps the most
convincing criterion but is not readily applicable in a routine se' ing! A lthough thefocus of this book is inevitably on histomorphology and associated ancillary tests,
basic clinical data are also provided for most lesions, because these contribute
significantly to accurate classification. The relevance of pathologic assessment in
guiding treatment is also emphasized where appropriate. Guidelines to differential
diagnosis (with appropriate cross-references where necessary) are described for those
tumors that pose a particular or common problem.
This introductory chapter provides an opportunity to put forward, with due
modesty, some personal approaches and views regarding the routine practice of
diagnostic tumor pathology. The philosophy propounded hereinafter is individual
and should not be construed as representing any policy agreed upon by the
contributors. S ome of the suggestions put forward below undoubtedly are unoriginal
but represent simply the “folklore” of surgical pathology, passed down from great
teachers in this field. I n some quarters today, the passage of such valuable
information is regarded as being of li' le value, and we, as practicing
histopathologists, are often encouraged to concentrate on purportedly more objective
or “scientific” assessments of diagnosis or prognosis. This is reflected in the
remarkable extent to which the content of some large academic meetings worldwide
is governed by fashionable, but often transient, techniques, antibodies, genes, or
speculations. For as long as human tumors remain more varied, unpredictable, and
idiosyncratic than their hosts, in terms of both morphology and behavior, then a clear
and unassailable need will exist for good surgical pathology, based principally on
careful and experienced light microscopic examination, supported, where appropriate
or necessary, by more modern techniques. For the time being at least, such skilled
morphologic examination remains the gold standard in anatomic pathology, and it is
unlikely to be surpassed in terms of either reliability or cost-effectiveness in the near
future. A lthough it is true that some aspects of diagnostic pathology are subjective to
a troubling degree, and although we should all work toward diagnostic
reproducibility and objectivity by whichever means are most effective, it is a simple
fact (at least in tumor medicine) that surgical pathology has never played a more
important and pivotal role than at the present time. This is largely due to the central
role of histopathologic parameters in determining therapy (at least for the large
majority of tumors) and hence the wish of clinicians to obtain (and often discuss)
detailed pathology reports. The manner in which expertise in surgical pathology is
often taken for granted in some academic centers, especially in Europe and the
United S tates, is reprehensible and, if it continues, may lead to the progressive loss of
important diagnostic skills, because of erosion of experiential training and
realignment of priorities in academic departments. I n part this trend reflects an
increasing tendency to shorten training time before certification, as well as the
importance a' ached to grant raising by MD -PhD s and PhD s engaged in basic
research, one outcome of which has been to widen the gap between much of the
research undertaken in academic medical centers and the primary clinical mission of
a hospital environment. A clear need exists for increased numbers of true physician
scientists, increased funding for clinical and translational research, and greater
mutual respect and collaboration between physicians and laboratory scientists. N o
one is be' er placed to take advantage of such collaborative opportunities than
The guidelines that follow are set out in an order that corresponds, as far as
possible, to the events in a surgical pathology laboratory from receipt of a specimen
to the issuance of a report.To diagnose a tumor in the absence of clear and complete clinical data is foolhardy,
dangerous, and sometimes impossible. Many of our clinical colleagues often need to
be reminded of this fact; even simple information concerning age, sex, or location
may be missing on the request form. This may raise compliance issues in addition to
the potentially negative impact on patient care. I f a specimen arrives in the laboratory
without such data, then a medically qualified member of staff should not hesitate to
contact the errant clinician or his or her staff; sometimes it may be appropriate to
withhold the report until the pathologist is fully apprised of the necessary
information. I f a history of any previous neoplasm exists, especially at the same
anatomic location, then the date of biopsy, diagnosis, and laboratory reference (when
available) should be requested and recorded. I f ancillary data, such as the radiologic
findings or serum chemistry in a bone tumor, are necessary to make a diagnosis, then
these should be requested, if not demanded!
A ccurate and careful macroscopic description of a tumor specimen, particularly the
definitive resection, is vital to diagnosis, prognosis, and retrospective data analysis for
pathologic or clinical studies. The first occasion on which a resection specimen is
examined in the pathology laboratory is usually the one and only time at which tumor
size, weight, approximate extent of necrosis, and distance to resection margins can be
gauged properly; once the specimen has been dissected, cut up, fixed, and otherwise
distorted, then such valuable parameters often cannot be assessed. S imilarly, features
such as the type of margin (encapsulated, circumscribed, or infiltrative), the presence
of satellite nodules, the presence (or involvement) of lymph nodes, and the extent of
spread or invasion of adjacent structures are often best determined at the time of
specimen dissection. The macroscopic description of the tumor in the final report
should be sufficiently detailed to enable any other pathologist to conjure a clear
mental image of the neoplasm. I f this is done well, then often, in combination with
the clinical data, it is possible to have a good idea of the final diagnosis, even before
seeing the slides, especially in the more common tumor types. The other important
role of good macroscopic examination is to ensure that a tumor is adequately
sampled. The type or extent of sampling varies according to the size and anatomic
location of the neoplasm, but, as a general rule of thumb, all lesions of appreciable
size (perhaps >2 cm) should be sliced serially, and all areas showing a differing
appearance should be examined histologically. I n the appropriate organ systems, care
should be taken to obtain blocks at the most likely site of muscular, serosal, or
capsular invasion, as determined by naked-eye examination. Given the currently
prevailing fashion for inking specimen margins, I would like to make a plea in this
regard—think before you ink! The indiscriminate inking of specimens, almost
irrespective of type, has led in some contexts to the time-wasting and often irrelevant
examination of margins in lesions that either have no potential to recur or else have
been so obviously marginally or incompletely excised that the positive (or at least
oncologically inadequate) margins can be recorded grossly. I n some cases, lesions (or
biopsies) that are so small that they are embedded and sectioned in their entirety in
one block are still inked, yet it is hardly a challenge to assess the margins (without
inking) in such cases. This trend in specimen handling is almost antiintellectual,
often obliterates the benefit of examining a specimen in a thoughtful manner, and
taints the validity of inking, which can be invaluable in an appropriate context.
Turning now to histologic evaluation, clearly this is a complex, often organ-specific
process, the details of which are described in the separate chapters of this book.
However, one or two pertinent generalizations can be made. Generalizationsadmi' edly are dangerous and stand only to be shot down by exceptions to each rule;
however, I believe that they provide useful guidelines. I n any patient with a previous
primary (or recurrent) neoplasm, the slides should always be reviewed. This serves
four main purposes: (1) it provides a simple but useful form of audit; (2) it enables
comment to be made as to whether a tumor has advanced (or sometimes decreased)
in histologic grade, thereby possibly influencing clinical outcome; (3) it is the only
way of determining with certainty if a patient has developed two separate primary
neoplasms, whether of the same or different types; and (4) sometimes such review
provides a vital clue to diagnosis because recurrent or metastatic neoplasms,
especially of mesenchymal type, show a remarkable capacity to alter their phenotype
or to lose evidence of specific differentiation. What appears to be a weird or
undiagnosable neoplasm, on occasion, can suddenly become a simple case when the
previous histology is reviewed! I n this regard, the principle of Occam's razor should
be remembered: a patient is always more likely to have a single primary neoplasm
with an odd pattern of recurrence than to have two separate primaries.
A second generalization, which, although possibly a philosophic point, I personally
regard to be of paramount importance, is that strict histologic criteria should be used
for all tumor diagnoses. With rare exceptions, usually relating to specialist expertise
based on experience, it is not acceptable to make an arbitrary diagnosis founded on
personal whim. I f a colleague or trainee asks how a diagnosis was reached, one
should be able to enumerate reasons or criteria, be they positive or negative findings;
hopefully, the days of saying “I t is what it is because I say it is” are gone! The merits
of this practice are that (1) uniformity in diagnosis is increased, thereby facilitating
treatment decisions; (2) when analyzing published data or initiating new studies
(whether clinical, pathologic, genetic or genomic), one can ideally compare like with
like—a vital step toward understanding tumor morphology and behavior, especially if
large multicenter studies are required; and (3) the provision of clear diagnostic
criteria is the only reliable means by which trainee pathologists can be taught. I n this
regard we need to introduce morphologic objectivity whenever possible, even though
surgical pathology, by necessity, remains a subjective art, at least in part.
The third, hopefully well-known, generalization applicable to light microscopic
examination of tumors using hematoxylin and eosin (H&E)-stained sections is that, in
most (but not all!) cases, low-power appearances often provide the best guide to the
separation of benign from malignant lesions. Features such as the preservation of
normal (often lobular) architecture, lesional symmetry, and the general impression of
overall cellularity and nuclear atypia are exceedingly helpful in this distinction.
Conversely, if one rushes straight to the high-power lenses, it is remarkably easy to
find (and be misled by) cells with atypical or worrisome features in a very wide range
of tumors or pseudoneoplastic lesions. Good examples of this phenomenon are the
bizarre, often multinucleate, stromal cells found in the submucosa or lamina propria
of reactive, often polypoid lesions at almost any mucosal or cutaneous location and
the densely hyperchromatic, irregular, degenerative (“ancient”) nuclei encountered in
a variety of soft tissue neoplasms. S imilarly, the presence of single, or very rare,
abnormal mitotic figures need not equate with malignancy: I will always remember
being shown such a mitosis in an otherwise normal proliferative endometrium during
my first year in pathology!
With regard to the application of more modern techniques to diagnostic practice,
this is mentioned (where relevant) in each chapter and is discussed in greater detail
i n Chapter 31. I mmunohistochemistry, which now is more than 30 years old andtherefore no longer regarded as modern by the arbiters of fashion, is indeed very
useful but must always be interpreted in context. A seemingly aberrant result,
especially if this is a negative result, should never be allowed to overrule an obvious
morphologic diagnosis. Conversely, it should be recognized that the current fashion
for enthusiastic antigen retrieval often leads to many confusing false-positive results
—for example, in recent years, this has been a notable problem in the use of CD 117
positivity to accurately confirm a diagnosis of gastrointestinal stromal tumor. Quality
control is vital if immunohistochemistry is to have any worthwhile role, and often this
requires that any given laboratory should have a “minimum throughput,” albeit this
required level of work activity is poorly defined. Laboratories that perform a large
number of immunostains on a daily basis and do not change the staff around
unnecessarily almost invariably produce more consistent and be' er-quality results
than their smaller, intermi' ently utilized counterparts. The value of using large
antibody panels or complex algorithms for immunodiagnosis is somewhat
controversial, but, in these days of cost-effectiveness, it is my view that the choice of
immunostains, where necessary, should be governed (and limited) by a carefully
assessed differential diagnosis, based on H&E morphology, through which specific
questions need to be answered. The broader and more mindless a panel of antibodies
becomes, the greater is the likelihood of obtaining inexplicable, misleading, or
aberrant results. Equally, if reliance is placed on an algorithm (especially one
generated by a laboratory other than one's own), then a single aberrant or
falsepositive (or negative) result can lead to an irrational diagnosis, as well as a lengthy
and costly trail of immunostains. A separate point of contemporary importance is the
increasing trend of using immunohistochemistry or molecular testing for
identification of potential therapeutic targets (e.g., c-kit or various growth factor
receptors). Meaningful target identification and validation are an important and
expanding activity in pathology, but pathologists must not allow themselves to be
bullied into undertaking such testing unless the protein or gene in question has been
proved to have biologic relevance (usually through activation or mutation) in the
given tumor type and unless well-validated, reliable, and reproducible antibodies are
available for this purpose.
With regard to many of the more recent molecular genetic techniques, some of
which undoubtedly have proved (and will continue to prove) to be valuable in tumor
pathology, two points should be borne in mind. First, the published results
concerning a pa' ern of gene expression or karyotypic abnormality in a given tumor
type are only as meaningful (or as valid) as the corresponding morphologic
diagnoses. I f the diagnoses on which these results are based happen to be
inconsistent or even wrong, then the conclusions made are often rendered worthless.
Therefore collaboration and mutual respect between anatomic pathologists and basic
scientists are absolute prerequisites for continued progress in this se' ing. A s
expression profiling and sequencing technologies begin to allow rapid and detailed
molecular profiling of large numbers of tumors, such professional interactions will be
crucial in validating such data and in extracting maximal clinical value from this new
information. I n this regard, it is important to note that the majority of genomic
profiling studies in recent years, trumpeting new-found diagnostic or prognostic
accuracy, have failed (with a few notable exceptions) to improve on the daily
achievements of routine light microscopic techniques. This may in part reflect the fact
that many such studies have not included expert pathologists in the research team.
Thus the second key point, despite initial optimism, is that many of the molecularand genetic parameters assessed in recent years, with important exceptions (e.g., N -
myc amplification in neuroblastoma, cytogenetic and molecular characterization of
many leukemias and sarcomas, detection of minimal residual disease in
hematolymphoid neoplasms, and the detection of therapeutically important
mutations in certain tumor types, for example non–small cell lung cancer and
melanoma), have not improved on careful (or expert) light microscopic examination
for diagnosis and prognosis. The la' er therefore remains the gold standard against
which all new technology needs to be assessed; claims that newer modalities provide
greater objectivity should be weighed not only against financial cost and problems of
reproducibility in nonspecialized laboratories, but also against the frequency with
which such claims seem to be proved wrong, as witness previous descriptions of
socalled cancer-specific antigens or mutations, the short-lived misapprehension that
expression of p53 was a reliable marker of the malignant phenotype, or the
persistently unproved (and unvalidated) tests, often aggressively marketed, that claim
to accurately predict primary site or response to chemotherapy.
Once a diagnosis has been reached, then a report must be formulated, guidelines
for which are well beyond the remit of a book of this type. However, it is important to
ensure that any report provides as much useful information to the clinician as
possible, and, in this context, increasingly good reasons exist to use synoptic (or
template) reporting formats, especially for common tumor types. I n this way, key
elements of information are not forgo' en and the clinician's ability to interpret a
report is maximized. N ot only does this mean the inclusion of clear statements
regarding tumor type, grade, or stage (where applicable) and status of resection
margins, but the report offers a unique opportunity to provide general data
concerning clinical features, likely behavior, and ideal management, supported by
references to the published literature where appropriate. The transmission of such
information may be appropriate only in the case of uncommon or unusual neoplasms,
and the extent to which a surgical pathologist will feel able or comfortable to offer
advice on therapy will depend greatly on local circumstances and the tolerance or
insight of clinical colleagues. I n my view, however, surgical pathologists should never
forget that they are providing a clinical, often subjective, opinion quite different from
the type of report required of some other specialties in pathology, and in this
circumstance we should not shy away from offering whatever expertise or background
data are available to us. I t is an extraordinary but undoubted fact that the key articles
describing clinical features and therapeutic outcome in many tumor types are
published, at least initially, in pathology, rather than clinical, journals. Often,
therefore, surgical pathologists are more likely to have received (and hopefully read!)
the latest published studies on the general aspects of a given neoplasm than their
clinical colleague. However, any tendency to try and achieve “one-upmanship” in this
relationship should be carefully curbed until such time as pathologists can feel sure
that they have also scanned the relevant clinical literature!
To conclude this introductory chapter, I would like to offer some simple truisms
applicable to diagnostic tumor pathology that notably have not changed in the past 20
years. Many of these are self-evident and most likely are widely known; the frequency
with which they are forgotten is therefore all the more remarkable and regrettable:
1. By virtue of simple statistical probability, common things remain common;
therefore do not be tempted into an esoteric (or exciting!) diagnosis until you
have confidently excluded a more probable diagnosis. A good example that
typifies this pitfall is the characterization of spindle-celled malignantneoplasms arising in breast or epithelial-lined viscera, such as the upper
aerodigestive tract or urinary bladder; sarcomatoid (or spindle cell)
carcinomas are a far more likely prospect than some unusual sarcoma or
socalled carcinosarcoma.
2. Pathologists should never be afraid to request a larger (or repeat) biopsy if
they are having difficulty in coming to a firm diagnosis before definitive
therapy. It is a matter of fact that some tumor biopsies are inadequate or
unrepresentative. In fact the increasing trend for our clinical and radiologic
colleagues to provide smaller and smaller biopsies (in the names of
costeffectiveness and convenient patient care) is not only limiting our ability to
make definitive diagnoses but also diminishing the opportunity to provide
valuable prognostic information. This tide needs to be stemmed, or at least
challenged and first validated, especially because the use of preoperative
neoadjuvant therapy is also increasing and often renders the ultimate
resection specimen relatively useless for diagnostic or prognostic purposes.
Painful hours, or even days, of indecision followed by an inconclusive or,
worse, inappropriately confident report are far better avoided by a clear
request for more tissue. On occasion this undoubtedly prevents the
institution of inappropriate therapy. Any attempt to hedge (or spread) one's
bets in a diagnostic report should be avoided whenever possible.
3. Pathologists should never be afraid to admit that they cannot diagnose or
classify a given neoplasm. No pathologist on this planet does not sometimes
benefit from a second opinion, however intermittent this need may be.
Pathologists who believe that they never need a second or specialist opinion
are dangerous. Increasingly this becomes true in anatomic pathology, which
is ever more subspecialized and in which the days of the true generalist are
numbered. Conversely, a subset of human tumors will always remain that
defy rational classification by anyone. In this context clues may exist (but not
always) to the likely clinical behavior of such a neoplasm, even if the line of
differentiation is obscure, but such clues should be interpreted only
tentatively; the reality is that if one cannot categorize a neoplasm reliably on
morphologic grounds, then any attempt at prognostication is inevitably
unreliable and only amounts to more or less sophisticated guesswork!
4. The (possibly obvious) corollary of the previous point is that pathologists can
diagnose only what they have seen, read, or heard about previously. This sets
clear limitations on the interpretative skills of any pathologist and
underlines the need to keep abreast of recent continued developments, by
either regular attendance at postgraduate meetings or the routine perusal of
major journals in our specialty. Those (increasingly few) who insist on
regarding the recognition or recategorization of diagnostic entities as
worthless “splitting” do so at their peril; those who attempt to force all
tumor diagnoses into categories with which they are already familiar do
5. A further point that is related, at least peripherally, to the “don't know”
situation, is that a pathologist (or, for that matter, any other practicing
physician) should never be afraid to admit a mistake. Every pathologist has
made at least an occasional error, however trivial or clinically insignificant,
and anyone who suggests otherwise is probably deluded. Our specialty is an
interpretative skill or art, not a black-or-white measurement, and thereforehuman error is unfortunately inevitable. Far more trouble can be generated
by concealment or dishonesty in this regard than by admitting a suboptimal
6. Prognostication in cancer management, especially among clinical oncologists,
is often believed to rely largely on tumor grade and stage, both of which the
pathologist may be instrumental in assessing. Some clinicians believe that
such parameters (particularly grade) can be determined in the absence of a
specific diagnosis. In the light of the foregoing discussion, this is clearly
nonsensical, and it is up to surgical pathologists to resist this trend. In very
many organ systems, the principal determinant of likely outcome is accurate
histologic typing, and the importance of an unequivocal diagnosis should
never be underestimated. Equally in some types of cancer, substratification
by grade is meaningless because a given tumor type may invariably be
biologically low grade (e.g., infantile fibrosarcoma) or high grade (e.g.,
pleural malignant mesothelioma), irrespective of histologic appearances.
Therefore it is important to recognize that grading (and often also staging)
systems need to be tailored, in many cases, to the individual tumor type, and
this is one circumstance in which generalizations can undoubtedly be
dangerous. In parallel, we need to take care that the rush to incorporate
mutational analysis as a component of prognosis or treatment selection (as,
for example, in gastrointestinal stromal tumors and non–small cell lung
carcinomas) does not bypass careful validation studies, remains confined to
the tumor types for which such validation has been achieved, and has
demonstrable clinical impact. For the relative lack of significant therapeutic
advances in some tumor types to hide behind the use of ever more
sophisticated (and expensive) diagnostic or prognostic technologies is not a
desirable outcome.
This discussion also begs the question of what constitutes a high-grade
neoplasm; there are no easy or clear answers to this question, but the
following examples provide food for thought and should prompt careful
appraisal of the manner in which we, as doctors, assess malignant
neoplasms. Consider the following three patients: the first is a 60-year-old
man with an inoperable small cell carcinoma of bronchus; we know that his
tumor is likely to disseminate rapidly, despite chemotherapy, and his
prospects of surviving more than 12 months are slim. The second is a
25year-old woman with localized alveolar soft-part sarcoma of the thigh; we
know that her 5-year survival probability is 60% to 70%, and, with this
information, she may well form a stable relationship and start a family—but
we also know that her chances of surviving beyond the age of 45 years are no
more than 15%, because most patients with this type of tumor eventually
have distant metastases. The third is a 45-year-old with a grade 2 astrocytoma
in the frontal lobe; we know that the risk of extracranial spread (metastasis)
is very small but that the chances of postsurgical recurrence are high; we also
know that such recurrences are likely to be progressively fatal over a 5- to
10year period. I believe that all three patients would be justified in claiming
that they had a biologically high-grade neoplasm, yet the perception of the
physician, pathologist, or scientist in each case would undoubtedly be
different, particularly with regard to the inherent biology of these tumors.
This variability underlines the need to treat tumors on the basis of biologic,rather than histologic, grade, at least in those circumstances in which our
therapeutic options allow any flexibility.
7. The last, and perhaps most straightforward, truism is that histology reports,
whether on specimens from one's own hospital or from a patient thousands
of miles away, should be as prompt as is feasible and safe. The surgical
pathology report is not simply a matter of record or a means of
rubberstamping a clinical suspicion; in the context of tumor pathology, almost
always it is the diagnostic arbiter and one of the major determinants of
therapy. It impinges enormously on patients, even if they are commonly
unaware of this fact. Any pathologist who fails to recognize or shoulder this
responsibility might best be advised to consider alternative employment!C H A P T E R 2
Tumors of the Heart and Pericardium
Henry D. Tazelaar, Joseph J. Maleszewski
General Clinical Features 6
Benign Tumors of the Heart and Pericardium 7
Malignant Tumors of the Heart and Pericardium 32
A ll of the entities presented here form tumors. A mong the benign tumors, some are correctly classified as neoplasms, some as
pseudoneoplasms, some as hamartomas or heterotopias, and some as processes somewhere in between. N o firm distinctions are
drawn in this discussion as the emphasis is on accurate diagnosis, not histogenesis. I t is important to note that, although the tumors
discussed in this chapter represent primary cardiac tumors, by far the most commonly encountered cardiac tumors are metastatic
lesions from other primary sites (most commonly lung, breast, and cutaneous melanoma).
More than 90% of primary cardiac tumors are benign, with the majority in adults being myxomas. I n infants and children the most
common primary tumor of the heart is the rhabdomyoma. Malignant cardiac and pericardial tumors, like malignant tumors elsewhere
in the body, have the ability to invade and metastasize. Benign cardiac tumors as well, however, can have clinically malignant
consequences given the frequency of endocardial or conduction system involvement. Table 2-1 lists the most common cardiac tumors,
including true neoplasms, hamartomas, and pseudoneoplasms.
M ajor P rimary T umors (N eoplasms, H amartomas, and P seudotumors) of the H eart and P ericardium
Benign Malignant
Myxoma Angiosarcoma
RhabdomyomaFibromaLipoma and lipomatous hypertrophy of atrial septumPapillary fibroelastomaPurkinje Undifferentiate
cell tumor–hamartomaTeratomaHemangiomaCystic tumor of the atrioventricular nodeHamartoma of adult d
highcardiac myocytesParagangliomaCalcified amorphous tumor (CAT)Mesothelial/monocytic incidental cardiac grade
excrescences (MICE) pleomorphi
c sarcoma
General Clinical Features
The clinical manifestations of cardiac tumors are often nonspecific. I ndeed, many other diseases may be mimicked. The clinical
presentation is usually subdivided under three major headings: (1) systemic, (2) embolic, and (3) cardiac. Clinical features reported to
occur with each tumor will not be mentioned in the discussion of that tumor, unless specific to that tumor for some reason.
Systemic Manifestations
The systemic manifestations of tumors of the heart are manifold and include findings such as fever, cachexia, and malaise. A bnormal
laboratory findings that may develop include an elevated erythrocyte sedimentation rate, hypergammaglobulinemia, thrombocytosis
or thrombocytopenia, polycythemia, leukocytosis, and/or anemia. The mechanisms that underlie these systemic manifestations are
1-3not as yet fully understood, but it is likely that they relate to release of cytokines as part of an inflammatory reaction.
Many cardiac tumors are also associated with clinical systemic syndromes and genetic diseases. A summary is found in Table 2-2.TABLE 2-2
Genetic Syndromes Associated with Cardiac Tumors
Chromosome Inheritance Syndrome withTumor Type Associated Syndrome Involved Gene(s) Location Pattern Prevalence Syndrome
Myxoma1,2 Myxoma syndrome PRKAR1A 17q2 AD Rare (~500 cases ~7
Rhabdomyoma3 Tuberous sclerosis TSC1/TSC2 9q34/16p13 AD (1/3), 1 in 6000 (at ~90
sporadic birth)
Fibroma4,5 Nevoid basal cell PTCH1 9q22.3 AD (1/3), 1 in 57,000 ~4
carcinoma syndrome sporadic
(Gorlin syndrome) (2/3)
Paraganglioma6,7 VHL VHL 3p25 (VHL) AD and AD 1 in 36,000 ~5
Neurofibromatosis with (VHL)NF1 17q11 (NF1)type 1, MEN-2A, - maternal 1 in 35,000
2B RET 10q11 (RET) imprinting (MEN-2)
FPPS (SDHD) 1 inSDHB 1p36 SDHB 1,000,000
Histiocytoid H1CMP Multiple Mitochondrial AR, X-linked Rare ~100
cardiomyopathy8,9 mitochondrial DNA and and
DNA genomic maternal
mutations locations
AD, Autosomal dominant; AR, autosomal recessive; FPPS, familial pheochromocytoma-paraganglioma syndrome; MEN, multiple
endocrine neoplasia; VHL, von Hippel–Lindau syndrome
Modified from Jain D, Maleszewski J J, Halushka M K 2010 Benign cardiac tumors and tumorlike conditions. Ann Diagn Pathol 14:
Embolic Manifestations
These events can be due to embolization either of fragments of the tumor itself or of thrombi aggregated on the surface of the tumor.
Embolization of tumor fragments can occur only when the tumor itself shows intracavitary extension. Thromboemboli, on the other
hand, can also occur with intramural tumors, which compromise the function of the heart leading to intracavitary thrombosis.
The pathologist may be the first to suspect the presence of a cardiac tumor on the basis of examination of a peripheral embolus. I n
fact sudden occlusion of a peripheral artery in an otherwise healthy person should always raise the possibility of a cardiac tumor. A n
embolectomy specimen, therefore, should be examined most carefully for the presence of tumor fragments. However, even when only
recent thrombotic material is found, it is wise to mention the possibility of a coexistent cardiac tumor. Moreover, multiple systemic
emboli may mimic systemic vasculitis or infective endocarditis, particularly when associated with systemic manifestations. Primary
tumors of the right heart chambers may cause pulmonary emboli, which may be indistinguishable from those occurring as a result of
venous thrombosis.
Cardiac Manifestations
The cardiac events that can develop as a result of cardiac tumors are largely determined by the location and size of the tumor. Tumors
that are localized in the myocardium usually lead to impaired myocardial function either through substantial replacement of the
myocardium by tumor or because of extension into a cardiac cavity. I ntramural location may lead to a wide variety of rhythm
disturbances, including atrial fibrillation and ventricular fibrillation. S udden death may thus be the first manifestation of a tumor of
the heart. Primary tumors of the heart with intracavitary extension may cause obstruction and may interfere with valve function.
Pericardial effusion, sometimes with signs and symptoms of cardiac tamponade, is usually a result of either epicardial extension or
a primary pericardial tumor.
Benign Tumors of the Heart and Pericardium
Clinical Aspects
This is frequently cited as the most common primary heart tumor, although the exact frequency differs among series. I t is a tumor of
adults, occurring most often in women aged 20 to 60 years. Most occur sporadically, but about 7% are associated with the myxoma
syndrome. The autosomal dominant myxoma syndrome characterized by the presence of multiple myxomas, spoEy pigmentation, and
4,5 6endocrine overactivity has been given a variety of eponyms and acronyms: S wiss syndrome, Carney syndrome, N A ME syndrome
(nevi, atrial myxoma, myxoid neurofibroma and neurofibromata, and ephelides), LA MB syndrome (lentigines, atrial myxoma,
mucocutaneous myxoma, blue nevi), and myxoma syndrome. “Familial endocrine myxolentiginosis” captures the major features of
the disease, but for the sake of simplicity the name “myxoma syndrome” will be used here (Table 2-3). I n patients with myxoma
syndrome, the myxomas tend to occur in locations other than the left atrium, may be multiple, and have a much higher recurrence
6rate compared with that in patients who have sporadic myxomas (21% vs. 1%-2%). Moreover, recurrences tend to show more rapid
7 8growth and more pronounced local invasiveness. A complete list of the features that differentiate sporadic myxomas from thosethat arise in the seEing of myxoma syndrome can be found in Table 2-4. Cutaneous myxomas should not be mistaken for metastatic
9-13cardiac myxomas in such patients.
Clinicopathologic Features of the Myxoma Syndrome*
Feature Comments
Gender (men): 67% Compared with 24% for nonfamilial cases
Mean age at presentation: 24 yr Compared with 51 yr for nonfamilial cases
Cardiac Unusual locations, multiple, recurrent
Skin Multiple
Breast Myxoid fibroadenomas
Spotty mucocutaneous pigmentation Scleral and vermillion borders of lips: lentigines, blue nevi, and combinations
Psammomatous melanotic schwannomas
Primary pigmented nodular adrenocortical disease Cushing syndrome
Testicular tumors Characteristically Sertoli cell tumors, usually bilateral and multicentric
Pituitary growth hormone–secreting adenomas Acromegaly or gigantism
*Not all features occur in any one patient.
Differences Between Sporadic and Familial Myxomas
14 Sporadic FamilialFeatures
Average age (yr) 51 24
Age range (yr) 17-75 4-48
Sex ratio (male/female) 1 : 3 2 : 1
By location* 86% in left atrium 62% in left atrium
18% in right atrium 37% in right atrium
21% in right ventricle
4% in left ventricle
Multicentric (%) 6 33
Recurrence rate (%) 3 20
*Some patients have myxomas in more than one anatomic location.
Gross Pathology
The vast majority of cases (approximately 90% or more) originate in the atria, with a significant predilection for the left atrium, in the
14-20region of the fossa ovalis. Tumors may also less commonly arise in the right atrium and much less often the ventricles. Tumors
arising in a location other than the classic left atrium increase the likelihood that that the patient has myxoma syndrome. A lthough
14,19,21-24historical debate about this has occurred, myxomas may also originate from any cardiac valve. I t is of additional interest
that, among the reported valvular cases of such myxomas, a right-sided heart location appears to be more common than a left-sided
one and that the tumors may be attached either to the atrial or to the ventricular side of the leaflets.
Cardiac myxomas are either pedunculated or sessile. They may be globular, almost round masses with a smooth surface (Fig. 2-1) or
polypoid with multiple thick papillary fronds (Fig. 2-2). They range from pale gray to dark red, and variegation within a single tumor is
common. Occasionally surface thrombus may be present, particularly on papillary variants. Myxomas are usually soft and friable with
a distinctive gelatinous appearance and consistency (Fig. 2-3). S omewhat expectedly, it is these friable papillary myxomas that have
the highest propensity to embolize and may be seen in downstream vessels (Fig. 2-4). S ome myxomas may be firm, and occasionally
gross calcifications may be observed, even to the extent that the bulk of the tumor consists of a calcified mass. This condition is known
25also as petrified cardiac myxoma (Figs. 2-5 and 2-6) and may be mistaken for an atrial thrombus clinically. Multiple tumors are most
often associated with myxoma syndrome (Fig. 2-7).FIGURE 2-1 Myxoma with stalk and smooth globular shape. (Courtesy Dr. William D. Edwards, Mayo Clinic,
Rochester, Minn.)
FIGURE 2-2 Myxoma with papillae. Note that the papillae are broad and thick. (Courtesy Dr. Caterina Giannini,
Mayo Clinic, Rochester, Minn.)
FIGURE 2-3 Myxoma with glistening surface and gelatinous consistency.
FIGURE 2-4 The undersurface of the brain shows bilateral internal carotid artery obstruction (arrows) by myxoma
emboli. (Courtesy Dr. Joseph E. Parisi, Mayo Clinic, Rochester, Minn.)FIGURE 2-5 Markedly calcified myxoma, so-called petrified myxoma from the left atrium of a 48-year-old man (A)
and its specimen radiograph highlighting heavy calcifications (B).
FIGURE 2-6 Markedly calcified myxoma. Histology of specimen depicted in Figure 2-5 shows foci of calcification
adjacent to nests of myxoma cells revealing the myxomatous nature of this lesion.
FIGURE 2-7 Multiple myxomas in a patient with myxoma syndrome.
The surgeon, aware of the possibility of recurrence after excision, will usually remove the tumor together with its site of origin.
Thus, in atrial myxoma, the surgical specimen almost certainly will contain a through-and-through segment of the atrial septum or of
the atrial wall. When so excised, it is extremely rare to find myxoma at the margin. Recurrences at any rate are rare.
Microscopically, the tumors are dominated by a myxomatous matrix and a dispersed cellular component. The laEer consists of
26 26-28different types of cells. The principal cell type, known as the myxoma cell, is considered the true neoplastic cell. These cells may
appear elongated and fusiform, polyhedral, or stellate (Fig. 2-8). The cytoplasm is mostly homogeneous, is sometimes finelyvacuolated, and is usually slightly eosinophilic. The nucleus may be elongated, rounded, or oval, and its staining characteristics may
vary from pale to intensely hyperchromatic. Mitoses are virtually absent and, when present in more than an occasional cell, should
raise suspicion that the tumor may be a sarcoma, rather than myxoma. The large polyhedral myxoma cells are occasionally referred to
also as “lepidic cells” (from the Greek lepis meaning “scale” and based on a rather fanciful resemblance to the scales on buEerfly
29wings). The term was introduced by Orr in 1942, who at the time considered these cells to be of endocardial origin. At the
ultrastructural level the cytoplasm of a “typical” myxoma cell is characterized by scant organelles. Variable numbers are seen of
mitochondria, elements of smooth and rough endoplasmic reticulum, and cytoplasmic filaments. The laEer consist of two types. The
majority are thick (10 nm) nonbranching filaments, often arranged in parallel bundles coursing in various directions. The second type
are smaller (6-8 nm) and more irregular in outline.
FIGURE 2-8 Myxoma cells, some stellate, some elongate, set in myxoid stroma.
The myxoma cells may assume a variety of paEerns. Most commonly they are arranged in single or multiple layers surrounding
vascular channels (Fig. 2-9). This may appear as complex interlacing networks or single strands. These clusters of myxoma cells are
often associated with an extensive halo of myxoid extracellular matrix, almost optically empty, which contrasts with the surrounding
and slightly more condensed matrix that stains palely eosinophilic (Fig. 2-10, and see Fig. 2-9). Other possible arrangements of
myxoma cells include the formation of small nests (Fig. 2-11) and as single cells dispersed throughout the myxoid stroma (Fig. 2-12).
Multinucleate cells can also develop, but ultrastructurally they are composed of small groups of closely apposed cells with single
26nuclei. The surface of the tumor may be covered by a single layer of endothelial cells or may be absent, possibly because of surgical
FIGURE 2-9 Myxoma cells arranged as a complex interlacing network that often surrounds capillaries.
FIGURE 2-10 Myxoma cells with an extensive halo of myxoid tissue that contrasts with the surrounding more
eosinophilic matrix.FIGURE 2-11 Myxoma cells in small clusters partially cuffing capillaries.
FIGURE 2-12 Myxoma cells with an almost singular arrangement dispersed in the myxoid stroma.
Other cell types that may be present include elongated, spindle-shaped cells that resemble fibroblasts, myofibroblasts, or smooth
26muscle cells (Fig. 2-13). These cells are usually seen in close association with undisputed myxoma cells and vascular spaces lined by
distinct endothelial cells. Macrophages are an almost universal finding in myxomas, often diffusely dispersed throughout the myxoid
stroma, although generally condensed toward the base and at sites of hemorrhage. These occasionally coalesce into giant cells (Fig.
214). Lymphocytes and plasma cells (Fig. 2-15) may occasionally be prominent. These cellular aggregates occur predominantly in the
19base of the tumor and can also be found in the adjacent myocardium. Mast cells and foci of extramedullary hematopoiesis may also
be present.
FIGURE 2-13 Myxoma cells merging with elongate spindle-shaped cells that resemble smooth muscle cells.
FIGURE 2-14 Myxoma with giant cells.FIGURE 2-15 Myxoma with large number of lymphocytes.
The myxoid stroma itself stains strongly with alcian blue, unaffected by predigestion with hyaluronidase, and may show patchy
reactivity with mucicarmine and the periodic acid–S chiff (PA S ) stain, resistant to diastase. I t contains variably prominent connective
tissue fibers having characteristics of reticulin, collagen, and elastin. Fibrous tissue is most pronounced in the stalk of the tumor, a
site often dominated by the presence of large, thick-walled (and occasionally dysplastic) arteries (Fig. 2-16). The “tumor blush”
occasionally observed at coronary angiography has its anatomic substrate in this vascular tuft. I t is important to emphasize that, like
the cellular components, the stroma may also show extensive variability from one part of the tumor to the other. D istinct fibrous areas
and foci of liquefaction of the myxoid stroma, leading to cyst-like areas, may be seen (Fig. 2-17). These laEer changes should not be
confused with necrosis or features of malignancy.
FIGURE 2-16 Myxoma with dysplastic vessels in the stalk. (Courtesy Dr. William D. Edwards, Mayo Clinic,
Rochester, Minn.)
FIGURE 2-17 Myxoma stromal liquefaction resulting in a “cyst” filled with clear fluid.
Hemorrhage within the stroma is an almost universal finding. A lthough slightly more pronounced in surgical specimens than in
14autopsy cases, these foci are most likely the consequence of trauma resulting from the mobile nature of the intracavitary tumor.Histologic evidence of old and recent episodes of hemorrhage are manifest by the presence of hemosiderin-laden macrophages (Fig.
218) and connective tissue fibers encrusted with iron and calcium (so-called Gamna-Gandy bodies [Fig. 2-19]). Occasionally these can
be so prominent that the tumor itself is overshadowed and not easily recognized. I t has been suggested that these fibrosclerotic
30 31nodules may be related to anticoagulant and/or antiplatelet therapy, but they can be seen even in the absence of such treatment.
FIGURE 2-18 Myxoma with hemosiderin-laden macrophages dispersed throughout the myxoid stroma adjacent to
recent hemorrhage.
FIGURE 2-19 Myxoma with stromal Gamna-Gandy bodies.
A part from elastic fiber encrustation, myxomas can exhibit several additional histologic features, such as microscopic foci of
calcification. Occasionally the dystrophic calcifications in the tumor may become so extensive that the tumor is almost completely
transformed to a calcified mass (see Figs. 2-5 and 2-6).
I n approximately 5% of cardiac myxomas gland-like structures occur, lined by cells that may vary from flat to cuboidal or columnar
(Fig. 2-20). These cells stain positively with alcian blue, mucicarmine, and PA S (diastase resistant) and show immunoreactivity with
27,28antibodies to cytokeratins and carcinoembryonic antigen. The ultrastructural features of these cells are characteristic for
mucin27secreting epithelium. S ignificant cytologic atypia and mitotic activity may be present and cause concern that such glands may
represent metastatic adenocarcinoma. Thymic epithelial rests may also be seen in myxomas (as well as in the myocardium) and may
occasionally become so proliferative as to warrant the designation “thymoma” (Fig. 2-21). The observation that myxomas may contain
32-36epithelial, as well as mesenchymal, elements has suggested to some that they should be classified as hamartomas.FIGURE 2-20 Myxoma with glands (A-C) lined by alternating flat and columnar cells. The cells are reactive with
antibodies to cytokeratin (D). (C and D courtesy Dr. R.J. van Suylen, Department of Pathology, Academic Hospital,
Maastricht, The Netherlands.)
FIGURE 2-21 Myxoma with thymic rest that has given rise to thymoma.
I n myxoma syndrome, myxomas may be less cellular (i.e., more myxoid) than sporadic ones. Valvular myxomas reportedly have
fewer cellular clusters, fewer syncytial tumor giant cells, and more infrequent perivascular cuffing of tumor cells than myxomas
14occurring elsewhere.
37Recurrence of a cardiac myxoma after surgical excision is a relatively rare but undisputed phenomenon. I t is for this reason that
38,39excision of the entire area of aEachment of myxoma is recommended. Recurrence is highest in patients with myxoma syndrome,
4,6and the development of a myxoma recurrence should prompt investigation into the possibility of the myxoma syndrome.
The potential for malignant degeneration in myxoma is controversial. Most cases of malignant myxomas likely represent cases of
14,40,41misdiagnosis or the inclusion of false metastases based on “invasiveness” of embolized myxoma fragments, causing ischemic
infarction and subsequent infiltration of the arterial wall and/or extracardiac parenchyma. N evertheless, the possibility of malignant
transformation of cardiac myxomas remains a maEer of concern with three possible cases having been reported, one with glandular
40,42,43elements. Given that myxoid sarcomas may mimic a myxoma, it would seem that, similar to tumors in other locations (e.g.,
malignant Brenner tumor of the ovary), the best way to document malignant transformation would be to have benign and clearly
44malignant elements adjacent to one another, as has rarely been reported.
20,27Immunohistochemical studies indicate differences in the phenotypic expression of the various cell types present in these tumors.
The myxoma cells are reactive with antibodies to calretinin (75%) and vimentin (50%). Calretinin can be particularly useful in
45differentiating myxoma from other entities. The vascular channels are lined by endothelial cells that react with antibodies to von
27,28,30,46Willebrand factor, CD31, or Ulex europaeus agglutinin I. S mooth muscle actin may stain cells that immediately surround the
endothelial cells.Differential Diagnosis
Cardiac myxomas can potentially be confused with any number of other neoplasms that arise in or involve the heart (Table 2-5).
Myxomas can be differentiated from organizing thrombi by the presence of characteristic myxoma cells and matrix. Thrombi on the
surface and foci of organizing intratumoral hemorrhage can occasionally make this distinction difficult, and calretinin stains may be
helpful in the distinction, as the cells of organizing thrombi fail to react with this antibody. Papillary fibroelastomas have more
complex papillary architecture, lack the myxoid stroma, and also have characteristic avascular elastic fiber cores. Myxoid intimal
fibroplasia can occur on valvular or endocardial surfaces (Fig. 2-22) and, because of the myxoid stroma, can mimic myxomas; however,
the location and a lack of myxoma cells should help in the distinction.
Differential Diagnosis of Myxomas
Differential Diagnosis Differentiating Features
Thrombus Zonated usually with prominent fibrin
Absence of myxoma cells
Intimal fibroplasia Lacks myxoma cells
Often previous history of instrumentation
Myxoid sarcoma Pleomorphic spindle cells
Often necrotic with high mitotic rate
Papillary fibroelastoma Typically valvular location
Endothelial-lined avascular papillary fronds
Calcified amorphous tumor of the heart (cardiac CAT) Prominent calcification
Absence of myxoma cells
Mesothelial incidental cardiac excrescence (MICE) Lacks myxoid stroma
Often previous history of instrumentation
Fibroma Abundant collagenous stroma
Typically ventricular location
Hemangioma Lobular arrangement of vessels
Lacks myxoid stroma
FIGURE 2-22 Intimal fibroplasia with myxoid change can mimic a myxoma.
S eparation from the variety of myxoid sarcomas is based on characteristics of the stroma, cellularity, mitotic activity, necrosis, and
location. The major histopathologic features to distinguish between a benign cardiac myxoma and the myxoid variant of so-called
47,48undifferentiated high-grade pleomorphic sarcoma (myxofibrosarcoma) are foci of hypercellularity with pleomorphism, mitotic
figures, necrosis, and extensive vascularity in myxofibrosarcoma, features that are strikingly absent in cardiac myxomas. Frequently,
the surgeon will not suspect that a tumor presenting as a myxoma is malignant, and it may be the pathologist who is the first to raise
the possibility. The rare myxosarcoma (if it is truly different from a myxoid undifferentiated high-grade pleomorphic sarcoma) can be
49,50differentiated on the basis of its cellularity, invasive growth, and lack of hemorrhage or myxoma cells. The lepidic cells of a
myxoma typically are absent from the pedicle.
Cytogenetic analysis of cardiac myxomas, thus far, has shown a variety of clonal and nonclonal abnormalities. A s it stands now,
cytogenetic analysis is of liEle or no value in the differential diagnosis of cardiac myxomas, although these studies may eventually
51,52contribute to understanding their molecular pathogenesis.
Clinical Features
This is one of the more frequent primary tumors of the heart and by far the most common in infants and children. Only five reports
53-55have been made of rhabdomyoma in adults. Cardiac rhabdomyomas have a close association with tuberous sclerosis (see later).
A smaller proportion occur sporadically or in association with congenital heart disease. Because of its development in utero, the
clinical presentation may differ from that of some other cardiac tumors. I n some instances, the tumor may have led to stillbirth or
56,57perinatal death, as well as intrauterine myocardial infarction resulting from coronary arterial compression by a large
57rhabdomyoma. The clinical manifestations of cardiac rhabdomyomas are determined by their size, multiplicity, and location (in58,59 60relation to the conduction system) and whether they expand into a chamber. I n a meta-analysis, Chao and colleagues found
that large tumor size and fetal hydrops are significantly associated with poor neonatal outcome.
61Echocardiographic studies of patients with tuberous sclerosis reveal a high incidence of cardiac rhabdomyomas. However, a
56significant difference exists between children and infants. Fenoglio and colleagues reported a 37% incidence of tuberous sclerosis in
their autopsy series of patients with cardiac rhabdomyoma. However, many of their cases were stillborns or newborns, and the
diagnosis of tuberous sclerosis may be difficult in this age group. A retrospective study in 33 infants and children with cardiac
62 63rhabdomyoma collected from three pediatric cardiology centers showed that 91% had tuberous sclerosis. I ndeed, D avies
suggested that cardiac rhabdomyomas are always accompanied by tuberous sclerosis of the brain, whether or not the laEer condition
is clinically manifest. This contention is further strengthened by the observation that in each of five infants, in whom fetal or early
64postnatal echocardiography revealed a cardiac tumor, tuberous sclerosis was subsequently diagnosed.
65 66-68S pontaneous regression of rhabdomyomas, initially observed in 1923, is an important phenomenon. A retrospective
evaluation of patients with tuberous sclerosis, over a 10-year period (1984-1994), revealed that 63% of patients had a cardiac
rhabdomyoma identified at the time of the initial study. However, the number of rhabdomyomas steadily declined with follow-up, so
69that by age 6 years, they completely disappeared by echocardiography. Hence, once an intracardiac tumor has been detected in an
infant who otherwise has no signs or symptoms, the tendency is not to resect in the hope that the tumor will spontaneously regress.
S uch biologic behavior supports the concept that cardiac rhabdomyomas, whether or not associated with tuberous sclerosis, may be
70,71hamartomatous rather than truly neoplastic. Genetic studies have linked tuberous sclerosis to the TSCI gene on chromosome
9q34 and TSC2 on 16q13.3; it has been suggested, on the basis of similar allelic losses in the associated hamartomas, that these genes
72,73act as growth suppressors.
Gross Pathology
The vast majority of rhabdomyomas are multiple (Fig. 2-23), although this may not be immediately apparent. The lesion has a distinct
predilection for the ventricles, with left ventricular involvement in almost 100% and right ventricular involvement in approximately
56 56,6280% of cases. I nvolvement of the atria is much less common (Fig. 2-24), ranging from 1% to 30%. Multiple small
74rhabdomyomas originating from the ventricular aspect of the mitral valve have also been documented. D iffuse rhabdomyomatosis
75of the heart is exceedingly rare. I n this condition the myocardium is diffusely replaced by cells that show the characteristics of
76rhabdomyoma cells (see later discussion), although small strands and islands of normal-looking myocardium are still present.
FIGURE 2-23 Rhabdomyomas are typically multiple.FIGURE 2-24 Rhabdomyoma arising in the right atrium extending through the tricuspid orifice into the right
ventricular inlet.
Rhabdomyomas are circumscribed but unencapsulated lesions, easily distinguished from the surrounding myocardium. They have
a wax-like consistency and a white to yellowish-gray coloration. The size may vary from millimeters to several centimeters.
Occasionally the lesions may grow to bizarre proportions, with intracavitary extension (see Fig. 2-24) that can obliterate cardiac
The histopathologic features of cardiac rhabdomyomas are distinct. The tissue is composed of markedly swollen myocytes, showing
almost “empty” cytoplasm with a centrally placed cytoplasmic mass and nucleus (Fig. 2-25). Cytoplasmic strands extend to the
periphery of the cell, hence the term spider cell (Fig. 2-26). The myocytes may appear quite bizarre and sometimes reach monstrous
sizes of up to 80 µm in diameter (Fig. 2-27). At high magnification, striations are often seen in the tiny strands. The stromal
component is usually scanty, although occasionally areas with distinct collagen may occur. I n some cases calcifications can be seen
77associated with foci of necrosis. The older the patient, the more likely extensive calcification is present. The lesions have a low
78proliferative rate, although those in adults may be more mitotic. Diagnosis on endomyocardial biopsy is possible.
FIGURE 2-25 Rhabdomyoma characterized by grotesquely swollen myocytes.FIGURE 2-26 Rhabdomyoma. A high-power view of the specimen in Figure 2-25 shows the typical “spider cells,”
characterized by a centrally placed cytoplasmic mass and nucleus connected to the perimeter of the cell by strands
of cytoplasm.
FIGURE 2-27 Rhabdomyoma cells compared with adjacent normal myocytes (lower left). The rhabdomyoma cells
are very large in comparison.
The cells contain copious glycogen, best demonstrated with the PA S method on alcohol-fixed or on frozen-tissue sections. The type
of polysaccharide involved is rather labile (diastase sensitive), a striking contrast with that present in glycogen storage disease
65(diastase resistant).
Rhabdomyoma cells are reactive for muscle markers, including myoglobin, actin, desmin, and vimentin. They may also react with
79antibodies to HMB45, an interesting observation given their association with tuberous sclerosis, but are negative for S -100
80protein. S pider cells are also reactive with antibodies to ubiquitin, a trafficking protein that plays a role in apoptosis, providing a
81 56possible explanation for spontaneous regression. Ultrastructural studies confirm the myogenic nature of the cells involved.
Differential Diagnosis
The histopathologic diagnosis should not normally be a problem because of the clinical seEing and the bizarre appearance of the
swollen myocytes. Cardiac rhabdomyoma should not be confused with other types of rhabdomyoma, which generally do not occur
55 54within the heart, with the exception of rare reports of cellular rhabdomyoma and a single case of adult rhabdomyoma. A lthough
“spider” cells are described in adult rhabdomyoma, they are few and admixed with large, densely eosinophilic polygonal cells.
D istinction from glycogen storage disease may occasionally pose a problem. However, in the laEer, the myocytes are usually not so
large, nor do they show the “spider” appearance, although they appear empty with a peripheral rim of myofibrils. Finally, cardiac
rhabdomyomas should not be confused with a rare condition known as Purkinje cell tumor nor with the hamartoma of mature cardiac
myocytes, which lacks the cytoplasmic vacuolation of a rhabdomyoma (see p 23).
Cardiac Fibroma
Clinical Features
82The cardiac fibroma is generally a tumor of infants and children, although it also occurs in adults (15%), with one of the oldest
83-85adults being 77 years old (see Table 2-1). Gorlin syndrome (multiple nevoid basal cell carcinomas of the skin, jaw cysts, with bifid
82-84,86-88ribs) may be present in up to 4% of patients with cardiac fibroma. This is due to PTCH1 mutations, and loss of the PTCH1
89 90,91locus has been reported in a sporadic cardiac fibroma. S tructural rearrangements of chromosome 9q22, corresponding to the
92PTCH1 locus, have also been described. Cardiac fibroma has been associated with the Beckwith-Wiedemann and S otos
Gross Pathology
Cardiac fibromas present as circumscribed solid, firm, white lesions, which are clearly demarcated from the surrounding myocardium
94and range from 2 to 10 cm (Fig. 2-28). Rare tumors may be as large as the heart and still be asymptomatic. A lthough grossly
95circumscribed, the tumors are somewhat infiltrative microscopically (see later). The cut surface reveals the fibrous nature of the
lesion (Fig. 2-29). Occasionally calcifications may be apparent.FIGURE 2-28 Cardiac fibroma in situ in the left ventricle. (Courtesy Dr. William D. Edwards, Mayo Clinic,
Rochester, Minn.)
FIGURE 2-29 Cardiac fibroma cut surface shows whorled appearance, not unlike that of a leiomyoma.
Fibromas are composed of bland spindle cells and dense connective tissue composed mostly of collagen (Fig. 2-30, A). Generally
speaking, lesions observed in younger patients (less than a year old) are often more cellular whereas those in older patients contain
proportionally more collagen (see Fig. 2-30, B). At the periphery, the fibroma intermingles with the surrounding myocardium, being
less well demarcated than the gross appearance might suggest (Fig. 2-31). Occasionally, myocytes may be intermingled in the more
central portions of the tumor. I ndividual cells may be difficult to distinguish but are elongated bland fibroblasts. Mitotic figures are
extremely rare, even in areas that are distinctly cellular. Elastin fibers may sometimes be present, leading to the former term
96fibroelastic hamartoma, but a fibroma should not be confused with papillary fibroelastoma. Microscopic foci of calcification may
often be observed (Fig. 2-32) and, when seen on imaging, offer a diagnostic clue. Centrally, the lesions may become either cystic or
hyalinized. S mall groups of chronic inflammatory cells may be present around blood vessels. D iagnosis by endomyocardial biopsy is
possible.FIGURE 2-30 Cardiac fibroma. Typical hyalinized fibroma in an older patient (A), compared with more cellular
fibroma (B) in a young child.
FIGURE 2-31 Cardiac fibromas typically intermingle with myocardium at the periphery (trichrome stain). (Courtesy
Dr. William D. Edwards, Mayo Clinic, Rochester, Minn.)
FIGURE 2-32 Cardiac fibromas are typically calcified.
97I mmunohistochemically, most cells express vimentin and α-smooth muscle actin. Ultrastructural studies have shown that the
principal cellular component of the cardiac fibroma is the fibroblast, set in a matrix composed of glycosaminoglycans and
96,98 99collagen. Myofibroblasts may be intermingled. S ometimes, the tumors may not be completely resected, and fibroma cells may83,100be present at the margin. Even so, they typically do not recur.
Differential Diagnosis
Because of the age of most patients with cardiac fibroma, the differential diagnosis is limited. The relatively paucicellular nature of the
tumors and low-grade cytology, as well as lack of necrosis, help to differentiate them from fibrosarcomas. The infiltrative nature of the
spindle cells, however, does bring desmoid-type fibromatosis into the differential diagnosis. This is of more than academic interest as
101fibromatoses recur and cardiac fibromas do not. However, no β-catenin (CTTNB1) mutations have been identified in cardiac
fibroma, and they lack the nuclear staining characteristic of fibromatoses.
Lipoma and Lipomatous Hypertrophy of the Atrial Septum
Clinical Features
102Epicardial fat stores increase with advancing age. They have a characteristic distribution on the anterior surface of the right
ventricle and along the course of the epicardial coronary arteries. Moreover, an excessive increase of epicardial fat is usually
accompanied by faEy infiltration of the right ventricular myocardium and the interatrial groove. Thus the question may arise as to at
what stage, if any, an increase in adipose tissue should lead to a diagnosis of lipoma. The classification of benign lipomatous
103-114processes of the heart, therefore, includes true neoplasms, diffuse lipomatoses (see also Chapter 24), and expansion of the fat
115-118in the atrial septum (so-called lipomatous hypertrophy of the atrial septum [LHA S ]). A n association with tuberous sclerosis
41,119,120has been documented for some true lipomas. LHA S is likely a result of entrapped embryonic fat during atrial septation and
appears related to body mass. I t is often identified incidentally in older adults. The association of cardiac arrhythmias and sudden
41,116,121-123cardiac death in cases of LHAS is well established.
Lipomatous hamartoma of an atrioventricular (AV) valve is another extremely rare condition of which fewer than 10 examples have
124been documented ; lesions have affected both the mitral and the tricuspid valve, with an age spread from 2 to 76 years. Valvar
125insufficiency may occur, in which case the lipomatous change also involved the papillary muscle. Finally, at least two cases of
126,127hibernoma of the heart and pericardium have been reported.
Gross Pathology
The gross pathology depends highly on the type of “lipoma.” I n the case of a true lipoma, the gross morphology will be identical to
that seen with lipomas in other locations (Fig. 2-33).
FIGURE 2-33 Lipoma arising from the right atrial free wall.
When encountered in an autopsy, explant, or (rarely) surgical pathology specimens, LHA S presents as a distinct bulge of the
posterior limbus, directly adjacent to the oval fossa (Fig. 2-34). The fossa may occasionally be barely visible as it may be masked by the
protruding atrial wall. I n fact, the protruding wall can be so pronounced as to cause vena caval obstruction. On the cut surface the
117interatrial groove appears extremely thickened (even >2 cm) and composed of yellow-gray adipose tissue, often with a brown tinge,
infiltrating into adjacent atrial myocardium. Close inspection will usually reveal strands of preexisting heart muscle amid the adipose
tissue. I n cases of valvular involvement the valve will show a deformity with localized thickening, which on the cut surface will appear
as adipose tissue (Fig. 2-35). The cephalad portion of the atrial mass is usually thicker than the caudal portion, and the fossa ovalis is
115generally spared, giving it a characteristic “dumbbell” or “bilobed” appearance (see Fig. 2-34).FIGURE 2-34 A and B, Lipomatous hypertrophy of the atrial septum. Note the bilobed, dumbbell-shaped
FIGURE 2-35 A and B, Lipomatous hypertrophy of the tricuspid valve.
The histopathology of lipomas, defined as circumscribed encapsulated tumors, is no different from that encountered in lipomas
elsewhere in the body (Fig. 2-36). Mature adipose tissue and occasional muscle cells may be encountered, and variably admixed
fibrous tissue and vessels may be seen, leading to subclassification of such tumors as myolipoma, fibrolipoma, and angiolipoma.FIGURE 2-36 A, Lipoma of the right ventricle. B, Adipose tissue is intermingled with myocytes.
I n LHA S the histology is dominated by massive infiltration of mature fat cells with displacement of preexisting myocardial cells
(Fig. 2-37, A). The laEer can be either atrophic or large and atypical and suggest the possibility of malignancy. Usually the
bestpreserved parts of the myocardium are subendocardial in location, but islands of myocytes are trapped in the lipoma and often appear
to be totally surrounded by faEy tissue. Occasionally, areas can be traced where mature fat cells intermingle with vacuolated,
sometimes multivacuolated, fat cells (see Fig. 2-37, B). I n addition, granular eosinophilic cells may be seen, which resemble fetal fat
cells by light and electron microscopy.
FIGURE 2-37 Lipomatous hypertrophy of the atrial septum with marked infiltration of mature fat cells in between
remaining myocytes (A). Sometimes, vacuolated, multiglobular fat cells may be prominent and may resemble
lipoblasts (B).
Lipomatous hamartomas of cardiac valves show diffuse infiltration by mature fat cells, with almost complete replacement of the
preexisting tissue architecture of the valve leaflet.
Differential Diagnosis
Because of the presence of myocytes intermingled with adipocytes in LHA S and the resemblance of some of the multivacuolated cells
to lipoblasts, liposarcoma may occasionally enter the differential diagnosis. This concern may be furthered by the surgical findings of
what appears to be a grossly infiltrative mass. Knowledge of the location, however, is usually sufficient to allow accurate classification.
Papillary Fibroelastoma
Clinical Features
This lesion is also known as fibroelastic papilloma, papillary tumor of the cardiac valve, or giant Lambl excrescence. Only an
128-130occasional report documents a fibroelastoma in an infant or child. I t is mainly a tumor of adults and occurs on any endocardial
131,132surface, although left-sided valves are the most common location. Valves with abnormal hemodynamics (e.g., chronic
131,133-135rheumatic disease) appear to be disproportionately affected. A subset of cases appear to be iatrogenic in origin (prior
136surgery or radiation), and such lesions may be multiple. Occasionally they may produce clinical signs and symptoms, including
137-143cerebral embolization. Location on the aortic valve may lead to obstruction of coronary ostia or coronary arterial embolization
128,144-147resulting in acute myocardial infarction. A s with several cardiac tumors, it is not clear whether fibroelastoma should be
48,148regarded as a neoplasm or reactive growth.Gross Pathology
149These tumors have the appearance of a sea anemone, particularly when examined in water (Fig. 2-38). They consist of a bouquet of
filiform threads aEached to the endocardium, being either sessile or connected by a distinct but short pedicle. They may be very
small, no more than a few millimeters in diameter, or quite large (Fig. 2-39), with a diameter up to 3.0 cm. These tumors most
frequently arise on the valves, with a distinct preference for the aortic valve (Fig. 2-40), but may also arise from mural endocardium of
both atria and ventricles. On the mitral and tricuspid valves the lesions are usually found on the atrial aspect, often near the
midportion. On the aortic and pulmonary valves these papillary tumors occur with near-equal frequency on the ventricular and the
arterial side of the cusp. Occasionally, a patient may have multiple fibroelastomas (Fig. 2-41).
FIGURE 2-38 Papillary fibroelastoma photographed under water to highlight its papillary fronds and resemblance
to a sea anemone.
FIGURE 2-39 Papillary fibroelastoma measuring 1 cm in greatest dimension. (Courtesy Dr. William D. Edwards,
Mayo Clinic, Rochester, Minn.)
FIGURE 2-40 Papillary fibroelastoma arising on the aortic valve. A probe is in the coronary artery ostia. (Courtesy
Dr. William D. Edwards, Mayo Clinic, Rochester, Minn.)FIGURE 2-41 Multiple papillary fibroelastomas from a 40-year-old woman occurring 17 years after surgery for
hypertrophic cardiomyopathy. (From Kurup A N, Tazelaar H D, Edwards W D, et al. 2002 Iatrogenic cardiac
papillary fibroelastoma: a study of 12 cases [1990 to 2000]. Hum Pathol 33: 1165-1169)
These tumors are always obviously papillary (Fig. 2-42). The fronds consist of a central avascular core of dense, almost acellular
collagen, occasionally surrounded by a myxomatous matrix. One case has been reported with chondroid metaplasia of the fibrous
150core. The peripheral rim and/or core contain coarse and fragmented elastic fibers (Fig. 2-43). The surface lining consists of a layer
150of endothelial cells, which may appear hyperplastic. The central core of collagen is continuous with that of the subendothelium.
The amount and distribution of elastin vary considerably among the various fronds in a single tumor, but usually elastic stains
highlight their presence.
FIGURE 2-42 Papillary fibroelastoma showing multiple fronds. The surface lining consists of endothelial cells.
FIGURE 2-43 Papillary fibroelastoma on elastic tissue stain highlights the presence of elastic fibers in the central
The cells covering the surface of papillary fibroelastomas are positive for vimentin, factor VI I I –related antigen, and CD 34, in keeping
with their presumed vascular endothelial origin. I nterestingly, the surface lining cells have also been reported positive for S -100
151protein. Collagen type I V shows multilayered linear staining beneath the surface, virtually identical to the staining paEern for
151elastic tissue.
Differential Diagnosis
Grossly, papillary fibroelastomas may look somewhat myxoid and (without immersion in water) the papillary fronds may not be
evident, causing one to consider a diagnosis of cardiac myxoma. Histologically, however, the similarities with cardiac myxoma are
limited to the collar of loose connective tissue surrounding the central cores of dense collagen and its prominent lining with
endothelial cells (see Fig. 2-42), but this should not pose a differential diagnostic problem as fibroelastomas are virtually acellular and
do not contain myxoma cells. Myxomas also tend to lack the fine papillae of these lesions. Lambl excrescences also have a core ofelastic tissue, but they are architecturally much simpler, usually comprising a few (fewer than five) shorter and broader papillary
fronds (Fig. 2-44). A dditionally, Lambl excrescences are found exclusively along the lines of closure on semilunar valves and are not
seen on AV valves.
FIGURE 2-44 Lambl excrescence gross (A and B). Note the lack of complex papillary architecture characteristic
of papillary fibroelastoma.
Purkinje Cell Tumor—Hamartoma
Clinical Features
This is a peculiar and rare lesion reported under numerous names including histiocytoid cardiomyopathy, infantile cardiomyopathy,
152 153oncocytic cardiomyopathy, foamy myocardial transformation of infancy, infantile xanthomatous cardiomyopathy, infantile
154 155,156cardiomyopathy with histiocytoid change, and histiocytoid cardiomyopathy in infancy. I t has been described only in infants
below 2 years of age, with a distinct female predilection (3-4 : 1). I t is strongly associated with tachyarrhythmias and sudden death (the
157,158presenting sign in 20% of patients). I t appears to be due to a genetic defect of cardiac mitochondria. Other cardiac and
159 160extracardiac manifestations include ventricular noncompaction ; cardiomegaly ; and central nervous system, ocular, and
155,161-163 164endocrine abnormalities. When recognized, the disease is treated by ablation or cardiac transplantation.
Gross Pathology
Purkinje cell tumors present as circumscribed or diffuse lesions, tan-white or yellowish in color, ranging in size between 0.1 and
1.5 cm, usually less than 2.0 cm (Fig. 2-45). They can be located anywhere in the myocardium, including atria, but are most common in
165the subendocardium of the left ventricle.
FIGURE 2-45 Purkinje cell tumor as a cause of sudden death in a baby girl 4 weeks of age. A cross-section
through the heart reveals tan-white patches in subendocardial zone.
The involved areas show clusters or sheaths of myocardial cells transformed into swollen (up to twice the size of adjacent myocardial
cells), rounded, or polyhedral cells with a slightly granular eosinophilic and often abundantly vacuolated cytoplasm (Fig. 2-46). N uclei
are bland and characteristically dark. N o mitotic figures are seen. The cells have a foamy appearance (Fig. 2-47, A), hence the use of
terms such as lipoid and histiocytoid. I nterspersed mast cells may be present. I n contrast to the cardiac rhabdomyoma, the cells do not
contain large clear vacuoles, and they only stain faintly for PAS.FIGURE 2-46 Purkinje cell tumor. Histology of the patches shown in Figure 2-45 reveals that these areas are
composed of slightly swollen cells with vacuolated cytoplasm.
FIGURE 2-47 Purkinje cell tumor composed of vacuolated cells (A). An actin stain (B) confirms these are modified
muscle cells.
The cells express specific muscle actin (see Fig. 2-47, B), myoglobin, and cholinesterase and are faintly reactive with desmin and fast
myosin on immunohistochemical staining. They lack reactivity for CD 68, lysozyme, and antitrypsin. Ultrastructurally, the cells contain
numerous, often abnormal, mitochondria with distorted cristae, lipid vacuoles, only scaEered glycogen vacuoles, few myofibrils and Z
165bands, and rare intercalated disks. The absence of T tubules is characteristic.
Cardiac Teratoma
Clinical Features
166Cardiac teratomas occur in children and adolescents, primarily, with more than 75% developing before age 15 years. The
167pericardium is much more often the primary site than the myocardium. A slight female predominance exists. Because of the
168,169routine use of fetal echocardiography, an increasing number are being diagnosed in utero.
Gross Pathology
15Teratomas are usually intrapericardial and aEached, with or without a well-defined stalk, to the great arteries arising from the heart.
They may vary in size, but those that come to clinical aEention have usually grown to an appreciable size and may even be several
times larger than the heart itself. They typically displace the heart and cause it to rotate along its longitudinal axis. Externally, they are
lobulated with a smooth surface. On cut section they are typically both solid and cystic, with multilocular fluid-filled cavities of
varying sizes, intermingling with solid foci.
By definition, teratomas contain elements derived from all three germ layers. Teratomas of the heart are very much like those that
occur elsewhere in the body, such as those in the ovary (see Chapter 13A). D iagnosing these tumors is not a real problem for the
pathologist, except that malignancy has to be excluded.
Differential Diagnosis
The differential diagnosis is limited. Pericardial cysts may also be multiloculated but lack solid areas and are lined by a single layer of
mesothelial cells. Bronchogenic cysts also lack significant solid areas, are usually located intramyocardially, and are lined by ciliatedcolumnar or cuboidal epithelium, occasionally with squamous metaplasia. The presence in the wall of collagen, smooth muscle,
cartilage, and seromucinous glands may suggest the possibility of a teratoma, but these structures usually mimic their location in
normal airways in a bronchogenic cyst. A dditionally, the lack of other tissue components helps to differentiate it from a teratoma. The
possibility of a mixed germ cell tumor or foci of malignancy should also be considered as with teratomas arising elsewhere.
Clinical Features
Hemangiomas are generally sporadic and occur in patients of all ages with a male predominance. They may cause a variety of cardiac
170,171signs and symptoms including sudden death. Patients may also have cutaneous or visceral angiomas, a condition that may
171,172constitute a diagnosis of diffuse angiomatosis. Cardiac hemangiomas have limited growth potential but will persist if not
173 174surgically excised. Spontaneous involution has been documented, but surgical excision usually results in long-term cure.
Lymphangiomas (also known as hygromas) have also been reported to rarely involve the heart (usually the pericardium), typically
175occurring during childhood. Like hemangiomas, they are similar to those lymphangiomas that arise elsewhere in the body and
176may occur singly, or rarely as part of so-called lymphangiomatosis.
Gross Pathology
Hemangiomas can be located anywhere within the heart or pericardium with predilection for the lateral wall of the left ventricle
171,177 178(21%), the anterior wall of the right ventricle (21%), and the ventricular septum (17%). The valves are rarely involved. They
179-183also show preference for the visceral layer of the pericardium, where they may produce hemopericardium. A s mentioned
earlier, they are usually localized and single, although occasionally the lesion may present as angiomatosis with extensive and diffuse
involvement of a large part of the heart (Fig. 2-48). A lthough very large masses have been reported, most are small and measure no
more than 4 cm. They may be sessile or polypoid, if they grow into a chamber or the pericardium, and are usually red to purple.
FIGURE 2-48 Hemangiomatosis. Extensive diffuse hemangiomatosis involving the heart and pericardium in a
4month-old baby boy. The opened left atrium, left ventricle, and aorta are fully wrapped by the hemangioma.
The histologic appearance is not different from that of hemangiomas in general (see Chapter 3). Most can be classified as capillary
(Fig. 2-49), cavernous, or arteriovenous, with the two former being the most common varieties. The vascular channels are often
accompanied by interstitial fibrosis making the vascular nature of the process subtle, particularly in endomyocardial biopsy
184-189specimens (Fig. 2-50). Epithelioid variants of vascular tumors are extremely rare in the heart.FIGURE 2-49 Capillary hemangioma growing in myocardium.
FIGURE 2-50 Hemangioma. Endomyocardial biopsy in a 22-year-old man who was asymptomatic until 1 week
before admission when progressive dyspnea developed. Clinical studies revealed pericarditis (more than 1 L of
serosanguineous fluid), an unusual ground-glass appearance of a large part of the myocardium of the inferior heart
wall on echocardiography, and vascular convolutions on coronary angiography. The right ventricular endomyocardial
biopsy (from the septal aspect) revealed a hemangioma of the capillary type.
Differential Diagnosis
Hemangiomas should be differentiated from blood cysts, which occur almost exclusively in newborns and infants, with particular
preference for the tricuspid and mitral valves. These so-called blood cysts are not truly “cysts” but represent crevices in the valve
leaflets with trapped blood, thus mimicking a varicose lesion. Epithelioid hemangioendothelioma and angiosarcomas may also enter
into the differential diagnosis but are typically more complex and infiltrative than hemangiomas, and criteria used in soft tissue
tumors apply in the differential diagnosis (see Chapter 3). Lesions formerly referred to as histiocytoid (or epithelioid) hemangioma,
and now classified as either cardiac mesothelial/monocytic incidental cardiac excrescences (MI CE) or lesions of aggregated monocytes
and mesothelial cells (LAMM), are not vascular lesions at all (see later discussion) and do not usually cause histologic confusion.
Cystic Tumor of the Atrioventricular Node (Mesothelioma of the Atrioventricular Node, Congenital Polycystic
Tumor of the Atrioventricular Node, Intracardiac Endodermal Heterotopia)
Clinical Features
Cystic tumor of the AV node is a congenital tumor located in the triangle of Koch in the AV nodal region of the atrial septum. I t is not
190,191classified as a neoplasm but as an embryonic rest of endodermal origin. S imilar to solid cell nests in the thyroid, cystic tumor
192of the AV node likely represents ultimobranchial heterotopic elements. These tumors have been reported with other congenital
193 194disorders including midline developmental defects. These are among the smallest mass lesions that can cause sudden death.
Patients usually present in the third to fourth decades, but a broad age range exists (11 months to 89 years), and they occur most
162,190,192,194-201commonly in women (approximately 3 : 1). More than 60% of patients present with complete heart block.
Gross Pathology
They may present as a thickening of the atrial septum or as a slightly elevated nodule in the region of the AV node ranging in size
from 0.2 to 2.0 cm. The multicystic nature of the lesion may be appreciated on close inspection of larger tumors.
The lesions may appear to replace the AV node and are composed of cysts, ducts, and solid nests of cells (Fig. 2-51). The cysts vary in
size considerably. The cells lining the cysts are either single or multilayered and flat or cuboidal in shape, often in a palisaded
arrangement along the innermost lining. N uclei are bland. The cell nests are embedded in a dense stroma that contains collagen and
elastin fibers; remnants of AV node are rarely identifiable. The cells stain with alcian blue and PA S , exhibiting resistance to both
hyaluronidase and diastase digestion, respectively. S ome cell nests fail to show mucin staining and exhibit prominent eosinophilic
cytoplasm, resembling squamous or transitional epithelium. I mmunohistochemically, these cells stain with antibodies to keratin,
epithelial membrane antigen, B72.3, and carcinoembryonic antigen (CEA). I n contrast to true mesothelium, the cells are usually
negative for calretinin.FIGURE 2-51 Cystic tumor of atrioventricular node, low (A) and high (B) power.
199Electron microscopically, two principal cell types exist. One population of cells is characterized by an almost oval shape,
numerous desmosomes, and cytoplasm containing many tonofibrillar bundles circumferentially arranged around the nucleus. The
second cell type contains intermediate filaments and dense granules limited by a single membrane, in part fused with the surface
membrane, suggesting secretory activity.
Differential Diagnosis
Bronchogenic and mesothelial cysts, as well as teratomas, are the main considerations and can be differentiated from cystic AV node
tumors by the number of germ cell layers: bronchogenic and mesothelial cysts are composed of mesoderm and endoderm, and
166teratomas are composed of all three layers.
Hamartoma of Adult Cardiac Myocytes
Clinical Features
202 203,204This unusual tumor was first described in 1988 and is still relatively unknown. A s bulky intramural ventricular masses they
typically raise clinical suspicion for cardiac fibroma, rhabdomyoma, or invasive malignancy. Histologically they show only the cellular
pleomorphism associated with mature (adult) myocyte hypertrophy. Hamartoma of adult cardiac myocytes (HA CM) may be detected
203,204at any age, but the majority are detected before age 20 years. A distinct male predominance exists (4 : 1 male/female).
Gross Pathology
HA CM occurs in the ventricles (>90%) (usually left), and the reported atrial occurrences are exclusively right sided. The tumor appears
paler than the surrounding myocardium and often has a fibrous texture and pale sheen (Fig. 2-52). These lesions are generally
circumscribed but with poorly defined borders, imparting a somewhat infiltrative appearance. They can resemble an old infarct,
though the wall is usually thicker rather than thinner as would be more typical for an infarct.FIGURE 2-52 Hamartoma of adult cardiac myocytes at autopsy. Short-axis cross-sectional view near the apex
showing two infiltrative and mass-forming areas of thickening at the anterior and inferior ventricular septum. The
masses have a silver-white texture and sheen. (From Miller D V, Tazelaar H D 2010 Cardiovascular
pseudoneoplasms. Arch Pathol Lab Med 134: 362-368)
These tumors can show a variety of histopathologic paEerns. They can show myocyte hypertrophy, disorganization, or disarray and
205interstitial fibrosis or adiposity, similar to the features of hypertrophic cardiomyopathy ( Fig. 2-53). I n addition, focal myocyte
204vacuolization, thick-walled arteries, and dilated venules have been noted. A lternatively, they can be rather bland appearing with
low cellularity and liEle to no atypia. I n the case of the laEer, this resemblance to normal myocardium can be a source of diagnostic
discordance between pathologist and surgeon, particularly on frozen section. I n these instances, the abrupt change in fascicular
arrangement (best appreciated at low power) can be a clue to the diagnosis. A s mentioned above, the similarity to hypertrophic
cardiomyopathy can also cause diagnostic confusion, particularly on endomyocardial biopsy (Fig. 2-54); however, the diagnosis of
hypertrophic cardiomyopathy should rarely (if ever) be made on endomyocardial biopsy.
FIGURE 2-53 Hamartoma of adult cardiac myocytes (A). The microscopic features of this tumor may be almost
identical to hypertrophic cardiomyopathy and (B) characterized by myocyte disarray in a herringbone pattern and
marked nuclear enlargement and hyperchromasia.FIGURE 2-54 Hamartoma of adult cardiac myocytes on endomyocardial biopsy.
Differential Diagnosis
Once the hypertrophied myocardium is recognized as representing a mass, the main histologic mimic is rhabdomyoma, a tumor
composed of vacuolated immature “spider cell” myocytes as opposed to mature hypertrophied muscle cells. A dditionally,
rhabdomyoma, particularly when multiple, occurs in the seEing of tuberous sclerosis. HA CM must be distinguished from
hypertrophic cardiomyopathy, which can show asymmetric involvement of the ventricles (particularly the septum). A lthough HA CM
usually presents as a focal mass lesion, only the uncommon apical variant of hypertrophic cardiomyopathy presents in a similar
Paraganglioma (Extraadrenal Pheochromocytoma)
Clinical Features
These tumors originate from chromaffin paraganglia localized at the base of the heart, in close association with the aortic and
206-208pulmonary trunks. Most patients are young adults. The clinical presentation is usually dominated by signs and symptoms of
excessive norepinephrine secretion, with hypertension as the principal sign, although the clinical manifestations may be rather
Gross Pathology
Cardiac paragangliomas are usually positioned intraepicardially, with a preference for the epicardial surface of the left atrial
inferoposterior wall, the interatrial groove, and the root of the great arteries, but they may occur in other locations, such as the
proximal parts of either the right or the left coronary artery. They may also protrude into the atrial cavities from a primary location
214within the interatrial groove. I n the laEer position these tumors may mimic an atrial myxoma on two-dimensional
echocardiography. A s with paragangliomas elsewhere, they are typically homogeneous and brown (Fig. 2-55) and generally range in
215size from 3 to 8 cm.
FIGURE 2-55 Cardiac paraganglioma with characteristic brown hue.
The tumors show the characteristic paEern of a paraganglioma, composed mainly of so-called chief cells, grouped together in cell
clusters or “Zellballen” surrounded by a capillary network with varying amounts of connective tissue (Fig. 2-56; see also Chapter 28).
If necessary, immunohistochemistry can be used to demonstrate neuroendocrine differentiation or the presence of sustentacular cells.FIGURE 2-56 Cardiac paraganglioma with classic “Zellballen” architecture.
Calcified Amorphous Tumor
Clinical Features
A lthough the pathogenesis of this entity is not well understood, calcified amorphous tumor (CAT) is clinically important because it
may raise suspicion for malignancy. A s bulky intracavitary masses with calcification evident on imaging studies, these are often
mistaken for osteosarcoma or calcified myxoma. The histopathology, fortunately, is straightforward and entirely benign, characterized
by degenerating fibrin debris and dystrophic calcification without significant cellularity or atypia. The initiating factors leading to
fibrin aggregation, as well as the reason for this thrombotic material to “mummify” and undergo dystrophic calcification rather than
the usual process of involution through organization, are not clear.
The lesions have been described in adolescents and adults from 16 to 75 years (mean 52 years) and are more common in women.
216Their behavior is benign, though one patient had a recurrence develop at the site of resection 29 months later and two patients
217have had residual calcium at the site of the original mass but no symptoms.
Gross Pathology
CATs have been identified in all cardiac chambers and have also occurred on the mitral valve. They can reach a size of up to 9 cm in
217greatest dimension (a right atrial CAT with extension along a central line in a patient receiving total parenteral nutrition). They
consist of conglomerated red-brown dry thrombus-like material with a tendency to crumble and fall apart. Chalky (Fig. 2-57) and
focally mineralized calcification is typically present in the center, and decalcification may be necessary before processing.
FIGURE 2-57 Calcified amorphous tumor. A, Tissue fragments showing an endocardial mass-forming lesion with
white fibrous areas, chalky calcifications, and central red-brown degenerating thrombus. B, The distribution and
variable density of the calcifications are highlighted by radiographic examination. (From Miller D V, Tazelaar H D
2010 Cardiovascular pseudoneoplasms. Arch Pathol Lab Med 134: 362-368)
The calcified amorphous tumor is remarkably similar from case to case. The lesions are composed predominantly of what appears to
be degenerating fibrin with variable, usually central, nodular calcium deposits (Figs. 2-58 and 2-59). Osseous metaplasia has been217described rarely (Fig. 2-60). Mild to moderate chronic inflammation, especially near the base of the lesion, may be seen.
Organization (proliferating fibroblasts, capillaries, and loose myxoid extracellular matrix) is conspicuously absent. Hemosiderin
deposition and cholesterol clefts are rarely seen. A majority of cases (60%) show fresh fibrin on the surface—a potential source of
FIGURE 2-58 Calcified amorphous tumor. Calcifications suspended in degenerating fibrin and surrounded by
fibroblasts and loose collagen.
FIGURE 2-59 Calcified amorphous tumor. Calcification and fibrin. Note lack of neovascularity.
FIGURE 2-60 Calcified amorphous tumor with osseous metaplasia.
Differential Diagnosis
They are distinct from ordinary mural thrombi in that they lack significant fibroblastic proliferation and organization. A lthough
sometimes confused with myxomas, they lack both myxoma cells and myxoid stroma.
Mesothelial/Monocytic Incidental Cardiac Excrescences (MICE)—Lesion of Aggregated Monocytes and
Mesothelial Cells (LAMM)
Clinical Features
This pseudoneoplasm was originally reported as an unusual cardiac lesion resembling “histiocytoid (epithelioid) hemangioma” but
218also demonstrating mesothelial differentiation. Two additional reports confirmed the presence of mesothelial cells in these lesions
219,220but regarded the lesions as pseudoneoplasms with an artifactual (iatrogenic) genesis. The term MI CE was proposed and the
theory put forward that they formed through aggregation of histiocytes, mesothelial cells, and fibrin, similar to the means used in
preparing cell blocks from cytologic fluid specimens. I n the body, this process may be initiated by suction catheter tips and other
surgical and endoluminal instruments but also may occur spontaneously when a mesothelial-lined space is entered or opened. Cases
originally diagnosed as “chemoreceptor tissue” and “metastatic adenocarcinoma” have since been shown to be MI CE, and thus it is
221clear that these lesions caused at least some confusion to experienced pathologists and continued to be the subject of case
222reports. MI CE have been identified in cardiac chambers, on cardiac valves, in the pericardial space, and in the ascending aorta,
mediastinum, and pleural space. They have also been reported in microscopic sections of endomyocardial and transbronchial biopsies223-226and have been identified incidentally in specimens submiEed as lymph nodes during sampling for lung cancer staging. MI CE
are usually identified incidentally (rather than being the reason for a procedure) and are often described as being “free-floating” by
the surgeon, sometimes a clue to diagnosis.
226The term nodular histiocytic/mesothelial hyperplasia has been proposed for these lesions. However, this implies a capacity to grow
via a supporting stroma and blood supply, neither of which has been demonstrated. A lthough the mesothelial clusters and strips may
appear hyperplastic, MI CE are different from mesothelial hyperplasia. LA MM has been suggested as an alternative terminology for
lesions occurring outside of the heart (where MI CE is a misnomer), a term that also aptly describes these lesions. Their significance
lies not so much in what they are called but in what they are not called, for example, metastatic adenocarcinoma. However, one report
227has been made of metastatic adenocarcinoma involving a cardiac MICE in a patient with known adenocarcinoma.
They have been reported in patients from 5 to 76 years of age and appear to have no gender predilection.
Gross Pathology
MI CE vary from gray-white to dark red to brown and are frequently associated with obvious thrombus (Fig. 2-61). They are usually
discrete and distinct from other tissue submiEed (e.g., valves, myocardial biopsies, portions of the aorta). The lesions range in size
from microscopic up to 3 cm.
FIGURE 2-61 Mesothelial/monocytic incidental cardiac excrescence removed from left atrium at the time of valve
replacement. Note attached red-brown thrombus.
They are composed of two predominant cell types (Fig. 2-62), a histiocytoid cell (round to oval with pink cytoplasm, well-defined
nuclei with prominent nuclear grooves and occasional nucleoli) and a taller columnar or cuboidal cell. The cuboidal cells are usually
present in small groups, strips, or tubular arrangements and have smaller amounts of eosinophilic cytoplasm and small round nuclei
with inconspicuous nucleoli. I nflammatory cells (neutrophils, occasional lymphocytes, and eosinophils), adipocyte-like vacuoles, and
218,220foreign material can also be seen within MICE. The lesions lack blood vessels or capillaries and have no supporting stroma.
FIGURE 2-62 Mesothelial/monocytic incidental cardiac excrescence. Note strip of epithelial cells (mesothelial
cells), fibrin, and histiocytes admixed with spaces (probably representing fat dissolved in processing).
The histiocytoid cells are positive for CD 68 (Fig. 2-63) and lysozyme and, ultrastructurally, have features typical of histiocytes with
convoluted nuclei, prominent nucleoli, cytoplasm rich in reticulin, and surface pseudopodia. The cuboidal cells react with antibodies
to keratin, calretinin, and cytokeratin (CK) 5/6, (Fig. 2-64) but are negative for CEA , CD 15, factor VI I I –related antigen, CD 31, CD 68,
and lysozyme. Mesothelial cell features are seen by electron microscopy, including haphazardly arranged intermediate filaments and
surface microvilli with well-developed desmosomes.FIGURE 2-63 Mesothelial/monocytic incidental cardiac excrescence. CD68 stains the histiocytes but not
mesothelial cells.
FIGURE 2-64 Mesothelial/monocytic incidental cardiac excrescence. Cytokeratin 5/6 stains the mesothelial cells
but not the histiocytes.
Differential Diagnosis
A s noted above, MI CE have been diagnosed as many entities. Knowledge of this entity usually leads to prompt accurate diagnosis.
Distinction from metastatic adenocarcinoma can be approached as one would differentiate mesothelioma from adenocarcinoma in the
227pleura or elsewhere, with such stains as CEA , MOC31, and Ber-EP4. A s noted earlier, metastatic adenocarcinoma has also been
identified in one of these lesions. Nodular mesothelial hyperplasia has a supporting stroma (Fig. 2-65).
FIGURE 2-65 Nodular mesothelial hyperplasia. In contrast to mesothelial/monocytic incidental cardiac
excrescence, note the presence of a supporting stroma containing capillaries.
Additional Benign Tumors and Heterotopias
S everal other benign tumors and some heterotopias that generally occur in other parts of the body have been reported in the heart
228-235and are shown in Table 2-6. The reader is referred to other chapters for discussion.
O ther B enign T umors and H eterotopias R eported in the H eartAdenomatoid tumor228
Granular cell tumor
Inflammatory myofibroblastic tumor229
Tumor of perivascular epithelioid cells (PEComa)230
Thymic rests231
Thyroid rests232
Malignant Tumors of the Heart and Pericardium
Primary malignant cardiac tumors are much less common than benign neoplasms and pseudoneoplasms. Most represent soft tissue
236sarcomas and lymphomas described elsewhere in this book. A mong the sarcomas, most are high grade. This section will highlight
important features of the most common primary sarcomas and specific features of their involvement in the heart including
differential diagnosis. Table 2-7 includes a more complete list of sarcomas and other malignancies (including mimics) reported to
41,166,237-240involve the heart.
L ess C ommon P rimary C ardiac S arcomas, M alignancies, and M imics
Synovial sarcoma41
Fibrosarcoma, including myxofibrosarcoma (likely representing previous cases reported as myxosarcoma237
Malignant peripheral nerve sheath tumor41,166
Malignant germ cell tumors41,166
Erdheim-Chester disease238,239
Sinus histiocytosis with massive lymphadenopathy240
Clinical Features
A ngiosarcoma is probably the most common primary malignant cardiac tumor, although referral bias is a significant problem with
241-244such rare tumors. Two main forms of clinical presentation exist; more common is presentation as a large obstructing mass with
associated clinical signs and symptoms such as heart failure and dyspnea. Less common and less symptomatic is presentation as a
245locally infiltrative tumor. Pericardial lesions simulate pericarditis and may present with cardiac tamponade. Presentation with
246,247hemorrhagic lung metastases is not uncommon.
The mean age at presentation is approximately 40 years, but a broad range exists, from 10 to 76 years. The natural history is usually
reflected in a short clinical course, with most patients being dead of their disease within 10 months of the onset of symptoms. The
cause of death almost always relates directly to cardiac effects of the tumor, such as cardiac tamponade or intracavitary obstruction.
Cardiac rupture may occur but is rare. However, multimodality therapy has made an impact on the dismal prognosis with more
236,248-250patients living longer with their disease and possibly with some apparent cures.
251 243The diagnosis can be made on endomyocardial biopsy, surgical biopsy specimens, or pericardial fluid cytology. S ometimes,
early pericardial involvement may lead to pericardial biopsy during emergency surgical cardiac decompression for tamponade.
Gross Pathology
A ngiosarcoma most commonly arises from the right atrium near the AV groove (80%) but may also arise from any of the other three
41,237chambers or the pericardium. Given the bulky nature of the tumors, involvement of more than one chamber is also common. I t
typically forms a lobulated variegated mass in the right atrial wall (Fig. 2-66), protruding into the chamber. A ngiosarcomas typically
range from 2 to 10 cm in size. The masses are classically dark, gray-brown to black, and may resemble a melanoma, but tumors with
less well-developed vascular spaces may appear firm, yellow-white. A hemorrhagic pericardial effusion may be present. A lthough
involvement of the tricuspid valve and extension into or invasion of the venae cavae may occur, involvement of the pulmonary artery
and interatrial septum is unusual.FIGURE 2-66 Angiosarcoma arising from the right side of the heart with a bloody pericardial effusion.
Most cardiac angiosarcomas are well to moderately differentiated showing easily recognized irregular, anastomosing, and sinusoidal
vascular channels (Fig. 2-67) with or without papillae, although histologic grade is not prognostic. The lining cells are usually
pleomorphic and atypical. Mitoses are usually identifiable. S ome are very poorly differentiated and composed only of anaplastic
spindle or epithelioid cells (Fig. 2-68). I n angiosarcoma with a focal or dominant spindle cell paEern, poorly formed vascular channels
and extravascular red blood cells can usually be identified focally. Generous sampling may be necessary to identify diagnostic areas in
such cases. Diagnosis by endomyocardial biopsy is possible (Fig. 2-69).
FIGURE 2-67 Angiosarcoma of the right atrium characterized by large sinusoidal spaces lined by atypical
endothelial cells.
FIGURE 2-68 Angiosarcoma of the right atrium with solid or high-grade spindle cell morphology.FIGURE 2-69 Angiosarcoma involving right ventricle diagnosed by endomyocardial biopsy. The tumor was
composed of spindle cells (A), which express CD31 (B).
I mmunohistochemical staining is an important adjunct for the definitive diagnosis, especially those that are predominantly spindle
cell in nature. Most angiosarcomas express, to variable degrees, usual endothelial cell antigens including factor VI I I (von Willebrand
factor), CD 31, Fli-1, and CD 34. Of these, CD 31 is the most consistently positive (seFe ig. 2-69, B). Experience with Fli-1 in cardiac
angiosarcomas is limited. Cytokeratin and epithelial membrane antigen may be focally positive in conventional angiosarcoma and
may be diffusely positive in epithelioid angiosarcomas.
Differential Diagnosis
The differential diagnosis of angiosarcoma includes lower-grade vascular sarcomas such as epithelioid hemangioendothelioma, other
primary cardiac sarcomas such as synovial sarcoma and leiomyosarcoma, and, when occurring with prominent pericardial
involvement, mesothelioma. Immunoperoxidase studies will usually be helpful in arriving at the correct diagnosis.
Undifferentiated High-Grade Pleomorphic Sarcoma
Clinical Features
Combining tumors previously classified as malignant fibrous histiocytomas and undifferentiated sarcomas into this group makes
252,253undifferentiated high-grade pleomorphic sarcoma the second most common cardiac sarcoma. Cases previously classified as
254myxosarcoma are probably best classified as myxofibrosarcoma.
47The average age of patients, approximately 36 years, is younger than the usual age of presentation of undifferentiated high-grade
pleomorphic sarcoma of soft tissues.
Gross Pathology
The vast majority of undifferentiated high-grade pleomorphic sarcomas arise from the posterior wall or septum of the left atrium (Fig.
2-70), although they have been reported to arise in the walls of all chambers and the pericardium and also apparently from
237,252 255-257valves. Because of its predilection for the left atrium the tumor may easily be mistaken clinically for an atrial myxoma.
256Multiple tumors can be encountered.FIGURE 2-70 Undifferentiated high-grade pleomorphic sarcoma replacing much of the heart such that chambers
are virtually unrecognizable.
These tumors are described more fully in Chapter 24. I n brief, this lesion contains foci of hypercellularity with pleomorphism, mitotic
figures, necrosis, and extensive vascularity and lacks any of the characteristic features of a cardiac myxoma (other than the
257myxomatous matrix). I t is only because these tumors were “cardiac and myxomatous” that otherwise experienced pathologists
255,258,259have been led astray.
Differential Diagnosis
I n the heart, the main distinction is from cardiac myxoma, which typically lacks the striking cytologic atypia noted in undifferentiated
pleomorphic sarcoma. A dditionally, the high mitotic rate seen in pleomorphic sarcoma can be of further help in discriminating this
entity from that of cardiac myxoma.
Clinical Features
41,166,260Rhabdomyosarcoma is the most common primary cardiac malignancy in children and is usually of the embryonal variant. I t
also occurs in adults, however, and the mean age at presentation is approximately 20 years, compared with 40 to 50 years of age for
other cardiac sarcomas. Rhabdomyosarcoma is more likely than other primary cardiac sarcomas to involve the valves.
Gross Pathology
Rhabdomyosarcomas occur anywhere in the heart with equal frequency in the atria and ventricles. A dditionally, in contrast to many
other sarcomas, they are not usually endocardial and intracavitary but arise murally. Cardiac rhabdomyosarcomas are bulky (often
larger than 10 cm), invasive tumors that may be grossly mucoid or gelatinous, similar to a myxoma, or soft and necrotic, with
Cardiac rhabdomyosarcomas are almost exclusively embryonal (Fig. 2-71). Embryonal rhabdomyosarcoma is a small cell neoplasm
with variable numbers of eosinophilic rhabdomyoblasts (tadpole or strap cells). Well-differentiated embryonal rhabdomyosarcoma
has numerous tadpole-shaped rhabdomyoblasts. S arcoma botryoides, with characteristic exophytic grape-like structures and a
socalled cambium layer, a form of embryonal rhabdomyosarcoma, has also been described in the heart. Pleomorphic
rhabdomyosarcoma also occurs in the heart. When alveolar rhabdomyosarcoma involves the heart, it is usually as a metastatic lesion.
FIGURE 2-71 Embryonal rhabdomyosarcoma from the right atrium of a 42-year-old woman.
N uclear staining with antibodies against myogenin greatly facilitates the diagnosis. D esmin is also useful in documenting muscular
Differential Diagnosis
D espite similarity in names, the clinical presentation and morphology of the rhabdomyoma are very different and should not present
a diagnostic dilemma. The differential diagnosis includes other cardiac sarcomas, especially undifferentiated sarcomas and metastatic
small round cell tumors. I mmunohistochemical stains are vital to making an accurate diagnosis. A dult cellular rhabdomyomas lack
260-262significant mitotic activity and necrosis and do not express myogenin.Leiomyosarcoma
Clinical Features
237,263N o gender predilection exists, and most lesions occur in patients between 40 and 50 years of age. Most of them arise in the
264posterior left atrial wall and may invade pulmonary veins or the mitral valve. D espite this fact, they are often thought to represent
myxomas (which arise most commonly near the fossa ovalis), and it is frequently the pathologist who is the first to suggest that the
tumor is not a myxoma.
Gross Pathology
The tumors tend to be firm, fleshy, gray, and sessile. They may present as multiple intracavitary nodules.
Leiomyosarcoma is composed of compact bundles of spindle cells that possess blunt-ended nuclei and are often oriented at a sharp
265angle or 90 degrees to one another. Epithelioid (Fig. 2-72), pleomorphic, and giant cells may be present. Zones of necrosis and
mitotic figures are generally plentiful. A ntibodies to smooth muscle α -actin and desmin are usually reactive with the tumor cells.
Aberrant expression of cytokeratin and epithelial membrane antigen may occasionally occur.
FIGURE 2-72 Epithelioid leiomyosarcoma of the left atrium.
Differential Diagnosis
Because of frequent location in the left atrium, cardiac myxoma is often considered in the differential diagnosis. Careful aEention to
the site of origin (atrial septum near the fossa ovalis for myxomas and posterior wall for leiomyosarcoma) may help in arriving at the
265correct diagnosis. Additionally, as stated previously, mitotic activity and necrosis are extraordinarily rare in myxomas.
266Primary cardiac malignant mesothelioma accounts for fewer than 5% of mesotheliomas diagnosed (Fig. 2-73). Most pericardial
41,166,266-268involvement by mesothelioma represents secondary involvement in association with pleural disease. A lthough dyspnea
and pericardial effusion are often the leading clinical findings, the possibility of metastatic disease is much more likely than primary
pericardial mesothelioma. The differential diagnosis in such circumstances will rely heavily on exfoliative cytology and tissue biopsy
studies. A correct diagnosis will usually be established by those means, but the diversity in cell forms and histologic paEerns (Fig.
274) may occasionally hamper the differentiation between malignant mesothelioma and metastatic deposits. However, the diagnosis of
mesothelioma at a primary pericardial location is not different from that in other sites in the body (see Chapter 5).
FIGURE 2-73 Pericardial mesothelioma with visceral and parietal involvement and intracavitary growth.FIGURE 2-74 Pericardial mesothelioma with sarcomatous features.
Primary Cardiac Lymphoma
Clinical Features
Lymphoma may present in the heart or involve the heart late in the course of systemic disease. Primary cardiac tumors account for
269-271only 0.5% of extranodal lymphomas. I t may occur in immunocompetent hosts but has also been reported in patients with solid
organ transplants, as well as patients positive for human immunodeficiency virus. The median age of the reported cases is 62 years
(range 5-90 years) with a male-to-female ratio of 3  :  1. D iagnosis may be made by surgical biopsy, endomyocardial biopsy, or
271,272pericardial fluid sampling.
Cardiac involvement as part of disseminated malignant lymphoma, late in the course of the disease, appears to be rather common
273and has been observed in almost 20% of autopsied patients with lymphoma.
Gross Pathology
Primary lymphoma usually arises in right-sided chambers (Fig. 2-75). Left-sided involvement is exceedingly rare. Usually the tumor is
large, infiltrating myocardium and extending into the chambers in the form of multiple intracavitary polypoid nodules, which may
eventually obliterate the cavities. The pericardium is usually thickened and gray-white.
FIGURE 2-75 Large cell lymphoma forming a large polypoid mass in the right ventricle.
The histopathologic diagnosis is based on the same criteria as applied to lymphomas in general (see Chapter 21). D iffuse large B-cell
271lymphoma is the subtype most frequently observed (in nearly 80% of published cases), although most lymphomas have been
274 271described to arise in the heart, including peripheral T-cell and BurkiE lymphoma. D iagnosis on endomyocardial biopsy is
possible (Fig. 2-76).
FIGURE 2-76 Large B-cell lymphoma (cells reactive with antibodies to CD20) diagnosed by endomyocardial
biopsy. Abundant necrosis exists beneath the endocardial band of tumor cells.
Differential DiagnosisI n the nonimmunocompromised population, the differential diagnosis includes other inflammatory myocardial conditions, such as
idiopathic lymphocytic myocarditis, vasculitis, or drug reaction. A lthough knowing whether a mass lesion is being biopsied is helpful,
some lymphomas do not present with a discrete mass. Cytologic features may be helpful in suggesting that the cells are malignant,
but immunohistochemistry and other ancillary techniques may well be necessary for accurate classification. I n the
immunocompromised patient, testing for Epstein-Barr virus may be helpful for the diagnosis of posEransplant lymphoproliferative
disorders. I n heart transplant recipients the differential diagnosis includes not only rejection but the Quilty lesion. Both of these,
however, lack an association with Epstein-Barr virus, and therefore in situ hybridization studies are usually helpful in distinguishing
between these entities and posttransplant lymphoproliferative disorders.
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C H A P T E R 3
Vascular Tumors
J. Eduardo Calonje, Christopher D.M. Fletcher
Reactive Vascular Proliferations 42
Vascular Ectasias 45
Capillary Hemangioma 46
Cavernous Hemangioma 50
Arteriovenous Hemangioma 51
Microvenular Hemangioma 52
Hobnail Hemangioma (Targetoid Hemosiderotic Hemangioma) 52
Acquired Elastotic Hemangioma 53
Epithelioid Angiomatous Nodule 53
Epithelioid Hemangioma (Angiolymphoid Hyperplasia with Eosinophilia) 54
Venous Hemangioma 55
Spindle Cell Hemangioma (Formerly Spindle Cell Hemangioendothelioma) 55
Symplastic Hemangioma 56
Deep Hemangiomas 57
Angiomatosis 58
Kaposiform Hemangioendothelioma 59
Giant Cell Angioblastoma 60
Retiform Hemangioendothelioma 60
Papillary Intralymphatic Angioendothelioma (PILA) (Endovascular Papillary Angioendothelioma,
Dabska Tumor) 60
Pseudomyogenic Hemangioendothelioma 61
Composite Hemangioendothelioma 62
Polymorphous Hemangioendothelioma 62
Kaposi Sarcoma 62
Epithelioid Hemangioendothelioma 66
Angiosarcoma 68
“Intimal” Sarcomas 71
Cavernous Lymphangioma and Cystic Hygroma 72
Lymphangioma Circumscriptum 72
Benign Lymphangioendothelioma (Acquired Progressive Lymphangioma) 73
Lymphangiomatosis 74
Lymphangiomyomatosis 75
Glomus Tumor 75
Hemangiopericytoma (So-Called), Including Myopericytoma 77
Few groups of tumors can show such a broad spectrum of morphologic appearances and clinical behavior as vascular
tumors. Classification is a problem, not only because the line between neoplasia and malformation (or so-called hamartoma)
remains undefined but also, and more important, because it is frequently difficult to distinguish benign from malignant
lesions. It is interesting that, in comparison with other soft tissue tumors (see Chapter 24), cytogenetic and molecular genetic
analysis, as yet, has provided very li le useful information in vascular lesions, principally because these tumors are very
hard to grow or maintain in culture and also because available material is often inextricably admixed with nonneoplastic
tissue components. In this chapter, an updated classification of vascular tumors is used, including recently described entities
and reclassification of some be er-known entities in the light of recent developments in the understanding of their biology
(Table 3-1). Emphasis is placed on lesions presenting in soft tissue and skin as vascular tumors are more common in these
locations. Distinctive vascular tumors in other organs are dealt with in the appropriate chapters.
C lassification of V ascular T umorsBlood Vessels
Benign Tumors and Tumor-like Conditions
Reactive vascular proliferations
Papillary endothelial hyperplasia (Masson tumor)
Reactive angioendotheliomatosis
Glomeruloid hemangioma
Papillary hemangioma
Bacillary angiomatosis
Vascular ectasias
Nevus flammeus (salmon patch, port-wine stain)
Nevus araneus
Venous lake
Angioma serpiginosum
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu)
Capillary hemangioma (including congenital hemangiomas)
Variants: Tufted angioma
Verrucous hemangioma
Cherry angioma
Lobular hemangioma (pyogenic granuloma)
Cavernous hemangioma
Variant: Sinusoidal hemangioma
Arteriovenous hemangioma
Variants: Superficial (cirsoid aneurysm)
Microvenular hemangioma
Hobnail (“targetoid hemosiderotic”) hemangioma
Acquired elastotic hemangioma
Cutaneous epithelioid angiomatous nodule
Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia)
Venous hemangioma
Spindle cell hemangioma (“hemangioendothelioma”)
Symplastic hemangioma
Deep hemangiomas
Variants: Intramuscular
Intermediate Vascular Tumors
Locally aggressive
Kaposi-like hemangioendothelioma
Giant cell angioblastoma
Rarely metastasizing
Retiform hemangioendothelioma
Malignant endovascular papillary angioendothelioma (Dabska tumor)
Pseudomyogenic hemangioendothelioma
Composite hemangioendothelioma
Polymorphous hemangioendothelioma
Kaposi sarcoma
Malignant Vascular Tumors
Epithelioid hemangioendothelioma
Variants: Idiopathic (head and neck)
Associated with lymphedema (“lymphangiosarcoma”)
Soft tissue$
“Intimal” sarcomas
Lymph Vessels
Variants: Lymphangioma circumscriptum
Cavernous lymphangioma/cystic hygroma
Benign lymphangioendothelioma (acquired progressive lymphangioma)
Multifocal lymphangiomatosis with thrombocytopenia
Tumors of Perivascular Cells
Glomus tumor
Variant: Infiltrating glomus tumor
“Hemangiopericytoma,” so called
Benign Tumors
Reactive Vascular Proliferations
Intravascular Papillary Endothelial Hyperplasia (Masson Tumor)
Clinical Features
1-5I ntravascular papillary endothelial hyperplasia is a relatively common reactive condition representing an unusual form of
organizing thrombus. I t presents in three different se ings: (1) as a pure form involving an isolated dilated blood vessel
(primary); (2) as a focal change in a variety of preexisting vascular lesions including hemangiomas, hemorrhoidal veins, and
5varices (secondary); and, rarely, (3) in an extravascular location in association with a hematoma. Trauma does not appear to
be related consistently to any of these forms. I n the primary type the lesion typically presents as an asymptomatic bluish
nodule in the finger or head and neck region of young adults; no sex predilection is seen. Presentation in the breast has also
6been described, and, in this se ing, distinction from angiosarcoma may be difficult. The phenomenon can also be seen in
internal organs, mainly the upper respiratory and gastrointestinal tracts, but it is rare. Lesions are generally less than 2 cm in
diameter, and, after excision, recurrence is rare. Multiple lesions are uncommon and have been exceptionally described in
7,8association after treatment with interferon-β. When papillary endothelial hyperplasia arises in a preexisting vascular
lesion, clinical findings are related to the primary vascular abnormality and lesions tend to be larger. These secondary
lesions theoretically can present in any vascular tumor and in any anatomic site but are particularly common in association
with deep-seated hemangiomas, especially of the cavernous type.
Histologic Appearances
Primary forms appear as well-circumscribed hemorrhagic lesions, which on closer examination reveal a preexisting dilated
vascular space, most commonly a thin-walled vein. The appearances of secondary cases depend on the nature of the
preexisting primary lesion. I n extravascular lesions no obvious vascular structure is identified even after serial sectioning.
A ll forms are typified by the presence of multiple small papillary structures, covered by a single layer of a enuated
endothelial cells showing li le or no atypia (Fig. 3-1). Mitoses are usually absent. The papillary core is composed of
hypocellular, hyaline collagen with occasional small capillaries. I n the earliest lesions, papillae appear to be composed of
fibrin. A lthough most papillae seem to be lying free in the vascular lumina, some of them appear to be a ached to the
vascular wall. N umerous red blood cells surround the papillae, and usually associated thrombus is seen, which may be
organized to a variable degree; at the edge of the thrombus one may identify the early stages of the formation of fibrinoid
FIGURE 3-1 Masson tumor. Note the typically hyaline papillae and adjacent thrombus.
Differential Diagnosis
Well-differentiated angiosarcoma occurs in a different clinical se ing and is generally an extravascular process characterized
by an infiltrative or dissecting growth pa ern, moderate to prominent cytologic atypia, endothelial multilayering, and
mitotic activity.
Reactive Angioendotheliomatosis
Clinical Features
Until the early 1980s, angioendotheliomatosis was traditionally classified into malignant and benign variants, which were
thought, in some cases, to be difficult to separate from each other on clinical and histologic grounds. However, it became
clear that the malignant variant is a systemic angiotrophic lymphoma (associated with a poor prognosis; see Chapter 21), not
9,10related at all to the reactive variant that is truly endothelial, self-limiting, and generally confined to the skin. Clinically,
reactive angioendotheliomatosis is a very rare condition that presents as erythematous macules, papules, or plaques, which
can be associated with petechiae and ecchymoses and more rarely with a livedo-like pa ern. I t has no age predilection, and
11most cases occur in adults, children being only exceptionally affected. I t can be idiopathic or associated with a wide range
of systemic diseases including paraproteinemia, renal disease, amyloidosis, antiphospholipid syndrome, rheumatoid
arthritis, cirrhosis, polymyalgia rheumatica, sarcoidosis, myelodysplastic syndrome, and a well-differentiated angiosarcoma,
10,12-18although the latter may have been coincidental. However, the association with systemic disease, particularly bacterial
endocarditis, is not as strong as previously believed. A variant of reactive angioendotheliomatosis has been described as
19angiomatosis with luminal cryoprotein deposition in patients with cryoglobulinemia. The clinicopathologic spectrum of
the disease has recently been expanded to include rare localized forms of the disease, including a variant associated with
peripheral vascular atherosclerotic disease and iatrogenic arteriovenous fistulas, described as diffuse dermal
20-23angiomatosis. Recently, the la er was described in the breast of two female patients with pendulous breasts, one of
24whom had immunoglobulin M anticardiolipin and antinuclear antibodies. These lesions might be a consequence of
Histologic Appearances
10The histology is variable. I n the dermis and superficial subcutis multiple clusters of closely packed capillaries are often
seen (Fig. 3-2) lined by larger than normal endothelial cells, which show no cytologic atypia and are surrounded by pericytes.
Many cases have a rather lobular architecture. These endothelial cells may occlude the vascular lumina, but no multilayering
exists. Focal extravasation of red blood cells and occasional fibrin thrombi are also seen. Adjacent dermis shows mild chronic
inflammation, sometimes associated with fasciitis-like changes. I n angiomatosis with luminal cryoprotein deposition, many
capillaries appear occluded by refractile eosinophilic thrombi. I n diffuse dermal angiomatosis, proliferation of poorly
canalized capillaries is seen.$
FIGURE 3-2 Reactive angioendotheliomatosis. Note the irregular clusters of closely packed variably
canalized capillaries in the dermis.
Glomeruloid Hemangioma
Glomeruloid hemangioma is a distinctive reactive vascular proliferation that occurs in patients with multicentric Castleman
25-28disease and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes). Clinically,
patients present with numerous cutaneous angiomas, which on histologic examination can show features of cherry angioma
or, less frequently, those of glomeruloid hemangioma. The cutaneous angiomas can be the first manifestation of the disease.
Histologically, multiple dilated vascular spaces are seen, especially in the superficial dermis, and these contain in their
lumina clusters of capillaries with a striking resemblance to renal glomeruli (Fig. 3-3). A round the capillaries are pericytes
and larger cells with clear cytoplasm and occasional periodic acid–S chiff (PA S )–positive hyaline globules, probably
representing deposits of immunoglobulin. However, by electron microscopy the inclusions appear to represent enlarged
29secondary lysosomes (thanatosomes). These large cells are positive for endothelial markers. Human herpesvirus 8 (HHV-8)
30has not been detected in lesions of glomeruloid hemangioma. S olitary lesions with histologic features of glomeruloid
31-33hemangioma have been documented. These lesions may be related to the recently described papillary hemangioma (see
later discussion).
FIGURE 3-3 Glomeruloid hemangioma. Capillary lobules protrude into preexisting vessels. Note the
eosinophilic droplets.
Papillary Hemangioma
Papillary hemangioma is a recently described cutaneous vascular lesion that presents as a long-standing papule on the head
34and neck of adults, with predilection for men. Local recurrence is exceptional. Histologically it is characterized by dermal
dilated, thin-walled vascular spaces with papillary projections containing pericytes and thick basement membrane–like
material and lined by plump nonatypical endothelial cells. The la er contain numerous cytoplasmic eosinophilic globules. I t
has been suggested that these lesions represent a variant of solitary glomeruloid hemangioma and that the inclusions as in
29the la er represent giant lysosomes with cellular debris and fat vacuoles (thanatosomes). Papillary hemangioma, however,
lacks a glomeruloid architecture and contains thick basement membrane–like material and pericytes in the papillary
Vascular Ectasias
36-38A s opposed to true hemangiomas, vascular ectasias do not show an increase in the number of blood vessels, but rather
they are composed of dilated preexisting normal blood vessels. However, some vascular ectasias may be associated with an$
39underlying cavernous hemangioma or arteriovenous malformation. Vascular ectasias include nevus flammeus (port-wine
stain and salmon patch), spider nevus (nevus araneus), venous lakes, angioma serpiginosum, and angiokeratomas.
Nevus Flammeus
N evus flammeus includes salmon patch and port-wine stain. Both lesions are also known as the common birthmark and may
40occur in as many as 50% of infants. The salmon patch is characterized by a red-pink macule, located in the head and neck
area, which tends to involute with time. I n a study of cutaneous findings in hospitalized neonates, a salmon patch was found
41in 91.2% of patients. By contrast, the port-wine stain shows progressive growth with no tendency to regress and can
acquire an elevated surface. Most lesions are congenital, but rare acquired cases have been documented, including a case
42 43,44presenting after trauma. Familial cases also occur, and in such cases the gene has been mapped to chromosome 5q.
Port-wine stains may be associated with vascular malformations of the meninges, brain, or retina in S turge-Weber syndrome
and with limb hypertrophy, varicosities, and partial venous agenesis in Klippel-Trénaunay syndrome. I f the la er is
associated with an arteriovenous fistula, it is known as Parkes Weber syndrome. Other vascular lesions, particularly
45-47pyogenic granuloma and, exceptionally, tufted angioma, may occur within a port-wine stain. Histologically, both
conditions show ectatic dermal blood vessels of differing size (Fig. 3-4), with usually deeper subcutaneous involvement in
the port-wine stain.
FIGURE 3-4 Port-wine stain. Dilated thin-walled vessels are evenly distributed in the upper dermis.
Nevus Araneus (Spider Nevus)
S pider nevi are very common acquired lesions. They present over a wide age range as tiny, red, pinhead papules from which
tortuous blood vessels radiate. They are commonly associated with pregnancy, chronic liver disease, and hyperthyroidism.
Typical histologic findings are the presence of a thick-walled, dilated arteriole in the superficial dermis communicating with
several anastomosing capillaries.
Venous Lake
48Venous lakes are common vascular ectasias that occur in elderly people; sun-exposed areas are affected, especially the face,
with predilection for the lips and ears. Histologically, a markedly dilated and congested vein is seen in the superficial dermis
and is surrounded by an irregular layer of smooth muscle.
Angioma Serpiginosum
49-51A ngioma serpiginosum is an uncommon, slowly progressive lesion that mainly affects the lower limbs of children,
especially girls. I t presents as tiny punctate red-purple papules in a gyrate or serpiginous arrangement. A linear pa ern is
52 53,54exceptionally seen. I nvolvement of the eye and the central nervous system may rarely occur. Familial cases are very
55rare. Histology of individual lesions shows small, dilated blood vessels in the dermal papillae.
Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu)
56Hereditary hemorrhagic telangiectasia is an autosomal dominant inherited condition characterized by numerous
telangiectasias involving skin, mucosae, and internal organs, especially gastrointestinal tract and lungs. A n association with
arteriovenous malformations may exist. Histologically, dilated capillaries and venules are seen in the affected organs.
Cytogenetic studies have demonstrated mutations in genes at 9q33-q34.1 and 12q11-q14 encoding endoglin (EN G) and
57activin receptor-like kinase 1 (A CVRLI or A LKI ), respectively. I n a group of patients, hereditary hemorrhagic
telangiectasia is associated with juvenile polyposis syndrome, and in these patients mutations in the MADH4 gene on
58chromosome 18 have been found.
59Angiokeratomas are not true vascular neoplasms but represent superficial vascular ectasias with overlying warty
epidermal changes. Four clinical types of angiokeratoma are seen:
1. Angiokeratoma corporis diffusum in association with Fabry disease, in which multiple angiokeratomas appear late
in childhood. Fabry disease is associated with inherited deficiency of the lysosomal enzyme α-galactosidase A.
However, not all patients with angiokeratoma corporis diffusum have Fabry disease. Identical lesions have been60 61described in patients with other enzyme deficiencies, including α-L-fucosidase, β-mannosidase,
α-N62,63 64 65acetylgalactosaminidase, and β-galactosidase and exceptionally in a patient with normal enzyme activity.
66Treatment with the enzyme α-galactosidase may induce regression of the angiokeratomas.
672. Angiokeratoma of Mibelli, characterized by bilateral papules on dorsum of fingers and toes.
68,693. Angiokeratoma of Fordyce, characterized by lesions on the scrotum or, more rarely, the vulva.
704. Solitary angiokeratoma.
The histologic features are identical in all forms. I n Fabry disease, the epidermal changes tend to be minimal, and lipid
deposits in the form of cytoplasmic vacuoles can be detected in skin lesions in the endothelial cells, pericytes, and
71fibroblasts. Distinction from verrucous hemangioma is discussed later.
Capillary Hemangioma
Clinical Features
36-38,72Capillary hemangioma is the most common benign vascular tumor of infancy, affecting as many as 1 in every 100 live
38 36,72births and comprising between 32% and 42% of all vascular tumors. I t can affect almost any organ, but by far the
most common location is the skin and soft tissues, especially in the head and neck area.
I n infants the lesion is also known as cellular hemangioma of infancy, infantile hemangioendothelioma, strawberry nevus,
or juvenile hemangioma. Girls are affected slightly more often than boys. The tumor presents at birth or shortly thereafter as
a red-purple macule that slowly becomes raised and then tends to regress in more than 70% of cases after a period of months
73to years. Large lesions are usually disfiguring and can be associated with high morbidity if located near vital structures.
74-76Recently, a subgroup of vascular lesions have been described under the rubric congenital hemangiomas. These
proliferations have been divided into two categories: rapidly involuting congenital hemangioma (RI CH) and noninvoluting
congenital hemangioma (N I CH). A lthough they seem to represent distinctive entities, some degree of clinical and histologic
overlap exists among RI CH, N I CH, and capillary hemangioma, and the diagnosis requires close clinicopathologic
77correlation. I n the past RI CH and N I CH were mainly classified under capillary hemangiomas, and lesions in the N I CH
category are likely to overlap with vascular malformations. Both RI CH and N I CH develop in utero and are fully developed at
birth, affect boys and girls equally, and present mainly in the head followed by the limbs. I n RI CH involution occurs within
the first 2 years of life, and in NICH no tendency for regression is seen.
Histologic Appearances
The histologic features change as the lesion evolves. The overall low-power architecture in all cases, regardless of the organ
involved, is that of a multilobular tumor (Fig. 3-5). In early lesions the lobules are highly cellular and composed of mitotically
active, plump endothelial cells forming tiny, rounded, often uncanalized vascular spaces (see Fig. 3-5). For this reason, in
very early lesions the endothelial nature of the tumor might not be immediately apparent. A s lesions mature the vessels
become canalized and more easily recognized, often showing congested lumina and flat endothelial cells. A small feeding
vessel is often found in the vicinity of the tumor. Older lesions become progressively fibrotic with almost complete
regression or absence of the vascular elements. Perineural invasion is not uncommon in infantile cases, but this does not
78,79imply malignant behavior.
FIGURE 3-5 Capillary hemangioma (infantile hemangioendothelioma). Note the lobular growth pattern
(A) and closely packed, largely uncanalized capillaries (B).
A reticulin stain is useful, especially in immature solid lesions, to highlight the tubular vascular architecture (Fig. 3-6).
A lthough histologically immature tumors appear to be composed only of endothelial cells, ultrastructural and
immunohistochemical studies have demonstrated a prominent number of other cells, including fibroblasts, pericytes, and
80-82mast cells. The demonstration of an almost consistent layer of actin-positive pericytes around individual vascular
channels may be helpful in excluding malignancy.$
FIGURE 3-6 Capillary hemangioma. Reticulin staining reveals a clearly tubular architecture even in the
least canalized examples (same case as in Fig. 3-5).
These tumors have a unique immunophenotype that is shared by placental microvessels and is characterized by
expression of glucose transporter 1 (GLUT1) and Lewis Y antigen (LeY). GLUT1, the erythrocyte-type glucose transporter
83,84protein, is expressed in these lesions at all stages of their evolution. Because GLUT1 is not expressed in other vascular
tumors usually occurring in children, expression of this marker is a valuable aid in differential diagnosis, particularly in the
se ing of vascular malformations, which do not express this marker. S imilarly, WT-1 seems to be expressed in hemangiomas
85and not malformations. S tudies have suggested that these lesions are composed, at least in part, of CD 133-positive
86 87,88endothelial progenitor cells. I n addition, juvenile capillary hemangiomas have been shown to be clonal.
Histologically, RI CH often overlaps with capillary hemangioma. I t involves the dermis and subcutis and consists of lobules
of congested, slightly dilated capillaries, each of which is surrounded by a layer of pericytes. Between tumor lobules fibrosis,
dystrophic calcification, and hemosiderin deposition occur with few sca ered larger, feeding blood vessels. Perineural
74,75extension is not usually seen. Late lesions can display intralobular fibrosis. A s opposed to classic examples of capillary
hemangioma, GLUT1 is negative or very focally positive in most cases.
I n N I CH tumor lobules display more variation in size, and, although capillaries predominate, larger blood vessels are seen
76both within and outside the lobules. These vessels have features of arteries and veins. A rteriovenous fistulae can be seen.
Many of these features are like those seen in vascular malformations. GLUT1 staining is usually negative.
Variants of Capillary Hemangioma
Tufted Angioma (“Angioblastoma of Nakagawa”)
89-94Tufted angioma is a highly distinctive benign vascular tumor closely related to capillary hemangioma. A lthough it was
89first recognized as an entity in the English literature in 1976, identical cases had been described in the J apanese literature
95since 1949 under the name angioblastoma.
Clinically, tufted angioma presents as an acquired lesion, most often on the neck or trunk of small children but rarely at
96mucosal sites ; no sex predilection is seen. Rare cases can occur in adults. Congenital presentation is seen in a small
97,98 99 100number of cases. Multifocal lesions are very rare. I solated familial cases have been described. Lesions progress
slowly over years as ill-defined red or brown macules, papules, and nodules, which are commonly tender. S pontaneous
101,102regression has been reported in some cases. A lthough the clinical course is benign, complete excision is not usually
possible because of the extensive nature of the disease process. Furthermore, local recurrence beyond the apparent disease
103,104margin is quite common. Rarely, the Kasabach-Merri syndrome may occur and may indicate a relationship or
105similarity with kaposiform hemangioendothelioma (see p 59). Exceptionally, a low-grade coagulopathy is seen.
106Association with a vascular malformation has also been documented.
Histologic Appearances.
The cardinal feature of tufted angioma is the presence of sca ered round or ovoid lobules of closely packed capillaries in the
dermis and superficial subcutis in a typically discohesive “cannonball” distribution (Fig. 3-7). I ndividual lobules are very
similar to those seen in the early stages of strawberry nevus and consist of varying proportions of poorly canalized bloodless
capillaries surrounded by pericytes. The endothelial cells are bland, and mitotic figures are rare. Focally, cytoplasmic
107crystalline inclusions can be seen in the endothelial cells. The nature of these inclusions is unknown. A distinctive feature
is the presence of dilated, crescent-shaped, lymphatic-like vascular channels at the periphery of some of the tumor lobules.
108I ntravascular location has been described, and in rare cases histologic overlap exists between kaposiform
109,110hemangioendothelioma and tufted angioma, further suggesting a relationship between both tumors.$
FIGURE 3-7 Tufted angioma. Note the irregular distribution of capillary lobules and semilunar vascular
spaces at their periphery (top right).
Differential Diagnosis.
A common source of confusion is nodular Kaposi sarcoma (KS ), from which tufted angioma is easily distinguished by its
“cannonball” pa ern, lack of a significant spindle cell population, and vasoformative reticulin pa ern. Kaposiform
hemangioendothelioma is generally a larger or more extensive lesion in which the lobules are more confluent.
Verrucous Hemangioma
111-113Verrucous hemangioma usually presents as a warty blue-black lesion on the lower extremities of children. Because of
its warty appearance, clinical misdiagnosis is not uncommon. Histologically, most lesions consist of numerous dilated
capillaries and occasional cavernous-like vascular spaces in the superficial dermis, extending into the deep dermis and
subcutaneous tissue (Fig. 3-8). Overlying epidermis shows very marked acanthosis and hyperkeratosis. Wide excision is
necessary to avoid local recurrence, which is common. A lthough verrucous hemangiomas have a superficial resemblance to
angiokeratomas, the latter represent vascular ectasias, involve only the papillary dermis, and are cured by simple excision.
FIGURE 3-8 Verrucous hemangioma. Beneath a markedly hyperkeratotic epidermis, thin-walled vessels
fill the papillary and deep dermis.
Cherry Angioma (Senile Angioma, Campbell de Morgan Spot)
27Cherry angiomas are very common and present as red papules on the trunk and upper limbs of middle-aged and elderly
adults. They increase in number with age and are characterized histologically by dilated and congested capillaries, with a
lobular architecture, situated in the papillary dermis.
Lobular Capillary Hemangioma (Pyogenic Granuloma)
Clinical Features.
114,115Pyogenic granuloma is a very common vascular lesion of the skin and mucous membranes, which for many years was
considered to be a reactive or infective process. This was based on the presence of extensive superficial secondary
116,117inflammatory changes (due to frequent ulceration) and an apparent association with trauma in up to a third of cases.
The underlying process, however, is a lobular vascular proliferation, which appears to be neoplastic, has deep and
intravascular counterparts (see discussion below), and has been redesignated, appropriately, as lobular capillary
118hemangioma. Lesions can appear at any age, in either sex, and with special predilection for the fingers and head and neck
119,120area, especially the nasal and oral mucosae. Congenital lesions have been described rarely. The classical appearance$
is that of a solitary, rapidly growing, ulcerated, bleeding, polypoid blue-red nodule that is usually less than 2 cm in diameter.
121-123Rare cases of disseminated (“eruptive”) pyogenic granuloma have been reported. S ome of these cases have
exceptionally been associated with a drug hypersensitivity reaction, a land mine injury, a burn, or an acquired arteriovenous
124-127malformation. Complete spontaneous regression does not occur, and local recurrence is seen in up to 10% of cases,
especially after incomplete excision. This is especially notable in lesions of the nasal septum. A n unusual phenomenon,
which tends to occur mainly on the trunk of children and young adults, is the development of recurrence characterized by
128,129 45,47multiple sessile nodules (“satellitosis”). Lesions may rarely occur within port-wine stains, and pyogenic
130 131granuloma-like lesions have been described in association with therapy with capecitabine, topical tretinoin,
132,133 134 135 136isotretinoin, gefitinib, 5-fluorouracil, and erythropoietin. Lesions have also been documented in association
137 138with pulse dye laser and after hydroxyapatite implants.
Histologic Appearances.
Most lesions are exophytic, ulcerated, and surrounded by an acanthotic epidermal collare e. N ear the surface, if ulcerated, a
prominent acute inflammatory cell infiltrate and exuberant, often edematous granulation tissue occur, but the core of the
tumor shows lobules of small capillaries, with or without discernible lumina, lined by prominent endothelial cells (Fig. 3-9).
The stroma is loose and edematous, and normal mitotic figures can be numerous, especially in mucosal lesions (Fig. 3-10).
139Moderate cytologic atypia can be present, especially in lesions arising in the mouth and conjunctiva; such atypia is often
most striking adjacent to an ulcerated surface and is likely reactive in nature. Rarely, epithelioid endothelial cells are seen
focally lining the vascular spaces. Older lesions can show marked fibrosis. The resemblance to granulation tissue is lost in
deep or intravascular lesions. S atellite nodules show similar histologic findings with involvement of the reticular dermis and
even the subcutis. Immunostaining with actin highlights a layer of pericytes surrounding each individual blood vessel.
FIGURE 3-9 Pyogenic granuloma. This low-power view of an early nonulcerated lesion shows the
typical lobular architecture.
FIGURE 3-10 Pyogenic granuloma. A, Ulcerated lesions show stromal edema and acute inflammatory
cells. B, Despite considerable cellularity and frequent mitoses, no endothelial nuclear atypia or
multilayering is seen.
Granuloma gravidarum refers to identical lesions occurring in the gingivae of pregnant women; these usually involute after
delivery. S ubcutaneous pyogenic granuloma presents as an asymptomatic nodule, mainly in the upper limb, and shows
140identical histologic features without the secondary changes associated with classical pyogenic granuloma. I ntravenous
141pyogenic granuloma is a rare variant presenting predominantly in adults, especially in the neck and upper extremity.
Secondary inflammatory changes are not seen, and the clinical behavior is benign.
Differential Diagnosis.
The traditional differential diagnosis is from well-differentiated angiosarcoma and nodular KS . I n the first, usually poor$
circumscription, cellular atypia, and dissection of collagen bundles occur. I n the second, invariably a prominent spindle cell
component occurs with formation of slit-like spaces. The main differential diagnosis in recent years has been with bacillary
angiomatosis, an infectious vascular proliferation caused by a gram-negative organism, Bartonella henselae (formerly
142,143Rochalimaea henselae) and much less commonly by Bartonella quintana. This condition occurs almost exclusively in
patients with acquired immunodeficiency syndrome (A I D S ) or other immunosuppressive conditions and rarely in normal
individuals. I ts recognition is important because of the dramatic response to antibiotic therapy, especially erythromycin. The
incidence of this condition has diminished dramatically in the last 10 years because of the sensitivity of the causative
organism to the prophylactic antituberculous treatment routinely received by human immunodeficiency virus (HI V)–
positive individuals. The architecture of both conditions is very similar, the main difference being the presence in bacillary
angiomatosis of pale epithelioid endothelial cells, focal cytoplasmic vacuolation, clusters of polymorphs with leukocytoclasis
throughout the lesion, and granular basophilic or amphophilic material in relation to the inflammatory cells (Fig. 3-11).
When stained with Warthin-Starry or Giemsa this material is shown to contain aggregates of short bacilli.
FIGURE 3-11 Bacillary angiomatosis. Note the epithelioid endothelium along with inflammatory and
karyorrhectic debris (center).
Cavernous Hemangioma
Clinical Features
36-38,79A lthough less common, cavernous hemangioma has the same age, sex, and anatomic distribution as capillary
hemangioma. A s opposed to capillary hemangioma, however, these lesions tend to be larger, deeper, and less well
circumscribed; very few, if any, show a tendency to regress. Virtually any organ in the body can be affected by cavernous
hemangioma. A ssociated clinical syndromes include Maffucci syndrome with multiple enchondromas, occasional
144lymphangiomas, and often spindle cell hemangiomas; Kasabach-Merri syndrome with consumption coagulopathy ; and
145,146blue rubber bleb nevus syndrome with numerous hemangiomas in the skin and gastrointestinal tract.
Histologic Appearances
Cavernous hemangiomas consist of poorly circumscribed, irregularly dilated blood vessels lined by flat endothelium and
with walls of varying thickness (Fig. 3-12). A reas resembling capillary hemangioma can often be found focally, especially in
the superficial portion, and many lesions represent combined capillary and cavernous hemangiomas. Thrombosis, secondary
dystrophic calcification, and mild inflammation are frequently found.
FIGURE 3-12 Cavernous hemangioma. The blood vessels are dilated, congested, and focally
Variant of Cavernous Hemangioma
Sinusoidal Hemangioma
Clinical Features.
147S inusoidal hemangioma is a more recently described distinctive variant of cavernous hemangioma. I t has a wide$
anatomic distribution with special predilection for the subcutaneous tissue of the breast. I n this anatomic location it can be
confused with angiosarcoma. Most lesions occur in middle-aged adults, predominantly women, as a superficially located
blue nodule. Simple excision is curative.
Histologic Appearances.
Typically, lesions are lobular, relatively circumscribed, and composed of irregular, dilated and congested, thin-walled gaping
blood vessels with a typical sinusoidal or sieve-like appearance (Fig. 3-13). Cross-sectioning of back-to-back blood vessels
with li le intervening stroma results in prominent pseudopapillary structures, reminiscent of Masson tumor. The vascular
spaces are lined mainly by an a enuated monolayer of endothelial cells, which can be focally prominent with mild reactive
nuclear hyperchromasia. A n outer layer of actin-positive pericytes can also often be discerned. A s in ordinary cavernous
hemangioma, thrombosis with dystrophic calcification is commonly seen, and this may be the cause of abnormality on
mammographic screening. Rarely, central infarction is present. Old lesions show fibrosis and hyalinization of blood vessels.
FIGURE 3-13 Sinusoidal hemangioma. Note the delicate vessel walls producing a sieve-like pattern.
Differential Diagnosis.
The main differential diagnosis is from well-differentiated angiosarcoma, especially in lesions occurring in the breast.
Mammary angiosarcoma is intraparenchymal, rather than dermal or subcutaneous, and shows a clearly infiltrative or
dissecting pattern with at least focal nuclear atypia and hyperchromasia.
Arteriovenous Hemangioma
Clinical Features
148-150A rteriovenous hemangioma (arteriovenous malformation) is an uncommon lesion. I t is divided into two distinctive
variants according to the depth of involvement. The deep type usually presents in the head and neck or limbs of adolescents
and young adults and can be associated with severe degrees of arteriovenous shunting and soft tissue hypertrophy. These
deep lesions probably represent congenital malformations. S ymptoms can be severe, and patients may present with heart
failure or Kasabach-Merri syndrome. Clinicopathologic correlation, including arteriographic studies, is very important in
establishing the diagnosis. Persistent growth and symptoms are common after incomplete excision.
151The superficial type, which is also known as cirsoid aneurysm or acral arteriovenous tumor, typically presents in the
skin of the head and neck (especially the lip) of middle-aged or elderly adults (often men) as a small red-blue papule. A
152 153variant presenting on the digits has been documented. S ome cases have been associated with chronic liver disease.
S ymptoms are minimal and include pain and intermi ent bleeding. S hunting is not usually a major feature. S uperficial
cutaneous changes associated with deep arteriovenous hemangiomas can mimic KS clinically and histologically and have
154been named pseudo-KS or acroangiodermatitis. However, similar changes can be associated with any cause of venous
Histologic Appearances
The histologic features are very variable, especially in the deep variant of arteriovenous hemangioma. S uperficial lesions
tend to be be er circumscribed than deep lesions. Both variants are said to show a mixture of thick- and thin-walled blood
vessels that correspond to arteries and veins of varying caliber with a predominance of the la er (Fig. 3-14), as can be
demonstrated by the use of elastic stains (Fig. 3-15). Focally, some tumors can resemble capillary or cavernous hemangiomas.
S erial sections are helpful in demonstrating arteriovenous anastomosis. Focal thrombosis and stromal calcification are
sometimes seen. I n reality, convincing demonstration of arteries in superficial lesions is often very difficult. Conceivably
155these vessels can represent arterialized veins, and it is likely that many superficial lesions are true venous hemangiomas.FIGURE 3-14 Arteriovenous hemangioma. Superficial examples are often known as cirsoid aneurysm.
FIGURE 3-15 Arteriovenous hemangioma. This deep lesion is composed of large vessels (A) that are
distinguishable by the distribution of their elastic laminae (B). (Elastic van Gieson.)
Microvenular Hemangioma
Microvenular hemangioma is a distinctive cutaneous hemangioma proposed to be a form of acquired venous
156,157hemangioma. Lesions most often present in young adults as red or bluish papules, especially on the limbs. Eruptive
158 159lesions are exceptional. Occurrence in children is very rare. N o apparent tendency to recur is seen. A case has been
160documented in a patient with POEMS syndrome. Histologically (Fig. 3-16), the tumor is composed of irregular branching,
thin-walled venules, lined by a monolayer of endothelial cells with plump nuclei, occupying the superficial and deep dermis,
and surrounded by sclerotic collagen bundles. The vessels show angular ramification through the dermis and generally have
an easily identified outer layer of pericytes. A more lobular component may be evident at the base of the lesion.$
FIGURE 3-16 Microvenular hemangioma. Note the angular ramification of vessels between dermal
collagen bundles.
Hobnail Hemangioma (Targetoid Hemosiderotic Hemangioma)
161-163 161Hobnail hemangioma, first described under the rubric targetoid hemosiderotic hemangioma, is a distinctive
cutaneous vascular tumor that usually presents on the trunk or extremities of young or middle-aged adults, with male
predilection. I ts original descriptive name refers to what was regarded as the distinctive clinical presentation of a small
round lesion with a purple center, surrounded by successive pale and ecchymotic haloes. However, it has become clear that
relatively few lesions have this appearance and, furthermore, the same appearance may be associated with other pathologies,
164 165including trauma. Some patients have described cyclic changes in the lesion. Simple excision is curative.
Histologically, in the superficial dermis, irregular dilated thin-walled vascular channels are seen, lined by distinctive,
bland, hobnail endothelial cells with focal papillary projections (Fig. 3-17). A s the lesion extends deeper into the dermis, the
endothelial cells become fla er and narrower vascular channels dissect between collagen bundles. The surrounding stroma
frequently shows extravasated red blood cells and hemosiderin deposition. We consider this lesion to be at the benign end of
the spectrum of vascular tumors characterized by hobnail endothelial cells, which includes papillary intralymphatic
166angioendothelioma (PI LA ; D abska tumor) and retiform hemangioendothelioma. The differential diagnosis is discussed
in the section on papillary intralymphatic angioendothelioma (see p 60), but it should also be noted that histologic changes
almost identical to hobnail hemangioma may be seen after radiation therapy (see p 74). I mmunohistochemistry for HHV-8 is
167consistently negative in these lesions.FIGURE 3-17 Hobnail hemangioma. The vascular channels are lined by protuberant endothelial nuclei;
note the focal papillae (top).
Acquired Elastotic Hemangioma
A cquired elastotic hemangioma is a rare lesion that develops in sun-exposed skin of the forearms and neck, with
168predilection for middle-aged and elderly women. I t presents as a small, solitary, asymptomatic erythematous plaque.
Histologically, in the background of dermal solar elastosis, a band-like superficial dermal proliferation of capillaries is seen.
Epithelioid Angiomatous Nodule
Clinical Features
169Epithelioid angiomatous nodule is a recently described cutaneous lesion in the spectrum of epithelioid vascular tumors.
I t presents as a papule or nodule in adults, of usually short duration, with predilection for the trunk, followed by the limbs
169 170and face. Multiple lesions are exceptional. No tendency for recurrence exists.
Histology shows a single, usually circumscribed superficial dermal nodule composed of plump, pink epithelioid endothelial
cells with intracytoplasmic lumina and only very focal formation of vascular channels (Fig. 3-18). D espite the worrisome solid
growth, no nuclear hyperchromasia or pleomorphism is seen. I n the background may be seen mild fibrosis, hemosiderin
deposition, and scattered inflammatory cells, including some eosinophils.
FIGURE 3-18 Epithelioid angiomatous nodule. This characteristically exophytic nodule (A) is composed
of close-packed epithelioid endothelial cells (B).
Differential Diagnosis
170I t has been suggested that this lesion is a variant of epithelioid hemangioma. A lthough both conditions have several$
features in common, histologic features are different enough to justify separating them. D istinction from epithelioid
hemangioma can be made on the basis of the different clinical presentation and the presence of a single lobule of poorly
vasoformative epithelioid endothelial cells and fewer inflammatory cells in cutaneous epithelioid angiomatous nodule. I n
bacillary angiomatosis, the endothelial cells are pale pink and form small vascular channels in a lobular architecture.
Furthermore, throughout the lesion, aggregates of neutrophils with nuclear dust and clumps of amorphous basophilic
material representing bacteria are seen.
Epithelioid Hemangioma (Angiolymphoid Hyperplasia with Eosinophilia)
171Epithelioid hemangioma is also sometimes known as angiolymphoid hyperplasia with eosinophilia, pseudopyogenic or
172 172 173atypical pyogenic granuloma, inflammatory angiomatous nodule, papular angioplasia, intravenous atypical
174 175vascular proliferation, and histiocytoid hemangioma. A lthough accurately descriptive, the term histiocytoid
176-179hemangioma is controversial and has gradually been abandoned because, as originally formulated, it included a
175broader group of tumors. Epithelioid hemangioma represents the benign end of the spectrum of a family of vascular
tumors characterized by epithelioid endothelial cells, which includes the recently described cutaneous epithelioid
angiomatous nodule (see earlier discussion) and, at the malignant end of the spectrum, epithelioid hemangioendothelioma
and epithelioid angiosarcoma. A lthough separation between these tumor types is usually possible, rare cases show a degree
of overlap, especially within the two la er categories. S ome controversy still exists over whether epithelioid hemangioma
180represents a true vascular neoplasm or a reaction to various stimuli, especially trauma, but the former is generally
Clinical Features
Epithelioid hemangioma typically presents as single or multiple cutaneous red nodules in the head and neck area (especially
181,182around the ear) of middle-aged adults, with slight predilection for men. Lesions can also occur in the trunk and limbs
183-185 186,187 188and involve deeper soft tissues. Cases have also been reported in the oral mucosa, tongue, breast, lymph
189 190 191 192node, bone, testis, and even an ovarian teratoma. A group of morphologically similar lesions in the heart,
considered in the past to be epithelioid hemangiomas, are probably mesothelial or histiocytic in nature (see Chapter
193,194 179,1812). Circulating eosinophilia is infrequent but has been reported to occur in up to 15% of patients. I n contrast
to Kimura disease, generally no lymph node involvement exists. I n up to a third of the cases there is local recurrence, but
178,179,181,182metastasis does not occur. Transient angiolymphoid hyperplasia and KS have been reported after primary
195infection with HHV-8 in a patient with HI V infection. However, HHV-8 has not been found in lesions of epithelioid
196hemangioma. Lesions with similar histologic features to those seen in epithelioid hemangioma have been described
197rarely in association with vascular malformations.
Histologic Appearances
Most lesions are fairly well circumscribed and composed of numerous small to medium-sized, thin-walled blood vessels
lined by plump endothelial cells with copious eosinophilic cytoplasm and oval vesicular nuclei with inconspicuous nucleoli.
Often at least a partially lobular architecture exists (Fig. 3-19). Frequently the epithelioid endothelial cells protrude into the
vascular lumina in a “hobnail” or “tombstone” fashion (Fig. 3-20). These cells may show cytoplasmic vacuoles that, if
confluent, can form vascular lumina. Mitotic figures are uncommon, and pleomorphism is not a feature. Occasional thicker
blood vessels, with muscular walls showing myxoid change, and solid aggregates of epithelioid cells can be seen.
D emonstrable origin from a small artery or vein is common, and the entire lesion quite often can be intravascular. Origin
198,199from a large peripheral artery has occasionally been described. S urrounding the blood vessels, often a prominent
inflammatory infiltrate is seen composed of histiocytes, lymphocytes, plasma cells, mast cells, and eosinophils. Occasionally
germinal center formation occurs, but this is less frequent than in Kimura disease. Tumor cells stain for endothelial markers,
190and, although keratin positivity is not generally seen in cutaneous lesions, it has been reported in cases arising in bone.
FIGURE 3-19 Epithelioid hemangioma. Note the somewhat lobular architecture and prominent lymphoid
infiltrate.FIGURE 3-20 Epithelioid hemangioma. Note the very plump, focally vacuolated endothelial cells and
prominent stromal eosinophils.
174The intravascular lesions described as intravenous atypical vascular proliferation have been thought to represent a variant
of epithelioid hemangioma. They occur predominantly in young to middle-aged adults as a solitary nodule, most often in the
head and neck region or upper limb. They differ somewhat from conventional epithelioid hemangioma in that they usually
have a prominent spindle cell (pericytic) component (closely admixed with the epithelioid endothelial channels), which
enhances the pseudomalignant appearance of these lesions (Fig. 3-21). However, at least in our experience (and in the
150original article ), no evident tendency to recur is seen.
FIGURE 3-21 Intravenous atypical vascular proliferation. The lesion in this vein lumen is composed of
epithelioid cells and spindle cells.
Differential Diagnosis
200-204Kimura disease is no longer considered synonymous with epithelioid hemangioma, as the former clinically affects
mainly young A sian men and more commonly is associated with lymphadenopathy, eosinophilia, and other systemic
features of an immunologically mediated disorder. Histologically, lesions are deeper, show more fibrosis, and, most
important of all, do not show epithelioid endothelial cells lining the blood vessels. Eosinophil microabscesses are common.
I n injection-site granuloma, epithelioid cells are absent and histiocytes containing violaceous material representing
205-207aluminum are seen. Bacillary angiomatosis shows epithelioid cells with pale cytoplasm and numerous neutrophils
and is associated with basophilic clusters of bacteria. Epithelioid hemangioendothelioma has a prominent myxoid or hyaline
stroma, and tumor cells are arranged in cords or nests, generally lacking formation of overt vascular channels.
Venous Hemangioma
Venous hemangioma has been described as a distinctive entity in the mesentery, retroperitoneum, and skeletal muscle of
208the limbs in adults. A lthough it has been described formally only in deep soft tissues, in our experience similar lesions
present with equal incidence in superficial locations and also occasionally at visceral locations. S ometimes the designation
“venous” hemangioma is rendered on radiologic grounds, but the histopathologic correlate of such a diagnosis is unclear.
Many of those cases occurring in skeletal muscle are probably best classified as examples of intramuscular hemangioma (see
later discussion). Tumors are composed of numerous, irregular, dilated or congested muscular veins (Fig. 3-22), which are
occasionally thrombosed. D ystrophic calcification is sometimes seen within thrombi. Focally, the tumor resembles a
cavernous hemangioma.$
FIGURE 3-22 Venous hemangioma. This subcutaneous lesion is composed of large thick-walled veins.
Spindle Cell Hemangioma (Formerly spindle Cell Hemangioendothelioma)
Clinical Features
S pindle cell hemangioma is a distinctive vascular tumor, which was first described in 1986 under the rubric spindle cell
209hemangioendothelioma, at which time it was regarded as a low-grade variant of angiosarcoma. Typically, the lesion
presents as solitary, or often multiple, red-blue nodules in the dermis or subcutis of the distal extremities, especially the
210hands; the nodules may be painful. Extremely rarely, lesions may occur in skeletal muscle and in the head and neck. N o
sex predilection exists, and the tumor may present over a wide age range with a tendency to cluster in the second and third
decades. The clinical course is indolent, and patients with multiple lesions tend to have new lesions over a period of many
209,211,212years. These new lesions, which were originally interpreted as recurrences, appear to be lesions arising de novo in
normal neighboring skin. S pontaneous regression occurs only infrequently. A ssociation with other anomalies such as
lymphedema, early onset varicose veins, Klippel-Trénaunay syndrome, or Maffucci syndrome is seen in up to 10% of
209,211-214cases. I t seems likely that the association between these lesions and Maffucci syndrome is stronger than was
214previously realized. The basis for considering spindle cell hemangioendothelioma as a form of angiosarcoma was the
209development of lymph node metastasis in a patient from the original series. However, in this patient a separate
radiationinduced high-grade sarcoma appears to have developed. Mounting evidence in recent years suggested that spindle cell
hemangioma may be a nonneoplastic lesion, associated with either abnormalities of local blood flow or else a vascular
211,212,215,216 212,217malformation, hence the revised nomenclature. However, lesions associated with Maffucci syndrome
218have been demonstrated to have IDH-1 or IDH-2 mutations, suggesting instead that these are neoplasms.
Histologic Appearances
Histologically the lesion is poorly circumscribed and consists of irregular, cavernous thin-walled vascular spaces intermixed
with solid areas composed mainly of spindle-shaped cells (Fig. 3-23). I n perhaps 40% to 50% of cases the process is
predominantly intravascular, affecting mainly medium-sized veins. I n the periphery of the tumor, thick-walled muscular
vessels that often show fibrointimal thickening, reminiscent of an arteriovenous malformation, are commonly seen. The
cavernous spaces are lined by an a enuated monolayer of endothelial cells and show organizing thrombus with frequent
phleboliths. Papillary projections, superficially resembling Masson tumor but clearly more cellular, are often present. The
solid areas are composed of bland spindle cells with scanty eosinophilic cytoplasm and elongated or plump rounded nuclei,
along with small numbers of more epithelioid cells, variable numbers of which show large intracytoplasmic vacuoles (Fig.
324). S lit-like vascular spaces are also commonly found in these solid areas. Bundles of smooth muscle cells are often present,
not only around some of the dilated vascular spaces but also in the solid areas. Very rarely focal degenerative endothelial
atypia is seen. I mmunohistochemically, only the cells lining the vascular spaces and the epithelioid cells in the solid areas
stain for endothelial markers. Most spindle cells stain only for vimentin and a smaller percentage for actin and/or desmin.
211,219Rare cases showing combined features with epithelioid hemangioendothelioma have been described, but it is most
likely that these represent examples of composite hemangioendothelioma (see p 62).$
FIGURE 3-23 Spindle cell hemangioma. The typical combination of solid spindle cell areas and
cavernous foci (associated with pseudopapillary structures) is evident.
FIGURE 3-24 Spindle cell hemangioma. Note the strikingly vacuolated endothelial cells.
Differential Diagnosis
N odular KS generally lacks either cavernous vascular spaces or epithelioid vacuolated cells and shows cytoplasmic hyaline
globules in the spindle cell population. Moreover, the spindle cells in KS invariably express HHV-8, which is negative in
spindle cell hemangioma.
Symplastic Hemangioma
S ymplastic hemangioma defines a preexisting hemangioma that develops prominent degenerative alterations within stromal
cells and less commonly within the smooth muscle cells of the blood vessel walls, but not usually involving the endothelial
220-222cells lining the vascular channels. Few cases have been reported, and usually the variant of hemangioma from which
the lesion develops is not identified. I n our experience, however, some lesions appear to develop from cirsoid aneurysms.
Patients are adults with a long-standing lesion that may develop sudden growth. Histologically tumors are often polypoid
and well circumscribed with usual involvement of the dermis only. D ilated congested vascular thin- or thick-walled vascular
spaces are seen in association with a myxoid and hemorrhagic stroma. S tromal cells and smooth muscle cells within the
vessel walls display variable cytologic atypia consisting of nuclear enlargement and hyperchromasia. Bizarre cells, some of
which are multinucleate, are not uncommon. Mitotic figures are rare but can be found. Endothelial cells can be plump but
are not atypical, and no multilayering or mitotic activity is seen, allowing distinction from angiosarcoma. Focal changes of
intravascular papillary endothelial hyperplasia can be seen. D istinction from pleomorphic hyalinizing angiectatic tumor can
be made on the basis of the la er's usually deeper location, prominently dilated thin-walled vascular channels with fibrinoid
change, and the fact that the bizarre cells are not present in vessel walls and typically have nuclear inclusions.
Deep Hemangiomas
Intramuscular Angioma
Clinical Features
I ntramuscular angioma, although relatively uncommon, is one of the most frequent deeply located soft tissue tumors (Fig.
3223-22525). I t presents at any age but has a tendency to manifest in adolescents and young adults; no sex predilection is seen.
The lower limbs are most commonly affected, followed by the head and neck area, upper limbs, and trunk. A typical lesion
develops as a slowly growing mass, which is often painful, especially after exercise. Trauma does not appear to play a role in
its pathogenesis, and most cases are probably congenital in origin. Radiologically, frequently soft tissue calcification is seen,
223,225corresponding to either phleboliths or metaplastic ossification. Recurrence rates are high, ranging from 30% to 50%,
usually as a result of incomplete primary excision.$
FIGURE 3-25 Intramuscular hemangioma. Note the obviously thrombosed vessels centrally and the
diffuse fatty pallor of the adjacent muscle, all of which is irregularly infiltrated by tumor.
Histologic Appearances
Traditionally, intramuscular angiomas have been classified histologically, according to vessel size and predominant blood
223vessel type, into small (capillary), large (cavernous), and mixed types. I n practice, however, most lesions appear to be of
225the mixed type and can consist of capillaries, veins, small arteries, and even lymphatic-like channels, making reliable
subclassification difficult, if not impossible ( Fig. 3-26). However, pure intramuscular capillary hemangiomas are mainly seen
in the head and neck area, whereas intramuscular lymphangioma is most common in the trunk. A ll intramuscular angiomas
are associated with variable amounts of mature fat, explaining why these lesions have in the past sometimes been called
226infiltrating angiolipomas (Fig. 3-27). D egenerative or reactive sarcolemmal nuclei are a common feature in the stroma.
Earlier reports suggesting a correlation between histologic subtype and risk of recurrence have not been confirmed, and it
seems that recurrence correlates only with adequacy of excision, reflecting the infiltrative nature of all intramuscular
225angiomas, regardless of histologic subtype.
FIGURE 3-26 Intramuscular hemangioma. Note the complex admixture of vessels of varying size.
FIGURE 3-27 Intramuscular hemangioma. Most cases have a very prominent adipocytic component.
Differential Diagnosis
A lthough histologic diagnosis is usually easy, intramuscular angioma has to be distinguished from intramuscular lipoma,
which has a more indolent course with less tendency to recur. I n the la er, however, a prominent vascular component is
never found. Pure intramuscular capillary hemangioma is occasionally confused with angiosarcoma, but the usual presence
of a lobular architecture and the absence of endothelial atypia or multilayering in the former should make distinction easy.
Synovial Hemangioma$
S ynovial hemangiomas are uncommon lesions that have traditionally included tumors arising in the intraarticular space,
bursae, and even tendon sheath. However, it has been proposed that this name should be reserved for lesions occurring in
227the first two sites. S ynovial hemangioma presents in young adults or children, especially males, as a slowly growing
227asymptomatic or painful mass, affecting especially the knee and elbow and, rarely, the finger. Lesions that affect
surrounding soft tissue or bone are best regarded as examples of angiomatosis. The behavior of purely synovial lesions is
benign; there is no tendency to recur. A bout half of the cases of synovial hemangioma represent cavernous lesions, and the
rest are examples of capillary hemangioma, arteriovenous hemangioma, or pure venous hemangioma.
Intraneural Hemangioma
228-230N eural hemangiomas are extremely uncommon, and very few convincing cases have been reported. S ymptoms are
related to the nerve involved and include pain, paresthesias, and numbness. Extensive epineurial, perineurial, and
230endoneurial involvement can occur and is associated with significant morbidity. The cases described have involved large
230nerves from the limbs and, in one case, the trigeminal nerve. Multiple lesions within the same nerve have been
231documented in a case. Histologically, most lesions are cavernous hemangiomas.
A ngiomatosis is an uncommon condition that presents almost exclusively in childhood or adolescence and is characterized
232 233by the diffuse proliferation of blood vessels affecting large contiguous areas of the body. Familial cases occur rarely.
Typically this process involves the limbs, affecting multiple tissue planes, including dermis, subcutis, muscle, and even
bone. Commonly, hypertrophy of the affected limb occurs, and some patients present clinically with the features of
234angiokeratoma. Rare cases have been associated with visceral and central nervous system hemangiomas. I n view of the
extensive disease, surgical treatment is difficult, and recurrences are common (varying from 60% to 90% of cases in different
233Two histologic pa erns have been described. I n both types abundant mature fat is seen surrounding the proliferating
vessels, a feature that seems to confirm the probably hamartomatous nature of angiomatosis. The most common pa ern
consists of a mixture of veins, cavernous vascular spaces, and capillaries, the first of which show irregular walls with a
233variable incomplete muscle layer. Frequently, clusters of small vessels are present in the walls of larger vessels. The
second pa ern consists of small capillaries and sparse larger feeding vessels (Fig. 3-28). I n both pa erns, perineural invasion
can be seen.
FIGURE 3-28 Capillary angiomatosis. Note the diffuse infiltration of fat and fascia.
I ntramuscular angioma, although very similar histologically to angiomatosis, is usually limited to one muscle group, and
clinicopathologic correlation is therefore necessary to allow confident distinction. D eep arteriovenous malformations usually
show clinical evidence of shunting and a histologic admixture of veins and arteries, of which the la er are only occasionally
seen in angiomatosis.
Vascular Tumors of Intermediate Malignancy
A lthough the concept of tumors of intermediate or borderline malignancy is well established in other fields of pathology, it
has only been introduced more recently in the classification of soft tissue neoplasms and, in particular, in that of vascular
235tumors (reviewed by Fletcher ). The term hemangioendothelioma, originally used very loosely to refer to several benign
(i.e., infantile capillary hemangioma) and malignant (i.e., angiosarcoma) vascular tumors, has been chosen to denote many of
the lesions in this new category. S trictly, the concept of borderline tumors refers to neoplasms that have very low but
definite metastatic potential (e.g., retiform hemangioendothelioma). Less commonly, it has been used to refer to tumors
whose biologic behavior cannot be predicted accurately on histologic grounds. I n the 2002 World Health Organization
(WHO) classification of soft tissue tumors, the concept was expanded to include tumors that do not have potential for
236metastatic spread but may be locally aggressive. I n this classification, low-grade or borderline malignant tumors are
classified as of intermediate potential. Tumors classified as locally aggressive include kaposiform hemangioendothelioma
and giant cell angioblastoma. The la er tumor and polymorphous hemangioendothelioma were not included by the WHO
working group in the classification of vascular neoplasms because it was considered that, as a result of the very small
number of cases reported, available data were insufficient for definitive classification of these lesions. I n this chapter we
describe them in the intermediate category group. Epithelioid hemangioendothelioma has been moved to the category of$
malignant vascular tumors, as it is associated with significant morbidity and mortality (see later discussion). The controversy
continues whether KS represents a reactive or a neoplastic process, but we have decided to keep it in the category of
intermediate tumors. I t is likely that in future years the classification of borderline vascular tumors will undergo further
changes as our understanding of this fascinating group of neoplasms evolves.
Kaposiform Hemangioendothelioma
Clinical Features
Kaposiform hemangioendothelioma is a distinctive but rare neoplasm that was originally described in the retroperitoneum
of infants but appears to present more often in subcutaneous or deep soft tissue of the extremities, chest wall, and head and
237-240 241,242 243neck area. Pure cutaneous involvement also occurs. Multifocal lesions are very rare. Most cases present in
244the first decade of life, especially during the first 2 years, but tumors in adults have also been described. N o sex
predilection is seen. I n some cases morbidity and mortality are associated with complications arising from the tumor as a
result of its destructive and infiltrative growth. Retroperitoneal tumors are usually associated with intestinal obstruction and
jaundice. A common association with these tumors at almost any site is Kasabach-Merri syndrome. A few cases have been
associated with lymphangiomatosis of bone and soft tissue. These lesions may be hard to resect properly (because of their
anatomic location), but it seems that true recurrence is infrequent. Rare perinodal or nodal metastasis has been
240described, but distant metastasis has not been reported to date. A close association between tufted angioma and
kaposiform hemangioendothelioma has been suggested on the basis of clinical and histologic overlap and the fact that both
104,109,245conditions may induce Kasabach-Merri syndrome. Both tumors share a similar immunophenotype with
246expression of Prox1, a lymphatic endothelial nuclear transcription factor. Overexpression of this factor has been shown to
247promote invasion in two murine models of kaposiform hemangioendothelioma.
Histologic Appearances
Histologically, the tumor is composed of lobules of differing size, which infiltrate surrounding tissues in an irregular
manner and are separated by fibrous septa. Retroperitoneal tumors frequently show involvement of adjacent structures such
as the pancreas, small intestine, and lymph nodes. Tumor lobules are composed of different proportions of short fascicles of
bland spindle cells, slit-like vascular spaces, and congested capillaries with sca ered fibrin thrombi ( Fig. 3-29). Rarely,
especially in cases from skin and soft tissues, small nests of epithelioid cells can be found, and glomeruloid whorls may be
seen. These cells can contain hemosiderin granules, hyaline globules, and even cytoplasmic vacuoles. Rare hyaline globules
are also seen in the spindle cells. I nflammatory cells are usually sparse, and mitotic figures are rare. Ectatic blood vessels are
found in the periphery of the tumor lobules. Some examples are associated with a florid adjacent proliferation of thin-walled,
dilated lymphatics. Cases arising in association with lymphangiomatosis show transition between both conditions.
Endothelial cells in the tumor are positive for CD 31, CD 34, and FLI -1 but negative for GLUT1 and LeY (juvenile
240hemangioma-associated antigens). von Willebrand factor is only very focally positive. The spindle-shaped cells are
variably positive for endothelial cell markers and may be focally positive for actin. HHV-8 has not been demonstrated.
FIGURE 3-29 Kaposiform hemangioendothelioma. This spindle-celled vascular tumor has a lobular
architecture (A); at higher power, note the resemblance to Kaposi sarcoma, as well as fibrin microthrombi
Differential Diagnosis
The histologic resemblance to nodular KS is striking. Clinically, however, KS is very rare in children, tends to be multicentric,
and shows predilection for lymph nodes in this age group. Morphologically, nodular KS has am ore prominent chronic
inflammatory cell infiltrate and lacks a lobular architecture, and individual lobules are not surrounded by dense fibrous
bands. I nfantile capillary hemangioma (“juvenile hemangioendothelioma”; see later discussion) is composed of solid
nodules of incompletely canalized capillaries without a spindle cell component. Kaposiform hemangioendothelioma can be
distinguished from angiosarcoma by its lack of cytologic atypia and the absence of individually infiltrative, anastomosing
Giant Cell Angioblastoma
Very rare examples of what appears to be a distinctive vascular tumor with aggressive local behavior have been described
248,249under the name giant cell angioblastoma. These have presented as infiltrative congenital or neonatal lesions at a
variety of sites. Histologically, they are composed of bundles and nodules of spindle-shaped and plump histiocyte-like cells$
intermixed with multinucleate giant cells, simulating granulomas, generally oriented around ramifying vascular spaces lined
by plump endothelial cells.
Retiform Hemangioendothelioma
Clinical Features
Retiform hemangioendothelioma is an uncommon lesion that falls into the intermediate, rarely metastasizing
166,250,251category. I t is significantly more common than PI LA (D abska tumor). I t presents as a slowly growing cutaneous
tumor, most often in young adults; no sex predominance is seen. Tumors show predilection for the distal extremities,
especially the lower limb. Very rarely, these lesions can arise after radiotherapy or in the se ing of chronic lymphedema. A
252patient with multiple lesions has been described. Persistent local recurrences are common, but metastatic spread to
regional lymph nodes has been described in only one case, and a further case has metastasized to soft tissues close to the
253primary tumor. Distant spread or tumor-related death has not been reported to date.
Histologic Appearances
Retiform hemangioendothelioma is an ill-defined dermal and/or subcutaneous tumor with a striking histologic resemblance
to normal rete testis. This appearance is conferred by the presence of elongated, arborizing blood vessels (Fig. 3-30) lined by
monomorphic, strikingly protuberant (hobnail) endothelial cells (Fig. 3-31). A prominent stromal and intraluminal
lymphocytic infiltrate is present in perhaps 50% of cases. These endothelial cells have limited, usually basal, cytoplasm, and
vacuolation is rare. The vascular lumina may contain occasional papillae with hyaline collagenous cores. Most tumors show
focally solid areas composed of monomorphic spindle or epithelioid cells, which usually stain positively for endothelial
FIGURE 3-30 Retiform hemangioendothelioma. Typical arborizing channels are associated with a
prominent lymphoid infiltrate.
FIGURE 3-31 Retiform hemangioendothelioma. Note the protuberant “hobnail” endothelial nuclei.
Differential Diagnosis
The differential diagnosis of retiform hemangioendothelioma is described under PILA (see next section).
Papillary Intralymphatic Angioendothelioma (pila) (Endovascular Papillary Angioendothelioma,
Dabska Tumor)
Clinical Features
254PI LA is a rare vascular tumor, described by D abska in 1969 as a locally invasive neoplasm with low malignant potential,
255occurring in infants and children. I n a recent series, however, 25% of the cases occurred in adults. N o sex predilection is
254,255seen, and the topographic distribution is wide, with a slight predominance on the limbs and trunk. Local recurrence,
metastatic spread to regional lymph nodes, and death in at least one patient were reported in the original series. Recently,
255however, follow-up in eight of 12 reported cases revealed neither local recurrences nor metastatic spread. I t now appears$
that D abska tumor is part of a family of vascular neoplasms typified by the presence of characteristic cells with a hobnail
256appearance, possibly indicating high endothelial cell differentiation. This group of neoplasms includes retiform
166hemangioendothelioma and a group of benign lesions initially described as targetoid hemosiderotic hemangioma and
161now known as hobnail hemangioma. I t seems likely that at least some of D abska's original cases would nowadays be
classified as retiform hemangioendothelioma. Therefore the issue about the true malignant potential of this tumor will
remain unsolved until further series are reported. While this doubt remains, complete excision of the tumor should be
Histologic Appearances
255Using stringent diagnostic criteria, our experience and that of others suggest that these tumors are usually composed of
dilated, irregular vascular channels resembling a cavernous lymphangioma, although some cases have smaller, irregularly
branching vascular channels. Tumors usually involve subcutaneous tissue. N umerous lymphocytes are seen not only in the
surrounding stroma but also within the vascular channels. The endothelial cells lining some of the spaces have a prominent
atypical nucleus and inconspicuous cytoplasm, giving a typical hobnail or matchstick appearance. Most characteristic is the
presence of prominent endothelial intraluminal papillary tufts (Fig. 3-32) with hyaline cores surrounded by lymphocytes.
These hyaline cores appear to be composed of basement membrane material synthesized by the tumor cells. Recent
255immunohistochemical evidence has suggested lymphatic endothelial differentiation, although the specificity of vascular
endothelial growth factor receptor-3 (VEGFR-3) in this context is questionable.
FIGURE 3-32 Papillary intralymphatic angioendothelioma. Cavernous lymphatic-like spaces contain
prominent endothelial papillae and clusters of lymphocytes.
Differential Diagnosis
PI LA shares with retiform hemangioendothelioma similar clinical and histologic features, to the point that it has been
proposed that retiform hemangioendothelioma might be the adult counterpart of PI LA . However, although very similar
cytologically, PI LA lacks the arborizing architecture of retiform hemangioendothelioma and shows prominent papillary
tufts, which are, at best, only poorly developed in the la er. Hobnail hemangioma occurs mainly in children and young
adults and in a wide range of anatomic sites, including the oral cavity. Histologically, the lesions tend to be superficial and
circumscribed, with a sparse inflammatory infiltrate and only focal hobnail endothelial cells. Large papillary structures are
not seen. A ngiosarcoma usually occurs in a different clinical se ing and is characterized by irregularly infiltrative vascular
channels, lined by atypical endothelial cells, which usually show multilayering.
Pseudomyogenic Hemangioendothelioma
Clinical Features
Pseudomyogenic hemangioendothelioma is a recently described and uncommon tumor that has very distinctive clinical
257features. These lesions affect mainly adolescents and young adults with a striking male predominance, and they arise
most often on the limbs as variably painful nodules, usually less than 3 cm in size. More than 50% of patients have multiple
nodules, often involving multiple tissue planes in the same general anatomic region—most often skin, subcutis, and skeletal
257muscle and less often bone. Despite this very worrisome presentation, metastasis appears to be very infrequent.
Histologic Features
These are poorly marginated nodules composed mainly of plump, brightly eosinophilic spindle cells with vesicular nuclei,
arranged in fascicles or sheets. Tumor cells commonly resemble rhabdomyoblasts (Fig. 3-33). Focally the cytology may be
258epithelioid, and it is likely that lesions described as epithelioid sarcoma-like hemangioendothelioma belong in this
category. N uclear atypia is generally minimal, and mitoses are sparse. A prominent neutrophilic inflammatory infiltrate
sometimes is found. I mmunohistochemically these lesions are distinctive in being positive for CD 31, ERG, and keratin
A E1/A E3, whereas CD 34, epithelial membrane antigen (EMA), and other keratins are negative. Limited genetic data have
259shown that these lesions have a t(7;19)(q11;q13) translocation.$
FIGURE 3-33 Pseudomyogenic hemangioendothelioma. Note the predominance of brightly eosinophilic
spindle-shaped or polygonal cells.
Differential Diagnosis
The most frequent differential diagnosis is epithelioid sarcoma, but the la er is generally not dominated by
myoidappearing spindle cells. Furthermore, most examples of epithelioid sarcoma are EMA positive, show loss of I N I -1, and are
CD34 positive in 50% of cases.
Composite Hemangioendothelioma
260Composite hemangioendothelioma is the term coined for a remarkable group of vascular lesions usually arising in the
hands and feet of adult patients. A ssociated lymphedema is sometimes seen. Two congenital cases and a patient with
261,262Maffucci disease have been documented. These lesions behave similarly to retiform hemangioendothelioma, being
characterized by frequent local recurrence, whereas metastasis is rare. However, we have seen occasional cases progress to
high-grade angiosarcoma over a period of many years. Histologically, composite hemangioendothelioma generally consists
of admixed components of benign, intermediate, and morphologically malignant vascular elements. A combination of
epithelioid and retiform hemangioendothelioma is most common. Many cases also have areas indistinguishable from
lowgrade angiosarcoma (which, in other circumstances, might have heralded more aggressive behavior), and some examples
additionally show features of spindle cell hemangioma. I n cases with a benign component, areas with features of a
lymphangioma may be seen.
Polymorphous Hemangioendothelioma
263,264Polymorphous hemangioendothelioma is an extremely rare vascular neoplasm, which occurs more often in lymph
node than soft tissue. Prolonged follow-up has revealed its ability to metastasize and to pursue a fatal clinical course,
suggesting that it may in fact represent an unusual variant of angiosarcoma. Histologically it consists of an unusual
admixture of solid, angiomatous, and primitive vascular pa erns. Whether this tumor represents a discrete entity remains
Kaposi Sarcoma
265-271KS, a fascinating entity first described more than 100 years ago, has in the last three decades been the subject of
renewed interest in view of its common association with A I D S . A lthough the cell of origin remains controversial, most
272-276evidence points toward endothelial cells, particularly lymphatic endothelium, as the principal cellular component ;
increasingly, however, it would seem that these lesions comprise a mixed-cell population. For many years epidemiologic and
clinicopathologic findings suggested that an etiologic association with an infectious organism was likely, and several viral
271,277,278organisms, including cytomegalovirus, were initially implicated as the culprit. I n 1994 a breakthrough finally
279occurred with the identification by polymerase chain reaction of herpesvirus-like sequences in A I D S -associated KS . S ince
then, this finding has consistently been reproduced in all types of KS , including both the classic and endemic
280,281variants. The virus, which has been isolated in culture and visualized by electron microscopy, has been designated as
280,282,283 280HHV-8. Other neoplasms in which the virus has been reported include A I D S -related body cavity lymphoma,
280 284multicentric Castleman disease, nonmelanoma skin cancer in immunocompromised organ transplant recipients, and
285other vascular tumors, including some angiosarcomas. However, detection of the virus in the la er tumors is very
286,287rare, and it is unlikely that an etiologic association exists. The isolation of this novel virus in all types of KS seems to
288give some support to the epidemiologic and clinical evidence that KS is a reactive multifocal vascular process. A lthough
289initial findings of monoclonality in multifocal lesions of KS argue in favor of KS being a neoplastic process in which the
290,291virus might have an oncogenic role, findings in other studies have been contradictory, and in a large recent study of
multifocal lesions of the disease it was shown that, although some tumors are monoclonal, most advanced lesions represent
292oligoclonal proliferations favoring a reactive process. Clearly, more research in this area is needed before this intriguing
question is solved.
Clinical Features
267,269-271KS can be classified into four clinical groups as follows.$
Classic Endemic Kaposi Sarcoma
This presents as one or more indolent tumors in the distal extremities of elderly patients, especially men of Mediterranean or
267J ewish A shkenazic origin. Women are very infrequently affected. I n this se ing, rare familial cases have been reported.
Lesions have been documented in children born to consanguineous parents, and this suggests an autosomal recessive
293predisposition that facilitates induction of the tumor by HHV-8. Progression to systemic disease is rare, but a proportion
of cases are associated with hemopoietic neoplasms, especially non-Hodgkin lymphoma, suggesting the possibility of
immune dysregulation in this group of patients also.
Acquired Immunodeficiency Syndrome–Related Kaposi Sarcoma
This was originally characterized by the presence of disseminated aggressive disease especially, but not exclusively, in young
267,269,270men with A I D S . I n western (as opposed to A frican) patients with A I D S , most cases occur in the homosexual risk
group. Organs commonly involved include the skin (Fig. 3-34), gastrointestinal tract, lymph nodes, lungs, and spleen and,
less frequently, organs as diverse as liver, kidney, eye, prostate, heart, bladder, gallbladder, thyroid, pancreas, and bone
294,295marrow. I nvolvement of muscle, bone, and central nervous system, if existent, must be vanishingly rare. S kin
involvement is usually extensive and not confined to the lower limbs; it is characterized by the presence of bluish-brown
macules, plaques, or nodules. Mucosal, especially oral, involvement is frequent. I mproved treatment of HI V infection has
been associated with a markedly reduced incidence of KS in certain populations. Lesions of KS can develop as a result of the
296immune reconstitution inflammatory syndrome.
FIGURE 3-34 Kaposi sarcoma. Extensive patch and plaque disease in a young homosexual male with
acquired immunodeficiency syndrome. (Courtesy St. John's Institute of Dermatology, London, United
269,270,297,298Immunosuppression-Associated Kaposi Sarcoma
This rare form of KS presents as an indolent or, rarely, aggressive disease in patients receiving immunosuppressive therapy,
especially in relation to kidney transplantation. Regression of lesions is sometimes seen after withdrawal or reduction of
African Kaposi Sarcoma
For many years, well before the AIDS epidemic, this form of KS had been endemic in sub-Saharan Central Africa, accounting
269,270for up to 9% of “malignancies” in some countries, such as Uganda. Two principal categories of endemic A frican KS
288,299,300exist: one arises in young children, with generalized lymphadenopathy and a generally fatal course ; another arises
in middle-aged adults, especially men, and commonly follows an indolent course, favoring the lower limbs. At least some
aggressive cases described in the past might have been related to HI V infection, and the most common form of KS in
subSaharan Africa is now AIDS-related (see earlier discussion).
Histologic Appearances
Regardless of the clinical subgroup, all cases show similar histologic features. Three distinctive stages, which can overlap, are
described according to the evolution of a particular lesion: patch, plaque, and nodular stage. The first two stages are seen
most often in the context of A I D S , as early lesions are more likely to be biopsied in these patients. Early changes in the patch
stage can be very subtle: confusion with an inflammatory dermatosis is possible. I n the reticular dermis, especially near the
surface and around preexisting blood vessels and adnexal structures, a proliferation of irregular, small, jagged vascular
channels is seen, lined by a single layer of mildly atypical endothelial cells (Fig. 3-35). These vascular spaces tend to be
oriented parallel to the epidermis. S urrounding these vessels are extravasated red blood cells associated with hemosiderin
deposition and a sparse inflammatory infiltrate composed of lymphocytes and plasma cells (Fig. 3-36). The la er, although
not invariably present, are a helpful diagnostic clue. N ormal blood vessels and adnexal structures may protrude into the
neoformed blood vessels in a fashion described as the promontory sign. This change, however, is not specific for KS and can
be seen in other benign and malignant conditions, including benign lymphangioendothelioma and angiosarcoma. Focally,
often striking collagen dissection is seen, very similar to that in angiosarcoma. S pindle cells are only occasionally seen
around blood vessels. The plaque stage represents an exaggeration of the patch stage with involvement of the whole reticular
dermis and even the subcutis. The spindle cell component is more pronounced, and hemosiderin deposition becomes more
prominent (Fig. 3-37); eosinophilic globules are easily found.FIGURE 3-35 Patch-stage Kaposi sarcoma. Numerous jagged vascular spaces dissect through the
dermis and around skin adnexa.
FIGURE 3-36 Patch-stage Kaposi sarcoma. The vascular channels tend to be parallel to the epidermis
(A) and are commonly associated with extravasated red blood cells, plasma cells, and hemosiderin
deposition (B).
FIGURE 3-37 Plaque-stage Kaposi sarcoma. The spindle cell component is now much more obvious.
N odular KS is characterized by a well-circumscribed, most often dermal, tumor composed of intersecting fascicles of
uniform eosinophilic spindle cells, which usually show minimal cytologic atypia and frequent mitotic figures. Between the
spindle cells are numerous slit-like vascular spaces containing extravasated red blood cells (Fig. 3-38). I n the periphery of the
nodules, ectatic blood vessels may be present. I ntracellular or extracellular hyaline (eosinophilic) globules (Fig. 3-39),
267,270,301measuring from 0.4 to 10 mm and probably representing degenerate red blood cells, are commonly seen. These
globules, although present in all types of KS, are more frequent in AIDS-related KS.FIGURE 3-38 Nodular Kaposi sarcoma. Monomorphic spindle cells are arranged around slit-like or
sieve-like spaces.
FIGURE 3-39 Nodular Kaposi sarcoma. Note the numerous eosinophilic hyaline globules.
302Rare cases of nodular KS can be partially or entirely intravascular.
A lthough the blood vessels in KS show variable reactivity for different endothelial markers, the spindle cell population is
usually negative for factor VI I I –related antigen but consistently and extensively positive forC D 34 (Fig. 3-40) and also often
303CD 31. The vascular channels in KS are positive for D 2-40, giving support to a lymphatic line of differentiation.
Pleomorphism and necrosis are generally not features of nodular KS ; vascular or perineural invasion, if they occur, are
304,305exceedingly rare. The so-called lymphangiomatous variant of KS represents classical patch- or plaque-stage KS in
which proliferating vascular channels dissecting between collagen bundles appear moderately dilated, resembling focally a
benign lymphangioendothelioma (Fig. 3-41). The existence of an anaplastic variant of KS , mainly reported in A frican cases
265,306some years ago, is controversial, and it seems likely that most cases represent other types of tumor, showing clear
evidence of malignancy. We have, however, encountered very rare but convincing examples of pleomorphic KS in A frican
307patients, and a small series on anaplastic transformation of classic KS has been reported.
FIGURE 3-40 Nodular Kaposi sarcoma. The spindle cell component is consistently CD34 positive.$
FIGURE 3-41 So-called lymphangiomatous Kaposi sarcoma. Note the resemblance to benign
lymphangioendothelioma except for the stromal spindle and inflammatory cells.
Lesions from patients receiving highly active antiretroviral therapy can show changes suggestive of regression including
308decreased cellularity, more circumscription, and fibrosis.
I n patients with HI V-A I D S , more than one pathology can be found in a single biopsy. A ssociations include cryptococcosis,
309-311tuberculosis, and Mycobacterium avium intracellulare.
A monoclonal antibody against the latent nuclear antigen-1 of HHV-8 is available for use in paraffin-embedded
312,313biopsies. This represents an invaluable tool in the histologic diagnosis of KS , as this marker is consistently positive in
all clinical variants of the disease (Fig. 3-42). Furthermore, other vascular tumors are only exceptionally positive for HHV-8.
FIGURE 3-42 Kaposi sarcoma. The spindle cells show striking nuclear positivity for human herpesvirus
Differential Diagnosis
Histologically, the differential diagnosis includes benign lymphangioendothelioma, hobnail hemangioma, spindle cell
hemangioma, kaposiform hemangioendothelioma, cutaneous angiosarcoma, acroangiodermatitis, aneurysmal benign
fibrous histiocytoma, and so-called multinucleate cell angiohistiocytoma. Clinically, bacillary angiomatosis and pyogenic
granuloma can simulate KS, but histologic distinction is usually not a problem.
A lthough it shares with KS the dissection of collagen bundles by newly formed vascular spaces, angiosarcoma shows
endothelial multilayering and more cytologic atypia. A neurysmal benign fibrous histiocytoma is more polymorphic with
314foam cells, multinucleate giant cells, and absence of vascular clefts. Features of acroangiodermatitis comprise
proliferation of small blood vessels of the superficial vascular plexus, commonly in a nodular arrangement, accompanied by
fibrosis, hemosiderin deposition, and very few inflammatory cells. A s opposed to patch-stage KS , the newly formed blood
vessels are smaller and not irregular, no involvement of adnexal structures is seen, and plasma cells are not conspicuous. I n
multinucleate cell angiohistiocytoma, the lesion is more circumscribed and contains giant cells and sca ered nonirregular
blood vessels, which are not located around preexisting normal blood vessels.
Malignant Vascular Tumors
Epithelioid Hemangioendothelioma
Clinical Features
315Epithelioid hemangioendothelioma, described as a distinctive entity in soft tissues in 1982, is a low-grade malignant
178,316vascular neoplasm in the spectrum of epithelioid endothelial tumors. We regard this tumor, however, as fully
317malignant in view of its significant morbidity and mortality (see later discussion). Previously, similar cases were classified
175,318with other epithelioid lesions under the term histiocytoid hemangioma. I dentical tumors occur in other organs,
319 320 321including the lung (where they were formerly known as intravascular bronchioloalveolar tumor), liver, bone,
322 323-326 263 327 313pleura and peritoneum, skin, lymph node, and even stomach, brain, and meninges. I n lung, liver, and
bone, multicentricity is common (see Chapters 5, 10, and 25). Primary cutaneous lesions are usually small, and the behavior$
323 328tends to be indolent, although a cutaneous tumor with metastasis to a lymph node has been reported in a child. I n
316-318,329soft tissue, 30% to 50% of the lesions arise from a large or medium-sized blood vessel, especially a vein, and this
tumor can therefore arise potentially from any organ. Epithelioid hemangioendothelioma occurs over a wide age range but is
330most common in middle-aged adults; it is distinctly rare in children. S oft tissue lesions have no sex predilection, as
opposed to those in the lung and liver, where females predominate. Tumors in soft tissue are usually solitary, in contrast to
the multicentricity at other sites, which can be mistaken for metastasis. Clinical presentation varies according to the organ
involved; in soft tissue, as well as a mass, symptoms such as intractable pain can be related to the effects of vascular
occlusion by tumor. Up to 30% of soft tissue cases are associated with metastasis. Reported mortality rates vary from 17% in
316 320 316soft tissue to 43% in liver and 65% in lung.
Histologic Appearances
Macroscopically, these tumors typically have a pale, very firm, and sometimes rather hyaline appearance, especially when
arising in deep soft tissue. Most tumors are ill defined and infiltrative and are composed of round polygonal, or less
commonly, short spindle-shaped endothelial cells with variable amounts of glassy pink cytoplasm and a vesicular nucleus
with inconspicuous nucleolus. Tumor cells are arranged in cords, small nests, or short trabeculae surrounded by a variably
hyaline or myxoid stroma, which commonly has a rather chondroid appearance (Fig. 3-43). Prominent cytoplasmic vacuoles
containing occasional erythrocytes, reminiscent of primitive vascular channels, are frequently seen (Fig. 3-44), but
wellformed blood vessels are, at best, only focally present. When the tumor arises from a blood vessel, the cells fill the lumen
and extend centrifugally through the wall into the surrounding tissue. Complete occlusion or obliteration of the preexisting
vessel is common. A reticulin stain shows a tubular pa ern, highlighting the vascular architecture (Fig. 3-45). I n some cases,
316,331dystrophic calcification and metaplastic ossification are prominent features. S tromal inflammation is generally not a
330-333prominent feature, but some cases are associated with a prominent osteoclast-like giant cell reaction. What appears
possibly to be a variant of epithelioid hemangioendothelioma has been described as spindle and histiocytoid (epithelioid)
179,263,334,335hemangioendothelioma. Cases have so far only been described in lymph node and spleen.
FIGURE 3-43 Epithelioid hemangioendothelioma. Typically cord-like growth pattern in a hyaline stroma.
FIGURE 3-44 Epithelioid hemangioendothelioma. Note the prominent intracytoplasmic lumina and
intraluminal red blood cells in this dermal lesion.$
FIGURE 3-45 Epithelioid hemangioendothelioma. Reticulin staining highlights the vasoformative
A lthough tumor cells are usually only mildly atypical, with a low mitotic count, a spectrum of morphology exists,
sometimes within the same lesion; a small proportion of cases show larger nests of cells with prominent cytologic atypia and
316,317high mitotic count (Fig. 3-46), and even areas indistinguishable from epithelioid angiosarcoma can be seen. Cases
316,317with such features are usually associated with a poor prognosis and have been labeled malignant. A recent study
found that large size (more than 3 cm) and mitotic activity (more than 3 mitotic figures/50 high-power fields) are associated
336with higher mortality. I n this study, tumor site, necrosis, cytologic atypia, and spindling of tumor cells were not
associated with prognosis.
FIGURE 3-46 “Malignant” epithelioid hemangioendothelioma. This lesion shows more cytologic atypia
and small, solid clusters of cells.
I mmunohistochemically, most epithelioid hemangioendotheliomas show a typical vascular phenotype with expression of
337endothelial markers, most notably CD 31, FlI -1 F( ig. 3-47), and von Willebrand factor. Positivity for podoplanin and CD 10
338is also seen. The la er marker, however, is very nonspecific. Up to 45% of cases show positivity for α-smooth muscle
316,339,340actin, and 26% show positivity for cytokeratin (Fig. 3-48). A s opposed to epithelial tumors, EMA is usually
negative. The keratin positivity, which is most frequent in lesions arising in bone, most likely reflects the high intermediate
filament content of the cell cytoplasm. Cytogenetic studies in a few cases of epithelioid hemangioendothelioma have shown
341a translocation t(1;3)(p36.3;q25), and in a further case a t(10;14)(p13;q24) involving the placental growth factor gene was
342demonstrated. The (1;3) translocation has recently been shown to result in a WWTR1-CAMTA1 gene fusion, shown to be
343,344present in virtually all cases of epithelioid hemangioendothelioma.
FIGURE 3-47 Epithelioid hemangioendothelioma. CD31 (JC70) is one of the most sensitive
immunohistochemical markers of endothelial differentiation.$
FIGURE 3-48 Epithelioid hemangioendothelioma. Keratin positivity is a common finding, although this is
not as consistent as in epithelioid angiosarcoma. Note the negatively stained normal endothelium.
Differential Diagnosis
The main differential diagnosis, especially in parenchymal organs and bone, is with metastatic or primary carcinoma.
Helpful distinguishing features are the presence of erythrocytes and absence of mucin in the cytoplasmic vacuoles of
epithelioid hemangioendothelioma, coupled with the immunopositivity for vascular markers. A lso, the degree of nuclear
pleomorphism in carcinomas is usually more pronounced. I n soft tissues, the differential diagnosis also includes epithelioid
sarcoma. The la er generally shows a more sheet-like growth pa ern (at least in areas) and only occasional cytoplasmic
vacuoles and is positive for both keratin and EMA , often CD 34 positive, but negative for more specific endothelial markers
such as CD 31 or von Willebrand factor. Cases with a very prominent myxoid stroma can be confused with myxoid
liposarcoma or myxoid chondrosarcoma, but the la er has a lobular architecture, lacks cytoplasmic vacuoles, and is S -100
protein positive. Myxoid liposarcoma is best distinguished by identification of the typical branching vascular pa ern and
small multivacuolated lipoblasts.
This term covers lesions previously known as lymphangiosarcoma and malignant hemangioendothelioma. Until recently no
reliable means existed of distinguishing blood vascular from lymphatic endothelial differentiation (or origin). Recently with
the advent of markers of lymphatic endothelium, an a empt has been made to elucidate line of differentiation. I t has been
shown that some angiosarcomas, particularly those arising in the head, express lymphatic markers, mainly D 2-40 and Prox1,
345suggesting pure lymphatic differentiation in a subset of tumors. The other angiosarcomas may be purely vascular or
differentiate in both directions. We will refer here mainly to cutaneous and soft tissue angiosarcomas, as visceral lesions are
described in their relevant chapters. I nterestingly, angiosarcomas of deep soft tissue were formerly regarded as exceedingly
rare, but they are more often recognized nowadays, perhaps because their predominant epithelioid cytomorphology was
easily mistaken for epithelial or mesothelial differentiation in the past.
346-352Cutaneous angiosarcoma almost always occurs in one of three different clinical se ings: (1) idiopathic
angiosarcoma of the head and neck, (2) lymphedema-associated angiosarcoma, and (3) postirradiation angiosarcoma. Vinyl
chloride exposure, an association frequently considered in hepatic angiosarcoma, has been reported only exceptionally in
353 354cutaneous angiosarcoma. Very rarely angiosarcoma can arise within a large blood vessel, a hemangioma or a vascular
355 356 357 356,358malformation, a nerve, a plexiform neurofibroma in a patient with neurofibromatosis, or a schwannoma or
356,359as part of a malignant peripheral nerve sheath tumor. I t may also rarely develop as the sarcomatous component in a
malignant germ-cell tumor. A ngiosarcoma in children is very rare, tends to be more common in the mediastinum and head
360-363 364,365and neck, and exceptionally can be associated with xeroderma pigmentosum. Exceptional cases of
366 367angiosarcoma have also been documented with epidermolysis bullosa, with chronic venous ulceration, in association
368 369 370with massive localized lymphedema of morbid obesity, in a gouty tophus, in association with arthroplasty, and in
371an ovarian teratoma. A n association with immunosuppression in transplant recipients has also been reported; however,
HHV-8 plays no evident role in the pathogenesis of angiosarcomas, but tumors occurring in HI V-positive patients can be
372-375positive for HHV-8.
Idiopathic Angiosarcoma of the Face, Neck, and Scalp
I diopathic angiosarcoma typically presents in elderly, predominantly white patients, with a higher incidence in men, as
multifocal bruise-like erythematous-purplish areas, plaques, and nodules, especially on the scalp and central face (Fig.
3346-351,37649). The clinical diagnosis may be missed in atypical cases presenting as diffuse facial edema. The prognosis is
376,377very poor, with a 5-year survival rate reported in initial studies of between 12% and 33%. A further study combining
angiosarcoma of the face and scalp with angiosarcomas occurring in internal organs has reported an overall 5-year survival of
378 37924%. A recent retrospective study found an improved 43% survival a ributed to combined modality therapy.
However, a recent retrospective review of 270 cases from the S urveillance, Epidemiology, and End Results program found a
352 38013.8% 10-year survival rate. Poor prognosis is correlated with size of the tumor and depth of invasion. D eath is usually
due to extensive local disease or widespread metastasis, especially to the lungs. Younger patients appear to have a be er
352,381,382prognosis, and radiation therapy appears to improve survival.$
FIGURE 3-49 Cutaneous angiosarcoma. Typical bruise-like head lesion in an elderly patient. (Courtesy
St. John's Institute of Dermatology, London, United Kingdom.)
Lymphedema-Associated Angiosarcoma
383-389This type of tumor has often been known as lymphangiosarcoma. Classically, it arises in the arm of women 1 to 30
years after mastectomy with removal of axillary lymph nodes, with or without radiation therapy (S tewart-Treves syndrome).
A lthough overlap may occur with radiation-induced angiosarcoma, most cases occur outside the radiation field. Clinically
gross lymphedema is not always apparent. More rarely this type of angiosarcoma can also occur in other types of chronic
lymphedema, including congenital lymphedema, iatrogenic lymphedema, lymphatic malformations, and filarial
lymphedema. The clinical appearances consist of bluish plaques, nodules, and vesicles involving large areas of the affected
limb. Prognosis is similar to that of idiopathic angiosarcoma. MYC amplification has been found in chronic
lymphedemaassociated and postradiation angiosarcoma (see later discussion) but not in primary angiosarcomas, confirming that they are
390genetically distinct.
Postradiation Angiosarcoma
391-394Postradiation angiosarcoma was formerly rare but is an increasingly common variant and usually presents many
years after radiation therapy for benign or malignant conditions. By far the most frequent are lesions arising in skin or less
often parenchyma of the breast after breast-conserving therapy for carcinoma. I n cutaneous postirradiation angiosarcoma of
the breast no associated lymphedema usually occurs, and the latency period is shorter than that in S tewart-Treves
395syndrome. S ome cases of postradiation angiosarcoma of the breast may be associated with chronic lymphedema, and this
396may contribute to the development of the disease. The prognosis generally appears to be just as ominous as in other
types of angiosarcoma, although the course may be somewhat more indolent. Postradiation angiosarcomas show high-level
amplification of MYC as a result of gains in chromosome 8q24, and this has been regarded as an early necessary alteration in
397the development of tumors. In approximately 25% of these cases coamplification of FLT4 occurs, which encodes VEGFR-3.
397By contrast, these alterations have not been found in atypical vascular proliferations associated with radiotherapy.
Soft Tissue Angiosarcoma
350,398,399A s mentioned previously, although angiosarcomas in deep soft tissue were regarded in the past as rare, they are
now diagnosed with increasing frequency, perhaps as a result of altered diagnostic criteria and sensitivity, because the
majority of cases show epithelioid cytomorphology (see p 70). These tumors are most common in older adults, with a
predilection for men, and arise most often in the lower limb or abdominal cavity (including retroperitoneum). S ome are
associated with prior radiation. Five-year survival, as for cutaneous lesions, is at best 20% to 30%. A recent retrospective
study found that, after liver angiosarcomas, soft tissue angiosarcomas have a worse prognosis than those arising at other
Histologic Appearances
The histologic features of cutaneous angiosarcoma occurring in each clinical se ing are very similar and show a wide
spectrum of appearances, ranging from clearly vasoformative to poorly differentiated solid tumors in which the vascular
nature is not readily apparent. The typical case is an infiltrative dermal tumor, composed of numerous irregular,
anastomosing vascular spaces with a distinctive dissecting pa ern between collagen bundles (Fig. 3-50). I nvasion of the
subcutis and even skeletal muscle and periosteum can be seen. The vascular channels are lined by variably pleomorphic,
hyperchromatic endothelial cells that frequently show multilayering and papillary growth (Fig. 3-51). N ormal and abnormal
mitoses are usually easily found. S olid areas are not uncommon, and poorly differentiated lesions can be predominantly
solid with no obvious suggestion of a vascular architecture (Fig. 3-52). A reticulin stain may be useful, especially in the la er
tumors, to highlight be er differentiated areas in which the neoformed blood vessels are encircled by a reticulin sheath. I n
401perhaps 5% of cutaneous tumors epithelioid cells predominate (Fig. 3-53). A very rare variant of angiosarcoma composed
402,403predominantly of granular cells has been reported, and a variant with foamy cells mimicking histiocytes has also
404been documented. A chronic inflammatory infiltrate is often present and can be prominent. S uch lesions can mimic a
405 371lymphoma. I t has been suggested that a heavy mononuclear inflammatory infiltrate correlates with a be er prognosis
380,406,407and that a high mitotic rate correlates with poor prognosis although, in our experience, histologic features
(including grade) do not correlate reliably with outcome, and tumor size or resectability seems more important. I n
postradiation angiosarcomas, capillary-type lobules have rarely been described, and this finding does not exclude the408,409possibility of malignancy. I n poorly differentiated tumors, immunohistochemistry may be helpful as angiosarcoma is
variably positive for different endothelial markers. A lthough many cases are factor VI I I –related antigen negative, a high
proportion stain for CD 31, von Willebrand factor (monoclonal) (Fig. 3-54), or, less specifically, CD 34. Fli-1, a marker of Ewing
410sarcoma, has been described as having similar sensitivity and specificity to CD 31 in the diagnosis of vascular neoplasms
but in our experience is less specific. The demonstration of endothelial cell features by electron microscopy, especially
Weibel-Palade bodies, is also occasionally useful, but these are often very hard to find in cutaneous lesions. Cytogenetic
analysis in a few deep and superficial angiosarcomas has shown complex chromosomal abnormalities mainly involving
411 412chromosomes 5, 7, 8, 13, 15, 20, 22, and Y. A ctivating mutations in KDR and other genes have also been documented
but seemingly only in breast angiosarcomas (see Chapter 16).
FIGURE 3-50 Cutaneous angiosarcoma. Note the numerous vascular channels dissecting between
collagen bundles.
FIGURE 3-51 Cutaneous angiosarcoma. Endothelial multilayering and marked nuclear atypia are evident
in this case.
FIGURE 3-52 Poorly differentiated angiosarcoma. Solid spindle-celled lesions may be hard to diagnose.FIGURE 3-53 Cutaneous epithelioid angiosarcoma. Cases such as this in the skin may easily be
mistaken for melanoma or carcinoma.
FIGURE 3-54 Lymphedema-associated angiosarcoma. This tumor from the foot is positive for von
Willebrand factor.
Differential Diagnosis
The distinction between angiosarcoma and benign vascular tumors has already been described elsewhere in this chapter.
Atypical vascular lesions (see later discussion) can develop in the skin of the breast after radiotherapy for breast cancer and
391can be misdiagnosed as angiosarcoma. The former, however, consist of focal proliferation of dilated vascular spaces with
a single layer of hyperchromatic endothelial cells with no multilayering or mitotic figures. Poorly differentiated
angiosarcoma can simulate other spindle cell sarcomas, melanoma, and carcinoma. I n these cases the use of reticulin stains,
immunohistochemistry, and (more rarely) electron microscopy is very helpful in reaching the correct diagnosis. I t is
important to remember that, among endothelial markers, Ulex europaeus lectin type I is also positive in many carcinomas.
Epithelioid Angiosarcoma
Clinical Features
Epithelioid angiosarcoma is a distinctive but uncommon tumor, representing the malignant end of the spectrum of
177,398epithelioid vascular neoplasms. This term is reserved for neoplasms composed almost exclusively of epithelioid cells,
as conventional angiosarcomas may also show epithelioid foci. This histologic variant was originally recognized in the
413,414thyroid gland, particularly in association with endemic goiter. A lthough its occurrence in skin and soft tissue has
398been acknowledged in the past, it was only fairly recently delineated as a distinctive entity. A lthough the majority of
415cases occur in deep soft tissue (see earlier discussion), occasional cases also occur in the adrenal gland, and individual
322 416 417 418 419cases have been described arising in sites such as pleura, pulmonary artery, breast, bone, and vagina.
391,420,421Cutaneous and the more common soft tissue examples usually present in middle age to late adult life; a marked
male predominance exists. Lesions generally grow rapidly and have no distinctive clinical features other than the
development of hemorrhagic cutaneous satellite lesions in some patients. Cutaneous lesions have predilection for the
422 350limbs. S ome cases arise as a type of malignant change in schwannomas, and rare cases have been associated with a
423 424 389,425,426 384,389,427peristomal site, a foreign body, an arteriovenous fistula, or previous irradiation. Exceptionally
epithelioid angiosarcoma originating in another organ may metastasize to the skin, especially those originating in a large
428blood vessel. Most cases including those presenting in the skin have a very aggressive clinical course, with the$
development of systemic metastasis and death within 2 to 3 years of presentation in most patients.
Histologic Appearances
Epithelioid angiosarcoma commonly shows necrosis and hemorrhage. I t is composed of solid sheets (Fig. 3-55) of large, oval
or rounded, epithelioid cells with abundant eosinophilic or amphophilic cytoplasm, having a large, pale vesicular nucleus
with a conspicuous eosinophilic nucleolus. Pleomorphism is not marked, but mitoses are frequent. Focally, some cells show
intracytoplasmic vacuoles, occasionally containing red blood cells. At least focal blood vessel formation can be identified in
most cases, and this is associated rarely with a papillary arrangement. Origin from a large blood vessel is evident in some
cases. A reticulin stain typically reveals a tubular vasoformative architecture (Fig. 3-56). I mmunohistochemically, tumor cells
are positive for factor VI I I –related antigen and CD 31 in almost all cases. Positivity for cytokeratin is also a feature in around
50% of cases, whereas only rare cases are focally positive for EMA . Exceptional focal positivity for melan-A has been reported
422 429in cutaneous neoplasms. In a further case CD30 was expressed by tumor cells.
FIGURE 3-55 Epithelioid angiosarcoma. Note the sheet-like growth pattern and very prominent nucleoli.
FIGURE 3-56 Epithelioid angiosarcoma. Reticulin staining helps to demonstrate the tubular
vasoformative architecture.
Differential Diagnosis
Epithelioid angiosarcoma has to be included in the differential diagnosis of almost any epithelioid malignant neoplasm,
including metastatic carcinoma, mesothelioma, melanoma, epithelioid sarcoma, and epithelioid malignant schwannoma,
especially when located in skin and soft tissues. Recognition is usually possible by the identification of intracytoplasmic
lumina, vasoformative areas, and, most important, positivity of tumor cells for specific endothelial markers (especially factor
VIII–related antigen and CD31).
“intimal” Sarcomas
Primary sarcomas of major blood vessels are rare; altogether fewer than 200 cases have been reported in the
430-439literature. A lthough most mural sarcomas, especially those presenting in large veins such as the inferior vena cava,
434are leiomyosarcomas, a group of luminal sarcomas appear to arise from the intima and are therefore known as intimal
sarcomas. Most of these cases present in the aorta or pulmonary artery as poorly differentiated spindle cell sarcomas. They
may rarely show immunohistochemical evidence of endothelial differentiation but are more commonly positive for smooth
439 437muscle actin. Most recently, positivity for osteopontin has also been documented. However, a large proportion are
only positive for vimentin. On the basis of these findings it has been proposed that intimal sarcomas arise from intimal
endothelial cells, fibroblasts, or myofibroblasts. These lesions are virtually confined to adulthood and are associated with a
very poor prognosis. A study of a small number of cases by comparative genomic hybridization has shown that the most
439consistent cytogenetic abnormality consists of gains and amplifications 12q13-14. These tumors show frequent
amplification of the platelet-derived growth factor receptor-α, and this is associated with activation of the receptor and also
with activation of the epidermal growth factor receptor. The la er patients can provide a rationale for targeted therapies in
440this group of neoplasms.$
Tumors of Lymph Vessels
21Tumors of lymphatic vessels are much less common than hemangiomas and comprise about 4% of all vascular tumors.
The great majority of tumors are benign, and it is believed that most of them represent developmental malformations rather
than true neoplasms. D istinction between tumors of lymphatic vessels and blood vessels is not always possible, even with
the use of immunohistochemistry or electron microscopy, and in some lesions a combination of both vessel types is seen, as,
for example, in intramuscular angioma (see earlier discussion). Lymphangiomas can be classified into six main types: (1)
cavernous lymphangioma, (2) cystic hygroma, (3) lymphangioma circumscriptum, (4) the more recently characterized
acquired progressive lymphangioma (benign lymphangioendothelioma), (5) lymphangiomatosis, and (6) multifocal
lymphangiomatosis with thrombocytopenia. It is doubtful whether capillary lymphangioma exists.
Cavernous Lymphangioma and Cystic Hygroma
Clinical Features
Both conditions are described together, as cystic hygroma appears simply to be a variant of cavernous lymphangioma in
which macroscopic dilatation of the vascular channels occurs. I t seems that cystic hygromas develop at anatomic sites in
441which there is less resistance to expansion from surrounding structures. Most lesions present at birth or in the first years
442-444 445of life, with an equal sex incidence ; a minority of cases are detected in adults. Cystic hygromas tend to occur more
commonly in the neck, axillae, and groins, whereas cavernous lymphangioma also occurs in the oral cavity (especially the
tongue), limbs, and abdomen (principally the mesentery and less often the retroperitoneum). A lthough both lesions are
prone to local recurrence, this is more common in cavernous lymphangioma.
Histologic Appearances
The dermis, subcutis, or deeper tissues contain dilated thin-walled lymphatic channels lined by a enuated, bland
endothelial cells (Fig. 3-57), which rarely can be plump or cuboidal. Vascular lumina may be empty or contain proteinaceous
lymph, lymphocytes, and occasional erythrocytes. I n the surrounding stroma are variable numbers of lymphocytes and,
rarely, lymphoid follicles. A round larger channels is often an incomplete layer of smooth muscle (Fig. 3-58). Long-standing
lesions can show prominent stromal fibrosis. For reasons that are unclear, intra-abdominal examples may present acutely,
446and histologically such cases are associated with marked inflammation, adjacent fat necrosis, and reactive changes.
FIGURE 3-57 Cavernous lymphangioma. Note the dilated lymphatic vessels with variably thick walls.
FIGURE 3-58 Cavernous lymphangioma. Note the lymphoid aggregates and prominent smooth muscle in
some of the vessel walls.
Differential Diagnosis
D istinction from cavernous hemangioma may sometimes be impossible, especially in the presence of hemorrhage and
intraluminal erythrocytes. The finding of lymphoid aggregates tends to favor the diagnosis of lymphangioma. Lesions in the
peritoneum have to be distinguished from cystic mesothelioma, which usually shows more variation in the size of the cystic
spaces and in which the lining cells are positive for keratin and negative for endothelial markers.$
Lymphangioma Circumscriptum
Clinical Features
Lymphangioma circumscriptum presents as a developmental malformation in infancy, often in association with cavernous
lymphangioma, cystic hygroma, or lymphangiomatosis, or as an acquired lesion in adults, usually in relation to radiotherapy
447-449 450or chronic lymphedema. Vulvar lesions have been associated with Crohn disease, carcinoma, and hidradenitis
451suppurativa. This la er form is be er regarded as lymphangiectasia. A n equal sex incidence exists, and lesions can occur
at any site, with predilection for the limbs. Clinically, they are characterized by the presence of numerous asymptomatic,
circumscribed vesicles containing clear fluid or blood. Recurrence after excision is common only in those lesions developing
in childhood.
Histologic Appearances
The lesions are composed of numerous dilated lymphatic vessels in the superficial and papillary dermis, associated with
overlying epidermal hyperplasia (Fig. 3-59) and a lymphocytic infiltrate in the surrounding stroma. Often the lymphatic
channels appear almost to be intraepidermal, because of cross-cu ing. S ome lesions, especially those in children, are
connected with a deep muscular lymphatic, which, if not ligated when the lesion is excised, is associated with a high rate of
452local recurrence.
FIGURE 3-59 Lymphangioma circumscriptum. Note the dilated lymphatics in the papillary dermis and the
associated inflammation, a common secondary feature.
Benign Lymphangioendothelioma (Acquired Progressive Lymphangioma)
Clinical Features
Benign lymphangioendothelioma (acquired progressive lymphangioma) is a rare, benign lymphatic abnormality. A lthough it
453was described as early as 1970 under the name angioendothelioma (lymphatic type), relatively few cases have been
454-457reported in the literature since that time. A lthough any age group may be affected, a predilection exists for
middleaged to older adults. The incidence is equal in men and women. Most lesions are located on the extremities, especially the
lower limb, but this lesion also occurs on the face, back, and abdomen. Clinically, it presents as a solitary, well-defined
erythematous macule or plaque that can mimic a bruise but that slowly enlarges over a period of years. A published report
458of multifocal progressive lymphangioma is more likely to represent an example of lymphangiomatosis. Lesions only very
459rarely recur after simple excision, and focal, but subtotal, spontaneous regression has been described. A case associated
460with HI V has been documented. Exceptional (and perhaps questionable) cases have been said to occur after
461 462radiotherapy and after arteriography.
Histologic Appearances
The typical lesion consists of horizontal, irregular thin-walled vascular channels, showing dissection of collagen bundles and
an anastomosing growth pa ern; these spaces are lined by a single layer of flat endothelial cells with, at most, only very mild
cytologic atypia (Fig. 3-60). Their lumina often appear empty or contain a few red blood cells and/or proteinaceous material.
A lthough most channels are located in the superficial dermis, extension into the deep dermis and subcutaneous tissue is
sometimes seen. I nvolvement of the papillary dermis is not present, and no connection exists with deep large muscular
lymphatics, as seen in lymphangioma circumscriptum.$
FIGURE 3-60 Benign lymphangioendothelioma (“progressive lymphangioma”). Note the dissection of
collagen but complete absence of endothelial atypia.
Differential Diagnosis
I n view of the presence of collagen dissection by vascular channels, the main differential diagnosis is with well-differentiated
angiosarcoma, despite the differences in clinical se ing. D istinction from the la er is based on the absence of endothelial
atypia, multilayering, or mitotic activity in progressive lymphangioma. Patch-stage KS is clinically multifocal and shows
histologically irregular vascular channels around preexisting dermal vessels and adnexa, associated with plasma cells and
extravasation of red blood cells with hemosiderin deposition. A lthough clinically different, benign lymphangioendothelioma
may show a striking architectural resemblance to hobnail hemangioma. The former, however, generally lacks prominent
hobnail cells, intraluminal red cells are sparse, and hemosiderin deposition is usually less conspicuous.
Lymphangiomatosis is a very rare developmental abnormality characterized by diffuse involvement of parenchymal organs,
463,464bone, and/or soft tissue. I n a significant proportion of cases, the disease is confined to one limb with or without bone
465 464,465involvement. Typically, it presents in children, sometimes from birth, with no sex predilection. Clinical overlap
with conventional angiomatosis or other vascular malformations may exist, and in some cases a firm diagnosis cannot be
made without angiography. Cases in soft tissue present as diffuse, boggy, fluctuant swellings, which can be associated with a
cutaneous fistula or, less often, as lesions indistinguishable from lymphangioma circumscriptum. I nvolvement of visceral
464organs, as opposed to soft tissues and bone, is associated with a poor prognosis. Gorham-S tout syndrome describes a
variant of lymphangiomatosis in which a proliferation of lymphatic and vascular channels is associated with extensive
466osteolytic lesions.
Histologic appearances in soft tissue can simulate those of cavernous lymphangioma or, more commonly, those of benign
lymphangioendothelioma, with typically extensive dissection of normal tissues reminiscent of angiosarcoma. However, the
lymphatic channels are far more extensive and involve dermis and subcutis widely (Fig. 3-61). A n additional finding,
especially in lymphangiomatosis of soft tissues, is the presence of abundant hemosiderin in the interstitium despite the
relative absence of red blood cells in the vascular lumina. Long-standing cases show prominent stromal fibrosis.$
FIGURE 3-61 Lymphangiomatosis. Note the very extensive, diffuse dissection between normal
Multifocal Lymphangiomatosis with Thrombocytopenia (Cutaneovisceral Angiomatosis with Thrombocytopenia)
This is a distinctive clinicopathologic entity, also described as cutaneovisceral angiomatosis with thrombocytopenia and
467-470infantile hemorrhagic angiodysplasia. Typically, it presents at birth with numerous, sometimes hundreds of lesions
varying from red-brown to blue discrete papules to macules, nodules, and plaques ranging in size from a few millimeters to
several centimeters. N ew lesions continue to develop throughout childhood, and other sites are involved including
gastrointestinal tract, lungs, bone, liver, spleen, muscle, and synovium. Thrombocytopenia is an associated finding, and
patients may die of bleeding or sepsis. Histologically multiple, irregular, thin-walled dilated lymphatic-like vascular channels
are seen in the reticular dermis and subcutaneous tissue. These channels are lined by endothelial cells that often display
hobnail morphology. Intraluminal papillary projections are frequent.
Atypical Vascular Lesions After Radiotherapy
A ngiomatous lesions occasionally (but seemingly increasingly) present in the field of prior radiation therapy, most often in
381,471-474the skin of the breast and rarely at the site of radiotherapy for other malignancies, mainly female genital cancer.
Histology of some of these lesions may display architecturally atypical features, raising the possibility of a postirradiation
angiosarcoma, and these are the ones described here. The relationship between these proliferations and postirradiation
475angiosarcoma is controversial. A lthough some authors believe that all these lesions are benign, in a minority of cases
473,474,476histologic overlap exists with or, rarely, there is progression to angiosarcoma.
Lesions usually develop a few years after radiotherapy for breast cancer. The time elapsed between radiotherapy and
473development of the lesions is usually shorter than that for angiosarcomas. The clinical presentation is not distinctive and
varies from skin-colored to red, usually multiple macules and papules.
448The histologic features vary, and occasional lesions may resemble lymphangioma circumscriptum or benign
461lymphangioendothelioma. Most biopsies show irregular, variably dilated lymphatic-like vascular channels lined by a
single layer of endothelial cells in the superficial and/or deep dermis.
The lesions are usually fairly circumscribed but may have a dissecting growth pa ern. The endothelial cells lining the
channels are flat or have a somewhat hyperchromatic hobnail appearance, and papillary projections may occasionally be
seen (Fig. 3-62). N o nuclear pleomorphism or endothelial multilayering is seen, and mitoses are usually absent. A recent
study has separated this type of proliferation into lymphatic type and vascular type, suggesting that the la er, in which
congested capillary-like vascular channels surrounded by a layer of pericytes predominate, is associated with a higher risk of
FIGURE 3-62 Atypical postradiation vascular proliferation. This skin lesion from the breast is composed
of architecturally atypical lymphatic-like channels, but no endothelial multilayering or pleomorphism is
The differential diagnosis includes well-differentiated angiosarcoma, hobnail hemangioma, and KS . A s opposed to
hobnail hemangioma, the lesion is not symmetric, and the vascular channels do not always have a predominantly superficial
dermal location. However, in some cases this distinction may be impossible on morphologic grounds and may best be
predicated on the history of radiation. The clinical se ing, the absence of inflammation, and the presence of hobnail
endothelial cells with focal papillary projections should allow distinction from KS . Careful examination of multiple sections
is recommended to make sure that no mitotic figures and cytologic atypia are seen to distinguish it from a
welldifferentiated angiosarcoma.
Lymphangiomyomatosis is a very rare hamartomatous condition characterized by diffuse proliferation of smooth muscle
within lymphatics and lymph nodes of the retroperitoneum, mediastinum, and, in up to 70% of cases, the lung
477-479parenchyma. When the condition is localized, it is usually referred to as lymphangiomyoma. I t presents exclusively in
women, mainly during the reproductive years, suggesting a hormonal role in its pathogenesis. However, this relationship is
479-481controversial. Patients with lung involvement present with dyspnea, pneumothorax, and chylothorax, and, when
477-479involvement is extensive, the disease commonly pursues a fatal course unless lung transplantation is performed. A
well-recognized association with renal angiomyolipoma exists, and lymphangiomyomatosis develops in some patients with
479,482tuberous sclerosis. I t has now also been demonstrated that sporadic lymphangiomyomatosis is tightly linked to a
483,484mutation of one of the tuberous sclerosis complex genes (TSC2) on chromosome 16. A similar alteration has been
demonstrated in perivascular epithelioid cell tumors (PEComas) occurring sporadically and in association with tuberous
485sclerosis, confirming the close relationship between this group of neoplasms. Histologically, the lesions are composed of
lymphatic channels surrounded by clusters of bland smooth muscle cells, often with granular cytoplasm, arranged in short
fascicles (Fig. 3-63). I mmunohistochemically, these cells express a typical smooth muscle phenotype and are also positive
consistently for human melanoma black (HMB)-45, a melanoma-associated marker that reacts with a
premelanosome486 487associated glycoprotein ; similar staining may also be seen for melanoma antigen recognized by T cells (MA RT)-1. This
reactivity is shared with the smooth muscle component in angiomyolipomas (but not with any other type of smooth muscle)
and also with clear cell (sugar) tumors of the lung and other locations. A lthough this may reflect cross-reaction with a
different protein, it identifies a distinctive subtype of perivascular smooth muscle cells (referred to as perivascular
488epithelioid cells ; see Chapter 24), and this phenotype is helpful in differential diagnosis. The notion that these lesions
489express CD1a has been dispelled.$
FIGURE 3-63 Lymphangiomyomatosis. Nodules of bland smooth muscle cells arranged around
numerous lymphatic channels.
Tumors of Perivascular Cells
Glomus Tumor
Clinical Features
490-492Glomus tumors arise from a modified smooth muscle cell located in the walls of specialized arteriovenous
anastomoses (the S ucquet-Hoyer canal) involved in temperature regulation. These lesions are relatively common and occur
most often in young adults; no sex predilection is seen except for digital and subungual lesions, which tend to predominate
in women. Most tumors are less than 1 cm in diameter and develop in the dermis or subcutis of the upper and lower
extremities, especially the hands; any site, however, including mucosae and visceral locations, can be affected. Cutaneous
lesions present as red-blue nodules and may be associated with paroxysmal pain in relation to tactile stimulation. Pain is
most often a feature of the histologically solid type of lesion (see later discussion).
Multiple lesions, some of which can be segmental, are seen occasionally, most often in children, and most are thought to
493,494be inherited in an autosomal dominant fashion. The genetic aberration associated with multiple inherited
495,496 497glomangiomas has been linked to chromosome 1p21-22. The gene is named glomulin. When multiple, these
lesions often simulate cavernous hemangiomas and can be confused clinically with the lesions seen in the blue rubber bleb
nevus syndrome. Occasional cases of glomus tumor can occur at a wide variety of sites, including the trachea, lung,
mediastinum, esophagus, stomach, small bowel, colon, rectum, mesentery, bone, vagina, cervix, pterygoid fossa, liver,
498-511pancreas, ovary, kidney and even an ovarian teratoma. Very rarely a glomus tumor can originate in a blood
512,513 514vessel or a nerve. A n association between solitary and multiple glomus tumors mainly on the digits and von
Recklinghausen disease (neurofibromatosis type 1) has also been described, and this finding is now regarded as part of the
515-518spectrum of the disease. Multiple gastric lesions with intravascular spread and benign behavior have been described
519exceptionally. I t is important to be aware of a normal prominent glomus body, the glomus coccygeum, located near the
520tip of the coccyx, that can measure up to several millimeters; if found incidentally, this can be confused with a neoplasm.
492,521The majority of glomus tumors are entirely benign, and local recurrence is very uncommon. D espite worrying
histologic features in occasional cases (see later discussion), malignant glomus tumors (or glomangiosarcomas) are very
Histologic Appearances
Histologically, most glomus tumors are well circumscribed and composed of varying proportions of glomus cells, blood
vessels, and smooth muscle. Glomangiomas are by far the most common, accounting for up to 60% of glomus tumors (Fig.
364). They are followed by solid glomus tumors (Fig. 3-65; 25% of cases) and glomangiomyomas (Fig. 3-66; 15% of cases). A
typical solid glomus tumor is composed of numerous monotonous, rounded glomus cells with palely eosinophilic cytoplasm
and a large central round or oval punched-out uniform nucleus. Cell borders are typically sharply defined and can be
highlighted by PA S positivity. The surrounding stroma often appears edematous and can show extensive myxoid
degeneration. S mall blood vessels are sca ered between the tumor cells, but they are usually difficult to detect in the
527absence of special stains. Rare variants of glomus tumor showing oncocytic change or composed predominantly of
528epithelioid cells have been described. I n glomangiomas and glomangiomyomas the proportion of glomus cells varies,
and in some cases they are seen only as a thin rim around blood vessels. I n glomangiomyomas, the proportion of tumor
composed of well-formed smooth muscle bundles is also variable. I n the vicinity of glomus tumors it is common to find
groups of glomus cells surrounding normal blood vessels.FIGURE 3-64 Glomangioma. In this most common variant of glomus tumor, attenuated layers of glomus
cells are sometimes overlooked.
FIGURE 3-65 Glomus tumor. The solid type shows typical glomus cytomorphology with well-defined cell
FIGURE 3-66 Glomangiomyoma. Many of the tumor cells are eosinophilic and spindle shaped.
526,529Glomangiomatosis is defined as a tumor with features of angiomatosis and excess glomus cells.
The so-called infiltrating glomus tumor (Fig. 3-67) is a rare variant of histologically otherwise typical glomus tumor that is
530,531usually deep-seated and shows diffuse infiltration of surrounding soft tissues. I ts recognition is important because it
is associated with a high local recurrence rate.$
FIGURE 3-67 Infiltrating glomus tumor. This lesion from the thigh was infiltrating in and around the
femoral nerve. (Courtesy Dr. W. K. Blenkinsopp.)
Glomus tumor cells are typically immunopositive for smooth muscle actin (Fig. 3-68) and muscle-specific actin and are
532-534 535occasionally focally positive for desmin. Positivity for CD 34 may also be seen. I nterestingly, BRAF mutations have
535abeen identified in some glomus tumors.
FIGURE 3-68 Glomangioma. The tumor cells are strongly and uniformly smooth muscle actin positive.
The diagnosis of glomangiosarcoma is usually based on the histologic presence of a benign glomus tumor associated with
522-526,536,537a frankly sarcomatous component ; most such cases have either a round-cell or leiomyosarcomatous
appearance. The histologic diagnosis is difficult, and, only recently, refined criteria have been proposed to define malignant
526lesions. The proposed criteria for malignancy are deep location and a size of more than 2 cm, or atypical mitotic figures,
or moderate to high nuclear grade and 5 or more mitotic figures per 50 high-power fields. Lesions with marked nuclear
atypia but no other malignant features are termed symplastic. Glomus tumors of uncertain malignant potential are defined
as lesions that lack criteria for the diagnosis of malignant glomus tumor or symplastic glomus tumor but have high mitotic
526activity and superficial location, or large size only, or deep location only. Thirty-eight percent of cases fulfilling criteria for
526malignancy metastasized in the largest series published.
Differential Diagnosis
D istinction between solid glomus tumor and cutaneous adnexal neoplasms, especially eccrine spiradenoma, is based on the
presence of focal ductal differentiation, two populations of cells, and positivity for epithelial markers in the la er.
I ntradermal nevus with pseudovascular spaces shows at least focal nesting, evidence of maturation, and positivity for S -100
Hemangiopericytoma (so-called), including Myopericytoma
538S o-called hemangiopericytoma was described by S tout and Murray in 1942 as a vascular tumor originating from the
pericyte, a perivascular modified smooth muscle cell. This proposal was mainly based on the architectural pa ern with
tumor cells surrounding branching blood vessels and was supported to some extent (at least in the past) by ultrastructural
539-541studies. However, immunohistochemistry has failed to support this theory, as most tumors (at least in adulthood)
542 541,543stain only (and nonspecifically) for vimentin and CD34 but not for actin or other myoid markers.
Traditionally, hemangiopericytoma has been classified into adult and infantile variants, which have li le in common,
either clinically or histologically, except for the presence of a branching “pericytomatous” vascular pa ern, a feature that is
544-546also shared with many other tumors. Most common among those tumors that consistently share this pa ern are
solitary fibrous tumor, synovial sarcoma, infantile myofibromatosis, low-grade endometrial stromal sarcoma, mesenchymal
chondrosarcoma, deep benign fibrous histiocytoma, and infantile fibrosarcoma. I n recent years it has become clear that
infantile and adult hemangiopericytoma are two completely independent entities, the former being closely related to
infantile myofibromatosis and the latter being most likely synonymous with solitary fibrous tumor (see Chapter 24).
A mong the lesions traditionally diagnosed as hemangiopericytoma in adults considerable inhomogeneity seems to exist,
likely reflecting the absence of reproducible diagnostic criteria. I n fact the personal opportunity to review some of S tout's$
original cases has suggested that this entity may have been heterogeneous and relatively noncohesive from the outset, as is
easy to understand given the absence of more modern diagnostic techniques at that time. A s a consequence, this has become
(like so-called malignant fibrous histiocytoma) something of a wastebasket diagnosis, yet discrete subsets remain (detailed
later) for which there is no be er name. I n parallel with this realization, it is also increasingly appreciated that a group of
538,547truly pericytic lesions probably exists (examples of which were included in S tout's early work on this topic ). These
548lesions, which include examples of so-called myofibromatosis occurring in adults, are best categorized as myopericytoma
and are described in more detail later.
Clinical Features
549,550Adult hemangiopericytoma is said to occur in middle to late adult life with an equal sex distribution. Probably the
majority of the cases so classified in the past would nowadays be regarded as examples of solitary fibrous tumor at the more
cellular end of that morphologic spectrum (see Chapter 24). This would also include the cellular lesions located in pelvis and
retroperitoneum, seemingly most often in adult women, which may be associated with hypoglycemia because of secretion of
551insulin-like growth factor. A supposedly distinct group comprises those lesions that arise in the meninges (formerly
552,553often known as angioblastic meningioma: see Chapter 26). However, many would argue that these are also cellular or
malignant examples of solitary fibrous tumor, and certainly no criteria for distinguishing these tumor types seem to be
convincing. A lthough histologic grading of these so-called meningeal hemangiopericytomas is unreliable, many seem
ultimately to pursue an aggressive course: a distinctive feature of considerable relevance to general pathologists is the
propensity of meningeal lesions to give rise to osseous, intra-abdominal, or (less often) pulmonary metastases, often after a
prolonged latent period.
Sinonasal hemangiopericytoma, which is discussed in more detail in Chapter 4, is a histologically distinct subset composed
of more obviously myoid (actin positive) cells. I t occurs principally in adults and is characterized by the tendency for local
554,555recurrence but not metastasis.
Infantile hemangiopericytoma can be congenital or present in the first years of life as a solitary, most often deep, dermal or
549,556,557 557subcutaneous mass. S ome patients have multiple lesions, further underlining the (essentially complete)
overlap with infantile myofibromatosis. Recurrence is common, but the ultimate behavior is generally benign. Rare cases
558with metastasis have been reported ; however, these might represent an unusual manifestation of multicentricity rather
than true metastasis. The clinicopathologic features are virtually identical to those of infantile myofibromatosis, and it is
556,557,559nowadays generally agreed that they represent different stages or patterns of the same entity.
Myopericytoma is the term we currently prefer to use to embrace lesions described as myofibromatosis in adults—
548,560,561glomangiopericytoma and myopericytoma. We also believe that this is usually a more appropriate term for
562infantile myofibromatosis (see Chapter 24) and solitary myofibroma in adults, although general adoption of such changes
in terminology has been gradual to date. A s a group, these lesions most commonly develop in superficial soft tissue of the
extremities (particularly the distal lower limb) followed by the head and neck of adults, although often they have been
560noticed since birth or early childhood. Men are more often affected than women. The lesions may be solitary or multiple,
are sometimes painful, and appear to recur locally in 10% to 20% of patients, although this probably represents multifocal
(or “field change”) disease. Two cases of glomangiopericytoma associated with oncogenic osteomalacia have been
563,564 560,565described, and we have seen similar cases. Examples of malignant myopericytoma are very rare.
Myopericytomas can occur in association with HI V-A I D S , and, in this se ing, tumors are often multiple; have predilection
566,567for internal organs including bronchus, larynx, liver, and brain; and are positive for Epstein-Barr virus.
Histologic Appearances
A dult hemangiopericytomas (so called) are indistinguishable from cellular examples of solitary fibrous tumor (see Chapter
24). They are usually well circumscribed, are often lobulated, and are composed of cytologically uniform small, basophilic,
ovoid to spindled cells with an oval nucleus and ill-defined cytoplasm. These cells are arranged in a pa ernless fashion
around numerous thin-walled ramifying blood vessels, which often adopt a typical staghorn configuration (Fig. 3-69). Focal
or diffuse myxoid change and stromal fibrosis can be a feature. A silver stain shows that the tumor cells are located outside
the vascular spaces and are each surrounded by a reticulin sheath. Features that have been said to indicate malignancy are
549the presence of increased cellularity, necrosis, hemorrhage, and more than 4 mitotic figures per 10 high-power fields, the
la er being the most important feature—these are essentially the same criteria as are nowadays employed in solitary fibrous
FIGURE 3-69 So-called hemangiopericytoma. A, Typical branching, staghorn vessels, patternless
architecture, and nondescript fibroblastic cytology. B, Pleomorphism is usually minimal, even in malignant
lesions: this case showed up to 15 mitoses per 10 high-power fields. The appearances in fact represent
cellular examples of solitary fibrous tumor.
I nfantile hemangiopericytoma is a multinodular tumor in which the lesional cells tend to be more polymorphic and focally
spindle shaped or myoid in appearance (Fig. 3-70). Mitotic figures and focal necrosis are common findings, as is
subendothelial proliferation, which may simulate vascular invasion. I n essentially all cases it is possible to distinguish a
second tumor cell population composed of micronodules and fascicles of plump spindle-shaped cells with myoid features
that stain positively for α-smooth muscle actin. This creates a subtle zoning phenomenon, indistinguishable from (but often
less marked than) that seen in myofibromatosis.
FIGURE 3-70 Infantile hemangiopericytoma. Note the focal transition to a more spindle-shaped, myoid
Myopericytoma encompasses a morphologic continuum of lesions ranging from those with the appearance of
myofibromatosis (Fig. 3-71) to those that almost resemble glomus tumor (Fig. 3-72) (but often with “pericytoma-like”
vessels) or angioleiomyoma. A ll are composed of actin-positive perivascular contractile cells showing a variable degree of
560myoid (spindle celled or glomoid) cytomorphology. The majority also show positivity for caldesmon. I n many cases
admixed pa erns closely resemble myofibromatosis and so-called hemangiopericytoma, except that the perivascular spindle
cells in these lesions are eosinophilic and clearly myogenic (Fig. 3-73). I t is common, particularly at the periphery of these
lesions, to find perivascular proliferation of similar spindle-shaped cells (outside the main tumor nodule), and these cells
may proliferate in either the adventitial or subendothelial layers. The la er closely mimics true vascular invasion, except for
the intact overlying layer of endothelium, and this is the feature that has previously been well described in both infantile
myofibromatosis and infantile hemangiopericytoma (which in reality are points on this same morphologic spectrum).
Examples of true intravascular myopericytoma are rarely seen mainly in an intravenous location, more exceptionally within
560,569,570 560,565an artery. Malignant examples of myopericytoma display cytologic atypia and increased mitotic activity.$
FIGURE 3-71 Myopericytoma. This lesion closely resembles myofibromatosis. Note the perivascular
orientation of the spindle cells.
FIGURE 3-72 Myopericytoma. At the most glomoid end of the spectrum, myoid spindle cells are
arranged concentrically around small vessels—the appearances are truly pericytic.
FIGURE 3-73 Myopericytoma. Lesions with intermediate morphology are composed of eosinophilic
spindle cells arranged around prominent branching vessels.
Differential Diagnosis
With the advent of immunohistochemistry, the diagnosis of so-called hemangiopericytoma has become one of exclusion
543,545because many neoplasms can show, at least focally, a pericytoma-like pa ern. Most particularly these include the
• Synovial sarcoma, which may show a biphasic pattern and is EMA and keratin positive
• Mesenchymal chondrosarcoma, which shows islands of mature cartilage
• Deep benign fibrous histiocytoma, which is more polymorphic (showing a storiform pattern and
inflammatory cells)
• Phosphaturic mesenchymal tumor, which has a variety of histologic patterns and is often associated with
stromal calcification and osteoclast-like giant cells
Other tumors that commonly show this vascular pa ern are solitary fibrous tumor and infantile fibrosarcoma (see
Chapter 24), and, in truth, almost any type of sarcoma may show focally a perfect resemblance to so-called
hemangiopericytoma on occasion. Hence this diagnostic term has largely fallen into disuse and should, in the future,
perhaps be reapplied instead to the spectrum of true myopericytic neoplasms.R e f e r e n c e s
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report. Ann Pathol. 2010;30:325–327.C H A P T E R 4
Tumors of the Upper Respiratory Tract
Bruce M. Wenig
▪ Nasal Cavity, Paranasal Sinuses, and Nasopharynx
Chapter Outline
Benign Epithelial and Neuroectodermal Neoplasms 92
Benign Mesenchymal Neoplasms 99
Osseous, Fibroosseous, and Cartilaginous Lesions 105
Tumors of Indeterminant Malignant Potential 110
Malignant Epithelial and Neuroectodermal Neoplasms 111
Nonepithelial Malignant Neoplasms 133
Pseudoneoplastic Lesions 144
The nasal cavity and paranasal sinuses—including the maxillary, ethmoid, sphenoid, and frontal sinuses—are collectively
referred to as the sinonasal tract. The sinonasal tract is anatomically and embryologically distinct from the nasopharynx.
A lthough the sinonasal tract and nasopharynx have identical-appearing ciliated respiratory epithelium, the epithelium of the
sinonasal tract is ectodermally derived, whereas that of the nasopharynx is endodermally derived. This embryologic
difference may be a factor in the development of certain epithelial lesions unique to these surfaces (e.g., S chneiderian
papillomas of the sinonasal tract and nasopharyngeal carcinomas [N PCs]). D espite these differences, the sinonasal tract and
nasopharynx are composed of similar structures such as minor salivary glands and connective tissue. These structures may
give rise to identical neoplasms that differ only in their location and resulting clinical symptomatology. The classification of
neoplasms of the nasal cavity and paranasal sinus is listed in Table 4A-1, and the neoplasms of the nasopharynx are listed in
Table 4A-2.
C lassification of N asal C avity and P aranasal S inus N eoplasmsBenign
Schneiderian papillomas
Squamous papilloma (nasal vestibule)
Minor salivary gland tumors
Lobular capillary hemangioma (pyogenic granuloma)
Solitary fibrous tumor
Ossifying and nonossifying fibromyxoid tumor
Peripheral nerve sheath tumors
Fibrous histiocytoma
Fibroosseous lesions (ossifying fibroma, psammomatoid ossifying fibroma)
Myxoma/fibromyxoma/chondromyxoid fibroma
Indeterminant for malignancy/low-grade malignant potential
Sinonasal-type hemangiopericytoma
Epithelioid hemangioendothelioma
Squamous cell carcinoma:
• Keratinizing squamous cell carcinoma
• Nonkeratinizing squamous cell carcinoma
• Variants of squamous cell carcinoma (verrucous carcinoma, papillary squamous cell carcinoma, spindle cell
squamous carcinoma, basaloid squamous cell carcinoma, lymphoepithelial carcinoma, adenosquamous
Sinonasal undifferentiated carcinoma
• Intestinal types
• Nonsalivary, nonintestinal types
Minor salivary gland neoplasms
Mucosal malignant melanoma
Olfactory neuroblastoma
Non-Hodgkin malignant lymphomas
Extraosseous Ewing sarcoma/primitive neuroectodermal tumor
Undifferentiated pleomorphic sarcoma
Malignant schwannoma
Secondary tumors
C lassification of N eoplasms of the N asopharynxBenign
Squamous papilloma
Minor salivary gland tumors
Granular cell tumor
Lymphangioma/cystic hygroma
Fibrous histiocytoma
M a l i g n a n t
Nasopharyngeal carcinoma
• Differentiated type
• Undifferentiated type
Low-grade papillary adenocarcinoma
Minor salivary gland tumors
Mucosal malignant melanoma
Lymphomas (non-Hodgkin and Hodgkin)
Undifferentiated pleomorphic sarcoma/fibrosarcoma
Malignant peripheral nerve sheath tumor
Kaposi sarcoma
Synovial sarcoma
Secondary tumors
Benign Epithelial and Neuroectodermal Neoplasms
Sinonasal-Type (Schneiderian) Papillomas
The ectodermally derived lining of the sinonasal tract, termed the S chneiderian membrane, may give rise to three
morphologically distinct benign papillomas collectively referred to as S chneiderian or sinonasal-type papillomas. The three
morphologic types are inverted, oncocytic (cylindrical or columnar cell), and fungiform (exophytic, septal) papillomas (Table
4A-3).TABLE 4A-3
Sinonasal (Schneiderian) Papillomas: Clinicopathologic Features
Septal Inverted Oncocytic
Percentage 20-50 47-73 3-8
Sex, age (yr) M > F, 20-50 M > F, 40-70 M = F, >50
Location Nasal septum Lateral nasal wall in region of middle Lateral nasal wall and sinuses
turbinates with extension into sinuses (maxillary or ethmoid)
(maxillary or ethmoid)
Focality Unilateral Typically unilateral; rarely bilateral Unilateral
Histology Papillary fronds Endophytic or “inverted” growth consisting Multilayered epithelial
composed of a of thickened squamous epithelium proliferation composed of
predominantly composed of squamous, transitional, and columnar cells with
squamous columnar cells (all three may be present abundant eosinophilic and
(epidermoid) in a given lesion) with admixed granular cytoplasm; outer
epithelium; mucocytes (goblet cells) and surface of the epithelial
mucocytes (goblet intraepithelial mucous cysts; mixed proliferation may
cells) and chronic inflammatory cell infiltrate demonstrate cilia;
intraepithelial characteristically is seen within all layers intraepithelial mucous cysts,
mucous cysts are of the surface epithelium often containing
present; delicate polymorphonuclear
fibrovascular leukocytes
Incidence of HPV Approximately 50% Approximately 38% positive; HPV 6 and 11; Typically absent
positive; HPV 6 less frequently HPV 16, 18; rarely HPV 57
and 11; less
frequently HPV
16, 18; rarely HPV
Incidence of Rare 2-27 4-17
HPV, Human papillomavirus.
1Collectively, S chneiderian papillomas represent fewer than 5% of all sinonasal tract tumors. The literature indicates that,
among sinonasal-type papillomas, the septal papilloma is the most common type. However, practical experience indicates
that the inverted type is the most common subtype seen. The oncocytic type is the least common. I n general, the
sinonasal1-8type papillomas occur over a wide age range but are rare in children. I nverted papillomas are most common in the fifth to
eighth decades; cylindrical papillomas occur in a somewhat older age range (greater than 50 years) and are uncommon in
1,2patients younger than the fourth decade of life; septal papillomas tend to occur in a younger age group. The septal
papillomas almost invariably are limited to the nasal septum. I nverted papillomas occur along the lateral nasal wall (middle
turbinate or ethmoid recesses) with secondary extension into the paranasal sinuses (maxillary and ethmoid, and less often
sphenoid and frontal); less frequently, inverted papillomas may originate in a paranasal sinus. Oncocytic papillomas also are
most often seen along the lateral nasal wall but may originate within a paranasal sinus (maxillary or ethmoid). The inverted
and oncocytic subtypes rarely occur on the nasal septum. Typically, the S chneiderian papillomas are unilateral; bilateral
1,7-9papillomas, in particular the inverted subtype, may occur with reported incidence of up to 10%. I n the presence of
bilaterality, clinical evaluation to exclude the possibility of extension from unilateral disease (i.e., septal perforation) should
10be undertaken. Inverted papillomas may occur in a paranasal sinus without involvement of the nasal cavity.
S chneiderian papillomas have a tendency to spread along the mucosa into adjacent areas. S ymptoms vary according to site
of occurrence and include airway obstruction, epistaxis, an asymptomatic mass, and pain.
Human papillomavirus (HPV) types 6/11, less often 16/18, and rarely other HPV types (e.g., HPV-57) have been found in
septal and inverted papillomas by molecular biologic analysis (in situ hybridization [I S H] and/or polymerase chain reaction
11-15 16[PCR]). I n a review of the literature, Barnes reported that 38% (131/341) of inverted papillomas were positive for HPV.
Whether a cause and effect exists between the presence of HPV and the development of S chneiderian papillomas remains to
be determined. Molecular biologic analysis on oncocytic papillomas to date has not identified the presence of HPV. N o
association is found with the development of additional papillomas elsewhere in the upper respiratory tract. Epstein-Barr
17virus (EBV) has also been identified in inverted papillomas, possibly implicating EBV in the development of these tumors ;
18however, other studies failed to confirm the presence of EBV in tumor cells.
S eptal papillomas are papillary, exophytic, verrucoid lesions with a pink to tan appearance and a firm to rubbery
consistency. They are often aOached to the mucosa by a narrow or broad-based stalk. Histologically, papillary fronds are
seen, being composed of a thick epithelium that is predominantly squamous (epidermoid) and, less frequently, respiratory
type (Fig. 4A -1). S urface keratinization is uncommon. Mucocytes (goblet cells) and intraepithelial mucous cysts are present.
The stromal component is composed of delicate fibrovascular cores.FIGURE 4A-1 Schneiderian papilloma, exophytic (septal) type. A, The tumor has an exophytic and
papillary growth protruding from the surface respiratory epithelium and is composed of thickened
nonkeratinized squamous (epidermoid) epithelium; note the presence of minor salivary glands in the
submucosa indicative of mucosal rather than cutaneous origin. B, At higher magnification the epithelium is
bland with uniform cells, retention of cellular polarity, absence of cytologic atypia, presence of scattered
mucous cells, and intraepithelial inflammatory cells; residual nonneoplastic ciliated respiratory epithelium is
seen along the surface.
I nverted papillomas are large, bulky, translucent masses with a red to gray color, varying from firm to friable in
consistency. Histologically, these tumors have an endophytic or “inverted” growth paOern consisting of markedly thickened
squamous epithelial proliferation growing downward into the underlying stroma (Fig. 4A -2). The epithelium varies in
cellularity and is composed of squamous, transitional, and columnar cells (all three may be present in a given lesion) with
admixed mucocytes (goblet cells) and intraepithelial mucous cysts. A mixed chronic inflammatory cell infiltrate
characteristically is seen within all layers of the surface epithelium. The cells are generally bland in appearance with uniform
nuclei and no piling up. However, pleomorphism and cytologic atypia may be present. The epithelial component may
demonstrate extensive clear cell features indicative of abundant glycogen content. Mitotic figures may be seen in the basal
and parabasal layers, but atypical mitotic figures are not seen. S urface keratinization may be present. The stromal
component varies from myxoid to fibrous with admixed chronic inflammatory cells and variable vascularity.FIGURE 4A-2 Schneiderian papilloma, inverted type. A, In contrast to the exophytic type, in the inverted
type the squamous epithelial cell proliferation grows in downward trajectory into underlying edematous
stroma. B, Bulbous downward (inverted) growth of benign epithelium taking origin from squamous
metaplasia of the normally respiratory epithelial-lined Schneiderian mucosa; an intraepithelial cyst with
inflammatory cells is present. C, At higher magnification the epithelial component is bland with
uniformappearing nuclei and retention of polarity; scattered mucocytes, intraepithelial inflammatory cells, and
small cysts (toward top) are present.
S chneiderian papillomas, oncocytic type, are dark red to brown, papillary or polypoid lesions. Histologically, a
multilayered epithelial proliferation is seen, composed of columnar cells with abundant eosinophilic and granular cytoplasm
(Fig. 4A -3). The nuclei vary from vesicular to hyperchromatic; nucleoli are usually indistinct. The outer surface of the
epithelial proliferation may demonstrate cilia. I ntraepithelial mucin cysts, often containing polymorphonuclear leukocytes,
are seen; cysts are not identified in the submucosa. The stromal component varies from myxoid to fibrous with admixed
chronic inflammatory cells and variable vascularity.FIGURE 4A-3 Schneiderian papilloma, oncocytic type. A, Exophytic epithelial proliferation with readily
apparent eosinophilic appearance. B, At higher magnification the epithelium is multilayered, composed of
columnar cells with abundant eosinophilic and granular cytoplasm; intraepithelial mucin cysts, some with
polymorphonuclear leukocytes, are present. C, Malignant transformation of an oncocytic-type papilloma
showing residual benign epithelium (top) with areas of carcinoma in situ (lower). Invasive keratinizing
squamous cell carcinoma was present in this case (not shown).
The differential diagnosis for septal papillomas includes verruca vulgaris and squamous papilloma. In contrast to all of the
sinonasal-type papillomas, squamous papilloma of the nasal vestibule does not have mucocytes as part of the neoplastic
proliferation. The differential diagnosis for inverted papillomas includes inflammatory sinonasal polyps, nonkeratinizing
respiratory (“transitional”) carcinoma, and verrucous carcinoma. The differential diagnosis for oncocytic papilloma includes
rhinosporidiosis and (low grade) papillary adenocarcinoma. The differential diagnosis for exophytic (septal) papilloma is
primarily with a cutaneous squamous lesion (e.g., papilloma, verruca) arising distal to the limen nasi from cutaneous
19The treatment for all sinonasal-type papillomas is complete surgical excision, including adjacent uninvolved mucosa.
The laOer is necessary as growth and extension along the mucosa result from the induction of squamous metaplasia in the
20adjacent sinonasal mucosa. This group of neoplasms will recur if incompletely resected; recurrence probably represents
persistence of disease rather than multicentricity of the neoplasm. I n general, prognosis is good after complete surgical
excision; however, if left unchecked, these neoplasms have the capability of continued growth with extension along the
mucosal surface with destruction of bone and invasion of vital structures.
I nverted papillomas and oncocytic papillomas can undergo malignant transformation. The incidence of malignant
transformation varies per subtype: malignant transformation reported for the inverted subtype ranges from 2% to
1,3,16,21-24 1,3,17-2027% ; for the oncocytic subtype the range is from 4% to 17% ; malignant transformation in septal
papilloma rarely, if ever, occurs. The majority of the malignancies occurring in association with S chneiderian papillomas are
squamous cell carcinomas (S CCs) (keratinizing and nonkeratinizing), varying in appearance from well to poorly
differentiated. Less frequently, other carcinomas may occur including verrucous carcinoma, mucoepidermoid carcinoma,
small cell carcinoma, adenocarcinoma (nononcocytic, oncocytic), and sinonasal undifferentiated carcinoma. The carcinoma
may occur synchronously or metachronously with the papilloma; metachronous carcinomas develop with a mean interval of
1663 months (range 6 months to 13 years) from the onset of the papilloma to the development of the carcinoma. Thecarcinomatous foci may be limited or extensive. Evidence of a preexisting papilloma may be present with obvious transition
from benign papilloma to overt carcinoma. I n some cases, no residual evidence may be seen of a preexisting benign tumor
and only by history was the patient known to have had a previous benign sinonasal papilloma. N o reliable histologic
features predict which papillomas are likely to become malignant. Papillomas with increased cellularity, pleomorphism, and
increased mitotic activity do not necessarily become malignant. The presence of moderate to severe epithelial dysplasia is a
potential indicator of malignant transformation. S imilarly, surface keratinization and dyskeratosis have anecdotally been
considered as possible predictors of malignant transformation. A ny sinonasal papilloma that shows moderate to severe
dysplasia or has surface keratinization should prompt thorough histologic examination of all resected tissue to exclude the
presence of malignancy. No correlation exists between the number of recurrences and the development of carcinoma.
The prognosis varies. I n some patients the carcinomas are only locally invasive with favorable prognosis after treatment.
I n other patients extensive invasion may be seen with involvement of vital structures and/or metastatic disease; these
patients generally have a poor clinical outcome irrespective of therapeutic intervention.
Squamous Papillomas
S quamous papillomas represent the most common benign neoplasms of the upper aerodigestive tract mucosa and are
commonly seen in the oral cavity and larynx. Less often, squamous papillomas occur in the nasopharynx and nasal
25,26vestibule. The nasal vestibular squamous papillomas are of cutaneous origin. I n contrast to the sinonasal-type
papillomas, cutaneous squamous papillomas lack intraepithelial mucocytes and submucosal glands. I n contrast to the
sinonasal-type papillomas, squamous papillomas of the nasopharynx are endodermally derived. S quamous papillomas are
exophytic, warty, or cauliflower-like tumors ranging in size from a few millimeters up to 3 cm in greatest dimension.
Histologically, these tumors are composed of benign squamous epithelium arranged in multiple finger-like projections with
prominent fibrovascular cores. The squamous epithelium is free of any dysplastic change. I n general, these tumors lack
surface keratin, but in any tumor (hyper)keratosis, as well as parakeratosis and orthokeratosis, may occur. The presence of
surface keratin carries no additional risk for the development of carcinoma. A lthough uncommon, the sinonasal-type
(S chneiderian) papillomas may originate in the nasopharynx without any connection to the sinonasal tract, probably arising
27from misplaced ectodermal-derived epithelial rests from the sinonasal tract. Recurrences occur infrequently and relate to
27inadequate excision. Malignant transformation does not occur.
Benign Neoplasms of Minor Salivary Glands
Benign salivary gland tumors of the sinonasal region and nasopharynx are uncommon. I n general, minor salivary gland
tumors occur most often in the nasal cavity and rarely in the paranasal sinuses. Pleomorphic adenoma is the dominant
28histologic type seen ; less often, monomorphic adenomas such as myoepithelioma and oncocytoma occur.
Pleomorphic adenomas tend to originate along the nasal septum (bony or cartilaginous component) more than any other
28site. A lthough these tumors may arise from within the paranasal sinus, more often paranasal sinus involvement occurs as
a result of extension from an intranasal lesion. These tumors appear as polypoid or exophytic growths, usually covered by
intact mucosa, and vary in size from 1 to 7 cm. A s is true of all upper aerodigestive tract minor salivary gland tumors (benign
or malignant), the pleomorphic adenomas are unencapsulated. However, in contrast to malignant minor salivary gland
tumors, these tumors are relatively circumscribed without invasive growth; involvement of surface epithelium does not
constitute invasion. Histologically, these tumors are identical to those of major salivary glands (see Chapter 7), including an
admixture of ductular or tubular structures, spindle-shaped myoepithelial cells, and a myxochondroid stroma. A tendency
exists for pleomorphic adenomas of the nasal cavity to be cellular, with a predominant myoepithelial component, usually in
the form of plasmacytoid (hyaline cell) rather than spindle-shaped myoepithelial cells (Fig. 4A -4). Given the presence of
ductular or tubular structures and myxochondroid stroma, these tumors would not be considered as myoepitheliomas.
Myoepitheliomas represent a monomorphic adenoma showing only a single cell type, the myoepithelial cell. Typically,
myoepitheliomas are of the spindle cell type, and, rarely, the tumor cells are of the plasmacytoid type. Myoepithelial
29differentiation can be shown by immunoreactivity for cytokeratin, S -100 protein, and smooth muscle actin, as well as more
specific markers of myoepithelial differentiation including p63 and calponin (see Fig. 4A-4). S urgery is usually curative with
28local recurrence being seen in fewer than 10% of patients. Rarely, malignant transformation may occur (i.e., carcinoma ex
pleomorphic adenoma), characterized by overtly malignant cytomorphology and/or infiltrative growth. The laOer may
include neurotropism or osseous invasion.FIGURE 4A-4 Intranasal myoepithelial-predominant pleomorphic adenoma. A, Submucosal
unencapsulated cellular proliferation with associated myxochondroid stroma. B, Admixture of glands,
myxochondroid stroma, and prominent plasmacytoid myoepithelial cells; the presence of the ductular
structures, glands, and myxochondroid stroma allows categorization as a pleomorphic adenoma,
myoepithelial predominant, and not as a myoepithelioma, which is better regarded as a monomorphic
adenoma. C, At higher magnification details of the plasmacytoid (hyaline cell) myoepithelial cells are
better seen; in addition to cytokeratin staining, myoepithelial cells are immunoreactive for S-100 protein
(nuclear and cytoplasmic) (D) and p63 (nuclear staining) (E). Calponin, another myoepithelial specific
marker, will also be positive (not shown).
Pituitary Adenoma
Pituitary neoplasms originating from the sella turcica may occasionally extend into the sinonasal tract or nasopharynx and
appear to present as a primary neoplasm of those regions. Radiographic analysis will identify the lesion as originating from
the sella turcica. Ectopic pituitary adenomas without any continuity with the sella turcica may arise in various upper
aerodigestive tract sites from remnants of Rathke pouch. I n these locations, misdiagnosis with other neuroendocrine tumors
or with malignant epithelial neoplasms may occur. Ectopic pituitary adenomas occur in adults with no sex predilection and
present with airway obstruction, chronic sinusitis, visual field defects, cerebrospinal fluid leakage, and endocrine
30,31manifestations (e.g., Cushing syndrome, hirsutism). The most common ectopic sites of occurrence are the sphenoid
sinus followed by the nasopharynx. Other less common sites include the nasal cavity and ethmoid sinus. The tumors may be
polypoid in appearance. Histologically, a submucosal epithelioid neoplastic proliferation is seen with solid, organoid, and
trabecular growth paOerns (Fig. 4A -5). The epithelioid cells have round nuclei with a dispersed chromatin paOern and
granular eosinophilic cytoplasm. Pleomorphism, necrosis, or mitotic activity is not seen. N o evidence is seen of glandular or
squamous differentiation. I mmunohistochemical stains show reactivity with neuroendocrine markers (e.g., chromogranin,
synaptophysin, CD 56), cytokeratin, and a variety of pituitary hormones, including growth hormone, adrenocorticotropic
hormone, prolactin, thyroid-stimulating hormone, follicle-stimulating hormone, and luteinizing hormone. Reactivity with
two or more hormones, so-called plurihormonal pituitary adenoma, is not infrequently seen; in some tumors, reactivity withany pituitary hormone marker may be absent (null cell pituitary adenoma). Complete removal is curative without recurrent
31or progressive tumor, and with resolution of any endocrinopathy. Rarely, malignant transformation of ectopic pituitary
32adenoma may occur.
FIGURE 4A-5 Ectopic (nasopharyngeal) pituitary adenoma. A, The neoplastic infiltrate is submucosal
and is composed of an epithelioid neoplastic proliferation with an organoid growth pattern. B, The
epithelioid cells have round nuclei with dispersed chromatin pattern and granular eosinophilic cytoplasm.
Immunohistochemical stains confirmed a pituitary neoplasm.
Extraadrenal paragangliomas are identified throughout the body and are classified according to the anatomic site of
occurrence. Paragangliomas in the head and neck region include those of carotid body, jugulotympanic, and vagal origin (see
Chapter 28). Paragangliomas may rarely occur in other mucosal sites of the upper aerodigestive tract, including the nasal
cavity, where they produce nasal obstruction and/or epistaxis. Parasympathetic paraganglia are found throughout the body
33and give rise to almost all of the paragangliomas of the upper aerodigestive tract. Most paragangliomas in this location are
nonfunctional, although rare cases exist of adrenocorticotropic hormone–producing nasal paraganglioma associated with
34Cushing syndrome. I rrespective of the site of origin, the histologic appearance of all extraadrenal paragangliomas is the
same. A s at other sites, the hallmark histologic feature is the presence of a cell nest or “Zellballen” paOern. The stroma
surrounding and separating the nests is composed of fibrovascular tissue. Paragangliomas are predominantly composed of
chief cells, which are round or oval with uniform nuclei, dispersed chromatin paOern, and abundant eosinophilic, granular,
or vacuolated cytoplasm. The sustentacular cells are located at the periphery of the cell nests as spindle-shaped,
basophilicappearing cells but are difficult to identify by light microscopy. Cellular and nuclear pleomorphism can be seen, but these
features are not indicative of malignancy; mitoses and necrosis are infrequently identified. Paragangliomas lack glandular or
alveolar differentiation. The immunohistochemical profile of paragangliomas includes chromogranin, synaptophysin, and
neuron-specific enolase (N S E) positivity in the chief cells and S -100 protein staining localized to the peripherally located
35,36 36sustentacular cells. Only rare cases have been cytokeratin reactive. The prognosis is excellent after complete
resection. A lthough the majority of these tumors are benign and behave in an indolent manner, they may recur locally and
37be invasive. Rarely, these tumors are malignant. The histology is not predictive of malignant behavior, and malignancy in
paraganglioma should be determined by the presence of metastatic disease.
38Meningiomas are benign neoplasms of meningothelial cells representing 13% to 18% of all intracranial tumors.
Occurrence outside the central nervous system is considered ectopic; these meningiomas are divided into those with no
identifiable central nervous system connection (primary) and those with central nervous system connection (secondary). The
most common sites of occurrence of the ectopic meningiomas of the head and neck region include the middle ear and
39temporal bone, sinonasal cavity, orbit, oral cavity, and parotid gland. S inonasal tract meningiomas most often involve the
40nasal cavity, or a combination of nasal cavity and paranasal sinuses ; less frequently, involvement may be isolated to the
40nasopharynx, frontal sinus, or sphenoid sinus. I n the sinonasal cavity, symptoms include nasal obstruction, epistaxis,
headache, pain, visual disturbances, and facial deformity. The tumors may erode the bones of the sinuses with involvement
40of surrounding soft tissues, the orbit, and occasionally the base of the skull. These tumors appear as a polypoid mass.
Often, the tumor is cureOed out and received as fragments of solid, white tissue. A griOy consistency may be noted. The
histology is similar to that of its intracranial counterparts (see Chapter 26). A mong the histologic subtypes of meningioma,
the meningotheliomatous type is the most common in the sinonasal cavity (Fig. 4A -6). Psammoma bodies, typical and
numerous in intracranial meningothelial meningiomas, may be seen but are not as common in the ectopically located
meningiomas. The immunohistochemical profile of meningiomas includes reactivity with epithelial membrane antigen
(EMA) and vimentin, with absence of cytokeratin or neuroendocrine markers (chromogranin and synaptophysin). Complete
39-41surgical excision may be difficult to achieve, resulting in recurrence; recurrence rates range up to 30%. A fter the
histologic diagnosis, it is essential to exclude spread from a primary intracranial neoplasm.FIGURE 4A-6 Sinonasal tract (ectopic) meningioma. A, This submucosally situated cellular proliferation
shows a lobular growth pattern with tumor nests separated by a variable amount of fibroconnective tissue
and with a whorled arrangement. B, The neoplastic cells have round to oval nuclei with pale-staining
cytoplasm, indistinct cell borders, and characteristic punched-out or empty appearance resulting from
intranuclear cytoplasmic inclusions; several psammoma bodies are present.
Benign Mesenchymal Neoplasms
Lobular capillary hemangiomas (LCH), which were formerly often known as pyogenic granulomas, are benign vascular
tumors representing the polypoid form of capillary hemangioma primarily occurring on skin and mucous membranes (see
42,43Chapter 3). A side from the LCH, other types of hemangiomas of the sinonasal cavity and nasopharynx are rare.
Hemangiomas of the sinonasal tract tend to be mucosally based but also may arise from within the osseous components of
this region (intraosseous hemangiomas).
LCH occur equally in both sexes. The age range is wide, but these lesions are most commonly seen in the fourth to fifth
decades of life and are uncommon under 16 years of age. LCH are most often found in the anterior portion of the nasal
42,44septum in an area referred to as LiOle area or Kiesselbach triangle; the second most common sinonasal location is the
42,44turbinates. The most common clinical complaint is epistaxis; an obstructive painless mass may be present.
The pathogenesis remains unclear. A minority of cases may be associated with prior trauma. LCH may occur in association
with pregnancy and in association with oral contraceptive use, suggesting that hormonal factors may be involved. A
hormonal role is further supported by the regression of these tumors after parturition. However, in an
45immunohistochemical study of 21 cases of LCH, N ichols and colleagues did not identify estrogen or progesterone
receptors in any of these tumors. The mechanism for the regression of pregnancy-related LCH after parturition remains
46unclear. Yuan and Lin evaluated the role of vascular endothelial growth factor (VEGF) and angiopoietin-2 (A ng-2) in the
regression of pregnancy-related LCH. These authors found that the amount of VEGF was high in LCH in pregnancy and
almost undetectable after parturition and concluded that a lack of VEGF is associated with apoptosis of endothelial cells and
regression of granuloma. They found no role for Ang-2 alone in regression.
The gross appearance of LCH is a smooth, lobulated, polypoid red mass measuring up to 1.5 cm in diameter.
Histologically, LCH is characterized by a submucosal vascular proliferation arranged in lobules or clusters composed of
central capillaries and smaller ramifying tributaries (Fig. 4A-7). The central capillaries vary in caliber, as well as in shape, and
in more “mature” lesions may show a “staghorn” appearance. The endothelial cell lining may be prominent and may display
endothelial tufting, as well as mitoses. S urrounding and intimately associated with the vascular component are granulation
tissue and a mixed chronic inflammatory cell infiltrate. The surface epithelium is often ulcerated with associated necrosis.
The diagnosis of LCH and its differentiation from other lesions are usually accomplished by light microscopic evaluation,
and immunohistochemical staining is generally not required. However, at times immunohistochemical staining may be
needed in the diagnosis and differential diagnosis of LCH. The neoplastic cells are reactive for CD 31, CD 34, and factor VI I I –
related antigen. I n contrast to Kaposi sarcoma, no immunoreactivity is present for human herpesvirus 8 (HHV-8) latent
47nuclear antigen-1 (LNA-1) in LCH.FIGURE 4A-7 Sinonasal lobular capillary hemangioma. A, Submucosal lobular proliferation in which
variable-sized vascular spaces are present, including some with irregular to staghorn shapes. B,
Surrounding the endothelial-lined irregularly shaped vascular space is a mixed cellular infiltrate including
inflammatory cells and fibroblasts. These findings contrast with the diffuse growth pattern and
monomorphic cellular proliferation seen in sinonasal-type hemangiopericytoma.
The prognosis after excision is excellent. Recurrences are relatively infrequent.
Cavernous hemangiomas occur less frequently in the upper respiratory tract when compared with the capillary
hemangioma. I n general, cavernous hemangiomas have a similar clinical presentation to capillary hemangiomas but are
48more often identified in the turbinates, in the lateral nasal wall, or within bone (intraosseous) than in the nasal septum.
S imilar to cavernous hemangiomas of other sites, those of the sinonasal tract are composed of multiple, variably sized,
dilated and thin-walled, endothelial cell–lined vascular spaces. Surgical resection is curative.
Congenital hemangiomas are primarily cutaneous lesions and include infantile (juvenile) hemangiomas. I nfantile
(juvenile) hemangiomas are common benign vascular tumors of infancy and are distinctive for their perinatal presentation,
49rapid growth in the first year of life, and subsequent involution. I nfantile (juvenile) hemangiomas may involve the nasal
cavity. Histologically, infantile (juvenile) hemangiomas are composed of solid masses of small capillaries consisting of
plump endothelial cells grouped in defined lobules separated by fibroconnective tissue or by normal intervening tissue.
N eural pseudoinvasion is a common feature, and occasional mitotic figures may be present. I n addition to immunoreactivity
for endothelial cell markers including CD 31 and CD 34, infantile (juvenile) hemangiomas are immunoreactive for glucose
49,50 49,50transporter 1 (GLUT1) and Lewis Y antigen. In contrast, LCH are nonreactive for GLUT1.
Nasopharyngeal Angiofibroma
51-54N asopharyngeal angiofibroma is a relatively rare neoplasm, accounting for fewer than 1% of all head and neck tumors.
55This tumor occurs almost exclusively in men, and some believe that it is a tumor limited to the male population.
N asopharyngeal angiofibromas occur over a wide age range but are most common in the second decade. They are
uncommon over the age of 25 years. However, these tumors may rarely occur in older ages, thereby negating the use of the
52designation “juvenile” angiofibroma. The most common clinical complaints are persistent nasal obstruction and epistaxis.
Late signs and symptoms include facial swelling or deformity (swelling of the cheek), nasal discharge, proptosis, diplopia,
52headache, sinusitis, cranial nerve palsies, anosmia, and hearing deficits. Pain is considered an unusual finding. Typically,
symptoms have been present for more than 1 year before diagnosis. The site of occurrence is usually the posterolateral
portion of the roof of the nasal cavity in the area of the sphenopalatine foramen. Large tumors may extend anteriorly into the
nasal cavity, causing nasal obstruction and simulating a primary intranasal or paranasal sinus tumor. Extension posteriorly
may fill the nasopharynx and extend into the oropharynx, causing displacement of the soft palate. Extension can occur
through the sphenopalatine foramen with involvement of the pterygomaxillary fossa and infratemporal fossa, resulting in
56facial deformities. Extension into the middle cranial fossa can occur if the tumor involves and destroys the pterygoid
A s a result of the overwhelming occurrence in men, this tumor is thought to be hormonally driven, being dependent on
57 58testosterone and inhibited with estrogen. A ndrogen receptors have been found in these tumors but not estrogen
57,59receptors. A familial predisposition for nasopharyngeal angiofibromas has been suggested in patients with familial60,61adenomatous polyposis (FA P). Patients with FA P have nasopharyngeal angiofibroma 25 times more frequently than an
60,61age-matched population. A ctivating β-catenin mutation without APC gene mutation has been reported in sporadic
62,63 64nasopharyngeal angiofibroma. Zhang and colleagues found that expression of β-catenin, c-kit (CD 117), and neural
growth factor (N GF) was higher and more frequent in stromal cells of nasopharyngeal angiofibromas than those of nasal
polyps. On the basis of their findings Zhang and colleagues suggested the potential involvement of c-kit and N GF signaling
pathways in nasopharyngeal angiofibromas. I n a limited number of patients, consumptive coagulopathy has been found as a
complication of nasopharyngeal angiofibromas suggesting that preoperative coagulation studies may be useful in ensuring
65perioperative hemostasis.
66Routine radiographs show characteristic bowing of the posterior wall of the maxillary antrum, as well as distortion and
52,54posterior displacement of the pterygoid plates (Holman-Miller sign). A rteriographic findings are usually diagnostic and
include a tumor with marked vascular hypertrophy and increased number of arteries without beading, dilatation, segmental
narrowing, or aneurysmal dilatation. Radiographic staging of nasopharyngeal angiofibromas based on extent of disease has
67-70been proposed (Table 4A-4).
R adiographic S taging of N asopharyngeal A ngiofibroma
Stage Extent of Disease
I Limited to nasopharynx with no bone destruction
II Invasion into nasal cavity or maxillary, ethmoid, or sphenoid sinuses with no bone destruction
III Invasion of pterygopalatine fossa, infratemporal fossa, orbit, or parasellar region
IV Massive invasion of the cranial cavity, cavernous sinus, optic chiasm, or pituitary fossa
A ngiofibromas appear as sessile or lobulated masses but may occasionally be polypoid or pedunculated. Histologically,
angiofibromas are unencapsulated and are characterized by a fibrocollagenous stromal proliferation with an admixture of
variably sized vascular spaces (Fig. 4A -8). The vascular component is made up of thin-walled, small to large vessels varying
in appearance from stellate or staghorn to barely conspicuous because of marked compression by stromal fibrous tissue. The
endothelial cells form a single layer and are flat or plump in appearance. The vessel walls lack elastic fibers and are
distinctive in having a smooth muscle layer that may be incomplete or discontinuous and that shows marked variation in
71thickness. Central areas of the tumor may be relatively hypovascular. The stroma is composed of fibrous tissue with fine or
coarse collagen fibers. The stromal cells are spindle shaped and stellate with plump nuclei, and they tend to radiate around
vessels. N uclear pleomorphism and multinucleate giant cells may be seen. Mitotic figures are rare. The stroma may be
focally myxoid. Mast cells are common; however, other inflammatory cells are absent except near areas of surface ulceration.
Tumors of longer duration tend to be more fibrous and less vascular. S mooth muscle actin–positive cells can be found
71around the circumference of the vascular spaces. The spindle-shaped and stellate stromal cells are vimentin positive. I n
58addition, Hwang and colleagues found the stromal cells to be strongly reactive for testosterone receptors.
FIGURE 4A-8 Nasopharyngeal angiofibroma. These tumors are composed of a variable admixture of
fibrocollagenous stroma with variably sized vascular spaces. The vascular component includes thin-walled
structures varying in appearance from (A) readily apparent to (B) less conspicuous because of marked
compression from the collagenized stroma. Note that the vascular walls have an incomplete or absent
smooth muscle layer.
I n uncomplicated cases (with tumor limited to the nasopharynx), surgical excision via a transverse palatal approach is the
72treatment of choice. Vascular embolization usually precedes surgical intervention to control bleeding. Over the last
decades a marked shift to less invasive endonasal approaches and procedures has taken place. S uccessful management using
73less invasive techniques has led to reduction in morbidity without increasing the chance of recurrence. N onsurgical
59 74management has been proposed, including estrogen therapy, use of testosterone receptor blockers such as flutamide, or
75-77irradiation. These treatment modalities reduce the angiomatous component of the tumor and may be used in patientswhose tumors are deemed unresectable. Complications associated with angiofibromas include excessive bleeding,
recurrence of tumor, and extension of the tumor beyond the nasopharynx to involve adjacent anatomic compartments
(sinonasal cavities, oropharynx, pterygomaxillary fossa, superior buccal sulcus, orbit, infratemporal fossa, and cranial
56 78cavity). Given the propensity to bleed, biopsies of the tumor should be performed with extreme caution. Recurrence
79rates vary from 6% to as high as 24%. High recurrence rates and early recurrence may occur in nasopharyngeal
angiofibromas involving the skull base. Recurrences are more common in cases with intracranial extension. Tumor
recurrence in cases without intracranial extension usually occurs within 2 years of treatment. I n general, the prognosis is
53 52 80,81excellent after surgical removal; mortality rates range from 3% to 9%. Rarely, spontaneous regression may occur.
Malignant (sarcomatous) transformation is a rare event and has been linked to treatment with radiotherapy (postirradiation
Solitary Fibrous Tumor
S olitary fibrous tumor (S FT) is a distinctive neoplasm composed of CD 34-positive fibroblasts that is typically serosal-based
85,86 87or a soft tissue proliferation and that includes most lesions formerly classified as hemangiopericytoma (HPC).
However, sinonasal-type HPC shares more features similar to glomangiopericytoma than to soft tissue HPC and is addressed
separately in this chapter.
88-90S FTs of the head and neck are rare tumors most often involving the nasal cavity and paranasal sinuses. Patients with
tumors in these sites present with nasal obstruction. Usually, the symptoms have been present for an extended period of
time (a year or more).
These tumors typically are polypoid. Histologically (see Chapter 24), they are unencapsulated and are composed of a
variably cellular proliferation of bland spindle-shaped cells lacking any paOern of growth and associated with ropey, keloidal
collagen bundles and associated, often branching, thin-walled vascular spaces (Fig. 4A -9). I mmunohistochemical analysis
will show CD34, bcl-2, and CD99 reactivity but absence of S-100 protein, desmin, or actin.FIGURE 4A-9 Solitary fibrous tumor of the sinonasal tract. A, This tumor was unencapsulated and is
composed of a variably cellular proliferation of bland spindle-shaped cells lacking any pattern of growth
with associated ropey collagen or (B) keloidal collagen bundles; (C) cells are immunoreactive for CD34.
The differential diagnosis primarily includes sinonasal HPC (see later discussion). Other tumors that need to be
differentiated from SFT include smooth muscle tumors, nerve sheath tumors, and fibrohistiocytic tumors.
88,89 91Complete surgical resection is curative. Recurrence is primarily due to incomplete resection. S FT of the
nasopharynx may be more difficult to excise completely. D espite incomplete resection, these tumors are not generally
89associated with adverse biologic behavior at this anatomic location.
Fibromatosis (Extra-abdominal Desmoid, Desmoid-Type Fibromatosis)
Fibromatosis is a locally infiltrative or aggressive, nonmetastasizing, fibroblastic neoplasm. I nvolvement of the head and
neck region occurs primarily in the soft tissues of the neck. Excluding the neck, the common sites of occurrence are the
92,93sinonasal tract, nasopharynx, tongue, and oral cavity. I n the sinonasal tract, the maxillary sinus is the most common
94site. This lesion is seen in both children and adults but most commonly occurs in the third to fourth decades of life.
S ymptoms vary according to site. I n the sinonasal tract and nasopharynx, the clinical presentation includes a painless
92,93enlarging mass or nasal obstruction. With progression of disease, other symptoms, including epistaxis, facial deformity,
proptosis, and dysphagia, may occur. Fibromatosis may represent a manifestation of Gardner syndrome, although the
majority of fibromatosis associated with Gardner syndrome occurs intra-abdominally.
The gross and histologic appearances are the same as those in fibromatoses at more common locations (see Chapter 24).
93The differential diagnosis primarily includes reactive fibrosis and fibrosarcoma. I n contrast to fibrosarcoma,
fibromatoses lack a herringbone growth paOern, hypercellularity, and increased mitotic rate. Other differential diagnostic
considerations include peripheral nerve sheath tumors, myxoma and fibromyxoma, solitary fibrous tumor, myofibromatosis,
nodular fasciitis, fibroosseous lesions, and myofibroblastic tumors (inflammatory myofibroblastic tumor, low-grade
myofibroblastic sarcoma).These lesions present difficulties in management because of insinuation of the lesion into adjacent structures without
clear demarcation, making complete excision difficult. A s a result of the difficulties in completely excising the lesion,
94recurrent disease is common. Recurrence usually occurs within the first few years after surgery. Radiotherapy has been
95,96used with some success in patients with residual tumor and/or recurrent disease. Hormonal therapy has been used with
97,98varying results. D eath due to uncontrolled local disease may occur but is an extraordinary occurrence. S pontaneous
92regression of the lesion may occur but is rare. I n extremely rare cases, transformation to an overt malignancy
94(fibrosarcoma) has been reported to occur and likely relates to prior radiation therapy.
Benign Peripheral Nerve Sheath Tumors (Schwannoma and Neurofibroma)
Benign peripheral nerve sheath tumors of the head and neck are common, perhaps accounting for as many as 45% of all
cases. However, benign peripheral nerve sheath tumors of the sinonasal tract and nasopharynx are uncommon, accounting
99-101for fewer than 4%. In this location schwannomas are substantially more common than neurofibromas. Adults are most
commonly affected, with no sex predilection. Patients present with symptoms related to nasal obstruction and epistaxis.
101N asopharyngeal involvement may result in unilateral serous otitis media. I n two of the cases reported by Hasegawa and
101colleagues, visual disturbances were present because of intracranial extension of the tumor. These tumors may cause
99,100pressure erosion of bone. No association with neurofibromatosis is seen.
Unlike their soft tissue counterparts, benign schwannomas of the upper aerodigestive tract are unencapsulated (Fig. 4A -
10). A side from this finding, the histologic features are similar to those described for benign peripheral nerve sheath tumors
at other sites (see Chapter 27). D iffuse and intense S -100 protein immunoreactivity (cytoplasmic and nuclear paOern) is
present. Cytokeratin, actins, and desmin staining are absent. Proliferation rate (i.e., MI B-1 staining) is low with staining of
1021% to 5% of tumor cell nuclei. Surgical resection is the treatment of choice and is curative.
FIGURE 4A-10 Sinonasal benign peripheral nerve sheath tumor (benign schwannoma). A, The tumor is
submucosal, unencapsulated, and composed of a bland spindle-shaped cellular proliferation with wavy or
buckled-appearing nuclei, admixed inflammatory cells, and perivascular hyalinization. B, Diffuse and
intense S-100 protein immunoreactivity is present.
N eurofibromas are submucosal, circumscribed tumors composed of spindle-shaped cells with “wavy” or buckled,
hyperchromatic nuclei, and indistinct cytoplasm. A n associated collagenized and/or myxoid stromal component is present.
N eoplastic cells are S -100 protein positive, but extent of staining is less than that seen in schwannomas. S urgical resection is
I n general, leiomyomas are one of the least common mesenchymal tumors in the head and neck area. The most frequent
sites of occurrence are the skin and oral cavity (lips, tongue, and palate). Less often, leiomyomas may arise from within the
103,104sinonasal cavity, presenting as a painless mass with nasal obstruction. This is a tumor of adults with a peak incidence
in the sixth decade of life. Within the sinonasal tract, leiomyomas most often involve the turbinates. Histologically, these
tumors are localized to the submucosa, appearing delineated and characterized by the presence of interlacing bundles orfascicles of cells composed of blunt-ended or “cigar-shaped” nuclei with abundant eosinophilic cytoplasm. N uclear
palisading and perinuclear vacuolization may be seen but no significant pleomorphism or mitotic activity. The neoplastic
cells are seen in intimate association with vascular spaces. D egenerative changes, including stromal fibrosis and myxoid
change, may be present. Hypercellular tumors, referred to as cellular leiomyoma, characterized by an absolute increase in
cells but lacking significant pleomorphism, mitotic activity, necrosis, or invasive growth, may be identified. A nother
suggested category among sinonasal tract smooth muscle tumors is the so-called smooth muscle tumor of uncertain
104malignant potential (S MTUMP). S MTUMP is histologically characterized by increased cellularity, moderate nuclear
104pleomorphism, and the presence of no more than 4 mitoses per 10 high-power fields. Locally, infiltrative growth (i.e., into
104bone) may occur in S MTUMP. The neoplastic cells in leiomyoma and S MTUMP are immunoreactive with actin (smooth
muscle and muscle specific) and desmin; S -100 protein reactivity is absent. MI B-1 index for both leiomyoma and S MTUMP is
104low (less than or equal to 5%). Simple surgical excision is curative.
105-107A dult or fetal types of rhabdomyoma (see Chapter 24) rarely occur in the sinonasal tract or nasopharynx. The cellular
features of fetal rhabdomyomas show rhabdomyoblasts in different stages of differentiation, including spindle-shaped and
strap cells. These findings may be worrisome for a diagnosis of rhabdomyosarcoma (RMS ); however, in contrast to RMS , fetal
107rhabdomyomas tend to be circumscribed and lack nuclear atypia or mitotic activity.
Sinonasal Myxoma and Fibromyxoma
Myxomas and fibromyxomas are benign neoplasms of uncertain histogenesis with a characteristic histologic appearance and
often behaving in an aggressive (infiltrative) manner. When a relatively greater amount of collagen is present, the term
fibromyxoma (or myxofibroma) is used. I n the sinonasal tract, these tumors appear to be of osseous derivation. N o sex
predilection is seen; these tumors occur over a wide age range but are most frequently seen in the second and third decades
108,109of life. I n general, these are gnathic tumors, the mandible (posterior and condylar regions) being involved more often
than the maxilla (zygomatic process and alveolar bone). Extragnathic tumors are uncommon and primarily involve the
sinonasal tract; specifically, the maxillary sinus (antrum) is most often involved with secondary extension into the nasal
cavity. The presentation usually is as a painless swelling of the affected area. Localization to the jaw bones has led to the
belief that these tumors take origin from the primordial odontogenic mesenchyme or from osteogenic embryonic connective
The radiologic appearance is that of a unilocular or multilocular radiolucency with a “honeycomb” or “soap-bubble”
appearance. Grossly, these are delineated but unencapsulated multinodular, gelatinous-appearing lesions. Histologically,
these tumors show a scant, loosely cellular proliferation consisting of spindle-shaped or stellate-appearing cells embedded
in an abundant mucinous stroma (Fig. 4A -11). The nuclei are small and hyperchromatic. Cellular pleomorphism, mitotic
figures, and necrosis are absent. The amount of collagenous fibrillary material varies between cases, and, depending on the
extent, the tumor may be called a fibromyxoma (Fig. 4A -12). The periphery of the tumor appears circumscribed, but local
infiltration with replacement of bone can be seen. Vessels are generally sparse.
FIGURE 4A-11 Sinonasal myxoma. A, Submucosal loose cellular proliferation with compressed but
identifiable vascularity. B, The cells are spindle shaped or stellate appearing with uniform, small,
hyperchromatic nuclei embedded and copious mucinous stroma.FIGURE 4A-12 Sinonasal fibromyxoma. As compared with myxomas the stromal component includes
greater collagenous fibrillary material, and the lesion is often more cellular. The absence of specific
immunoreactivity excludes other diagnoses and is required to make the diagnosis of fibromyxoma.
These tumors tend to be slow growing and usually follow a benign course but may have the potential for local destruction
after inadequate excision. Metastasis from a presumptive sinonasal myxoma or fibromyxoma should seriously place that
diagnosis in doubt and probably indicates a myxoid sarcoma (e.g., liposarcoma, myxofibrosarcoma, RMS).
The differential diagnosis includes dental papillae, nasal inflammatory polyps, peripheral nerve sheath tumors, low-grade
110fibromyxoid sarcoma, and other myxoid sarcomas (e.g., myxofibrosarcoma, liposarcoma, RMS , others) and chondroid
Osseous, Fibroosseous, and Cartilaginous Lesions
Osteomas are benign bone-forming tumors that are almost exclusively identified in the craniofacial skeleton. I n the
111,112sinonasal tract, osteomas may be found in all sites but are most common in the frontal and ethmoid sinuses. These
tumors are usually asymptomatic and are found only by radiographic studies. S ymptoms that may be associated with
113paranasal sinus osteomas include headaches, facial swelling or deformity, and ocular disturbances. S inonasal osteomas
are more common in men and occur over a wide age range but are most often encountered in the second to fourth decades of
114life. S inonasal osteomas usually occur as a single lesion but may be associated with Gardner syndrome. The radiographic
appearance is that of a sharply delineated radiopaque lesion confined to bone or protruding into a sinus. Histologically,
osteomas are well circumscribed and are composed of dense, mature, predominantly lamellar bone sometimes rimmed by
osteoblasts. I nterosseous spaces may be composed of fibrous, fibrovascular, or faOy tissue, and hematopoietic elements may
be present. Unless symptomatic, osteomas require no treatment. Complete surgical excision is curative.
Ossifying Fibroma
I n contrast to fibrous dysplasia (see later discussion; Table 4A -5), ossifying fibromas are commoner in women and tend to
occur in older age groups, being most frequently seen in the third and fourth decades of life, although patients of any age
115 116may be affected. A predilection to occur in black women has been reported. S inonasal tract involvement is generally
asymptomatic and is often diagnosed incidentally after radiographic examination. S ymptomatic tumors manifest by
displacement of teeth or as an expansile mass. Radiologic features include the presence of a sharply demarcated lesion with
smooth contours.TABLE 4A-5
Benign Fibroosseous Lesions: Clinicopathologic Comparison
Sex, age F > M; third- F = M; younger age groups (first and second F = M; first two decades of life
fourth decades) but may occur in older individuals
Location No specific site Ethmoid sinus; supraorbital frontal region No specific site of involvement
Focality Single site Single site or involvement of multiple Monostotic (75%-80%);
(contiguous) sites or sinuses polyostotic (20%-25%)
Radiology Well- Lytic or mixed lytic-radiopaque osseous and/or Poorly defined expansile
circumscribed soft tissue mass varying from well osseous lesion with a thin
or sharply demarcated to invasive with bone erosion intact cortex; predominantly
demarcated fibrous lesions are
lesion with radiolucent; predominantly
smooth osseous lesions are
contours radiodense; lesions with an
equal admixture of fibrous
and osseous components
have a ground-glass
Histology Randomly Bony spicules and distinctive mineralized or Fibrous tissue component is
distributed calcified “psammomatoid” bodies or ossicles nondescript and of variable
mature admixed with a fibrous stroma; cellularity; osseous
(lamellar) psammomatoid bodies vary from a few in component includes
bone spicules number to a dense population of irregularly shaped
rimmed by innumerable spherical bodies; osteoclasts are trabeculae of osteoid and
osteoblasts present within the ossicles, and osteoblasts immature (woven) bone that
admixed with can be seen along their peripheral aspects; is poorly oriented with
a fibrous the bony trabeculae vary in appearance and misshapen bony trabeculae
stroma; include odd shapes with a curvilinear pattern. with odd geometric patterns
central The trabeculae are composed of lamellar including C- or S-shaped
portions may bone with associated osteoclasts and configurations; the
be woven osteoblastic rimming trabeculae typically lack
bone with osteoblastic rimming
lamellar bone
at the
Syndromes No known No known association Albright syndrome (1%-3%)
Treatment Surgical Surgical resection Disease may stabilize at
resection puberty, and, in children,
therapy should be delayed if
possible until after puberty;
surgical resection indicated
in cases with compromise of
function, progression of
deformity, associated
pathologic fracture(s), or the
development of a
Prognosis Excellent Good after complete excision; recurrence(s) often Good prognosis; recurrence
occurs because of incomplete excision; may rates are low, and death due
behave in an aggressive manner with local to extension into vital
destruction and potential invasion into vital structures rarely occurs
Malignant Not known to Not known to occur Malignant transformation
transformation occur (osteosarcoma) occurs in
fewer than 1%
FD, Fibrous dysplasia; OF, ossifying fibroma; POF, psammomatoid ossifying fibroma.
Ossifying fibromas appear as tan or gray to white, griOy, and firm, varying in size from 0.5 to 10 cm. Histologically,
ossifying fibromas are composed of randomly distributed mature (lamellar) bone spicules rimmed by osteoblasts admixedwith a fibrous stroma (Fig. 4A -13). A lthough the osseous component is generally described as mature, the central portions
may be woven bone with lamellar bone at the periphery. Complete bone maturation is seldom seen. The fibrous stroma may
be densely cellular; mitotic figures are rare to absent. S econdary changes, including hemorrhage, inflammation, and giant
cells, may be seen. The differential diagnosis of ossifying fibroma is primarily with fibrous dysplasia (see later discussion
and Table 4A -5). For ossifying fibromas, surgical excision is the treatment of choice, and the well-circumscribed nature of
this lesion allows for relatively easy removal. The prognosis is excellent after complete excision. Recurrences are rare.
FIGURE 4A-13 Ossifying fibroma of the paranasal sinuses composed of mature (lamellar) bone spicules
rimmed by osteoblasts with an admixed fibrous stroma.
Psammomatoid (Active) Ossifying Fibroma (Cementifying or Cementoossifying Fibroma)
This is a variant of ossifying fibroma that typically occurs in the sinonasal tract and potentially may behave aggressively with
117locally invasive and destructive capabilities. N o sex predilection is seen, and, although generally occurring in younger age
117groups (first and second decades), this lesion can occur over a wide age range, including older individuals. Presenting
symptoms include facial swelling, nasal obstruction, pain, sinusitis, headache, and proptosis. These lesions may occur in any
117,118area of the sinonasal tract but are most frequent in the ethmoid sinus and supraorbital frontal region. A single site or
multiple sinuses may be involved; the orbit may also be involved. The radiologic appearance is that of a lytic or mixed lytic
and radiopaque osseous and/or soft tissue mass varying from well demarcated to invasive with bone erosion. Ossifying
fibroma has been suggested to arise from mesenchyme of the periodontal ligament and, as such, is related to the
118cementifying fibroma and cementoossifying fibroma.
The histology is that of a benign fibroosseous proliferation composed of bony spicules and spherules admixed with a
fibrous stroma. The most distinctive component is the presence of mineralized or calcified “psammomatoid” bodies or
ossicles (Fig. 4A -14). These ossicles vary from a few in number to a dense population of innumerable spherical bodies. The
ossicles are demarcated with a central blue to black appearance surrounded by a pink-appearing rim and with concentric
laminations. The ossicles vary from small with a round to oval shape to being larger and irregularly shaped and are present
within the bony trabeculae, as well as within the adjacent cellular stroma. Osteoclasts are present within the ossicles, and
osteoblasts can be seen along their peripheral aspects. The bony trabeculae vary in appearance and include odd shapes with
a curvilinear paOern. The trabeculae are composed of lamellar bone with associated osteoclasts and osteoblastic rimming.
Transition zones between the spherical ossicles and bony trabeculae can be seen. The nonosseous component includes a
cellular stroma with a fascicular to storiform growth composed of round to polyhedral to spindle-shaped cells with
prominent basophilic nuclei and inapparent cytoplasmic borders. Mitotic figures can be seen, but mitotic activity is not
prominent. Giant cells can be seen among the psammomatoid ossicles or scaOered throughout the nonosseous stromal
component. Osteoid formation may be present focally.
FIGURE 4A-14 Aggressive psammomatoid ossifying fibroma. This variant of ossifying fibroma is
composed of bony spicules and numerous spherules admixed with a fibrous stroma. The most distinctive
component is the presence of mineralized or calcified “psammomatoid” bodies or ossicles.
The prognosis is good after complete excision, but, if margins are involved, recurrences quite often occur and the tumors
117may behave in an aggressive manner with local destruction and potential invasion into vital structures.Fibrous Dysplasia
Fibrous dysplasia is a benign bone tumor characterized by GNASI mutations in which normal medullary bone is replaced by
structurally weak fibrous and osseous tissue (see Chapter 25). Fibrous dysplasia may be monostotic (only a single osseous
site is involved) or polyostotic (involvement of two or more bones). The majority of patients affected by fibrous dysplasia are
under 30 years of age, usually in the first two decades of life. Craniofacial symptoms of fibrous dysplasia include painless,
asymmetric swelling associated with functional disturbances. I n the sinonasal tract, signs and symptoms may include
headaches, proptosis, and nasal obstruction. I nvolvement of the craniofacial or jaw regions occurs in up to 50% of patients
119,120with polyostotic lesions and in up to 25% of patients with monostotic lesions. A small percentage (1%-3%) of fibrous
dysplasia lesions are associated with A lbright syndrome (or McCune-A lbright syndrome), characterized by the triad of
polyostotic fibrous dysplasia, endocrine dysfunction (hyperthyroidism and/or sexual precocity, the laOer predominantly
identified in female patients), and cutaneous hyperpigmentation.
The radiologic appearance is that of a poorly defined expansile osseous lesion with a thin intact cortex. Predominantly
fibrous lesions are radiolucent whereas predominantly osseous lesions are radiodense. Lesions with an equal admixture of
fibrous and osseous components have a ground-glass appearance. Histologically, the fibrous component is nondescript and
of variable cellularity. The osseous component includes irregularly shaped trabeculae of osteoid and immature (woven) bone
arising within the fibrous stroma, being poorly oriented with misshapen bony trabeculae, increased cellularity, and irregular
margins, and forms odd geometric paOerns including C- or S-shaped configurations (so-called Chinese characters) (Fig. 4A -
15). The trabeculae typically lack osteoblastic rimming. Multinucleated giant cells, macrophages, increased vascularity, and
calcification may be seen.
FIGURE 4A-15 Sinonasal fibrous dysplasia includes irregularly shaped immature (woven) bone, typically
lacking osteoblastic rimming, with an associated nondescript fibrous tissue component.
Gnathic fibroosseous lesions (fibrous dysplasia and ossifying fibromas) may be histologically indistinguishable; therefore
the diagnosis and differentiation rest on the clinical-radiologic-histopathologic correlation. D ifferentiation of ossifying
fibromas from fibrous dysplasia is important because the therapeutic rationale differs for these lesions. For fibrous
dysplasia, conservative surgical excision is the preferred treatment and is indicated only in cases with compromise of
function, progression of deformity, pain, associated pathologic fracture(s), or the development of a malignancy. The disease
121may stabilize at puberty, and, in children, therapy should be delayed if possible until after puberty. Recurrence rates are
low, and death due to extension into vital structures rarely occurs. Malignant transformation occurs in fewer than 1% of
122,123cases and when it occurs is most often as an osteosarcoma.
Giant Cell (Reparative) Granuloma
Giant cell (reparative) granuloma is a benign reactive osseous proliferation. Giant cell granuloma shares many features with
124aneurysmal bone cyst, and in many regards these lesions may be indistinguishable. I n the head and neck area, the
maxilla and mandible are the most common sites of occurrence. S inonasal tract or nasopharyngeal involvement is
uncommon. Those lesions predominantly confined to intraosseous sites (e.g., jaws) are referred to as central giant cell
granulomas, and those primarily involving soft tissues (e.g., sinonasal or oral) are termed peripheral giant cell
125,126granulomas. S inonasal tract involvement is associated with pain and swelling. Head and neck giant cell reparative
127granulomas are more common in women and occur in patients under 30 years of age (most are less than 20 years old).
128,129Hormonal factors may influence the growth of giant cell reparative granulomas.
The central and peripheral giant cell granulomas are histologically identical and are composed of a cellular fibroblastic
stroma that includes multinucleate osteoclast-like giant cells. The giant cells tend to aggregate in and around foci of
hemorrhage; less often, the giant cells are diffusely distributed in the fibroblastic stroma. Mitotic figures are seen in the
fibroblasts but not the giant cells. Cyst formation and reactive bone may be present. Peripheral giant cell granulomas are
submucosal lesions lying underneath an intact and uninvolved respiratory or squamous epithelium. S urgical cureOage is the
129treatment of choice. Up to 15% of gnathic lesions will recur, but sinonasal tract lesions are less likely to recur after
cureOage. Because the giant cell granulomas are histologically identical to brown tumor of hyperparathyroidism, prudent
management includes laboratory evaluation of parathyroid gland function.
Giant Cell Tumor
Giant cell tumors of bone are potential aggressive but benign tumors that only very rarely occur in the head and
125,130,131neck. S inonasal tract and nasopharyngeal involvement is rare. I n contrast to giant cell reparative granulomas,giant cell tumors are characterized by the presence of abundant multinucleated giant cells that are more diffusely
distributed, are larger, have more numerous nuclei (50-100), and are associated with a mononuclear cell stromal component
rather than a fibroblastic background. Mitoses are seen in the stromal mononuclear cells, but atypical mitoses are not
132present. The presence of atypical mitoses has been identified as an indicator of malignancy. Telomeric associations
132represent the most frequent chromosomal aberration. Malignant giant cell tumor of the sphenoid arising in a patient
133with Paget disease has been reported.
Chondromas of the sinonasal tract and nasopharynx are rare. The most frequent sites of occurrence include the nasal septum
134,135and the nasopharynx. S inus opacification or a circumscribed radiolucent lesion can be seen by radiographic studies.
S inonasal chondromas appear as a polypoid, firm, smooth-surfaced nodule measuring usually from 0.5 to 2.0 cm and rarely
being greater than 3.0 cm. Histologically, these are lobulated tumors composed of chondrocytes recapitulating the normal
histology of cartilage. Cellular pleomorphism, binucleate chondrocytes, or increased mitotic activity are not present.
Recurrences are uncommon.
Odontogenic and Other Tumors
A meloblastomas are locally aggressive jaw tumors with a high propensity for recurrence that are thought to arise from
remnants of odontogenic epithelium, lining of odontogenic cysts, and the basal layer of the overlying oral mucosa (see
136Chapter 6). A meloblastomas can occur in either the maxilla or mandible at almost any age but are most frequently
137discovered as a painless expansion in the mandible of patients in their third to fifth decades. S inonasal tract involvement
is uncommon and usually occurs by secondary extension from the maxilla. However, true primary sinonasal ameloblastomas
138without connection to gnathic sites uncommonly occur. S chafer and colleagues reported a series of 24 primary sinonasal
ameloblastomas. I n their series a decided male predilection of 3.8 : 1 was seen, with a mean age at presentation of 59.7 years
(approximately 15-25 years later than in patients with ameloblastoma occurring within the jaws). The patients usually
presented with a mass lesion and nasal obstruction. S ites of involvement included the nasal cavity only, the paranasal
sinuses only, or both the nasal cavity and the paranasal sinuses.
I n contrast to the characteristic multilocular and radiolucent presentation of ameloblastomas within the jaws, sinonasal
138ameloblastomas are described radiographically as solid masses or opacifications. Bone destruction, erosion, and
remodeling (remnant of bony shell delimiting the lesion as it grew) may be present.
Histologically, sinonasal ameloblastomas are similar in appearance to their gnathic counterparts (see Chapter 6). The
plexiform paOern, composed of a network of long anastomosing cords of odontogenic epithelium, represents the
138predominant histologic paOern (Fig. 4A -16). The stellate reticulum-like component associated with other paOerns of
139ameloblastoma is often less conspicuous in the plexiform histologic type. The acanthomatous paOern, characterized by
squamous metaplasia and keratin formation in the central portions of the epithelial islands, can also be seen but is usually
limited.FIGURE 4A-16 Sinonasal ameloblastoma. A, The tumor was unencapsulated and is composed of
proliferating nests or islands of odontogenic epithelium including central area of loosely arranged cells
similar to the stellate reticulum of the enamel organ and a peripheral area of palisading columnar or
cuboidal cells with hyperchromatic small nuclei oriented away from the basement membrane (reverse
polarity). B, Acanthomatous changes can be seen as a focal alteration or as the dominant finding. C,
Ameloblastomatous proliferation is arising in direct continuity with the intact sinonasal surface mucosal
epithelium. This finding, in the face of an isolated sinonasal mass without continuity with gnathic sites,
supports the histogenesis of these sinonasal tumors from totipotential cells of the sinonasal mucosal
138S urgical excision is the treatment of choice in all cases, but the type and extent of surgery vary. S chafer and colleagues
reported a 22% recurrence rate. Recurrence of the tumor was generally within 1 to 2 years of the initial procedure, but in one
of their patients the recurrence was 13 years after initial surgery. Overall treatment success correlated most positively with
complete surgical eradication when performed in conjunction with thoroughly detailed radiographic imaging. N o tumor
deaths, metastases, or malignant transformation has been reported.
Craniopharyngiomas arise from Rathke pouch in the area of the pituitary gland (sella turcica) or along the developmental
tract leading to Rathke pouch and the pituitary gland. Extrasellar craniopharyngiomas may occur in the sinonasal tract or
140-143nasopharynx, either by direct extension from a sellar tumor or independent of sellar involvement. S ymptoms include
140nasal obstruction, epistaxis, headache, and impaired vision. Most patients are in the first decade of life. Histologically,
craniopharyngiomas are epithelial neoplasms composed of centrally situated stellate cells with small nuclei and clear
cytoplasm surrounded by a row of basaloid-appearing columnar cells with polarized nuclei in a palisaded arrangement.
D egenerative necrobiotic changes, such as ghost cells and calcification, can be identified in the tumor. These features closely
resemble the appearance of gnathic ameloblastomas. However, the clinical features of craniopharyngiomas markedly
contrast with those of sinonasal tract ameloblastomas so that the lesions should be readily separable. Complete surgical
140removal is the treatment of choice and generally is curative.
Benign Teratoma
Teratomas in the upper aerodigestive tract mucosal areas are rare neoplasms, accounting for fewer than 2% of all144teratomas. N o sex predilection is seen. Teratomas may be seen in the adult population, but the majority occur in
newborns or infants, and these lesions are rarely seen over the age of 1 year (cervical teratoma) and 2 years (nasopharyngeal
teratoma). The most common location for teratomas within the upper aerodigestive tract mucosa is the nasopharynx; other
less commonly involved sites include the oral cavity (tonsil, tongue, palate), sinonasal cavity, and the ear and temporal bone.
N asopharyngeal teratoma presents as a mass protruding into the oral cavity or pharynx causing associated dysphagia and/or
145airway obstruction. Teratomas may be associated with maternal hydramnios and stillbirth. I n contrast to teratomas
occurring in the pediatric population, teratomas of the head and neck in adults occur much less frequently, but a much
larger percentage of these tumors will be malignant.
Teratomas are encapsulated cystic, solid, or multiloculated, measuring from 5 to 17 cm in diameter. The histologic
composition of teratomas includes tissues arising from all three germ layers, including epithelia (keratinizing squamous,
columnar, ciliated respiratory, or gastrointestinal-type epithelium), cutaneous adnexa, minor salivary glands,
neuroectodermal and central nervous system tissue, cartilage, bone, fat, and smooth muscle. Epithelial-lined cystic spaces
are prominent. I mmature or embryonal tissue components can be identified throughout the tumor but are not of any
prognostic significance. I n nasopharyngeal teratomas, neuroectodermal and neural tissue components predominate.
N ecrosis and hemorrhage may be seen. I n adults with malignant teratomas a prominent neural component exists, associated
with poorly differentiated carcinoma and/or sarcoma (see later section on Malignant Teratoma).
Complete surgical excision is the treatment of choice. Morbidity may be high because of the size and location of the
tumors. Mortality rates are low if surgical intervention is initiated early; however, death may ensue in inadequately treated
cases and is usually caused by complications of respiratory obstruction. N asopharyngeal teratomas may extend
intracranially. I n the pediatric age group, malignant transformation (or behavior) of a head and neck teratoma has not been
146The differential diagnosis of nasopharyngeal teratoma includes the nasopharyngeal dermoid (so-called hairy polyp).
N asopharyngeal dermoid is a developmental (congenital) anomaly composed predominantly of skin (ectodermal derived)
but also may include well-formed cartilage (mesodermal derived); the absence of endodermal-derived structures and the
presence of limited heterogeneity of tissue types argue against inclusion as a teratoma. That these lesions contain skin, a
tissue type not normally found in the nasopharynx, suggests that these lesions may be beOer classified as a choristoma
147,148rather than a hamartoma, and possibly of first branchial arch origin. However, some authors argue that these lesions
149are best classified as a subset of benign teratoma.
Tumors of Indeterminant Malignant Potential
Sinonasal-Type Hemangiopericytoma
The term HPC has largely been abandoned at most anatomic locations (seeC hapter 3). However, sinonasal-type HPC, which
represents fewer than 1% of all sinonasal tract tumors, is a tumor showing perivascular myoid differentiation and typically
150-153behaves in a benign manner. Given light microscopic and immunohistochemical evidence of myoid differentiation
and that the light microscopic features of sinonasal-type HPC differ from those of soft tissue HPC, a more apt designation
151for the sinonasal tract lesion may be glomangiopericytoma. D espite the overwhelming indolent behavior of this sinonasal
tumor, the most recent World Health Organization (WHO) classification of sinonasal tract tumors has classified the
154sinonasal type of HPC as having indeterminant biologic potential.
For sinonasal-type HPC no sex predilection is seen; it occurs over a wide age range but is most commonly seen in the sixth
155to seventh decades of life. S inonasal-type HPC typically presents as a unilateral nasal mass with obstruction and
epistaxis. Extension into adjacent paranasal sinuses may occur, but isolated involvement of a paranasal sinus is uncommon.
The radiologic appearance of sinonasal-type HPC is usually opacification of the involved sinus. Bone erosion due to pressure
may be seen. Arteriographic findings reveal a richly vascular neoplasm. No known etiologic factors exist.
The gross appearance of sinonasal-type HPC is that of a red to tan-gray, soft to firm polypoid mass of varying size.
Histologically, sinonasal-type HPC is a submucosal, circumscribed but unencapsulated cellular tumor. I n contrast to LCH,
sinonasal-type HPC has a diffuse growth paOern and is composed of single cell type distributed around endothelial-lined
vascular spaces (Fig. 4A -17). The tumor cells are usually arrayed in short fascicles and less often may show storiform,
whorled, or even palisaded growth paOerns. The tumor cells are usually uniform with round to oval nuclei, vesicular to
hyperchromatic-appearing chromatin, and indistinct eosinophilic cytoplasm; occasionally, spindle-shaped cells are seen (see
Fig. 4A -17). Mild nuclear pleomorphism and an occasional mitotic figure can be seen, but typically no marked increase
occurs in mitotic activity, and atypical mitoses are not present. N ecrosis is not usually found. The vascular channels range
from capillary size to large sinusoidal spaces that may have a “staghorn” configuration. A characteristic but not
pathognomonic feature is the presence of perivascular hyalinization (see Fig. 4A-17). The cellular proliferation may compress
and obscure blood vessels of smaller size. Extravasated erythrocytes are often identified. A n inflammatory component,
usually including mast cells but also eosinophils, is present scaOered throughout the tumor. Multinucleate (tumor) giant
151cells can be seen in a minority of cases. Fibrosis or a myxoid stroma may be seen, especially in tumors with degenerative
change. Heterologous metaplastic elements, including bone and cartilage, may occasionally be seen.FIGURE 4A-17 Sinonasal-type hemangiopericytoma. A, The tumor characteristically is submucosal
without involvement of the surface epithelium and is cellular, diffuse in its growth, and well vascularized.
The neoplastic cells are tightly packed with hyperchromatic nuclei and are situated in and around
endothelial-lined vascular spaces; the latter appear dilated and irregularly shaped, but no
intercommunication of the vascular channels exists. B, A characteristic finding relative to the vascular
spaces is the presence of perivascular hyalinization that, in conjunction with the cytomorphology, assists
in recognizing this tumor.
Reticulin stain reveals a distinctive paOern characterized by envelopment of individual pericytes by reticulin fibers.
N eoplastic cells of so-called HPC (now more usually S FT) at soft tissue sites fail to stain with muscle-specific actin and
156,157desmin, but sinonasal-type HPC is positive for vimentin, smooth muscle actin, muscle-specific actin, factor XI I I a, and
Ultrastructural findings include the presence of pericellular basal lamina, pinocytotic vesicles, intracytoplasmic (thin)
159,160filaments, dense bodies, and membranous attachment plaques.
The differential diagnosis includes LCH, angiofibroma, glomus tumor (glomangioma), solitary fibrous tumor, smooth
muscle tumors (leiomyoma and leiomyosarcoma), and synovial sarcoma. Both sinonasal-type HPC and S FT may show CD 34
immunoreactivity, but in sinonasal-type HPC usually only focal CD 34 staining is seen, whereas in solitary fibrous tumors it
tends to be more diffuse. Furthermore, in contrast to S FT, sinonasal-type HPC lacks the presence of “ropey”
keloidal161appearing collagen or amianthoid fibers. Hansen and colleagues reported preferential D 2-40 immunostaining in
sinonasal-type HPC compared with SFT.
S urgery is the treatment of choice. HPC are considered radioresistant neoplasms. S inonasal-type HPC are
indolent151,155behaving tumors with overall 5-year survival rates of greater than 90%. Local recurrence may occur in as many as 30%
160 162of cases and is likely due to inadequate surgical excision. Eichorn and colleagues and El-N aggar and associates report
that recurrence of sinonasal-type HPC can be anticipated over extended follow-up periods (one to two decades). A ggressively
155behaving sinonasal-type HPC are uncommon and include tumors that are locally destructive or are metastatic. Findings
potentially linked to aggressive behavior include large tumor size (greater than 5 cm), marked nuclear pleomorphism,
151,163,164increased mitotic activity, necrosis, invasive growth (e.g., bone), and a proliferation index of greater than 10%.
155Metastatic tumor occurs to regional lymph nodes and lung and is usually preceded by recurrent tumor, but predicting the
biologic behavior is difficult (see Chapter 3).Malignant Epithelial and Neuroectodermal Neoplasms
Carcinoma of the Nasal Vestibule
Carcinoma of the nasal vestibule is uncommon and is considered to represent cutaneous carcinoma rather than mucosal
165 165carcinoma. Of the five cases reported by Taxy, four were men and one was a woman, ranging in age from 52 to 82
years. The tumors were located either in the nasal vestibule or at the mucocutaneous junction. The most common tumor type
is squamous carcinoma. The majority of these tumors are well differentiated. Basal cell carcinomas may also occur but are
165uncommon. The differential diagnosis includes squamous papilloma, S chneiderian papilloma, and verrucous carcinoma
(see later discussion). Treatment includes local excision and/or radiotherapy. Most patients have an excellent prognosis.
Five165year survival rates range from 70% to 80%. I nvasion of the subjacent nasal septal perichondrium or bone may occur.
Metastasis to cervical neck lymph nodes may occur but is uncommon.
Squamous Cell Carcinoma of the Sinonasal Tract and Nasopharynx
The epithelium lining the sinonasal tract and nasopharynx is capable of differentiating along various cell lines, accounting
for the morphologic variety of carcinomas seen to arise from these surfaces. S CCs of the upper aerodigestive tract mucosa
are divided according to histologic subtype. The most common type of S CC of the sinonasal tract is the conventional type,
including keratinizing and nonkeratinizing S CCs. I n addition, several variants of conventional squamous carcinoma exist,
including exophytic or papillary squamous carcinoma, verrucous carcinoma, spindle cell squamous carcinoma, basaloid S CC,
and adenosquamous carcinoma, that are sufficiently different in their pathologic features, biologic behavior, and therapeutic
approach to merit separate discussion. A staging system recommended for these tumors by the A merican J oint Commission
on Cancer is outlined in Tables 4A-6, A and B.
T N M S taging of C arcinoma of the M axillary S inus, N asal C avity, and E thmoid S inusPrimary Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
Maxillary Sinus
T1: Tumor limited to maxillary sinus mucosa with no erosion or destruction of bone
T2: Tumor causing bone erosion or destruction including extension into the hard palate and/or middle nasal
meatus, except extension to posterior wall of maxillary sinus and pterygoid plates
T3: Tumor invades any of the following: bone of the posterior wall of maxillary sinus, subcutaneous tissues, floor or
medial wall of orbit, pterygoid fossa, ethmoid sinuses
T4a: Moderately advanced local disease. Tumor invades anterior orbital contents, skin of cheek, pterygoid plates,
infratemporal fossa, cribriform plate, sphenoid or frontal sinuses
T4b: Very advanced local disease. Tumor invades any of the following: orbital apex, dura, brain, middle cranial
fossa, cranial nerves other than maxillary division of trigeminal nerve (V ), nasopharynx, or clivus2
Nasal Cavity and Ethmoid Sinus
T1: Tumor restricted to any one subsite, with or without bone invasion
T2: Tumor invading two subsites in a single region or extending to involve an adjacent region within the
nasoethmoidal complex, with or without bone invasion
T3: Tumor extends to invade the medial wall or floor of the orbit, maxillary sinus, palate, or cribriform plate
T4a: Moderately advanced local disease. Tumor invades any of the following: anterior orbital contents, skin of nose
or cheek, minimal extension to anterior cranial fossa, pterygoid plates, sphenoid or frontal sinuses
T4b: Very advanced local disease. Tumor invades any of the following: orbital apex, dura, brain, middle cranial
fossa, cranial nerves other than maxillary division of trigeminal nerve (V ), nasopharynx, or clivus2
Regional Lymph Nodes (N)*
pNX: Cannot be assessed
pN0: No regional lymph node metastasis
pN1: Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
pN2: Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension,
or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension, or in bilateral or contralateral
nodes, none more than 6 cm in greatest dimension
pN2a: Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension
pN2b: Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension
pN2c: Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension
pN3: Metastasis in a lymph node more than 6 cm in greatest dimension
*Metastases at level VII are considered regional lymph node metastases. Midline nodes are considered ipsilateral nodes.
Distant Metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
Anatomic Stage/Prognostic Groups
Stage 0 Tis N0 M0
Stage I T1N0M0
Stage II T2N0M0
Stage III T3N0M0
Stage IVA T4aN0M0
Stage IVB T4b Any N M0
Any T N3M0
Stage IVC Any T Any N M1
Reproduced with permission of the American Joint Committee on Cancer (AJCC), Chicago. The original source for this
material is 2010 AJCC Cancer Staging Manual, 7th ed. Springer-Verlag, New York (www.springeronline.com)
T N M S taging of C arcinoma of the N asopharynxPrimary Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
pT1: Tumor confined to nasopharynx, or tumor extends to oropharynx and/or nasal cavity without parapharyngeal
pT2: Tumor with parapharyngeal extension*
pT3: Tumor invades bony structures of skull base and/or paranasal sinuses
pT4: Tumor with intracranial extension and/or involvement of cranial nerves, hypopharynx, orbit, or with extension
to the infratemporal fossa/masticator space
*Parapharyngeal extension denotes posterolateral infiltration of tumor.
Regional Lymph Nodes (N)
pNX: Cannot be assessed
pN0: No regional lymph node metastasis
pN1: Unilateral metastasis in lymph node(s), 6 cm or less in greatest dimension, above the supraclavicular fossa†
pN2: Bilateral metastasis in lymph node(s), 6 cm or less in greatest dimension, above the supraclavicular fossa†
pN3: Metastasis in a lymph node greater than 6 cm and/or to supraclavicular fossa†
pN3a: Greater than 6 cm in dimension
pN3b: Extension to the supraclavicular fossa†
*Metastases at level VII are considered regional lymph node metastases. Midline nodes are considered ipsilateral nodes.
†Supraclavicular zone or fossa is relevant to the staging of nasopharyngeal carcinoma and is the triangular region
defined by three points: (1) the superior margin of the sternal end of the clavicle, (2) the superior margin of the
lateral end of the clavicle, (3) the point where the neck meets the shoulder. Note that this would include caudal
portions of levels IV and VB. All cases with lymph nodes (whole or part) in the fossa are considered N3b.
Distant Metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
Anatomic Stage/Prognostic Groups
Stage 0 Tis N0 M0
Stage I T1N0M0
Stage II T1N1M0
Stage III T1N2M0
Stage IVA T4N0M0
Stage IVB Any T N3M0
Stage IVC Any T Any N M1
Reproduced with permission of the American Joint Committee on Cancer (AJCC), Chicago. The original source for this
material is 2010 AJCC Cancer Staging Manual, 7th ed. Springer-Verlag, New York (www.springeronline.com)
Squamous Cell Carcinoma (Conventional Type) of the Sinonasal Tract
S CC is the most common type of malignant epithelial neoplasm of the sinonasal tract. However, it represents only
166,167approximately 3% of all head and neck malignant neoplasms and fewer than 1% of all malignant neoplasms.
S inonasal S CC affects men more than women and is most frequent in the sixth and seventh decades of life, with 95% of cases
arising in patients older than 40 years. I n decreasing order of frequency, the sites of occurrence include antrum of the
166,167maxillary sinus, nasal cavity, ethmoid sinus, and the sphenoid and frontal sinuses. Although the frontal and sphenoid
sinuses may be the sites of a primary carcinoma, most of the neoplasms involving these sinuses arise from the ethmoid sinus
or from the nasopharynx. Clinical presentations include facial asymmetry, unilateral nasal obstruction, epistaxis, a tumor
mass palpable or visible in the nasal or oral cavity, pain, persistent purulent rhinorrhea, nonhealing sore or ulcer, and
exophthalmos. The diagnosis of paranasal sinus carcinoma is often delayed as the clinical signs and symptoms in the earlier
stages of disease are similar to those of chronic sinusitis, whereas carcinoma of the nasal cavity is usually recognized
168relatively early as symptoms prompt earlier clinical detection. Risk factors that have been associated with sinonasal tract169,170squamous carcinoma include nickel exposure, as well as exposure to textile dust, smoking, prior Thorotrast use, and
development of S chneiderian papilloma. I n the laI er, HPV may be found, but a direct cause and effect has not definitively
been established. Patients with nasal cavity squamous carcinomas are at greater risk for a second primary malignancy, either
171at another mucosal site in the upper aerodigestive tract or involving the lung, gastrointestinal tract, or breast.
The gross appearance of sinonasal S CCs varies and includes exophytic, polypoid, papillary, fungating, or inverted growth
paI erns that may be well circumscribed, with an expansile growth and limited invasion, or necrotic and friable with a
hemorrhagic appearance and destructive growth.
S inonasal S CCs are histologically divided into keratinizing and nonkeratinizing subtypes. The keratinizing type is the
most common. These tumors can be divided into well-differentiated, moderately differentiated, and poorly differentiated
carcinomas. I n well-differentiated S CCs readily apparent keratinization with keratin pearl formation or individual cell
keratinization is seen (Fig. 4A -18). D yskeratosis (abnormal keratinization) may be prominent. I ntercellular bridges are
identifiable. The neoplastic cells show mild to moderate nuclear atypia with enlarged, hyperchromatic nuclei and low mitotic
activity. A s a squamous carcinoma becomes less differentiated (higher histologic grade), the tumor shows less keratinization
and more nuclear atypia with increased mitotic activity, including atypical forms. Even in the poorly differentiated
carcinomas, evidence of keratinization is usually focally present. S tromal invasion may include cohesive nests or cords of
malignant cells or may be represented by isolated invasive malignant cells. The host response to invasive carcinoma
(desmoplasia) includes collagen deposition with or without an associated chronic inflammatory cell reaction.
FIGURE 4A-18 Sinonasal squamous cell carcinoma, keratinizing. Left, Infiltrating keratinizing squamous
cell carcinoma. Right, Individual cell keratinization and intercellular bridges are present.
The nonkeratinizing subtype may also have a papillary or exophytic growth paI ern but often shows a downward (inverted
or endophytic) growth with broad interconnecting bands or nests of neoplastic epithelium (Fig. 4A-19). The tumor nests may
have rounded or smooth borders or may be delineated by basement membrane–like material. This paI ern of growth is
172similar to that of bladder cancers, hence the designation of these tumors as transitional-type carcinomas. This tumor type
is composed of elongated cells with a cylindrical or columnar appearance, oriented perpendicular to the surface and
generally lacking evidence of keratinization. Keratin may be present focally but does not represent a significant component
of the tumor. I n general, these are hypercellular tumors characterized by nuclear pleomorphism, hyperchromasia, increased
nucleus to cytoplasm ratio, loss of cell polarity, and increased mitotic activity, including atypical forms (see Fig. 4A -19).
Given the smooth borders or surrounding basement membrane–like material, these tumors may not be interpreted as
invasive and may be underdiagnosed as papillomas with severe dysplasia or as carcinoma in situ. For both types of
squamous carcinoma, dysplasia of the adjacent or overlying surface epithelium may be seen. Consistent immunoreactivity is
present for cytokeratins, and these tumors may be p16 positive. The differential diagnosis of sinonasal S CC includes
sinonasal (Schneiderian) papillomas (see earlier discussion).FIGURE 4A-19 Sinonasal squamous cell carcinoma, nonkeratinizing. A, The tumor invades into the
submucosa as broad interconnecting bands of the neoplastic epithelium growing down (“inverted”) into the
stroma. B, Marked cellular pleomorphism with loss of polarity, increased nucleus to cytoplasm ratio, and
increased mitotic activity.
S urgical advances now permit complex tumor removal and reconstruction of the surrounding structures resulting in
173,174functional and cosmetic improvements. Local recurrence is frequent, but metastatic disease is uncommon if the
tumor is confined to the involved sinus. Tumor extension beyond the sinus wall results in a higher incidence of regional
lymph node metastasis. Clinical stage is of more importance to prognosis than histologic type. Factors portending a poorer
prognosis include higher clinical stage disease with involvement of more than one anatomic area, extension beyond the nasal
cavity or paranasal sinuses, and regional lymph node metastasis. The paI ern of invasion may also impact prognosis. Tumors
with “diffuse spread” or single cell invasive growth pattern have a decreased survival of 30% to 40% as compared with 80% to
175 17690% survival in patients with a more cohesive or “pushing” paI ern of invasion. Crissman and Zarbo have discussed
the implications of paI ern of tumor invasion and correlation with prognosis, finding that invasive cancers with single cell or
small aggregates of tumor cells invading into the stroma are more often associated with lymphovascular invasion.
Variants of Squamous Cell Carcinoma
Histologic variants of S CC include papillary S CC, verrucous carcinoma, spindle cell squamous carcinoma, basaloid S CC, and
adenosquamous carcinoma. These histologic variants may occur in the sinonasal tract and nasopharynx but tend to be more
common in the hypopharynx (e.g., piriform sinus) and larynx and will be addressed in the second portion of this chapter.
Viral-related Squamous Cell Carcinomas
I ncreasing evidence exists that HPV and EBV play a pathogenic role in a subset of head and neck S CC(sH N S CC). HPV, in
particular the high-risk type 16 (HPV-16), is present in most oropharyngeal carcinomas (i.e., base of tongue, tonsils), being
177,178detected in greater than 90% of cases. For N PC, EBV is associated with the nonkeratinizing types of N PCs, including
both differentiated and undifferentiated subtypes in practically 100% of cases, irrespective of the ethnic background of the
patient. The most reliable detection method for EBV is I S H for EBV encoded early RN A (EBER), which is present in cells
latently infected by EBV; this can facilitate the diagnosis of NPC.
The viral-related HN S CCs may be termed HPV–head and neck S CC (HPV-HN S CC) and EBV-associated head and neck
S CC (EBV-HN S CC). S uch designations are not yet universally accepted but have merit given the unique clinical, pathologic,
therapeutic, and prognostic implications associated with these cancers.
Oropharyngeal Nonkeratinizing Squamous Cell Carcinoma (Human Papillomavirus–Associated Squamous Cell
A pproximately 20% to 25% of S CCs of the upper aerodigestive tract are related to HPV infection, and the incidence of
HPV178associated HN S CC is rising. I n contrast, the incidence of HPV-unrelated HN S CC has stabilized or is decreasing with thedecreasing use of tobacco products (Table 4A-7). The majority of HPV-associated S CC of the upper aerodigestive tract occur
179in the oropharynx, predominantly arising at the base of the tongue or palatine tonsil. The propensity for HPV to infect the
base of tongue and tonsil might be due to greater accessibility of the virus to the basal and proliferating squamous cells in
180these locations, possibly as a result of epithelial disruption.
Comparison Between Human Papillomavirus–Positive and Human Papillomavirus–Negative Squamous Cell
HPV-Positive SCC HPV-Negative SCC
Age Younger Older
Sex M = F M > F
Race White > African American White = African American
Risk factors (tobacco or No known risk factors (usually nonsmokers, Associated with tobacco and/or alcohol
alcohol) nondrinkers) use or abuse
Primary location Oropharynx (base of tongue; tonsil) All mucosal sites of the UADT
Histology Nonkeratinizing carcinoma predominantly composed Keratinizing SCC
of basaloid cells
p16 Positive Negative
Prognosis Better disease-free and overall survival Worse disease-free and overall survival
Tumor stage at Often higher (more nodal metastasis) Often lower
HPV, Human papillomavirus; SCC, squamous cell carcinoma; UADT, upper aerodigestive tract.
HPV-associated oropharyngeal S CC represents a unique subtype of HN S CC frequently occurring in patients with no
known risk factors for HN S CC (i.e., nonsmokers and nondrinkers), in younger patients, and associated with a beI er
outcome (better overall and disease-specific survival) than non–HPV-associated HNSCCs. Furthermore, these carcinomas are
highly curable even in presence of advanced disease. S ymptoms associated with HPV-associated oropharyngeal S CC often
relate to a mass. However, these cancers may be small and clinically or radiographically difficult to detect. Furthermore,
HPV-associated oropharyngeal S CC frequently develops early neck metastasis and may present as metastatic cancer to a
cervical neck lymph node from an unknown primary site. Positron emission tomography or computed tomography (PET/CT)
scan can play an important role in the imaging of these cancers, in particular in trying to localize or identify the primary
The HPV-associated HN S CC are nonkeratinizing carcinomas characterized by basaloid cytomorphologyF (ig. 4A -20). The
carcinoma often grows in solid sheets, trabecula, cords, and nests, but individual infiltrative cells can be seen. These
carcinomas are often cystic with central areas of necrosis, and metastases are frequently cystic (see Fig. 4A -20). I n the
absence of a known primary carcinoma, such cystic neck masses may be considered branchial cleft cysts with malignant
transformation, a diagnosis of questionable existence. The neoplastic cells show marked nuclear pleomorphism with
increased mitotic activity including atypical mitoses. Focal keratinization may be seen. Given their basaloid morphology
including features of a histologic higher grade carcinoma, such carcinomas (on fine needle aspiration or biopsy) have often
been erroneously designated as poorly differentiated. I n fact, these nonkeratinizing carcinomas are considered beI er
differentiated carcinomas recapitulating the crypt epithelium from which they may arise. I t should be noted that initial
181designation of these cancers as “basaloid” may result in confusion with basaloid S CC, which is a high-grade variant of
conventional S CC most often involving the hypopharynx (i.e., piriform sinus) and supragloI ic larynx and not associated with
HPV (or EBV). Oropharyngeal nonkeratinizing carcinomas are often associated with a dense lymphocytic infiltrate. These
cancers may invade without associated desmoplasia, and, as such, the neoplastic cells may be obscured by the lymphocytic
infiltrate. Oropharyngeal HPV-associated S CCs may demonstrate papillary growth or may show cytomorphologic
characteristics similar to nasopharyngeal nonkeratinizing undifferentiated-type carcinoma, including syncytial growth and
182cells with enlarged vesicular nuclei and prominent nucleoli. A lthough this morphology overlaps with EBV-associated
182NPCs, this subset of oropharyngeal carcinomas is associated with HPV rather than EBV.FIGURE 4A-20 Human papillomavirus–associated squamous cell carcinomas are predominantly or
exclusively nonkeratinizing carcinomas characterized by (A) basaloid cell morphology, (B) solid and solid
growth central areas of necrosis, (C) p16 immunoreactivity (nuclear and cytoplasmic), and (D) human
papillomavirus in situ hybridization.
The neoplastic cells of oropharyngeal nonkeratinizing carcinomas are immunoreactive for cytokeratins, including
A E1/A E3, CA M5.2, and cytokeratin 5/6 (CK5/6), which may be extremely helpful in identifying the malignant cells in the
presence of a prominent lymphoid infiltrate. Oropharyngeal nonkeratinizing carcinomas are positive for HPV-16, and the
183presence of HPV-16 represents a reliable predictor of origin from the oropharynx. At present, no standard assay for HPV
detection exists. D etection methods include immunohistochemical staining with surrogate biomarkers (i.e., p16 protein) (see
Fig. 4A -20), D N A I S H (seeF ig. 4A -20), and PCR-based (consensus and type specific) real-time assays to quantify viral load.
The presence of p16 immunostaining correlates with the presence of HPV-16. The reactivity paI ern for p16 includes nuclear
183,184 185and cytoplasmic staining and is usually diffuse and strong. S inghi and Westra found that, in comparison with
PCR-based methods, I S H is more practical, and they recommended combined immunohistochemical and I S H testing. Using
the combined strengths of HPV I S H and p16 immunohistochemistry, these authors reported that (1) given a sensitivity
approaching 100%, negative p16 staining serves to identify HPV-16–negative cases that would not benefit from additional
analysis; (2) given specificity approaching 100%, positive HPV-16 I S H reduces the number of false-positive cases by p16
staining alone; and (3) p16 positive and HPV-16 I S H negative singles out a subset of tumors requiring more rigorous analysis
185for other HPV types. Using a combined approach including immunohistochemistry and I S H, S inghi and Westra found
HPV in a remarkably high percentage of oropharyngeal S CC (82%), which was greater than the previously reported
prevalence ranging from 19% to 72%.
Guidelines for p16 and/or HPV testing in head and neck carcinomas may include the following:
• In an oropharyngeal biopsy showing atypical basaloid cells, the presence of p16 confirms the diagnosis of
HPV-associated HNSCC.
• In tumors with overlapping morphology (e.g., basaloid SCC), the presence of p16 helps confirm the diagnosis
of HPV-associated HNSCC.
• In the presence of cervical nodal metastatic disease, p16 staining would confirm the diagnosis of metastatic
cystic SCC, localize the primary site of origin (i.e., oropharynx), and establish the tumor classification.
HPV-associated HN S CC have unique therapeutic and prognostic parameters. HPV-HN S CC are radioresponsive tumors
associated with a beI er outcome (beI er overall and disease-specific survival) and are highly curable even with advanced
186,187disease. Factors that may be in play relative to their beI er outcome include the possibility of absence of field
cancerization and enhanced radiation sensitivity.
Nasopharyngeal Carcinoma
N PC (Table 4A -8) is an S CC arising from the surface epithelium and subtyped according to the WHO into two histologic
188variants: keratinizing and nonkeratinizing. The nonkeratinizing type is further subdivided as being “differentiated” and“undifferentiated.” The current WHO classification retains the terminology of the 1991 classification and adds the category
189of basaloid S CC to this classification. S ynonyms for N PC include lymphoepithelioma, Regaud and S chmincke types of
lymphoepithelioma, and transitional carcinoma. The designation lymphoepithelioma is a misnomer. This is a tumor entirely
of epithelial origin with a secondary associated benign lymphoid component. Use of the term lymphoepithelioma may result
in confusion with a diagnosis of malignant lymphoma. The prior numeric designations of WHO types 1 (S CC), 2
(nonkeratinizing carcinoma), and 3 (undifferentiated carcinoma) are no longer used. I t should be noted that, although they
share the unfortunate designation of “undifferentiated,” no relationship exists between the sinonasal undifferentiated
carcinoma (see later discussion) and the nasopharyngeal undifferentiated carcinoma. These tumors are anatomically distinct
with differing therapeutic approaches and biologic outcome. The terms should not be used synonymously, nor should the
tumors be confused clinically and pathologically.
Nasopharyngeal Carcinoma
† ‡Keratinizing* Nonkeratinizing Undifferentiated
Percentage Approximately 25 Least common, Most common, >60
Sex, age M > F; fourth-sixth decades M > F; fourth-sixth decades M > F; fourth-sixth decades; may occur in
Histology Keratinization, Little to absent keratinization, Absence of keratinization, syncytial growth,
intercellular bridges; growth pattern cohesive or noncohesive cells with round
conventional squamous interconnecting cords nuclei, prominent eosinophilic nucleoli,
carcinoma graded as (similar to transitional scant cytoplasm, and limited mitoses;
well, moderately, or urothelial carcinoma); prominent nonneoplastic lymphoid
poorly differentiated; typically, limited to absent component; typically, absence of
desmoplastic response desmoplastic response to desmoplastic response to invasion
to invasion invasion
EBV Weak association Strong association Strong association
Treatment Radioresponsiveness is not Radioresponsive Radioresponsive
Prognosis 20%-40% 5-year survival 65% 5-year survival 65% 5-year survival
*World Health Organization (WHO) designation as nasopharyngeal carcinoma, keratinizing.
†WHO designation as nonkeratinizing, differentiated.
‡WHO designation as nonkeratinizing, undifferentiated.
EBV, Epstein-Barr virus.
190,191Overall, N PC is an uncommon neoplasm in the United S tates, accounting for approximately 0.25% of all cancers. I n
192 193China, it accounts for 18% of all cancers, and N PC develops in 1 in 40 men before the age of 72 years. N PC affects men
more than women and occurs over a wide age range but is most common in the fourth to sixth decades of life. Fewer than
20% of cases occur in pediatric age groups. Pediatric N PC is most common in northern and central A frica, accounting for
194-19710% to 20% of all cases, whereas only approximately 2% of N PCs in China occur in children. I rrespective of the
histologic type, the clinical presentation is similar and includes the presence of an asymptomatic cervical neck mass typically
localized to the posterior cervical triangle or the superior jugular nodal chain, with additional clinical signs and symptoms
198that include nasal obstruction, nasal discharge, epistaxis, pain, serous otitis media, otalgia, hearing loss, and headache.
The signs and symptoms are often subtle and nonspecific and thereby may cause a delay in the diagnosis, often resulting in
199clinical presentation at an advanced stage of disease. Up to 25% of patients may have cranial nerve involvement. Cranial
nerve involvement occurs by spread of tumor laterally through the cavernous sinus, with involvement of cranial nerves I I I ,
I V, ophthalmic branch of V, and VI , and by direct tumor extension with involvement of cranial nerves I X, X, XI , XI I , and the
199third division of V through the parapharyngeal space. The lateral wall of the nasopharynx (fossa of Rosenmüller) is the
197most common site of occurrences, followed by the superior posterior wall.
200Radiologic imaging is an important diagnostic aid in assessing the extent of disease and presence of metastatic disease.
Multiple interactive etiologic factors have been linked to the development of N PC. Genetic and geographic factors play an
important role in the genesis of N PC. A n increased incidence of N PC is seen in China, especially in southern (Kwantung)
192and northern provinces and Taiwan. A lthough the incidence among Chinese people decreases after emigration to
low192,201incidence areas, it still remains higher than in non-Chinese populations. HLA -A 2, HLA -B17, HLA -Bw46, and HLA -
192BW58 histocompatibility loci have been suggested as the marker for genetic susceptibility to N PC. Perhaps the most
192,202,203important link to the development of N PC is EBV. A strong association exists between certain N PCs and the
203presence of EBV, indicating a probable oncogenic role of EBV in the development of N PC. Both the nonkeratinizing and
undifferentiated types of nasopharyngeal squamous carcinoma are linked with the presence of EBV D N A . Elevated titers of
immunoglobulin A antibodies (against viral capsid antigen) and immunoglobulin G antibodies (against early antigen) are
204-210 189seen in patients with N PC, with detection rates for N PC ranging up to 93% ; elevated titers have been used as a
205,206,210marker to screen populations in high-risk areas and as a potential indicator of disease relapse. Positive EBV211serology in 90% of patients with nonkeratinizing carcinoma have been reported. N ewer antibody tests based on
recombinant EBV antigens (e.g., EBV nuclear antigens, membrane antigen) have been used in the diagnosis of N PC as has
quantitative PCR to test for elevated circulating EBV D N A in plasma and serum with sensitivity rates in N PC of up to
212-21596%. Molecular biologic analysis of N PC by either I S H for EBER or PCR detects EBV D N A or RN A in 75% to 100% of
216,217NPC. This is not true of the keratinizing subtype, in which the detection of EBV is variable and, if present, is generally
218limited to scaI ered dysplastic intraepithelial cells. Pathmanathan and colleagues report that EBV is an early initiating
event in the development of N PC. These authors note that EBV was present in preinvasive (precursor) nasopharyngeal
lesions; that the EBV-D N A was clonal, suggesting that the preinvasive lesions arose from a single EBV-infected cell; and that
218 219these preinvasive lesions progressed to invasive cancer within 1 year. Hording and colleagues evaluated 38 cases of
N PC for the presence of HPV and report that four of 15 keratinizing squamous carcinomas were HPV positive but that none
of the nonkeratinizing or undifferentiated N PC had HPV. HPV may have a pathogenetic role for some nasopharyngeal
keratinizing S CCs but not for the nonkeratinizing or undifferentiated types. Other suggested factors implicated in N PC
include diet (salted fish high in nitrosamines); poor hygiene; and nondietary environmental factors, including atmospheric
agents such as dust, smoke, chemical fumes, domestic smoke from burning wood, grass, and incense, and inhalation (active
or passive) of tobacco smoke, the use of herbal medicines, and the use of nasal inhalants in the treatment of nasal
220-222Consistent nonrandom deletions and rearrangement of the short arm of chromosome 3 have been found in N PC.
Genetic instabilities (losses and gains) are common molecular events in N PC and play an important role in the development
and progression of N PC. Loss of heterozygosity and comparative genomic hybridization have shown high frequent allelic
223-225losses on chromosomes 1p, 3p, 9p, 9q, 11q, 13q, 14q, 16q, and 19q. Comparative genomic hybridization analysis
showed that gains on chromosome 1q, 8q, and 18q and loss on 9p were closely related to advanced stage of N PC. Frequent
loss of heterozygosity is seen on 3p in normal nasopharyngeal epithelium (74%) and dysplastic lesions (75%) from the
224Southern Chinese, suggesting that this may be an earlier genetic event in NPC tumorigenesis.
Linkage analysis indicates that the HLA and cytochrome p4502E genes may be susceptibility genes for N PC.
Complementary D N A microarray demonstrates differential expression of cell cycle proteins, antiapoptotic factors,
oncogenes and tumor suppressors, growth-enhancing factors of EGR1, tumor-derived growth factor 1, and platelet-derived
growth factor A chain. Through loss of heterozygosity, comparative genomic hybridization, linkage analysis, and
224complementary D N A microarray, specific biomarkers of N PC can be used for earlier diagnosis and prognosis of N PC.
The development of N PC likely involves cumulative genetic and epigenetic changes, in a background of genetic
226predisposition, as well as environmental factors. Genome-wide studies have identified multiple chromosomal
abnormalities with involvement of specific oncogenes and tumor suppressor genes, including inactivation of the p16 tumor
227,228suppressor gene on 9p21, the most common molecular alteration in N PC tumorigenesis. A lterations of genes such as
Ras association domain family 1A (RA S S F1A), p16/I N K4A , and p14/A RF suggest that multiple cellular pathways are
dysregulated in the NPC cells.
The gross appearance of N PC varies from a mucosal bulge with an overlying intact epithelium to a clearly demonstrable
mass with extensive involvement of the surface epithelium and/or frankly infiltrative growth to a totally unidentifiable lesion
fortuitously sampled and identified by microscopic evaluation. Three histologic types are recognized on the basis of the
229predominant appearance. The keratinizing conventional squamous carcinoma is characterized by the presence of
keratinization and intercellular bridges and graded as well, moderately, or poorly differentiated. A desmoplastic reaction is
typically found in response to invasive growth by this histologic type of N PC. The keratinizing N PC represents
230approximately 25% of all NPC and rarely occurs in patients under 40 years of age.
The nonkeratinizing carcinomas show liI le to absent keratinization and have a growth paI ern similar to transitional cell
carcinoma of the bladder, including stratified cells with sharp delineation from the surrounding stroma (Fig. 4A -21).
Welldefined cell borders and vague intercellular bridges may be present; rarely, an occasional keratinized cell may be identified.
Typically, no desmoplastic response to invasive growth occurs. These tumors may undergo cyst formation with associated
necrosis and may metastasize as such to the cervical nodes (see Fig. 4A -21). Furthermore, the primary carcinomatous focus
may be small and lie within the submucosa (e.g., in crypt epithelium) with an overlying intact, nondescript surface
epithelium representing an occult primary carcinoma (Fig. 4A -22). This type of N PC is the least common, representing
230approximately 12% of all NPCs.FIGURE 4A-21 Nasopharyngeal nonkeratinizing carcinoma, differentiated type. A, The neoplasm
invades in broad anastomosing cords and trabeculae. B, The neoplastic cells have pleomorphic nuclei
with increased mitotic activity lacking keratinization.
FIGURE 4A-22 Nasopharyngeal nonkeratinizing carcinoma, differentiated type originating in crypt
epithelium. The overlying surface epithelium is unremarkable. This may represent the primary (occult)
focus for a metastatic carcinoma to a lateral cervical neck lymph node. The metastatic foci recapitulate
the appearance of the primary focus with cyst formation and, in the presence of an occult primary
carcinoma, raise concern for a branchial cleft cyst or a carcinoma arising in a branchial cleft cyst
(socalled branchiogenic carcinoma).
230The undifferentiated type of N PC represents approximately 60% of all N PCs and is the most frequent tumor type seen
195in pediatric age groups. The neoplastic cells are characterized by the presence of round nuclei, prominent eosinophilic
nucleoli, dispersed nuclear chromatin, and scant eosinophilic to amphophilic cytoplasm (Fig. 4A -23). Keratinization is
absent. I ncreased mitoses, including atypical forms, are present. A prominent nonneoplastic lymphoid component
comprising mature lymphocytes and plasma cells is seen in association with the malignant epithelial component, although
this is not invariable. Other inflammatory cell types that can be present include eosinophils and neutrophils, and scaI ered
epithelioid granulomas may be present. This tumor type may show syncytial growth with cohesive or nested cells or may
show a diffuse cellular infiltrate composed of noncohesive cells. The diffuse paI ern is the one that is difficult to differentiate
from a malignant lymphoma by light microscopy (see Fig. 4A -23). The Regaud and S chmincke types of N PC refer to those
neoplasms with a syncytial versus an individual cell growth paI ern, respectively. These designations and their correlated
growth have no bearing on the biology of the disease. The infiltrative growth of this tumor generally does not produce a host
desmoplastic response. This may be problematic in biopsy samples as the tumor may be overrun by the lymphohistiocytic
infiltrate and thus is easily overlooked (Fig. 4A -24). S imilarly, metastasis to cervical lymph nodes may not elicit a
desmoplastic response in the involved lymph node.FIGURE 4A-23 Nasopharyngeal nonkeratinizing carcinoma, undifferentiated type. A, Tumor nests are
readily apparent and are clearly delineated from surrounding nonneoplastic lymphocytic cell infiltrate. B,
The neoplastic cells are characterized by the presence of enlarged round nuclei, vesicular chromatin,
prominent eosinophilic nucleoli, and scant eosinophilic to amphophilic cytoplasm. A nonneoplastic lymphoid
component is present. C, The carcinoma may show a diffuse growth and raise suspicion for a diffuse
large cell B-cell lymphoma. D, Irrespective of the growth characteristics, the neoplastic cells are
cytokeratin positive and (E) consistently positive for Epstein-Barr virus encoded early RNA.FIGURE 4A-24 Nasopharyngeal nonkeratinizing carcinoma, undifferentiated type. A, In this example the
absence of a desmoplastic response coupled with the presence of coexisting nonneoplastic lymphocytic
cell infiltrate obscures the neoplastic cells, creating difficulties in the diagnosis. B, Cytokeratin staining
(right) delineates the presence of the neoplastic cells (left).
Because distinction between the nonkeratinizing differentiated and the nonkeratinizing undifferentiated types is of no
189clinical or prognostic significance, subclassification into differentiated and undifferentiated subtypes is optional.
231Shanmugaratnam and colleagues reported that, in their study, 26% of the N PC had features of more than one tumor type.
I n such a situation, classification is according to the dominant component. I t should be noted that the histologic distinction
among the three types of NPC may not always be clear, with overlapping histology in any given tumor.
I t is uncommon to identify the presence of a precursor lesion in the form of intraepithelial dysplasia or an in situ
carcinoma. I f present the changes are similar to those of other upper aerodigestive tract sites, being characterized by the
presence of a variably thickened epithelium with nuclear hyperchromasia, loss of cell polarity with nuclear crowding,
increased nucleus to cytoplasm ratio, prominent nucleoli, and increased mitotic activity. These changes can be seen in the
surface or crypt epithelium. However, in most examples invasive carcinoma is present without identification of surface
epithelial dysplasia and/or carcinoma in situ. N evertheless, N PC originates from nasopharyngeal surface or crypt
A ll three histologic types of N PC are immunoreactive with cytokeratin, including pancytokeratins and high molecular
weight cytokeratins; weak immunoreactivity is present for low molecular weight cytokeratins (see Figs. 4A -23 and 4A-24).
The nonkeratinizing carcinomas, differentiated and undifferentiated, are highly associated with EBV as detected by I S H for
232EBER (seeF ig. 4A -23). Cytokeratins 7 and 20 are usually negative. Franchi and colleagues evaluated differential
cytokeratin staining in various S CC types of the head and neck and found N PCs to express CK5/6, CK8, CK13, and CK18
(Table 4A -9). The diagnosis of both the keratinizing and nonkeratinizing types of N PC is usually straightforward.
Undifferentiated N PC, when it occursa s a diffuse cellular infiltrate composed of discohesive cells, may be difficult to
distinguish from non-Hodgkin lymphoma. D ifferentiation is readily accomplished by immunohistochemical stains. N PC will
be reactive with cytokeratin and not leukocyte common antigen (LCA); non-Hodgkin lymphomas of the nasopharynx are
predominantly of B-cell lineage and will be reactive with LCA and B-cell lineage markers.
Cytokeratin Expression in Various Carcinoma Types of the Sinonasal Tract and Nasopharynx
AE1/AE3 CK5/6 CK7 CK8 CK13 CK14 CK19
SCC + + (9/10) + (6/10) + (9/10) + (9/10) + (8/10) + (9/10)
NKSCC + + (9/10) − + (9/10) + (9/10) + (8/10) + (9/10)
SNUC + − + (3/6) + (6/6) − − + (3/6)
NPC + + (4/5) − + (4/5) + (4/5) − + (5/5)
CK, Cytokeratin; NKSCC, nonkeratinizing squamous cell carcinoma; NPC, nasopharyngeal carcinoma, undifferentiated type;
SCC, squamous cell carcinoma; SNUC, sinonasal undifferentiated carcinoma.
Data from Franchi A, Moroni M, Massi D et al. 2002 Sinonasal undifferentiated carcinoma, nasopharyngeal-type undifferentiated
carcinoma, and keratinizing and nonkeratinizing squamous cell carcinoma express different cytokeratin patterns. Am J Surg
Pathol 26: 1597-1604
A s a result of the anatomic constraints imposed by the nasopharynx and the tendency of these neoplasms to present at an
advanced stage, overall 5-year survival for keratinizing S CC is 20% to 40% and for nonkeratinizing carcinomas (differentiated
230and undifferentiated) is approximately 65%. The 5-year disease-specific survival is as follows:
• For stage I, 98%
• For stage IIA-B, 95%
• For stage III, 86%
189• For stage IVA-B, 73%
Factors that may affect prognosis include clinical stage, patient age and sex, presence of keratinization, lymph node
metastasis, and possibly genetic factors. BeI er prognosis is associated with lower clinical stage, younger patient age, and192,231female sex, whereas worse prognosis is seen with higher stage tumors, older patients, and male sex. Reddy and
233colleagues evaluated 50 patients with N PC and found that the patients with the keratinizing type of N PC had a higher
incidence of locally advanced tumor but a lower incidence of lymphatic and/or distant spread. D espite these findings, the
patients with keratinizing N PC had a poorer 5-year survival rate than those with the other histologic subtypes because of a
233higher incidence of deaths resulting from local uncontrollable disease and nodal metastases. N PC frequently
metastasizes to regional lymph nodes, and the presence of lymph node metastasis decreases survival by approximately 10%
231to 20%. S imilarly, a large percentage of N PCs, particularly of the undifferentiated type, metastasize to sites below the
234,235clavicle, including the lungs, bone (ribs and spine), and liver. Poorer prognosis is seen in those patients with the
192HLA -A w33-C3-B58/D R3 haplotype, whereas patients with A 2-Cw11-Bw46/D R9 haplotype have longer survival. D N A
236ploidy has been studied in N PC with mixed results. Cheng and colleagues report that diploid D N A tumors had a beI er
237survival rate than D N A aneuploid tumors. However, Costello and colleagues report that D N A ploidy in N PC was not a
significant determinant of tumor prognosis. Prominent tumor angiogenesis and c-erbB2 expression have been suggested as
238indicators of a poor prognosis.
239Chua and colleagues evaluated long-term outcome in patients with N PC treated with induction chemotherapy and
radiotherapy versus radiotherapy alone. A lthough they report a modest but significant decrease in relapse and improvement
in disease-specific survival in advanced-stage N PC with the addition of cisplatin-based induction chemotherapy to
239radiotherapy alone, no improvement in overall survival was seen. The risk for development of a synchronous or
240metachronous second primary malignancy in patients with N PC is approximately 4%. The second malignancies tend to
occur in the upper aerodigestive tract.
Metastatic Carcinoma in the Neck with an Unknown Primary
Metastatic carcinoma in the neck with an unknown primary (MCUP) is the histologic diagnosis of metastatic carcinoma
241without a diagnosis of a primary tumor. A side from oropharynx and nasopharynx, metastatic S CC to neck lymph nodes
may originate from any mucosal site in head and neck. MCUP is most frequently diagnosed between the fifth and seventh
242decades with a peak incidence in the sixth decade of life. However, HPV-associated MCUP occurs in younger patients
than non–HPV-associated S CC. MCUP can present anywhere within the neck, but the jugulodigastric lymph node group is
242the most common location. S pecifically, level I I is most common followed by levels I and I I I . A n isolated nodal mass in
the submental triangle is rarely carcinoma. Patients typically present with a painless, fixed neck mass that has enlarged over
recent months. MCUP may be bilateral in 10% of patients.
Once a metastasis is diagnosed, the primary carcinoma can be sought, and the workup aI empting to find the primary
carcinoma includes (1) panendoscopy (nasal cavity, nasopharynx, oral cavity, oropharynx, esophagus, larynx), (2)
highresolution PET/CT scans to determine biopsy sites, and (3) “blind” biopsies of various mucosal sites performed specially
242targeting the oropharynx and nasopharynx. A pproximately 30% of patients never have the primary identified. A bout 30%
of patients with metastatic S CC show exclusively cystic metastases. I t should be noted that a primary carcinoma in the tonsil
or base of tongue may be very small (
The histologic features for metastatic keratinizing S CC include the presence of keratinization in most cases. The histologic
grades include well, moderately, and poorly differentiated. I n poorly differentiated S CC, evidence of keratinization may be
minimal. This type of carcinoma is typically associated with a desmoplastic response. The paI ern of carcinoma and presence
of desmoplasia contrast with features seen in nonkeratinizing and undifferentiated SCC.
Metastatic nonkeratinizing S CC often appears as cystic lesion with central necrotic material F( ig. 4A -25). The carcinoma
shows ribbon-like or band-like, uniformly thick epithelium lining cystic spaces, frequently thrown into papillary folds or
projections. A n endophytic paI ern can be seen with budding into lymphoid stroma. A n absence of maturation exists toward
the cyst lumen with a loss of cellular polarity, disorganization, and enlarged cells showing a high nucleus to cytoplasm ratio.
S ignificant nuclear pleomorphism, focally or diffusely, can be found. Limited keratinization may be present, and the
presence of keratinization does not exclude a diagnosis of nonkeratinizing S CC. Transitional-like epithelium with limited
atypia may be present. S uch benign-appearing epithelium may mistakenly suggest a possible diagnosis of a branchial cleft
cyst.FIGURE 4A-25 A, Metastatic nonkeratinizing squamous cell carcinoma appearing as cystic lesion with
central necrotic material. B, The tumor is composed of malignant basaloid cells lacking evidence of
keratinization. C, p16 positive (nuclear and cytoplasmic staining) represents a reliable predictor of origin
from the oropharynx (i.e., tonsil, base of tongue).
Metastatic undifferentiated carcinoma may appear as a cystic metastasis with central necrotic material. S yncytial growth in
the form of cohesive nests can be identified. The neoplastic cells are characterized by enlarged nuclei with vesicular
chromatin and prominent nucleoli. Limited keratinization may be present, and the presence of keratinization does not
exclude a diagnosis of undifferentiated carcinoma. A desmoplastic response may be absent, and the neoplastic cells may be
overrun and obscured by lymphocytes.
The immunohistochemical staining of these carcinomas includes consistent positivity for cytokeratins, as well as p63
(nuclear) staining.
HPV-associated S CC are p16 positive (nuclear and cytoplasmic staining) (seeF ig. 4A-25). p16 immunoreactivity represents
a reliable predictor of origin from the oropharynx (i.e., tonsil, base of tongue). Oropharyngeal carcinomas with the
182morphology of nasopharyngeal-type undifferentiated carcinoma may be p16 positive and EBER negative. S uch
carcinomas may metastasize as MCUP; therefore workup should include both p16 and EBER staining. EBV-associated S CC
are EBER positive (nuclear staining) and p16 negative.
The differential diagnosis for MCUP includes a branchial cleft cyst, which has benign epithelium lining cystic spaces,
usually showing an admixture of epithelium with stroma. Maturation is noted without atypia or mitotic figures. Branchial
179,243cleft cysts lack associated desmoplasia or thickened fibrous capsule and are typically p16 and EBER negative. The
existence of primary branchiogenic carcinoma has been challenged sufficiently as to render it nonexistent.
Radiation is the mainstay of therapy. When the primary carcinoma is identified, intensity-modulated radiation therapy can
244 244be used. Five-year survival rates range from 18% to 48%. Those carcinomas associated with HPV have a better outcome
than non–HPV-associated SCC. EBV-associated SCC have reported 65% 5-year survival rates.Sinonasal Undifferentiated Carcinoma
245The original definition for sinonasal undifferentiated carcinoma (S N UC) was reported by Frierson and colleagues as a
high-grade malignant epithelial neoplasm of the nasal cavity and paranasal sinuses of uncertain histogenesis with or without
neuroendocrine differentiation but without evidence of squamous or glandular differentiation. S ubsequently, the WHO
classification defined S N UC as a highly aggressive and clinicopathologically distinctive carcinoma of uncertain histogenesis
that typically presents with locally extensive disease; it is composed of pleomorphic tumor cells with frequent necrosis and
246should be differentiated from lymphoepithelial (and other) carcinomas or olfactory neuroblastoma.
246,247S N UC is an uncommon tumor but is now increasingly recognized. A male predominance exists (2-3 : 1). S N UCs
occur over a wide age range, including the third to ninth decades of life, with a median at presentation in the sixth
245,247decade. Generally, S N UC is extensive at presentation and involves multiple sites, including the nasal cavity, one or
245,248more paranasal sinuses, orbit, skull base, and the brain. Most patients have unilateral disease, but bilateral disease
may occur. Typically, patients present with multiple symptoms that include nasal obstruction, epistaxis, proptosis, visual
disturbances (e.g., diplopia), facial pain, and symptoms of cranial nerve involvement. A rather characteristic clinical
phenomenon is that patients with SNUC have symptoms usually of relatively short duration (weeks to months).
S N UC is a tumor of uncertain histogenesis. I t seems likely that S N UC arises from the S chneiderian epithelium and
therefore is of ectodermal derivation. However, although speculative, given overlapping clinical, light microscopic,
immunohistochemical, and ultrastructural features with olfactory neuroblastoma and neuroendocrine carcinoma, the cell of
origin may be related to both the S chneiderian membrane and olfactory epithelia. On the basis of neuroendocrine features
249by immunohistochemistry and electron microscopy, Mills suggests that S N UC may be a neuroendocrine carcinoma with
classification essentially equivalent to the pulmonary large cell (neuroendocrine) carcinoma. Evidence of very limited foci of
250squamous differentiation has been reported, a finding that supports surface (S chneiderian) epithelial origin. However,
focal keratinization in the presence of a predominantly undifferentiated carcinoma should prompt concern for a possible
diagnosis of nuclear protein in testis (NUT) midline carcinoma (see later discussion).
251,252N o etiologic agents are known. S N UCs are typically negative for EBV, even though reports exist of EBV RN A
253,254identified in A sian and I talian patients with S N UC but not in other Western patients with S N UC. S N UCs are
251typically p16 negative. S ome cases have been reported to develop after radiation therapy for N PC. A lthough no specific
etiology is linked to the development of S N UC, cigareI e smoking and nickel exposure have been identified in patients with
245 255SNUC. Deletion of the retinoblastoma gene has been implicated in the development of SNUC.
S N UCs are usually large tumors, typically measuring more than 4 cm in greatest dimension, and tend to be fungating with
poorly defined margins, associated with invasion into adjacent structures and/or anatomic compartments, including bone
destruction. The histologic appearance is characterized by a hypercellular proliferation with varied growth, including
trabecular, sheet-like, ribbons, solid, lobular, and organoid paI erns ( Fig. 4A -26). S urface involvement may be seen in the
form of severe dysplasia or carcinoma in situ, but often ulceration is seen that precludes evidence of surface epithelial
derivation. The tumor consists of polygonal cells with medium to large-sized, round to oval, hyperchromatic to vesicular
nuclei, inconspicuous to prominent nucleoli, and a varying amount of eosinophilic cytoplasm with poorly defined cell
membranes, although in some examples distinct cell borders may be present; occasionally, cells with clear cytoplasm can be
identified. The nucleus to cytoplasm ratio is high. I ncreased mitotic activity is present, including atypical mitoses, and
prominent tumor necrosis (confluent areas and individual cells) and apoptosis are often seen (see Fig. 4A -26).
Lymphovascular invasion and neurotropism are often present. S quamous or glandular differentiation is not present;
however, more recent evidence indicates that the presence of very focal squamous differentiation is acceptable in sinonasal
undifferentiated carcinoma as long as the overwhelming majority of the tumor shows morphologic features associated with
250sinonasal undifferentiated carcinoma. Neurofibrillary material and true rosettes are not identified.
FIGURE 4A-26 Sinonasal undifferentiated carcinoma. A, Hypercellular and infiltrative neoplasm showing
trabecular and lobular growth. B, At higher magnification, the cellular infiltrate includes pleomorphic round
to oval, hyperchromatic and pleomorphic nuclei, prominent nucleoli, increased mitotic activity. and
individual cell necrosis.
The immunohistochemical antigenic profile may vary from case to case, but S N UCs are consistently immunoreactive with
epithelial markers, including pankeratins and simple keratins (i.e., CK7, CK8, and CK19); reactivity for pankeratins is often
232intense and diffuse. S taining for CK4, CK5/CK6, and CK14 is reported to be negative (seTe able 4A -9). Variable reactivity
can be identified for p63. S N UCs are EBER negative and typically p16 negative. Fewer than half of the cases have been252reported to be positive for EMA , N S E, or p53. Reactivity for synaptophysin, chromogranin, S -100 protein, or Leu-7 is only
rarely observed. By electron microscopy, rare membrane-bound, dense core neurosecretory granules have been noted, and
245,249,256poorly formed desmosomes may occasionally be found.
The differential diagnosis of S N UC includes olfactory neuroblastoma (high grade), small cell undifferentiated
neuroendocrine carcinoma, nasopharyngeal-type undifferentiated carcinoma, lymphoepithelial carcinoma, mucosal
malignant melanoma, nasal-type natural killer (N K)/T-cell lymphoma, RMS , and others. A lthough differences can be
identified by light-microscopic evaluation, often the differentiation of all these tumor types rests on the
immunohistochemical staining profile for a given tumor (Table 4A-10).
TABLE 4A-10 Immunohistochemical (Selective) Reactivity of Sinonasal Tract Malignancies
Rights were not granted to include this table in electronic media. Please refer to the printed book.
American Society for Clinical Pathology
S N UC is a highly aggressive neoplasm that cannot be completely eradicated by surgery, nor is it responsive to radiation
257,258 245treatment. Frierson and colleagues report a mean survival of 4 months with no disease-free patients. Other studies
257-259report median survival of less than 18 months with 5-year survival rates of less than 20%. I n all cases, the cervical
260,261nodes should be addressed with primary treatment. N evertheless, survival for sinonasal undifferentiated carcinoma
247remains poor. Local recurrence is common and is the major cause of morbidity and mortality. Metastatic disease to bone,
252brain, liver, and cervical lymph nodes may occur.
NUT Midline Carcinoma
N UT midline carcinoma (N MC) is an aggressive carcinoma genetically defined by rearrangement of N UT characterized by a
262unique chromosomal translocation as the sole identifier of this disease. A balanced chromosomal translocation t(15;19)
263results in a novel fusion oncogene BRD4-NUT. N MCs are underrecognized and underdiagnosed. Most N MCs are S CCs
and can be identified only by molecular or immunohistochemical testing. The diagnosis of N MC should be considered in
any nonsmoking patient with poorly differentiated S CC. N UT carcinomas arise almost exclusively from midline epithelial
structures. I n the head and neck, the sinonasal tract is the most common site of occurrence followed by the nasopharynx and
264larynx. N on-head and neck sites of occurrence reported include the mediastinum, thorax (lung), thymus, orbit, bladder,
262and iliac bone. N MCs tend to occur more commonly in women than in men. They occur in children, young adults, and
adult patients with ages ranging from 3 to 78 years (average 47 years). The proposed cell of origin is neural crest–derived
262cells. The etiology is unknown.
The histology is that of a poorly differentiated or undifferentiated carcinoma showing at least focal squamous
differentiation in greater than 80% of cases. S quamous differentiation is typically abrupt. N MCs are p63 immunoreactive but
negative for EBV. Rearrangements ofN UT and BRD4 can be detected by FI S H. Greater than 90% of cases show nuclear
expression of NUT by immunohistochemical staining.
However, the mean survival is less than 1 year (9.5 months). D eath results from the local effects of tumor and
262complications of therapy.
Olfactory Neuroblastoma
Olfactory neuroblastomas (ONB) is a malignant neuroectodermal neoplasm thought to arise from the olfactory membrane of
the sinonasal tract. A variety of terms exist for this tumor, including olfactory placode tumor, esthesioneuroblastoma,
esthesioneurocytoma, esthesioneuroepithelioma, and esthesioneuroma. I t appears that ON B takes origin from the olfactory
neuroepithelium found in the upper one third to one half of the nasal septum, the cribriform plate, and the superior-medial
surface of the superior turbinate. With aging, the olfactory epithelium degenerates and is replaced by respiratory
265epithelium. The olfactory neuroepithelium is composed of bipolar sensory neurons, supporting cells, and the reserve
(basal) cells. The latter are mitotically active and are the presumed progenitor of ONB.
ON B is an uncommon malignant neoplasm representing approximately 2% to 3% of sinonasal tract tumors. N o sex
266predilection is seen ; ON B occurs over a very wide age range from 3 years to the ninth decade, with a bimodal peak in the
266-271second and sixth decades of life. The main presenting symptoms are unilateral nasal obstruction and epistaxis; less268common manifestations include anosmia, headache, pain, excessive lacrimation, and ocular disturbances. The most
common site of occurrence is the upper nasal cavity in the area of the cribriform plate; often the ethmoid sinus is involved.
“Ectopic” origin in the lower nasal cavity, within one of the paranasal sinuses (e.g., maxillary sinus) and nasopharynx may
272 273occur. Radiologically, a sinonasal mass causing sinus opacification with or without bone erosion may be seen.
274,275N o etiologic agent(s) is known. A dministration of diethylnitrosamine to hamsters and N-nitrosopiperidine to
276rats produces nasal tumors that are histologically identical to ON B. D ata are conflicting regarding the inclusion of ON B
in the category of peripheral neuroectodermal tumors (PN ETs). Classically, PN ETs show reactivity with monoclonal
MIC2 277,278antibodies that recognize the Ewing sarcoma cell surface glycoprotein p30/32 , as well as a t(11;22) translocation
279with EWS/FLI1 gene fusion. On the basis of these features of PN ET, the t(11;22) translocation, which has rarely been
280 281reported in ON B, and the presence of EWS/FLI1 gene fusion in ON B would support the inclusion of ON B within the
spectrum of PN ET. However, other studies using immunohistochemistry, fluorescent I S H, and reverse transcriptase PCR
282-286have failed to identify these “markers” of PN ET, thereby failing to confirm this translocation in ON B. A s such, ON B
should be seen as an entity distinct from PNET and the Ewing sarcoma family of tumors.
Grossly, ON B is a glistening, mucosa-covered, soft, polypoid mass varying from a small nodule less than 1 cm to a mass
filling the nasal cavity, with possible extension into adjacent paranasal sinuses and nasopharynx. The histologic appearance
287is divided into four grades as defined by Hyams (Table 4A -11). Grade I is the most differentiated; the architecture is
lobular with intercommunication between lobules. The neoplastic cells are well differentiated with uniform round to
vesicular nuclei with or without nucleoli (Fig. 4A -27) and have indistinct borders. The nuclei are surrounded by
neurofibrillary material. A pseudoroseI e paI ern (Homer Wright roseI es) is frequently seen. Varying amounts of
calcification may be noted. The interlobular fibrous stroma is often extremely vascular. Mitotic activity and necrosis are
absent. Grade I I tumors share many of the histologic features described for grade I lesions, but the neurofibrillary element
is less well defined, and the neoplastic nuclei show increased pleomorphism. S caI ered mitoses can be seen. Grade I I I
tumors may retain a lobular architecture with an interstitial vascular stroma. These tumors are characterized by a
hypercellular neoplastic cell proliferation in which the cells are more anaplastic and hyperchromatic and have increased
mitotic activity as compared with grade I or I I tumors. N ecrosis is seen. The neurofibrillary component may be focally
present but is much less conspicuous as compared with grades I or I I tumors (Fig. 4A -28). True neural roseI es
(FlexnerWintersteiner rosettes) may be seen (Fig. 4A-29); however, in general, these structures are rare. Calcification is absent. Grade
I V tumors may also retain the overall lobular architecture, but the neoplastic element is the most undifferentiated and
anaplastic of all the histologic grades. I n these high-grade tumors, the cellular infiltrate is characterized by pleomorphic
nuclei, often with prominent eosinophilic nucleoli and indistinct cytoplasm. N ecrosis is commonly seen, and mitotic activity
is increased, including atypical mitoses. True neural roseI es may be seen but, as in grade I I I tumors, are uncommon. The
neurofibrillary component is generally absent. Calcification is absent.
341Hyams' Histologic Grading System for Olfactory Neuroblastoma
Microscopic Features Grade 1 Grade 2 Grade 3 Grade 4
Architecture Lobular Lobular ± Lobular ± Lobular
Pleomorphism Absent to slight Present Prominent Marked
NF matrix Prominent Present May be present Absent
Rosettes Present* Present* May be present† May be present†
Mitoses Absent Present Prominent Marked
Necrosis Absent Absent Present Prominent
Glands May be present May be present May be present May be present
Calcification Variable Variable Absent Absent
*Homer Wright rosettes (pseudorosettes).
†Flexner-Wintersteiner rosettes (true neural rosettes).
NF, Neurofibrillary.
From Hyams V J 1982 Olfactory neuroblastoma (case 6). In: Batsakis J G, Hyams V J, Morales A R (eds) Special tumors of
the head and neck. ASCP Press, Chicago, p 24-29FIGURE 4A-27 Olfactory neuroblastoma, grade I. A, Typical lobular pattern of growth. B,
Uniformappearing round cells surrounded by a neurofibrillary material.FIGURE 4A-28 Olfactory neuroblastoma, grade III. A, In contrast to its lower grade counterpart, this
high-grade neoplasm lacks neurofibrillary matrix and includes a pleomorphic cellular infiltrate with
increased mitotic activity. In this setting immunohistochemical stains become important in the diagnosis
and in differentiation from other malignant neoplasms. B, Olfactory neuroblastomas, irrespective of
histologic grade, are consistently immunoreactive for neuron-specific enolase and (C) show S-100 protein
staining usually limited to the periphery of tumor nests (sustentacular cell–like pattern).
FIGURE 4A-29 Olfactory neuroblastomas are associated with the presence of rosettes. This illustration
contrasts (left) Homer Wright pseudorosettes seen in grades I and II olfactory neuroblastomas
characterized by grouping of cells in a circumferential fashion around neurofibrillary matrix but without a
defining basement membrane with (right) Flexner-Wintersteiner true neural rosettes in which cells align in
a glandular fashion around spaces lined by distinct cell membranes.
ON B may coexist with foci of adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma, when it is referred to
288 288as mixed ONB and carcinoma. Miller and colleagues proposed basal cells of the olfactory epithelium as the progenitorfor these mixed neoplasms. A lternatively, these mixed tumors may originate from the seromucous glands (Bowman glands)
lying subjacent to the olfactory epithelium. We have designated a limited number of such tumors as olfactory carcinomas.
I n general, the lower grade ON Bs are readily recognizable and diagnosable by light microscopy. A djunct studies,
particularly in the higher histologic grade tumors, may assist in the diagnosis.
The most consistent marker is N S E (seeF ig. 4A -28). S -100 protein staining typically is limited to the sustentacular cells
situated along the periphery of the neoplastic lobules, although such cells may be sparse in the higher grade tumors (see Fig.
4A-28). A majority of cases are positive for synaptophysin, neurofilament protein, class I I I β -tubulin, and
microtubuleassociated protein, and variable immunoreactivity may be present for chromogranin, glial fibrillary acidic protein, and
Leu289,2907. Cytokeratin is usually negative, but some cases can show positive cells in a patchy, punctate fashion. More diffuse
and intense cytokeratin should prompt alternative diagnostic considerations (e.g., neuroendocrine carcinoma, ectopic
pituitary adenoma, others). LCA , HMB-45, desmin, and CD 99 are absent. Proliferation marker studies using Ki-67 and MI B-1
have shown a high proliferative index of 10% to 50%, and flow cytometric analysis shows a high rate of polyploidy or
291,292aneuploidy. Electron microscopy evaluation may be a useful adjunct in the diagnosis and reveals the presence of
272,293,294dense-core neurosecretory granules measuring from 80 to 250 nm in diameter. I n addition, neurofilaments and
neurotubules, and occasionally Schwann-like cells, can be seen.
The differential diagnosis includes a variety of other sinonasal malignant neoplasms discussed in this chapter. A lthough
differences can be identified by light microscopic evaluation, often the differentiation of all these tumor types rests on the
immunohistochemical staining profile for a given tumor (see Table 4A-10).
Complete surgical eradication (craniofacial resection that includes removal of the cribriform plate) followed by full-course
269,270,295radiotherapy is the treatment of choice. With chemotherapy, the overall 5-, 10-, and 15-year survival rates have
296been reported to be 78%, 71%, and 68%, respectively. I nitial multimodality therapy is associated with 5-year survival of
29580% for low-grade tumors and 40% for high-grade tumors. The majority of the recurrences occur within the first 2
280years. The most frequent recurrence is local, with rates around 30%. Prognosis has traditionally been correlated with
297clinical staging as defined by Kadish and colleagues (Table 4A-12) with 5-year survival of 75%, 68%, and 41% for stage A ,
268,297B, and C tumors, respectively. Complete tumor resection was found by some to be of more prognostic importance
271than clinical staging. Histologically lower grade tumors (grades I and I I ) have been reported to have a beI er 5-year
298survival than higher grade tumors (grades I I I and I V). High proliferation indexes and high rate of ploidy or aneuploidy
291,292have been correlated with increased morbidity (i.e., tumor recurrence, metastasis) and mortality. The majority of
tumors behave as locally aggressive lesions, mainly involving adjacent structures (orbit and cranial cavity). Local recurrence
and distant metastasis may occur years after the initial diagnosis. A pproximately 15% to 70% of patients will have local
recurrence, 10% to 25% will have cervical lymph node metastasis, and approximately 10% to 60% will have distant
268,275,296,299metastasis. The more common sites of metastatic disease include lymph nodes, lungs, and bone. A ll
histologic grades have the capacity to metastasize.
268,297Clinical Staging for Olfactory Neuroblastoma
Stage Extent of Tumor 5-Year Survival (%)
A Tumor confined to the nasal cavity 75-91
B Tumor involves the nasal cavity plus one or more paranasal sinuses 68-71
C Extension of tumor beyond the sinonasal cavities 41-47
Mucosal Malignant Melanoma
Malignant melanomas are neural crest–derived neoplasms demonstrating melanocytic differentiation. A pproximately 15% to
30025% of all malignant melanomas arise in head and neck sites. Of the head and neck malignant melanomas, more than
80% are of cutaneous origin. Mucosal malignant melanomas (MMM) of the upper aerodigestive tract represent from 0.5% to
3013% of malignant melanomas of all sites. Of the noncutaneous head and neck malignant melanomas, the majority are of
ocular origin (see Chapter 29), and approximately 6% to 8% originate in the mucous membranes of the upper aerodigestive
300tract. The sinonasal tract is considered to be an uncommon site for the development of MMM, accounting for fewer than
302,3035% of all sinonasal tract neoplasms. I rrespective of the site of occurrence, upper aerodigestive tract MMM are more
common in men than women. This is primarily a disease of adults, occurring over a wide age range but with a peak incidence
300,304-306in the seventh decade. Most cases of upper aerodigestive tract MMM occur in whites, but blacks are also affected.
S ymptoms vary according to the site of occurrence and, in the sinonasal tract and nasopharynx, include airway obstruction,
epistaxis, pain, nonhealing ulcer, and dysphagia. I n the sinonasal tract, nasal cavity involvement is more common than that
of the paranasal sinuses. In the nasal cavity, the most frequent site of occurrence is the septum (anterior portion) (Fig. 4A -30)
and the lateral nasal wall. I n the sinuses, the maxillary sinus is the most common site of occurrence followed by the ethmoid,
frontal, and sphenoid sinuses. Concurrent nasal cavity and paranasal sinus melanomas frequently occur either as a result of
direct extension or as multicentric tumors. N o etiologic agents are known to be linked to the development of MMM.
307However, Reuter and Woodruff speculated that tobacco smoking plays an important factor in the development of
laryngeal malignant melanomas.FIGURE 4A-30 Mucosal malignant melanoma of the nasal septum.
A variety of gross appearances can be seen: tumors may be polypoid or sessile, brown, black, pink, or white, friable to
rubbery masses measuring from 1.0 cm to large, resulting in obstructive signs and symptoms. I n general, surface ulceration
is a common finding. I n tumors with an intact surface epithelium, continuity of the tumor with the surface epithelium
(junctional or pagetoid changes) usually can be identified. The presence of a junctional or in situ component suggests origin
from the surface epithelium but is not a requirement for MMM as melanocytes are also found in both the seromucous glands
308-310and the submucosa of the upper aerodigestive tract.
The cytomorphologic features of MMM include epithelioid or spindled cells F( ig. 4A -31). Tumors with mixed epithelioid
and spindle cells are frequently seen. I n predominantly or exclusively epithelioid MMM, the growth paI erns vary and may
be solid, organoid, nested, trabecular, alveolar, or any combination of these paI erns. The cells are round to oval and tend to
be markedly pleomorphic, having increased nucleus to cytoplasm ratio, vesicular to hyperchromatic nuclei, prominent
eosinophilic nucleoli, and eosinophilic to clear-appearing cytoplasm. The epithelioid cells may have plasmacytoid features
with eccentrically located nuclei and eosinophilic cytoplasm. However, in contrast to plasma cell proliferations, the nuclear
chromatin paI ern is more densely hyperchromatic and no paranuclear clear zone exists. I n predominantly or exclusively
spindle cell MMM, the growth paI ern may be storiform or fascicular. The cells are oblong to cigar shaped and markedly
pleomorphic with large vesicular to hyperchromatic nuclei, absent to prominent nucleoli, and scant eosinophilic cytoplasm.
S pindle cell MMM may have an associated myxoids troma. I n both cytomorphologic types of MMM, necrosis and prominent
mitoses with atypical mitotic figures are common findings. Uncommon features that may be seen include neoplastic giant
301cells and glandular or squamous differentiation.
FIGURE 4A-31 Sinonasal mucosal malignant melanoma. These tumors may demonstrate
cytomorphologic heterogeneity including (A) pleomorphic epithelioid cells with large nuclei, prominent
nucleoli, nuclear molding, and increased mitotic activity and (B) pleomorphic spindle-shaped cells with
storiform growth reminiscent of mesenchymal tumors.
By light microscopy, MMM may demonstrate heavy melanin deposition, but approximately one third of tumors have only
306,307focal, weak pigmentation or are nonpigmented.
I mmunohistochemistry remains the diagnostic tool of choice with S -100 protein and HMB-45 positivity in both the
301,306epithelioid and spindle cells. For both S -100 protein and HMB-45, the intensity of staining is strong, and the extent of
staining is diffuse. Exceptions to this staining paI ern may occur in desmoplastic melanomas where HMB-45 may be
311nonreactive. I n addition melanomas express reactivity with T311 (antityrosinase), A 103, and D 5. N o immunoreactivity is
301seen for cytokeratin, EMA, or myogenic markers. Ultrastructurally, melanosomes and premelanosomes can be seen.
The differential diagnosis includes a variety of other sinonasal malignant neoplasms discussed in this chapter. A lthough
differences can be identified by light microscopic evaluation, often the differentiation of all these tumor types rests on the
immunohistochemical staining profile for a given tumor (see Table 4A-10).
312I rrespective of their site of origin, MMM as a group represent aggressive and highly lethal tumors. Radical surgical
excision is the treatment of choice. A djuvant radiotherapy and chemotherapy are of questionable value in the management
of MMM. Overall, the prognosis for MMM of all upper aerodigestive tract sites is considered poor, 5-year survival rates being
303 302,303generally less than 30%. Tumor stage seems to be the best predictor of outcome. Malignant melanoma is
notorious for remaining quiescent for long periods after the initial diagnosis, only to resurface years to decades later.Recurrence, metastasis, and death may occur decades after “curative” therapy. Metastatic disease occurs most frequently to
the lungs, lymph nodes, and brain. Before a diagnosis of a primary MMM of the upper aerodigestive tract is made, metastasis
from a cutaneous primary malignant melanoma or even another mucosal-based malignant melanoma must be excluded.
Cutaneous malignant melanomas are capable of spontaneous regression, lying dormant only to reemerge as a metastasis
313(distant from the primary cutaneous site of occurrence) many years later. I n the absence of a previous or concurrent
malignant melanoma elsewhere, the MMM can be considered as the primary neoplasm.
Sinonasal (Mucosal) Adenocarcinoma
314A denocarcinomas of the sinonasal tract represent from 10% to 20% of all primary malignant neoplasms of this region
315but, exclusive of salivary gland types, represent only 6.3% of all malignant sinonasal tract tumors. Two main categories of
nonsalivary gland–type adenocarcinomas are recognized in the sinonasal tract including intestinal-type adenocarcinomas
and nonintestinal-type adenocarcinomas.
Intestinal-Type Adenocarcinomas
I ntestinal-type adenocarcinomas (I TA Cs) are malignant epithelial glandular tumors of the sinonasal tract that histologically
resemble intestinal adenocarcinoma and adenoma. I TA Cs are more common in men than in women and occur over a wide
age range but are most common in the fifth to seventh decades of life. I TA Cs most frequently involve the ethmoid sinus
followed by the nasal cavity (inferior and middle turbinates) and maxillary sinus; however, I TA Cs may arise anywhere in the
314sinonasal tract. Early symptoms tend to be nonspecific and vary from nasal stuffiness to obstruction that, with
persistence, may be associated with epistaxis, prompting further clinical evaluation. Because of the delay in diagnosis,
tumors may reach a large size with extensive invasion at the time of presentation. A dvanced tumors present with pain,
cranial nerve deficits, visual disturbances, and exophthalmos. Etiologic factors associated with the development of I TA Cs
include exposure to hardwood dust, leather, and softwood; increased incidences of adenocarcinoma are seen in woodworkers
314,316-320and workers in the shoe and furniture industries. S poradic I TA Cs unassociated with occupational exposure tend
314to affect women more than men, with most tumors involving the maxillary antrum.
These tumors have a variable appearance; they may be well demarcated to poorly defined and invasive, flat to exophytic or
papillary growths with a tan or white to pink color and a friable to firm consistency. A mucinous or gelatinous quality may
be readily identifiable. Histologically, I TA Cs are invasive tumors with various growth paI erns, including papillary-tubular,
314,316,321,322alveolar-mucoid, or alveolar goblet, signet ring, and mixed. Two classifications of I TA Cs have been proposed
314(Table 4A-13). Barnes divided these tumors into five categories, including papillary, colonic, solid, mucinous, and mixed.
316Kleinsasser and S chroeder divided I TA Cs into four categories, including papillary tubular cylinder (PTCC) types I
through I I I (I = well differentiated, I I = moderately differentiated, and I I I = poorly differentiated), alveolar goblet type,
signet ring type, and transitional type. Barnes's papillary, colonic, and solid types correspond to Kleinsasser and S chroeder's
PTCC-I , PTCC-I I , and PTCC-I I I , respectively. Either classification is acceptable, but for simplicity the Barcn laesss ification is
preferred and will be the one used in this section. The most common histologic types seen in association with woodworkers,
314,316as well as in sporadically occurring cases, are the papillary and colonic types.
Classification of Sinonasal Tract Intestinal-Type Adenocarcinomas
314 316 316Percentage of CasesBarnes Kleinsasser and Schroeder 3-Year Cumulative Survival (%)
Papillary type PTCC-I 18 82
Colonic type PTCC-II 40 54
Solid type PTCC-III 20 36
Mucinous type Alveolar goblet Uncommon 48
Signet ring Uncommon 0
Mixed Transitional Rare 71
PTCC, Papillary tubular cylinder cell.
The papillary type (papillary tubular cylinder I or well-differentiated adenocarcinoma), representing approximately 18% of
cases, shows a predominantly papillary architecture with occasional tubular glands, minimal cytologic atypia, and rare
mitotic figures (Fig. 4A-32).FIGURE 4A-32 Sinonasal intestinal type adenocarcinomas have various subtypes including (A) papillary,
(B) colonic, (C) solid, and (D) mucinous.
The colonic type (papillary tubular cylinder I I or moderately differentiated adenocarcinoma) shows a mainly
tubuloglandular architecture and rare papillae, with increased nuclear pleomorphism and mitotic activity (see Fig. 4A -32).
The solid type (papillary tubular cylinder I I I or poorly differentiated adenocarcinoma) shows loss of differentiation
characterized by solid and trabecular growth with isolated tubule formation, marked increase in the number of smaller
cuboidal cells with nuclear pleomorphism, round vesicular nuclei, prominent nucleoli, and increased mitotic figures (see Fig.
A nalogous to colonic adenocarcinoma, some I TA Cs are predominantly composed of abundant mucus production and are
classified as the mucinous type of I TA C (seeF ig. 4A -32). The mucinous type (alveolar goblet cell and signet ring) includes
two growth paI erns. I n one paI ern are seen solid clusters of cells, individual glands, signet-ring cells, and short papillary
fronds with or without fibrovascular cores; mucin is predominantly intracellular, and a mucomyxoid matrix may be present.
316,322,323The other paI ern shows large, well-formed glands distended by mucus and extracellular mucin pools ; pools of
extracellular mucin are separated by thin connective tissue septa creating an alveolar paI ern. Predominantly cuboidal or
goblet tumor cells are present in single layers at the periphery of mucus lakes. Mucus extravasation may elicit an
inflammatory response that may include multinucleate giant cells. I n tumors where the mucus component predominates
323(>50%), these tumors, similar to their gastrointestinal counterparts, may be classified as mucinous adenocarcinomas. The
mixed type (transitional) is composed of an admixture of two or more of the previously defined patterns.
I rrespective of the histologic type, I TA Cs histologically simulate normal intestinal mucosa and may include villi, Paneth
324cells, enterochromaffin cells, and muscularis mucosa. I n rare instances, the lesion is composed of well-formed villi lined
by columnar cells resembling resorptive epithelium; in such cases, bundles of smooth muscle cells resembling muscularis
mucosae may also be identified under the villi.
I TA Cs are diffusely positive for epithelial markers including EMA , B72.3, Ber-EP4, BRS T-1, Leu-M1, and human milk fat
325globule-2 and are strongly reactive with anticytokeratin cocktails. Carcinoembryonic antigen staining is variable with
325,326conflicting results in the literature. I TA Cs show CK20 positivity (73% to 86%)a nd variable CK7 reactivity (43% to 93%
327-332of cases). CD X-2, a nuclear transcription factor involved in the differentiation of intestinal epithelial cells and
327,329-331diffusely expressed in intestinal adenocarcinomas, can be found in I TA Cs. Expression of claudins and villin is
329also noted. N eoplastic cells may express a variety of hormone peptides, including serotonin, cholecystokinin, gastrin,
333 325,329somatostatin, and leu-enkephalin. Chromogranin- and synaptophysin-positive cells can be identified.
D epending on the extent and histology of the neoplasm, surgery varies from local excision to more radical procedures
(maxillectomy, ethmoidectomy, and additional exenterations). Radiotherapy may be used for extensive disease or for higher
grade neoplasms.
A ll the intestinal-type adenocarcinomas are considered as potentially lethal tumors with frequent local failure (about
50%). Metastasis to cervical lymph nodes and spread to distant sites are infrequent, occurring in about 10% and 20%,
316,318,322,323respectively. The 5-year cumulative survival rate is around 40%, with most deaths occurring within 3 years.
D eath results from uncontrollable local or regional disease with extension and invasion of vital structures and/or metastatic
disease. Because most patients present with advanced local disease, clinical staging generally has no prognostic significance.
The histologic subtype has been identified as indicative of clinical behavior, with the papillary type (grade I ) lesions314,316,322,323behaving more indolently than the other variants (see Table 4A -12). N o difference is seen in behavior
between ITACs occurring in occupationally exposed individuals and sporadic cases.
Nonintestinal (Nonsalivary Gland) Adenocarcinomas
The nonintestinal, nonsalivary gland adenocarcinomas are those sinonasal tract tumors that are not of minor salivary gland
origin and do not demonstrate histopathologic features of the sinonasal “intestinal” types of adenocarcinoma. These
334adenocarcinomas are divided into low- and high-grade types.
S inonasal nonintestinal types of adenocarcinomas predominantly occur in adults but have been identified over a wide age
335range from 9 to 80 years. The low-grade adenocarcinomas have an average age at presentation of 53 years, and the
high335grade adenocarcinomas have a mean age at presentation of 59 years. A slight male predominance is seen for the
low335,336grade adenocarcinomas but a much higher male predilection in the high-grade adenocarcinomas. The low-grade
nonintestinal adenocarcinomas show a predilection for the ethmoid sinus (to a lesser extent as compared with the
335,336“intestinal” type), and the high-grade nonintestinal-type adenocarcinomas are most frequent in the maxillary sinus.
Either tumor type may also originate in the nasal cavity, in other paranasal sinuses, or (not infrequently) in multiple
335,336sinonasal sites in various combinations. For low-grade adenocarcinomas patients primarily present with nasal
335obstruction and epistaxis. Pain is an infrequent feature. The duration of symptoms ranges from 2 months to 5 years with
a median duration of 5.5 months. For high-grade adenocarcinomas the primary presenting symptoms include nasal
obstruction, epistaxis, pain, and facial deformity (e.g., proptosis). The duration of symptoms range from 2 weeks to 5 years
335with a median duration of 2.5 months.
N o known occupational or environmental factors are associated with the nonintestinal-type adenocarcinomas. J o and
337colleagues described the occurrence of respiratory epithelial adenomatoid hamartoma in association with low-grade
sinonasal adenocarcinomas suggesting that respiratory epithelial adenomatoid hamartomas may be related to some
sinonasal nonintestinal low-grade adenocarcinomas.
These tumors have a variable appearance, including well demarcated to poorly defined and invasive, flat to exophytic or
papillary growths with a tan or white to pink color and a friable to firm consistency.
These tumors, whether low or high grade, may be seen entirely within the submucosa without surface involvement or may
involve the overlying ciliated respiratory epithelium. The low-grade adenocarcinomas have a glandular or papillary growth
and may be circumscribed but are unencapsulated tumors. N umerous uniform small glands or acini are seen, often with a
back-to-back growth paI ern without intervening stroma (Fig. 4A-33). Occasionally, large, irregular cystic spaces can be seen.
The glands are lined by a single layer of nonciliated, cuboidal to columnar cells with uniform, round nuclei that may be
limited to the basal aspect of the cell or that may demonstrate stratification with loss of nuclear polarity and eosinophilic
cytoplasm. Cellular pleomorphism is mild to moderate, and occasional mitotic figures are seen, but atypical mitoses and
necrosis are absent. D espite the relatively bland histology, the complexity of growth, absence of two cell layers, absence of
encapsulation, and presence of invasion into the submucosa confer a diagnosis of adenocarcinoma. Variants include
papillary, clear cell, and oncocytic adenocarcinomas. Multiple morphologic patterns may be seen in any one neoplasm.
FIGURE 4A-33 Sinonasal nonintestinal, nonsalivary gland adenocarcinomas include invasive low-grade
and high-grade tumors. A, Low-grade adenocarcinoma is characterized by the presence of numerous
small glands or acini with a back-to-back growth pattern without intervening stroma; glands are lined by a
single layer of nonciliated, cuboidal to columnar cells with uniform, round nuclei. Cellular pleomorphism is
limited. The complexity of growth, absence of two cell layers, absence of encapsulation, and presence of
invasion into the submucosa are diagnostic of adenocarcinoma. B, High-grade adenocarcinoma. These
tumors are characterized by the presence of moderate to marked cellular pleomorphism; increased
mitotic activity, including atypical forms; and necrosis.
The high-grade sinonasal adenocarcinomas are invasive tumors predominantly with a solid growth paI ern, but glandular
and papillary growth paI erns can also be seen. These tumors are characterized by the presence of moderate to marked
cellular pleomorphism; increased mitotic activity, including atypical forms; and necrosis (see Fig. 4A-33).
The nonintestinal adenocarcinomas are consistently and intensely CK7 reactive but, in contrast to the I TA Cs, are
327-329,331,336nonreactive for CK20, CDX2, villin, claudins, chromogranin, or synaptophysin.
D epending on the extent and histology of the neoplasm, surgery varies from local excision to more radical procedures.
Radiotherapy may be used for extensive disease or for higher grade neoplasms. The low-grade neoplasms have an excellent
335prognosis, whereas high-grade neoplasms have a dismal prognosis with approximately 20% 3-year survival rates.Malignant Salivary Gland Tumors
The most common malignant salivary gland tumor of the sinonasal tract and nasopharynx is adenoid cystic carcinoma. The
more common malignant neoplasms of major salivary glands, including mucoepidermoid carcinoma and acinic cell
adenocarcinoma, are uncommon in the sinonasal tract and nasopharynx. The reader is referred to Chapter 7 for detailed
discussion of these and other types of salivary gland malignancies.
Adenoid Cystic Carcinoma
Adenoid cystic carcinoma (ACC) is a malignant salivary gland neoplasm characterized by a distinctive histologic appearance,
a tendency to invade nerves, and its protracted but nonetheless relentless clinical course. A pproximately 20% of all A CCs
338 315,339occur in the sinonasal tract. A CCs represent approximately 5% of sinonasal malignancies. The most common site
338of involvement is the maxillary sinus (57%), followed by the nasal cavity (24%), ethmoid sinus (14%), and other sites (5%).
A CC of the sinonasal tract is a tumor of adults and rarely occurs in the first two decades of life. S ymptoms may include
airway obstruction, epistaxis, and pain. These tumors can attain large sizes with extensive infiltrative growth at presentation.
Grossly, A CC is a variably encapsulated, solid, rubbery to firm, tan-white to gray-pink mass measuring from 2 to 4 cm in
greatest dimension. The histologic appearance of A CC is that of an unencapsulated, infiltrating neoplasm with varied
architecture consisting of cribriform, tubular or ductular, and solid paI erns. I ndividual neoplasms may have a single growth
paI ern but characteristically show multiple paI erns, any one of which may predominate. The most common paI ern is the
cribriform type, considered the “classic” paI ern, demonstrating arrangement of cells in a “S wiss cheese” configuration with
many oval or circular spaces. These spaces contain basophilic mucinous substance or hyalinized eosinophilic material. The
tubular type has cells arranged in ducts or tubules. The ducts or tubules contain faintly eosinophilic mucinous material.
Cribriform and tubular paI erns often occur together. The least common paI ern is the solid type, composed of neoplastic
cells arranged in sheets or nests of varying size and shape, with minimal if any cystic spaces, tubules, or ducts. I rrespective
of the growth paI ern, the tumors are composed of fairly uniformly sized cells with small, hyperchromatic round to oval or
angulated nuclei, scant amphophilic to clear cytoplasm, and indistinct cell borders. The majority of the neoplastic cells are
abluminal-type myoepithelial cells. The cystic spaces seen in the cribriform or classic type are pseudocysts, which are
extracellular and lined by replicated basement membrane. S caI ered among these abluminal cells are ductal cells, which
surround small true lumens (glands). True duct-like lumens are an infrequent feature of A CC but are most frequently seen
in cases with a tubular paI ern. I n the solid paI ern, the cell population is dominated by the basaloid myoepithelial cells. The
interstitial stroma, from which the epithelial component is sharply demarcated, varies in appearance from myxoid to
hyalinized. Cellular and nuclear pleomorphism, necrosis, and mitotic activity are limited in the cribriform and tubular
paI erns. However, these features are more frequently seen in the solid paI ern. Common to all histologic variants is the
proclivity for nerve invasion (neurotropism), including perineural and intraneural invasion. However, A CC is not the only
salivary gland tumor to show neurotropism.
The histochemical features of A CC include the presence of diastase-resistant, periodic acid–S chiff–positive, and
mucicarmine-positive material within the pseudocysts. A lcian blue staining is also present within the pseudocysts. The
immunohistochemistry of A CC varies according to cell type. The myoepithelial cells show cytokeratin, S -100 protein, p63,
calponin, vimentin, and actin positivity with variable glial fibrillary acidic protein reactivity. The ductal cells show
cytokeratin, EMA , and carcinoembryonic antigen positivity. Ultrastructural studies show the presence of cells with
340bidirectional differentiation, including the luminal or ductal cells and the abluminal or myoepithelial or basal cells.
Problems in the surgical removal of A CC relate to the infiltrative nature of these neoplasms with their tendency to extend
along nerve segments, which is further compounded by their deceptively circumscribed macroscopic appearance.
338Recurrence rates are high, ranging from 75% to 90%, and directly related to inadequate surgical excision. A CCs are
radiosensitive, and radiotherapy is particularly useful in controlling microscopic disease after initial surgery, in treating
locally recurrent disease, or as palliation in unresectable tumors. S inonasal and nasopharyngeal A CCs have similar biologic
behavior to A CCs at other locations. The short-term prognosis is generally good because tumor growth is slow, but the
longterm prognosis is poor. These facts are reflected in the 5-year and 20-year survival rates of adenoid cystic carcinomas of all
341head and neck sites of 75% and 13%, respectively. Tumor location affects prognosis. A CCs located in major salivary
glands have a beI er prognosis than their minor salivary gland counterparts. Clinical staging plays a more decisive role than
342,343 342histologic grading in predicting prognosis in ACC. Spiro and Huvos reported a cumulative 10-year survival of 75%,
43%, and 15% for patients with stage I, II, and III and IV, respectively.
Low-Grade Nasopharyngeal Papillary Adenocarcinoma
Low-grade nasopharyngeal papillary adenocarcinoma is an uncommon nasopharyngeal surface epithelium–derived
344,345malignant tumor with adenocarcinomatous differentiation and indolent biologic behavior. N o sex predilection is
seen, and this tumor occurs over a wide age range from the second to seventh decades of life (median 37 years). The tumor
may occur anywhere in the nasopharynx but most often involves the posterior nasopharyngeal wall. The most common
symptom is nasal obstruction. No etiologic factors are known.
These tumors are exophytic, papillary, nodular, or cauliflower-like with a soft to griI y consistency, measuring from a few
millimeters to 4.0 cm. Histologically, they are unencapsulated and have papillary and glandular growth paI erns. The
papillary structures are complex with arborization and hyalinized fibrovascular cores ( Fig. 4A -34). S imilarly, the glandular
paI ern is complex and is characterized by back-to-back and cribriform architecture. The cells vary in appearance from
pseudostratified columnar to cuboidal. The nuclei are round to oval with vesicular to optically clear-appearing chromatin,
indistinct nucleoli, and eosinophilic cytoplasm (see Fig. 4A -34). Mild to moderate nuclear pleomorphism is seen. S caI ered
mitotic figures can be seen, but atypical mitoses are not present. Focal necrosis can be found. Psammoma bodies may be
present (see Fig. 4A -34). This tumor has an infiltrative growth into the submucosa. I n adequately sampled material, surface
epithelial derivation can be seen in the form of transitional zones from normal nasopharyngeal surface epithelium to tumor.FIGURE 4A-34 Low-grade nasopharyngeal papillary adenocarcinoma. A, These tumors are
unencapsulated and infiltrative and show a complex papillary growth with fibrovascular cores. B, Papillary
frond with fibrovascular core and nuclear features similar to those in thyroid papillary carcinoma. C,
Psammoma bodies may be present. D, Immunostaining for thyroid transcription factor 1 (nuclear staining)
is consistently found, but thyroglobulin staining is negative (not shown).
Histochemical stains for epithelial mucin are positive. D iffuse immunoreactivity is seen for cytokeratin and EMA . Focal
reactivity is seen with carcinoembryonic antigen. N o immunoreactivity is found with S -100 protein or glial fibrillary acidic
protein. Low-grade nasopharyngeal papillary adenocarcinomas are consistently immunoreactive for thyroid transcription
346factor 1 (see Fig. 4A -36), and, given their histologic similarity to thyroid papillary carcinoma, misdiagnosis as thyroid
papillary carcinoma (metastatic or primary origin from ectopic gland) may occur. However, nasopharyngeal papillary
adenocarcinomas are thyroglobulin negative; the absence of thyroglobulin immunoreactivity excludes a tumor of thyroid
follicular epithelial cell origin. No association is seen with EBV.
FIGURE 4A-36 Extranodal natural killer/T-cell lymphoma of nasal type. A, The neoplastic cells surround
and invade vascular spaces (angiocentricity). B, Elastic stain shows disruption of the elastic membranes
with tumor invasion through the wall with plugging of the vessel lumen.
344,345Conservative surgical excision with complete removal is the treatment of choice and is curative. These are
slowgrowing tumors with the potential to recur if incompletely excised; metastatic disease does not occur.Nonepithelial Malignant Neoplasms
Non-Hodgkin Lymphoma of the Sinonasal Tract
347N on-Hodgkin lymphomas of the sinonasal tract (S N T-ML) are heterogeneous and can be clinically aggressive. A lthough
the terms polymorphic reticulosis, lethal midline granuloma, midline malignant reticulosis, and idiopathic midline
destructive disease have been used over the years synonymously with S N T-ML, this is categorically incorrect. N onneoplastic
lesions, inflammatory and infectious diseases, and numerous benign and malignant neoplasms of the sinonasal tract may all
result in a destructive process occurring in the midline aspect of this region. Therefore idiopathic midline destructive disease
is not a specific term and should never be used to indicate a diagnosis of a malignant lymphoproliferative neoplasm. Other
designations for these lesions include angiocentric immunoproliferative lesions and peripheral T-cell lymphoma, the current
348established designation being angiocentric N K/T-cell lymphoma of nasal type. S N T-ML also include lymphomas of B-cell
349lineage with diffuse large B-cell lymphoma (D LBCL) being the most common type. Other B-cell lymphomas of these sites
include BurkiI lymphoma, extranodal marginal B-cell lymphoma of the mucosa-associated lymphoid tissue type, and
349follicular lymphoma. A n immunophenotypic difference exists between primary nasal cavity lymphomas and primary
paranasal sinus lymphomas: the nasal cavity lymphomas are predominantly of N K/T-cell type, whereas the majority of B-cell
347lymphomas occur in the paranasal sinus.
350,351S N T-ML are uncommon and account for only 1.5% of non-Hodgkin malignant lymphomas in the United S tates. The
incidence has been reported to be higher, however, in A sian and S outh A merican countries where the incidence of primary
350,352,353non-Hodgkin malignant lymphoma is approximately 6.7% to 8.0% of all malignant lymphomas. Virtually the
entire spectrum of morphologic types of lymphoma can be seen (see Chapter 21). The most common type of lymphoma in
347,354the sinonasal tract is extranodal N K/T-cell lymphoma of nasal type. N K/T-cell lymphoma of nasal type primarily
354affects men and is a disease of adults with a median age in the sixth decade of life. I t is most common in A sians and has
355,356been reported with significant frequency in S outh and Central A merica and Mexico. I n these populations, the disease
is seen primarily in individuals of N ative A merican origin. These findings suggest a racial predisposition for the disease.
348A lthough uncommon, N K/T-cell lymphomas of nasal type also occur in Western populations and can affect whites.
347,354D LBCL of the sinonasal tract also primarily affects men, with a median age in the seventh decade of life. The sites of
347involvement may include the nasal cavity, one or more paranasal sinuses, or multiple regions within the sinonasal tract.
The clinical presentations vary according to histologic type and/or immunophenotype. Low-grade lymphomas may present
as a nasal cavity or paranasal sinus mass associated with airway obstructive symptoms. High-grade lymphomas are more
likely to present with aggressive signs and symptoms including nonhealing ulcer, cranial nerve manifestations, facial
swelling, epistaxis, or pain. High-grade B-cell lymphomas tend to present with soft tissue or osseous destruction, particularly
347of the orbit, with associated proptosis. N K/T-cell lymphoma of nasal type commonly presents as a destructive process in
the midfacial region with nasal septal destruction, palatal destruction, or orbital swelling or with obstructive symptoms
related to a mass.
349,353I rrespective of ethnic background, N K/T-cell lymphoma of the nasal type is strongly associated with EBV. However,
349B-cell lymphomas of the sinonasal tract have only a weak association with EBV. A n increased risk of sinonasal
lymphomas, primarily D LBCL but also N K/T-cell lymphoma of nasal type, is also associated with immunosuppression,
357-359including posttransplantation and human immunodeficiency virus (HIV) infection.
NK/T-Cell Lymphoma of Nasal Type
Histologically, nasal-type N K/T-cell lymphomas may show a broad cytologic spectrum, but usually cytologically atypical cells
348,360are present. The atypical cells may vary from small and medium-sized cells to large, hyperchromatic cells. The
atypical cells may have irregular and elongated nuclei, prominent nucleoli, or clear cytoplasm (Fig. 4A -35) with frequent
mitoses. Epitheliotropism and pseudoepitheliomatous hyperplasia may be present. A n associated prominent admixed
inflammatory cell infiltrate may be present. The polymorphous cell population may obscure the atypical cells, causing
diagnostic difficulties. The benign inflammatory cell infiltrate may include plasma cells, histiocytes, and eosinophils.
FIGURE 4A-35 Extranodal natural killer/T-cell lymphoma of nasal type. A, At low magnification areas of
geographic necrosis are seen (left) with cellular infiltrate present including surrounding vascular spaces
(right). B, Diffuse discohesive cellular proliferation composed of medium to large cells with round to oval
to irregular and elongated nuclei, vesicular to hyperchromatic nuclei, and indistinct eosinophilic cytoplasm.I n adequately sampled material, the low-power appearance includes the presence of geographic necrosis characterized by
bluish or so-called griI y necrosis (see Fig. 4A -35). N ecrosis is a virtually constant (but not pathognomonic) feature. The
zonal paI ern of necrosis suggests a vascular pathogenesis. The atypical cells invade and destroy blood vessels (Fig. 4A -36).
The vascular invasion and destruction is responsible for the designation “angiocentric lymphomas.” A ngiocentricity is
defined as the presence of tumor cells around and within vascular spaces with infiltration and destruction of the vessel wall.
Perivascular localization is not sufficient for the designation of angiocentricity.
I mmunohistochemically, an N K-cell immunophenotype is most commonly present including CD 2 positive, surface
348,353(membranous) CD 3 negative, cytoplasmic CD 3e positive, and CD 56 (neural cell adhesion molecule) positive. T-cell
markers including CD 43 and UCHL1 (CD 45RO) are positive. Expression of perforin, TI a1, and granzyme B indicative of a
349,353 348cytotoxic phenotype is present. T-cell receptor genes are often in germline configuration. Tumors that are CD 56
negative may still be classified as N K/T-cell lymphomas if they express T-cell markers and cytotoxic markers and are EBV
349,353 361N K/T-cell lymphomas are positive for EBV in greater than 95% of cases by I S H for EBER. The global distribution
353of EBV subtypes shows predominance of strain subtype A , 89%, and subtype B, 11%, with no caseso f dual infection.
Because EBV-positive cells are typically absent in the nasal cavity mucosa or in inflammatory diseases of the nasal cavity, the
presence of EBV by I S H can be used in conjunction with light microscopy in the diagnosis of nasal cavity N K/T-lymphomas.
EBV may induce expression of cytokines (e.g., tumor necrosis factor-α), which could lead to the presence of necrosis. This
might then represent the pathogenesis for the observed necrosis in those cases without vascular invasion. Expression of Fas
361,362and Fas ligand, a frequent finding in N K/T-cell lymphomas, also may account for the presence of necrosis. A n
epithelial and myoepithelial cell marker, p63, can be reactive in N K/T-cell lymphoma but typically is only focally
The differential diagnosis includes a variety of other sinonasal malignant neoplasms discussed in this chapter. A lthough
differences can be identified by light microscopic evaluation, often the differentiation of all these tumor types rests on the
immunohistochemical staining profile for a given tumor (see Table 4A-10). The differential diagnosis also includes infectious
disease of the sinonasal tract and Wegener granulomatosis (WG) (Table 4A -14). I dentification of microorganisms by special
stains or microbiologic cultures will assist in confirming an infectious etiology. The constellation of histologic features
associated with WG (see later discussion) coupled with the presence of elevated antineutrophil cytoplasmic antibodies
(ANCA) assist in confirming a diagnosis of WG and differentiating it from NK/T-cell lymphoma.
Clinicopathologic Comparison among Sinonasal Malignant Lymphomas, Wegener Granulomatosis, and Allergic
Granulomatosis and Vasculitis
AllergicAngiocentric NK/T-Cell
DLBCL WG Granulomatosis andLymphoma Vasculitis*
Sex, age M > F, sixth decade M > F, seventh decade M > F, fourth-fifth M > F, wide age range
Most common in decades (third-sixth
Asians; occurs in Laryngeal WG decades)
Western affects F > M
population but
with less
Location Generally limited to the Nasal cavity and one or Localized UADT WG Multisystem disease
sinonasal region; more paranasal most common in including
extrasinonasal sinuses nasal cavity > pulmonary, nasal,
involvement occurs paranasal sinuses; renal, cutaneous,
and represents a other sites may cardiac, and
higher stage tumor include nervous system
nasopharynx, larynx involvement
(subglottis), oral
cavity, trachea, ear,
salivary glands
Symptoms Destructive process of Nonhealing ulcer, SNT: sinusitis, with Asthma, allergic
midfacial region: epistaxis, facial or without rhinitis, evidence of
nasal septal swelling, pain, cranial purulent eosinophilia, serum
perforation, nerve manifestations rhinorrhea, and tissue (e.g.,
obstruction, palate obstruction, eosinophilic
destruction, orbital pain, epistaxis, pneumonia,
swelling anosmia, eosinophilic
headaches gastroenteritis),
Larynx: dyspnea, evidence of
hoarseness, vasculitis
voice changes
Oral: ulcerative
lesionEar: hearing loss, AllergicAngiocentric NK/T-Cell painDLBCL WG Granulomatosis andLymphoma Vasculitis*Systemic Majority are localized Majority are localized ELK classification: Typically patients have
involvement (stage IE-IIE) (stage IE-IIE) E: Ear, nose, throat multisystem
May progress to May progress to L: Lung involvement,
disseminated or disseminated or K: Kidney although limited
systemic systemic E, EL = limited form forms of disease
involvement involvement WG exist
ELK = systemic WG
Serology ANCA negative; no ANCA negative; no ANCA positive: ANCA levels may or
specific serologic specific serologic • Increased in both may not be present;
marker(s) marker(s) primary disease peripheral
and recurrent eosinophilia
• (C-ANCA more
specific than
Histology Overtly malignant Diffuse discohesive Polymorphous Polymorphous
cellular infiltrate, cellular proliferation (benign) cellular (benign)
but in early of medium to large infiltrate cellular
phases malignant cells with large round Vasculitis infiltrate,
cells may not be to oval vesicular Ischemic-type predominantly
overtly (noncleaved) nuclei, necrosis eosinophils
identifiable prominent nucleoli, Isolated Vasculitis, which
Angiocentricity and increased mitotic multinucleated may be a
angioinvasion activity and necrosis giant cells (not granulomatous
Ischemic-type well-formed vasculitis
necrosis granulomas) (multinucleated
No giant cells or Negative cultures giant cells in
granulomas and stains for the wall of
Negative cultures organisms involved blood
and stains for vessels)
organisms Eosinophilic
Negative cultures
and stains for
IHC CD56, CD2, Leukocyte common Polymorphous and Polymorphous and
cytoplasmic CD3e antigen and B-cell polyclonal polyclonal
positive marker (CD20, CD79)
T-cell marker (CD3, positive
UCHL-1) positive
EBV Strong association No to weak association Negative Negative
Treatment Radiotherapy for Radiotherapy and/or Cyclophosphamide and Systemic
localized disease; chemotherapy prednisone corticosteroids
chemotherapy for
disseminated disease
Prognosis Overall survival 30%- Dependent on stage Limited disease 62% 5-year survival;
50% Survival rates 35%- associated with a increased
Local 60% good to excellent morbidity and
recurrence/relapse prognosis and mortality due to
and systemic occasional cardiac
failure common spontaneous involvement
remissions resulting in CHF or
Mortality related to MI
complications of
renal and
*Also known as Churg-Strauss syndrome.
ANCA, Antineutrophilic cytoplasmic antibody; C-ANCA, cytoplasmic antineutrophilic cytoplasmic antibody; CHF, congestive heart
failure; DLBCL, diffuse large cell B-cell lymphoma; EBV, Epstein-Barr virus; MI, myocardial infarction, IHC,
immunohistochemistry; P-ANCA, perinuclear antineutrophilic cytoplasmic antibody; UADT, upper aerodigestive tract; WG,
Wegener granulomatosis.
Diffuse Large B-Cell LymphomaI n D LBCL a diffuse submucosal discohesive cellular infiltrate is composed of medium to large cells with large round to oval
vesicular (noncleaved) nuclei and several small nucleoli or a single centrally located prominent eosinophilic nucleolus.
Mitotic activity, necrosis, and apoptotic figures can be seen.
I mmunohistochemistry is essential in confirming the diagnosis and in differentiating a malignant lymphoma from
carcinoma. I mmunoreactivity is seen for LCA or CD 45 and pan B-cell markers, including CD 20, CD 79a, and PA X5. p63 can
364be reactive in D LBCL. A s such, the presence of p63 does not exclude a diagnosis of lymphoma and, in the absence of
cytokeratin immunoreactivity, should prompt more extensive evaluation for a possible diagnosis of lymphoma.
365The majority of N K/T-cell lymphomas of nasal type are localized at presentation (stage I E-I I E). N K/T-cell lymphomas
are radiosensitive tumors, but the prognosis is generally poor once dissemination occurs. The treatment in disseminated
disease is aggressive chemotherapy. I n some patients, surgical resection may be needed for symptomatic relief (e.g., airway
354,365,366obstruction). The overall survival is 30% to 50%. Local recurrence or relapse and systemic failure are
365,367 367common. S ystemic failure includes increased risk of dissemination to skin, testes, and gastrointestinal tract. A
complication seen in some cases of N K/T-cell lymphoma of nasal type is hemophagocytic syndrome, which adversely affects
For B-cell lymphomas, including D LBCL, the prognosis is dependent on the clinical stage. Patients with sinonasal D LBCL
349,354present with low clinical stage disease (I E-I I E). Treatment primarily includes radiotherapy and/or chemotherapy.
354,357S urgical resection may be needed for symptomatic relief. S urvival rates range from 35% to 60%. S ystemic failure
includes increased risk of dissemination to nodal and extranodal sites below the diaphragm (e.g., paraaortic lymph nodes,
367gastrointestinal tract).
Malignant Lymphomas of Waldeyer Tonsillar Tissues
Waldeyer tonsillar ring includes the lymphoid tissues of the nasopharynx, tonsils, and base of tongue. I t represents an
extranodal but not an extralymphatic site. Waldeyer ring lymphomas account for approximately 50% of all extranodal
nonHodgkin malignant lymphoma in the head and neck, where the incidence of extranodal non-Hodgkin lymphomas is second
368,369only to that in the gastrointestinal tract. I n Western countries Waldeyer ring lymphomas are overwhelmingly B-cell
lymphomas with the most common subtype being D LBCL. B-cell lymphomas of Waldeyer ring tend to affect men slightly
370-373more than women and are most common in the fifth to seventh decades of life. The most common sites of occurrence
(in order of frequency) are the tonsils, nasopharynx, and base of tongue. The most common symptoms include airway
obstruction, otalgia, decreased hearing, pain, and sore throat. N o specific association of Waldeyer ring lymphoma with EBV
Grossly, a large submucosal mass with or without surface ulceration may be seen. I n the majority of cases involvement is
370-373unilateral. A lthough any paI ern and cell type can be seen, the most common type is D LBCL. Typically, the cellular
infiltrate is discohesive, but occasionally it may demonstrate syncytial or cohesive growth, simulating an epithelial
malignancy. I n large cell lymphoma, the cells are medium to large with a large round to oval vesicular (noncleaved) nucleus
with several nucleoli often located at the periphery of the nucleus. N umerous macrophages (giving a starry sky appearance)
or epithelioid cells may be present. I n immunoblastic lymphoma, the cells are large with round to oval nuclei and a large,
prominent, and usually centrally located nucleolus. N ecrosis (individual cell or confluent areas) and increased mitotic
activity with atypical forms are common features. These tumors may show plasmacytic differentiation.
I mmunohistochemistry is essential in confirming the diagnosis and in differentiating a malignant lymphoma from
carcinoma. LCA or CD 45 will be positive in almost all malignant lymphomas. The overwhelming majority of Waldeyer ring
lymphomas are of follicle center cell origin, reflected in their expression of B-cell lineage markers (CD 20) and absence of
Tcell lineage markers.
I n addition to the immunohistochemical features, other findings associated with D LBCL include the presence of
immunoglobulin or T-cell receptor gene rearrangement and EBV and human T-lymphotropic virus-1 in a proportion of cases;
374the chromosomal translocation t(14;18) is present in many of the B-cell neoplasms. The histology of infectious
mononucleosis may present diagnostic difficulties with D LBCL. I nfectious mononucleosis typically occurs in younger-aged
people and has corroborating laboratory findings, including absolute lymphocytosis (with >50% lymphocytes in a total
3leukocyte population of >5000/mm ), prominent atypical lymphocytes (D owney cells), which are often >10% of the total
leukocyte count, and the presence of serum antibodies to horse red cells (positive Monospot test) or sheep erythrocytes
(positive Paul-Bunnell heterophile antibody test). The pathology of infectious mononucleosis that may assist in its
recognition includes the presence of large cells with maturation to plasma cells, immunoreactivity for both B-cell and T-cell
markers, and the absence of gene rearrangements.
374,375The most important prognostic factor for patients with Waldeyer ring lymphoma is the clinical stage. Treatment
primarily includes radiotherapy and/or chemotherapy. S urgical resection may be needed for symptomatic relief. The
349majority of patients have localized disease (stage I E-I I E). I n patients with D LBCL and stage I E diseases reported 5-year
370,371,376survival rates range from 58% to 86% Patients with stage IIE or higher have a much worse prognosis.
Extramedullary Plasmacytoma
377Extramedullary plasmacytoma (EMP) comprises approximately 3% to 5% of all plasma cell neoplasms. Eighty percent of
EMP occur in the head and neck, and most cases primarily involve the upper aerodigestive tract, including the sinonasal tract
377-379and nasopharynx. Eighty percent of EMP are primary (solitary) without evidence of tumor elsewhere; 20% are part of
377the generalized picture associated with multiple myeloma. EMP is more common in men than women; it occurs over a
wide age range, but the vast majority of patients are over 40 years of age. EMP tends to develop in mucosa-associated sites,
including the sinonasal tract, nasopharynx, pharynx (including tonsil), larynx, oral cavity, salivary glands, and thyroid gland.The clinical presentation is dependent on the site of occurrence and may include a soft tissue mass, airway obstruction,
379epistaxis, pain, proptosis, or cranial nerve involvement. S erum immunoelectrophoresis may show monoclonal
abnormalities in both the systemic and localized forms of the disease; up to 25% of patients with EMP will have a
378monoclonal gammopathy (M component). Radiologic features of EMP include a soft tissue density; bone destruction may
378be present; in patients with primary EMP, skeletal survey will be negative.
EMP may appear as a sessile or pedunculated, mucosa-covered mass measuring from 1 to 7.5 cm in greatest dimension.
The lesions have a soft to rubbery to firm consistency with a variable color. These tumors bleed easily on biopsy. Typically,
EMP is submucosal with a diffuse growth paI ern, replacing the normal tissue parenchyma. Plasma cell malignancies are
composed of plasma cells with varying degrees of maturation and atypicality (see also Chapter 22). Plasma cells are round to
oval with an eccentrically situated round nucleus; the nucleus has a characteristic “clock face” chromatin paI ern, but
dispersed nuclear chromatin can be seen; a characteristic paranuclear clear zone represents the Golgi apparatus where
378immunoglobulin is processed and glycosylated for secretion. The cytoplasm is abundant and basophilic. A myloid
deposits may be present in association with the plasma cell infiltrate. On immunohistochemistry, monotypic cytoplasmic
immunoglobulin heavy and/or light chain restriction is present, as are plasma cell–associated antigens (CD 38, CD 138, VS 38);
379plasma cell malignancies generally are LCA (CD45) and pan-B-cell marker (CD20 or L26) negative.
A n anaplastic variant of plasmacytoma may occur in upper aerodigestive tract sites and is characterized by cells with
enlarged pleomorphic nuclei, indistinct to prominent eosinophilic nucleoli, and a variable amount of eosinophilic cytoplasm.
Tumor giant cells may be present, and increased mitotic activity occurs, including atypical forms. I n these anaplastic lesions,
the cells may have a plasmacytoid appearance, but, by and large, there is loss of the histologic features diagnostic of plasma
cell tumor. D ifferentiation from large cell (immunoblastic) lymphomas may be extremely difficult. Of assistance would be a
previous history of plasmacytoma, residual evidence of a plasma cell neoplasm with transformation to less differentiated
(i.e., anaplastic) foci, and/or immunohistochemical features supporting a plasma cell neoplasm.
A s in non-Hodgkin malignant lymphoma, staging is required before the initiation of therapy and may necessitate a bone
marrow biopsy. Many cases of EMP remain localized, and surgical resection with postoperative radiotherapy (30-50 Gy) is
380 380curative. Seventy percent of patients with EMP are alive at 10 years, with a median survival of 7 to 9 years. Involvement
of a head and neck site may represent dissemination from multiple myeloma, or dissemination may occur to other sites from
the primary head and neck involvement. The prognosis is drastically affected by the presence of disseminated disease—
378,379median survival after dissemination is less than 2 years. A diagnosis of EMP warrants complete skeletal examination
and clinical staging to determine the extent of disease and thus predict the outcome.
Other Hematolymphoid Malignancies and Related Lesions
Other malignancies of hematolymphoid origin occurring in Waldeyer ring include N K/T-cell lymphoma, anaplastic large cell
lymphoma, Burkitt lymphoma, and Hodgkin lymphoma.
The B-cell predominance of Waldeyer ring malignant lymphomas is less true in A sian populations, where B-cell
lymphomas comprise up to 60% of cases as a result of a higher proportion of N K/T-cell lymphoma and peripheral T-cell
354lymphomas. Waldeyer ring extranodal N K/T-cell lymphoma of nasal type tends to occur more commonly in men than in
354women with a median age in the sixth decade of life. Extranodal anaplastic large cell lymphoma of the head and neck is
381,382rare but may be seen in HI V-infected patients. BurkiI lymphoma is a highly aggressive lymphoma composed of B
cells that often present in extranodal sites, including the head and neck (e.g., jaws, sinonasal tract, nasopharynx) and tend to
383occur in children and young adults.
Primary upper aerodigestive tract mucosal Hodgkin lymphoma is rare; nasopharyngeal Hodgkin lymphoma is often
384-386associated with EBV infection.
Follicular dendritic cell tumor (sarcoma) (FD CT) is a rare neoplasm composed of spindled to ovoid cells showing
morphologic and phenotypic features of follicular dendritic cells (see Chapter 21). FD CT is typically a tumor of adults with
equal sex predilection. FD CTs present with painless lymphadenopathy most often in the cervical neck region and, less often,
in the axillary region. Extranodal sites of occurrence include the mucosal sites of the upper aerodigestive tract, most often
387-391the tonsil and pharynx ; I n mucosal sites of the upper aerodigestive tract patients present with a variety of symptoms
including an enlarging, painless mass that may be associated with dysphagia or other obstructive features. FD CTs occur in
association with Castleman disease in about 10% to 20% of patients; most often it is Castleman disease of the hyaline
392vascular type and, less frequently, the plasma cell type.
FD CTs in the mucosa of the upper aerodigestive tract are usually polypoid with an intact surface epithelium. Growth
paI erns include diffuse, storiform, fascicular, and whorled. The cellular proliferation includes oval to spindle-shaped cells
with round to oval, uniform-appearing, elongated nuclei with vesicular or granular-appearing chromatin, inconspicuous
nucleoli, and pale to slightly eosinophilic cytoplasm with indistinct borders. A bsent to scaI ered mitotic figures (0-10
mitoses/high-power field) can be found, but atypical mitoses, significant pleomorphism, and necrosis are rare. A
background lymphocytic infiltrate either as individual cells or in clusters can be identified throughout the tumor and often
in a perivascular (cuffing) location; occasional germinal centers can be identified.
FD CT typically express CD 21, CD 35, CD 23, and vimentin (see alsCo hapter 21). I n addition, consistent expression is
present for follicular dendritic cell specific markers (e.g., R4/23, Ki-M4P, Ki-FD RC1p), fascin, HLA -D R, and EMA , the laI er
despite the fact that normal follicular dendritic cells are EMA negative. D iffuse strong staining for clusterin was found in
100% of FD CTs, including cases that were negative for traditional markers (CD 21, CD 23, CD 35) but that were classified on
393the basis of characteristic ultrastructural features. Ultrastructurally, FD CTs show the presence of complex interdigitating
(villous) cytoplasmic processes or extensions, often joined through numerous cell junctions, including well-formed
desmosomes. Treatment includes surgical excision with or without adjunctive therapy (i.e., radiotherapy, chemotherapy).
394The overall behavior is rather indolent and has been likened to low-grade sarcomas. D eath due to local recurrence and/or
distant metastasis is uncommon.Malignant Peripheral Nerve Sheath Tumor (Malignant Schwannoma; Neurogenic Sarcoma;
Malignant peripheral nerve sheath tumors (MPN S Ts) of the sinonasal tract and nasopharynx are uncommon neoplasms. Up
to 14% of MPN S Ts (see alsoC hapter 27) occur in the head and neck, with the neck being the most common site of
395involvement; all areas may be involved, including the sinonasal cavity and nasopharynx. MPN S Ts may occur de novo or
396occur in the setting of neurofibromatosis 1.
Histologically, MPN S Ts of the sinonasal tract may be spindle or epithelioid and low-grade or high-grade tumors. The
majority of sinonasal MPN S Ts are low-grade spindle cell type, appearing as a nondescript spindle cell proliferation in and
395around a benign glandular proliferation. These tumors are unencapsulated and infiltrating cellular tumors composed of
spindle-shaped cells arranged in fascicles. The nuclei are irregular in contour and are often wavy or buckled in appearance;
the cytoplasm is indistinct. A s compared with benign schwannomas, increased cellularity, cellular pleomorphism, and
increased mitotic activity are seen. Hypocellular areas with a myxoid stroma can be seen alternating with areas of greater
cellularity. Heterologous elements, including bone and cartilage, may be present. I n contrast to benign schwannomas, S -100
protein reactivity is focal and less intensely positive in low-grade MPN S Ts and is only variably present in high-grade
397MPNSTs. S inonasal MPN S Ts generally have a favorable prognosis. Unfavorable prognosis is associated with occurrence
395,396in the setting of neurofibromatosis 1, male sex, and higher histologic grade tumors.
Fibrosarcoma and Undifferentiated Pleomorphic Sarcoma (So-Called Malignant Fibrous
S inonasal and nasopharyngeal fibrosarcomas and unclassified pleomorphic sarcomas (see also Chapter 24) are
92,395,398uncommon. The most common sites of occurrence are the paranasal sinuses. Patients present with signs and
symptoms of a mass lesion, including nasal obstruction, epistaxis, facial swelling, and pain. Histologically, fibrosarcomas are
composed of spindle-shaped cells in a fascicular or “herringbone” paI ern of growth with associated collagen deposition.
The tumors lack any specific differentiation on light microscopy and lack immunohistochemical evidence supportive of
another tumor type (e.g., S -100 protein in malignant peripheral nerve sheath tumors; cytokeratin in spindle cell squamous
395carcinoma). The microscopic grading of these tumors includes low-grade and high-grade forms. I n low-grade
fibrosarcomas, mild cellular pleomorphism and readily identifiable mitotic figures are seen (but atypical forms are not seen),
and retention of the fascicular growth paI ern occurs. I n contrast to low-grade tumors, the high-grade fibrosarcomas have
less distinct fascicular growth; show marked cellular pleomorphism with marked increase in mitotic activity, including
atypical forms; and have associated hemorrhage and necrosis. These tumors, however, lack bizarre or giant neoplastic cells
with hyperchromatic nuclei and prominent nucleoli. The presence of the laI er would support the diagnosis of unclassified
pleomorphic sarcoma. Because many malignant tumors may share these growth paI erns, it is important to demonstrate the
absence of immunoreactivity with markers that may be diagnostic for another tumor type such as cytokeratin, S -100 protein,
395,399or HMB-45. Local recurrence is the most significant cause of morbidity and mortality in these patients.
RMS is a malignant mesenchymal tumor of skeletal muscle cells (rhabdomyoblasts). I n the head and neck, RMS is primarily
400but not exclusively a disease of the pediatric population. I f all ages are considered, RMS comprises up to 50% of all soft
tissue sarcomas of the head and neck (see Chapter 24). RMS restricted to pediatric age groups represents up to 75% of all soft
400,401tissue sarcomas of the head and neck ; in this age group, RMS represents the most common aural malignant
neoplasm. N o sex predilection is seen. I n the head and neck, the most common sites of occurrence of RMS (in descending
402-404order of occurrence) include the orbit, nasopharynx, middle ear or temporal bone, and the sinonasal tract. I f adults
405,406only are considered, the most frequent site of occurrence is the sinonasal tract. S ymptoms vary according to site.
Patients with sinonasal tract RMS may present with such symptoms as sinusitis, rhinorrhea, nasal obstruction, epistaxis,
pain, otalgia, facial swelling, and headaches. I n contrast with pediatric patients, RMS in adults often is a more aggressive
404-408neoplasm. I n the sinonasal tract, progression of disease may result in proptosis, facial deformity, visual field
disturbances, and/or cranial nerve deficits.
RMS of the sinonasal tract most often appears as a nodular, lobular, or polypoid mass with an appearance similar to that of
sinonasal inflammatory polyps. The gross appearance may vary according to the site involved. N asopharyngeal RMS tends to
be fairly well circumscribed, polypoid or multinodular, tan-white, glistening, or gelatinous and is capable of aI aining large
sizes; sinonasal RMS tends to be small and appears as a nasal polyp. A pproximately 25% of nasopharyngeal and sinonasal
cavity RMS assume a sarcoma botryoides appearance with a grape-like, multinodular, or polypoid configuration.
The majority of RMS of the head and neck are of the embryonal type or botryoid type (80%-85%) followed by alveolar
(10%40215%) (Figs. 4A -37 and 4A-38). The other histologic types, including spindle cell and pleomorphic, may occur in the head
and neck but are considered uncommon. Histologic appearances are the same as at other sites (see Chapter 24).
I mmunohistochemistry is an important adjunct in the diagnosis of RMS and includes immunoreactivity with desmin,
myoglobin, myf-4, and muscle-specific actin (see Fig. 4A-40).FIGURE 4A-37 Embryonal rhabdomyosarcoma of the sinonasal tract. A, At low power the submucosal
infiltrate shows alternating cellular and myxoid areas. B, At high magnification cells with eosinophilic
cytoplasm characteristic of rhabdomyoblasts are present.
FIGURE 4A-38 Alveolar rhabdomyosarcoma of the nasopharynx. The neoplastic cells adhere to the
fibrous septa with central loss of cellular cohesion giving the appearance of spaces or alveoli and creating
an “alveolar” growth.
FIGURE 4A-40 Antrochoanal polyp with associated atypical stromal cells. The atypical stromal cells
(i.e., myofibroblasts) have enlarged, pleomorphic, and hyperchromatic nuclei, indistinct to prominent
nucleoli, and eosinophilic- to basophilic-appearing fibrillary cytoplasm. These cells are usually focally
identified with a tendency to cluster near areas of injury, including thrombosed vascular spaces as seen at
extreme right.
409,410Cytogenetic evaluation may play a critical role in the diagnosis and differential diagnosis of RMS . For embryonal
RMS consistent loss of heterozygosity exists at chromosome 11p15.5. For the botryoid type of embryonal RMS deletion of
short arm of chromosome 1 and trisomies of chromosomes 13 and 18 occur. For the alveolar RMS the majority of cases have
t(2;13)(q36;q14) translocation, and in a minority of cases there is t(1;13)(p36;q14) translocation. These translocations result in
juxtaposition of PAX3 or PAX7 genes on chromosomes 2 and 1, respectively, with the FOXO1 gene on chromosome 13.
PAX7/FOXO1 fusion transcript–positive cases tend to occur in young patients, more often arise in extremities, and are
associated with longer event-free survival.
The differential diagnosis includes a variety of other sinonasal malignant neoplasms discussed in this chapter. A lthough
differences can be identified by light microscopic evaluation, often the differentiation of all these tumor types rests on the
immunohistochemical staining profile for a given tumor (see Table 4A-10).
401Before the efforts of the I ntergroup Rhabdomyosarcoma S tudy (I RS ), the treatment for RMS was surgical excision, and
the 5-year survival rate for RMS of the head and neck was less than 20%. However, the I RS developed a staging system for
411RMS and showed that multimodality therapy, including surgery, radiotherapy, and chemotherapy, enhances survivalrates over single-modality therapy.
Tumor staging is an important element in the overall approach to treating the disease; because there is a tendency to bone
marrow metastasis, a bone marrow aspiration and biopsy are part of the staging process.
Favorable and unfavorable factors are listed in Table 4A -15. Overall 5-year survival rates based on clinical staging include
411groups I and I I , 85% to 88%; group I I I , 66%; and group I V, 26%. The I RS subsequently divided head and neck RMS into
412three categories for statistical purposes, including (1) eye-orbit RMS with 5-year survival rates of 92%; (2) parameningeal
RMS , including the middle ear–mastoid, external auditory canal, nasopharynx, sinonasal region, and infratemporal fossa,
with 5-year survival rates of 70%; and (3) other head and neck sites, including neck, scalp, oropharyngeal region, larynx, and
parotid gland, with 5-year survival rates of 55%. Those patients who remain free of tumor for a 2-year period are probably
401cured, although the I RS study showed that 8% of their patients who were tumor free at 2 years subsequently had
413recurrences. I n addition to clinical stage, the prognosis is also related to patient age and histology. A s previously stated,
405-407RMS in adults is a more aggressive tumor with tumor deaths occurring (on the average) 2 years after diagnosis. The
aggressive behavior in adults as compared with children may relate to the histology of the tumor. A dult RMS is more
frequently of the alveolar subtype (associated with a worse prognosis); in children, the embryonal subtype is more frequent
414(associated with a more favorable outcome), as also is spindle cell variant.
F avorable and U nfavorable P rognostic F actors for R M S
Prognostically Favorable
Infants and children
Orbital or genitourinary location (non-bladder or prostate)
Small size (less than 5 cm)
Botryoid or spindle cell type
Localized noninvasive tumor without regional lymph node involvement or distant metastasis
Complete initial resection
Prognostically Unfavorable
Location in head and neck (nonorbital), paraspinal region, abdomen, biliary tract, retroperitoneum, perineum, or
Large size (greater than 5 cm)
Alveolar (especially PAX3/FKHR fusion transcript positive) or pleomorphic type
Local tumor invasion, especially parameningeal or paraspinal region, paranasal sinuses, or skeleton
Local recurrence whether during or not during therapy
Regional lymph node or distant metastasis
Incomplete initial resection or unresectability
Sinonasal or nasopharyngeal angiosarcomas are rare tumors presenting as a mass lesion with or without epistaxis and airway
415,416obstruction. A ngiosarcomas tend to be nodular or ulcerative, ill-defined lesions with a bluish red color.
Histologically, most of these tumors are morphologically low grade including a proliferation of ramifying and anastomosing
vascular channels that dissect through surrounding structures. The endothelial cells lining the vascular spaces are plump,
increased in number, and pleomorphic and pile up along the lumen creating papillations. They demonstrate mitotic activity,
including atypical mitoses. The endothelial cells may appear spindled, epithelioid, or polygonal. I mmunohistochemical
stains assist in the diagnosis; reactivity is identified with either factor VI I I –related antigen, CD 31, or CD 34. Epithelioid
angiosarcomas may be cytokeratin positive, potentially creating diagnostic problems with carcinoma. Rare examples of
417epithelioid hemangioendotheliomas may occur in the sinonasal tract.
Kaposi Sarcoma
Kaposi sarcoma is a vascular neoplasm that occurs in three forms: classic, epidemic or acquired immunodeficiency syndrome
(A I D S ) related, and transplantation associated (seeC hapter 3). S inonasal or nasopharyngeal involvement is uncommon and
418-420usually occurs only in patients with A I D S . I n this form of Kaposi sarcoma, the tumor appears as a blue-red or
421violaceous mucosal papule or nodule and may simulate the appearance of a benign vascular proliferation. Histologically,
the tumor is unencapsulated and infiltrative, composed of eosinophilic spindle cells in a fascicular paI ern. The spindle cells
are elongated and rather uniform with scant cytoplasm. S eparating the spindle cell proliferation are slit-like spaces
containing erythrocytes. I ntracellular and extracellular diastase-resistant, periodic acid–S chiff–positive hyaline globules can
be seen. I mmunoreactivity for CD 34 and CD 31 is usually present. I mmunohistochemical evidence of Kaposi sarcoma–
422associated herpesvirus/HHV-8 supports the diagnosis of Kaposi sarcoma. The presence of HHV-8 in nasal secretions and
saliva by PCR indicates frequent shedding of multiple herpesviruses in nasal secretions and saliva, particularly in patients
423,424with Kaposi sarcoma.
425Up to 10% of all leiomyosarcomas arise in the head and neck. I n the sinonasal tract, leiomyosarcomas occur in adults; nosex predilection is seen. These tumors present with nasal obstruction, pain, and epistaxis. Given the relative lack of smooth
muscle in the head and neck region, particularly in the sinonasal region, these tumors appear to originate from vascular
structures. S inonasal leiomyosarcomas are circumscribed but not encapsulated, polypoid or sessile masses, usually
426measuring greater than 5 cm in diameter. Histologically, they are cellular neoplasms comparable with leiomyosarcomas
at other locations (see Chapter 24). S trong and intense immunoreactivity can be seen with actins (smooth muscle and muscle
426specific), desmin, and h-caldesmon. Epithelioid cells and myxoid change may be seen and occasionally may predominate.
Wide surgical resection is the treatment of choice. The prognosis is dependent on the site and extent of tumor and is not
426contingent on the histology. Tumors limited to the nasal cavity are associated with a good prognosis and are cured after
104,426complete removal. Those tumors involving both the nasal cavity and paranasal sinuses tend to behave aggressively
426with increased recurrence, morbidity, and mortality rates. Metastases occur infrequently, usually to the lung.
Osteosarcoma (Osteogenic Sarcoma)
427,428Up to about 10% of conventional osteosarcomas occur in the head and neck region. Craniofacial osteosarcomas
(excluding those arising in the seI ing of Paget disease) have an equal sex predilection and occur in patients who are
429,430generally a decade or two older than those with extrafacial osteosarcomas. The jaws are most commonly affected, the
427-429mandible being more often involved than the maxilla. The most common clinical complaints include painful swelling
of the face, dentition problems, nasal obstruction, and epistaxis. Radiographically, osteosarcomas are destructive, poorly
delineated, osteolytic, osteosclerotic, or mixed lesions.
The gross appearance of osteosarcoma depends on the extent of mineralization as compared with the extent of the stromal
component. A s such, osteosarcomas vary from firm, hard, and griI y to fleshy and fibrous. The histopathologic features of
osteosarcoma in the head and neck are comparable with those at other locations (see Chapter 25). The prognosis in
431,432osteosarcoma does not correlate with the histologic subclassification.
431Osteosarcomas of the head and neck are aggressive tumors that are prone to local recurrence and distant metastasis.
428,431Craniofacial osteosarcomas are associated with a beI er prognosis than extrafacial tumors. This has been aI ributed to
their tendency to remain localized with metastatic spread occurring only late in the disease course, as well as lower
histologic grade. I n spite of the overall beI er prognosis of craniofacial osteosarcomas, the overall 5-year survival rate is no
428,431,433beI er than 35%. Osteosarcomas arising in Paget disease are highly malignant with negligible 5-year survival
434,435The incidence of chondrosarcoma of head and neck sites varies from 5% to 12%. I n the head and neck,
chondrosarcomas are slightly more common in men than in women and primarily occur in the fourth to seventh decades of
434-437life. A pproximately 2% of chondrosarcomas occur in patients less than 20 years of age. The most common site of
occurrence in the head and neck is the larynx; chondrosarcomas occur in virtually all other sites in which cartilage is found
but primarily occur in the craniofacial area, including the mandible, maxilla, and maxillofacial skeleton (nose and paranasal
434,436,438,439sinuses), as well as base of skull and the nasopharynx. S ymptoms vary according to the site of origin.
Craniofacial chondrosarcomas may cause nasal obstruction, epistaxis, changes in dentition (loosening or eruption of teeth),
proptosis, visual disturbances, and an expanding mass associated with pain, trismus, headaches, and neurologic deficits. The
radiologic appearance of craniofacial chondrosarcomas is that of a destructive lesion with single or multiple radiolucent,
radiopaque, or mixed-appearing areas and coarse calcifications. The radiographic appearance may correlate with histologic
The gross appearance of chondrosarcoma is that of a smooth, lobulated, hard submucosal mass larger than 2 cm in
diameter. Histologically, the appearances are comparable with those of chondrosarcomas at other locations (see Chapter 25),
and grade I lesions are the most common in the head and neck region. Histologic variants of chondrosarcoma, including
dedifferentiated chondrosarcoma, mesenchymal chondrosarcoma, and clear cell chondrosarcoma, are rare in the sinonasal
tract and nasopharynx.
Maxillofacial chondrosarcomas are more lethal than laryngeal chondrosarcoma, perhaps because they tend to be of a
438histologically higher grade, but more likely because of their proximity to vital structures and the difficulty in achieving
negative margins. D eath is generally due to uncontrolled local disease with invasion and destruction of vital structures,
including intracranial extension. N euraxial or base of skull chondrosarcomas often are extensively infiltrative at the time of
diagnosis precluding complete resection and giving rise to local recurrence. The overall 5-year survival rate for head and
435,436neck chondrosarcoma is approximately 70%.
Chordomas are low- to intermediate-grade malignant tumors that recapitulate the notochord. Chordomas are more common
in men than in women and can occur at any age but are generally not common below the fourth decade of life. Craniocervical
441chordomas are identified most frequently in the dorsum sella, clivus, and nasopharyngeal regions. S ymptoms vary
according to the site of occurrence and extension of tumor and include diplopia, visual field defects, headaches, pain, nasal
obstruction, epistaxis, nasal discharge, soft tissue mass, and endocrinopathies (as a result of destruction of the sella turcica).
The radiographic appearance is that of an expansile and destructive osteolytic lesion often associated with a soft tissue mass.
Nasopharyngeal chordomas appear as a soft tissue density.
Chordomas are well-demarcated or encapsulated, soft, mucoid, or gelatinous tumors with a variegated appearance,
including solid and cystic areas. Histologically, chordomas are similar to those at more common spinal locations (see
Chapter 25) and most often contain characteristic physaliferous cells (Fig. 4A-39). I mmunoreactivity is seen with cytokeratin,442,443EMA , and S -100 protein (seeF ig. 4A -39). Brachyury is recognized as a specific marker for notochord-derived tissues
444-446and neoplasms and has become a defining immunohistochemical feature of chordoma. The main differential
diagnostic consideration for chordoma is chondrosarcoma, which is known to lack brachyury expression.
FIGURE 4A-39 Nasopharyngeal chordoma. A, The neoplastic cells are epithelioid with vesicular nuclei
and abundant, granular to vacuolated cytoplasm. The vacuolization corresponds to the presence of
glycogen or mucus; when extensive it can produce a soap-bubble appearance, compressing the nucleus
and creating the characteristic physaliferous cells; neoplastic cells are immunoreactive for (B) cytokeratin
and (C) S-100 protein. Brachyury immunoreactivity (not shown) represents a defining feature of
Complete surgical excision is the treatment of choice. D espite their slow growth, chordomas are relentless neoplasms that
usually present with extensive local infiltration and destruction of adjacent, often vital, structures. More recent evidence
suggests that optimal treatment may include photon or proton radiotherapy alone or, when possible, combined with gross
447total resection. The 5-year survival rate for patients under 40 years is 100% as compared with 22% for patients over 40
443years of age.
T he chondroid chordoma is considered a histologic variant of chordoma characterized by its more frequent occurrence in
women and patients of a younger age than typical chordoma, virtually exclusive occurrence at the base of skull, the presence
of a prominent cartilaginous component, and the presence of S -100 protein immunoreactivity but absence of cytokeratin
immunoreactivity. The existence of chondroid chordoma distinct from low-grade chondrosarcoma has been questioned, but
there appear to be immunohistochemical differences that support the contention that chondroid chordoma is a distinct
442,443 443lesion. Mitchell and colleagues found no statistical differences in the survival of patients with chondroid
chordoma as compared with conventional chordoma. D edifferentiation of chordomas to high-grade sarcomas occurs and
448includes transformation to fibrosarcoma, unclassified pleomorphic sarcoma, osteosarcoma, or chondrosarcoma.
Malignant Teratoma (Teratocarcinosarcoma)
Malignant teratoma of the sinonasal tract is a rare tumor showing combined histologic features of carcinosarcoma and
449,450teratoma. These tumors occur in adults with a male predominance and median age of 60 years. S inonasal malignantteratomas are rapidly growing neoplasms. The most common site of involvement is the nasal cavity; other sites of
involvement include the ethmoid and maxillary sinuses. S ymptoms include nasal obstruction and epistaxis. These tumors
are friable to firm, red-brown masses. Histologically, malignant teratomas are characterized by a combination of epithelial
449and mesenchymal tissue components with very variable growth paI erns. The epithelial components include glandular or
ductal structures lined by benign-appearing, partly ciliated columnar epithelium with transitional areas to nonkeratinizing
squamous epithelium, with or without clear cells. I n addition, areas of squamous carcinoma and adenocarcinoma are
present. The mesenchymal components may include fibroblasts or myofibroblasts of benign and malignant appearance,
RMS , benign cartilage with an immature appearance and chondrosarcoma, or osteogenic tissue. The teratoid components
include “fetal-appearing” clear cell squamous epithelium, organoid structures, or neural tissue in the form of neural roseI es
and neurofibrillary matrix. The “fetal-appearing” clear cell squamous epithelium represents a characteristic histologic
finding in this entity and is supportive evidence of the teratoid nature of this neoplasm, given its description in teratomas of
449other organ systems. Foci of seminoma, choriocarcinoma, or embryonal carcinoma have not been found in association
with these tumors. I mmunohistochemical staining is dependent on the cell type: epithelial components are cytokeratin and
EMA positive; neuroepithelial components are N S E, CD 99, chromogranin, synaptophysin, glial fibrillary acidic protein, and
S -100 protein positive; mesenchymal components are vimentin positive and depending on cell types may be reactive for
450,451myogenic markers or smooth muscle actin. S inonasal malignant teratomas are highly malignant neoplasms with an
449average survival of less than 2 years. Recurrence of tumor is common with extensive local invasion. Metastasis occurs
primarily to cervical lymph nodes.
Miscellaneous Tumors
452,453Other malignant tumors that may arise in the sinonasal tract or nasopharynx include lipogenic neoplasms, synovial
454 455sarcoma, alveolar soft part sarcoma, peripheral (primitive) neuroectodermal tumor–extraosseous Ewing
456-459 460,461sarcoma, and endodermal sinus tumor.
Secondary Tumors
Metastatic tumors to the sinonasal tract and nasopharynx may represent the initial manifestation of disease or the first
known site of metastatic tumor. More often, metastasis to the upper aerodigestive tract is part of widely metastatic disease.
A lthough virtually every conceivable malignancy may metastasize to the upper aerodigestive tract, the most common
462-464primary tumor metastatic to this region is renal cell carcinoma.
Pseudoneoplastic Lesions
Sinonasal (Inflammatory) Polyps
S inonasal inflammatory polyps are nonneoplastic inflammatory swellings of the sinonasal mucosa. N o sex predilection is
seen; sinonasal polyps occur in all ages but are commonly seen in adults over 20 years of age and rarely seen in children
465younger than 5 years of age. The exception to this age restriction occurs in patients with cystic fibrosis, in whom nasal
466polyps develop in the first and second decades of life. Most polyps arise from the lateral nasal wall or from the ethmoid
recess. Polyps may be unilateral or bilateral, single or multiple. S ymptoms include nasal obstruction, rhinorrhea, and
467headaches. The triad of nasal polyps, asthma, and aspirin intolerance is well recognized. The etiology is linked to
multiple factors, including allergy, cystic fibrosis, infections, diabetes mellitus, and aspirin intolerance.
468A ntrochoanal polyps are sinonasal polyps specifically arising from the maxillary antrum. They represent approximately
4693% to 6% of all sinonasal polyps. A ntrochoanal polyps are more common in men than in women and primarily occur in
younger patients than those with nasal polyps. The majority of antrochoanal polyps are single, unilateral lesions with
associated nasal obstruction. Posterior extension from the maxillary sinus toward the nasopharynx may result in obstruction
of the nasopharynx and clinical suspicion of a primary nasopharyngeal tumor. A ntrochoanal polyps are often associated with
bilateral maxillary sinusitis and may also be associated with more typical sinonasal polyps. I n up to 40% of cases a
469,470documented history of allergies may exist.
S inonasal polyps are soft, fleshy, polypoid lesions with a myxoid or mucoid appearance. Polyps vary in size, ranging up to
several centimeters in diameter. A ntrochoanal polyps are identical to other nasal polyps except for the presence of a stalk
with aI achment to the maxillary sinus. Histologically, the surface epithelium is composed of intact respiratory epithelium
but may show squamous metaplasia. The basement membrane may be thickened and eosinophilic in appearance. The
stroma is markedly edematous and is noteworthy for the absence of mucoserous glands. A mixed chronic inflammatory cell
infiltrate is present and is predominantly composed of eosinophils, plasma cells, and lymphocytes. N eutrophils may
predominate in polyps of infectious origin. The stroma contains bland-appearing fibroblasts and small to medium-sized
blood vessels. S econdary changes include surface ulceration, fibrosis, infarction, granulation tissue, deposition of an
amyloid-like stroma, osseous and/or cartilaginous metaplasia, glandular hyperplasia, granuloma formation, and atypical
stromal cells. Granulomas result from ruptured mucous cysts or cholesterol granulomas or as a reaction to medicinal
intranasal injections (steroids) or inhalants. Atypical stromal cells can be seen in sinonasal and antrochoanal polyps but tend
to be more common in the laI er. These are bizarre-appearing cells with enlarged, pleomorphic and hyperchromatic nuclei,
indistinct to prominent nucleoli, and eosinophilic to basophilic cytoplasm (Fig. 4A-40). These cells tend to cluster near areas
of tissue injury (e.g., near thrombosed vascular spaces). These cells are of myofibroblastic origin and likely represent a
470component of wound healing.
471 472A prominent vascular component, variably termed angiomatous or angioectatic nasal polyps, may clinically and
histologically simulate a malignant tumor. These lesions may undergo infarction or be associated with acellular eosinophilic
472material simulating amyloid deposition.
A pproximately 50% of patients will have recurrence of their nasal polyps after surgery, recurrence rates being highest in465patients with aspirin intolerance and asthma. The development of functional endoscopic sinus surgery has contributed to
473decreasing the morbidity of sinonasal surgery and the recurrence of nasal polyposis in patients with cystic fibrosis and in
474-476improving sinonasal-related symptomatology for patients with asthma. A high recurrence rate also exists in
antrochoanal polyps, especially in patients with a history of allergies; endoscopic removal may result in a higher recurrence
477rate. Surgical removal of the polyp with its stalk markedly decreases the likelihood of recurrence.
Heterotopic Central Nervous System Tissue (Glial Heterotopias, Nasal Glioma)
Heterotopic central nervous system tissue (HCN S T) is thought to represent nonneoplastic displacement of neuroglial tissue
in extracranial sites. Glial heterotopias are generally considered to represent a variant of encephalocele in which the
communication to the central nervous system has closed, remains undetected, or has become fibrotic. A lthough these
lesions have been referred to as gliomas this may be a misnomer as they are not clearly neoplasms. HCN S T generally
478presents at birth or within the first few years of life, although any age group may be affected. I n the sinonasal tract and
nasopharynx, HCN S T most commonly occurs in and around the nasal cavity but may involve the ethmoid sinus,
148nasopharyngeal, and pharyngeal areas. S ubcutaneous lesions appear as a blue or red mass along the bridge of the nose.
I ntranasal lesions present with nasal obstruction, respiratory distress, epistaxis, septal deviation, cerebrospinal fluid
rhinorrhea, or meningitis. I ntranasal lesions may be confused with nasal polyps. Mixed extranasal and intranasal HCN S T
occurs and develops via a communication through a defect in the nasal bone. I n contrast to HCN S T, encephaloceles
represent herniation of brain tissue with direct continuity with the central nervous system tissue. Radiographic studies,
especially magnetic resonance imaging, are indicated to rule out a bony defect that may identify communication to the
479cranial cavity (encephalocele).
Histologically, HCN S T is composed of astrocytes and neuroglial fibers associated with a fibrous, vascularized connective
tissue (see Chapter 27). I n contrast to nasal lesions, those of the nasopharynx may include the presence of ependymal
148elements, as well as intracytoplasmic melanin. I mmunohistochemical reactivity will be identified with glial fibrillary
480acidic protein and S-100 protein. Rarely, recurrence or persistence of the lesion may be seen after excision.
Respiratory Epithelial Adenomatoid Hamartoma
Respiratory epithelial adenomatoid hamartoma is an uncommonly occurring benign nonneoplastic overgrowth of
indigenous glands of the nasal cavity, paranasal sinuses, and nasopharynx arising from the surface epithelium and devoid of
481,482ectodermal, neuroectodermal, and/or mesodermal elements. The majority of hamartomas of this region are of the
482 483,484pure epithelial type, and some are predominantly seromucinous. Mesenchymal hamartomas or mixed
epithelial481-483mesenchymal hamartomas may occur. Respiratory epithelial adenomatoid hamartomas predominantly occur in adult
patients with a decided male predominance; patients range in age from the third to ninth decades of life with a reported
482median age in the sixth decade of life. The majority of respiratory epithelial adenomatoid hamartomas occur in the nasal
cavity, in particular the posterior nasal septum; involvement of other intranasal sites occurs less often and may be identified
482along the lateral nasal wall, middle meatus, and inferior turbinate. Other sites of involvement include the nasopharynx,
ethmoid sinus, and frontal sinus. The majority of lesions are unilateral, but occasionally bilateral lesions may occur. Patients
present with nasal obstruction or stuffiness, deviated septum, epistaxis, and chronic (recurrent) rhinosinusitis. The
symptoms may occur over months to years.
481The hamartoma appears as a polypoid mass lesion with a slightly more indurated quality than an inflammatory polyp.
Histologically, these lesions are characterized by prominent widely spaced, small to medium-sized glands separated by
stromal tissue. I n areas the glands are seen arising in direct continuity with the surface epithelium, which invaginate
downward into the submucosa (Fig. 4A -41). The glands are round to oval, composed of multilayered ciliated respiratory
epithelium often with admixed mucin-secreting (goblet) cells. Glandular dilatation with mucus can be seen. A characteristic
finding is the presence of stromal hyalinization with envelopment of glands by a thick, eosinophilic basement membrane.
Atrophic glandular alterations may be present in which the glands are lined by a single layer of flaI ened to
cuboidalappearing epithelium. S mall reactive-appearing seromucinous glands can be seen. The stroma is edematous or fibrous,
containing a mixed chronic inflammatory cell infiltrate.FIGURE 4A-41 Respiratory epithelial adenomatoid hamartoma. A, These lesions originate from the
surface epithelium with invagination and proliferation of glands in the submucosa. B, The glands are lined
by ciliated respiratory epithelium with stromal hyalinization characteristically enveloping the adenomatous
proliferation; residual minor salivary glands are seen in and around the adenomatoid proliferation.
The differential diagnosis includes S chneiderian papillomas of the inverted type and adenocarcinomas. Limited but
481complete surgical resection is curative.
Teratoid Lesions (Nasopharyngeal Dermoid; Nasopharyngeal “Hairy Polyp”)
Teratoid lesions of the nasopharynx are developmental (congenital) anomalies rather than neoplastic lesions; they are
predominantly composed of ectodermal structures (e.g., skin) but may also include mesodermal structures (e.g., cartilage)
480but not endodermal or neuroectodermal components. The absence of endodermal-derived structures and the presence of
limited heterogeneity of tissue types argue against inclusion as a teratoma. That these lesions contain skin, a tissue type not
normally found in the nasopharynx, suggests that these lesions may be beI er classified as a choristoma rather than a
148,485,486hamartoma, and possibly of first branchial arch origin. S ome authors argue that these lesions are best classified
149as a subset of benign teratoma.
N asopharyngeal dermoids are polypoid, predominantly solid, but partially cystic lesions and may be pedunculated or
sessile. Histologically, a combination of various ectodermal and mesodermal tissues is seen, including skin (keratinizing
squamous epithelium), cutaneous adnexa, cartilage, bone, muscle (striated or smooth), and fibrous or mature adipose tissue.
These lesions are polypoid and covered by skin with identification of hair follicles and sebaceous glands within the
submucosa. I n addition, cartilage is identified. These histologic findings identified in a lesion of the ear have suggested to
some authors that these lesions are of branchial cleft origin, representing congenital accessory auricles, akin to accessory
486tragus. I n addition to cartilage, other tissue types found to a varying degree may include muscle (smooth and striated),
fibroadipose tissue, and vascular tissue.
Given the definition of these lesions as a nonneoplastic developmental anomaly, the differential diagnosis is primarily
with a teratoma. The absence of endodermally derived tissue and absence of the wide variety of tissue types usually seen in
teratoma will allow for distinction of these lesions. Simple surgical excision is curative.
Nasal and Sinonasal Hamartomas
N asal chondromesenchymal hamartoma is a tumefactive process of the sinonasal tract composed of an admixture of
487chondroid and stromal elements with cystic features that are analogous to chest wall hamartoma. These lesions have
some histologic similarities to respiratory epithelial adenomatoid hamartomas, and they may be within the spectrum of the
same type of lesion. They are distinguished, however, by mostly presenting in the neonatal age group and by a tendency to
487be larger and more aggressive than the respiratory epithelial adenomatoid hamartomas. Fewer than 30 cases have been
487-489reported to date. A male predilection is seen. Most of these lesions occur in newborns within the first 3 months of life
487,489but may occur in the second decade of life or later. Patients present with respiratory difficulty, and an intranasal mass
or facial swelling may be present. S ome of these tumors have eroded into the cranial cavity (through the cribriform plate
490area), a finding that may clinically simulate the appearance of a meningoencephalocele.
Histologically, these lesions are characterized by the presence of nodules of cartilage varying in size, shape, and contour.
Furthermore, the degree of differentiation varies with some nodules appearing similar to the chondromyxomatous nodules
of chondromyxoid fibroma whereas others consist of well-differentiated cartilage. A loose spindle cell stroma or abrupt
transition to hypocellular fibrous stroma is present at the periphery of the cartilaginous nodules. Other paI erns include a
myxoid to spindle cell stroma, fibroosseous proliferation with cellular stromal component, and ossicles or trabeculae of
immature (woven) bone. A dditional findings may include focal osteoclast-like giant cells in the stroma and erythrocyte-filled
487,491spaces resembling those of the aneurysmal bone cyst. Proliferating epithelial elements are not a prominent feature.
The chondromesenchymal elements are relatively cellular and “immature,” probably reflecting the immature age of most of
the patients. For these reasons, the lesions deserve recognition as a distinct clinicopathologic subgroup of nasal
The cartilaginous nodules show immunoreactivity for S -100 protein, and the spindle cell stroma shows immunoreactivity
for vimentin and smooth muscle actin.
Lymphangiomatous Polyp of the Tonsil (Lymphoid Polyp)
Lymphangiomatous polyps are nonneoplastic developmental lesions composed of tissue elements native to the nasopharynx492and categorized as a hamartoma. Lymphangiomatous polyps are considered uncommon. A n equal sex predilection exists;
492lesions occur over a wide age range from the first decade to the seventh decade with a mean age of occurrence at 25 years.
The clinical presentation includes dysphagia, sore throat, and the sensation of a mass lesion in the throat. S ymptoms may be
present from a few weeks to years. These lesions are unilateral. The majority are of palatine tonsil origin but occasionally
492may originate from the nasopharynx or from the nasopharyngeal tonsil (i.e., adenoids).
The majority of these lesions are polypoid or pedunculated with a smooth external surface and spongy to firm consistency
and on cut section have a white, tan, or yellow appearance, measuring from 0.5 to 3.8 cm in greatest dimension. S ome lesions
are sessile. The polyps are covered by squamous or respiratory epithelium, beneath which is a submucosal proliferation of
dilated lymphatic vascular channels and varying amounts of fibrous connective tissue. The vascular components are thin
walled and usually contain proteinaceous fluid and mature lymphocytes. I n addition, mature adipose tissue may be present,
and prominent fibrosis may dominate in any given lesion. S ome lesions may exclusively or predominantly papillary with a
lymphoid and edematous stroma.
A dditional findings that can be identified include epithelial hyperplasia, hyperkeratosis, and dyskeratosis without
492epithelial dysplasia and nested epitheliotropism. The laI er includes the presence of mature lymphocytes packed into
rounded intramucosal spaces.
The differential diagnosis includes nasopharyngeal (juvenile) angiofibroma, fibroepithelial polyps, papillomas, and
lymphangioma. N asopharyngeal (juvenile) angiofibroma is a nasopharyngeal-based lesion that occurs in adolescent boys,
that typically presents with epistaxis due to its rich blood supply, and that often aI ains large sizes with extensive growth and
even bone erosion. Histologically, nasopharyngeal angiofibromas have a cellular stroma composed of stellate fibroblasts and
staghorn-shaped thin-walled vascular structures, the laI er typically lacking or with an aI enuated smooth muscle
component. I n contrast to nasopharyngeal angiofibromas, the lymphangiomatous polyps may occur in women and tend to
have a relatively paucicellular fibrous stroma with a prominent lymphoid component.
27Rare examples of S chneiderian-type papillomas may occur in the pharynx (oropharynx and nasopharynx), but the
histology of the lesions contrasts so distinctly from the lymphangiomatous polyps that it makes differentiation
Lymphangiomas are neoplasms of endothelial-lined lymphatic spaces that are histologically characterized by the presence
of widely dilated and irregularly appearing vascular channels, features not usually associated with lymphangiomatous
Sinonasal and Nasopharyngeal Infectious Diseases
I nfectious diseases of the sinonasal tract and nasopharynx may clinically simulate the appearance of a neoplastic disease.
493,494 495S ome of the more common infections of these areas include fungal disease such as aspergillosis, rhinosporidiosis,
496 497and mucormycosis ; bacterial diseases such as rhinoscleroma and Pseudomonas aeruginosa causing a bacterial ball
498(botryomycosis) ; and mycobacterial diseases such as leprosy and tuberculosis. S arcoidosis, a noncaseating
granulomatous disease of uncertain etiology, may involve the nasal cavity as part of systemic involvement or as an isolated
499 500occurrence. In the immunocompromised patient, viral diseases such as herpes simplex, cytomegalovirus, and HIV and
501protozoa such as in microsporidiosis may produce ulcerative and/or mass lesions of the sinonasal cavity or nasopharynx
that clinically simulate a neoplasm (see later discussion). I nfectious mononucleosis is a systemic, benign, self-limiting
lymphoproliferative disease, caused by EBV, that may result in enlargement of the nasopharyngeal tonsils (adenoids) or
palatine tonsils that clinically and histologically simulates a neoplasm (i.e., malignant lymphoma). Very similar pathology
may be caused by other microorganisms, including Toxoplasma gondii, rubella, hepatitis A virus, and adenoviruses.
Myospherulosis, a pseudomycotic mass, is a reactive phenomenon that results from the alteration of red blood cells after
502interaction with petrolatum-based ointments found in surgical packing material.
Human Immunodeficiency Virus Infection of Waldeyer Tonsillar Tissues
HI V infection may first present clinically as enlargement of the lymphoid tissues of Waldeyer ring, including the tonsils and
500adenoids. These tissues are a major site of viral replication. Primary HI V infection results in a spectrum of
histopathologic changes that may represent the initial manifestation of HI V infection in otherwise asymptomatic patients.
The clinical enlargement of tonsillar and particularly nasopharyngeal lymphoid tissue (adenoids) may represent the earliest
500clinical manifestation of HI V. Clinically the enlargement may be unilateral and raise concern for a possible diagnosis of
The presence of HI V in these tissues causes a unique constellation of diagnostic features, including florid follicular
hyperplasia, follicle lysis, and productively HI V-infected multinucleated giant cells. S erologic evaluation is confirmatory of
HIV infection. The histomorphologic changes in HI V-induced tonsillar and adenoidal enlargement vary with the progression
of disease. I n the early stages of infection, the histomorphology may include florid follicular hyperplasia with and without
follicular fragmentation and follicle lysis with areas of follicular involution (Fig. 4A -42). A dditional findings included the
presence of monocytoid B-cell hyperplasia, paracortical and interfollicular zone expansion with immunoblasts and plasma
cells, interfollicular clusters of high endothelial venules, intrafollicular hemorrhage, and the presence of multinucleate giant
cells (see Fig. 4A -42). The giant cells characteristically cluster adjacent to or within the adenoidal surface epithelium or the
503tonsillar crypt epithelium. The origin of the giant cells is the subject of some debate and includes dendritic cell origin,
504activated macrophages or macrophage origin, and shared dendritic cell–associated antigens reflecting a common CD 34+
505bone marrow progenitor.FIGURE 4A-42 Human immunodeficiency virus (HIV) infection of the tonsils. A, Florid follicular
hyperplasia. B, Left panel, follicle lysis with attenuation and loss of mantle lymphocytes; right panel,
clustering of multinucleated giant cells near surface (and/or crypt) epithelium. C, HIV p24 immunoreactivity
confirms HIV infection.
The histologic features in patients with more advanced stages of disease contrast with those described earlier and
correlate with the lymphoid obliteration seen in the terminal stages of HI V infection or A I D S . I n these cases, effacement of
nodal architecture, loss of the normal lymphoid cell population with replacement by a benign plasma cell infiltrate, and the
presence of increased vascularity are seen. The multinucleate giant cells characteristically seen in the early and chronic
stages of disease are not identified in the more advanced stages of HIV infection.
Reactivity for HI V p24 (gag protein), an indicator of active HI V infection, is consistently identified in the early and chronic
stages of disease (see Fig. 4A-42). A nti-HI V p24 reactivity is seen within the follicular dendritic cell network of the germinal
centers, in scaI ered interfollicular lymphocytes, in the multinucleated giant cells, and within intraepithelial cells of crypt
epithelium. The HIV p24-positive intraepithelial cells are S-100 protein positive, and their morphologic appearance correlates
with the appearance of dendritic cells.
The patients in more advanced stages of disease, characterized by loss of germinal centers and the presence of a
predominant plasma cell infiltrate, show a relative absence of lymphoid cell markers (CD 45RB, CD 3, or OPD 4). I n these
cases, the plasma cell infiltrate shows reactivity with kappa and lambda light chains indicative of a benign proliferation.
Wegener Granulomatosis
WG is a systemic necrotizing vasculitis that typically involves the kidneys, lung, and upper aerodigestive tract. The classic
506,507definition of WG includes involvement of the head and neck region, the lung, and the kidney. I t should be noted that
the majority of patients with WG do not exhibit this classic clinical triad simultaneously at the time of initial presentation.
WG may present as an isolated disease confined to the sinonasal tract without systemic involvement; sinonasal involvement
508,509may represent the initial manifestation of systemic disease. The etiology of WG remains unknown.
WG may be systemic or limited (localized). The extent of disease is reflected in the clinical manifestations such thatlimited or localized disease may be asymptomatic whereas in systemic involvement the patient is always sick. Limited and
generalized WG likely represents a single disease; disease may progress from limited to systemic involvement or may
506remain limited or even regress with treatment. The ELK Classification of WG includes the following:
E = Ear, nose, and throat involvement
L = Lung involvement
K = Kidney involvement
Patients with E or EL disease are considered to have the limited form of WG, whereas patients with ELK disease
506correspond to systemic WG. The incidence of limited WG varies from 29% to 58%. Localized WG to the upper
aerodigestive tract tends to affect men more than women (except for laryngeal WG, which is predominantly a disease of
women). WG occurs over a wide age range with the average age of occurrence in the fourth and fifth decades of life. WG is
infrequent in patients younger than 10 years of age. I n the upper aerodigestive tract, the most common site of occurrence is
the sinonasal region with the nasal cavity > maxillary > ethmoid > frontal > sphenoid; other sites of involvement may include
the nasopharynx, larynx (subgloI is), oral cavity, ear (external and middle ear including the mastoid), and salivary glands.
WG of the sinonasal tract and nasopharyngeal may present with sinusitis with or without a purulent rhinorrhea, obstruction,
septal perforation, pain, epistaxis, anosmia, and headaches.
I mportant laboratory findings in WG include elevated antineutrophilic cytoplasmic antibody (A N CA) and proteinase 3
(PR3). WG is characteristically associated with cytoplasmic A N CA (C-A N CA) and only infrequently with perinuclear A N CA
508-510(P-ANCA). C-A N CA is of greater specificity than P-A N CA . The sensitivity of the test varies with the extent of
disease. Patients with limited WG have a 50% to 67% C-A N CA positivity, whereas patients with systemic WG have a 60% to
509,511 512100% positivity. A negative test does not rule out WG. A lthough identified in other vasculitides and in
513,514inflammatory bowel disease and hepatobiliary diseases, A N CA titers are elevated in WG but are not elevated in
infections or in lymphomas. PR3 is a neutral serine proteinase present in azurophil granules of human polymorphonuclear
leukocytes and monocyte lysosomal granules. PR3 serves as the major target antigen of A N CA s with a cytoplasmic staining
515-518 515paI ern (C-A N CA) in WG. A N CA with specificity for PR3 is characteristic for patients with WG. The detection of
A N CA directed against PR3 (PR3-A N CA) is highly specific for WG. A N CA positivity is found in only about 50% of the
patients with localized WG, whereas PR3-ANCA positivity is seen in 95% of the patients with generalized WG.
The head and neck manifestations of WG are dominated by nasal cavity and paranasal sinus involvement. The clinical
appearance is that of diffuse mucosal swelling with ulcerative and crusted lesions and tissue destruction; in advanced cases,
septal perforation may be seen resulting in a “saddle nose” deformity. I n view of the destructive nature of many lesions of
WG, clinical suspicion of malignancy is sometimes raised.
The histologic features include the classic triad of vasculitis, tissue necrosis, and granulomatous inflammation (which may
involve vessel walls, as well as the supporting tissues) (Fig. 4A-43). I n practice, however, it has become apparent that finding
all three of these “characteristic” features in a single biopsy specimen or even a series of biopsies is actually very
519uncommon. The presence of all three defining criteria in the same head and neck region biopsy is decidedly unusual and
519is seen in only 16% of biopsies from patients with proved WG. Vasculitis involving small to medium-sized arteries
consists of a polymorphous inflammatory infiltrate composed of lymphocytes and histiocytes and less often eosinophils and
polymorphonuclear leukocytes. N ecrosis is of “ischemic” or “geographic” type with a basophilic smudgy appearance.
Granulomatous inflammation in the form of scaI ered multinucleate giant cells is the typical appearance, and well-formed
granulomas generally are not a common finding in upper aerodigestive tract WG. The parenchymal inflammatory infiltrate
in WG is typically mixed, being composed of lymphocytes, histiocytes, plasma cells, and neutrophils; eosinophils, although
generally uncommon, may be numerous in an occasional case. Microabscess formation may be identified. N o cytologic
atypia is seen.FIGURE 4A-43 Wegener granulomatosis of the sinonasal tract. A, At low magnification the changes
include the presence of multifocal necrobiosis (“geographic or ischemic-type” necrosis) with a basophilic
smudgy appearance surrounding an obliterated vascular space in the center of the illustration. B, The
inflammatory infiltrate of Wegener granulomatous is polymorphous, composed of a variable admixture of
mature lymphocytes, plasma cells, histiocytes, eosinophils, and neutrophils without evidence of atypical or
overtly malignant cells; in all the illustrations are isolated multinucleated giant cells representing the
granulomatous component of the disease (“poor man” granuloma) because well-formed granulomas are
not typically identified in Wegener granulomatosis despite its designation as a granulomatous process. C,
Vasculitis, a potentially difficult finding on histology, is seen here with the inflammatory infiltrate
concentrically surrounding a blood vessel (angiocentric) and invades through the wall (angioinvasion) with
occlusive changes of the endothelial-lined lumen.
Elastic stains may assist in the identification of vasculitis (see Fig. 4A -43). Because WG is a diagnosis of exclusion, stains
for microorganisms should be performed but are invariably negative. I mmunohistochemical staining shows
immunoreactivity for both B-cell (L-26) and T-cell (UCHL) markers indicative of a benign (polyclonal) cellular population.
Because the histologic findings are often meager, a “negative” biopsy may be of liI le or no help in excluding WG. I f the
clinical findings are of relatively high concern, additional tissue biopsies may be indicated. I f the patient has been given
treatment with steroids before biopsy, this can suppress the histologic features and make the histologic diagnosis even more
difficult and problematic.
The key histologic differential diagnostic considerations are infectious and neoplastic. A granulomatous response to an
infectious process (e.g., fungal, mycobacterial, parasitic) must be ruled out. A s a result, the exclusion of infectious agents by
tissue stains and culture should form a part of the basic evaluation of all patients with suspected WG. A granulomatous
response to some foreign material (e.g., myospherulosis) likewise may be a consideration in some biopsies, and so
examination of the tissues for polarizable foreign material is recommended in all cases of suspected WG.
Because some sinonasal N K/T-cell lymphomas are angiocentric, the vessel infiltrate can be mistaken for the vasculitis of
WG (see Table 4A -14). The cytologic characteristics of the lymphoid infiltrate often permit distinction between the two
entities. I n general, the lymphoid infiltrates in WG lack an appreciable degree of cytologic atypia. Atypia is characteristic of
the tumor cells of malignant lymphoma. I n view of the fact that some degree of subjectivity may enter into the recognition of
lymphoid atypia by light microscopic features alone, demonstration of monoclonality by immunohistochemical or molecular
biologic studies may be helpful. Typically, the inflammatory infiltrate of WG will be polymorphic and show reactivity with
both B-cell and T-cell lineage markers. Furthermore, the presence of microabscesses and scaI ered giant cells of WG andelevated C-A N CA levels would not be expected with malignant lymphoma. Because the inflammatory infiltrate in WG can
include appreciable numbers of eosinophils, the question of Churg-S trauss granulomatosis may arise (see Table 4A -14).
Churg-S trauss disease (allergic granulomatosis and vasculitis) is characterized by asthma, systemic vasculitis, and tissue and
peripheral eosinophilia. These findings should assist in the differential diagnosis of WG. Because elevated A N CA levels
520,521have been reported in Churg-S trauss disease, this finding cannot be used to differentiate Churg-S trauss disease from
WG. I t should be kept in mind that Churg-S trauss disease is not expected to present clinically as a sinonasal disorder, and
the chance of this happening is extremely remote.
Extranodal Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman Disease)
S inus histiocytosis with massive lymphadenopathy (S HML) is an idiopathic, nodal-based histiocytic proliferative disorder
522-524that usually resolves spontaneously. I mmunophenotypic studies support the interpretation that the S HML cells are
part of the mononuclear phagocyte and immunoregulatory effector system belonging to the macrophage-histiocytic
525family. S HML may occur as part of a generalized process involving lymph nodes or may involve extranodal sites
526independent of lymph node status. The head and neck region is one of the extranodal areas more commonly affected by
524,526 526SHML. Within the head and neck, predilection is for the nasal cavity and paranasal sinuses. S inonasal tract
involvement results in a polypoid, nodular, or exophytic mass producing nasal obstruction and simulating a neoplasm. The
histopathologic features include the presence in the submucosa of lymphoid aggregates alternating with pale-appearing
areas composed of histiocytes, lymphocytes, and plasma cells diffusely involving the submucosa. The typical histiocytes or
S HML cells are characterized by round to oval, vesicular to hyperchromatic nuclei, with abundant amphophilic to
eosinophilic, granular, foamy to clear cytoplasm (Fig. 4A-44). The nuclei do not demonstrate nuclear lobation, indentation, or
longitudinal grooving as seen in Langerhans cell histiocytes. The histiocytes demonstrate emperipolesis. The phagocytized
cells usually are lymphocytes, but plasma cells, erythrocytes, and neutrophils can also be seen engulfed within the histiocytic
526-528 529cell cytoplasm. The S HML cells are diffusely S -100 protein positive (seeF ig. 4A-44). No ideal treatment exists. Rare
530 522,523deaths have been reported. The etiology for S HML remains obscure. A n infectious etiology has been suggested,
but an infectious agent has never been isolated. Other considerations implicated but never substantiated as the cause of
524SHML include immunodeficiency, autoimmune disease, or a neoplastic process.
FIGURE 4A-44 Extranodal sinus histiocytosis with massive lymphadenopathy of the sinonasal tract. A,
Submucosal diffuse inflammatory cell infiltrate with effacement of the normal submucosal structures; a
benign lymphoid aggregate is present to the right of center that in conjunction with the cellular infiltrate
has an architectural appearance reminiscent of that of lymph node parenchyma. B, At higher
magnification the infiltrate includes mature lymphocytes and plasma cells that somewhat obscure the
histiocytic cell infiltrate; the latter demonstrate phagocytization of mononuclear cells (emperipolesis).R e f e r e n c e s
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