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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.

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Date de parution 07 février 2020
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Diagnostic
Histopathology of
Tumors
FOURTH EDITION/VOLUME 1
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
Copyright
Contributors
Preface
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
References
Chapter 3 Vascular Tumors
Benign Tumors
Vascular Tumors of Intermediate Malignancy
Malignant Vascular Tumors
Tumors of Lymph Vessels
Tumors of Perivascular Cells
References
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
References
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
References
Chapter 5 Tumors of the Lung and Pleura
Classification
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
References
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
Epithelium
Malignant Odontogenic Neoplasms
Odontogenic Cysts
References
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
References
Chapter 8 Tumors of the Esophagus and Stomach
Esophagus
Stomach
References
Chapter 9 Tumors of the Small and Large Intestines, Including Anal Canal
Small Intestine
AppendixLarge Intestine
Anal Canal
Anal Margin
References
Chapter 10 Tumors of the Liver, Biliary Tree, and Gallbladder
Liver
Biliary Tree
Gallbladder
References
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
Pancreatoblastoma
Solid Pseudopapillary Neoplasm
Tumors in Infants and Children
Nonepithelial Tumors and Secondary Tumors
Tumor-like Lesions
References
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
References
Benign Tumors and Tumor-like Lesions
Urothelial Carcinoma
Squamous Cell Carcinoma
Adenocarcinoma
Small Cell Carcinoma
Other Tumors
References
Bladder
Urethra
References
Chapter 13 Tumors of the Female Genital Tract
Tumors of the Ovary
Tumors of the Fallopian Tube
Tumors of the Broad and Round Ligaments
References
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
References
Placental Chorangioma
Other Rare, Benign Placental Tumors
Fetal Malignancies Identified in the PlacentaMaternal Metastatic Tumors in the Placenta
Gestational Trophoblastic Disease
References
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
References
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
References
Epithelial Tumors
Mesenchymal Neoplasia and Tumor-Like Conditions
Mixed Epithelial–mesenchymal Neoplasia
Melanocytic Lesions
Lymphoid and Hematopoietic Tumors
Other Rare Tumors
Metastatic Tumors
References
Squamous Neoplasia
Glandular NeoplasiaMelanocytic Lesions
mesenchymal Lesions
Other Rare Neoplasms
References
Chapter 14 Tumors and Tumor-like Conditions of the Male Genital Tract
Prostate
Tumors and Tumor-Like Conditions of theSeminal Vesicles
References
Tumors and Tumor-like Conditions of the Testes
Tumors and Tumor-like Conditions of Paratesticular Tissues
References
Penis
Scrotum
References
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
References
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
Carcinoma
Myoepithelial Neoplasms
Stromal Tumors
Nonintrinsic Tumors
References
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
References
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
Hyperparathyroidism
Parathyroid Adenoma
Parathyroid Carcinoma
Atypical Parathyroid Adenoma
Other Tumors
Intraoperative Diagnosis for Hyperparathyroidism
References
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
Pheochromocytoma
Myelolipoma
Malignant Lymphoma and Plasmacytoma
Malignant Melanoma
Other Unusual Primary Adrenal Tumors
Tumors Metastatic to the Adrenal Gland
References
Chapter 20 Tumors of the Endocrine Pancreas
Terminology and Classification
Etiology, Pathogenesis, and Genetics
Epidemiology
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
References
The Normal Spleen
Patterns of Splenic Involvement in Lymphomas and Leukemias: Approach to
Diagnosis
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
References
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
References
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
References
Chapter 23 Tumors of the Skin
Tumors of the Epidermis
Adnexal Tumors
Cutaneous Cysts
Merkel Cell (Neuroendocrine) Carcinoma
Melanocytic Tumors
Mesenchymal Tumors
Lymphoid Tumors
Metastasis
References
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
References
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
References
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
References
Chapter 27 Peripheral Neuroectodermal Tumors
Reactive Lesions
Hamartomatous Lesions
Benign nerve sheath Tumors
Malignant Tumors
Miscellaneous Neuroectodermal Tumors Presenting in Soft Tissue
References
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
Ganglioneuroma
References
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
References
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
References
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
Conclusion
References
IndexCopyright

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DIAGNOSTIC HISTOPATHOLOGY OF TUMORS
Volume 1 PN 9996090442
FOURTH EDITION
Volume 2 PN 9996090388
Two-volume set ISBN: 978-1-4377-1534-7
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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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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,
California
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
Tumors
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,
Minnesota
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
Paraganglia
Gregory Y. Lauwers MD, Professor of Pathology, Harvard Medical School; Vice
Chairman, Department of Pathology, Massachusetts General Hospital, Boston,
Massachusetts
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,
Massachusetts
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
Kingdom
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
Kingdom
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
Paraganglia
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
King.
Christopher D.M. Fletcher
Boston, 2012Volume 1
O U T L I N E
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
publication!
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
pathologists.
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
likewise.
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
diagnosis.
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
CHA P T E R OUT LINE
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.
TABLE 2-1
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
Rhabdomyosar
coma
Leiomyosarco
ma
Malignant
mesothelio
ma
Lymphoma
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
Association
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
worldwide)
Rhabdomyoma3 Tuberous sclerosis TSC1/TSC2 9q34/16p13 AD (1/3), 1 in 6000 (at ~90
sporadic birth)
(2/3)
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
SDHC 1q21 SDHC (FPPS)
SDHD 11q23 SDHD
Histiocytoid H1CMP Multiple Mitochondrial AR, X-linked Rare ~100
cardiomyopathy8,9 mitochondrial DNA and and
DNA genomic maternal
mutations locations
and
chromosomal
aberrations
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:
215230
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
Myxoma
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.
TABLE 2-3
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
Myxomas
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.
TABLE 2-4
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.
Histopathology
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
manipulation.
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.
Immunohistochemistry
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.
TABLE 2-5
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.
Rhabdomyoma
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
chambers.
Histopathology
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).
Immunohistochemistry
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
93syndromes.
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.
Histopathology
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.
Immunohistochemistry
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
morphology.
FIGURE 2-35 A and B, Lipomatous hypertrophy of the tricuspid valve.
Histopathology
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)
Histopathology
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
cores.
Immunohistochemistry
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.
Histopathology
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.
Histopathology
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.
Hemangiomas
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.
Histopathology
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.
Histopathology
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)
Histopathology
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
78fashion.
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
209-213diverse.
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.
Histopathology
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)
Histopathology
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
217emboli.
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.
Histopathology
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).
Immunohistochemistry
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.
TABLE 2-6
O ther B enign T umors and H eterotopias R eported in the H eartAdenomatoid tumor228
Granular cell tumor
Neurofibroma
Inflammatory myofibroblastic tumor229
Tumor of perivascular epithelioid cells (PEComa)230
Thymic rests231
Thyroid rests232
Vasculitis233-235
Malignant Tumors of the Heart and Pericardium
Introduction
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.
TABLE 2-7
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
Liposarcoma166
Chondrosarcoma166
Osteosarcoma166
Malignant peripheral nerve sheath tumor41,166
Malignant germ cell tumors41,166
Erdheim-Chester disease238,239
Sinus histiocytosis with massive lymphadenopathy240
Angiosarcoma
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.
Histopathology
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).
Immunohistochemistry
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.
Histopathology
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.
Rhabdomyosarcoma
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
variegation.
Histopathology
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
differentiation.
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.
Histopathology
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.
Mesothelioma
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.
Histopathology
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.
References
1. Reynen K. Cardiac myxomas. N Engl J Med. 1995;333:1610–1617.
2. Bjessmo S, Ivert T. Cardiac myxoma: 40 years’ experience in 63 patients. Ann Thorac Surg. 1997;63:697–700.
3. Yokomuro H, Yoshihara K, Watanbe Y, et al. The variations in the immunologic features and interleukin-6 levels for the
surgical treatment of cardiac myxomas. Surg Today. 2007;37:750–753.
4. Hedinger C. [Combination of heart myxoma with primary nodular adrenal cortex dysplasia, spot-shaped skin pigmentation
and myxoma-like tumors in other locations—a rare familial symptom complex (“Swiss syndrome”)]. Schweiz Med Wochenschr.
1987;117:591–594.
5. Schweizer-Cagianut M, Froesch ER, Hedinger C. Familial Cushing's syndrome with primary adrenocortical microadenomatosis
(primary adrenocortical nodular dysplasia). Acta Endocrinol (Copenh). 1980;94:529–535.
6. McCarthy PM, Piehler JM, Schaff HV, et al. The significance of multiple, recurrent, and “complex” cardiac myxomas. J Thorac
Cardiovasc Surg. 1986;91:389–396.
7. Meyer BJ, Weber R, Jenzer HR, et al. Rapid growth and recurrence of atrial myxomas in two patients with Swiss syndrome. Am
Heart J. 1990;120:220–222.
8. Martin LW, Wasserman AG, Goldstein H, et al. Multiple cardiac myxomas with multiple recurrences: unusual presentation of
a “benign” tumor. Ann Thorac Surg. 1987;44:77–78.
9. Kotani K, Matsuzawa Y, Funahashi T, et al. Left atrial myxoma metastasizing to the aorta, with intraluminal growth causing
renovascular hypertension. Cardiology. 1991;78:72–77.
10. Oemus K, Rath FW. [Subcutaneous metastasis of an atrial myxoma? Case report and literature review]. Zentralbl Allg Pathol.
1990;136:189–197.
11. Panossian DH, Marais GE, Marais HJ. Familial endocrine myxolentiginosis. Clin Cardiol. 1995;18:675–678.
12. Carney JA, Gordon H, Carpenter PC, et al. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine
(Baltimore). 1985;64:270–283.
13. Carney JA. Carney complex: the complex of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas. Semin
Dermatol. 1995;14:90–98.
14. Wold LE, Lie JT. Cardiac myxomas: a clinicopathologic profile. Am J Pathol. 1980;101:219–240.
15. Molina JE, Edwards JE, Ward HB. Primary cardiac tumors: experience at the University of Minnesota. Thorac Cardiovasc Surg.
1990;38(Suppl 2):183–191.
16. Blondeau P. Primary cardiac tumors—French studies of 533 cases. Thorac Cardiovasc Surg. 1990;38(Suppl 2):192–195.
17. Sezai Y. Tumors of the heart. Incidence and clinical importance of cardiac tumors in Japan and operative technique for large
left atrial tumors. Thorac Cardiovasc Surg. 1990;38(Suppl 2):201–204.
18. Li GY. Incidence and clinical importance of cardiac tumors in China—review of the literature. Thorac Cardiovasc Surg.
1990;38(Suppl 2):205–207.
19. Becker AE. Cardiac myxoma. Eur J Cardiol. 1973;1:119–122.
20. Burke AP, Virmani R. Cardiac myxoma. A clinicopathologic study. Am J Clin Pathol. 1993;100:671–680.
21. Pessotto R, Santini F, Piccin C, et al. Cardiac myxoma of the tricuspid valve: description of a case and review of the literature. J
Heart Valve Dis. 1994;3:344–346.
22. Cole DJ, Hendren WG, Sink JD, et al. Myxoma attached solely to the tricuspid valve. Am J Cardiol. 1989;64:546–547.
23. Sharma SC, Kulkarni A, Bhargava V, et al. Myxoma of tricuspid valve. J Thorac Cardiovasc Surg. 1991;101:938–940.
24. Kulshrestha P, Rousou JA, Tighe DA. Mitral valve myxoma: a case report and brief review of the literature. J Heart Valve Dis.
1995;4:196–198.
25. Lie JT. Petrified cardiac myxoma masquerading as organized atrial mural thrombus. Arch Pathol Lab Med. 1989;113:742–745.
26. Ferrans VJ, Roberts WC. Structural features of cardiac myxomas. Histology, histochemistry, and electron microscopy. Hum
Pathol. 1973;4:111–146.
27. Goldman BI, Frydman C, Harpaz N, et al. Glandular cardiac myxomas. Histologic, immunohistochemical, and ultrastructural
evidence of epithelial differentiation. Cancer. 1987;59:1767–1775.
28. Johansson L. Histogenesis of cardiac myxomas. An immunohistochemical study of 19 cases, including one with glandular
structures, and review of the literature. Arch Pathol Lab Med. 1989;113:735–741.
29. Orr JW. Endothelioma (pseudomyxoma) of the heart. J Pathol Bacteriol. 1942;54:125–128.
30. Kawano H, Sueyoshi N, Kawai S, et al. The Gamna-Gandy body in cardiac myxoma. Cardiovasc Pathol. 1993;2:93–96.
31. Lie JT. Gamna-Gandy body of the heart: petrified cardiac myxoma mimicking atrial thrombus. Cardiovasc Pathol. 1993;2:97–98.
32. Schultrich S. [Histogenesis of cardiac myxoma based on a myxoma with glandular structures]. Pathologe. 1990;11:220–223.
33. Pucci A, Barotoloni G, Tessitore E, et al. Cytokeratin profile and neuroendocrine cells in the glandular component of cardiac
myxoma. Virchows Arch. 2003;443:618–624.
34. Mohr HJ, Kolmeier KH. [Fibro-adenomatous, mucousforming hamartoma in the right cardiac ventricle]. Zentralbl Allg Pathol.
1959;100:142–149.
35. Vacek R. [Intracardial hamartoblastoma.]. Zentralbl Allg Pathol. 1963;104:383–391.
36. Suvarna SK, Royds JA. The nature of the cardiac myxoma. Int J Cardiol. 1996;57:211–216.
37. Loire R, Termet H. [Recurrence of intracardiac myxoma. A propos of 6 patients among 85 surgically treated]. Ann Cardiol
Angeiol (Paris). 1991;40:1–7.
38. Gerbode F, Kerth WJ, Hill JD. Surgical management of tumors of the heart. Surgery. 1967;61:94–101.
39. Kabbani SS, Cooley DA. Atrial myxoma. Surgical considerations. J Thorac Cardiovasc Surg. 1973;65:731–737.
40. Loire R. [Is there a carcinologic malignant potentiality of cardiac myxoma?]. Arch Mal Coeur Vaiss. 1991;84:395–399.
41. McAllister HA, Fenoglio JJ Jr. Tumors of the cardiovascular system. Atlas of tumor pathology. Armed Forces Institute of
Pathology: Washington, D.C.; 1978.42. Kasugai T, Sakurai M, Yutani C, et al. Sequential malignant transformation of cardiac myxoma. Acta Pathol Jpn. 1990;40:687–692.
43. Scarpelli M, Montironi R, Ricciuti R, et al. Cardiac myxoma with glandular elements metastatic to the brain 12 years after the
removal of the original tumor. Clin Neuropathol. 1997;16:190–194.
44. Kusumi T, Minakawa M, Fukui K, et al. Cardiac tumor comprising two components including typical myxoma and atypical
hypercellularity suggesting a malignant change. Cardiovasc Pathol. 2009;18:369–374.
45. Terracciano LM, Mhawech P, Suess K, et al. Calretinin as a marker for cardiac myxoma. Diagnostic and histogenetic
considerations. Am J Clin Pathol. 2000;114:754–759.
46. Abenoza P, Sibley RK. Cardiac myxoma with glandlike structures. An immunohistochemical study. Arch Pathol Lab Med.
1986;110:736–739.
47. Laya MB, Mailliard JA, Bewtra C, et al. Malignant fibrous histiocytoma of the heart. A case report and review of the literature.
Cancer. 1987;59:1026–1031.
48. Tazelaar HD, Locke TJ, McGregor CG. Pathology of surgically excised primary cardiac tumors. Mayo Clin Proc. 1992;67:957–965.
49. Vaideeswar P, Butany JW. Benign cardiac tumors of the pluripotent mesenchyme. Semin Diagn Pathol. 2008;25:20–28.
50. Burke A, Jeudy J Jr, Virmani R. Cardiac tumours: an update: cardiac tumours. Heart. 2008;94:117–123.
51. Richkind KE, Wason D, Vidaillet HJ. Cardiac myxoma characterized by clonal telomeric association. Genes Chromosomes Cancer.
1994;9:68–71.
52. Dijkhuizen T, van den Berg E, Molenaar WM, et al. Rearrangements involving 12p12 in two cases of cardiac myxoma. Cancer
Genet Cytogenet. 1995;82:161–162.
53. Aktoz M, Tatli E, Ege T, et al. Cardiac rhabdomyoma in an adult patient presenting with right ventricular outflow tract
obstruction. Int J Cardiol. 2008;130:e105–e107.
54. Yu GH, Kussmaul WG, DiSesa VJ, et al. Adult intracardiac rhabdomyoma resembling the extracardiac variant. Hum Pathol.
1993;24:448–451.
55. Burke AP, Gatto-Weis C, Griego JE, et al. Adult cellular rhabdomyoma of the heart: a report of 3 cases. Hum Pathol.
2002;33:1092–1097.
56. Fenoglio JJ Jr, McAllister HA, Ferrans VJ. Cardiac rhabdomyoma: a clinicopathologic and electron microscopic study. Am J
Cardiol. 1976;38:241–251.
57. Geva T, Santini F, Pear W, et al. Cardiac rhabdomyoma. Rare cause of fetal death. Chest. 1991;99:139–142.
58. Bohm N, Krebs G. Solitary rhabdomyoma of the heart. Clinically silent case with sudden, unexpected death in an 11-month-old
boy. Eur J Pediatr. 1980;134:167–172.
59. Grellner W, Henssge C. Multiple cardiac rhabdomyoma with exclusively histological manifestation. Forensic Sci Int. 1996;78:1–5.
60. Chao AS, Chao A, Wang TH, et al. Outcome of antenatally diagnosed cardiac rhabdomyoma: case series and a meta-analysis.
Ultrasound Obstet Gynecol. 2008;31:289–295.
61. Smith HC, Watson GH, Patel RG, et al. Cardiac rhabdomyomata in tuberous sclerosis: their course and diagnostic value. Arch
Dis Child. 1989;64:196–200.
62. Bosi G, Lintermans JP, Pellegrino PA, et al. The natural history of cardiac rhabdomyoma with and without tuberous sclerosis.
Acta Paediatr. 1996;85:928–931.
63. Davies MJ. Tumours of the heart and pericardium. Pomerance A, Davies MJ. The pathology of the heart. Blackwell, Oxford:
United Kingdom; 1975:423–440.
64. Wallace G, Smith HC, Watson GH, et al. Tuberous sclerosis presenting with fetal and neonatal cardiac tumours. Arch Dis Child.
1990;65(4 Spec No):377–379.
65. Fine G. Primary tumors of the pericardium and heart. Edwards JE, Lev M, Abell MR. The heart. Williams & Wilkins: Baltimore;
1974:189–210.
66. Matsuoka Y, Nakati T, Kawaguchi K, et al. Disappearance of a cardiac rhabdomyoma complicating congenital mitral
regurgitation as observed by serial two-dimensional echocardiography. Pediatr Cardiol. 1990;11:98–101.
67. Farooki ZQ, Ross RD, Paridon SM, et al. Spontaneous regression of cardiac rhabdomyoma. Am J Cardiol. 1991;67:897–899.
68. Nir A, Tajik AJ, Freeman WK, et al. Tuberous sclerosis and cardiac rhabdomyoma. Am J Cardiol. 1995;76:19–21.
69. DiMario FJ Jr, Diana D, Leopold H, et al. Evolution of cardiac rhabdomyoma in tuberous sclerosis complex. Clin Pediatr (Phila).
1996;35:615–619.
70. Fenoglio JJ Jr, Diana DJ, Bowen TE, et al. Ultrastructure of a cardiac rhabdomyoma. Hum Pathol. 1977;8:700–706.
71. Bruni C, Prioleau PG, Ivey HH, Nolan SP. New fine structural features of cardiac rhabdomyoma: report of a case. Cancer.
1980;46:2068–2073.
72. Green AJ, Johnson PH, Yates JR. The tuberous sclerosis gene on chromosome 9q34 acts as a growth suppressor. Hum Mol
Genet. 1994;3:1833–1834.
73. Green AJ, Smith M, Yates JR. Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients.
Nat Genet. 1994;6:193–196.
74. Pillai R, Kharma N, Brom G, et al. Mitral valve origin of pedunculated rhabdomyomas causing subaortic stenosis. Am J Cardiol.
1991;67:663–664.
75. Schmincke A. [Congenital cardiac hypertrophy, caused by diffuse rhabdomyombildung]. Beitr Pathol Anat. 1922;70:513–515.
76. Shrivastava S, Jacks JJ, White RS, et al. Diffuse rhabdomyomatosis of the heart. Arch Pathol Lab Med. 1977;101:78–80.
77. Steinbiss W. [To the knowledge of rhabdomyoma of the heart and its relationship to brain tuberose sclerosis]. Virchows Arch
Path Anat. 1923;243:22–38.
78. Travis WD, Brambilla E, Muller-Hermelink HK, et al. Pathology and genetics of tumours of the lung, pleura, thymus and heart. World
Health Organization classification of tumours. IARC Press: Lyon, France; 2004 [p 344].
79. Weeks DA, Chase DR, Malott RL, et al. HMB45 staining in angiomyolipoma, cardiac rhabdomyoma, other mesenchymal
processes and tuberous sclerosis-associated brain lesions. Int J Surg Pathol. 1994;1:191–197.
80. Burke AP, Virmani R. Cardiac rhabdomyoma: a clinicopathologic study. Mod Pathol. 1991;4:70–74.
81. Wu SS, Collins MH, de Chadarevian JP. Study of the regression process in cardiac rhabdomyomas. Pediatr Dev Pathol.
2002;5:29–36.
82. Burke AP, Rosado-de-Christenson M, Templeton PA, et al. Cardiac fibroma: clinicopathologic correlates and surgical
treatment. J Thorac Cardiovasc Surg. 1994;108:862–870.
83. Cotton JL, Kavey RE, Palmier CE, et al. Cardiac tumors and the nevoid basal cell carcinoma syndrome. Pediatrics. 1991;87:725–
728.
84. Coffin CM. Congenital cardiac fibroma associated with Gorlin syndrome. Pediatr Pathol. 1992;12:255–262.
85. Gorlin RJ. Nevoid basal-cell carcinoma syndrome. Medicine (Baltimore). 1987;66:98–113.
86. Littler BO. Gorlin's syndrome and the heart. Br J Oral Surg. 1979;17:135–146.87. Harris SA, Large DM. Gorlin's syndrome with a cardiac lesion and jaw cysts with some unusual histological features. A case
report and review of the literature. Int J Oral Surg. 1984;13:59–64.
88. Jones KL, Wolf PL, Jensen P, et al. The Gorlin syndrome: a genetically determined disorder associated with cardiac tumor. Am
Heart J. 1986;111:1013–1015.
89. Scanlan D, Radio SJ, Nelson M, et al. Loss of the PTCH1 gene locus in cardiac fibroma. Cardiovasc Pathol. 2008;17:93–97.
90. Ferguson HL, Hawkins EP, Cooley LD. Infant cardiac fibroma with clonal t(1;9)(q32;q22) and review of benign fibrous tissue
cytogenetics. Cancer Genet Cytogenet. 1996;87:34–37.
91. Viswanathan S, Gibbs JL, Roberts P. Clonal translocation in a cardiac fibroma presenting with incessant ventricular tachycardia
in childhood. Cardiol Young. 2003;13:101–102.
92. Reddy JK, Schimke RN, Chang CH, et al. Beckwith-Wiedemann syndrome. Wilms’ tumor, cardiac hamartoma, persistent
visceromegaly, and glomeruloneogenesis in a 2-year-old boy. Arch Pathol. 1972;94:523–532.
93. Marci M, Ziino O, D’Angelo P, et al. Fibroma of the left ventricle in a patient with Sotos syndrome. Echocardiography.
2001;18:171–173.
94. Tahernia AC, Bricker JT, Ott DA. Intracardiac fibroma in an asymptomatic infant. Clin Cardiol. 1990;13:506–512.
95. Van der Hauwaert LG, Corbeel L, Maldague P. Fibroma of the right ventricle producing severe tricuspid stenosis. Circulation.
1965;32:451–456.
96. Feldman PS, Meyer MW. Fibroelastic hamartoma (fibroma) of the heart. Cancer. 1976;38:314–323.
97. Gotlieb AI. Cardiac fibromas. Semin Diagn Pathol. 2008;25:17–19.
98. Turi GK, Albala A, Fenoglio JJ Jr. Cardiac fibromatosis: an ultrastructural study. Hum Pathol. 1980;11:577–580.
99. Churg AM, Kahn LB. Myofibroblasts and related cells in malignant fibrous and fibrohistiocytic tumors. Hum Pathol.
1977;8:205–218.
100. Bertolini P, Meisner H, Paek SU, et al. Special considerations on primary cardiac tumors in infancy and childhood. Thorac
Cardiovasc Surg. 1990;38(Suppl 2):164–167.
101. Miller DV, Edwards WD. Cardiovascular tumor-like conditions. Semin Diagn Pathol. 2008;25:54–64.
102. Reiner L, Mazzoleni A, Rodriguez FL. Statistical analysis of the epicardial fat weight in human hearts. AMA Arch Pathol.
1955;60:369–373.
103. Rokey R, Mulvagh SL, Cheirif J, et al. Lipomatous encasement and compression of the heart: antemortem diagnosis by cardiac
nuclear magnetic resonance imaging and catheterization. Am Heart J. 1989;117:952–953.
104. Verkkala K, Kupari M, Maamies T, et al. Primary cardiac tumours—operative treatment of 20 patients. Thorac Cardiovasc Surg.
1989;37:361–364.
105. Reece IJ, Cooley DA, Frazier OH, et al. Cardiac tumors. Clinical spectrum and prognosis of lesions other than classical benign
myxoma in 20 patients. J Thorac Cardiovasc Surg. 1984;88:439–446.
106. Li J, Ho SY, Becker AE, et al. Multiple cardiac lipomas and sudden death: a case report and literature review. Cardiovasc Pathol.
1998;7:51–55.
107. Estevez JM, Thompson DS, Levinson JP. Lipoma of the heart. Review of the literature and report of two autopsied cases. Arch
Pathol. 1964;77:638–642.
108. Pansard Y, Hvass U, de Brux JL, et al. [Lipoma of the right ventricle. Clinical, echocardiographic, angiographic and anatomic
aspects]. Ann Chir. 1985;39:403–407.
109. Harada K, Seki I, Kobayashi H, et al. Lipoma of the heart in a child. Clinical, echocardiographic, angiographic, and pathological
features. Jpn Heart J. 1980;21:903–910.
110. Pilichowski P, Wolf JE, Delgove L, et al. [Lipoma of the left ventricle. A surgically treated case]. Ann Chir. 1987;41:85–88.
111. Bellin J, Lermuziaux M, Fabiani JN, et al. [Lipoma of the heart. Apropos of a case and review of the literature]. Ann Chir.
1987;41:405–410.
112. Anderson DR, Gray MR. Mitral incompetence associated with lipoma infiltrating the mitral valve. Br Heart J. 1988;60:169–171.
113. Reynen K, Rein J, Wittekind C, et al. Surgical removal of a lipoma of the heart. Int J Cardiol. 1993;40:67–68.
114. Wajon E M C J, Jaarsma W, Knaepen PJ, et al. Lipoma of the heart. Neth J Cardiol. 1992;2:63–67.
115. Cunningham KS, Veinot JP, Feindel CM, Butany J. Fatty lesions of the atria and interatrial septum. Hum Pathol. 2006;37:1245–
1251.
116. Page DL. Lipomatous hypertrophy of the cardiac interatrial septum: its development and probable clinical significance. Hum
Pathol. 1970;1:151–163.
117. Burke AP, Litovsky S, Virmani R. Lipomatous hypertrophy of the atrial septum presenting as a right atrial mass. Am J Surg
Pathol. 1996;20:678–685.
118. Soft tissue tumours. Enzinger FM, Weiss SW. Mosby: St. Louis; 1988:301–345.
119. Murphy ES, Fujii Y, Yasuda A, et al. The tuberous sclerosis complex; a study of a new case. AMA Arch Pathol. 1958;65:166–173.
120. Lie JT. Cardiac, pulmonary, and vascular involvements in tuberous sclerosis. Ann N Y Acad Sci. 1991;615:58–70.
121. Heggtveit HA, Fenoglio JJ Jr, McAllister HA Jr. Lipomatous hypertrophy of the interatrial septum: an assessment of 41 cases.
Lab Invest. 1976;34:318.
122. Bhattacharjee M, Neligan MC, Dervan P. Lipomatous hypertrophy of the interatrial septum: an unusual intraoperative finding.
Br Heart J. 1991;65:49–50.
123. Corbi P, Jebara V, Fabiani JN, et al. [The benign tumors of the heart (excluding myxoma). Experience with nine surgically
treated cases]. Ann Cardiol Angeiol (Paris). 1990;39:433–436.
124. Crotty TB, Edwards WD, Oh JK, et al. Lipomatous hamartoma of the tricuspid valve: echocardiographic-pathologic
correlations. Clin Cardiol. 1991;14:262–266.
125. Behnam R, Williams G, Gerlis L, et al. Lipoma of the mitral valve and papillary muscle. Am J Cardiol. 1983;51:1459–1460.
126. Kindblom LG, Svensson U. Multiple hibernomas of the heart. A case report. Acta Pathol Microbiol Scand A. 1977;85A:122–126.
127. Heifetz SA, Parikh SR, Brown JW. Hibernoma of the pericardium presenting as pericardial effusion in a child. Pediatr Pathol.
1990;10:575–580.
128. Deodhar AP, Tometzki AJP, Hudson AN, et al. Aortic valve tumor causing acute myocardial infarction in a child. Ann Thorac
Surg. 1997;64:1482–1484.
129. Chang YS, Chu PH, Jung SM, et al. Unusual cardiac papillary fibroelastoma in the right ventricular outflow tract. Cardiovasc
Pathol. 2005;14:104–106.
130. de Menezes IC, Fragata J, Martins FM. Papillary fibroelastoma of the mitral valve in a 3-year-old child: case report. Pediatr
Cardiol. 1996;17:194–195.
131. Klarich KW, Enriquez-Sarano M, Gura GM, et al. Papillary fibroelastoma: echocardiographic characteristics for diagnosis and
pathologic correlation. J Am Coll Cardiol. 1997;30:784–790.132. Sun JP, Asher CR, Yang XS, et al. Clinical and echocardiographic characteristics of papillary fibroelastomas: a retrospective
and prospective study in 162 patients. Circulation. 2001;103:2687–2693.
133. Almagro UA, Perry LS, Choi H, et al. Papillary fibroelastoma of the heart. Report of six cases. Arch Pathol Lab Med.
1982;106:318–321.
134. Bedi HS, Sharma VK, Mishra M, et al. Papillary fibroelastoma of the mitral valve associated with rheumatic mitral stenosis. Eur
J Cardiothorac Surg. 1995;9:54–55.
135. Kalman JM, Lubicz S, Brennan JB, et al. Multiple cardiac papillary fibroelastomas and rheumatic heart disease. Aust N Z J Med.
1991;21:744–746.
136. Kurup AN, Tazelaar HD, Edwards WD, et al. Iatrogenic cardiac papillary fibroelastoma: a study of 12 cases (1990 to 2000). Hum
Pathol. 2002;33:1165–1169.
137. McFadden PM, Lacy JR. Intracardiac papillary fibroelastoma: an occult cause of embolic neurologic deficit. Ann Thorac Surg.
1987;43:667–669.
138. Gowda RM, Khan IA, Nair CK, et al. Cardiac papillary fibroelastoma: a comprehensive analysis of 725 cases. Am Heart J.
2003;146:404–410.
139. Valente M, Basso C, Thiene G, et al. Fibroelastic papilloma: a not-so-benign cardiac tumour. Cardiovasc Pathol. 1992;1:161–166.
140. Wolfe JT III, Finck SJ, Safford RE, et al. Tricuspid valve papillary fibroelastoma: echocardiographic characterization. Ann
Thorac Surg. 1991;51:116–118.
141. Butterworth JS, Poindexter CA. Papilloma of cusp of the aortic valve. Report of a patient with sudden death. Circulation.
1973;48:213–215.
142. Topol EJ, Biern RO, Reitz BA. Cardiac papillary fibroelastoma and stroke. Echocardiographic diagnosis and guide to excision.
Am J Med. 1986;80:129–132.
143. Kasarskis EJ, O’Connor W, Earle G. Embolic stroke from cardiac papillary fibroelastomas. Stroke. 1988;19:1171–1173.
144. Etienne Y, Jobic Y, Houel JF, et al. Papillary fibroelastoma of the aortic valve with myocardial infarction: echocardiographic
diagnosis and surgical excision. Am Heart J. 1994;127:443–445.
145. Grote J, Mugge A, Schfers HJ, et al. Multiplane transoesophageal echocardiography detection of a papillary fibroelastoma of
the aortic valve causing myocardial infarction. Eur Heart J. 1995;16:426–429.
146. Eckstein FS, Schafers HJ, Grote J, et al. Papillary fibroelastoma of the aortic valve presenting with myocardial infarction. Ann
Thorac Surg. 1995;60:206–208.
147. Pasteuning WH, Zijnen P, van der Aa MA, et al. Papillary fibroelastoma of the aortic valve in a patient with an acute
myocardial infarction. J Am Soc Echocardiogr. 1996;9:897–900.
148. Pomerance A. Papillary “tumours” of the heart valves. J Pathol Bacteriol. 1961;81:135–140.
149. Heath D, Thompson IM. Papillary “tumours” of the left ventricle. Br Heart J. 1967;29:950–954.
150. Fishbein MC, Ferrans VJ, Roberts WC. Endocardial papillary elastofibromas. Histologic, histochemical, and electron
microscopical findings. Arch Pathol. 1975;99:335–341.
151. Rubin MA, Snell JA, Tazelaar HD. Cardiac papillary fibroelastoma: an immunohistochemical investigation and unusual
clinical manifestations. Mod Pathol. 1995;8:402–407.
152. Witzleben CL, Pinto M. Foamy myocardial transformation of infancy: ‘lipid’ or ‘histiocytoid’ myocardiopathy. Arch Pathol Lab
Med. 1978;102:306–311.
153. MacMahon HE. Infantile xanthomatous cardiomyopathy. Pediatrics. 1971;48:312–315.
154. Ferrans VJ, McAllister HA Jr, Haese WH. Infantile cardiomyopathy with histiocytoid change in cardiac muscle cells. Report of
six patients. Circulation. 1976;53:708–719.
155. Amini M, Bosman C, Marino B. Histiocytoid cardiomyopathy in infancy: a new hypothesis? Chest. 1980;77:556–558.
156. Becker AE, Anderson RH. Pathology of congenital heart disease. Butterworth: London; 1981 [p 407-412].
157. Voth D. [On arachnocytosis of the myocardium (A contribution to the problem of rhabdomyoma of the heart)]. Frankf Z
Pathol. 1962;71:646–656.
158. Finsterer J. Histiocytoid cardiomyopathy: a mitochondrial disorder. Clin Cardiol. 2008;31:225–227.
159. Edston E, Perskvist N. Histiocytoid cardiomyopathy and ventricular non-compaction in a case of sudden death in a female
infant. Int J Legal Med. 2009;123:47–53.
160. Shehata BM, Patterson K, Thomas J, et al. Histiocytoid cardiomyopathy: three new cases and a review of the literature. Pediatr
Dev Pathol. 1998;1:56–69.
161. Callender GG, Rich TA, Perrier ND. Multiple endocrine neoplasia syndromes. Surg Clin North Am. 2008;88:863–895 [viii].
162. James TN, Galakhov I. De subitaneis mortibus. XXVI. Fatal electrical instability of the heart associated with benign congenital
polycystic tumor of the atrioventricular node. Circulation. 1977;56:667–678.
163. Garson A Jr, Smith RT, Moak JP, et al. Incessant ventricular tachycardia in infants: myocardial hamartomas and surgical cure. J
Am Coll Cardiol. 1987;10:619–626.
164. Murphy MC, Sweeney MS, Putnam JB Jr, et al. Surgical treatment of cardiac tumors: a 25-year experience. Ann Thorac Surg.
1990;49:612–617 [discussion 617-618].
165. Kearney DL, Titus JL, Hawkins EP, et al. Pathologic features of myocardial hamartomas causing childhood tachyarrhythmias.
Circulation. 1987;75:705–710.
166. Burke A, Virmani R. Tumors of the heart and great vessels. Atlas of tumor pathology. Armed Forces Institute of Pathology:
Washington, D.C.; 1996.
167. Farooki ZQ, Chang CH, Jackson WL, et al. Intracardiac teratoma in a newborn. Clin Cardiol. 1988;11:642–644.
168. Benatar A, Vaughan J, Nicolini U, et al. Prenatal pericardiocentesis: its role in the management of intrapericardial teratoma.
Obstet Gynecol. 1992;79:856–859.
169. Cox JN, Frildi B, Mechmeche R, et al. Teratoma of the heart. A case report and review of the literature. Virchows Arch A Pathol
Anat Histopathol. 1983;402:163–174.
170. Cina SJ, Smialek JE, Burke AP, et al. Primary cardiac tumors causing sudden death: a review of the literature. Am J Forensic Med
Pathol. 1996;17:271–281.
171. Burke A, Johns JP, Virmani R. Hemangiomas of the heart. A clinicopathologic study of ten cases. Am J Cardiovasc Pathol.
1990;3:283–290.
172. Chang JS, Young ML, Chuu WM, et al. Infantile cardiac hemangioendothelioma. Pediatr Cardiol. 1992;13:52–55.
173. Palmer TE, Tresch DD, Bonchek LI. Spontaneous resolution of a large, cavernous hemangioma of the heart. Am J Cardiol.
1986;58:184–185.
174. Tabry IF, Nassar VH, Rizk G, et al. Cavernous hemangioma of the heart: case report and review of the literature. J Thorac
Cardiovasc Surg. 1975;69:415–420.175. Daubeney PE, Ogilvie BC, Moore IE, et al. Intrapericardial lymphangioma presenting as neonatal cardiac tamponade. Pediatr
Cardiol. 1996;17:129–131.
176. Kim DH, Byun JN, Jang JY, et al. Lymphangiomatosis involving the inferior vena cava, heart, pulmonary artery and pelvic
cavity. Korean J Radiol. 2010;11:115–118.
177. Brizard C, Latremouille C, Jebara VA, et al. Cardiac hemangiomas. Ann Thorac Surg. 1993;56:390–394.
178. Muzzi L, Davoli G, Specchia L, et al. Primary hemangioma of the mitral valve: an unusual presentation. J Heart Valve Dis.
2007;16:209–211.
179. Stoupel E, Primo G, Kahn RJ, et al. Cardiac tamponade with renal failure due to hemangioma of the heart. Acta Cardiol.
1979;34:345–351.
180. Chao JC, Reyes CV, Hwang MH. Cardiac hemangioma. South Med J. 1990;83:44–47.
181. Weir I, Mills P, Lewis T. A case of left atrial haemangioma: echocardiographic, surgical, and morphological features. Br Heart J.
1987;58:665–668.
182. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 4-1983. A 15-year-old girl with
a right ventricular mass. N Engl J Med. 1983;308:206–214.
183. Prichard RW. Tumors of the heart; review of the subject and report of 150 cases. AMA Arch Pathol. 1951;51:98–128.
184. de Nictolis M, Brancorsini D, Goteri G, et al. Epithelioid haemangioma of the heart. Virchows Arch. 1996;428:119–123.
185. Fletcher CD, Beham A, Bekir S, et al. Epithelioid angiosarcoma of deep soft tissue: a distinctive tumor readily mistaken for an
epithelial neoplasm. Am J Surg Pathol. 1991;15:915–924.
186. Weiss SW, Ishak KC, Dail DH, et al. Epithelioid hemangioendothelioma and related lesions. Semin Diagn Pathol. 1986;3:259–
287.
187. Mentzel T, Beham A, Calonje E, et al. Epithelioid hemangioendothelioma of skin and soft tissues: clinicopathologic and
immunohistochemical study of 30 cases. Am J Surg Pathol. 1997;21:363–374.
188. Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer.
1982;50:970–981.
189. Kuo TT, Hsueh S, Su IJ, et al. Histiocytoid hemangioma of the heart with peripheral eosinophilia. Cancer. 1985;55:2854–2861.
190. Burke AP, Anderson PG, Virmani R, et al. Tumor of the atrioventricular nodal region. A clinical and immunohistochemical
study. Arch Pathol Lab Med. 1990;114:1057–1062.
191. Saito S, Kobayashi J, Taqusari O, et al. Successful excision of a cystic tumor of the atrioventricular nodal region. Circ J.
2005;69:1293–1294.
192. Cameselle-Teijeiro J, Abdulkader I, Soares P, et al. Cystic tumor of the atrioventricular node of the heart appears to be the
heart equivalent of the solid cell nests (ultimobranchial rests) of the thyroid. Am J Clin Pathol. 2005;123:369–375.
193. Wong J, Ball RY. Endodermal heterotopia of the atrioventricular node associated with transposition of the great arteries.
Cardiovasc Pathol. 2003;12:159–162.
194. Wolf PL, Bing R. The smallest tumor which causes sudden death. JAMA. 1965;194:674–675.
195. Evans CA, Suvarna SK. Cystic atrioventricular node tumour: not a mesothelioma. J Clin Pathol. 2005;58:1232.
196. Armstrong H, Monckeberg JG. [Heart block due to primary Cardiac tumor in a 5-year-old child]. Deutsch Arch Klin Med.
1911;102:144–166.
197. Mahaim I. [The coeletheliome tawarien benin. A tumor sui generis Tawara node with heart block]. Cardiologia. 1942;6:57–82.
198. Rezek P. [About a primary epithelial tumor in the region of the conduction system in man (also a contribution to the
histogenesis of rare heart tumors)]. Virchows Arch [A]. 1938;301:305–320.
199. Linder J, Shelburne JD, Sorge JP, et al. Congenital endodermal heterotopia of the atrioventricular node: evidence for the
endodermal origin of so-called mesotheliomas of the atrioventricular node. Hum Pathol. 1984;15:1093–1098.
200. Travers H. Congenital polycystic tumor of the atrioventricular node: possible familial occurrence and critical review of
reported cases with special emphasis on histogenesis. Hum Pathol. 1982;13:25–35.
201. Bharati S, Bauernfeind R, Josephson M. Intermittent preexcitation and mesothelioma of the atrioventricular node: a hitherto
undescribed entity. J Cardiovasc Electrophysiol. 1995;6:823–831.
202. Tanimura A, Kato M, Morimatsu M. Cardiac hamartoma. A case report. Acta Pathol Jpn. 1988;38:1481–1484.
203. Burke AP, Ribe JK, Bajaj AK, et al. Hamartoma of mature cardiac myocytes. Hum Pathol. 1998;29:904–909.
204. Fealey ME, Edwards MD, Miller DV, et al. Hamartomas of mature cardiac myocytes: report of 7 new cases and review of
literature. Hum Pathol. 2008;39:1064–1071.
205. Lamke GT, Allen RD, Edwards WD, et al. Surgical pathology of subaortic septal myectomy associated with hypertrophic
cardiomyopathy. A study of 204 cases (1996-2000). Cardiovasc Pathol. 2003;12:149–158.
206. Becker AE. The glomera in the region of the heart and great vessels: a microscopic-anatomical study. Pathol Eur. 1966;1:410–
424.
207. Lack EE. Tumors of the adrenal gland and extra-adrenal paraganglia. Atlas of tumor pathology. Armed Forces Institute of
Pathology: Washington, D.C.; 1997.
208. Besterman E, Bromley LL, Peart RS. An intrapericardial phaeochromocytoma. Br Heart J. 1974;36:318–320.
209. Johnson TL, Shapiro B, Beierwaltes WH, et al. Cardiac paragangliomas. A clinicopathologic and immunohistochemical study
of four cases. Am J Surg Pathol. 1985;9:827–834.
210. Hui G, McAllister HA, Angelini P. Left atrial paraganglioma: report of a case and review of the literature. Am Heart J.
1987;113:1230–1234.
211. Stowers SA, Gilmore P, Stirling M, et al. Cardiac pheochromocytoma involving the left main coronary artery presenting with
exertional angina. Am Heart J. 1987;114:423–427.
212. Shimoyama Y, Kawada K, Imamura H. A functioning intrapericardial paraganglioma (pheochromocytoma). Br Heart J.
1987;57:380–383.
213. Chang CH, Lin PJ, Chang JP, et al. Intrapericardial pheochromocytoma. Ann Thorac Surg. 1991;51:661–663.
214. Aravot DJ, Banner NR, Cantor AM, et al. Location, localization and surgical treatment of cardiac pheochromocytoma. Am J
Cardiol. 1992;69:283–285.
215. Hoey ET, et al. MRI and CT appearances of cardiac tumours in adults. Clin Radiol. 2009;64:1214–1230.
216. Fealey ME, Edwards WD, Reynolds CA, et al. Recurrent cardiac calcific amorphous tumor: the CAT had a kitten. Cardiovasc
Pathol. 2007;16:115–118.
217. Reynolds C, Tazelaar HD, Edwards WD. Calcified amorphous tumor of the heart (cardiac CAT). Hum Pathol. 1997;28:601–606.
218. Luthringer DJ, Virmani R, Weiss SW, et al. A distinctive cardiovascular lesion resembling histiocytoid (epithelioid)
hemangioma. Evidence suggesting mesothelial participation. Am J Surg Pathol. 1990;14:993–1000.
219. Courtice RW, Stinson WA, Walley VM. Tissue fragments recovered at cardiac surgery masquerading as tumoral proliferations.Evidence suggesting iatrogenic or artefactual origin and common occurrence. Am J Surg Pathol. 1994;18:167–174.
220. Veinot JP, Tazelaar HD, Edwards WD, et al. Mesothelial/monocytic incidental cardiac excrescences: cardiac MICE. Mod Pathol.
1994;7:9–16.
221. Courtice RW, Stinson WA, Walley VM. Correspondence re: J.P. Veinot, H.D. Tazelaar, W.D. Edwards, and T.V. Colby.
Mesothelial/monocytic incidental cardiac excrescences: cardiac MICE. Mod Pathol. 1994;7:9–16 [1994].
222. Ikeda Y, Yutani C, Imakita M, et al. Two cases of mesothelial/monocytic incidental cardiac excrescences of the heart. Pathol Int.
1998;48:641–644.
223. Rosai J, Dehner LP. Nodular mesothelial hyperplasia in hernia sacs: a benign reactive condition simulating a neoplastic
process. Cancer. 1975;35:165–175.
224. Wu M, Anderson A, Kahn LB. A report of mesothelial/monocytic incidental cardiac excrescences and a literature review. Ann
Diagn Pathol. 2000;4:39–43.
225. Bando Y, Kitagawa T, Uehara H, et al. So-called mesothelial/monocytic incidental cardiac excrescences obtained during valve
replacement surgery: report of three cases and literature review. Virchows Arch. 2000;437:331–335.
226. Chan JK, Loo KT, Yau BK, et al. Nodular histiocytic/mesothelial hyperplasia: a lesion potentially mistaken for a neoplasm in
transbronchial biopsy. Am J Surg Pathol. 1997;21:658–663.
227. Argani P, Sternberg SS, Burt M, et al. Metastatic adenocarcinoma involving a mesothelial/monocytic incidental cardiac
excrescence (cardiac MICE). Am J Surg Pathol. 1997;21:970–974.
228. Natarajan S, Luthringer DJ, Fishbein MC. Adenomatoid tumor of the heart: report of a case. Am J Surg Pathol. 1997;21:1378–
1380.
229. Burke A, Li L, Kling E, et al. Cardiac inflammatory myofibroblastic tumor: a “benign” neoplasm that may result in syncope,
myocardial infarction and sudden death. Am J Surg Pathol. 2007;31:1115–1122.
230. Tazelaar HD, Batts KP, Srigley JR. Primary extrapulmonary sugar tumor (PEST): a report of four cases. Mod Pathol. 2001;14:615–
622.
231. Lanks KW, Lautsch EV. Pathogenesis of intramyocardial epithelial inclusion cysts. Arch Pathol. 1966;81:365–367.
232. Rose AG, Novitzky D, Price SK. Heterotopic thyroid tissue in the heart. Am J Cardiovasc Pathol. 1988;1:401–404.
233. Otto S, Figulla HR, Goebel B, et al. Churg-Strauss syndrome presenting with cardiac mass and right ventricular obstruction.
Clin Cardiol. 2009;32:E77–E79.
234. Hara M, Nishino M, Yamada Y. Cardiac tumor-like mass in a patient with systemic vasculitis. J Am Coll Cardiol. 2010;55:1882.
235. Adams EE, Aluquin VP, Bingham CA, et al. Cardiac tumor in juvenile onset Behcet's disease: case report and review of the
literature. Pediatr Cardiol. 2010;31:277–279.
236. Zhang PJ, Brooks JS, Goldblum JR, et al. Primary cardiac sarcomas: a clinicopathologic analysis of a series with follow-up
information in 17 patients and emphasis on long-term survival. Hum Pathol. 2008;39:1385–1395.
237. Putnam JB Jr, Sweeney MS, Colon R, et al. Primary cardiac sarcomas. Ann Thorac Surg. 1991;51:906–910.
238. Egan AJ, Boardman LA, Tazelaar HD, et al. Erdheim-Chester disease: clinical, radiologic, and histopathologic findings in five
patients with interstitial lung disease. Am J Surg Pathol. 1999;23:17–26.
239. Alharthi MS, Calleja A, Panse P, et al. Multimodality imaging showing complete cardiovascular involvement by
ErdheimChester disease. Eur J Echocardiogr. 2010;11:E25.
240. Maleszewski JJ, Hristov AC, Halushka MK, et al. Extranodal Rosai-Dorfman disease involving the heart: report of two cases.
Cardiovasc Pathol. 2010;19:380–384.
241. McAllister HA Jr. Primary tumors of the heart and pericardium. Pathol Annu. 1979;14(Pt 2):325–355.
242. Chitwood WR Jr. Cardiac neoplasms: current diagnosis, pathology, and therapy. J Card Surg. 1988;3:119–154.
243. Randall MB, Geisinger KR. Angiosarcoma of the heart: pericardial fluid cytology. Diagn Cytopathol. 1990;6:58–62.
244. Loffler H, Grille W. Classification of malignant cardiac tumors with respect to oncological treatment. Thorac Cardiovasc Surg.
1990;38(Suppl 2):173–175.
245. Makhoul N, Bode FR. Angiosarcoma of the heart: review of the literature and report of two cases that illustrate the broad
spectrum of the disease. Can J Cardiol. 1995;11:423–428.
246. Yousem SA. Angiosarcoma presenting in the lung. Arch Pathol Lab Med. 1986;110:112–115.
247. Adem C, Aubry MC, Tazelaar HD, et al. Metastatic angiosarcoma masquerading as diffuse pulmonary hemorrhage:
clinicopathologic analysis of 7 new patients. Arch Pathol Lab Med. 2001;125:1562–1565.
248. Sorlie D, Myhre ES, Stalsberg H. Angiosarcoma of the heart. Unusual presentation and survival after treatment. Br Heart J.
1984;51:94–97.
249. Percy RF, Perryman RA, Amornmarn R, et al. Prolonged survival in a patient with primary angiosarcoma of the heart. Am
Heart J. 1987;113:1228–1230.
250. Hager W, Kremer K, Muller W. [Angiosarcoma of the heart.]. Dtsch Med Wochenschr. 1970;95:680 [passim].
251. Poletti A, Cocco P, Valente M, et al. In vivo diagnosis of cardiac angiosarcoma by endomyocardial biopsy. Cardiovasc Pathol.
1993;2:89–91.
252. Burke AP, Cowan D, Virmani R. Primary sarcomas of the heart. Cancer. 1992;69:387–395.
253. Donsbeck AV, Ranchere D, Coindre JM, et al. Primary cardiac sarcomas: an immunohistochemical and grading study with
long-term follow-up of 24 cases. Histopathology. 1999;34:295–304.
254. Shah AA, Churg A, Sbarbaro JA, et al. Malignant fibrous histiocytoma of the heart presenting as an atrial myxoma. Cancer.
1978;42:2466–2471.
255. Weiss SW, Enzinger FM. Myxoid variant of malignant fibrous histiocytoma. Cancer. 1977;39:1672–1685.
256. Ouzan J, Joundi A, Chapoutot L, et al. [Malignant histiocytofibroma of the heart simulating myxoma of the left atrium]. Arch
Mal Coeur Vaiss. 1990;83:1011–1013.
257. Pasquale M, Katz NM, Caruso AC, et al. Myxoid variant of malignant fibrous histiocytoma of the heart. Am Heart J.
1991;122:248–250.
258. Korbmacher B, Doering C, Schulte HD, et al. Malignant fibrous histiocytoma of the heart—case report of a rare left-atrial
tumor. Thorac Cardiovasc Surg. 1992;40:303–307.
259. Wahba A, Liebold A, Birnbaum DE. Recurrent malignant fibrous histiocytoma of the left atrium in a 27-year-old male. Eur J
Cardiothorac Surg. 1993;7:387–389.
260. Hui KS, Green LK, Schmidt WA. Primary cardiac rhabdomyosarcoma: definition of a rare entity. Am J Cardiovasc Pathol.
1988;2:19–29.
261. Hajar R, Roberts WC, Folger GM Jr. Embryonal botryoid rhabdomyosarcoma of the mitral valve. Am J Cardiol. 1986;57:376.
262. Small EJ, Gordon GJ, Dahms BB. Malignant rhabdoid tumor of the heart in an infant. Cancer. 1985;55:2850–2853.
263. Antunes MJ, Vanderdonck KM, Andrade CM, et al. Primary cardiac leiomyosarcomas. Ann Thorac Surg. 1991;51:999–1001.264. Fyfe AI, Huckell VF, Burr LH, et al. Leiomyosarcoma of the left atrium: case report and review of the literature. Can J Cardiol.
1991;7:193–196.
265. Pins MR, Ferrell MA, Madsen JC, et al. Epithelioid and spindle-celled leiomyosarcoma of the heart. Report of 2 cases and
review of the literature. Arch Pathol Lab Med. 1999;123:782–788.
266. Chun PK, Leeburg WT, Coggin JT, et al. Primary pericardial malignant epithelioid mesothelioma causing acute myocardial
infarction. Chest. 1980;77:559–561.
267. Sytman AL, MacAlpin RN. Primary pericardial mesothelioma: report of two cases and review of the literature. Am Heart J.
1971;81:760–769.
268. Klima M, Spjut HJ, Seybold WD. Diffuse malignant mesothelioma. Am J Clin Pathol. 1976;65:583–600.
269. Curtsinger CR, Wilson MJ, Yoneda K. Primary cardiac lymphoma. Cancer. 1989;64:521–525.
270. Zaharia L, Gill PS. Primary cardiac lymphoma. Am J Clin Oncol. 1991;14:142–145.
271. Nascimento AF, Winters GL, Pinkus GS. Primary cardiac lymphoma: clinical, histologic, immunophenotypic and genotypic
features of 5 cases of a rare disorder. Am J Surg Pathol. 2007;31:1344–1350.
272. Ceresoli GL, Ferreri AJ, Bucci E, et al. Primary cardiac lymphoma in immunocompetent patients: diagnostic and therapeutic
management. Cancer. 1997;80:1497–1506.
273. McDonnell PJ, Mann RB, Bulkley BH. Involvement of the heart by malignant lymphoma: a clinicopathologic study. Cancer.
1982;49:944–951.
274. Patel J, Melly L, Sheppard MN. Primary cardiac lymphoma: B- and T-cell cases at a specialist UK centre. Ann Oncol.
2010;21:1041–1045.$
$
C H A P T E R 3
Vascular Tumors
J. Eduardo Calonje, Christopher D.M. Fletcher
CHA P T E R OUT LINE
BENIGN TUMORS 42
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
VASCULAR TUMORS OF INTERMEDIATE MALIGNANCY 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
MALIGNANT VASCULAR TUMORS 66
Epithelioid Hemangioendothelioma 66
Angiosarcoma 68
“Intimal” Sarcomas 71
TUMORS OF LYMPH VESSELS 71
Cavernous Lymphangioma and Cystic Hygroma 72
Lymphangioma Circumscriptum 72
Benign Lymphangioendothelioma (Acquired Progressive Lymphangioma) 73
Lymphangiomatosis 74
Lymphangiomyomatosis 75
TUMORS OF PERIVASCULAR CELLS 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.
TABLE 3-1
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)
Angiokeratoma
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)
Deep
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
Synovial
Neural
Nodal
Angiomatosis
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
Angiosarcoma
Variants: Idiopathic (head and neck)
Associated with lymphedema (“lymphangiosarcoma”)
Postirradiation
Soft tissue$
$
$
$
$
Epithelioid
“Intimal” sarcomas
Lymph Vessels
Lymphangioma
Variants: Lymphangioma circumscriptum
Cavernous lymphangioma/cystic hygroma
Benign lymphangioendothelioma (acquired progressive lymphangioma)
Lymphangiomatosis
Lymphangiomyoma
Lymphangiomyomatosis
Multifocal lymphangiomatosis with thrombocytopenia
Tumors of Perivascular Cells
Glomus tumor
Glomangiomatosis
Variant: Infiltrating glomus tumor
Glomangiosarcoma
“Hemangiopericytoma,” so called
Myopericytoma
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
papillae.$
$
$
$
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
ischemia.
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
35projections.
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.
Angiokeratoma
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.$
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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.$
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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.
Variants.
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
thrombosed.
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$
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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
insufficiency.
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.
Histopathology
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
favored.
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$
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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.
Angiomatosis
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
233,234series).
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$
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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
(B).
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
channels.
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
markers.
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$
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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
advised.
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.$
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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
uncertain.
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.$
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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
Kingdom.)
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
immunosuppression.
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
8.
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
architecture.
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.$
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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.
Angiosarcoma
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.$
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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
400sites.
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.$
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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.$
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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
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.$
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FIGURE 3-61 Lymphangiomatosis. Note the very extensive, diffuse dissection between normal
structures.
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
476angiosarcoma.$
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
seen.
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
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
522-526rare.
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
margins.
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.$
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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
protein.
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$
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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
568tumor.$
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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
morphology.
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.$
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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
following:
• 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
1. Salyer WR, Salyer DC. Intravascular angiomatosis: development and
distinction from angiosarcoma. Cancer. 1975;36:995–1001.
2. Clearkin KP, Enzinger FM. Intravascular papillary endothelial hyperplasia.
Arch Pathol Lab Med. 1976;100:441–444.
3. Kuo TT, Sayers CP, Rosai J. Masson's “vegetant intravascular
hemangioendothelioma”: a lesion often mistaken for angiosarcoma. Study of
seventeen cases located in the skin and soft tissues. Cancer. 1976;38:1227–1236.
4. Hashimoto H, Daimaru Y, Enjoji M. Intravascular papillary endothelial
hyperplasia. A clinicopathologic study of 91 cases. Am J Dermatopathol.
1983;5:539–545.
5. Pins MR, Rosenthal DI, Springfield DS, et al. Florid extravascular papillary
endothelial hyperplasia (Masson's pseudoangiosarcoma) presenting as a soft
tissue sarcoma. Arch Pathol Lab Med. 1993;117:259–263.
6. Branton PA, Lininger R, Tavassoli FA. Papillary endothelial hyperplasia of the
breast: the great impostor for angiosarcoma: a clinicopathologic review of 17
cases. Int J Surg Pathol. 2003;11:83–87.
7. Reed CN, Cooper PH, Swerlick PA. Intravascular papillary endothelial
hyperplasia. Multiple lesions simulating Kaposi's sarcoma. J Am Acad
Dermatol. 1984;10:110–113.
8. Durieu C, Bayle-Lebey P, Gadroy A, et al. Intravascular papillary endothelial
hyperplasia: multiple lesions appearing in the course of treatment with
interferon beta. Ann Dermatol Venereol. 2001;128:1336–1338.
9. Wick MR, Rocamora A. Reactive and malignant “angioendotheliomatosis”: a
discriminant clinicopathological study. J Cutan Pathol. 1988;15:260–271.
10. McMenamin ME, Fletcher C D M. Reactive angioendotheliomatosis: a study of
15 cases demonstrating a wide clinicopathologic spectrum. Am J Surg Pathol.
2002;26:685–697.
11. Brazzelli V, Baldini F, Vassallo C, et al. Reactive angioendotheliomatosis in an
infant. Am J Dermatopathol. 1999;21:42–45.
12. Ortonne N, Vignon-Pennamen MD, Majdalani G, et al. Reactive
angioendotheliomatosis secondary to dermal amyloid angiopathy. Am J
Dermatopathol. 2001;23:315–319.
13. Creamer D, Black MM, Calonje E. Reactive angioendotheliomatosis in
association with the antiphospholipid syndrome. J Am Acad Dermatol.
2000;45:903–906.
14. Thai KE, Barrett W, Kossard S. Reactive angioendotheliomatosis in the setting
of antiphospholipid syndrome. Australas J Dermatol. 2003;44:151–155.
15. Tomasini C, Soro E, Pippione M. Angioendotheliomatosis in a woman with
rheumatoid arthritis. Am J Dermatopathol. 2000;22:334–338.
16. Shyong EQ, Gorevic P, Lebwohl M, et al. Reactive angioendotheliomatosis and
sarcoidosis. Int J Dermatol. 2002;41:894–897.
17. del Pozo J, Martinez W, Sacristan F, et al. Reactive angioendotheliomatosis
associated with myelodysplastic syndrome. Acta Derm Venereol. 2005;85:269–
270.
18. Clarke LE, Julian KG, Clarke JT, et al. Reactive angioendotheliomatosis with a
well-differentiated angiosarcoma. Am J Dermatopathol. 2005;27:422–427.
19. Le Boit PE, Solomon AR, Santa Cruz DJ, et al. Angiomatosis with luminal
cryoprotein deposition. J Am Acad Dermatol. 1992;27:969–973.20. Krell JM, Sánchez RL, Solomon AR. Diffuse dermal angiomatosis: a variant of
reactive cutaneous angioendotheliomatosis. J Cutan Pathol. 1994;21:363–370.
21. Kim S, Elenitsas R, James WD. Diffuse dermal angiomatosis: a variant of
reactive angioendotheliomatosis associated with peripheral vascular
atherosclerosis. Arch Dermatol. 2002;138:456–458.
22. Kimyai-Asadi A, Nousari HC, Ketabchi N, et al. Diffuse dermal angiomatosis:
a variant of reactive angioendotheliomatosis associated with atherosclerosis. J
Am Acad Dermatol. 1999;40:257–259.
23. Requena L, Farina MC, Renedo G, et al. Intravascular and diffuse dermal
reactive angioendotheliomatosis secondary to iatrogenic arteriovenous
fistulas. J Cutan Pathol. 1999;26:159–164.
24. Yang H, Ahmed I, Matthew V, et al. Diffuse dermal angiomatosis. Arch
Dermatol. 2006;142:343–347.
25. Chan J K C, Fletcher C D M, Hicklin GA, et al. Glomeruloid hemangioma. A
distinctive cutaneous lesion of multicentric Castleman's disease associated
with POEMS syndrome. Am J Surg Pathol. 1990;14:1036–1046.
26. Yang SG, Cho KH, Bang Y-J, et al. A case of glomeruloid hemangioma
associated with multicentric Castleman's disease. Am J Dermatopathol.
1998;20:266–270.
27. Tsai CY, Lai CH, Chan HL, et al. Glomeruloid hemangioma—a specific marker
of POEMS syndrome. Int J Dermatol. 2001;40:403–406.
28. Scheers C, Kolivras A, Corbisier A, et al. POEMS syndrome revealed by
multiple glomeruloid angiomas. Dermatology. 2002;204:311–314.
29. Lee H, Meier FA, Ma CK, et al. Eosinophilic globules in 3 cases of glomeruloid
hemangioma of the head and neck: a characteristic offering more evidence for
the thanatosomes with or without POEMS. Am J Dermatopathol. 2008;30:539–
544.
30. Obermoser G, Larcher C, Sheldon JA, et al. Absence of human herpesvirus-8
in glomeruloid haemangioma associated with POEMS syndrome and
Castleman's disease. Br J Dermatol. 2003;148:1276–1278.
31. Vélez D, Delgado-Jiménez Y, Fraga J. Solitary glomeruloid hemangioma
without POEMS syndrome. J Cutan Pathol. 2005;32:449–452.
32. Piña-Oviedo S, López-Patiño S, Ortiz-Hidalgo C. Glomeruloid hemangiomas
localized to the skin of the trunk with no clinical features of POEMS
syndrome. Int J Dermatol. 2006;45:1449–1450.
33. González-Guerra E, Haro MR, Fariña MC, et al. Glomeruloid hemangioma is
not always associated with POEMS syndrome. Clin Exp Dermatol. 2009;34:800–
803.
34. Suurmeijer AJ, Fletcher CD. Papillary hemangioma: a distinctive cutaneous
hemangioma of the head and neck area containing eosinophilic hyaline
globules. Histopathology. 2007;51:638–648.
35. Suurmeijer AJ. Papillary hemangiomas and glomeruloid hemangiomas are
distinct clinicopathologic entities. Int J Surg Pathol. 2010;18:48–54.
36. MacCollum DW, Martin LW. Hemangiomas in infancy and childhood. A
report based on 6479 cases. Surg Clin North Am. 1956;36:1647–1663.
37. Watson WL, McCarthy WB. Blood and lymph vessel tumors. A report of 1056
cases. Surg Gynecol Obstet. 1940;71:569–588.
38. Edgerton MT, Hiebert JM. Vascular and lymphatic tumors in infancy,
childhood and adulthood: challenge of diagnosis and treatment. Curr ProblCancer. 1978;2:4–44.
39. Finley JL, Noe JM, Arndt KA, et al. Port-wine stains. Morphologic variations
and developmental lesions. Arch Dermatol. 1984;120:1453–1455.
40. Johnson SC, Hanke CW. Unilateral acquired nevus flammeus in women. Cutis.
2001;67:225–228.
41. Ferahbas A, Utas S, Urcakus M, et al. Prevalence of cutaneous findings in
hospitalized neonates: a prospective observational study. Pediatr Dermatol.
2009;26:139–142.
42. Adams B, Lucky AW. Acquired port-wine stains and antecedent trauma: case
report and review of the literature. Arch Dermatol. 2000;136:897–899.
43. Berg JN, Quaba AA, Georgantopoulou A, et al. A family with hereditary port
wine stain. J Med Genet. 2000;37:E12.
44. Breugem CC, Alders M, Salieb-Beugelaar GB, et al. A locus for hereditary
capillary malformations mapped on chromosome 5q. Hum Genet.
2002;110:343–347.
45. Askar I, Kilinc N, Yucetas A. Pyogenic granuloma appearing on port-wine
stain: a case report. Acta Chir Plast. 2003;45:51–54.
46. Valeyrie L, Lebrun-Vignes B, Descamps V, et al. Pyogenic granuloma within
port-wine stains: an alarming clinical presentation. Eur J Dermatol.
2002;12:373–375.
47. Kim TH, Choi EH, Ahn SK, et al. Vascular tumors arising in port-wine stains:
two cases of pyogenic granuloma and a case of acquired tufted angioma. J
Dermatol. 1999;26:813–816.
48. Bean WB, Walsh JR. Venous lakes. Arch Dermatol. 1956;74:459–463.
49. Stevenson JR, Lincoln CS. Angioma serpiginosum. Arch Dermatol. 1967;95:16–
22.
50. Frain-Bell W. Angioma serpiginosum. Br J Dermatol. 1957;69:251–268.
51. Kumakiri M, Katoh N, Miura Y. Angioma serpiginosum. J Cutan Pathol.
1980;7:410–421.
52. Al Hawsawi K, Al Aboud K, Al Aboud D, et al. Linear angioma serpiginosum.
Pediatr Dermatol. 2003;20:167–168.
53. Erbagci Z, Erbagci I, Erkilic S, et al. Angioma serpiginosum with retinal
involvement in a male: a possible role of continuous cold exposure. J Eur Acad
Dermatol Venereol. 2004;18:238–239.
54. Gautier-Smith PC, Sanders MD, Sanderson KV. Ocular and nervous system
involvement in angioma serpiginosum. Br J Ophthalmol. 1971;55:433–443.
55. Marriot PJ, Munro DD, Ryan T. Angioma serpiginosum—familial incidence. Br
J Dermatol. 1975;93:701–706.
56. Johnson WC. Pathology of cutaneous vascular tumors. Int J Dermatol.
1976;15:239–270.
57. Bossler AD, Richards J, George C, et al. Novel mutations in ENG and ACVRL1
identified in a series of 200 individuals undergoing clinical genetic testing for
hereditary hemorrhagic telangiectasia (HHT): correlation of genotype and
phenotype. Hum Mutat. 2006;27:667–675.
58. Poletto ED, Trinh AM, Levin TL, et al. Hereditary hemorrhagic telangiectasia
and juvenile polyposis: an overlap of syndromes. Pediatr Radiol. 2010;40:1274–
1277.
59. Imperial R, Helwig EB. Angiokeratoma. A clinicopathological study. Arch
Dermatol. 1967;95:166–175.60. Epinette WW, Norins AL, Drew AL, et al. Angiokeratoma corporis diffusum
with α-L-fucosidase deficiency. Arch Dermatol. 1973;107:754–757.
61. Rodríguez-Serna M, Botella-Estrada R, Chabás A, et al. Angiokeratoma
corporis diffusum associated with B-mannosidase deficiency. Arch Dermatol.
1996;132:1219–1222.
62. Kanzaki T, Yokota M, Irie F, et al. Angiokeratoma corporis diffusum with
glycopeptiduria due to deficient lysosomal α-N-acetylgalactosaminidase
activity. Arch Dermatol. 1993;129:460–465.
63. Kodama K, Kobayashi H, Abe R, et al. A new case of
α-Nacetylgalactosaminidase deficiency with angiokeratoma corporis diffusum,
with Ménière's syndrome and without mental retardation. Br J Dermatol.
2001;144:363–368.
64. Ishibashi A, Tsuboi R, Shinmei M. β-galactosidase and neuraminidase
deficiency associated with angiokeratoma corporis diffusum. Arch Dermatol.
1984;120:1344–1346.
65. Holmes RC, Fensom AH, McKee PH, et al. Angiokeratoma corporis diffusum
in a patient with normal enzyme activities. J Am Acad Dermatol. 1984;10:384–
387.
66. Fauchais AL, Prev S, Quatara B, et al. Angiokeratoma regression in a Fabry
disease after treatment with agalside-beta clinical effectiveness. J Eur Acad
Dermatol Venereol. 2010;24:737–738.
67. Haye KR, Rebello D J A. Angiokeratoma. of Mibelli. Acta Dermat Venereol.
1961;41:56–60.
68. Imperial R, Helwig EB. Angiokeratoma of the scrotum (Fordyce type). J Urol.
1967;98:379–387.
69. Imperial R, Helwig EB. Angiokeratoma of the vulva. Obstet Gynecol.
1967;29:307–312.
70. Lynch PJ, Kosanovich N. Angiokeratoma circumscriptum. Arch Dermatol.
1967;96:665–668.
71. Tarnowski WM, Hashimoto K. New light microscopic findings in Fabry's
disease. Acta Derm Venereol. 1969;49:386–389.
72. Coffin CM, Dehner LP. Vascular tumors in children and adolescents: a
clinicopathologic study of 228 tumors in 222 patients. Pathol Annu. 1993;28:97–
120.
73. Lister WA. The natural history of strawberry naevi. Lancet. 1938;1:1429–1434.
74. Boon LM, Enjolras O, Mulliken JB. Congenital hemangioma: evidence of
accelerated involution. J Pediatr. 1996;128:329–335.
75. Berenguer B, Mulliken JB, Enjolras O, et al. Rapidly involuting congenital
hemangioma: clinical and histopathologic features. Pediatr Dev Pathol.
2003;6:495–510.
76. Enjolras O, Mulliken JB, Boon LM, et al. Noninvoluting congenital
hemangioma: a rare cutaneous vascular anomaly. Plast Reconstr Surg.
2001;107:1647–1654.
77. Mulliken JB, Enjolras O. Congenital hemangiomas and infantile hemangioma:
missing links. J Am Acad Dermatol. 2004;50:875–882.
78. Perrone T. Vessel-nerve intermingling in benign infantile
hemangioendothelioma. Hum Pathol. 1985;16:198–200.
79. Calonje E, Mentzel T, Fletcher C D M. Pseudomalignant perineural invasion in
cellular (“infantile”) capillary hemangiomas. Histopathology. 1995;26:159–164.80. Taxy JB, Gray SR. Cellular angiomas of infancy. An ultrastructural study of two
cases. Cancer. 1979;43:2322–2331.
81. Gonzalez-Crussi F, Reyes-Mugica M. Cellular hemangiomas
(“hemangioendotheliomas”) in infants. Light microscopic
immunohistochemical and ultrastructural observations. Am J Surg Pathol.
1991;15:769–778.
82. Smoller BR, Apfelberg DB. Infantile (juvenile) capillary hemangioma: a tumor
of heterogeneous cellular elements. J Cutan Pathol. 1993;20:330–336.
83. North PE, Waner M, Mizeracki A, et al. A unique microvascular phenotype
shared by juvenile hemangiomas and human placenta. Arch Dermatol.
2001;137:559–570.
84. North PE, Waner M, Mizeracki A, et al. GLUT1: a newly discovered
immunohistochemical marker for juvenile hemangiomas. Hum Pathol.
2000;31:11–22.
85. Lawley LP, Cerimele F, Weiss SW, et al. Expression of Wilms tumor 1 gene
distinguishes vascular malformations from proliferative endothelial lesions.
Arch Dermatol. 2005;141:1297–1300.
86. Yu Y, Flint AF, Mulliken JB, et al. Endothelial progenitor cells in infantile
hemangioma. Blood. 2004;103:1373–1375.
87. Boye E, Yu Y, Paranya G, et al. Clonality and altered behavior of endothelial
cells from hemangiomas. J Clin Invest. 2001;107:745–752.
88. Walter JW, North PE, Waner M, et al. Somatic mutation of vascular endothelial
growth factor receptors in juvenile hemangioma. Genes Chromos. Cancer.
2002;33:295–303.
89. Wilson-Jones E. Malignant vascular tumours. Clin Exp Dermatol. 1976;1:287–
312.
90. Wilson-Jones E, Orkin M. Tufted angioma (angioblastoma). A benign
progressive angioma, not to be confused with Kaposi's sarcoma or low-grade
angiosarcoma. J Am Acad Dermatol. 1989;20:214–225.
91. Padilla RS, Orkin M, Rosai J. Acquired “tufted” angioma (progressive capillary
hemangioma). Am J Dermatopathol. 1987;9:292–300.
92. Herron MD, Coffin CM, Vanderhooft SL. Tufted angiomas: variability of
clinical morphology. Pediatr Dermatol. 2002;19:394–401.
93. Wong SN, Tay YK. Tufted angioma: a report of five cases. Pediatr Dermatol.
2002;19:388–393.
94. Okada E, Tamura A, Ishikawa O, et al. Tufted angioma (angioblastoma): case
report and review of 41 cases in the Japanese literature. Clin Exp Dermatol.
2000;25:627–630.
95. Cho KH, Kim SH, Park KC, et al. Angioblastoma (Nakagawa)—is it the same as
tufted angioma? Clin Exp Dermatol. 1991;16:110–113.
96. Kleinegger CL, Hammond HL, Vincent SD, et al. Acquired tufted angioma: a
unique vascular lesion not previously reported in the oral mucosa. Br J
Dermatol. 2000;142:794–799.
97. Satter EK, Graham BS, Gibbs NF. Congenital tufted angioma. Pediatr Dermatol.
2002;19:445–447.
98. Osio A, Fraitag S, Hadi-Rabia S, et al. Clinical spectrum of tufted angioma in
childhood: report of 13 cases and a review of the literature. Arch Dermatol.
2010;146:758–763.
99. Maronn M, Chamlin S, Metry D. Multifocal tufted angiomas in 2 infants. ArchDermatol. 2009;145:847–848.
100. Tille JC, Morris MA, Brundler MA, et al. Familial predisposition to tufted
angioma: identification of blood and lymphatic vascular components. Clin
Genet. 2003;63:393–399.
101. Miyamoto T, Mihara M, Mishima E, et al. Acquired tufted angioma showing
spontaneous regression. Br J Dermatol. 1992;127:645–648.
102. Lam WY, Mac-Moune Lai F, Look CN, et al. Tufted angioma with complete
regression. J Cutan Pathol. 1994;21:461–466.
103. Maguiness S, Guenther L. Kasabach-Merritt syndrome. J Cutan Med Surg.
2002;6:335–339.
104. Enjolras O, Mulliken JB, Wassef M, et al. Residual lesions after
KasabachMerritt phenomenon in 41 patients. J Am Acad Dermatol. 2000;42:225–235.
105. Ramesh R, De Silva B, Atherton DJ. Congenital tufted angioma with persistent
low-grade coagulopathy. Clin Exp Dermatol. 2009;34:e766–e768.
106. Michel S, Hohenleutner U, Stolz W, et al. Acquired tufted angioma in
association with a complex cutaneous vascular malformation. Br J Dermatol.
1999;141:1142–1144.
107. Kumakiri M, Muramoto F, Tsukinaga I, et al. Crystalline lamellae in the
endothelial cells of a type of hemangioma characterised by the proliferation of
immature endothelial cells and pericytes—angioblastoma (Nakagawa). J Am
Acad Dermatol. 1983;8:68–75.
108. Fukunaga M. Intravenous tufted angioma. APMIS. 2000;108:287–292.
109. Brasanac D, Janic D, Boricic I, et al. Retroperitoneal kaposiform
hemangoendothelioma with tufted angioma-like features in an infant with
Kasabach-Merritt syndrome. Pathol Int. 2003;53:627–631.
110. Chu CY, Hsiao CH, Chiu HC. Transformation between Kaposiform
hemangioendothelioma and tufted angioma. Dermatology. 2003;206:334–337.
111. Imperial R, Helwig E. Verrucous hemangioma. A clinicopathologic study of 21
cases. Arch Dermatol. 1967;96:247–253.
112. Chan J K C, Tsang W Y W, Calonje E, et al. Verrucous hemangioma. A
distinctive but neglected variant of cutaneous hemangioma. Int J Surg Pathol.
1995;2:171–176.
113. Calduch L, Ortega C, Navarro V, et al. Verrucous hemangioma: report of two
cases and review of the literature. Pediatr Dermatol. 2000;17:213–217.
114. McGeoch AH. Pyogenic granuloma. Aust J Dermatol. 1961;6:33–40.
115. Bhaskar SM, Jacoway JR. Pyogenic granuloma. Clinical features, incidence,
histology and result of treatment: report of 242 cases. J Oral Surg. 1961;24:391–
398.
116. Patrice SJ, Wiss K, Mulliken JB. Pyogenic granuloma (lobular capillary
hemangioma): a clinicopathologic study of 178 cases. Pediatr Dermatol.
1991;8:267–276.
117. Harris MN, Desai R, Chuang TY, et al. Lobular capillary hemangiomas: an
epidemiologic report, with emphasis on cutaneous lesions. J Am Acad
Dermatol. 2000;42:1012–1016.
118. Mills SE, Cooper PH, Fechner RE. Lobular capillary hemangioma. The
underlying lesion of pyogenic granuloma. A study of 73 cases from the oral
and nasal mucous membranes. Am J Surg Pathol. 1980;4:471–479.
119. Ogunleye AO, Nwaorgu OG. Pyogenic granuloma, a cause of congenital nasal
mass: case report. Ann Trop Paediatr. 2000;20:137–139.120. Willies-Jacobo LJ, Isaacs H Jr, Stein MT. Pyogenic granuloma presenting as a
congenital epulis. Arch Pediatr Adolesc Med. 2000;154:603–605.
121. Nappi O, Wick MR. Disseminated lobular capillary hemangioma (pyogenic
granuloma). A clinicopathologic study of two cases. Am J Dermatopathol.
1986;8:379–385.
122. Wilson BB, Greer KE, Cooper PH. Eruptive disseminated lobular capillary
hemangioma (pyogenic granuloma). J Am Acad Dermatol. 1989;21:391–394.
123. Behne K, Robertson I, Weedon D. Disseminated lobular capillary
hemangioma. Australas J Dermatol. 2002;43:297–300.
124. Palmero ML, Pope E. Eruptive pyogenic granuloma developing after drug
hypersensitivity reaction. J Am Acad Dermatol. 2009;60:855–857.
125. Bakan V, Aliagaoglu C, Yidiz A, et al. Multiple pyogenic granulomas on the
face after landmine injury. Pediatr Dermatol. 2008;25:397–398.
126. Bozkurt M, Kulahci Y, Zor F, et al. Multiple giant disseminated pyogenic
granuloma in a burn lesion. J Burn Care Res. 2006;27:247–249.
127. Kim DH, Kim MY, Park YM, et al. Agminated lobular capillary hemangiomas
presumably associated with an acquired arteriovenous malformation. J
Dermatol. 2006;33:646–648.
128. Warner J, Wilson-Jones E. Pyogenic granuloma recurring with multiple
satellites. A report of 11 cases. Br J Dermatol. 1968;80:218–227.
129. Tursen U, Demirkan F, Ikizoglu G. Giant recurrent pyogenic granuloma on the
face with satellitosis responsive to systemic steroids. Clin Exp Dermatol.
2004;29:40–41.
130. Piguet V, Borradori L. Pyogenic granuloma-like lesions during capecitabine
therapy. Br J Dermatol. 2002;147:1270–1272.
131. MacKenzie-Wood AR, Wood G. Pyogenic granuloma-like lesions in a patient
using topical tretinoin. Australas J Dermatol. 1998;39:248–250.
132. Exner JH, Dahod S, Pochi PE. Pyogenic granuloma-like acne lesions during
isotretinoin therapy. Arch Dermatol. 1983;119:808–811.
133. Hagler J, Hodak E, David M, et al. Facial pyogenic granuloma-like lesions
under isotretinoin therapy. Int J Dermatol. 1992;31:199–200.
134. High WA. Gefitinib, a cause of pyogenic granuloma-like lesions of the nail.
Arch Dermatol. 2006;142:939.
135. Curr N, Saunders H, Murugasu A, et al. Multiple periungual pyogenic
granulomas following systemic 5-fluorouracil. Australas J Dermatol.
2006;47:130–133.
136. Suarez-Amor O, Cabanillas M, Monteaguado B, et al. Disseminated pyogenic
granuloma induced by erythropoietin? Actas Dermosifiliogr. 2009;100:439–440.
137. Liu S, Yang C, Xu S, et al. Pyogenic granuloma arising as a complication of
595 nm tunable pulsed dye laser treatment for port-wine stains: report of four
cases. Dermatol Surg. 2010;36:1341–1343.
138. Owji N, Sadeghipour A, Salour H, et al. Pyogenic granuloma as a presenting
sign of hydroxyapatite orbital implant exposure: a clinicopathologic study.
Ophthal Plast Reconstr Surg. 2006;22:467–471.
139. Renshaw AA, Rosai J. Benign atypical vascular lesions of the lip. A study of 12
cases. Am J Surg Pathol. 1993;17:557–565.
140. Cooper PH, Mills SE. Subcutaneous granuloma pyogenicum. Lobular capillary
hemangioma. Arch Dermatol. 1982;118:30–33.
141. Cooper PH, McAllister HA, Helwig EB. Intravenous pyogenic granuloma. Astudy of 18 cases. Am J Surg Pathol. 1979;3:221–228.
142. LeBoit PE, Berger TG, Egbert BM, et al. Bacillary angiomatosis. The
histopathology and differential diagnosis of a pseudoneoplastic infection in
patients with human immunodeficiency virus disease. Am J Surg Pathol.
1989;13:909–920.
143. Slater LN, Welch DF, Min KW. Rochalimaea henselae causes bacillary
angiomatosis and peliosis hepatis. Arch Intern Med. 1992;152:602–606.
144. Kasabach HH, Merritt KK. Capillary hemangioma with extensive purpura.
Report of a case. Am J Dis Child. 1961;59:1063–1070.
145. Fine RM, Derbes VJ, Clark WH Jr. Blue rubber bleb nevus. Arch Dermatol.
1961;84:802–805.
146. Rice SJ, Fischer DS. Blue rubber bleb nevus syndrome. Arch Dermatol.
1962;86:502–511.
147. Calonje E, Fletcher C D M. Sinusoidal hemangioma: a distinctive benign
vascular neoplasm within the group of cavernous hemangiomas. Am J Surg
Pathol. 1991;15:1130–1135.
148. Girard C, Graham JH, Johnson WC. Arteriovenous hemangioma
(arteriovenous shunt): a clinicopathologic and histochemical study. J Clin
Pathol. 1974;1:73–87.
149. Rusin LJ, Harrel E. Arteriovenous fistula. Cutaneous manifestations. Arch
Dermatol. 1976;112:1135–1138.
150. Connelly MG, Winkelmann RK. Acral arteriovenous tumor. Am J Surg Pathol.
1985;9:15–21.
151. Angervall L, Nielsen JM, Stener B, et al. Concomitant arteriovenous vascular
malformation in skeletal muscle. A clinical, angiographic and histologic
study. Cancer. 1979;44:232–238.
152. Kadono T, Kishi A, Onishi Y, et al. Acquired digital arteriovenous
malformation: a report of six cases. Br J Dermatol. 2000;142:362–365.
153. Akiyama M, Inamoto N. Arteriovenous haemangioma in chronic liver disease:
clinical and histopathological features in four cases. Br J Dermatol.
2001;144:604–609.
154. Strutton G, Weedon D. Acro-angiodermatitis: a simulant of Kaposi's sarcoma.
Am J Dermatopathol. 1987;9:85–89.
155. Koutlas IG, Jessurun J. Arteriovenous hemangioma: clinicopathological and
immunohistochemical study. J Cutan Pathol. 1994;21:343–349.
156. Hunt SJ, Santa Cruz DJ, Barr RJ. Microvenular hemangioma. J Cutan Pathol.
1991;18:235–240.
157. Aloi F, Tomasini C, Pippione M. Microvenular hemangioma. Am J
Dermatopathol. 1993;15:534–538.
158. Xu XL, Xu CR, Chen H, et al. Eruptive microvenular hemangiomas in 4
Chinese patients: clinicopathologic correlation and review of the literature.
Am J Dermatopathol. 2010;32:837–840.
159. Sánz-Trelles A, Ojeda-Martos A, Jiménez-Fernández A, et al. Microvenular
hemangioma: a new case in a child. Histopathology. 1998;32:89–90.
160. Hudnall SD, Chen T, Brown K, et al. Human herpesvirus-8–positive
microvenular hemangioma in POEMS syndrome. Arch Pathol Lab Med.
2003;127:1034–1036.
161. Santa Cruz DJ, Aronberg J. Targetoid hemosiderotic hemangioma. J Am Acad
Dermatol. 1988;19:550–558.162. Guillou L, Calonje E, Speight P, et al. Hobnail hemangioma: a
pseudomalignant vascular lesion with a reappraisal of targetoid
hemosiderotic hemangioma. Am J Surg Pathol. 1999;23:97–105.
163. Mentzel T, Partanen TA, Kutzner H. Hobnail hemangioma (“targetoid
hemosiderotic hemangioma”): clinicopathologic and immunohistochemical
analysis of 62 cases. J Cutan Pathol. 1999;26:279–286.
164. Christenson LJ, Stone MS. Trauma-induced simulator of targetoid
hemosiderotic hemangioma. Am J Dermatopathol. 2001;23:221–223.
165. Carlson JA, Daulad S, Godheart HP. Targetoid hemosiderotic hemangioma—a
dynamic vascular tumor: report of 3 cases with episodic and cyclic changes
and comparison with solitary angiokeratomas. J Am Acad Dermatol.
1999;41:215–224.
166. Calonje E, Fletcher C D M, Wilson-Jones E, et al. Retiform
hemangioendothelioma: a distinctive form of low-grade angiosarcoma
delineated in a series of 15 cases. Am J Surg Pathol. 1994;18:115–125.
167. Gutzmer R, Kaspari M, Herbst RA, et al. Absence of HHV-8 DNA in hobnail
hemangioma. J Cutan Pathol. 2002;29:154–158.
168. Requena L, Kutzner H, Mentzel T. Acquired elastotic hemangioma: a
clinicopathologic variant of hemangioma. J Am Acad Dermatol. 2002;47:371–
376.
169. Brenn T, Fletcher C D M. Cutaneous epithelioid angiomatous nodule: a
distinct lesion in the morphologic spectrum of epithelioid vascular tumors.
Am J Dermatopathol. 2004;26:14–21.
170. Sangueza OP, Walsh SN, Sheehan DJ, et al. Cutaneous epithelioid
angiomatous nodule: a case series and proposed classification. Am J
Dermatopathol. 2008;30:16–20.
171. Wells GC, Whimster IW. Subcutaneous angiolymphoid hyperplasia with
eosinophilia. Br J Dermatol. 1969;81:1–15.
172. Wilson-Jones E, Bleehen SS. Inflammatory angiomatous nodules with
abnormal blood vessels occurring about the ears and scalp (pseudo or atypical
pyogenic granuloma). Br J Dermatol. 1969;81:804–816.
173. Wilson-Jones E, Marks R. Papular angioplasia. Vascular papules of the face
and scalp simulating malignant vascular tumors. Arch Dermatol. 1970;102:422–
427.
174. Rosai J, Akerman LR. Intravenous atypical vascular proliferation. A cutaneous
lesion simulating a malignant blood vessel tumor. Arch Dermatol.
1974;109:714–717.
175. Rosai J, Gold J, Landy R. The histiocytoid hemangiomas. A unifying concept
embracing several previously described entities of skin, soft tissue, large
vessels, bone and heart. Hum Pathol. 1979;10:707–730.
176. Cooper PH. Is histiocytoid hemangioma a specific pathologic entity? Am J
Surg Pathol. 1988;12:815–817.
177. Rosai J. Angiolymphoid hyperplasia with eosinophilia of the skin. Its
nosological position in the spectrum of histiocytoid hemangioma. Am J
Dermatopathol. 1982;4:175–184.
178. Allen PW, Ramakrishna B, MacCormac LB. The histiocytoid hemangiomas and
other controversies. Pathol Annu. 1992;27(Pt 1):51–87.
179. Tsang W Y W, Chan J K C. The family of epithelioid vascular tumors. Histol
Histopathol. 1993;8:187–212.180. Fetsch JF, Weiss SW. Observations concerning the pathogenesis of epithelioid
hemangioma (angiolymphoid hyperplasia). Mod Pathol. 1991;4:449–455.
181. Olsen TG, Helwig EB. Angiolymphoid hyperplasia with eosinophilia. A
clinicopathologic study of 116 patients. J Am Acad Dermatol. 1985;12:781–796.
182. Castro C, Winkelmann RK. Angiolymphoid hyperplasia with eosinophilia in
the skin. Cancer. 1974;34:1696–1705.
183. Razquin S, Mayayo E, Citores MA, et al. Angiolymphoid hyperplasia with
eosinophilia of the tongue: report of a case and review of the literature. Hum
Pathol. 1991;22:837–839.
184. Park Y, Chung J, Cho CG. Angiolymphoid hyperplasia with eosinophilia of the
tongue: report of a case and review of the literature. Oral Oncol. 2002;38:103–
106.
185. Bartralot R, García-Patos V, Hueto J, et al. Angiolymphoid hyperplasia with
eosinophilia affecting the oral mucosa: report of a case and a review of the
literature. Br J Dermatol. 1996;134:744–748.
186. Mariatos G, Gorgoulis VG, Laskaris G, et al. Epithelioid hemangiomas
(angiolymphoid hyperplasia with eosinophilia) in the oral mucosa. A case
report and review of the literature. Oral Oncol. 1999;35:435–438.
187. Tsuboi H, Fujimura T, Katsuoka K. Angiolymphoid hyperplasia with
eosinophilia in the oral mucosa. Br J Dermatol. 2001;145:365–366.
188. Nair M, Aron M, Sharma MC. Angiolymphoid hyperplasia with eosinophilia
(epithelioid hemangioma) of the breast: report of a case. Surg Today.
2000;30:747–749.
189. Suster S. Nodal angiolymphoid hyperplasia with eosinophilia. Am J Clin
Pathol. 1987;88:236–239.
190. O’Connell JX, Kattapuram SV, Mankin HJ, et al. Epithelioid hemangioma of
bone. A tumor often mistaken for low-grade angiosarcoma or malignant
hemangioendothelioma. Am J Surg Pathol. 1993;17:610–617.
191. Banks ER, Mills SE. Histiocytoid (epithelioid) hemangioma of the testis. The
so-called vascular variant of “adenomatoid tumor. Am J Surg Pathol.
1990;14:584–589.
192. Madison JF, Cooper PH. A histiocytoid (epithelioid) vascular tumor of the
ovary: occurrence within a benign cystic teratoma. Mod Pathol. 1989;2:55–58.
193. Luthringer DJ, Virmani R, Weiss SW, et al. A distinctive cardiovascular lesion
resembling histiocytoid/epithelioid hemangioma, evidence suggesting
mesothelial participation. Am J Surg Pathol. 1990;14:993–1000.
194. Chan JK, Loo KT, Yau BK, et al. Nodular histiocytic/mesothelial hyperplasia: a
lesion potentially mistaken for a neoplasm in transbronchial biopsy. Am J
Surg Pathol. 1997;21:658–663.
195. Oksenhendler E, Cazals-Hatem D, Schulz TF, et al. Transient angiolymphoid
hyperplasia and Kaposi's sarcoma after primary infection with human
herpesvirus 8 in a patient with human immunodeficiency virus infection. N
Engl J Med. 1998;338:1585–1590.
196. Jang KA, Ahn SJ, Choi JH, et al. Polymerase chain reaction (PCR) for human
herpesvirus 8 and heteroduplex PCR for clonality assessment in
angiolymphoid hyperplasia with eosinophilia and Kimura's disease. J Cutan
Pathol. 2001;28:363–367.
197. Onishi Y, Ohara K. Angiolymphoid hyperplasia with eosinophilia associated
with arteriovenous malformation: a clinicopathological correlation withangiography and serial estimation of serum levels of renin, eosinophilic
cationic protein and interleukin 5. Br J Dermatol. 1999;140:1153–1156.
198. Reed RJ, Terazakis N. Subcutaneous angiolymphoid hyperplasia with
eosinophilia (Kimura's disease). Cancer. 1972;29:489–497.
199. Morton K, Robertson AJ, Hadden W. Angiolymphoid hyperplasia with
eosinophilia: report of a case arising from the radial artery. Histopathology.
1987;11:963–969.
200. Kung IT, Gibson JB, Bannatyne PM. Kimura's disease: a clinicopathological
study of 21 cases and its distinction from angiolymphoid hyperplasia with
eosinophilia. Pathology. 1984;16:39–44.
201. Urabe A, Tsuneyoshi M, Enjoji M. Epithelioid hemangioma versus Kimura's
disease. A comparative clinicopathologic study. Am J Surg Pathol. 1987;10:758–
766.
202. Googe PB, Harris NL, Mihm M C J. Kimura's disease and angiolymphoid
hyperplasia with eosinophilia: two distinct clinicopathological entities. J Cutan
Pathol. 1987;15:263–271.
203. Kuo TT, Shih LY, Chan HL. Kimura's disease, involvement of regional lymph
nodes and distinction from angiolymphoid hyperplasia with eosinophilia. Am
J Surg Pathol. 1988;12:843–854.
204. Chan JK, Hui PK, Ng CS, et al. Epithelioid haemangioma (angiolymphoid
hyperplasia with eosinophilia) and Kimura's disease in Chinese.
Histopathology. 1989;15:557–574.
205. Fawcett HA, Smith NP. Injection site granuloma due to aluminium. Arch
Dermatol. 1984;120:1318–1322.
206. Miliauskas JR, Mukherjee T, Dixon B. Postimmunization (vaccination)
injection-site reactions. A report of four cases and review of the literature. Am
J Surg Pathol. 1993;17:516–524.
207. Chong H, Brady K, Metze D, et al. Persistent nodules at injection sites
(aluminium granuloma)—clinicopathological study of 14 cases with a diverse
range of histological reaction patterns. Histopathology. 2006;48:182–188.
208. Weiss SW, Goldblum JR. Soft tissue tumors. 4th ed. Mosby: Philadelphia; 2001
[p 593].
209. Weiss SW, Enzinger FM. Spindle cell hemangioendothelioma, a low grade
angiosarcoma resembling a cavernous hemangioma and Kaposi's sarcoma.
Am J Surg Pathol. 1986;10:521–530.
210. Tosios KI, Gouveris I, Sklavounou A, et al. Spindle cell hemangioma
(hemangioendothelioma) of the head and neck: case report of an unusual (or
underdiagnosed) tumor. Oral Surg Oral Med Oral Pathol Oral Radiol Endod.
2008;105:216–221.
211. Fletcher C D M, Beham A, Schmid C. Spindle cell hemangioendothelioma: a
clinicopathological and immunohistochemical study indicative of a
nonneoplastic lesion. Histopathology. 1991;18:291–301.
212. Perkins P, Weiss SW. Spindle cell hemangioendothelioma: an analysis of 78
cases with reassessment of its pathogenesis and biologic behavior. Am J Surg
Pathol. 1996;20:1196–1204.
213. Scott GA, Rosai J. Spindle cell hemangioendothelioma. Report of seven
additional cases of a recently described vascular neoplasm. Am J
Dermatopathol. 1988;10:281–288.
214. Fanburg JC, Meis-Kindblom JM, Rosenberg AC. Multiple enchondromasassociated with spindle-cell hemangioendotheliomas. An overlooked variant
of Maffucci's syndrome. Am J Surg Pathol. 1995;19:1029–1038.
215. Imayama S, Murakamai Y, Hashimoto H, et al. Spindle cell
hemangioendothelioma exhibits the ultrastructural features of reactive
vascular proliferation rather than of angiosarcoma. Am J Clin Pathol.
1992;97:279–287.
216. Ding J, Hashimoto H, Imayama S, et al. Spindle cell hemangioendothelioma:
probably a benign vascular lesion not a low-grade angiosarcoma. A
clinicopathological, ultrastructural and immunohistochemical study.
Virchow's Arch [A]. 1992;420:77–85.
217. Fletcher C D M. Vascular tumors: an update with emphasis on the diagnosis
of angiosarcoma and borderline vascular neoplasms. Weiss S W, Brooks J S J.
Soft tissue tumors. Monographs in pathology. Williams & Wilkins: Baltimore;
1996:181–206.
218. Pansuriya TC, van Eijk R, d’Adamo P, et al. Somatic mosaic IDH1 and IDH2
mutations are associated with enchondroma and spindle cell hemangioma in
Ollier disease and Maffucci syndrome. Nat Genet. 2011;43:1256–1261.
219. Zoltie N, Roberts PF. Spindle cell haemangioendothelioma in association with
epithelioid haemangioendothelioma. Histopathology. 1989;15:544–546.
220. Tsang W Y W, Chan J K C, Fletcher C D M, et al. Symplastic hemangioma: a
distinctive vascular neoplasm featuring bizarre stromal cells. Int J Surg Pathol.
1994;1:202.
221. Kutzner H, Winzer M, Mentzel T. [Symplastic hemangioma]. Hautarzt.
2000;51:327–329.
222. Goh N, Dayrit J, Calonje E. Symplastic hemangioma. Report of two cases. J
Cutan Pathol. 2006;33:735–749.
223. Allen PW, Enzinger FM. Hemangioma of skeletal muscle. An analysis of 89
cases. Cancer. 1972;29:8–22.
224. Fergusson IL. Haemangiomata of skeletal muscle. Br J Surg. 1972;59:634–637.
225. Beham A, Fletcher C D M. Intramuscular angioma: a clinicopathological
analysis of 74 cases. Histopathology. 1991;18:53–59.
226. Lin JJ, Lin F. Two entities in angiolipoma. A study of 459 cases of lipoma with
review of the literature on infiltrating angiolipoma. Cancer. 1974;34:720–727.
227. Devaney K, Vinh TZ, Sweet DE. Synovial hemangioma: a report of 20 cases
with differential diagnostic considerations. Hum Pathol. 1993;24:737–745.
228. Losli EJ. Intrinsic hemangioma of the peripheral nerves: a report of two cases
and a review of the literature. Arch Pathol. 1952;53:226–232.
229. Wood MB. Intraneural hemangioma: report of a case. Plast Reconstr Surg.
1980;65:74–76.
230. Vigna PA, Kusior MF, Collins MB, et al. Peripheral nerve hemangioma.
Potential for clinical aggressiveness. Arch Pathol Lab Med. 1994;118:1038–1041.
231. Kim DH, Kang JW, Park JW. Multilevel ulnar neuropathy caused by multiple
intraneural hemangiomas. Muscle Nerve. 2010;41:562–566.
232. Rao VK, Weiss SW. Angiomatosis of soft tissue. An analysis of the histologic
features and clinical outcome in 51 cases. Am J Surg Pathol. 1992;16:764–771.
233. Howat AJ, Campbell PE. Angiomatosis: a vascular malformation of infancy
and childhood. Report of 17 cases. Pathology. 1987;19:377–382.
234. Kraus MD, Lind AC, Alder SL, et al. Angiomatosis with angiokeratoma-like
features in children: a light microscopic and immunophenotypic examinationof four cases. Am J Dermatopathol. 1999;21:350–355.
235. Fletcher C D M. Borderline malignancy in soft tissue neoplasia—a meaningful
concept? Pathol Case Rev. 1998;3:100–104.
236. Fletcher C D M, Unni KK, Mertens F. World Health Organization classification of
tumours. Pathology and genetics. Tumours of soft tissue and bone. IARC Press:
Lyon, France; 2002.
237. Tsang W Y W, Chan J K C. Kaposi-like infantile hemangioendothelioma. A
distinctive vascular neoplasm of the retroperitoneum. Am J Surg Pathol.
1991;15:982–989.
238. Tsang W Y W, Chan J K C, Fletcher C D M. Recently characterized vascular
tumours of skin and soft tissues. Histopathology. 1991;19:489–501.
239. Zukerberg LR, Nickoloff BJ, Weiss SW. Kaposiform hemangioendothelioma of
infancy and childhood. An aggressive neoplasm associated with
KasabachMerritt syndrome and lymphangiomatosis. Am J Surg Pathol. 1993;17:321–328.
240. Lyons LL, North PE, Lai F M M, et al. Kaposiform hemangioendothelioma. A
study of 33 cases emphasizing its pathologic, immunophenotypic, and
biologic uniqueness from juvenile hemangioma. Am J Surg Pathol.
2004;28:559–568.
241. Vin-Christian K, McCalmont TH, Frieden IJ. Kaposiform
hemangioendothelioma. An aggressive, locally invasive vascular tumor that
can mimic hemangioma of infancy. Arch Dermatol. 1997;133:1573–1578.
242. Lai F M M, Choi P C L, Leung PC, et al. Kaposiform hemangioendothelioma:
five patients with cutaneous lesions and long follow-up. Mod Pathol.
2001;14:1087–1092.
243. Deraedt K, Vander Poorten V, Van Geet C, et al. Multifocal kaposiform
hemangioendothelioma. Virchows Arch. 2006;448:843–846.
244. Mentzel T, Mazzoleni G, Dei Tos AP, et al. Kaposiform
hemangioendothelioma in adults. Clinicopathologic and
immunohistochemical analysis of three cases. Am J Clin Pathol. 1997;108:450–
455.
245. Halsley-Royster C, Enjolras O, Frieden IJ, et al. Kasabach-Merritt
phenomenon: a retrospective study of treatment with vincristine. J Pediatr
Hematol Oncol. 2002;24:459–462.
246. Lee Huu AR, Jokinen CH, Ruben BP, et al. Expression of prox1, lymphatic
endothelial nuclear transcription factor, in kaposiform
hemangioendothelioma and tufted angioma. Am J Surg Pathol. 2010;34:1563–
1573.
247. Dadras SS, Skrzypek A, Nguyen L, et al. Prox-1 promotes invasion of
kaposiform hemangioendothelioma. J Invest Dermatol. 2008;128:2798–2806.
248. Gonzalez-Crussi F, Choud P, Crawford SE. Congenital infiltrating giant cell
angioblastoma, a new entity? Am J Surg Pathol. 1991;15:175–183.
249. Vargas SO, Pérez-Atayde AR, Gonzalez-Crussi F, et al. Giant cell
angioblastoma: three additional occurrences of a distinct pathologic entity.
Am J Surg Pathol. 2001;25:185–196.
250. Dufau JP, Pierre C, De SaintMaur PP, et al. Hemangioendothelioma retiforme.
Ann Pathol. 1997;17:47–51.
251. Fukunaga M, Endo Y, Masui F, et al. Retiform haemangioendothelioma.
Virchows Arch. 1996;428:301–304.
252. Duke D, Dvorak A, Harris TJ, et al. Multiple retiformhemangioendotheliomas. A low-grade angiosarcoma. Am J Dermatopathol.
1996;18:606–610.
253. Mentzel T, Stengel B, Katenkamp D. Retiform hemangioendothelioma.
Clinico-pathologic case report and discussion of the group of low-grade
malignancy vascular tumors. Pathologe. 1997;18:390–394.
254. Dabska M. Malignant endovascular papillary angioendothelioma of the skin in
childhood. Clinicopathologic study of 6 cases. Cancer. 1969;24:503–510.
255. Fanburg-Smith JC, Michal M, Partanen T, et al. Papillary intralymphatic
angioendothelioma (PILA). A report of twelve cases of a distinctive vascular
tumor with phenotypic features of lymphatic vessels. Am J Surg Pathol.
1999;23:1004–1010.
256. Manivel JC, Wick MR, Swanson PE, et al. Endovascular papillary
angioendothelioma of childhood: a vascular lesion possibly characterized by
“high” endothelial cell differentiation. Hum Pathol. 1986;17:1240–1244.
257. Hornick JL, Fletcher C D M. Pseudomyogenic hemangioendothelioma: a
distinctive, often multicentric tumor with indolent behavior. Am J Surg Pathol.
2011;35:190–201.
258. Billings SD, Folpe AL, Weiss SW. Epithelioid sarcoma-like
hemangioendothelioma. Am J Surg Pathol. 2003;27:48–57.
259. Trombetta D, Magnusson L, von Steyern FH, et al. Translocation t(7;19)
(q22;q13)—a recurrent chromosome aberration in pseudomyogenic
hemangioendothelioma? Cancer Genet. 2011;204:211–215.
260. Nayler SJ, Rubin BP, Calonje E, et al. Composite hemangioendothelioma: a
complex low-grade vascular lesion mimicking angiosarcoma. Am J Surg Pathol.
2000;24:352–361.
261. Reis-Filho JS, Paiva ME, Lopes JM. Congenital composite
hemangioendothelioma: case report and reappraisal of the
hemangioendothelioma spectrum. J Cutan Pathol. 2002;29:226–231.
262. Fukunaga M, Suzuki K, Saegusa N, et al. Composite hemangioendothelioma:
report of 5 cases including one with associated Maffucci syndrome. Am J Surg
Pathol. 2007;31:1567–1572.
263. Chan J K C, Frizzera G, Fletcher C D M, et al. Primary vascular tumors of
lymph nodes other than Kaposi's sarcoma. Analysis of 39 cases and
delineation of two new entities. Am J Surg Pathol. 1992;16:335–350.
264. Nascimento AG, Keeney GL, Sciot R, et al. Polymorphous
hemangioendothelioma: a report of two cases, one affecting extranodal soft
tissues, and review of the literature. Am J Surg Pathol. 1997;21:1083–1089.
265. Templeton AC. Kaposi's sarcoma. Pathol Annu. 1981;16:315–336.
266. Gottlieb GJ, Ackerman AB. Kaposi's sarcoma: an extensively disseminated
form in young homosexual men. Hum Pathol. 1982;13:882–892.
267. Gottlieb GJ, Ackerman AB. Kaposi's sarcoma: a text and an atlas. Lea & Febiger:
Philadelphia; 1988.
268. Dorfman RF. Kaposi's sarcoma revisited. Hum Pathol. 1984;15:1013–1017.
269. Krigel RL, Friedman-Kien AE. Epidemic Kaposi's sarcoma. Semin Oncol.
1990;17:350–360.
270. Chor PJ, Santa Cruz DJ. Kaposi's sarcoma. A clinicopathologic review and
differential diagnosis. J Cutan Pathol. 1992;19:6–20.
271. Tappero JW, Conant MA, Wolfe SF, et al. Kaposi's sarcoma. Epidemiology,
pathogenesis, histology, clinical spectrum, staging criteria and therapy. J AmAcad Dermatol. 1993;28:371–395.
272. Beckstead JH, Wood GS, Fletcher V. Evidence for the origin of Kaposi's
sarcoma from lymphatic endothelium. Am J Pathol. 1985;119:294–300.
273. Russell Jones R, Spaull J, Spry C, et al. Histogenesis of Kaposi's sarcoma in
patients with and without acquired immune deficiency syndrome (AIDS). J
Clin Pathol. 1986;39:742–744.
274. Rutgers JL, Wieczorek R, Bonetti F, et al. The expression of endothelial cell
surface antigens by AIDS-associated Kaposi's sarcoma. Evidence for a
vascular endothelial cell origin. Am J Pathol. 1986;122:493–499.
275. Regezi JA, MacPhail LA, Daniels TE, et al. Human immunodeficiency virus–
associated oral Kaposi's sarcoma. A heterogeneous cell population dominated
by spindle-shaped endothelial cells. Am J Pathol. 1993;143:240–249.
276. Weninger W, Partanen TA, Breiteneder-Geleff S, et al. Expression of vascular
endothelial growth factor receptor-3 and podoplanin suggests a lymphatic
endothelial cell origin of Kaposi's sarcoma tumor cells. Lab Invest. 1999;79:243–
251.
277. Grody WW, Lewin KJ, Naeim F. Detection of cytomegalovirus DNA in classic
and epidemic Kaposi's sarcoma by in situ hybridization. Hum Pathol.
1988;19:524–528.
278. Ioachim HL, Dorsett B, Melamed J, et al. Cytomegalovirus, angiomatosis, and
Kaposi's sarcoma: new observations of a debated relationship. Mod Pathol.
1992;5:169–178.
279. Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus-like DNA
sequences in AIDS-associated Kaposi's sarcoma. Science. 1994;266:1865–1869.
280. Cesarman E, Knowles DM. Kaposi's sarcoma-associated herpesvirus: a
lymphotropic human herpesvirus associated with Kaposi's sarcoma, primary
effusion lymphoma and multicentric Castleman's disease. Semin Diagn Pathol.
1997;14:54–66.
281. Kennedy MM, Lucas SB, Jones RR, et al. HHV-8 and Kaposi's sarcoma: a time
cohort study. J Clin Pathol Mol Pathol. 1997;50:96–100.
282. Renne R, Zhong W, Herndier B, et al. Lytic growth of Kaposi's
sarcomaassociated herpesvirus (human herpesvirus 8) in culture. Nature Med.
1996;2:342–346.
283. O’Leary JJ, Kennedy MM, McGee JO. Kaposi's sarcoma associated herpes virus
(KSHV/HHV8): epidemiology, molecular biology and tissue distribution.
Molec Pathol. 1997;5:4–8.
284. Boshoff C, Talbot S, Kennedy M, et al. HHV-8 and skin cancers in
immunosuppressed patients. Lancet. 1996;347:338–339.
285. McDonagh DP, Liu J, Gaffey MJ, et al. Detection of Kaposi's
sarcomaassociated herpes virus-type DNA sequences in angiosarcoma. Am J Pathol.
1996;149:1363–1368.
286. Lebbe C, Pellet C, Avril MF, et al. Sequences of human herpesvirus 8 are not
detected in various non-Kaposi sarcoma vascular lesions. Arch Dermatol.
1997;133:919–920.
287. Lasota J, Miettinen M. Absence of Kaposi's sarcoma-associated virus (human
herpes virus-8) sequences in angiosarcoma. Virchows Arch. 1999;434:51–56.
288. Bayley AC, Lucas SB. Kaposi's sarcoma or Kaposi's disease? A personal
reappraisal. Fletcher C D M, McKee P H. The pathobiology of soft tissue tumours.
Churchill Livingstone: Edinburgh; 1990.289. Rabkin CS, Janz S, Lash A, et al. Monoclonal origin of multicentric Kaposi's
sarcoma lesions. N Engl J Med. 1997;336:988–993.
290. Delabesse E, Oksenhendler E, Lebbe C, et al. Molecular analysis of clonality in
Kaposi's sarcoma. J Clin Pathol. 1997;50:664–668.
291. Gill PS, Tsai YC, Rao AP, et al. Evidence for multiclonality in multicentric
Kaposi's sarcoma. Proc Natl Acad Sci USA. 1998;95:8257–8261.
292. Duprez R, Lacoste V, Briere J, et al. Evidence for a multiclonal origin of
multicentric advanced lesions of Kaposi sarcoma. J Natl Cancer Inst.
2007;99:1086–1094.
293. Sahin G, Palanduz A, Avdogan G, et al. Classic Kaposi sarcoma in 3 unrelated
Turkish children born to consanguineous kindreds. Pediatrics. 2010;125:e704–
708.
294. Moskowitz LB, Hensley GT, Gould EW, et al. Frequency and anatomic
distribution of lymphadenopathic Kaposi's sarcoma in the acquired
immunodeficiency syndrome: an autopsy series. Hum Pathol. 1985;16:447–456.
295. Lemlich G, Schwam L, Lebwohl M. Kaposi's sarcoma and acquired
immunodeficiency syndrome: postmortem findings in twenty-four cases. J Am
Acad Dermatol. 1987;16:319–325.
296. Papagatsia Z, Jones J, Morgan P, et al. Oral Kaposi's sarcoma: a case of
immune reconstitution inflammatory syndrome. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod. 2009;108:70–75.
297. Gange RW, Wilson Jones E. Kaposi's sarcoma and immunosuppressive
therapy: an appraisal. Clin Exp Dermatol. 1978;3:135–146.
298. Stribling J, Weitzner S, Smith GV. Kaposi's sarcoma in renal allograft
recipients. Cancer. 1978;42:442–446.
299. Dutz W, Stout AP. Kaposi's sarcoma in infants and children. Cancer.
1960;13:684–693.
300. Dorfman RF. Kaposi's sarcoma. With special reference to its manifestations in
infants and children and to the concepts of Arthur Purdy Stout. Am J Surg
Pathol. 1986;10(Suppl 1):68–77.
301. Kao GF, Johnson FB, Sulica VI. The nature of hyaline (eosinophilic) globules
and vascular slits of Kaposi's sarcoma. Am J Dermatopathol. 1990;12:256–267.
302. Luzar B, Antony F, Ramdial PK, et al. Intravascular Kaposi's sarcoma—a
hitherto unrecognized phenomenon. J Cutan Pathol. 2007;34:861–864.
303. Dubina M, Goldenberg G. Positive staining of tumor-stage Kaposi sarcoma
with lymphatic marker D2-40. J Am Acad Dermatol. 2009;61:276–280.
304. Gange RW, Wilson Jones E. Lymphangioma-like Kaposi's sarcoma. A report of
three cases. Br J Dermatol. 1979;100:327–334.
305. Cossu S, Satta R, Cottoni F, et al. Lymphangioma-like variant of Kaposi's
sarcoma. Clinicopathologic study of seven cases with review of the literature.
Am J Dermatopathol. 1997;19:16–22.
306. O’Connell KM. Kaposi's sarcoma: histopathological study of 159 cases from
Malawi. J Clin Pathol. 1977;30:687–695.
307. Satta R, Cossu S, Massarelli G, et al. Anaplastic transformation of classic
Kaposi's sarcoma: clinicopathological study of five cases. Br J Dermatol.
2001;145:847–849.
308. Pantanowitz L, Dezube BJ, Pinkus GS, et al. Histological characterization of
regression in acquired immunodeficiency syndrome–related Kaposi's
sarcoma. J Cutan Pathol. 2004;31:26–34.309. Ramdial PK, Sing Y, Subravan S, et al. Cutaneous colesional acquired
immunodeficiency syndrome associated Kaposi's sarcoma and cryptococcosis.
Am J Dermatopathol. 2010;32:780–786.
310. Ramdial PK, Sing Y, Subravan S, et al. Granulomas in acquired
immunodeficiency syndrome-associated Kaposi sarcoma: evidence for a role
for Mycobacterium tuberculosis. J Cutan Pathol. 2010;37:827–834.
311. Pietras TA, Baum CL, Swick BL. Coexistent Kaposi sarcoma, cryptococcosis
and Mycobacterium avium intracellulare in a solitary cutaneous nodule in a
patient with AIDS: report of a case and literature review. J Am Acad Dermatol.
2010;62:676–680.
312. Cheuk W, Wong KO, Wong CS, et al. Immunostaining for human herpesvirus
8 latent nuclear antigen-1 helps distinguish Kaposi sarcoma from its
mimickers. Am J Clin Pathol. 2004;121:335–342.
313. Robin YM, Guillou L, Michels JJ, et al. Human herpesvirus 8 immunostaining:
a sensitive and specific method for diagnosing Kaposi sarcoma in
paraffinembedded sections. Am J Clin Pathol. 2004;121:330–334.
314. Wilson Jones E, Cerio R, Smith NP. Multinucleate cell angiohistiocytoma: an
acquired vascular anomaly to be distinguished from Kaposi's sarcoma. Br J
Dermatol. 1990;122:651–653.
315. Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma. A vascular
tumor often mistaken for a carcinoma. Cancer. 1982;50:970–981.
316. Weiss SW, Ishak KG, Dail DH, et al. Epithelioid hemangioendothelioma and
related lesions. Semin Diagn Pathol. 1986;3:259–287.
317. Mentzel T, Beham A, Calonje E, et al. Epithelioid hemangioendothelioma of
skin and soft tissues: clinicopathologic and immunohistochemical study of 30
cases. Am J Surg Pathol. 1997;21:363–374.
318. Angervall L, Kindblom L-G, Karlsson K, et al. Atypical
hemangioendothelioma of venous origin. A clinicopathologic, angiographic,
immunohistochemical and ultrastructural study of two endothelial tumors
within the concept of histiocytoid hemangioma. Am J Surg Pathol. 1985;9:504–
516.
319. Dail DH, Liebow AA, Gmelich JT, et al. Intravascular, bronchiolar and
alveolar tumor of the lung (IVBAT). Cancer. 1983;51:452–464.
320. Makhlouf HR, Ishak KG, Goodman ZD. Epithelioid hemangioendothelioma of
the liver: a clinicopathologic study of 137 cases. Cancer. 1999;85:562–582.
321. Tsuneyoshi M, Dorfman HD, Bauer TW. Epithelioid hemangioendothelioma
of bone. A clinicopathologic, ultrastructural and immunohistochemical study.
Am J Surg Pathol. 1986;10:754–764.
322. Lin BT, Colby T, Gown AM, et al. Malignant vascular tumors of the serous
membranes mimicking mesothelioma. A report of 14 cases. Am J Surg Pathol.
1996;20:1431–1439.
323. Quante M, Patel NK, Hill S, et al. Epithelioid hemangioendothelioma
presenting in the skin. A clinicopathologic study of eight cases. Am J
Dermatopathol. 1998;20:541–546.
324. Tyring S, Guest P, Lee P, et al. Epithelioid hemangioendothelioma of the skin
and femur. J Am Acad Dermatol. 1989;20:362–366.
325. Resnik KS, Kantor GR, Spielvogel RL, et al. Cutaneous epithelioid
hemangioendothelioma without systemic involvement. Am J Dermatopathol.
1993;15:272–276.326. Polk P, Webb JM. Isolated cutaneous epithelioid hemangioendothelioma. J
Am Acad Dermatol. 1997;36:1026–1028.
327. Lee KC, Chan J K C. Epithelioid haemangioendothelioma presenting as a
gastric polyp. Histopathology. 1988;16:335–337.
328. Egberts F, Mentzel T, Leuschner I, et al. Metastasizing epithelioid
hemangioendothelioma of the nose in childhood. J Cutan Pathol.
2008;35(Suppl 1):80–82.
329. Suster S, Moran CA, Koss MN. Epithelioid hemangioendothelioma of the
anterior mediastinum. Clinicopathologic, immunohistochemical and
ultrastructural analysis of 12 cases. Am J Surg Pathol. 1994;18:871–881.
330. Roh HS, Kim YS, Suhr KB, et al. A case of childhood epithelioid
hemangioendothelioma. J Am Acad Dermatol. 2000;42:897–899.
331. Kiryu H, Hashimoto H, Hori Y. Ossifying epithelioid hemangioendothelioma.
J Cutan Pathol. 1996;23:558–561.
332. Lamovec J, Sobel H, Zidon A, et al. Epithelioid hemangioendothelioma of the
anterior mediastinum with osteoclast-like giant cells. Am J Clin Pathol.
1990;93:813–817.
333. Williams SB, Bulter CB, Gilkey GW, et al. Epithelioid hemangioendothelioma
with osteoclast like giant cells. Arch Pathol Lab Med. 1993;117:315–318.
334. Silva EG, Philips MJ, Langer B, et al. Spindle and histiocytoid (epithelioid)
haemangioendothelioma, primary in lymph node. Am J Clin Pathol.
1986;85:731–735.
335. Suster S. Epithelioid and spindle-cell hemangioendothelioma of the spleen,
report of a distinctive splenic vascular neoplasm of childhood. Am J Surg
Pathol. 1992;16:785–792.
336. Deyrup AT, Tighiouart M, Montag AG, et al. Epithelioid
hemangioendothelioma of soft tissue: a proposal for risk stratification based
on 49 cases. Am J Surg Pathol. 2008;32:924–927.
337. Fuji T, Zen Y, Sato Y, et al. Podoplanin is a useful marker for epithelioid
hemangioendothelioma of the liver. Mod Pathol. 2008;21:125–130.
338. Weinreb I, Cunningham KS, Perez-Ordonez B, et al. CD10 is expressed in
most epithelioid hemangioendotheliomas: a potential diagnostic pitfall. Arch
Pathol Lab Med. 2009;133:1965–1968.
339. Van Haelst U J G M, Pruszczynski M, Ten Cate LN, et al. Ultrastructural and
immunohistochemical study of epithelioid hemangioendothelioma of bone:
coexpression of epithelial and endothelial markers. Ultrastruct Pathol.
1990;14:141–149.
340. Gray MF, Rosenberg AE, Dickersin GR, et al. Cytokeratin expression in
epithelioid vascular neoplasms. Hum Pathol. 1990;21:212–217.
341. Mendick MR, Nelson M, Pickering D, et al. Translocation t(1;3)(p36.3;q25) is a
nonrandom aberration in epithelioid hemangioendothelioma. Am J Surg
Pathol. 2001;25:684–687.
342. He M, Das K, Blakcsin M, et al. A translocation involving the placental growth
factor gene is identified in epithelioid hemangioendothelioma. Cancer Genet
Cytogenet. 2006;168:150–154.
343. Errani C, Zhang L, Sung YS, et al. A novel WWTR1-CAMTA1 gene fusion is a
consistent abnormality in epithelioid hemangioendothelioma of different
anatomic sites. Genes Chromos Cancer. 2011;50:644–653.
344. Tanas MR, Sboner A, Oliveira A, et al. Identification of a disease-defininggene fusion in epithelioid hemangioendothelioma. Sci Transl Med.
2011;3:98ra82.
345. Mankey CC, McHugh JB, Thomas DG, et al. Can lymphangiosarcoma be
resurrected? A clinicopathological and immunohistochemical study of
lymphatic differentiation in 49 angiosarcomas. Histopathology. 2010;56:364–
371.
346. Wilson Jones E. Malignant angioendothelioma of skin. Br J Dermatol.
1964;76:21–39.
347. Girard C, Johnson WC, Graham JH. Cutaneous angiosarcoma. Cancer.
1970;26:868–883.
348. Rosai J, Summer HW, Kostianovsky M, et al. Angiosarcoma of the skin. A
clinicopathologic and fine structural study. Hum Pathol. 1976;7:83–109.
349. Wilson Jones E. Malignant vascular tumours. Clin Exp Dermatol. 1976;1:287–
312.
350. Maddox JC, Evans HL. Angiosarcoma of skin and soft tissues: a study of
fortyfour cases. Cancer. 1981;48:1907–1921.
351. Cooper PH. Angiosarcomas of the skin. Semin Diagn Pathol. 1987;4:2–17.
352. Albores-Saavedra J, Schwartz AM, Henson DE, et al. Cutaneous
angiosarcoma. Analysis of 434 cases from the Surveillance, Epidemiology and
End Results Program, 1973-2007. Ann Diagn Pathol. 2011;15:93–97.
353. Ghandur-Mnaymneh L, Gonzales MS. Angiosarcoma of the penis with hepatic
angiomas in a patient with low vinyl chloride exposure. Cancer. 1981;47:1318–
1324.
354. Abratt RP, Williams M, Raff M, et al. Angiosarcoma of the superior vena cava.
Cancer. 1983;52:740–743.
355. Rossi S, Fletcher C D M. Angiosarcoma arising in hemangioma/vascular
malformation: report of four cases and review of the literature. Am J Surg
Pathol. 2002;26:1319–1329.
356. Mentzel T, Katenkamp D. Intraneural angiosarcoma and angiosarcoma arising
in benign and malignant peripheral nerve sheath tumours: clinicopathological
and immunohistochemical analysis of four cases. Histopathology. 1999;35:114–
120.
357. Chaudhuri B, Ronan SG, Manaligod JR. Angiosarcoma arising in a plexiform
neurofibroma. Cancer. 1980;46:605–610.
358. McMenamin ME, Fletcher C D M. Expanding the spectrum of malignant
change in schwannomas: epithelioid malignant change, epithelioid malignant
peripheral nerve sheath tumor and epithelioid angiosarcoma: a study of 17
cases. Am J Surg Pathol. 2001;25:13–25.
359. Morphopoulos GD, Banerjee SS, Ali HH, et al. Malignant peripheral nerve
sheath tumour with vascular differentiation: a report of four cases.
Histopathology. 1996;28:401–410.
360. Deyrup AT, Miettinen M, North PE, et al. Pediatric cutaneous angiosarcoma: a
clinicopathologic study of 10 cases. Am J Surg Pathol. 2011;35:70–75.
361. Lezana-del Valle P, Gerald WL, Tsai J, et al. Malignant vascular tumors in
young patients. Cancer. 1998;83:1634–1639.
362. Deyrup AT, Miettinen M, North PE, et al. Angiosarcomas arising in the viscera
and soft tissue of children and young adults: a clinicopathologic study of 15
cases. Am J Surg Pathol. 2009;33:264–269.
363. Ayadi L, Khabir A. Pediatric angiosarcoma of soft tissue: a rareclinicopathologic entity. Arch Pathol Lab Med. 2010;134:481–485.
364. Leake J, Sheehan MP, Rampling D, et al. Angiosarcoma complicating
xeroderma pigmentosum. Histopathology. 1992;21:179–181.
365. Marcon I, Collini P, Casanova M, et al. Cutaneous angiosarcoma in a patient
with xeroderma pigmentosum. Pediatr Hematol Oncol. 2004;21:23–26.
366. Schmutz JL, Kue E, Baylac F, et al. Angiosarcoma complicating
HallopeauSiemens–type epidermolysis bullosa. Br J Dermatol. 1998;138:910–912.
367. Al-Najjar A-W, Harrington CI, Slater DN. Angiosarcoma: a complication of
varicose leg ulceration. Acta Derm Venereol. 1986;66:167–170.
368. Shon W, Ida CM, Boland-Froemming JM, et al. Cutaneous angiosarcoma
arising in massive localized lymphedema of the morbidly obese: a report of
five cases and review of the literature. J Cutan Pathol. 2011;38:560–564.
369. Folpe AL, Johnston CA, Weiss SW. Cutaneous angiosarcoma arising in a
gouty tophus: report of a unique case and a review of foreign
materialassociated angiosarcomas. Am J Dermatopathol. 2000;22:418–421.
370. Albert A, Lootvoet L, Lejeune E, et al. Angiosarcoma around a knee
arthroplasty. Report of a case and literature review. Acta Orthop Belg.
2009;75:549–553.
371. Contreras AL, Malpica A. Angiosarcoma arising in mature cystic teratoma of
the ovary: a case report and review of the literature. Int J Gynecol Pathol.
2009;28:453–457.
372. Kibe Y, Kishimoto S, Katoh N, et al. Angiosarcoma of the scalp associated
with renal transplantation. Br J Dermatol. 1997;136:752–756.
373. Ahmed I, Hamacher KL. Angiosarcoma in a chronically immunosuppressed
renal transplant recipient: report of a case and review of the literature. Am J
Dermatopathol. 2002;24:330–335.
374. Schmid H, Zeitz C. Human herpesvirus 8 and angiosarcoma: analysis of 40
cases and review of the literature. Pathology. 2005;37:284–287.
375. Naresh KN, Francis N, Sarwar N, et al. Expression of human herpesvirus 8
(HHV-8), latent nuclear antigen 1 (LAN1) in angiosarcoma in acquired
immunodeficiency syndrome (AIDS)—report of two cases. Histopathology.
2007;51:861–864.
376. Holden CA, Spittle MF, Wilson Jones E. Angiosarcoma of the face and scalp,
prognosis and treatment. Cancer. 1987;59:1046–1057.
377. Lydiatt WM, Shaha AR, Shah JP. Angiosarcoma of the head and neck. Am J
Surg. 1994;168:451–454.
378. Mark RJ, Poen JC, Tran LM, et al. Angiosarcoma. A report of 67 patients and a
review of the literature. Cancer. 1996;77:2400–2406.
379. Guadagnolo BA, Zagars GK, Araujo D, et al. Outcomes after definitive
treatment for cutaneous angiosarcoma of the face and scalp. Head Neck.
2011;33:661–667.
380. Deyrup AT, McKenney JK, Tighiouart M, et al. Sporadic cutaneous
angiosarcomas: a proposal for risk stratification based on 69 cases. Am J Surg
Pathol. 2008;32:72–77.
381. Pawlik TM, Paulino AF, McGinn CJ, et al. Cutaneous angiosarcoma of the
scalp: a multidisciplinary approach. Cancer. 2003;98:1716–1726.
382. Morrison WH, Byers RM, Garden AS, et al. Cutaneous angiosarcoma of the
head and neck. A therapeutic dilemma. Cancer. 1995;76:319–327.
383. Stewart FW, Treves N. Lymphangiosarcoma in postmastectomy lymphedema.A report of six cases in elephantiasis chirurgica. Cancer. 1948;1:64–81.
384. Woodward AH, Ivins JC, Soule EH. Lymphangiosarcoma arising in chronic
lymphedematous extremities. Cancer. 1972;30:562–572.
385. Alessi E, Sala F, Berti E. Angiosarcomas in lymphedematous limbs. Am J
Dermatopathol. 1986;8:371–378.
386. Capo V, Ozzello L, Fenoglio CM, et al. Angiosarcomas arising in edematous
extremities: immunostaining for factor VIII related antigen and
ultrastructural features. Hum Pathol. 1985;16:144–150.
387. Danese CA, Grishman E, Oh C, et al. Malignant vascular tumors of the
lymphedematous extremity. Ann Surg. 1967;166:245–253.
388. Mackenzie DH. Lymphangiosarcoma arising in chronic congenital and
idiopathic lymphoedema. J Clin Pathol. 1971;24:524–529.
389. Krasagakis K, Hettmannsperger U, Tebbe B, et al. Cutaneous metastatic
angiosarcoma with a lethal outcome, following radiotherapy for a cervical
carcinoma. Br J Dermatol. 1995;133:610–614.
390. Manner J, Radlwimmer B, Hohenberger P, et al. MYC high level gene
amplification is a distinctive feature of angiosarcomas after irradiation or
chronic lymphedema. Am J Pathol. 2010;176:34–39.
391. Goette DK, Detlefs RL. Postirradiation angiosarcoma. J Am Acad Dermatol.
1985;12:922–926.
392. Fineberg S, Rosen PP. Cutaneous angiosarcoma and atypical vascular lesions
of the skin and breast after radiation therapy for breast carcinoma. Am J Clin
Pathol. 1994;102:757–763.
393. Karlsson P, Holmberg E, Johansson KA, et al. Soft tissue sarcoma after
treatment for breast cancer. Radiother Oncol. 1996;38:25–31.
394. Cafiero F, Gipponi M, Peressini A, et al. Radiation-associated angiosarcoma.
Diagnostic and therapeutic implications—two case reports and a review of the
literature. Cancer. 1996;77:2496–2502.
395. Billings SD, McKenney JK, Folpe AL, et al. Cutaneous angiosarcoma following
breast-conserving surgery and radiation. Am J Surg Pathol. 2004;28:781–788.
396. Majeski J, Austin RM, Fitzgerald RH. Cutaneous angiosarcoma in an
irradiated breast after breast conservation therapy for cancer: association with
chronic breast lymphedema. J Surg Oncol. 2000;74:208–212.
397. Guo T, Zhang L, Chang NE, et al. Consistent MYC and FLT4 gene
amplification in radiation-induced angiosarcoma but not in other
radiationassociated atypical vascular lesions. Genes Chromos Cancer. 2011;50:25–33.
398. Fletcher C D M, Beham A, Bekir S, et al. Epithelioid angiosarcoma of deep soft
tissue: a distinctive tumor readily mistaken for an epithelial neoplasm. Am J
Surg Pathol. 1991;15:915–924.
399. Meis-Kindblom JM, Kindblom L-G. Angiosarcoma of soft tissue. A study of 80
cases. Am J Surg Pathol. 1998;22:683–697.
400. Fayette J, Martin E, Piperno-Neumann S, et al. Angiosarcomas: a
heterogeneous group of sarcomas with specific behavior depending on
primary site: a retrospective study of 161 cases. Ann Oncol. 2007;18:2030–2036.
401. Marrogi AJ, Hunt SJ, Santa Cruz DJ. Cutaneous epithelioid angiosarcoma. Am
J Dermatopathol. 1990;12:350–356.
402. McWilliam LJ, Harris M. Granular cell angiosarcoma of the skin: histology,
electron microscopy and immunohistochemistry of a newly recognised tumor.
Histopathology. 1985;9:1205–1216.403. Hitchcock MG, Hurt MA, Santa Cruz DJ. Cutaneous granular cell
angiosarcoma. J Cutan Pathol. 1994;21:256–262.
404. Tatsas AD, Keedy VL, Florell SR, et al. Foamy cell angiosarcoma: a rare and
deceptively bland variant of cutaneous angiosarcoma. J Cutan Pathol.
2010;37:901–906.
405. Requena L, Santoja C, Stutz N, et al. Pseudolymphomatous cutaneous
angiosarcoma: a rare variant of cutaneous angiosarcoma readily mistaken for
cutaneous lymphoma. Am J Dermatopathol. 2007;29:342–350.
406. Naka N, Ohsawa M, Tomita Y, et al. Prognostic factors in angiosarcoma: a
multivariate analysis of 55 cases. J Surg Oncol. 1996;61:170–176.
407. Morgan MB, Swann M, Somach S, et al. Cutaneous angiosarcoma: a case series
with prognostic correlation. J Am Acad Dermatol. 2004;50:867–874.
408. Di Tommaso L, Rosai J. The capillary lobule: a deceptively benign feature of
post-radiation angiosarcoma of the skin: report of three cases. Am J
Dermatopathol. 2005;27:301–305.
409. Gao Z, Chen S. Postradiation angiosarcoma of skin featuring capillary lobules.
Am J Dermatopathol. 2006;28:376.
410. Folpe AL, Chand EM, Goldblum JR, et al. Expression of Fli-1, nuclear
transcription factor, distinguishes vascular neoplasms from potential mimics.
Am J Surg Pathol. 2001;25:1061–1066.
411. Schuborg C, Mertens F, Rydholm A, et al. Cytogenetic analysis of four
angiosarcomas from deep and superficial soft tissue. Cancer Genet Cytogenet.
1998;100:52–56.
412. Antonescu CR, Yoshida A, Guo T, et al. KDR activating mutations in human
angiosarcomas are sensitive to specific kinase inhibitors. Cancer Res.
2009;69:7175–7179.
413. Eckert F, Schmid U, Gloor F, et al. Evidence of vascular differentiation in
anaplastic tumours of the thyroid: an immunohistochemical study. Virchow's
Arch [A]. 1986;410:203–215.
414. Eusebi V, Carcangiu ML, Dina R, et al. Keratin positive epithelioid
angiosarcoma of thyroid. A report of four cases. Am J Surg Pathol. 1990;14:737–
747.
415. Wenig BM, Abbondanzo SL, Heffer CS. Epithelioid angiosarcoma of the
adrenal glands. Am J Surg Pathol. 1994;18:62–73.
416. Goldblum JR, Rice TW. Epithelioid angiosarcoma of the pulmonary artery.
Hum Pathol. 1995;26:1275–1277.
417. Macias-Martínez V, Murrieta-Tiburcio L, Molina-Cárdenas H, et al. Epithelioid
angiosarcoma of the breast. Clinicopathological, immunohistochemical and
ultrastructural study of a case. Am J Surg Pathol. 1997;21:599–604.
418. Hasegawa T, Fujii Y, Seki K, et al. Epithelioid angiosarcoma of bone. Hum
Pathol. 1997;28:985–989.
419. McAdam JA, Stewart F, Reid R. Vaginal epithelioid angiosarcoma. J Clin
Pathol. 1998;51:928–930.
420. Prescott RJ, Banerjee SS, Eyden BP, et al. Cutaneous epithelioid angiosarcoma:
a clinicopathological study of four cases. Histopathology. 1994;25:421–429.
421. Bacchi CE, Silva TR, Zambrano E, et al. Epithelioid angiosarcoma of the skin: a
study of 18 cases with emphasis on its clinicopathologic spectrum and
unusual morphologic features. Am J Surg Pathol. 2010;34:1334–1343.
422. Suchak R, Thway K, Zelger B, et al. Primary cutaneous epithelioidangiosarcoma: a clinicopathologic study of 13 cases of a rare neoplasm
occurring outside the setting of conventional angiosarcomas and with
predilection for the limbs. Am J Surg Pathol. 2011;35:60–69.
423. Fessa CK, Sharma R, Fernandez-Penas P. Cutaneous epithelioid angiosarcoma
occurring at a peristomal site. J Am Acad Dermatol. 2010;63:e55–e56.
424. Jennings TA, Peterson L, Axiotis CA, et al. Angiosarcoma associated with
foreign body material. Cancer. 1988;62:2436–2444.
425. Byers RJ, McMahon R F T, Freemont AJ, et al. Epithelioid angiosarcoma
arising in an arteriovenous fistula. Histopathology. 1992;21:87–89.
426. Wehrli BM, Janzen DL, Shokeir O, et al. Epithelioid angiosarcoma arising in a
surgically constructed fistula: a rare complication of chronic
immunosuppression in the setting of renal transplantation. Am J Surg Pathol.
1998;22:1154–1159.
427. Seo IS, Min KW. Postirradiation epithelioid angiosarcoma of the breast: a case
report with immunohistochemical and electron microscopic study. Ultrastruct
Pathol. 2003;27:197–203.
428. Val-Bernal JF, Figols J, Arce FP, et al. Cardiac epithelioid angiosarcoma
presenting as cutaneous metastases. J Cutan Pathol. 2001;28:265–270.
429. Weed BR, Folpe AL. Cutaneous CD30-positive epithelioid angiosarcoma
following breast-conserving therapy and irradiation: a potential diagnostic
pitfall. Am J Dermatopathol. 2008;30:370–372.
430. Sebenik M, Ricci A Jr, DiPasquale B, et al. Undifferentiated intimal sarcoma of
large systemic blood vessels: report of 14 cases with immunohistochemical
profile and review of the literature. Am J Surg Pathol. 2005;29:1184–1193.
431. Herzberg AJ, Pizzo SV. Primary undifferentiated sarcoma of the thoracic
aorta. Histopathology. 1988;13:571–574.
432. Haber LM, Truong L. Immunohistochemical demonstration of the endothelial
nature of aortic intimal sarcoma. Am J Surg Pathol. 1988;12:798–802.
433. Seelig MH, Klinger PJ, Oldenburg WA, et al. Angiosarcoma of the aorta:
report of a case and review of the literature. J Vasc Surg. 1998;28:732–737.
434. Burke AP, Virmani R. Sarcomas of the great vessels. A clinicopathologic study.
Cancer. 1993;71:1761–1773.
435. Johansson L, Carlen B. Sarcoma of the pulmonary artery: report of four cases
with electron microscopic and immunohistochemical examinations, and
review of the literature. Virchows Arch. 1994;424:217–224.
436. Nonomura A, Kurumaya H, Kono N, et al. Primary pulmonary artery sarcoma.
Report of two autopsy cases studied by immunohistochemistry and electron
microscopy, and review of 110 cases reported in the literature. Acta Pathol Jpn.
1988;38:883–896.
437. Gaumann A, Petrow P, Mentzel T, et al. Osteopontin expression in primary
sarcomas of the pulmonary artery. Virchows Arch. 2001;439:668–674.
438. Santonja C, Martin-Hita AM, Dotor A, et al. Intimal angiosarcoma of the aorta
with tumour embolisation causing mesenteric ischaemia. Report of a case
diagnosed using CD31 immunohistochemistry in an intestinal resection
specimen. Virchows Arch. 2001;438:404–407.
439. Bode-Lesniewska B, Zhao J, Speel EJ, et al. Gains of 12q13-14 and
overexpression of mdm2 are frequent findings in intimal sarcomas of the
pulmonary artery. Virchows Arch. 2001;438:57–65.
440. Dewaele B, Floris G, Finalet-Ferreiro J, et al. Coactivated platelet-derivedgrowth factor receptor (alpha) and epidermal growth factor receptor are
potential therapeutic targets in intimal sarcoma. Cancer Res. 2010;70:7304–
7314.
441. Bill AH, Sumner DS. A unified concept of lymphangioma and cystic hygroma.
Surg Gynecol Obstet. 1965;120:79–86.
442. Gross RE, Goeringer CF. Cystic hygroma of the neck. Report of twenty-seven
cases. Surg Gynecol Obstet. 1939;69:48–60.
443. Harkin GA, Sabiston DC. Lymphangioma in infancy and childhood. Surgery.
1960;47:811–822.
444. Chervenak FA, Issacson G, Blakemore KJ, et al. Fetal cystic hygroma. Cause
and natural history. N Engl J Med. 1983;309:822–825.
445. De Perrot M, Rostan O, Morel P, et al. Abdominal lymphangioma in adults
and children. Br J Surg. 1998;85:395–397.
446. Hornick JL, Fletcher C D M. Intra-abdominal cystic lymphangiomas obscured
by marked superimposed reactive changes: clinicopathologic analysis of a
series. Hum Pathol. 2005;36:426–432.
447. Peachey R D G, Lim C-C, Whimster IW. Lymphangioma of the skin. A review
of 65 cases. Br J Dermatol. 1970;83:519–527.
448. Flanagan BP, Helwig EB. Cutaneous lymphangioma. Arch Dermatol.
1977;113:24–30.
449. Prioleau PG, Santa Cruz DJ. Lymphangioma circumscriptum following radical
mastectomy and radiation therapy. Cancer. 1978;42:1989–1991.
450. Papalas JA, Robboy SJ, Burchette JL, et al. Acquired vulvar lymphangioma
circumscriptum: a comparison of 12 cases with Crohn's associated lesions or
radiation therapy induced tumors. J Cutan Pathol. 2010;37:958–965.
451. Sims SM, McLean FW, Davis JD, et al. Vulvar lymphangioma circumscriptum:
a report of 3 cases, 2 associated with vulvar carcinomas and 1 with
hidradenitis suppurativa. J Low Genit Tract Dis. 2010;14:234–237.
452. Whimster IW. The pathology of lymphangioma circumscriptum. Br J
Dermatol. 1976;94:473–486.
453. Gold SC. Angioendothelioma (lymphatic type). Br J Dermatol. 1970;82:92–93.
454. Wilson Jones E, Winkelmann RK, Zachary CB, et al. Benign
lymphangioendothelioma. J Am Acad Dermatol. 1990;23:229–235.
455. Guillou L, Fletcher C D M. Benign lymphangioendothelioma (acquired
progressive lymphangioma): a lesion not to be confused with
welldifferentiated angiosarcoma and patch stage Kaposi's sarcoma. Am J Surg
Pathol. 2000;24:1047–1057.
456. Grunwald MH, Amichai B, Avinoach I. Acquired progressive lymphangioma. J
Am Acad Dermatol. 1997;37:656–657.
457. Sevila A, Botella-Estrada R, Sanmartín O, et al. Benign
lymphangioendothelioma of the thigh simulating a low grade angiosarcoma.
Am J Dermatopathol. 2000;22:151–154.
458. Watanabe M, Kishiyama K, Ohkawara A. Acquired progressive
lymphangioma. J Am Acad Dermatol. 1983;8:663–667.
459. Mehregan DR, Mehregan AH, Mehregan DA. Benign
lymphangioendothelioma: report of two cases. J Cutan Pathol. 1992;19:502–505.
460. Paik AS, Lee PH, O’Grady TC. Acquired progressive lymphangioma in an
HIV-positive patient. J Cutan Pathol. 2007;34:882–885.
461. Rosso R, Gianelli U, Carnevali L. Acquired progressive lymphangioma of theskin following radiotherapy for breast carcinoma. J Cutan Pathol. 1995;22:164–
167.
462. Kato H, Kadoya A. Acquired progressive lymphangioma following femoral
arteriography. Clin Exp Dermatol. 1996;21:159–162.
463. Asch MJ, Cohen AH, Moore TC. Hepatic and splenic lymphangiomatosis with
skeletal involvement: report of a case and review of the literature. Surgery.
1974;76:334–339.
464. Ramani P, Shah A. Lymphangiomatosis. Histological and
immunohistochemical analysis of four cases. Am J Surg Pathol. 1992;16:764–
771.
465. Singh Gomez C, Calonje E, Ferrar DW, et al. Lymphangiomatosis of the limbs:
clinicopathologic analysis of a series with a good prognosis. Am J Surg Pathol.
1995;19:125–133.
466. Vigorita VJ, Magitsky S, Bryk E. Gorham's disease: an autopsy report. Clin
Orthop Relat Dis. 2006;451:267–273.
467. North PE, Kahn T, Cordisco MR, et al. Multifocal
lymphangioendotheliomatosis with thrombocytopenia: a newly recognized
clinicopathological entity. Arch Dermatol. 2004;140:599–606.
468. Odell JM, Haas JE, Tapper D, et al. Infantile hemorrhagic angiodysplasia.
Pediatr Pathol. 1987;7:629–636.
469. Prasad V, Fishman SJ, Mulliken JB, et al. Cutaneovisceral angiomatosis with
thrombocytopenia. Pediatr Dev Pathol. 2005;8:407–419.
470. Madan V, Jamieson L, Wynn R, et al. Multifocal vascular lesions and
thrombocytopenia in a 10-year-old boy: retrospective review of a recently
recognized congenital disorder. Clin Exp Dermatol. 2010;35:942–944.
471. Díaz-Cascajo C, Borghi S, Weyers W, et al. Benign lymphangiomatous papules
of the skin after radiotherapy: a report of five new cases and review of the
literature. Histopathology. 1999;35:319–327.
472. Requena L, Kutzner H, Mentzel T, et al. Benign vascular proliferations in
irradiated skin. Am J Surg Pathol. 2002;26:328–337.
473. Brenn T, Fletcher C D M. Radiation-induced cutaneous atypical vascular
lesions and angiosarcoma: clinicopathologic analysis of 42 cases. Am J Surg
Pathol. 2005;29:983–996.
474. Brenn T, Fletcher C D M. Postradiation vascular proliferations: an increasing
problem. Histopathology. 2006;48:106–114.
475. Gengier C, Coindre JM, Leroux A, et al. Vascular proliferations of the skin
after radiation therapy for breast cancer: clinicopathologic analysis of a series
in favor of a benign process: a study from the French Sarcoma Group. Cancer.
2007;109:1584–1598.
476. Patton KT, Deyrup AT, Weiss SW, et al. Atypical vascular lesions after surgery
and radiation of the breast: a clinicopathologic study of 32 cases analyzing
histologic heterogeneity and association with angiosarcoma. Am J Surg Pathol.
2008;32:943–950.
477. Frack MD, Simon S, Dawson BH. The lymphangiomyomatosis syndrome.
Cancer. 1968;22:428–437.
478. Wolff M. Lymphangiomyoma: clinicopathologic study and ultrastructural
confirmation of its histogenesis. Cancer. 1973;31:988–1007.
479. Johnson S. Rare diseases. I. Lymphangioleiomyomatosis: clinical features,
management and basic mechanisms. Thorax. 1999;54:254–264.480. Berger U, Khaghani A, Pomerance A, et al. Pulmonary
lymphangioleiomyomatosis and steroid receptors. An immunocytochemical
study. Am J Clin Pathol. 1990;93:609–614.
481. Ohori NP, Yousem SA, Sonmez-Alpan E, et al. Estrogen and progesterone
receptors in lymphangioleiomyomatosis, epithelioid hemangioendothelioma,
and sclerosing hemangioma of the lung. Am J Clin Pathol. 1991;96:529–535.
482. Torres VE, Bjornsson J, King BF, et al. Extrapulmonary
lymphangioleiomyomatosis and lymphangiomatous cysts in tuberous
sclerosis complex. Mayo Clin Proc. 1995;70:641–648.
483. Smolarek TA, Wessner LL, McCormack FX, et al. Evidence that
lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13
loss of heterozygosity in angiomyolipomas and lymph nodes from women
with lymphangiomyomatosis. Am J Hum Genet. 1998;62:810–815.
484. Pacheco-Rodríguez G, Kristof AS, Stevens LA, et al. Giles F. Filley lecture.
Genetics and gene expression in lymphangioleiomyomatosis. Chest.
2002;121:56S–60S.
485. Pan CC, Chung MY, Ng FK, et al. Constant alteration on chromosome 16p
(TSC2 gene) in perivascular epithelioid cell tumour (PEComa): genetic
evidence for the relationship of PEComa with angiomyolipoma. J Pathol.
2008;214:387–393.
486. Chan J K C, Tsang W Y W, Pau MY, et al. Lymphangiomyomatosis and
angiomyolipoma: closely related entities characterized by hamartomatous
proliferation of HMB-45 positive smooth muscle. Histopathology. 1993;22:445–
455.
487. Fetsch PA, Fetsch JF, Marincola FM, et al. Comparison of melanoma antigen
recognized by T cells (MART-1) to HMB-45: additional evidence to support a
common lineage for angiomyolipoma, lymphangiomyomatosis and clear cell
sugar tumor. Mod Pathol. 1998;11:699–703.
488. Pea M, Martignoni G, Zamboni G, et al. Perivascular epithelioid cell. Am J Surg
Pathol. 1996;20:1149–1153.
489. Ahrens WA, Folpe AL. CD1a immunopositivity in perivascular epithelioid cell
neoplasms: true expression or technical artefact? Hum Pathol. 2011;42:369–374.
490. Bailey OT. The cutaneous glomus and its tumors—glomangiomas. Am J
Pathol. 1935;11:915–935.
491. Kohout E, Stout AP. The glomus tumor in children. Cancer. 1961;14:555–565.
492. Tsuneyoshi M, Enjoji M. Glomus tumor: a clinicopathologic and electron
microscopic study. Cancer. 1982;50:1601–1607.
493. Pepper MC, Laubenheimer R, Cripps DJ. Multiple glomus tumours. J Cutan
Pathol. 1977;4:244–257.
494. Happle R, Konig A. Type 2 segmental manifestation of multiple glomus
tumors: a review and reclassification of 5 case reports. Dermatology.
1999;198:270–272.
495. Boon LM, Brouillard P, Irrthum A, et al. A gene for inherited cutaneous
venous anomalies (“glomangiomas”) localizes to chromosome 1p21-22. Am J
Hum Genet. 1999;65:125–133.
496. Calvert JT, Burns S, Riney TJ, et al. Additional glomangioma family link to
chromosome 1p: no evidence for genetic heterogeneity. Hum Hered.
2001;51:180–182.
497. Brouillard P, Boom LM, Mulliken JB, et al. Mutations in a novel factor,glomulin, are responsible for glomovenous malformations (“glomangiomas”).
Am J Hum Genet. 2002;70:866–874.
498. Miettinen M, Paal E, Lasota J, Sobin LH. Gastrointestinal glomus tumors: a
clinicopathologic, immunohistochemical and molecular genetic study of 32
cases. Am J Surg Pathol. 2002;26:301–311.
499. Tomas D, Tomic K, Bekavac-Beslin M, et al. Primary glomangioma of the
esophagus mimicking esophageal papilloma. Dis Esophagus. 2006;19:208–211.
500. Kim YI, Kim JH, Suh J, et al. Glomus tumor of the trachea. Report of a case
with ultrastructural observations. Cancer. 1989;64:881–886.
501. Sunderraj S, Al-Kahalifa AA, Pal AK, et al. Primary intra-osseous glomus
tumour. Histopathology. 1989;14:532–536.
502. Geraghty JM, Everitt NJ, Blundell JW. Glomus tumour of the small bowel.
Histopathology. 1991;19:287–289.
503. Harvey JA, Walker F. Solid glomus tumor of the pterygoid fossa: a lesion
mimicking an epithelial neoplasm of low-grade malignancy. Hum Pathol.
1987;18:965–966.
504. Koss MN, Hochholzer L, Moran CA. Primary pulmonary glomus tumor: a
clinicopathologic and immunohistochemical study of two cases. Mod Pathol.
1998;11:253–258.
505. Gaertner EM, Steinberg DM, Huber M, et al. Pulmonary and mediastinal
glomus tumors—report of five cases including a pulmonary
glomangiosarcoma: a clinicopathologic study with literature review. Am J Surg
Pathol. 2000;24:1105–1114.
506. Hirose T, Hasegawa T, Seki K, et al. Atypical glomus tumor in the
mediastinum: a case report with immunohistochemical and ultrastructural
studies. Ultrastruct Pathol. 1996;20:451–456.
507. Jaiswal VR, Champine JG, Sharma S, et al. Primary glomangioma of the liver: a
case report and review of the literature. Arch Pathol Lab Med. 2004;128:46–49.
508. Miliauskas JR, Worthley C, Allen PW. Glomangiomyoma (glomus tumor) of
the pancreas: a case report. Pathology. 2002;34:193–195.
509. Gokten N, Peterdy G, Philpott T, et al. Glomus tumor of the ovary: report of a
case with immunohistochemical and ultrastructural observations. Int J Gynecol
Pathol. 2001;20:390–394.
510. Sasaki K, Bastacky SI, Hrebinko RL, et al. Glomus tumor of the kidney. Int J
Surg Pathol. 2011;19:393–397.
511. Silver SA, Tavassoli FA. Glomus tumor arising in a mature teratoma of the
ovary: report of a case simulating a metastasis from cervical squamous
carcinoma. Arch Pathol Lab Med. 2000;124:1373–1375.
512. Beham A, Fletcher C D M. Intravascular glomus tumour: a previously
undescribed phenomenon. Virchows Arch [A]. 1991;418:175–177.
513. Googe PB, Griffin WC. Intravenous glomus tumor of the forearm. J Cutan
Pathol. 1993;20:359–363.
514. Calonje E, Fletcher C D M. Cutaneous intraneural glomus tumor. Am J
Dermatopathol. 1995;17:395–398.
515. Sawada S, Honda M, Kamide R, et al. Three cases of subungual glomus tumors
with von Recklinghausen neurofibromatosis. J Am Acad Dermatol. 1995;32:277–
278.
516. Okada O, Demitsu T, Manabe M, et al. A case of multiple subungual glomus
tumors associated with neurofibromatosis type 1. J Dermatol. 1999;26:535–537.517. De Smet L, Sciot R, Legius E. Multifocal glomus tumours of the fingers in two
patients with neurofibromatosis type 1. J Med Genet. 2002;39:45.
518. Brems H, Park C, Maertens O, et al. Glomus tumors in neurofibromatosis type
1: genetic, functional and clinical evidence of a novel association. Cancer Res.
2009;69:7393–7401.
519. Haque S, Modlin IM, West AB. Multiple glomus tumors of the stomach with
intravascular spread. Am J Surg Pathol. 1992;16:291–299.
520. Albrecht S, Zbieranowski J. Incidental glomus coccygeum. When a normal
structure looks like a tumor. Am J Surg Pathol. 1990;14:922–924.
521. Van Geertruyden J, Lorea P, Goldschmidt D, et al. Glomus tumours of the
hand. A retrospective study of 51 cases. J Hand Surg (Br). 1996;21:257–260.
522. Brathwaite CD, Poppiti RJ Jr. Malignant glomus tumor. A case report of
widespread metastases in a patient with multiple glomus body hamartomas.
Am J Surg Pathol. 1996;20:233–238.
523. Watanabe K, Sugino T, Saito A, et al. Glomangiosarcoma of the hip: report of a
highly aggressive tumour with widespread distant metastases. Br J Dermatol.
1998;139:1097–1101.
524. Kayal JD, Hampton RW, Sheehan DJ, et al. Malignant glomus tumor: a case
report and review of the literature. Dermatol Surg. 2001;27:837–840.
525. Park JH, Oh SH, Yang MH, et al. Glomangiosarcoma of the hand: a case report
and review of the literature. J Dermatol. 2003;30:827–833.
526. Folpe AL, Fanburgh-Smith JC, Miettinen M, et al. Atypical and malignant
glomus tumors: analysis of 52 cases, with a proposal for the reclassification of
glomus tumors. Am J Surg Pathol. 2001;25:1–12.
527. Slater DN, Cotton D W K, Azzopardi JG. Oncocytic glomus tumour: a new
variant. Histopathology. 1987;11:523–531.
528. Pulitzer DR, Martin PC, Reed RJ. Epithelioid glomus tumor. Hum Pathol.
1995;26:1022–1027.
529. Jalali M, Netscher DT, Connelly JH. Glomangiomatosis. Ann Diagn Pathol.
2002;6:326–328.
530. Wood WS, Dimmiek JE. Multiple infiltrating glomus tumours in children.
Cancer. 1977;40:1680–1685.
531. Gould EW, Manivel JC, Albores-Saavedra J, et al. Locally infiltrative glomus
tumors and glomangiosarcoma. A clinical, ultrastructural and
immunohistochemical study. Cancer. 1990;65:310–318.
532. Dervan PA, Tobbin IN, Casey M, et al. Glomus tumours: an
immunohistochemical profile of 11 cases. Histopathology. 1989;14:483–491.
533. Porter PL, Bigler SA, McNutt M, et al. The immunophenotype of
hemangiopericytomas and glomus tumors with special reference to muscle
protein expression: an immunohistochemical study and review of the
literature. Mod Pathol. 1991;4:46–52.
534. Liapi-Avgeri G, Karabela-Bouropoulou X, Agnanti N. Glomus tumor. A
histological, histochemical and immunohistochemical study of the various
types. Pathol Res Pract. 1994;190:2–10.
535. Mentzel T, Hugel H, Kutzner H. CD34-positive glomus tumor:
clinicopathologic and immunohistochemical analysis of six cases with myxoid
stromal changes. J Cutan Pathol. 2002;29:421–425.
535a. Chakrapani A, Warrick A, Nelson D, et al. BRAF and KRAS mutations in
sporadic glomus tumors. Am J Dermatopathol. 2012;34:533–535.536. Hiruta N, Kameda N, Tokudome T, et al. Malignant glomus tumor: a case
report and review of the literature. Am J Surg Pathol. 1997;21:1096–1103.
537. López-Rios F, Rodríguez-Peralto JL, Castaño E, et al. Glomangiosarcoma of the
lower limb: a case report with a literature review. J Cutan Pathol. 1997;24:571–
574.
538. Stout AP, Murray MR. Hemangiopericytoma: a vascular tumor featuring
Zimmermann's pericytes. Ann Surg. 1942;116:26–33.
539. Battifora H. Hemangiopericytoma: ultrastructural study of five cases. Cancer.
1973;31:1418–1432.
540. Nunnery EW, Khan LB, Reddick RL, et al. Hemangiopericytoma: a light
microscopic and ultrastructural study. Cancer. 1981;47:906–914.
541. Dardick I, Hammar SP, Scheithauer BW. Ultrastructural spectrum of
hemangiopericytoma: a comparative study of fetal, adult, and neoplastic
pericytes. Ultrastruct Pathol. 1989;13:111–154.
542. Middleton LP, Duray PH, Merino MJ. The histologic spectrum of
hemangioperictyoma: application of immunohistochemical analysis including
proliferative markers to facilitate diagnosis and predict prognosis. Hum
Pathol. 1998;29:636–640.
543. Schurch W, Skalli O, Lagace R, et al. Intermediate filament proteins and actin
isoforms as markers for soft tissue tumor differentiation and origin III.
Hemangiopericytomas and glomus tumors. Am J Pathol. 1990;136:771–786.
544. Tsuneyoshi M, Daimaru Y, Enjoji M. Malignant hemangiopericytoma and
other sarcomas with hemangiopericytoma-like pattern. Pathol Res Pract.
1984;178:446–453.
545. Fletcher C D M. Haemangiopericytoma—a dying breed? Reappraisal of an
“entity” and its variants. Curr. Diagn Pathol. 1994;1:19–23.
546. Nappi O, Ritter JH, Pettinato G, et al. Hemangiopericytoma: histopathological
pattern or clinicopathologic entity? Semin Diagn Pathol. 1995;12:221–232.
547. Stout AP. Hemangiopericytoma. A study of twenty-five new cases. Cancer.
1949;2:1027–1035.
548. Granter SR, Badizadegan K, Fletcher C D M. Myofibromatosis in adults,
glomangiopericytoma and myopericytoma. A spectrum of tumors showing
perivascular myoid differentiation. Am J Surg Pathol. 1998;22:513–525.
549. Enzinger FM, Smith BH. Hemangiopericytoma. An analysis of 106 cases. Hum
Pathol. 1976;7:61–82.
550. Angervall L, Kindblom LG, Moller Nielsen JM, et al. Hemangiopericytoma, a
clinicopathologic, angiographic and microangiographic study. Cancer.
1978;42:2412–2427.
551. Pavelic K, Cabrijan T, Hrascan R, et al. Molecular pathology of
hemangiopericytomas accompanied by severe hypoglycemia: oncogenes,
tumor-suppressor genes and the insulin-like growth factor family. J Cancer Res
Clin Oncol. 1998;124:307–314.
552. Guthrie BL, Ebersold MJ, Scheithauer BW, et al. Meningeal
hemangiopericytoma: histopathological features, treatment and long-term
follow-up of 44 cases. Neurosurgery. 1989;25:514–522.
553. Mena H, Ribas JL, Pezeshkpour GH, et al. Hemangiopericytoma of the central
nervous system: a review of 94 cases. Hum Pathol. 1991;22:84–91.
554. Compagno J, Hyams VJ. Hemangiopericytoma-like intranasal tumors. A
clinicopathologic study of 23 cases. Am J Clin Pathol. 1976;66:672–683.555. Eichhorn JH, Dickersin GR, Bhan AK, et al. Sinonasal hemangiopericytoma. A
reassessment with electron microscopy, immunohistochemistry, and
longterm follow-up. Am J Surg Pathol. 1990;14:856–866.
556. Coffin CM, Dehner LP. Fibroblastic-myofibroblastic tumors in children and
adolescents: a clinicopathologic study of 108 examples in 103 patients. Pediatr
Pathol. 1991;11:569–588.
557. Mentzel T, Calonje E, Nascimento AG, et al. Infantile haemangiopericytoma
versus infantile myofibromatosis: a study of a series suggesting a spectrum of
infantile myofibroblastic lesions. Am J Surg Pathol. 1994;18:922–930.
558. Dictor M, Elner A, Andersson T, et al. Myofibromatosis-like
hemangiopericytoma metastasising as differentiated vascular smooth muscle
and myosarcoma. Myopericytes as a subset of “myofibroblasts.”. Am J Surg
Pathol. 1992;16:1239–1247.
559. Variend S, Bax NM, Van Gorp J. Are infantile myofibromatosis, congenital
fibrosarcoma and congenital haemangiopericytoma histogenetically related?
Histopathology. 1995;26:57–62.
560. Mentzel T, Dei Tos AP, Sapi Z, Kutzner H. Myopericytoma of skin and soft
tissues: clinicopathologic and immunohistochemical study of 54 cases. Am J
Surg Pathol. 2006;30:104–113.
561. Dray MS, McCarthy SW, Palmer AA, et al. Myopericytoma: a unifying term for
a spectrum of tumours that show overlapping features with myofibroma. A
review of 14 cases. J Clin Pathol. 2006;59:67–73.
562. Requena L, Kutzner H, Hugel H, et al. Cutaneous adult myofibroma: a
vascular neoplasm. J Cutan Pathol. 1996;23:445–457.
563. Sakamoto A, Oda Y, Nagayoshi Y, et al. Glomangiopericytoma causing
oncogenic osteomalacia. A case report with immunohistochemical analysis.
Arch Orthop Trauma Surg. 2001;121:104–108.
564. Brunschweiler B, Guedj N, Lenoir T, et al. Oncogenous osteomalacia and
myopericytoma of the thoracic spine: a case report. Spine. 2009;34:E857–E860.
565. McMenamin ME, Fletcher C D M. Malignant myopericytoma: expanding the
spectrum of tumors with myopericytic differentiation. Histopathology.
2002;41:450–460.
566. Lau PP, Wong OK, Lui PC, et al. Myopericytoma in patients with AIDS: a new
class of Epstein-Barr virus-associated tumor. Am J Surg Pathol. 2009;33:1666–
1672.
567. Calderaro J, Polivka M, Gallien S, et al. Multifocal Epstein Barr virus (EBV)–
associated myopericytoma in a patient with AIDS. Neuropathol Appl Neurobiol.
2008;34:115–117.
568. Vallet-Decouvelaere AV, Dry SM, Fletcher C D M. Atypical and malignant
solitary fibrous tumors in extrathoracic locations: evidence of their
comparability to intra-thoracic tumors. Am J Surg Pathol. 1998;22:1501–1511.
569. McMenamin ME, Calonje E. Intravascular myopericytoma. J Cutan Pathol.
2002;29:557–561.
570. Rullier A, Coindre JM, Sassoust G, et al. Arterial myopericytoma: a case
report. Ann Pathol. 2010;30:325–327.C H A P T E R 4
Tumors of the Upper Respiratory Tract
Bruce M. Wenig
PART A
▪ 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.
TABLE 4A-1
C lassification of N asal C avity and P aranasal S inus N eoplasmsBenign
Epithelial
Schneiderian papillomas
Squamous papilloma (nasal vestibule)
Minor salivary gland tumors
Mesenchymal
Lobular capillary hemangioma (pyogenic granuloma)
Solitary fibrous tumor
Ossifying and nonossifying fibromyxoid tumor
Peripheral nerve sheath tumors
Fibrous histiocytoma
Fibromatosis
Osteoma
Fibroosseous lesions (ossifying fibroma, psammomatoid ossifying fibroma)
Leiomyoma
Myxoma/fibromyxoma/chondromyxoid fibroma
Lipoma
Ameloblastoma
Others
Indeterminant for malignancy/low-grade malignant potential
Sinonasal-type hemangiopericytoma
Epithelioid hemangioendothelioma
Malignant
Epithelial
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
carcinoma)
Sinonasal undifferentiated carcinoma
Adenocarcinoma:
• Intestinal types
• Nonsalivary, nonintestinal types
Minor salivary gland neoplasms
Mesenchymal/neuroectodermal/lymphoid
Mucosal malignant melanoma
Olfactory neuroblastoma
Non-Hodgkin malignant lymphomas
Extraosseous Ewing sarcoma/primitive neuroectodermal tumor
Undifferentiated pleomorphic sarcoma
Fibrosarcoma
Malignant schwannoma
Leiomyosarcoma
Angiosarcoma
Osteosarcoma
Chondrosarcoma
Teratocarcinosarcoma
Others
Secondary tumors
TABLE 4A-2
C lassification of N eoplasms of the N asopharynxBenign
Epithelial
Squamous papilloma
Minor salivary gland tumors
Mesenchymal/neuroectodermal
Angiofibroma
Granular cell tumor
Lymphangioma/cystic hygroma
Hemangiomas
Schwannoma/neurofibroma
Lipoma
Paraganglioma
Fibrous histiocytoma
Leiomyoma
Rhabdomyoma
Teratomas
Others
M a l i g n a n t
Epithelial
Nasopharyngeal carcinoma
Keratinizing
Nonkeratinizing:
• Differentiated type
• Undifferentiated type
Low-grade papillary adenocarcinoma
Minor salivary gland tumors
Mesenchymal/neuroectodermal/lymphoid
Mucosal malignant melanoma
Lymphomas (non-Hodgkin and Hodgkin)
Rhabdomyosarcoma
Undifferentiated pleomorphic sarcoma/fibrosarcoma
Malignant peripheral nerve sheath tumor
Chordoma
Angiosarcoma
Kaposi sarcoma
Liposarcoma
Synovial sarcoma
Leiomyosarcoma
Others
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
cores
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
57
Incidence of Rare 2-27 4-17
malignant
transformation
(%)
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
mucosa.
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.
Paraganglioma
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.
Meningioma
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
Hemangiomas
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
process.
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).
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
82-84sarcoma).
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
curative.
Leiomyoma
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.
Rhabdomyoma
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
tissue.
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
tumors.
Osseous, Fibroosseous, and Cartilaginous Lesions
Osteoma
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
OF POF FD
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
decades
Location No specific site Ethmoid sinus; supraorbital frontal region No specific site of involvement
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
appearance
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
periphery
Syndromes No known No known association Albright syndrome (1%-3%)
association
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
malignancy
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
structures
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.
Chondroma
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
Ameloblastoma
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
epithelium.
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.
Craniopharyngioma
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
reported.
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
151,152,158VEGF.
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.
TABLE 4A-6A
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
T1N1M0
T2N1M0
T3N1M0
Stage IVA T4aN0M0
T4aN1M0
T1N2M0
T2N2M0
T3N2M0
T4aN2M0
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)
TABLE 4A-6B
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
Nasopharynx
pT1: Tumor confined to nasopharynx, or tumor extends to oropharynx and/or nasal cavity without parapharyngeal
extension*
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
T2N0M0
T2N1M0
Stage III T1N2M0
T2N2M0
T3N0M0
T3N1M0
T3N2M0
Stage IVA T4N0M0
T4N1M0
T4N2M0
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
Carcinoma)
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.
TABLE 4A-7
Comparison Between Human Papillomavirus–Positive and Human Papillomavirus–Negative Squamous Cell
Carcinomas
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
presentation
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
tumor.
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.
TABLE 4A-8
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
children
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
good
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
192disease.
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
epithelium.
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.
TABLE 4A-9
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.
TABLE 4A-11
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.
TABLE 4A-12
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.
TABLE 4A-13
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.
4A-32).
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
349positive.
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
363identified.
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.
TABLE 4A-14
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
frequency
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
disease
• (C-ANCA more
specific than
PANCA)
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
microabscesses
Negative cultures
and stains for
organisms
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
pulmonary
involvement
*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
348,367survival.
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
361exists.
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;
Neurofibrosarcoma)
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
Histiocytoma)
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.
Rhabdomyosarcoma
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.
TABLE 4A-15
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
Adults
Location in head and neck (nonorbital), paraspinal region, abdomen, biliary tract, retroperitoneum, perineum, or
extremities
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
Angiosarcoma
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.
Leiomyosarcoma
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
rates.
Chondrosarcoma
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
440grade.
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%.
Chordoma
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
chordoma.
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
hamartomas.
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
straightforward.
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
492polyps.
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
lymphoma.
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
1. Lampertico P, Russel WO, MacComb WS. Squamous papilloma of the upper
respiratory epithelium. Arch Pathol. 1963;75:293–302.
2. Hyams VJ. Papillomas of the nasal cavity and paranasal sinuses: a
clinicopathologic study of 315 cases. Ann Otol Rhinol Laryngol. 1971;80:192–
206.
3. Hyams VJ, Batsakis JG, Michaels L. Papilloma of the sinonasal tract. Tumors of
the upper respiratory tract and ear. Armed Forces Institute of Pathology:
Washington, D.C.; 1988:34–44 [series 2, fascicle 25].
4. Joseph M, Carroll E, Goodman ML, et al. Inverted papilloma of the nasal
septum. Arch Otolaryngol. 1980;106:767–771.
5. Christensen WN, Smith R R L. Schneiderian papillomas: a clinicopathologic
study of 67 cases. Hum Pathol. 1986;17:393–400.
6. Lawson W, Le Benger J, Som P, et al. Inverted papilloma: an analysis of 87
cases. Laryngoscope. 1989;99:1117–1124.
7. Siivonen L, Virolainen E. Transitional papillomas of the nasal cavity and
paranasal sinuses. ORL J Otorhinolaryngol Relat Spec. 1989;51:262–267.
8. Lawson W, Ho BT, Shaari CM, et al. Inverted papilloma: a report of 112 cases.
Laryngoscope. 1995;105:282–288.
9. Buchwald C, Franzmann M-B, Tos M. Sinonasal papillomas: a report of 82
cases in Copenhagen county, including a longitudinal clinical study.
Laryngoscope. 1995;105:72–79.
10. Peters BW, O’Reilly RC, Wilcox TO Jr, et al. Inverted papilloma isolated to the
sphenoid sinus. Otolaryngol Head Neck Surg. 1995;113:771–781.
11. Brandwein M, Steinberg B, Thung S, et al. Human papillomavirus 6/11 and
16/18 in schneiderian inverted papillomas: in situ hybridization with human
papillomavirus RNA probes. Cancer. 1989;63:1708–1713.
12. Judd R, Zaki SR, Coffield LM, et al. Sinonasal papillomas and human
papillomavirus: human papillomavirus 11 detected in fungiform Schneiderian
papillomas by in situ hybridization and polymerase chain reaction. Hum
Pathol. 1991;22:550–556.
13. Sarkar FH, Visscher DW, Kintanar EB, et al. Sinonasal Schneiderian
papillomas: human papillomavirus typing by polymerase chain reaction. Mod
Pathol. 1992;5:329–332.
14. Buchwald C, Franzmann M-B, Jacobsen GK, et al. Human papillomavirus
(HPV) in sinonasal papillomas: a study of 78 cases using in situ hybridization
and polymerase chain reaction. Laryngoscope. 1995;105:66–71.
15. Harris MO, Beck JC, Terrell JE, et al. Expression of human papillomavirus 6 in
inverted papilloma arising in a renal transplant patient. Laryngoscope.
1998;108:115–119.
16. Barnes L. Schneiderian papillomas and nonsalivary glandular neoplasms of
the head and neck. Mod Pathol. 2002;15:279–297.
17. Macdonald MR, Le KT, Freeman J, et al. A majority of inverted sinonasal
papillomas carries Epstein-Barr virus genomes. Cancer. 1995;75:2307–2312.
18. Gaffey MJ, Frierson HF, Weiss LM, et al. Human papillomavirus and
EpsteinBarr virus in sinonasal Schneiderian papillomas. An in situ hybridization and
polymerase chain reaction study. Am J Clin Pathol. 1996;106:475–482.
19. Myers EN, Fernau JL, Johnson JT, et al. Management of inverted papilloma.
Laryngoscope. 1990;100:481–490.20. Mendenhall WM, Million RR, Cassisi NJ, et al. Biologically aggressive
papillomas of the nasal cavity: the role of radiation therapy. Laryngoscope.
1985;134:73–79.
21. Klemi PJ, Joensu H, Siivonen L, et al. Association of DNA aneuploidy with
human papillomavirus-induced malignant transformation of sinonasal
transitional papillomas. Otolaryngol Head Neck Surg. 1989;100:563–567.
22. Ward BE, Fechner RE, Mills SE. Carcinoma arising in oncocytic Schneiderian
papilloma. Am J Surg Pathol. 1990;14:364–369.
23. Kapadia SB, Barnes L, Pelzman K, et al. Carcinoma ex oncocytic Schneiderian
(cylindrical cell) papilloma. Am J Clin Pathol. 1993;14:1–7.
24. Lesperanie MM, Esclamado RM. Squamous cell carcinoma arising in inverted
papilloma. Laryngoscope. 1995;105:178–183.
25. Norris HJ. Papillary lesions of the nasal cavity and paranasal sinuses. Part I:
Exophytic (squamous) papillomas. A study of 28 cases. Laryngoscope.
1962;72:1784–1797.
26. Batsakis JG. The pathology of head and neck tumors: nasal cavity and
paranasal sinuses, part 5. Head Neck Surg. 1980;2:410–419.
27. Sulica RL, Wenig BM, Debo RF, et al. Schneiderian papillomas of the pharynx.
Ann Otol Rhinol Laryngol. 1999;108:392–397.
28. Compagno J, Wong RT. Intranasal mixed tumors (pleomorphic adenomas). A
clinicopathologic study of 40 cases. Am J Clin Pathol. 1977;68:213–218.
29. Begin LR, Rochon L, Frenkiel S. Spindle cell myoepithelioma of the nasal
cavity. Am J Surg Pathol. 1991;15:184–190.
30. Lloyd RV, Chandler WF, Kovacs K, et al. Ectopic pituitary adenomas with
normal anterior pituitary glands. Am J Surg Pathol. 1986;10:546–552.
31. Wenig B, Heffess C, Adair C, et al. Ectopic pituitary adenomas: a
clinicopathologic study of 15 cases. Mod Pathol. 1995;8:56A [(abstract)].
32. Hosaka N, Kitajiri S, Hiraumi H, et al. Ectopic pituitary adenoma with
malignant transformation. Am J Surg Pathol. 2002;26:1078–1082.
33. Zak FG, Lawson W. The paraganglionic chemoreceptor system: physiology,
pathology and clinical medicine. Springer-Verlag, New York; 1982.
34. Apple D, Kreines K. Cushing's syndrome due to ectopic ACTH production by
a nasal paraganglioma. Am J Med Sci. 1982;283:32–35.
35. Kliewer KE, Wen D-R, Cancilla PA, et al. Paragangliomas: assessment of
prognosis by histologic, immunohistochemical, and ultrastructural
techniques. Hum Pathol. 1989;20:29–39.
36. Johnson TL, Zarbo RJ, Lloyd RV, et al. Paragangliomas of the head and neck:
immunohistochemical neuroendocrine and intermediate filament typing. Mod
Pathol. 1988;1:216–223.
37. Nguyen QA, Gibbs PM, Rice DH. Malignant nasal paraganglioma: a case
report and review of the literature. Otolaryngol Head Neck Surg. 1995;113:157–
161.
38. Burger PC, Scheithauer BW. Tumors of meningiothelial cells. Rosai J, Sobin
LH. Tumors of the central nervous system. Armed Forces Institute of Pathology:
Washington, D.C.; 1994:259–286 [series 3, fascicle 10].
39. Perzin KH, Pushparaj N. Non-epithelial tumors of the nasal cavity, paranasal
sinuses, and nasopharynx: a clinicopathologic study. XIII. Meningiomas.
Cancer. 1984;54:1860–1869.
40. Thompson LD, Gyure KA. Extracranial sinonasal tract meningiomas: aclinicopathologic study of 30 cases with a review of the literature. Am J Surg
Pathol. 2000;24:640–650.
41. Ho KL. Primary meningioma of the nasal cavity and paranasal sinuses. Cancer.
1980;46:1442–1447.
42. Fu YS, Perzin KH. Non-epithelial tumors of the nasal cavity, paranasal sinuses,
and nasopharynx: a clinicopathologic study. I. General features and vascular
tumors. Cancer. 1974;33:1275–1288.
43. Sheppard LM, Michaelson SA. Hemangioma of the nasal septum and
paranasal sinuses. Henry Ford Hosp Med J. 1990;38:25–27.
44. Mills SE, Cooper PH, Fechner RE. Lobular capillary hemangioma: the
underlying lesion of pyogenic granuloma. A study of 73 cases from the oral
and nasal mucous membranes. Am J Surg Pathol. 1980;4:471–479.
45. Nichols GE, Gaffey MJ, Mills SE, et al. Lobular capillary hemangioma. An
immunohistochemical study including steroid hormone receptor status. Am J
Clin Pathol. 1992;97:770–775.
46. Yuan K, Lin MT. The roles of vascular endothelial growth factor and
angiopoietin-2 in the regression of pregnancy pyogenic granuloma. Oral Dis.
2004;10:179–185.
47. Cheuk W, Wong KO, Wong CS, et al. Immunostaining for human herpesvirus
8 latent nuclear antigen-1 helps distinguish Kaposi sarcoma from its
mimickers. Am J Clin Pathol. 2004;121:335–342.
48. Batsakis JG, Rice DH. The pathology of head and neck tumors. Vasoformative
tumors, part 9A. Head Neck Surg. 1981;3:231–239.
49. North PE, Waner M, Mizeracki A, et al. GLUT1: a newly discovered
immunohistochemical marker for juvenile hemangiomas. Hum Pathol.
2000;31:11–22.
50. North PE, Waner M, James CA, et al. Congenital nonprogressive hemangioma:
a distinct clinicopathologic entity unlike infantile hemangioma. Arch
Dermatol. 2001;137:1607–1620.
51. Apostol JV, Frazell EL. Juvenile nasopharyngeal angiofibroma. A clinical
study. Cancer. 1965;18:869–878.
52. Neel HB, Whicker JH, Devine KD, et al. Nasopharyngeal angiofibroma. Review
of 120 cases. Am J Surg. 1973;126:547–556.
53. McGavran MH, Dorfman RF, Davis DO, et al. Nasopharyngeal angiofibroma.
Arch Otolaryngol. 1969;90:68–78.
54. Amedee R, Klaeyle D, Mann W, et al. Juvenile angiofibromas: a 40-year
surgical experience. ORL J Otorhinolaryngol Relat Spec. 1989;51:56–61.
55. Hyams VJ, Batsakis JG, Michaels L. Angiofibroma. Tumors of the upper
respiratory tract and ear. Armed Forces Institute of Pathology: Washington,
D.C.; 1988:130–134 [series 2, fascicle 25].
56. Hazarika P, Nayak RG, Chandran M. Extra-nasopharyngeal extension of
juvenile angiofibroma. J Laryngol Otol. 1985;99:813–817.
57. Johnson S, Kloster JH, Schiff M. The actions of hormones on juvenile
angiofibroma. Acta Otolaryngol. 1966;61:153–160.
58. Hwang HC, Mills SE, Patterson K, et al. Expression of androgen receptors in
nasopharyngeal angiofibroma: an immunohistochemical study of 24 cases.
Mod Pathol. 1998;11:1122–1126.
59. Johns ME, MacLeod RM, Cantrell RW. Estrogen receptors in nasopharyngeal
angiofibromas. Laryngoscope. 1980;90:628–634.60. Giardello FM, Hamilton SR, Krush AJ, et al. Nasopharyngeal angiofibroma in
patients with familial adenomatous polyposis. Gastroenterology. 1993;105:1550–
1552.
61. Ferouz AS, Mohr RM, Paul P. Juvenile nasopharyngeal angiofibroma and
familial adenomatous polyposis: an association? Otolaryngol Head Neck Surg.
1995;113:435–439.
62. Abraham SC, Montgomery EA, Giardiello FM, et al. Frequent β-catenin
mutations in juvenile nasopharyngeal angiofibromas. Am J Pathol.
2001;158:1073–1078.
63. Guertl B, Beham A, Zachner R, et al. Nasopharyngeal angiofibroma: an
APCgene–associated tumor? Hum Pathol. 2000;31:1411–1413.
64. Zhang PJ, Weber R, Liang H-H, et al. Growth factors and receptors in juvenile
nasopharyngeal angiofibroma and nasal polyps: an immunohistochemical
study. Arch Pathol Lab Med. 2003;127:1480–1484.
65. Baguley C, Sandhu G, O'Donnell J, et al. Consumptive coagulopathy
complicating juvenile angiofibroma. J Laryngol Otol. 2004;118:835–839.
66. Sessions RB, Wills PI, Alford BR, et al. Juvenile angiofibroma: radiographic
aspects. Laryngoscope. 1976;86:2–18.
67. Sessions RB, Bryan RN, Naclerio RM, et al. Radiographic staging of juvenile
angiofibroma. Head Neck Surg. 1981;3:279–283.
68. Fisch U. The infratemporal fossa approach for nasopharyngeal tumors.
Laryngoscope. 1983;93:36–44.
69. Chandler JR, Goulding R, Moskowitz L, et al. Nasopharyngeal angiofibromas:
staging and management. Ann Otol Rhinol Laryngol. 1984;93:322–329.
70. Radkowski D, McGill T, Healy GB, et al. Angiofibroma. Changes in staging and
treatment. Arch Otolaryngol Head Neck Surg. 1996;122:122–129.
71. Beham A, Fletcher C D M, Kainz J, et al. Nasopharyngeal angiofibroma: an
immunohistochemical study of 32 cases. Virchows Archiv A Pathol Anat.
1993;423:281–285.
72. Garcia-Cervigon E, Bien S, Rufenacht D, et al. Pre-operative embolization of
nasopharyngeal angiofibromas. Report of 58 cases. Neuroradiology.
1988;30:556–560.
73. Mann WJ, Jecker P, Amedee RG. Juvenile angiofibromas: changing surgical
concept over the last 20 years. Laryngoscope. 2004;114:291–293.
74. Gates GA, Rice DH, Koopman CF Jr, et al. Flutamide-induced regression of
angiofibroma. Laryngoscope. 1992;102:641–644.
75. Fields JN, Halverson KJ, Devineni VR, et al. Juvenile nasopharyngeal
angiofibroma: efficacy of radiation therapy. Radiology. 1990;176:263–265.
76. Gudea F, Vega M, Canals E, et al. Role of radiation therapy for juvenile
angiofibroma. J Laryngol Otol. 1990;104:725–726.
77. Kaspar ME, Parsons JT, Mancuso AA, et al. Radiation therapy for juvenile
angiofibroma: evaluation by CT and MRI, analysis of tumor regression, and
selection of patients. Int J Radiat Oncol Biol Phys. 1993;25:689–694.
78. Biller HF. Juvenile nasopharyngeal angiofibroma. Ann Otol Rhinol Laryngol.
1978;87:630–632.
79. Gullane PJ, Davidson J, O'Dwyer T, et al. Juvenile nasopharyngeal
angiofibroma: a review of the literature and a case series report. Laryngoscope.
1992;102:928–933.
80. Weprin LS, Siemers P. Spontaneous regression of juvenile nasopharyngealangiofibroma. Arch Otolaryngol Head Neck Surg. 1991;117:796–799.
81. Dohar JE, Duvall AJ. Spontaneous regression of juvenile nasopharyngeal
angiofibroma. Ann Otol Rhinol Laryngol. 1992;101:469–471.
82. Batsakis JG, Klopp CT, Newman N. Fibrosarcoma arising in a “juvenile”
nasopharyngeal angiofibroma following extensive radiation therapy. Am Surg.
1958;21:786–793.
83. Chen K T K, Bauer FW. Sarcomatous transformation of nasopharyngeal
angiofibroma. Cancer. 1982;49:369–371.
84. Spagnolo DV, Papadimitiou JM, Archer M. Postirradiation malignant fibrous
histiocytoma arising in juvenile nasopharyngeal angiofibroma producing
alpha-1-antitrypsin. Histopathology. 1984;8:339–352.
85. Hasegawa T, Hirose T, Seki K, et al. Solitary fibrous tumors of soft tissue. An
immunohistochemical and ultrastructural study. Am J Clin Pathol.
1996;106:325–331.
86. Suster S, Nascimento AG, Miettinen M, et al. Solitary fibrous tumors of soft
tissue. A clinicopathologic and immunohistochemical study of 12 cases. Am J
Surg Pathol. 1995;19:1257–1266.
87. Guillou L, Fletcher JA, Fletcher C D M, et al. Extrapleural solitary fibrous
tumour and haemangiopericytoma. Fletcher C D M, Unni KK, Mertens F.
World Health Organization classification of tumours. Pathology & genetics.
Tumours of soft tissue and bone. IARC Press: Lyon, France; 2002:86–90.
88. Zukerberg LR, Rosenberg AE, Randolph G, et al. Solitary fibrous tumor of the
nasal cavity and paranasal sinuses. Am J Surg Pathol. 1991;15:126–130.
89. Witkin GB, Rosai J. Solitary fibrous tumor of the upper respiratory tract. Am J
Surg Pathol. 1991;15:842–848.
90. Fukunaga M, Ushigome S, Nomura K, et al. Solitary fibrous tumor of the nasal
cavity and orbit. Pathol Int. 1995;45:952–957.
91. Ganly I, Patel SG, Stambuk HE, et al. Solitary fibrous tumors of the head and
neck: a clinicopathologic and radiologic review. Arch Otolaryngol Head Neck
Surg. 2006;132:517–525.
92. Fu YS, Perzin KH. Non-epithelial tumors of the nasal cavity, paranasal sinuses,
and nasopharynx: a clinicopathologic study. VI. Fibrous tissue tumors
(fibroma, fibromatosis, fibrosarcoma). Cancer. 1976;37:2912–2928.
93. Gnepp DR, Henley J, Weiss S, et al. Desmoid fibromatosis of the sinonasal
tract and nasopharynx. Cancer. 1996;78:2572–2579.
94. Batsakis JG, Raslan W. Extra-abdominal desmoid fibromatosis. Ann Otol
Rhinol Laryngol. 1994;103:331–334.
95. Sherman NE, Romsdahl M, Evans H, et al. Desmoid tumors: a 20-year
radiotherapy experience. Int J Radiat Oncol Biol Phys. 1990;19:37–40.
96. McCollough WM, Parsons JT, van der Griend R, et al. Radiation therapy for
aggressive fibromatosis: the experience of the University of Florida. J Bone
Joint Surg. 1991;73:717–725.
97. Lanari A. Effect of progesterone on desmoid tumors (aggressive fibromatosis).
N Engl J Med. 1983;309:1523.
98. Easter DW, Halasz NA. Recent trends in the management of desmoid tumors.
Summary of 19 cases and review of the literature. Ann Surg. 1989;210:765–769.
99. Shugar J M A, Som PA, Biller HF, et al. Peripheral nerve sheath tumors of the
paranasal sinuses. Head Neck Surg. 1981;4:72–76.
100. Fu YS, Perzin KH. Non-epithelial tumors of the nasal cavity, paranasalsinuses, and nasopharynx: a clinicopathologic study. XII. Schwann cell tumors
(neurilemmoma, neurofibroma, malignant schwannoma). Cancer. 1974;50:65–
69.
101. Hasegawa SL, Mentzel T, Fletcher C D M. Schwannomas of the sinonasal tract
and nasopharynx. Mod Pathol. 1997;10:777–784.
102. Buob D, Wacrenier A, Chevalier D, et al. Schwannoma of the sinonasal tract: a
clinicopathologic and immunohistochemical study of 5 cases. Arch Pathol Lab
Med. 2003;127:1196–1199.
103. Fu YS, Perzin KH. Non-epithelial tumors of the nasal cavity, paranasal
sinuses, and nasopharynx: a clinicopathologic study. IV. Smooth-muscle
tumors (leiomyoma, leiomyosarcoma). Cancer. 1976;35:1300–1308.
104. Huang HY, Antonescu CR. Sinonasal smooth muscle cell tumors: a
clinicopathologic and immunohistochemical analysis of 12 cases with
emphasis on the low-grade end of the spectrum. Arch Pathol Lab Med.
2003;127:297–304.
105. Fu YS, Perzin KH. Non-epithelial tumors of the nasal cavity, paranasal
sinuses, and nasopharynx: a clinicopathologic study. V. Skeletal muscle
tumors (rhabdomyoma, rhabdomyosarcoma). Cancer. 1976;37:364–376.
106. Gale N, Rott T, Kambic V. Nasopharyngeal rhabdomyoma. Report of a case
(light and electron microscopic studies) and review of the literature. Pathol
Res Pract. 1984;178:454–460.
107. Kapadia SB, Meis JM, Frisman DM, et al. Fetal rhabdomyoma of the head and
neck: a clinicopathologic and immunophenotypic study of 24 cases. Hum
Pathol. 1993;24:754–765.
108. Fu YS, Perzin KH. Non-epithelial tumors of the nasal cavity, paranasal
sinuses, and nasopharynx: a clinicopathologic study. VII. Myxomas. Cancer.
1977;39:195–203.
109. Heffner DK. Sinonasal myxomas and fibromyxomas in children. Ear Nose
Throat J. 1993;72:365–368.
110. Evans H. Low-grade fibromyxoid sarcoma. A clinicopathologic study of 33
cases with long-term follow-up. Am J Surg Pathol. 2011;35:1450–1462.
111. Fu YS, Perzin KH. Non-epithelial tumors of the nasal cavity, paranasal
sinuses, and nasopharynx: a clinicopathologic study. II. Osseous and
fibroosseous lesions, including osteoma, fibrous dysplasia, ossifying fibroma,
osteoblastoma, giant cell tumor and osteosarcoma. Cancer. 1974;33:1289–1305.
112. Earwaker J. Paranasal sinus osteomas: a review of 46 cases. Skeletal Radiol.
1993;22:417–423.
113. Atallah N, Jay MM. Osteomas of the paranasal sinuses. J Laryngol Otol.
1981;95:291–304.
114. Bulow S, Sondergaard JO, Witt I, et al. Mandibular osteomas in familial
polyposis coli. Dis Col Rectum. 1984;27:105–108.
115. Waldron CA, Giansati JS. Benign fibro-osseous lesions of the jaws: a
clinicopathologic-histologic review of sixty-five cases. II. Benign fibro-osseous
lesions of peridontal ligament origin. Oral Surg. 1973;35:340–350.
116. Nevelle BW, Albenesius RJ. The prevalence of benign fibro-osseous lesions of
the peridontal ligament origin in black women: a radiographic survey. Oral
Surg. 1986;62:340–344.
117. Wenig BM, Vinh TN, Smirniotopoulos JG, et al. Aggressive psammomatoid
ossifying fibromas of the sinonasal region. A clinicopathologic study of adistinct group of fibro-osseous lesions. Cancer. 1995;76:1155–1165.
118. Johnson LC, Yousefi M, Vinh TN, et al. Juvenile active ossifying fibroma. Its
nature, dynamics and origin. Acta Otolaryngol Suppl. 1991;488:1–40.
119. Harris WH, Dudley HR Jr, Barry RJ. The natural history of fibrous dysplasia.
An orthopedic, pathological and roentenographic study. J Bone Joint Surg Am.
1962;44A:207–233.
120. Gibson MJ, Middlemiss JH. Fibrous dysplasia of bone. Br J Radiol. 1971;44:1–
13.
121. Henry A. Monostotic fibrous dysplasia. J Bone Joint Surg Br. 1969;51:300–306.
122. Yabut SM Jr, Kenan S, Sissons HA, et al. Malignant transformation of fibrous
dysplasia. A case report and review of the literature. Clin Orthop.
1988;228:281–289.
123. Taconis WK. Osteosarcoma in fibrous dysplasia. Skeletal Radiol. 1988;17:1047–
1056.
124. Oda Y, Tsuneyoshi M, Shinohara N. “Solid” variant of aneurysmal bone cyst
(extragnathic giant cell reparative granuloma) in axial skeleton and long
bones. A study of its morphologic spectrum and distinction from allied bone
lesions. Cancer. 1993;70:2642–2649.
125. Smith GA, Ward PH. Giant cell lesions of the facial skeleton. Arch Otolaryngol.
1978;7:366–370.
126. Hirsch IS, Katz A. Giant cell reparative granuloma outside the jaw bone. Hum
Pathol. 1974;5:171–181.
127. Waldron CA, Shafer WG. The central giant cell reparative granuloma of the
jaws. An analysis of 38 cases. Am J Clin Pathol. 1966;45:437–447.
128. McGowan DA. Central giant cell tumours of the mandible in pregnancy. Br J
Oral Med. 1969;7:131–135.
129. Littler BO. Central giant-cell granuloma of the jaw—a hormonal influence. Br J
Oral Surg. 1979;17:43–46.
130. Bertoni F, Unni KK, Beabout JW, et al. Giant cell tumor of the skull. Cancer.
1992;70:1124–1132.
131. Saleh EA, Taibh AK, Naguib M, et al. Giant cell tumor of the lateral skull: a
case report. Otolaryngol Head Neck Surg. 1994;111:314–318.
132. Bridge JA, Neff JR, Bhatia PS, et al. Cytogenetic findings and biologic behavior
of giant cell tumors of bone. Cancer. 1990;65:2697–2703.
133. Chan J, Gannon FH, Thompson LD. Malignant giant cell tumor of the
sphenoid. Ann Diagn Pathol. 2003;7:100–105.
134. Fu YS, Perzin KH. Non-epithelial tumors of the nasal cavity, paranasal
sinuses, and nasopharynx: a clinicopathologic study. III. Cartilaginous tumor
(chondroma, chondrosarcoma). Cancer. 1974;34:453–463.
135. Kilby D, Amegaokar AG. The nasal chondroma. J Laryngol Otol. 1977;91:415–
426.
136. Shafer WG, Hine MK, Levy BM. A textbook of oral pathology. 4th ed. Saunders:
Philadelphia; 1983.
137. Waldron CA. Odontogenic cysts and tumors. Neville DW, Damm DD, Allen
CM, et al. Oral and maxillofacial pathology. Saunders: Philadelphia; 1995:453–
540.
138. Schafer DR, Thompson L D R, Smith BC, et al. Primary ameloblastoma of the
sinonasal tract. A clinicopathologic study of 24 cases. Cancer. 1998;82:667–674.
139. Guilemany JM, Ballesteros F, Alos L, et al. Plexiform ameloblastomapresenting as a sinonasal tumor. Eur Arch Otorhinolaryngol. 2004;261:304–306.
140. Bryne MN, Sessions DG. Nasopharyngeal craniopharyngioma. Case report
and literature review. Ann Otol Rhinol Laryngol. 1990;99:633–639.
141. Chakrabarty A, Mitchell P, Bridges LR. Craniopharyngioma invading the nasal
and paranasal spaces, and presenting as nasal obstruction. Br J Neurosurg.
1998;12:361–363.
142. Taguchi Y, Tanaka K, Miyakita Y, et al. Recurrent craniopharyngioma with
nasopharyngeal extension. Pediatr Neurosurg. 2000;32:140–144.
143. Buhl R, Nabavi A, Fritsch M. Nasopharyngeal extension of a
craniopharyngioma in a 4 year old girl. Acta Neurochir (Wien). 2004;143:1283–
5128.
144. Dehner LP. Gonadal and extragonadal germ cell neoplasia of childhood. Hum
Pathol. 1983;14:493–511.
145. Tharrington CL, Bosen EH. Nasopharyngeal teratomas. Arch Pathol Lab Med.
1992;116:165–167.
146. Coppit GL 3rd, Perkins JA, Manning S. Nasopharyngeal teratomas and
dermoids: a review of the literature and case series. Int J Pediatr
Otorhinolaryngol. 2000;52:219–227.
147. Heffner DK, Thompson L D R, Schall DG, et al. Pharyngeal dermoids (“hairy
polyps”) as accessory auricles. Ann Otol Rhinol Laryngol. 1996;10:819–824.
148. Heffner DK. Problems in pediatric otorhinolaryngic pathology. III. Teratoid
and neural tumors of the nose, sinonasal tract, and nasopharynx. Int J Pediatr
Otorhinolaryngol. 1983;6:1–21.
149. Ferlito A, Devaney KO. Developmental lesions of the head and neck:
terminology and biological behavior. Ann Otol Rhinol Laryngol. 1995;104:913–
918.
150. Gorenstein A, Facer GW, Weiland LH. Hemangiopericytoma of the nasal
cavity. ORL J Otorhinolaryngol Relat Spec. 1978;86:405–415.
151. Thompson LD, Miettinen M, Wenig BM. Sinonasal-type hemangiopericytoma:
a clinicopathologic and immunophenotypic analysis of 104 cases showing
perivascular myoid differentiation. Am J Surg Pathol. 2003;27:737–749.
152. Kuo FY, Lin HC, Eng HL, et al. Sinonasal hemangiopericytoma-like tumor with
true pericytic myoid differentiation: a clinicopathologic and
immunohistochemical study of five cases. Head Neck. 2005;27:124–129.
153. Fletcher C D M. Haemangiopericytoma: a dying breed? Reappraisal of an
“entity” and its variants. Curr Diagn Pathol. 1994;1:19–23.
154. Fanburg-Smith J, Thompson L D R, Wenig BM. Borderline and LMP tumours
of soft tissue. Barnes L, Eveson J, Reichart P, et al. World Health Organization
classification of tumours. Pathology and genetics of head and neck tumours. IARC
Press,: Lyon, France; 2005:44–45.
155. Compagno J, Hyams VJ. Hemangiopericytoma-like intranasal tumors. A
clinicopathologic study of 23 cases. Am J Clin Pathol. 1976;66:672–683.
156. Schürch W, Skalli O, Lagace R, et al. Intermediate filament proteins and actin
isoforms as markers for soft tissue differentiation and origin: III.
Hemangiopericytomas and glomus tumors. Am J Pathol. 1990;136:771–786.
157. Porter PL, Bigler SA, McNutt M, et al. The immunophenotype of
hemangiopericytomas and glomus tumors, with special reference to muscle
protein expression: an immunohistochemical study and review of the
literature. Mod Pathol. 1991;4:46–52.158. Kapadia SK, Meis JM, Wenig BM, et al. Sinonasal hemangiopericytoma. Mod
Pathol. 1993;6:81A [(abstract)].
159. Dardick I, Hammar SP, Sheithauer BW. Ultrastructural spectrum of
hemangiopericytoma: a comparative study of fetal, adult and neoplastic
pericytes. Ultrastruct Pathol. 1989;13:111–154.
160. Eichorn JH, Dickerson GR, Bhan AK, et al. Sinonasal hemangiopericytoma: a
reassessment with electron microscopy, immunohistochemistry and long
term follow-up. Am J Surg Pathol. 1990;14:856–866.
161. Hansen T, Katenkamp K, Katenkamp D. D2-40 staining in sinonasal-type
hemangiopericytoma—further evidence of distinction from conventional
hemangiopericytoma and solitary fibrous tumor. Virchows Arch. 2006;448
[492462].
162. El-Naggar A, Batsakis JG, Garcia GM, et al. Sinonasal hemangiopericytomas.
A clinicopathologic and DNA content study. Arch Otolaryngol Head Neck Surg.
1992;118:134–137.
163. Billings KR, Fu YS, Calcaterra TC, et al. Hemangiopericytoma of the head and
neck. Am J Otolaryngol. 2000;21:238–243.
164. Kowalski PJ, Paulino AF. Proliferation index as a prognostic marker in
hemangiopericytoma of the head and neck. Head Neck. 2001;23:492–496.
165. Taxy JB. Squamous carcinoma of the nasal vestibule. An analysis of five cases
and literature review. Am J Clin Pathol. 1997;107:698–703.
166. Jackson RT, Fitz-Hugh GS, Constable WC. Malignant neoplasms of the nasal
cavities and paranasal sinuses. Laryngoscope. 1977;87:726–736.
167. Hopkin N, McNicoll W, Dalley VM, et al. Cancer of the paranasal sinuses and
nasal cavities. Part I. Clinical features. J Laryngol Otol. 1984;98:585–595.
168. Batsakis JG, Rice DH, Solomon AR. The pathology of head and neck tumors:
squamous and mucous-gland carcinomas of the nasal cavity, paranasal
sinuses, and larynx, part 6. Head Neck Surg. 1980;2:497–508.
169. Pedersen EA, Hogetreit AC, Andersen A. Cancer of the respiratory organs
among workers at a nickel refinery in Norway. Int J Cancer. 1973;12:32–41.
170. Trojussen W, Solberg LA, Hogetveit AC. Histopathologic changes of nasal
mucosa in nickel workers. A pilot study. Cancer. 1979;44:963–974.
171. Shibuya H, Amagasa T, Hanai A, et al. Second primary carcinomas in patients
with squamous cell carcinoma of the maxillary sinus. Cancer. 1986;58:1122–
1125.
172. Osborn DA. Nature and behavior of transitional tumors in the upper
respiratory tract. Cancer. 1970;25:50–60.
173. Giri S P G, Reddy EK, Gemer LS, et al. Management of advanced squamous
cell carcinomas of the maxillary sinus. Cancer. 1992;69:657–661.
174. Day TA, Beas RA, Schlosser RJ. Management of paranasal sinus malignancy.
Curr Treat Options Oncol. 2005;6:3–18.
175. Crissman JD, Liu WY, Gluckman JL, et al. Prognostic value of
histopathological parameters in squamous cell carcinoma of the oropharynx.
Cancer. 1984;54:2995–3001.
176. Crissman JD, Zarbo RJ. Dysplasia, in situ carcinoma, and progression to
invasive squamous cell carcinoma of the upper aerodigestive tract. Am J Surg
Pathol. 1989;13(Suppl 1):5–16.
177. Kreimer AR, Clifford GM, Boyle P, et al. Human papillomavirus types in head
and neck squamous cell carcinomas worldwide: a systematic review. CancerEpidemiol Biomarkers Prev. 2005;14:467–475.
178. Gillison ML. Human papillomavirus and prevention and therapy of head and
neck cancer. Harrison LB, Sessions RB, Waun KH. Head and neck cancer: a
multidisciplinary approach. 3rd ed. Lippincott Williams & Wilkins:
Philadelphia; 2009:905–917.
179. Stelow EB, Jo VY, Stoler MH, et al. Human papillomavirus-associated
squamous cell carcinoma of the upper aerodigestive tract. Am J Surg Pathol.
2010;34:e15–e24.
180. Pai SI, Westra WH. Molecular pathology of head and neck cancer: implications
for diagnosis, prognosis, and treatment. Annu Rev Pathol. 2009;4:49–70.
181. Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association
between human papillomavirus and a subset of head and neck cancers. J Natl
Cancer Inst. 2000;92:709–720.
182. Singhi AD, Stelow EB, Mills SE, et al. Lymphoepithelial-like carcinoma of the
oropharynx. A morphologic variant of HPV-related head and neck cancer. Am
J Surg Pathol. 2010;34:800–805.
183. Begum S, Gillison ML, Ansari-Lari MA, et al. Detection of human
papillomavirus in cervical lymph nodes: a highly effective strategy for
localizing site of tumor origin. Clin Cancer Res. 2003;9:6469–6475.
184. Begum S, Gillison ML, Nicol TL, et al. Detection of human papillomavirus-16
in fine-needle aspirates to determine tumor origin in patients with metastatic
squamous cell carcinoma of the head and neck. Clin Cancer Res. 2007;13:1186–
1191.
185. Singhi AD, Westra WH. Comparison of human papillomavirus in situ
hybridization and p16 immunohistochemistry in the detection of human
papilloma virus–associated head and neck cancer based on a prospective
clinical experience. Cancer. 2010;116:2166–2173.
186. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of
patients with oropharyngeal cancer. N Engl J Med. 2010;363:24–35.
187. Nichols AC, Faquin WC, Westra WH, et al. HPV-16 infection predicts
treatment outcome in oropharyngeal squamous cell carcinoma. Otolaryngol
Head Neck Surg. 2009;140:228–234.
188. Shanmugaratnam K, Sobin LH, Barnes L, et al. World Health Organization
histological classification of tumours. Histological typing of tumours of the upper
respiratory tract and ear. 2nd ed. Springer-Verlag: Berlin; 1991.
189. Chan J K C, Bray F, McCarron P, et al. Nasopharyngeal carcinoma. Barnes L,
Eveson J, Reichart P, et al. World Health Organization classification of tumours.
Pathology and genetics of head and neck tumours. IARC Press: Lyon, France;
2005:87–99.
190. Easton JM, Levine PH, Hyams VJ. Nasopharyngeal carcinoma in the United
States. A pathologic study of 177 US and 30 foreign cases. Arch Otolaryngol.
1981;106:88–91.
191. Dickson RI, Flores AD. Nasopharyngeal carcinoma: an evaluation of 134
patients treated between 1971-1980. Laryngoscope. 1985;95:276–283.
192. Huang DP. Epidemiology and aetiology. van Hasselt CA, Gibb AG.
Nasopharyngeal carcinoma. The Chinese Free Press: Hong Kong; 1991:23–35.
193. Parkin DM, Whelan SL, Ferlay J, et al. Cancer incidence in five continents, vol VIII.
IARC Press: Lyon, France; 2003.
194. Jenkin R D T, Anderson JR, Jereb B, et al. Nasopharyngeal carcinoma—aretrospective review of patients less than thirty years of age: a report from
Childrens Cancer Study Group. Cancer. 1981;47:360–366.
195. Heffner DK. Problems in pediatric otorhinolaryngic pathology. IV. Epithelial
and lymphoid tumors of the sinonasal tract and nasopharynx. Int J Pediatr
Otorhinolaryngol. 1983;6:219–237.
196. Hawkins EP, Krisher JP, Smith BE, et al. Nasopharyngeal carcinoma in
children—a retrospective review and demonstration of Epstein-Barr virus
genomes in tumor cell cytoplasm: a report of the Pediatric Oncology Group.
Hum Pathol. 1990;21:805–810.
197. Batsakis JG, Solomon AR, Rice DH. The pathology of head and neck tumors:
carcinoma of the nasopharynx, part 11. Head Neck Surg. 1981;3:511–524.
198. Skinner DW, van Hasselt CA, Tsao SY. Nasopharyngeal carcinoma: a study of
the modes of presentation. Ann Otol Rhinol Laryngol. 1991;100:544–551.
199. Wang CC, Little JB, Schulz MD. Cancer of the nasopharynx. Its clinical and
radiotherapeutic considerations. Cancer. 1962;15:921–926.
200. Ng SH, Chang TC, Ko SF, et al. Nasopharyngeal carcinoma: MRI and CT
assessment. Neuroradiology. 1997;39:741–746.
201. Buell P. The effect of migration on the risk of nasopharyngeal cancer among
Chinese. Cancer Res. 1974;34:1189–1191.
202. Vasef MA, Ferlito A, Weiss LM. Nasopharyngeal carcinoma with emphasis on
its relationship to Epstein-Barr virus. Ann Otol Rhinol Laryngol. 1997;106:348–
356.
203. Raab-Traub N. Epstein-Barr virus in the pathogenesis of NPC. Semin Cancer
Biol. 2002;12:431–441.
204. Henderson BE, Louie E, Jing JS, et al. Risk factors associated with
nasopharyngeal carcinoma. N Engl J Med. 1976;295:1101–1106.
205. Zeng Y, Zhang LG, Li HY, et al. Serological mass survey for early detection of
nasopharyngeal carcinoma in Wuzhou City, China. Int J Cancer. 1982;29:139–
141.
206. de-Vaithaire F, Sancho-Garnier H, de-Thé H, et al. Prognostic value of EBV
markers in the clinical management of nasopharyngeal carcinoma (NPC): a
multicenter follow-up study. Int J Cancer. 1988;42:176–181.
207. Young LS, Dawson CW, Clark D, et al. Epstein-Barr virus gene expression in
nasopharyngeal carcinoma. J Gen Virol. 1988;69:1051–1065.
208. Gasmi J, Bachouchi M, Cvitkovic E, et al. Nasopharyngeal carcinoma: a
medical oncology viewpoint: the Gustave Roussy experience. Ann Oncol.
1990;1:245–253.
209. Feinmesser R, Miyazaki I, Chueng R, et al. Diagnosis of nasopharyngeal
carcinoma by fine-needle aspiration. N Engl J Med. 1992;326:17–21.
210. Tam JS. Epstein-Barr virus serologic markers. van Hasselt CA, Gibb AG.
Nasopharyngeal carcinoma. The Chinese Free Press: Hong Kong; 1991:147–156.
211. Hadar T, Rahima M, Kahan E, et al. Significance of specific Epstein-Barr virus
IgA and elevated IgG antibodies to viral capsid antigens in nasopharyngeal
carcinoma patients. J Med Virol. 1986;20:329–339.
212. Chan KC, Lo YM. Circulating EBV DNA as a tumor marker for
nasopharyngeal carcinoma. Semin Cancer Biol. 2002;12:489–496.
213. Lin JC, Chen KY, Wang WY, et al. Detection of Epstein-Barr virus DNA in the
peripheral-blood cells of patients with nasopharyngeal carcinoma:
relationship to distant metastasis and survival. J Clin Oncol. 2001;19:2607–2615.
214. Lo YM, Chan LY, Lo KW. Quantitative analysis of cell-free Epstein-Barr virus
DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res.
1999;59:1188–1191.
215. Shotelersuk K, Khorprasert C, Sakdikul S, et al. Epstein-Barr virus DNA in
serum/plasma as a tumor marker for nasopharyngeal cancer. Clin Cancer Res.
2000;6:1046–1051.
216. Akao I, Sato Y, Mukai K, et al. Detection of Epstein-Barr virus DNA in
formalin-fixed paraffin-embedded tissue of nasopharyngeal carcinoma using
polymerase chain reaction and in-situ hybridization. Laryngoscope.
1991;101:279–283.
217. Tsai S-T, Jin Y-T, Su I-J. Expression of EBER1 in primary and metastatic
nasopharyngeal carcinoma tissues using in-situ hybridization. A correlation
with WHO subtypes. Cancer. 1996;77:231–236.
218. Pathmanathan R, Prasad U, Sadler R, et al. Clonal proliferation of cells
infected with Epstein-Barr virus in preinvasive lesions related to
nasopharyngeal carcinoma. N Engl J Med. 1995;333:693–698.
219. Hording U, Nielsen HW, Daugaard S, et al. Human papillomavirus types 11
and 16 detected in nasopharyngeal carcinomas by polymerase chain reaction.
Laryngoscope. 1994;204:99–102.
220. Waghray M, Parhar RS, Taibah K. Rearrangements of chromosome arm 3q in
poorly differentiated nasopharyngeal carcinoma. Genes Chromosomes Cancer.
1992;4:326–330.
221. Choi P H R, Suen M W M, Huang DP, et al. Nasopharyngeal carcinoma:
genetic changes, Epstein-Barr virus infection, or both. A clinical and
molecular study of 36 patients. Cancer. 1993;72:2873–2878.
222. Wong N, Hui AB, Fan B, et al. Molecular cytogenetic characterization of
nasopharyngeal carcinoma cell lines and xenografts by comparative genomic
hybridization and spectral karyotyping. Cancer Genet Cytogenet. 2003;140:124–
132.
223. Shao JY, Zeng WF, Zeng YX. Molecular genetic progression on
nasopharyngeal carcinoma. Ai Zheng. 2002;21:1–10.
224. Shao JY, Huang XM, Yu XJ, et al. Loss of heterozygosity and its correlation
with clinical outcome and Epstein-Barr virus infection in nasopharyngeal
carcinoma. Anticancer Res. 2001;21:3021–3029.
225. Fang Y, Guan X, Guo Y, et al. Analysis of genetic alterations in primary
nasopharyngeal carcinoma by comparative genomic hybridization. Genes
Chromos. Cancer. 2001;30:254–260.
226. Lo KW, Huang DP. Genetic and epigenetic changes in nasopharyngeal
carcinoma. Semin Cancer Biol. 2002;12:451–462.
227. Lo KW, Huang DP, Lau KM. p16 gene alterations in nasopharyngeal
carcinoma. Cancer Res. 1995;55:2039–2043.
228. Lo KW, Cheung ST, Leung SF, et al. Hypermethylation of the p16 gene in
nasopharyngeal carcinoma. Cancer Res. 1996;56:2721–2725.
229. Nicholls JM. Nasopharyngeal carcinoma: classification and histologic
appearances. Adv Anat Pathol. 1997;4:71–84.
230. Barnes L. Nasopharyngeal carcinoma. Barnes L. Surgical pathology of the head
and neck. 2nd ed. Marcel Dekker: New York; 2001:527–535.
231. Shanmugaratnam K, Chan SH, de-The G, et al. Histopathology ofnasopharyngeal carcinoma: correlations with epidemiology, survival rates,
and other biological characteristics. Cancer. 1979;44:1029–1044.
232. Franchi A, Moroni M, Massi D, et al. Sinonasal undifferentiated carcinoma,
nasopharyngeal-type undifferentiated carcinoma, and keratinizing and
nonkeratinizing squamous cell carcinoma express different cytokeratin
patterns. Am J Surg Pathol. 2002;26:1597–1604.
233. Reddy SP, Raslan WF, Gooneratne S, et al. Prognostic significance of
keratinization in nasopharyngeal carcinoma. Am J Otolaryngol. 1995;16:103–
108.
234. Ahmad A, Stefani S. Distant metastases of nasopharyngeal carcinoma: a study
of 256 male patients. J Surg Oncol. 1986;33:194–197.
235. McGuire LJ, Suen M W M. Histopathology. van Hasselt CA, Gibb AG.
Nasopharyngeal carcinoma. The Chinese Free Press: Hong Kong; 1991:47–84.
236. Cheng DS, Campbell BH, Clowry LJ, et al. DNA content in nasopharyngeal
carcinoma. Am J Otolaryngol. 1990;11:393–397.
237. Costello F, Mason BR, Collins RJ, et al. A clinical and flow cytometric analysis
of patients with nasopharyngeal carcinoma. Cancer. 1990;66:1789–1795.
238. Roychowdhury DF, Tseng A, Fu KK, et al. New prognostic factors in
nasopharyngeal carcinoma. Tumor angiogenesis and C-erbB2 expression.
Cancer. 1996;77:1419–1426.
239. Chua DT, Ma J, Sham JS, et al. Long-term survival after cisplatin-based
induction chemotherapy and radiotherapy for nasopharyngeal carcinoma: a
pooled data analysis of two phase III trials. J Clin Oncol. 2005;23:1118–1124.
240. Cooper JS, Scott C, Marcial V, et al. The relationship of nasopharyngeal
carcinomas and second independent malignancies based on radiation therapy
oncology group experience. Cancer. 1991;67:1673–1677.
241. Pavlidis N, Briasoulis E, Hainsworth J, et al. Diagnosis and therapeutic
management of cancer of unknown primary. Eur J Cancer. 2003;39:1990–2005.
242. Luna MA. The occult primary and metastatic tumors to and from the head and
neck. Barnes L. Surgical pathology of the head and neck. 3rd ed. Informa: New
York; 2009:1147–1162.
243. Cao D, et al. Expression of p16 in benign and malignant cystic squamous
lesions of the neck. Hum Pathol. 2010;41:535–539.
244. Schiff BA, Mutyala S, Smith RS. Metastatic cancer to the neck from an
unknown primary site. Harrison LB, Sessions RB, Hong WK. Head and neck
cancer. A multidisciplinary approach. Lippincott Williams & Wilkins:
Philadelphia; 2009:232–243.
245. Frierson HF Jr, Mills SE, Fechner RE, et al. Sinonasal undifferentiated
carcinoma. An aggressive neoplasm derived from Schneiderian epithelium
and distinct from olfactory neuroblastoma. Am J Surg Pathol. 1986;10:771–779.
246. Frierson HF. Sinonasal undifferentiated carcinoma. Barnes L, Eveson J,
Reichart P, et al. World Health Organization classification of tumours. Pathology
and genetics of head and neck tumours. IARC Press: Lyon, France; 2005:19.
247. Righi PD, Francis F, Aron BS, et al. Sinonasal undifferentiated carcinoma: a
10year experience. Am J Otolaryngol. 1996;17:167–171.
248. Helliwell TR, Yeoh LH, Stell PM. Anaplastic carcinoma of the nose and
paranasal sinuses. Light microscopy, immunohistochemistry and clinical
correlation. Cancer. 1986;58:2038–2045.
249. Mills SE. Neuroectodermal neoplasms of the head and neck with emphasis onneuroendocrine carcinomas. Mod Pathol. 2002;15:264–278.
250. Ejaz A, Wenig BM. Sinonasal undifferentiated carcinoma. Clinical and
pathologic features and a discussion on classification, cellular differentiation,
and differential diagnosis. Adv Anat Pathol. 2005;12:134–143.
251. Jeng YM, Sung MT, Fang CL, et al. Sinonasal undifferentiated carcinoma and
nasopharyngeal-type undifferentiated carcinoma: two clinically, biologically,
and histopathologically distinct entities. Am J Surg Pathol. 2002;26:371–376.
252. Cerilli LA, Holst VA, Brandwein MS, et al. Sinonasal undifferentiated
carcinoma: immunohistochemical profile and lack of EBV association. Am J
Surg Pathol. 2001;25:156–163.
253. Lopategui JR, Gaffey MJ, Frierson HF Jr, et al. Detection of Epstein-Barr viral
RNA in sinonasal undifferentiated carcinoma from Western and Asian
patients. Am J Surg Pathol. 1994;18:391–398.
254. Gallo O, Di Lollo S, Graziani P, et al. Detection of Epstein-Barr virus genome
in sinonasal undifferentiated carcinoma by use of in situ hybridization.
Otolaryngol Head Neck Surg. 1995;112:659–664.
255. Greger V, Schirmacher P, Bohl J, et al. Possible involvement of the
retinoblastoma gene in undifferentiated sinonasal carcinoma. Cancer.
1990;66:1954–1959.
256. Mills SE, Fechner RE. “Undifferentiated” neoplasms of the sinonasal tract:
differential diagnosis based on clinical, light microscopic,
immunohistochemical, and ultrastructural features. Semin Diagn Pathol.
1989;6:316–328.
257. Kramer D, Durham JS, Sheehan F, et al. Sinonasal undifferentiated carcinoma:
case series and systemic review of the literature. J Otolaryngol. 2004;33:32–36.
258. Kim BS, Vongtama R, Juillard G. Sinonasal undifferentiated carcinoma: case
series and literature review. Am J Otolaryngol. 2004;25:162–166.
259. Gallo O, Graziani P, Fini-Storchi O. Undifferentiated carcinoma of the nose
and paranasal sinuses. An immunohistochemical and clinical study. Ear Nose
Throat J. 1993;72:588–590 [593-595].
260. Rischin D, Porceddu S, Peters L, et al. Promising results with chemoradiation
in patients with sinonasal undifferentiated carcinoma. Head Neck. 2004;26:435–
441.
261. Lin EM, Sparano A, Eisbruch A, et al. Sinonasal undifferentiated carcinoma: a
13-year experience at a single institution. Skull Base. 2010;20:61–67.
262. French CA. Demystified molecular pathology of NUT midline carcinoma. J
Clin Pathol. 2010;63:492–496.
263. French CA, Kutok JL, Faquin WC, et al. Midline carcinoma of children and
young adults with NUT rearrangement. J Clin Oncol. 2004;22:4135–4139.
264. Stelow EB, Bellizzi AM, Taneja K, et al. NUT rearrangement in
undifferentiated carcinomas of the upper aerodigestive tract. Am J Surg
Pathol. 2008;32:828–834.
265. Nakashima T, Kimmelman CP, Snow JB Jr. Structure of human fetal and adult
olfactory neuroepithelium. Arch Otolaryngol. 1984;110:641–646.
266. Wenig BM, Dulguerov P, Kapadia SB, et al. Neuroectodermal tumours. Barnes
L, Eveson J, Reichart P, et al. World Health Organization classification of
tumours. Pathology and genetics of head and neck tumours. IARC Press: Lyon,
France; 2005:66–76.
267. Baker DC, Perzin NH, Conley J. Olfactory neuroblastoma. Otolaryngol HeadNeck Surg. 1979;87:279–283.
268. Elkon D, Hightower SI, Lim ML, et al. Esthesioneuroblastoma. Cancer.
1979;44:1087–1094.
269. Dulguerov P, Calcaterra T. Esthesioneuroblastoma: the UCLA experience
1970-1990. Laryngoscope. 1992;102:843–849.
270. Dulguerov P, Allal AS, Calcaterra TC. Esthesioneuroblastoma: a meta-analysis
and review. Lancet Oncol. 2001;2:683–690.
271. Mills SE, Frierson HF Jr. Olfactory neuroblastoma. A clinicopathologic study
of 21 cases. Am J Surg Pathol. 1985;9:317–327.
272. Hirose T, Scheithauer BW, Lopes M B S, et al. Olfactory neuroblastoma. An
immunohistochemical, ultrastructural, and flow cytometric study. Cancer.
1995;76:4–19.
273. Woodhead P, Lloyd GA. Olfactory neuroblastoma: imaging by magnetic
resonance, CT and conventional techniques. Clin Otolaryngol. 1988;13:387–394.
274. Herrold KM. Induction of olfactory neuroepithelial tumors in Syrian hamsters
by diethylnitrosamine. Cancer. 1964;17:114–121.
275. Bailey BJ, Barton S. Olfactory neuroblastoma: management and prognosis.
Arch Otolaryngol. 1975;101:1–5.
276. Vollrath M, Altmannsberger M, Weber K, et al. Chemically induced tumors of
rat olfactory epithelium: a model for human esthesioneuroblastoma. J Natl
Cancer Inst. 1986;76:1205–1216.
277. Ambros IM, Ambros PF, Strehl S, et al. MIC2 is a specific marker for Ewing's
sarcoma and peripheral primitive neuroectodermal tumors. Evidence for a
common histogenesis of Ewing's sarcoma and peripheral primitive
neuroectodermal tumors from MIC2 expression and specific chromosome
aberration. Cancer. 1991;67:1886–1893.
278. Fellinger EJ, Garin-Chesa P, Triche TJ, et al. Immunohistochemical analysis of
MIC2Ewing's sarcoma cell surface antigen p30/32 . Am J Pathol. 1991;139:317–
325.
279. Ladanyi M. The emerging molecular genetics of sarcoma translocations. Diagn
Mol Pathol. 1995;4:162–167.
280. Whang-Peng J, Freier RE, Knutsen T. Translocation t(11;22) in
esthesioneuroblastoma. Cancer Genet Cytogenet. 1987;29:155–157.
281. Sorensen P H B, Wu JK, Berean KW, et al. Olfactory neuroblastoma is a
peripheral primitive neuroectodermal tumor related to Ewing sarcoma. Proc
Natl Acad Sci. 1996;93:1938–1943.
282. Nelson RS, Perlman EJ, Askin FB. Is esthesioneuroblastoma a peripheral
neuroectodermal tumor? Hum Pathol. 1995;26:639–641.
283. Devaney K, Wenig BM, Abbondanzo SL. Olfactory neuroblastoma and other
round cell lesions of the sinonasal cavity. Mod Pathol. 1996;9:658–663.
284. Argani P, Perez-Ordonez B, Xiao H, et al. Olfactory neuroblastoma is not
related to the Ewing family of tumors. Absence of EWS/FLI1 gene fusion and
MIC2 expression. Am J Surg Pathol. 1998;22:391–398.
285. Kumar S, Perlman E, Pack S, et al. Absence of EWS/FLI1 fusion in olfactory
neuroblastomas indicates these tumors do not belong to the Ewing's sarcoma
family. Hum Pathol. 1999;30:1356–1360.
286. Mezzelani A, Tornielli S, Minoletti F, et al. Esthesioneuroblastoma is not a
member of the primitive peripheral neuroectodermal tumour–Ewing's group.
Br J Cancer. 1999;81:586–591.287. Hyams VJ. Olfactory neuroblastoma (case 6). Batsakis JG, Hyams VJ, Morales
AR. Special tumors of the head and neck. ASCP: Press, Chicago; 1982:24–29.
288. Miller DC, Goodman ML, Pilch BZ, et al. Mixed olfactory neuroblastoma and
carcinoma. A report of two cases. Cancer. 1984;54:2019–2028.
289. Frierson HF Jr, Ross GW, Mills SE, et al. Olfactory neuroblastoma. Additional
immunohistochemical characterization. Am J Clin Pathol. 1990;94:547–553.
290. Faragalla H, Weinreb I. Olfactory neuroblastoma: a review and update. Adv
Anat Pathol. 2009;16:322–331.
291. Tatagiba M, Samii M, Dankoweit T, et al. Esthesioneuroblastomas with
intracranial extension. Proliferative potential and management. Arq
Neuropsiquiatr. 1995;53:577–586.
292. Vartanian RK. Olfactory neuroblastoma: an immunohistochemical,
ultrastructural and flow cytometric study. Cancer. 1996;77:1957–1959.
293. Kahn LB. Esthesioneuroblastoma. A light and electron microscopic study.
Hum Pathol. 1974;5:364–371.
294. Taxy JB, Hidvegi DF. Olfactory neuroblastoma. An ultrastructural study.
Cancer. 1977;39:131–138.
295. Morita A, Ebersold MJ, Olsen KD, et al. Esthesioneuroblastoma: prognosis
and management. Neurosurgery. 1993;32:706–715.
296. Eden BV, Debo RF, Larner JM, et al. Esthesioneuroblastoma. Long term
follow-up and patterns of failure—the University of Virginia experience.
Cancer. 1994;73:2556–2562.
297. Kadish S, Goodman M, Wang CC. Olfactory neuroblastoma. A clinical analysis
of 17 cases. Cancer. 1976;37:1571–1576.
298. Hyams VJ, Batsakis JG, Michaels L. Tumors of the upper respiratory tract and ear.
2nd ed. Armed Forces Institute of Pathology: Washington; 1988.
299. Kapadia S. Olfactory neuroblastoma. Barnes L. Surgical pathology of the head
and neck. Marcel Dekker: New York; 2001:841–845.
300. Barnes L. Malignant melanoma of the nasal cavity and paranasal sinuses.
Barnes L. Surgical pathology of the head and neck. 2nd ed. Marcel Dekker: New
York; 2001:523–527.
301. Wenig BM. Laryngeal mucosal malignant melanoma: a clinicopathologic,
immunohistochemical and ultrastructural study of four cases and a review of
the literature. Cancer. 1995;75:1568–1575.
302. Moreno MA, Roberts DB, Kupferman ME, et al. Mucosal melanoma of the
nose and paranasal sinuses, a contemporary experience from the MD
Anderson Cancer Center. Cancer. 2010;116:2215–2223.
303. Thompson LD, Wieneke JA, Miettinen M. Sinonasal tract and nasopharyngeal
melanomas: a clinicopathologic study of 115 cases with a proposed staging
system. Am J Surg Pathol. 2003;27:594–611.
304. Panje WR, Moran WJ. Melanoma of the upper aerodigestive tract: a review of
21 cases. Head Neck Surg. 1986;8:309–312.
305. Trapp TK, Fu YS, Calcaterra TC. Melanoma of the nasal and paranasal sinus
mucosa. Arch Otolaryngol Head Neck Surg. 1987;113:1086–1089.
306. Franquemont DW, Mills SE. Sinonasal malignant melanoma: a
clinicopathologic and immunohistochemical study of 14 cases. Am J Clin
Pathol. 1991;96:689–697.
307. Reuter VE, Woodruff JM. Melanoma of the larynx. Laryngoscope. 1986;94:389–
393.308. Goldman JL, Lawson W, Zak FG, et al. The presence of melanocytes in the
human larynx. Laryngoscope. 1972;82:824–835.
309. Busuttil A. Dendritic pigmented cells within the human laryngeal mucosa.
Arch Otolaryngol. 1976;102:43–44.
310. Taira K. Endocrine-like cells in the laryngeal mucosa of adult rabbits
demonstrated by electron microscopy and by the Grimelius
silverimpregnation method. Biomed Res. 1985;6:377–385.
311. Prasad ML, Jungbluth AA, Iversen K, et al. Expression of melanocytic
differentiation markers in malignant melanomas of the oral and sinonasal
mucosa. Am J Surg Pathol. 2001;25:782–787.
312. Wenig BM, Dulguerov P, Kapadia SB, et al. Mucosal malignant melanoma.
Barnes L, Eveson J, Reichart P, et al. World Health Organization classification of
tumours. Pathology and genetics of head and neck tumours. IARC Press: Lyon,
France; 2005:72–75.
313. McGovern VJ. The nature of melanoma: a critical review. J Cutan Pathol.
1982;9:61–81.
314. Barnes L. Intestinal-type adenocarcinoma of the nasal cavity and paranasal
sinuses. Am J Surg Pathol. 1986;10:192–202.
315. Robin PE, Powell DJ, Stansbie JM. Carcinoma of the nasal cavity and paranasal
sinuses: incidence and presentation of different histological types. Clin
Otolaryngol. 1979;4:432–456.
316. Kleinsasser O, Schroeder HG. Adenocarcinoma of the inner nose after
exposure to wood dust: morphological findings and relationships between
histopathology and clinical behavior in 79 cases. Arch Otorhinolaryngol.
1988;245:1–15.
317. Hadfield EH, Macbeth RG. Adenocarcinoma of ethmoids in furniture workers.
Ann Otol Rhinol Laryngol. 1971;80:699–703.
318. Hadfield EH. A study of adenocarcinoma of the paranasal sinuses in
woodworkers in the furniture industry. Ann R Coll Surg Engl. 1970;46:302–319.
319. Acheson ED, Cowdell RH, Hadfield EH, et al. Nasal cancer in the
Northamptonshire boot and shoe industry. Br Med J. 1970;1:385–393.
320. Cecchi F, Buiatti E, Kreibel D, et al. Adenocarcinoma of the nose and
paranasal sinuses in shoemakers and woodworkers in the province of
Florence, Italy (1963-77). Br J Ind Med. 1980;37:222–225.
321. Batsakis JG, Holtz F, Sueper RH. Adenocarcinoma of the nasal and paranasal
cavities. Arch Otolaryngol. 1968;77:625–633.
322. Franquemont DW, Fechner RE, Mills SE. Histologic classification of sinonasal
intestinal-type adenocarcinoma. Am J Surg Pathol. 1991;15:368–375.
323. Franchi A, Gallo O, Santucci M. Clinical relevance of the histological
classification of sinonasal intestinal-type adenocarcinomas. Hum Pathol.
1999;30:1140–1145.
324. Mills SE, Fechner RE, Cantrell RW. Aggressive sinonasal lesion resembling
normal intestinal mucosa. Am J Surg Pathol. 1982;6:803–809.
325. McKinney CD, Mills SE, Franquemont DW. Sinonasal intestinal-type
adenocarcinoma: immunohistochemical profile and comparison with colonic
adenocarcinoma. Mod Pathol. 1995;8:421–426.
326. Urso C, Ninu MB, Franchi A, et al. Intestinal-type adenocarcinoma of the
sinonasal tract: a clinicopathologic study of 18 cases. Tumori. 1993;79:205–210.
327. Franchi A, Massi D, Baroni G, et al. CDX-2 homeobox gene expression. Am JSurg Pathol. 2003;27:1390–1391.
328. Bashir AA, Robinson RA, Benda JA, et al. Sinonasal adenocarcinoma:
immunohistochemical marking and expression of oncoproteins. Head Neck.
2003;25:763–771.
329. Amre R, Ghali V, Elmberger G, et al. Sinonasal “intestinal type”
adenocarcinomas (SNITAC): an immunohistochemical (IHC) study of 22
cases. Mod Pathol. 2004;17:221A.
330. Kennedy MT, Jordan RC, Berean KW, et al. Expression pattern of CK7, CK20,
CDX-2, and villin in intestinal-type sinonasal adenocarcinoma. J Clin Pathol.
2004;57:932–937.
331. Cathro HP, Mills SE. Immunophenotypic differences between intestinal-type
and low-grade papillary sinonasal adenocarcinomas: an
immunohistochemical study of 22 cases utilizing CDX2 and MUC2. Am J Surg
Pathol. 2004;28:1026–1032.
332. Franchi A, Massi D, Palomba A, et al. CDX-2, cytokeratin 7 and cytokeratin 20
immunohistochemical expression in the differential diagnosis of primary
adenocarcinomas of the sinonasal tract. Virchows Arch. 2004;445:63–67.
333. Batsakis JG, Mackay B, Ordonez NG. Enteric-type adenocarcinoma of the nasal
cavity. An electron microscopic and immunocytochemical study. Cancer.
1984;54:855–860.
334. Stelow EB, Mills SE, Jo VY, et al. Adenocarcinoma of the upper aerodigestive
tract. Adv Anat Pathol. 2010;17:262–269.
335. Heffner DK, Hyams VJ, Hauck KW, et al. Low-grade adenocarcinoma of the
nasal cavity and paranasal sinuses. Cancer. 1982;50:312–322.
336. Stelow EB, Jo VY, Mills SE, et al. A histologic and immunohistochemical study
describing the diversity of tumors classified as sinonasal high-grade
nonintestinal adenocarcinomas. Am J Surg Pathol. 2011;35:971–980.
337. Jo VY, Mills SE, Cathro HP, et al. Low-grade sinonasal adenocarcinomas: the
association with and distinction from respiratory epithelial adenomatoid
hamartomas and other glandular lesions. Am J Surg Pathol. 2009;33:401–408.
338. Barnes L, Brandwein M. Adenoid cystic carcinoma. Barnes L. Surgical
pathology of the head and neck. 2nd ed. Marcel Dekker: New York; 2001:522–523.
339. Eby LS, Johnson DS, Baker HW. Adenoid cystic carcinomas of the head and
neck. Cancer. 1972;29:1160–1168.
340. Orenstein JM, Dardick I, van Nostrand AW. Ultrastructural similarities of
adenoid cystic carcinoma and pleomorphic adenoma. Histopathology.
1985;9:623–638.
341. Tomich CE. Adenoid cystic carcinoma. Ellis GL, Auclair PL, Gnepp DR.
Surgical pathology of the salivary glands. Saunders: Philadelphia; 1991:333–349.
342. Spiro RH, Huvos AG. Stage means more than grade in adenoid cystic
carcinoma. Am J Surg. 1992;164:623–628.
343. Kadish SB, Goodman ML, Wang CC. Treatment of minor salivary gland
malignancies of upper food and air passage epithelium. Cancer. 1972;29:1020–
1026.
344. Wenig BM, Hyams VJ, Heffner DK. Nasopharyngeal papillary
adenocarcinoma. A clinicopathologic study of a low-grade carcinoma. Am J
Surg Pathol. 1988;12:946–953.
345. Kuo TT, Chan J K C, Wenig BM, et al. Nasopharyngeal papillary
adenocarcinoma. Barnes L, Eveson J, Reichart P, et al. World HealthOrganization classification of tumours. Pathology and genetics of head and neck
tumours. IARC Press: Lyon, France; 2005:100.
346. Carrizo F, Luna MA. Thyroid transcription factor-1 expression in thyroid-like
nasopharyngeal papillary adenocarcinoma: report of 2 cases. Ann Diagn
Pathol. 2005;9:189–192.
347. Abbondanzo SL, Wenig BM. Non-Hodgkin's lymphoma of the sinonasal tract:
a clinicopathologic and immunophenotypic study of 120 cases. Cancer.
1995;75:1281–1291.
348. Jaffe ES, Chan J K C, Su I-H, et al. Report of the workshop on nasal and related
extranodal angiocentric T/natural killer cell lymphomas. Definitions,
differential diagnosis, and epidemiology. Am J Surg Pathol. 1996;20:103–111.
349. Chan A C L, Chan J K C, Cheung M M C, et al. Hematolymphoid tumours.
Barnes L, Eveson J, Reichart P, et al. World Health Organization classification of
tumours. Pathology and genetics of head and neck tumours. IARC Press: Lyon,
France; 2005:59–65.
350. Arber DA, Weiss LM, Albujar PF, et al. Nasal lymphomas in Peru: high
incidence of T-cell immunophenotype and Epstein–Barr virus infection. Am J
Surg Pathol. 1993;17:392–399.
351. Fellbaum C, Hansmann ML, Lennert K. Malignant lymphomas of the nasal
cavity and paranasal sinuses. Virchows Archiv A Pathol Anat. 1989;414:399–405.
352. Ho F C S, Loke SL, Ng RP, et al. Clinico-pathological features of malignant
lymphomas in 294 Hong Kong Chinese patients, retrospective study covering
an eight-year period. Int J Cancer. 1984;34:143–148.
353. Gualco G, Domeny-Duarte P, Chioato L, et al. Clinicopathologic and molecular
features of 122 Brazilian cases of nodal and extranodal NK/T-cell lymphoma,
nasal type, with EBV subtyping analysis. Am J Surg Pathol. 2011;35:1195–1203.
354. Cheung MM, Chan JK, Lau WH, et al. Primary non-Hodgkin's lymphoma of
the nose and nasopharynx: clinical features, tumor immunophenotype, and
treatment outcome in 113 patients. J Clin Oncol. 1998;16:70–77.
355. Anderson JR, Armitage JO, Weisenburger DD. Epidemiology of the
nonHodgkin's lymphomas: distributions of the major subtypes differ by
geographic locations. Non-Hodgkin's Lymphoma Classification Project. Ann
Oncol. 1998;9:717–720.
356. Quintanilla-Martinez L, Franklin JL, Guerrero I, et al. Histological and
immunophenotypic profile of nasal NK/T cell lymphomas from Peru: high
prevalence of p53 overexpression. Hum Pathol. 1999;30:849–855.
357. Cuadra-Garcia I, Proulx GM, Wu CL, et al. Sinonasal lymphoma: a
clinicopathologic analysis of 58 cases from the Massachusetts General
Hospital. Am J Surg Pathol. 1999;23:1356–1369.
358. Pomilla PV, Morris AB, Jaworek A. Sinonasal non-Hodgkin's lymphoma in
patients infected with human immunodeficiency virus: report of three cases
and review. Clin Infect Dis. 1995;21:137–149.
359. Canioni D, Arnulf B, Asso-Bonnet M, et al. Nasal natural killer lymphoma
associated with Epstein-Barr virus in a patient infected with human
immunodeficiency virus. Arch Pathol Lab Med. 2001;125:660–662.
360. Jaffe ES, Krenacs L, Kumar S, et al. Extranodal peripheral T-cell and NK-cell
neoplasms. Am J Clin Pathol. 1999;111:S46–S55.
361. Chan J K C, Yip T T C, Tsang W Y W, et al. Detection of Epstein-Barr viral
RNA in malignant lymphomas of the upper aerodigestive tract. Am J SurgPathol. 1994;18:938–946.
362. Ohshima K, Suzumiya J, Shimazaki K, et al. Nasal T/NK cell lymphomas
commonly express perforin and Fas ligand: important mediators of tissue
damage. Histopathology. 1997;31:444–450.
363. Bourne TD, Bellizzi AM, Stelow EB, et al. p63 Expression in olfactory
neuroblastoma and other small cell tumors of the sinonasal tract. Am J Clin
Pathol. 2008;130:213–218.
364. Hedvat CV, Teruya-Feldstein J, Puig P, et al. Expression of p63 in diffuse large
B-cell lymphoma. Appl Immunohistochem Mol Morphol. 2005;13:237–242.
365. Cheung MM, Chan JK, Lau WH, et al. Early stage nasal NK/T-cell lymphoma:
clinical outcome, prognostic factors, and the effect of treatment modality. Int J
Radiat Oncol Biol Phys. 2002;54:182–190.
366. Cheung MM, Chan JK, Wong KF. Natural killer cell neoplasms: a distinctive
group of highly aggressive lymphoma/leukemia. Semin Hematol. 2003;40:221–
232.
367. Kim GE, Koom WS, Yang WI. Clinical relevance of three subtypes of primary
sinonasal lymphoma characterized by immunophenotypic analysis. Head
Neck. 2004;26:584–593.
368. Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal
lymphomas. Cancer. 1972;29:252–260.
369. Otter R, Gerrits W, vd Sandt M, et al. Primary extranodal and nodal
nonHodgkin's lymphomas: survey of a population-based registry. Eur J Cancer
Clin Oncol. 1989;25:1203–1210.
370. Hoppe RT, Burke JS, Glatstein E, et al. Non-Hodgkin's lymphoma:
involvement of Waldeyer's ring. Cancer. 1978;42:1096–1104.
371. Barton JH, Osborne BM, Butler JJ, et al. Non-Hodgkin's lymphoma of the
tonsil: a clinicopathologic study of 65 cases. Cancer. 1984;53:86–95.
372. Saul SH, Kapadia SB. Lymphoma of Waldeyer's ring: clinicopathologic study
of 68 cases. Cancer. 1985;56:157–166.
373. Shima N, Kobashi Y, Tsutsui K, et al. Extranodal non-Hodgkin's lymphoma of
the head and neck: a clinicopathologic study in the Kyoto-Nara area of Japan.
Cancer. 1990;66:1190–1197.
374. Cossman J, Fend F, Staudt L. Application of molecular genetics to the
diagnosis of hematopoietic neoplasms. Knowles DM. Neoplastic
hematopathology. 2nd ed. Lippincott Williams & Wilkins: Philadelphia;
2001:365–390.
375. Carbone PP, Kaplan HS, Musshoff K, et al. Report of the committee on
Hodgkin's disease staging classification. Cancer Res. 1971;31:1860–1861.
376. Shimm DS, Dosooretz DE, Harris NL, et al. Radiation therapy of Waldeyer's
ring lymphoma. Cancer. 1984;54:426–431.
377. Kapadia S, Desai U, Cheng U. Extramedullary plasmacytoma of the head and
neck: a clinicopathologic study of 20 cases. Medicine. 1982;61:317–329.
378. Grogan TM, Spier CM. B cell immunoproliferative disorders, including
multiple myeloma and amyloidosis. Knowles DM. Neoplastic hematopathology.
2nd ed. Lippincott Williams & Wilkins: Philadelphia; 2001:1557–1588.
379. Kinney MC, Swerdlow SH. Plasma cell neoplasms. Barnes L. Surgical pathology
of the head and neck. Marcel Dekker: New York; 2001:1323–1329.
380. Alexanian R. Ten-year survival in multiple myeloma. Arch Intern Med.
1985;145:2073–2074.381. Carbone A, Vaccher E, Barzan L, et al. Head and neck lymphomas associated
with human immunodeficiency virus infection. Arch Otolaryngol Head Neck
Surg. 1995;121:210–218.
382. Hicks MJ, Flaitz CM, Nichols CM, et al. Intraoral presentation of anaplastic
large cell Ki-1 lymphoma in association with HIV infection. Oral Surg Oral
Med Oral Pathol. 1993;76:73–81.
383. Heffner DK. Problems in pediatric otorhinolaryngic pathology. IV. Epithelial
and lymphoid tumors of the sinonasal tract and nasopharynx. Int J Pediatr
Otorhinolaryngol. 1983;6:219–237.
384. Kapadia SB, Roman LN, Kingma DW, et al. Hodgkin's disease of Waldeyer's
ring. Clinical and histoimmunophenotypic findings and association with
Epstein-Barr virus in 16 cases. Am J Surg Pathol. 1995;19:1431–1439.
385. Moghe GM, Borges AM, Soman CS, et al. Hodgkin's disease involving
Waldeyer's ring: a study of four cases. Leuk Lymphoma. 2001;41:151–156.
386. Anselmo AP, Cavalieri E, Cardarelli L, et al. Hodgkin's disease of the
nasopharynx: diagnostic and therapeutic approach with a review of the
literature. Ann Hematol. 2002;81:514–516.
387. Perez-Ordonez B, Erlandson RA, Rosai J. Follicular dendritic cell tumor: report
of 13 additional cases of a distinctive entity. Am J Surg Pathol. 1996;20:944–955.
388. Perez-Ordonez B, Rosai J. Follicular dendritic cell tumor: review of the entity.
Semin Diagn Pathol. 1998;15:144–154.
389. Biddle DA, Ro JY, Yoon GS, et al. Extranodal follicular dendritic cell sarcoma
of the head and neck region: three new cases, with a review of the literature.
Mod Pathol. 2002;15:50–58.
390. Chan J K C, Pileri SA, Delsol G, et al. Follicular dendritic cell sarcoma.
Swerdlow SH, Campo E, Harris NL, et al. World Health Organization
classification of tumours of haematopoietic and lymphoid tissues. IARC Press:
Lyon, France; 2008:363–364.
391. Dominguez-Malagon H, Cano-Valdez AM, Mosqueda-Taylor A, et al. Follicular
dendritic cell sarcoma of the pharyngeal region: histologic, cytologic,
immunohistochemical, and ultrastructural study of three cases. Ann Diagn
Pathol. 2004;8:325–332.
392. Chan AC, Chan KW, Chan JK, et al. Development of follicular dendritic cell
sarcoma in hyaline-vascular Castleman's disease of the nasopharynx: tracing
its evolution by sequential biopsies. Histopathology. 2001;38:510–518.
393. Grogg KL, Lae ME, Kurtin PJ, et al. Clusterin expression distinguishes
follicular dendritic cell tumors from other dendritic cell neoplasms: report of
a novel follicular dendritic cell marker and clinicopathologic data on 12
additional follicular dendritic cell tumors and 6 additional interdigitating
dendritic cell tumors. Am J Surg Pathol. 2004;28:988–998.
394. Chan JK, Fletcher CD, Nayler SJ, et al. Follicular dendritic cell sarcoma.
Clinicopathologic analysis of 17 cases suggesting a malignant potential higher
than currently recognized. Cancer. 1997;79:294–313.
395. Heffner DK, Gnepp DR. Sinonasal fibrosarcomas, malignant schwannomas,
and “Triton” tumors. A clinicopathologic study of 67 cases. Cancer.
1992;70:1089–1101.
396. Loree TR, North JH Jr, Werness BA, et al. Malignant peripheral nerve sheath
tumors of the head and neck: analysis of prognostic factors. Otolaryngol Head
Neck Surg. 2000;122:667–672.397. Wick MR, Swanson PE, Scheithauer BW, et al. Malignant peripheral nerve
sheath tumor. An immunohistochemical study of 62 cases. Am J Clin Pathol.
1987;87:425–433.
398. Barnes L, Kanbour A. Malignant fibrous histiocytoma of the head and neck. A
report of 12 cases. Arch Otolaryngol Head Neck Surg. 1988;114:1149–1156.
399. Perzin KH, Fu YS. Non-epithelial tumors of the nasal cavity, paranasal
sinuses, and nasopharynx: a clinicopathologic study. XI. Fibrous
histiocytomas. Cancer. 1980;45:2616–2626.
400. Mauer HM, Beltangady M, Gehan EA, et al. The Intergroup
Rhabdomyosarcoma Study—I. A final report. Cancer. 1988;61:209–220.
401. Weiss SW, Goldblum JR. Rhabdomyosarcoma. Enzinger and Weiss's soft tissue
tumors. 5th ed. Mosby: St. Louis; 2008:595–631.
402. Barnes L. Rhabdomyosarcoma. Barnes L. Surgical pathology of the head and neck.
2nd ed. Marcel Dekker: New York; 2001:960–967.
403. Anderson GJ, Tom L W C, Womer RB, et al. Rhabdomyosarcoma of the head
and neck in children. Arch Otolaryngol Head Neck Surg. 1990;116:428–431.
404. Callender TA, Weber RS, Janjan N, et al. Rhabdomyosarcoma of the nose and
paranasal sinuses in adults and children. Head Neck Surg. 1995;112:252–257.
405. El-Naggar AK, Batsakis JG, Ordonez NG, et al. Rhabdomyosarcoma of the
adult head and neck: a clinicopathological study and DNA ploidy study. J
Laryngol Otol. 1993;107:716–720.
406. Nakleh RE, Swanson PE, Dehner LP. Juvenile (embryonal and alveolar)
rhabdomyosarcoma of the head and neck in adults. A clinical, pathologic, and
immunohistochemical study of 12 cases. Cancer. 1991;67:1019–1024.
407. Nayar RC, Prudhomme F, Parise O Jr, et al. Rhabdomyosarcoma of the head
and neck in adults. A study of 26 patients. Laryngoscope. 1993;103:1362–1366.
408. La Quaglia MP, Heller G, Ghavimi F, et al. The effect of age at diagnosis on
outcome in rhabdomyosarcoma. Cancer. 1994;73:109–117.
409. Parham DM, Barr FG. Embryonal rhabdomyosarcoma. Fletcher C D M, Unni
KK, Mertens F. World Health Organization classification of tumours. Pathology &
genetics. Tumours of soft tissue and bone. IARC Press: Lyon, France; 2002:146–
149.
410. Parham DM, Barr FG. Alveolar rhabdomyosarcoma. Fletcher C D M, Unni KK,
Mertens F. World Health Organization classification of tumours. Pathology &
genetics. Tumours of soft tissue and bone. IARC Press: Lyon, France; 2002:150–
152.
411. Maurer HM, Gehan EA, Beltangady M, et al. The Intergroup
Rhabdomyosarcoma Study II. Cancer. 1993;71:1904–1922.
412. Newton WA Jr, Gehan EA, Webber BL, et al. Classification of
rhabdomyosarcoma and related sarcomas. Pathologic aspects and proposal
for a new classification—an Intergroup Rhabdomyosarcoma study. Cancer.
1995;76:1073–1085.
413. Raney RB, Asmar L, Vassilopoulou-Sellin R, et al. Late complications of
therapy in 213 children with localized, nonorbital soft-tissue sarcoma of the
head and neck: a descriptive report from the Intergroup Rhabdomyosarcoma
Studies (IRS)-II and III. IRS Group of the Children's Cancer Group and the
Pediatric Oncology Group. Med Pediatr Oncol. 1999;33:362–371.
414. Cavazzana AO, Schmidt D, Ninfo V, et al. Spindle cell rhabdomyosarcoma. A
prognostically favorable variant of rhabdomyosarcoma. Am J Surg Pathol.1992;16:229–235.
415. Bankaci M, Myers EN, Barnes L, et al. Angiosarcoma of the maxillary sinus.
Head Neck Surg. 1979;1:274–280.
416. Panje WR, Moran WJ, Bostwick DG, et al. Angiosarcoma of the head and neck:
review of 11 cases. Laryngoscope. 1986;96:1381–1384.
417. Di Girolamo A, Giacomini PG, Coli A, et al. Epithelioid
haemangioendothelioma arising in the nasal cavity. J Laryngol Otol.
2003;117:75–77.
418. Goldberg AN. Kaposi's sarcoma of the head and neck in acquired
immunodeficiency syndrome. Am J Otolaryngol. 1993;14:5–14.
419. Fliss DM, Parikh J, Freeman JL. AIDS-related Kaposi's sarcoma of the
sphenoid sinus. J Otolaryngol. 1992;21:235–237.
420. Moazzez AH, Alvi A. Head and neck manifestations of AIDS in adults. Am
Fam Physician. 1998;57:1813–1822.
421. Wyatt ME, Finlayson CJ, Moore-Gillon V. Kaposi's sarcoma masquerading as
pyogenic granuloma of the nasal mucosa. J Laryngol Otol. 1998;112:280–282.
422. Hong A, Davies S, Lee CS. Immunohistochemical detection of the human
herpes virus 8 (HHV8) latent nuclear antigen-1 in Kaposi sarcoma. Pathology.
2003;35:448–450.
423. Blackbourn DJ, Lennette ET, Ambroziak J, et al. Human herpesvirus 8
detection in nasal secretions and saliva. J Infect Dis. 1998;177:213–216.
424. Gandhi M, Koelle DM, Ameli N, et al. Prevalence of human herpesvirus-8
salivary shedding in HIV increases with CD4 count. J Dent Res. 2004;83:639–
643.
425. Barnes L. Leiomyosarcoma. Barnes L. Surgical pathology of the head and neck.
2nd ed. Marcel Dekker: New York; 2001:979–984.
426. Kuruvuilla A, Wenig BM, Humphrey DM, et al. Leiomyosarcoma of the
sinonasal tract. A clinicopathologic study of nine cases. Arch Otolaryngol Head
Neck Surg. 1990;116:1278–1286.
427. Dahlin DC, Unni KK. Bone tumors: general aspects and data on 8,542 cases. 4th ed.
Charles C Thomas: Springfield, Ill; 1986.
428. Batsakis JG. Osteogenic and chondrogenic sarcomas of jaws. Ann Otol Rhinol
Laryngol. 1987;96:474–475.
429. Waldron CA. Osteosarcoma. Neville BD, Damm DD, Allen CM, et al. Oral and
maxillofacial pathology. Saunders: Philadelphia; 1985:482–485.
430. Mark RJ, Sercarz JA, Tran L, et al. Osteogenic sarcoma of the head and neck.
The UCLA experience. Arch Otolaryngol Head Neck Surg. 1991;117:761–766.
431. Garrington GE, Scofield HH, Coryn J, et al. Osteosarcoma of the jaws. An
analysis of 56 cases. Cancer. 1967;20:377–391.
432. Fechner RE, Mills SE. Conventional intramedullary osteosarcoma. Rosai J,
Sobin LH. Tumors of the bones and joints. Armed Forces Institute of Pathology:
Washington, D.C.; 1993:38–50 [series 3, fascicle 8].
433. Caron AS, Hajdu SI, Strong EW. Osteogenic sarcoma of the facial and cranial
bones. A review of forty-three cases. Am J Surg. 1971;122:719–725.
434. Ruark DS, Schlehaider UK, Shah JP. Chondrosarcomas of the head and neck.
World J Surg. 1992;16:1010–1016.
435. Burkey BB, Hoffman HT, Baker SR, et al. Chondrosarcoma of the head and
neck. Laryngoscope. 1990;100:1301–1305.
436. Mark RJ, Tran LM, Sercarz J, et al. Chondrosarcoma of the head and neck. TheUCLA experience, 1955-1988. Am J Clin Oncol. 1993;16:232–237.
437. Huvos AG, Marcove AC. Chondrosarcoma in the young. A clinicopathologic
analysis of 79 patients younger than 21 years of age. Am J Surg Pathol.
1987;11:930–942.
438. Finn DG, Goepfert H, Batsakis JG. Chondrosarcoma of the head and neck.
Laryngoscope. 1984;94:1539–1544.
439. Webber PA, Hussain SS, Radcliffe GJ. Cartilaginous neoplasms of the head
and neck. J Laryngol Otol. 1986;100:615–619.
440. Rosenthal DI, Schiller AL, Mankin HJ. Chondrosarcoma: correlation of
radiological and histological grade. Radiology. 1984;150:21–26.
441. Perzin KH, Pushparaj N. Non-epithelial tumors of the nasal cavity, paranasal
sinuses, and nasopharynx: a clinicopathologic study. XIV. Chordomas. Cancer.
1986;57:784–796.
442. Meis JM, Giraldo AA. Chordoma. An immunohistochemical study of 20 cases.
Arch Pathol Lab Med. 1988;112:553–556.
443. Mitchell A, Scheithauer BW, Unni KK, et al. Chordoma and chondroid
neoplasms of the spheno-occiput. An immunohistochemical study of 41 cases
with prognostic and nosologic implications. Cancer. 1993;72:2943–2949.
444. Jambhekar NA, Rekhi B, Thorat K, et al. Revisiting chordoma with brachyury,
a “new age” marker: analysis of a validation study on 51 cases. Arch Pathol Lab
Med. 2010;134:1181–1187.
445. Oakley GJ, Fuhrer K, Seethala RR. Brachyury, SOX-9, and podoplanin, new
markers in the skull base chordoma vs chondrosarcoma differential: a tissue
microarray-based comparative analysis. Mod Pathol. 2008;21:1461–1469.
446. Tirabosco R, Mangham DC, Rosenberg AE, et al. Brachyury expression in
extra-axial skeletal and soft tissue chordomas: a marker that distinguishes
chordoma from mixed tumor/myoepithelioma/parachordoma in soft tissue.
Am J Surg Pathol. 2008;32:572–580.
447. Mendenhall WM, Mendenhall CM, Lewis SB, et al. Skull base chordoma. Head
Neck. 2005;27:159–165.
448. Hefflinger MJ, Dahlin DC, MacCarty CS, et al. Chordomas and cartilaginous
tumors of the skull base. Cancer. 1973;32:410–420.
449. Heffner DK, Hyams VJ. Teratocarcinosarcoma (malignant teratoma?) of the
nasal cavity and paranasal sinuses. A clinicopathologic study of 20 cases.
Cancer. 1984;53:2140–2154.
450. Pai SA, Naresh KN, Masih K, et al. Teratocarcinosarcoma of the paranasal
sinuses: a clinicopathologic and immunohistochemical study. Hum Pathol.
1998;29:718–722.
451. Shimazaki H, Aida S, Tamai S. Sinonasal teratocarcinosarcoma: ultrastructural
and immunohistochemical evidence of neuroectodermal origin. Ultrastruct
Pathol. 2000;24:115–122.
452. Fu YS, Perzin KH. Non-epithelial tumors of the nasal cavity, paranasal
sinuses, and nasopharynx: a clinicopathologic study. VIII. Lipoma and
liposarcoma. Cancer. 1977;40:1314–1317.
453. McCullough TM, Makielski KH, McNutt MA. Head and neck liposarcoma. A
histopathologic reevaluation of reported cases. Arch Otolaryngol Head Neck
Surg. 1992;118:1045–1049.
454. Shmookler BM, Enzinger FM, Brannon RB. Orofacial synovial sarcoma. A
clinicopathologic study of 11 new cases and review of the literature. Cancer.1982;50:269–276.
455. Simmons WB, Haggerty HS, Ngan B, et al. Alveolar soft part sarcoma of the
head and neck. A disease of children and young adults. Int J Pediatr
Otorhinolaryngol. 1989;17:139–153.
456. Pontius KI, Sebek BA. Extra-skeletal Ewing's sarcoma arising in the nasal
fossa. Light- and electron-microscopic observations. Am J Clin Pathol.
1981;75:410–415.
457. Lane S, Ironside JW. Extra-skeletal Ewing's sarcoma of the nasal fossa. J
Laryngol Otol. 1990;104:570–573.
458. Toda T, Atari E, Sadi AM, et al. Primitive neuroectodermal tumor in sinonasal
region. Auris Nasus Larynx. 1999;26:83–90.
459. Windfuhr JP. Primitive neuroectodermal tumor of the head and neck:
incidence, diagnosis, and management. Ann Otol Rhinol Laryngol.
2004;113:533–543.
460. Lack EE. Extragonadal germ cell tumors of the head and neck region: review of
16 cases. Hum Pathol. 1985;16:56–64.
461. Manivel C, Wick MR, Dehner LP. Transitional (cylindric) cell carcinoma with
endodermal sinus tumor-like features of the nasopharynx and paranasal
sinuses. Clinicopathologic and immunohistochemical study of two cases. Arch
Pathol Lab Med. 1986;110:198–202.
462. Bernstein JM, Montgomery WW, Balogh K Jr. Metastatic tumors to the maxilla,
nose, and paranasal sinuses. Laryngoscope. 1966;76:621–650.
463. Kent SE, Majumdar B. Metastatic tumours in the maxillary sinus. A report of
two cases and a review of the literature. J Laryngol Otol. 1985;99:459–462.
464. McClatchey KD, Lloyd RV, Schaldenbard JD. Metastatic carcinoma to the
sphenoid sinus. Case report and review of the literature. Arch
Otorhinolaryngol. 1985;241:219–224.
465. Drake-Lee AB, Lowe D, Swanston A, et al. Clinical profile and recurrence of
nasal polyps. J Laryngol Otol. 1984;98:783–793.
466. Settipane GA, Chafee FH. Nasal polyps in asthma and rhinitis. A review of
6,037 patients. J Allergy Clin Immunol. 1977;59:17–21.
467. Patriarca G, Nucera E, Di Rienzo V, et al. Nasal provocation test with lysine
acetylsalicylate in aspirin-sensitive patients. Ann Allergy. 1991;67:60–62.
468. Killian G. The origin of choanal polypi. Lancet. 1906;2:81–82.
469. Sirola R. Choanal polyps. Acta Otolaryngol. 1966;61:42–48.
470. Nakayama M, Wenig BM, Heffner DK. Atypical stromal cells in inflammatory
nasal polyps: immunohistochemical and ultrastructural analysis in defining
histogenesis. Laryngoscope. 1995;105:127–134.
471. Sheahan P, Crotty PL, Hamilton S, et al. Infarcted angiomatous nasal polyps.
Eur Arch Otorhinolaryngol. 2005;262:225–230.
472. Yfantis HG, Drachenberg CB, Gray W, et al. Angiectatic nasal polyps that
clinically simulate a malignant process: report of 2 cases and review of the
literature. Arch Pathol Lab Med. 2000;124:406–410.
473. Gysin C, Alothman GA, Papsin BC. Sinonasal disease in cystic fibrosis: clinical
characteristics, diagnosis, and management. Pediatr Pulmonol. 2000;30:481–
489.
474. Uri N, Cohen-Kerem R, Barzilai G, et al. Functional endoscopic sinus surgery
in the treatment of massive polyposis in asthmatic patients. J Laryngol Otol.
2002;116:185–189.475. Batra PS, Kern RC, Tripathi A, et al. Outcome analysis of endoscopic sinus
surgery in patients with nasal polyps and asthma. Laryngoscope. 2003;113:1703–
1706.
476. Dunlop G, Scadding GK, Lund VJ. The effect of endoscopic sinus surgery on
asthma: management of patients with chronic rhinosinusitis, nasal polyposis,
and asthma. Am J Rhinol. 1999;13:261–265.
477. Orvidas LJ, Beatty CW, Weaver AL. Antrochoanal polyps in children. Am J
Rhinol. 2001;15:321–325.
478. Theaker JM, Fletcher C D M. Heterotopic glial nodules: a light microscopic
and immunohistochemical study. Histopathology. 1991;18:255–260.
479. Puppala B, Mangurten HH, McFadden J, et al. Nasal glioma presenting as
neonatal respiratory distress. Clin Pediatr. 1990;29:49–52.
480. Kapadia SB, Popek EJ, Barnes L. Pediatric otorhinolaryngic pathology:
diagnosis of selected lesions. Pathol Annu. 1994;29(Pt 1):159–209.
481. Graeme-Cook F, Pilch BZ. Hamartomas of the nose and nasopharynx. Head
Neck. 1992;14:321–327.
482. Wenig BM, Heffner DK. Respiratory epithelial adenomatous hamartomas of
the sinonasal tract and nasopharynx: a clinicopathologic study of 31 cases.
Ann Otol Rhinol Laryngol. 1995;104:639–645.
483. Baille EE, Batsakis JG. Glandular (seromucinous) hamartoma of the
nasopharynx. Oral Surg. 1974;38:760–762.
484. Weinreb I, Gnepp DR, Laver NM, et al. Seromucinous hamartomas: a
clinicopathological study of a sinonasal glandular lesion lacking myoepithelial
cells. Histopathology. 2009;54:205–213.
485. Burns BV, Axon PR, Pahade A. “Hairy polyp” of the pharynx in association
with an ipsilateral branchial sinus: evidence that the “hairy polyp” is a second
branchial arch malformation. J Laryngol Otol. 2001;115:145–148.
486. Heffner DK, Thompson L D R, Schall DG, et al. Pharyngeal dermoids (“hairy
polyps”) as accessory auricles. Ann Otol Rhinol Laryngol. 1996;105:819–824.
487. McDermott MB, Ponder TB, Dehner LP. Nasal chondromesenchymal
hamartoma: an upper respiratory tract analogue of the chest wall
mesenchymal hamartoma. Am J Surg Pathol. 1998;22:425–433.
488. Norman ES, Bergman S, Trupiano JK. Nasal chondromesenchymal
hamartoma: report of a case and review of the literature. Pediatr Dev Pathol.
2004;7:517–520.
489. Ozolek JA, Carrau R, Barnes EL, et al. Nasal chondromesenchymal
hamartoma in older children and adults: series and immunohistochemical
analysis. Arch Pathol Lab Med. 2005;129:1444–1450.
490. Kim B, Park SH, Min HS. Nasal chondromesenchymal hamartoma of infancy
clinically mimicking meningoencephalocele. Pediatr Neurosurg. 2004;40:136–
140.
491. Shet T, Borges A, Nair C, et al. Two unusual lesions in the nasal cavity of
infants—a nasal chondromesenchymal hamartoma and an aneurysmal bone
cyst like lesion. More closely related than we think? Int J Pediatr
Otorhinolaryngol. 2004;68:359–364.
492. Kardon DE, Wenig BM, Heffner DK, et al. Tonsillar lymphangiomatous
polyps: a clinicopathologic series of 26 cases. Mod Pathol. 2000;13:1128–1133.
493. Friedman GC, Hartwick WJ, Ro JY, et al. Allergic fungal sinusitis: report of
three cases associated with dematiaceous fungi. Am J Clin Pathol. 1991;96:368–372.
494. Saeed SR, Brooks GB. Aspergillosis of the paranasal sinuses. Rhinology.
1995;33:46–51.
495. Satyanarayana C. Rhinosporidiosis with a record of 225 cases. Acta
Otolaryngol. 1960;51:348–356.
496. Nussbaum ES, Hall WA. Rhinocerebral mucormycosis: changing patterns of
disease. Surg Neurol. 1994;41:152–154.
497. Hyams VJ, Batsakis JG, Michaels L. Rhinoscleroma. Tumors of the upper
respiratory tract and ear. Armed Forces Institute of Pathology: Washington,
D.C.; 1988:24–26 [series 2, fascicle 25].
498. Wenig BM, Smirniotopolous J, Heffner DK. Botryomycosis of the sinonasal
tract: a report of two cases. Arch Pathol Lab Med. 1996;120:1123–1128.
499. Gordon WW, Cohn AM, Greenberg SD, et al. Nasal sarcoidosis. Arch
Otolaryngol. 1976;102:11–14.
500. Wenig BM, Thompson L D R, Frankel SS, et al. Lymphoid changes of the
nasopharynx and tonsils that are indicative of human immunodeficiency virus
infection: a clinicopathologic study of 12 cases with a discussion on the
possibility of transmucosal infection. Am J Surg Pathol. 1996;20:572–587.
501. Moss R, Beaudet LM, Wenig BM, et al. Microsporidium-associated sinusitis.
Ear Nose Throat J. 1997;76:95–101.
502. Kyriakos M. Myospherulosis of the paranasal sinuses, nose and middle ear.
Am J Clin Pathol. 1977;67:118–130.
503. Frankel SS, Wenig BM, Burke AP, et al. Replication of HIV-1 in dendritic cell–
derived syncytia at the mucosal surface of the adenoid. Science. 1996;272:115–
117.
504. Dargent JL, Lespagnard L, Kornreich A, et al. HIV-associated multinucleated
giant cells in lymphoid tissue of the Waldeyer's ring: a detailed study. Mod
Pathol. 2000;13:1293–1299.
505. Orenstein JM, Wahl SM. The macrophage origin of the HIV-expressing
multinucleated giant cells in hyperplastic tonsils and adenoids. Ultrastruct
Pathol. 1999;23:79–91.
506. DeRemee RA, McDonald TJ, Harrison EG, et al. Wegener's granulomatosis,
anatomic correlates, a proposed classification. Mayo Clin Proc. 1976;51:777–
781.
507. DeRemee RA. Extrapulmonary manifestations of Wegener's granulomatosis
and other respiratory vasculitides. Semin Respir Med. 1988;9:403–408.
508. Specks U, Wheatley CL, McDonald TJ, et al. Anticytoplasmic autoantibodies
in the diagnosis and follow-up of Wegener's granulomatosis. Mayo Clin Proc.
1989;64:28–36.
509. Nolle B, Specks U, Ludemann J, et al. Anticytoplasmic autoantibodies: their
immunodiagnostic value in Wegener's granulomatosis. Ann Intern Med.
1989;111:28–40.
510. Fienberg R, Mark EJ, Goodman M, et al. Correlation of antineutrophil
cytoplasmic antibodies with the extrarenal histopathology of Wegener's
(pathergic) granulomatosis and related forms of vasculitis. Hum Pathol.
1993;24:160–168.
511. DeRemee RA. Antineutrophil cytoplasmic autoantibody–associated disease: a
pulmonolgist's perspective. Am J Kidney Dis. 1991;18:180–183.
512. Falk RJ, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies withspecificity for myeloperoxidase in patients with systemic vasculitis and
idiopathic necrotizing and crescenteric glomerulonephritis. N Engl J Med.
1988;318:1651–1657.
513. Hardarson S, Labrecque DR, Mitros FA, et al. Antineutrophil cytoplasmic
antibody in inflammatory bowel and hepatobiliary diseases: high prevalence
in ulcerative colitis, primary sclerosing cholamgitis, and autoimmune
hepatitis. Am J Clin Pathol. 1993;99:221–223.
514. Zholudev A, Zurakowski D, Young W, et al. Serologic testing with ANCA,
ASCA, and anti-OmpC in children and young adults with Crohn's disease and
ulcerative colitis: diagnostic value and correlation with disease phenotype. Am
J Gastoenterol. 2004;99:2235–2241.
515. Brockmann H, Schwarting A, Kriegsmann J, et al. Proteinase-3 as the major
autoantigen of c-ANCA is strongly expressed in lung tissue of patients with
Wegener's granulomatosis. Arthritis Res. 2002;4:220–225.
516. van Rossum AP, Rarok AA, Huitema MG, et al. Constitutive membrane
expression of proteinase 3 (PR3) and neutrophil activation by anti-PR3
antibodies. J Leukoc Biol. 2004;76:1162–1170.
517. von Vietinghoff S, Schreiber A, Otto B, et al. Membrane proteinase 3 and
Wegener's granulomatosis. Clin Nephrol. 2005;64:453–459.
518. Winek J, Mueller A, Csernok E, et al. Frequency of proteinase 3 (PR3)–specific
autoreactive T cells determined by cytokine flow cytometry in Wegener's
granulomatosis. J Autoimmun. 2004;22:79–85.
519. Devaney KO, Travis WD, Hoffman G, et al. Interpretation of head and neck
biopsies in Wegener's granulomatosis. Am J Surg Pathol. 1990;14:555–564.
520. Keogh KA, Specks U. Churg-Strauss syndrome: clinical presentation,
antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonists.
Am J Med. 2003;115:284–290.
521. Barnes L. Midfacial destructive diseases. Barnes L. Surgical pathology of the
head and neck. 2nd ed. Marcel Dekker: New York; 2001:759–786.
522. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: a
newly recognized benign clinicopathologic entity. Arch Pathol. 1969;87:63–70.
523. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: a
pseudolymphomatous benign disorder. Cancer. 1972;30:1174–1188.
524. Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive
lymphadenopathy (Rosai-Dorfman disease): review of the entity. Semin Diagn
Pathol. 1990;7:19–73.
525. Foucar K, Foucar E. The mononuclear phagocyte and immunoregulatory
effector (M-PIRE) system: evolving concepts. Semin Diagn Pathol. 1990;7:4–18.
526. Wenig BM, Abbondanzo SL, Childers EL. Extranodal sinus histiocytosis with
massive lymphadenopathy (Rosai-Dorfman disease) of the head and neck.
Hum Pathol. 1993;24:483–492.
527. Eisen RN, Buckley PJ, Rosai J. Immunophenotypic characterization of sinus
histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). Semin
Diagn Pathol. 1990;7:74–82.
528. Paulli M, Rosso R, Kindl S, et al. Immunophenotypic characterization of the
cell infiltrate in five cases of sinus histiocytosis with massive
lymphadenopathy (Rosai-Dorfman disease). Hum Pathol. 1992;23:647–654.
529. Comp DM. The treatment of sinus histiocytosis with massive
lymphadenopathy (Rosai-Dorfman disease). Semin Diagn Pathol. 1990;7:83–86.530. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive
lymphadenopathy: an analysis of 14 deaths occurring in a patient registry.
Cancer. 1984;54:1834–1840.+
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PART B
▪ Larynx, Hypopharynx, and Trachea
Chapter Outline
Normal Anatomy 162
Benign Neoplasms 163
Intraepithelial Precursor or Premalignant Lesions 168
Microinvasive, Superficial, or “Early” Invasive Squamous Cell Carcinoma 171
Invasive Squamous Cell Carcinoma 172
Salivary Gland Malignant Neoplasms 187
Neuroendocrine Carcinomas 188
Cartilaginous Tumors 192
Other Malignant Neoplasms 193
Secondary Tumors 194
Nonneoplastic Mass Lesions 194
Normal Anatomy
Larynx
The anatomic compartments of the larynx include (1) the supraglo is, which extends from the tip of the epiglo is to a
horizontal line passing through the apex of the ventricle; structures included in this compartment are the epiglo is (lingual
and laryngeal aspects), aryepiglo ic folds, arytenoids, false vocal cords, and the ventricle; (2) the glo is, which extends from
the ventricle to approximately 0.5 to 1.0 cm below the free level of the true vocal cord and includes the anterior and posterior
commissures and the true vocal cord; and (3) the subglo is, which extends from approximately 0.5 to 1.0 cm below the level
1of the true vocal cord to the inferior rim of the cricoid cartilage. Histologically, nonkeratinizing stratified squamous
2epithelium lines the epiglo is and true vocal cord. A pseudostratified ciliated respiratory epithelium lines the false vocal
2cord, ventricle, and subglo is. Mucoserous glands are found in the lower two thirds of the epiglo is and in the ventricular
submucosa. The thyroid, cricoid, and arytenoid cartilages are hyaline-type cartilage, whereas the epiglo is, cuneiform, and
corniculate cartilages are elastic-type cartilage. A transitional-type epithelium is present between the ciliated respiratory
3epithelium of the supraglo is or subglo is and the squamous epithelium of the true vocal cord. The transitional-type
epithelium appears abruptly. I t is predominantly composed of basaloid or immature squamous cells with hypercellularity,
disorganization, absence of maturation, and increased nucleus to cytoplasm ratio, and may be misdiagnosed on biopsy or by
frozen section as severe dysplasia or carcinoma in situ (CI S ). I n contrast to severe dysplasia or CI S the cells have vesicular
nuclei, smooth nuclear contours, absence of significant pleomorphism, and absence of mitoses away from the basement
membrane. D eep to the true vocal cord lies the vocal cord ligament; biopsy specimens taken in this anatomic location may
include the vocal cord ligament, which, if unrecognized, may be misdiagnosed as a myxoma or peripheral nerve sheath
neoplasm.
Hypopharynx
The hypopharynx, or laryngopharynx, has three components: (1) the piriform sinus, located between the aryepiglo ic folds
and the laminae of the thyroid cartilage, which expands bilaterally and forward around the sides of the larynx; (2) the
postcricoid region, located on the posterior surface of the cricoid cartilage; and (3) the posterior hypopharynx, located on the
posterior pharyngeal wall from the level of the epiglo is (border with the oropharynx) to the level of the inferior border of
4,5the cricoid cartilage (border with the esophagus). Histologically, the epithelium of the hypopharynx is a nonkeratinizing
2stratified squamous epithelium. Mucoserous glands are seen throughout the submucosa.
Trachea
1The trachea extends from the lower border of the cricoid cartilage to the carina. The superior border of the larynx is
continuous with the larynx; the inferior border is continuous with the bronchi; the anterior border is associated with the
thyroid gland; and the posterior border is associated with the esophagus. Histologically, the entire lining of the trachea is a
2ciliated respiratory epithelium. S eromucous glands are seen throughout the submucosa. The cartilaginous rings are
incomplete and form about two thirds of a circle. The rings are connected to each other by a fibroelastic annular ligament.
The posterior (noncartilaginous) membranous part contains smooth muscle.
Benign Neoplasms
The classification of neoplasms of the larynx, hypopharynx, and trachea is listed in Table 4B-1.
TABLE 4B-1
C lassification of L aryngeal, H ypopharyngeal, and T racheal N eoplasmsBenign
Epithelial
Papilloma/papillomatosis (recurrent respiratory papillomatosis)
Minor salivary gland tumors:
Pleomorphic adenoma
Others
Mesenchymal/Neuroectodermal
Granular cell tumor
Inflammatory myofibroblastic tumor
Lipoma
Paraganglioma
Chondroma
Rhabdomyoma
Hemangioma
Neurilemoma/neurofibroma
Leiomyoma
Fibrous histiocytoma
Others
Premalignant Epithelial Lesions
Dysplasias, keratinizing and nonkeratinizing
Malignant
Epithelial
Squamous cell carcinoma:
Carcinoma in situ
Microinvasive carcinoma
Invasive squamous cell carcinoma
Papillary (exophytic) squamous cell carcinoma
Verrucous carcinoma
Spindle cell squamous carcinoma
Basaloid squamous carcinoma
Adenosquamous carcinoma
Lymphoepithelial-like carcinoma
Giant cell carcinoma
Minor salivary gland tumors:
Adenoid cystic carcinoma
Mucoepidermoid carcinoma
Others
Neuroectodermal
Neuroendocrine carcinomas:
Carcinoid tumor
Atypical carcinoid tumor
Small cell undifferentiated neuroendocrine carcinoma
Mucosal malignant melanoma
Mesenchymal
Chondrosarcoma
Synovial sarcoma
Fibrosarcoma/undifferentiated pleomorphic sarcoma
Malignant peripheral nerve sheath tumor
Liposarcoma
Rhabdomyosarcoma
Angiosarcoma/Kaposi sarcoma
Leiomyosarcoma
Hematolymphoid
Others
Secondary Tumors
Recurrent Respiratory Papillomatosis (Laryngeal Papilloma/Papillomatosis)
Laryngeal papillomas are benign, exophytic epithelial neoplasms composed of branching fronds of squamous epithelium
with fibrovascular cores, which may be single or multiple and may be etiologically associated with human papillomavirus
6(HPV) types 6 and 11. S ynonyms include squamous papilloma; laryngeal papillomatosis; recurrent respiratory
papillomatosis (RRP), juvenile papillomatosis, adult papillomatosis; nonkeratinized papilloma; keratinized papilloma; and+
+
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papillary keratosis. Laryngeal papillomas have traditionally been divided into juvenile and adult types, but the multiple
recurring papillomas, whether presenting in childhood or adulthood, are now generally considered to represent the same
7,8 9basic entity, although childhood cases tend clinically to be more aggressive than those occurring initially in adults. At
present, the preferred terminology for those viral-associated papillomas that are nonkeratinizing, tend to persist or recur,
10,11and show a degree of resistance to treatment is RRP. Because of distinct clinical and histopathologic findings,
papillomas can be separated by age (juvenile vs. adult forms), number of lesions (solitary vs. multiple), and histology
(keratinizing vs. nonkeratinizing) (Table 4B-2).
TABLE 4B-2
Laryngeal Recurrent Respiratory Papillomatosis
JO-RRP AO-RRP Keratinizing Papilloma
Age Less than 20 yr* 20 yr and older* Occurs in adults
Sex No sex predilection Much more common in men No sex predilection
than in women
Symptoms Changes in phonation, Hoarseness Hoarseness
stridor, dysphagia, cough
Sites SCJ SCJ True vocal cord is the most common
location
Lesions Majority are multiple (80%- Majority are single (65%- Usually single
98%) 75%)
Pathology Papillary fronds of Papillary fronds of Papillary fronds of multilayered benign
multilayered benign multilayered benign squamous epithelium with
squamous epithelium squamous epithelium fibrovascular cores with associated
with fibrovascular cores with fibrovascular cores keratinization (parakeratosis or
with little or no keratin with little or no keratin orthokeratosis)
HPV Present, usually 6 and 11 but Present, usually 6 and 11 but Absent
may be 16, 18 may be 16, 18
Treatment Surgical excision Surgical excision Surgical resection
Prognosis Variable often with recurrent Variable Usually cured after excision
disease
Malignant From 2%-14% From 2%-14% Rare
transformation
*Not universally accepted as the dividing line.
AO-RRP, Adult-onset recurrent respiratory papillomatosis; HPV, human papillomavirus; JO-RRP, juvenile-onset recurrent
respiratory papillomatosis; SCJ, squamous epithelial-ciliated respiratory epithelial junction.
RRP (nonkeratinizing papilloma) represents the most common benign neoplasm occurring in the larynx, also in the
6,9,12,13pediatric age group, and may be divided into lesions that occur in early years, referred to as juvenile-onset RRP (J
ORRP), and lesions that occur in older ages, referred to as adult-onset RRP (A O-RRP). The age separating juvenile versus adult
onset is not established, and different studies cite different ages. A lthough not universally accepted, 20 years of age can
serve as a potential dividing line between J O-RRP and A O-RRP. For J O-RRP no sex predilection is seen, and most patients
have symptoms in early childhood. The clinical presentation includes changes in phonation (e.g., abnormal crying,
hoarseness), dyspnea, cough, dysphagia, and stridor. The majority of papillomas are multiple (rather than a single lesion)
with extensive growth and rapid recurrence. These lesions may remit spontaneously or persist into old age.
A O-RRP is more common in men than in women and affects all age groups but is most common from ages 20 to 40 years.
The clinical presentation includes changes in phonation (e.g., hoarseness). The majority of papillomas are single (rather than
multiple) and tend to recur less often.
Both J O-RRP and A O-RRP may occur anywhere in the larynx but most often involve the true and false vocal cords,
ventricles, and subglo is. S pread to nearby (extralaryngeal) areas may occur and includes the oral cavity and
tracheobronchial tree. Extralaryngeal spread occurs more commonly in children than in adults; extension down the
10tracheobronchial tree occurs in approximately 5% of patients. RRP tends to localize to those junctional areas where ciliated
respiratory epithelium meets squamous epithelium; these areas include histologically normal junctional mucosa (e.g.,
supraglo ic-glo ic or glo ic-subglo ic junctions), as well as areas in which metaplastic alteration occurs as a result of
injury, with squamous epithelium replacing ciliated respiratory epithelium, thereby creating a new squamous
epithelialciliated respiratory epithelial junction.
6,9,14-16 14-18RRP is caused by HPV, in particular HPV types 6 and 11. Rarely, HPV types 16, 18, 31, 33, and 35 have been
identified. I n J O-RRP a significant percentage of patients (up to 70%) have been shown to be born to women with uterine
6,13,19,20cervical condylomas with transmission related to maternal genital infection. The mode of transmission in A O-RRP
remains uncertain. Considerations include the possibility of maternal transmission during delivery, with the virus remaining
dormant until adulthood when activation of the virus takes place. Orogenital contact with an infected individual may be a
more likely mode of transmission.
Grossly, RRP are generally exophytic, friable, cauliflower-like masses presenting either singly or in clusters. The+
+
histopathology of RRP includes papillary fronds of multilayered benign squamous epithelium with fibrovascular cores (Fig.
4B-1). Typically, li le or no keratin production exists, although an occasional case may show keratinization (parakeratosis or
orthokeratosis). Viral-induced changes (i.e., koilocytosis) may be seen (Fig. 4B-2). Koilocytotic changes, as seen in the female
genital tract (cytoplasmic clearing around a dark, wrinkled nucleus, with occasional binucleate or trinucleate cells), are not
6,14,21infrequently observed but tend not to be as prominent as in the cervix. When laryngeal papillomatosis extends into
the subglo is or tracheobronchial tree, the epithelium can be squamous or ciliated columnar and can contain so-called
intermediate cells—polygonal cells intermediate in appearance between squamous and cuboidal or columnar epithelial
22cells.
FIGURE 4B-1 Squamous papilloma of the larynx. Finger-like papillae of thickened squamous epithelium
contain central fibrovascular cores.
FIGURE 4B-2 Squamous papilloma of the larynx. A, Koilocytosis, as evidenced by perinuclear clearing,
nuclear contour irregularity or “wrinkling,” and a binucleate cell, slightly above the middle of the
photomicrograph. B, Immunohistochemical stain for pan-human papillomavirus shows positive staining in
multiple nuclei.
A certain degree of cellular atypia may be seen, especially in those lesions that recur over short periods of time. Generally
the degree of dysplasia is limited, and the risk of progression to a more significant dysplastic lesion or carcinoma is low.
Atypical features include basal zone hyperplasia with nuclear pleomorphism, increased nucleus to cytoplasm ratio, loss of
cell polarity, prominent nucleoli, and increased mitotic activity; dyskeratosis may also be identified. The presence of severe+
atypia may be indicative of the development of a squamous carcinoma arising in papillomatosis or may in fact represent an
exophytic squamous cell carcinoma (SCC).
I mmunohistochemistry for HPV may be positive (seeF ig. 4B-2) but is unnecessary for the diagnosis and has no prognostic
importance. The majority of tumors show the presence of HPV 6/11. At the present time no utility to staining these lesions
for p16 is known.
The differential diagnosis includes verrucous carcinoma (VC) and papillary (exophytic) S CC. VC (see later discussion) is a
larger, broader-based lesion than squamous papilloma, with a thicker epithelial layer and surface keratin often being
prominent. VC tends to “infiltrate” subjacent tissue in a broad pushing manner and characteristically has a prominent
23,24chronic inflammatory infiltrate at its base. Verruca vulgaris has very rarely been reported in the larynx. This lesion
mimics the cutaneous verruca, with pointed, spire-like papillae, abundant keratin production, and a prominent granular cell
layer. This lesion is also related to HPV infection. Occasionally, the term c o n d y l o m a is applied to a papillary lesion in the
14,21upper aerodigestive tract. This term may be appropriate to refer to the subset of squamous papillomas that exhibit
prominent koilocytotic changes, thus reflecting their analogy to comparable lesions in the anogenital area. Papillary S CC is a
25malignant lesion that does not have the benign nuclear characteristics of squamous papilloma. Rarely, extensive
laryngotracheal papillomas may become aggressive and infiltrate surrounding tissue, although still maintaining a bland
cytologic appearance and a sharp stromal interface. S uch uncommon lesions have been termed i n v a s i v e
22,26,27p a p i l l o m a t o s i s. Because of the unpredictable nature of the disease, which may be characterized by periods of active
growth and remission, the best mode of treatment and the efficacy of treatment remain uncertain. At present, the
9recommended treatment for RRP is surgery, including microlaryngeal excision with CO laser surgery. The antiviral drug2
28,29cidofovir has shown efficacy against RRP.
Recurrence of tumor is common, requiring long-term and repeated management. Recurrence correlates with persistence of
30HPV. The variability of the disease course is reflected in the unpredictable nature of recurrent tumor. S ome patients have
one or two recurrences over a few-year period followed by spontaneous remission; other patients have frequent recurrences
over very short periods of time (weeks) necessitating multiple operative procedures; yet other patients may have repeated
recurrences over short periods of time and then remain disease free for decades only to have multiple recurrent disease later
in life, necessitating multiple operative procedures. Extension into the tracheobronchial tree occurs in 2% to 15%, and
7,26,27involvement of lower respiratory tract parenchyma is associated with increased mortality rates. D eath may be caused
by asphyxiation, superimposed infection, and malignant transformation. Carcinoma developing in RRP may occur in
31nonirradiated and in irradiated patients. The overall incidence of carcinoma in nonirradiated patients is 2%. The overall
32-35incidence of carcinoma in irradiated patients is 14%. Carcinomas developing in the se ing of RRP are S CCs.
Transformation of RRP to S CC may be spontaneous, may not be characterized by histologic progression through dysplasia
over time, or may develop through a continuum of dysplasia over time. Transformation to S CC may result in loss of HPV
expression.
Keratinizing Papilloma (Papillary Keratosis)
Keratinizing papilloma (see Table 4B-2) is a disease of adults but may occur over a wide age range including patients less
7than 50 years of age. N o sex predilection is seen. Keratinizing papillomas tend to occur on the true vocal cord. Patients
usually present with hoarseness. Unlike the nonkeratinizing papillomas, these papillomas are not etiologically linked to HPV
but have been reported to occur in patients with a smoking history.
Grossly, keratinizing papillomas are exophytic or papillary lesions with a white appearance and usually do not exceed 2 cm
in greatest dimension. Histologically, they are composed of papillary fronds of multilayered benign squamous epithelium
with fibrovascular cores and associated keratinization. Keratinization may be in the form of parakeratosis or orthokeratosis.
Keratohyaline granules can be identified. In most cases no cytologic atypia or dysplasia occurs, but atypia or dysplasia can be
seen ranging from mild to moderate to severe and should be reported as such (i.e., keratinizing papilloma, papillary
keratosis with mild, moderate, or severe atypia or dysplasia). A variable mixed inflammatory cell infiltrate may be present in
the stroma.
S urgical resection is usually curative. Local recurrence is infrequent. Rarely, these lesions undergo malignant
transformation to SCC.
Benign Salivary Gland Tumors
Benign neoplasms of salivary gland type are extremely rare in the larynx and trachea. I n fact, laryngeal malignant salivary
gland tumors are more common than benign ones. Pleomorphic adenomas, resembling their salivary gland counterparts in
36,37 38morphology and clinical behavior, have been reported in the larynx and trachea. A nother category of salivary gland
lesions is the oncocytic lesions, but these likely do not represent true neoplasms and more aptly are considered cystic
glandular hyperplasia and/or metaplasias. These lesions have been referred to as papillary cyst or cystadenoma; see later in
the chapter for a more complete discussion.
Benign Nonepithelial Tumors
Benign nonepithelial neoplasms of the larynx, hypopharynx, and trachea are rare and include mesenchymal and
neuroectodermal neoplasms.
Granular Cell Tumor
Granular cell tumors (GCTs) are relatively uncommon tumors, which occur most frequently in the skin and subcutaneous
39,40 39,41tissue (see Chapter 27). The oral cavity, particularly the tongue, is a frequent site, and the larynx is a
well42-44 45recognized although uncommon location. Only very occasional cases have been reported in the trachea. Laryngeal+
44,46GCTs typically present in the fourth or fifth decade of life, but patients aged 5 to 82 years have been described. The
42,44 43characteristic location is the vocal cord, particularly posteriorly.
Presenting complaints include hoarseness or a sore throat, and some lesions are discovered as asymptomatic incidental
42findings. Tracheal GCTs are more common in women than in men and occur over a wide age range, but peak incidence is
in the fourth decade. S ymptoms include stridor and airway obstruction. Most arise in the cervical trachea. I rrespective of site
of occurrence, the lesions are usually small, rounded, ill-defined submucosal masses and occur as single lesions, but
multiple tumors may be found. N o etiology is known. GCTs are thought to be of neural (S chwann cell) origin supported by
the fact that granular cells are S -100. Myelinated and nonmyelinated axon-like structures have been identified by
ultrastructural analysis.
These tumors often are solitary, polypoid or sessile, and tan-white to yellow and measure from 0.3 to 3.0 cm in diameter.
Most are submucosal with an intact overlying surface epithelium, although rarely they may be associated with epithelial
ulceration.
I rrespective of location the histology of GCTs is the same. Histologically, GS Ts are unencapsulated or poorly
circumscribed subepithelial lesions with a syncytial, trabecular, or nested growth pa ern. GCTs are characterized by masses
of large, rounded, polygonal, and occasionally fusiform to spindled cells with round to oval, vesicular to hyperchromatic,
centrally located small nuclei and the presence of ample coarsely granular eosinophilic-appearing cytoplasm (Fig. 4B-3). The
granular cells infiltrate adjacent tissue and are often intimately admixed with the constituent native tissue, including nerve
and muscle. Mitoses and necrosis are typically absent. Occasionally, within the collagenous tissue and in the proximity of
vessels, interstitial cells with large, “needle-shaped” bodies may be seen and are referred to as angulate bodies.
FIGURE 4B-3 Granular cell tumor of the larynx. A sheet of large cells with abundant granular cytoplasm
and ill-defined cell borders is associated with pseudoepitheliomatous hyperplasia of overlying mucosal
squamous epithelium.
A distinctive and noteworthy histologic feature of many mucosal GCTs is the presence of pseudoepitheliomatous
hyperplasia of the mucosa overlying the tumor (see Fig. 4B-3). This change can at times be striking, with strands and tongues
of cytologically bland surface epithelium extending into the underlying granular cell lesion. Care must be taken not to
misinterpret this change as invasive S CC. I n contrast to S CC, pseudoepitheliomatous hyperplasia displays no cytologic
evidence of malignancy, and the epithelial proliferation does not extend beyond the limit of the associated GCT. A diagnosis
of S CC in association with a GCT can be entertained in the presence of metastatic (e.g., nodal) S CC; otherwise, unless the
epithelial component extends below the depth of the GCT a diagnosis of S CC should not be rendered. GCT cells may involve
(“invade”) nerves, but this is not an indication of malignancy. The predominant current opinion is that most GCTs are
39,47,48neurally derived and probably of Schwann cell origin.
The granular cells are S -100 protein, neuron-specific enolase, laminin, and CD 68 (KP-1) positive. Proliferative activity, as
seen by Ki-67 reactivity, is low. Granular cells are negative for cytokeratins, neurofilament protein, and glial fibrillary acidic
protein.
The most significant differential diagnostic issue regarding a GCT in the head and neck is probably differentiating its
associated overlying pseudoepitheliomatous hyperplasia from S CC, as has been discussed earlier. A case of synchronous
S CC and GCT in the tongue, an extremely rare occurrence, has been reported and is notable for the fact that the
49pseudoepitheliomatous hyperplasia overlying the GCT was cytologically bland and distinct from the carcinoma. A
dulttype rhabdomyomas may resemble GCTs, especially in frozen sections; however, rhabdomyoma cells contain abundant
glycogen (diastase sensitive rather than resistant), have well-defined cell borders, and often have a characteristic “spider
cell” appearance with strands of cytoplasm extending from the nuclear region to the cell membrane, resembling a spider's
web. Oncocytomas have large granular eosinophilic cells, but their granularity is due to abundant packed mitochondria and
not autophagolysosomes. Oncocytoma cells, like rhabdomyoma cells, have well-defined cell borders rather than a syncytial
appearance and occur predominantly in epithelial, usually glandular, organs rather than in soft tissue.
Conservative but complete surgical excision is considered curative. Local recurrence may occur in a minority of patients
(fewer than 5%). Recurrent tumor may represent a new primary lesion in patients with multifocal disease. A lmost all GCTs
39,40,43,47,50in all locations are benign, with laryngeal tumors recurring uncommonly. A n “atypical” laryngeal tumor with
50aggressive (although nonmetastasizing) clinical behavior and histologic pleomorphism has been described.
51Malignant GCT (seeC hapter 27) is rare, accounting for approximately 1% of all GCTs, and is especially rare at mucosal
or visceral locations.
Other Benign Mesenchymal Neoplasms+
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52-56Benign nerve sheath tumors, both schwannomas and neurofibromas, occur in the larynx and trachea but are rare.
57Laryngeal neurofibromas may occur in the context of neurofibromatosis type I and may be of the plexiform variety. A
58single case of hypopharyngeal cellular neurothekeoma has been reported. Laryngeal nerve sheath tumors pathologically
resemble their counterparts elsewhere in the body. Benign muscular neoplasms also rarely occur in the larynx. Leiomyomas,
59 60both conventional and vascular (angioleiomyoma or angiomyoma), have been reported, as have rhabdomyomas of both
61 62,63 64,65adult and fetal type. Laryngeal fibromatosis in infants and children occurs rarely. Lipomas of the larynx and
66hypopharynx are rarely encountered. Case reports of benign neoplastic oddities occurring in the larynx and trachea
67 68,69 70-72 73include mention of fibrolipoma, so-called hemangiopericytoma, fibrous histiocytoma, fibromyxoma,
74 75 76glomangioma or glomus tumor, teratoma, and benign clear cell (“sugar”) tumor. Chondromas of the head and neck
77,78are uncommon, and those of the larynx are rare. Laryngeal chondrosarcomas are more common than chondromas (see
later discussion).
79-82Laryngeal paragangliomas are quite rare but do occur, associated with the superior laryngeal paraganglia located in
the false vocal cord region or, more rarely, the less consistently positioned inferior laryngeal paraganglia, located
subglo ically in the cricothyroid or cricotracheal region, in rare instances associated with the capsule of the thyroid
79,80,83gland. Their histologic features are identical to paragangliomas of all other sites including organoid, nested, or
socalled Zellballen growth surrounding by fibrovascular stroma (Figs. 4B-4 and 4B-5; see Chapter 28). Tracheal paragangliomas
84are even more uncommon.
FIGURE 4B-4 Paraganglioma of the inferior laryngeal paraganglion protruding in dumbbell fashion
between cartilages to abut the thyroid gland. (Reproduced with permission of the American Medical
Association, from Googe R B, Ferry J A, Bhan A K et al. 1988 A comparison of paraganglioma, carcinoid
tumor, and small cell carcinoma of the larynx. Arch Pathol Lab Med 112: 809-815 © 1988 American
Medical Association. All rights reserved)
FIGURE 4B-5 Paraganglioma of the larynx. Characteristic organoid or “Zellballen” growth pattern of
chief cells in intimate relation to capillaries. Chief cells are immunoreactive for neuroendocrine markers
but are nonreactive for epithelial markers (not shown).
S ubglo ic hemangioma of the larynx is a vasoproliferative lesion of infancy, which, although uncommon, is fraught with
85,86the potential danger of causing airway obstruction. I t has not definitely been established whether this lesion represents
86a vascular malformation or a true neoplasm ; however, for convenience it is considered here with the benign tumors. The
usual tendency of juvenile (capillary) hemangiomas of the head and neck, including the subglo ic variety, is to involute+
85-87spontaneously after several years ; however, obstructing lesions often necessitate more immediate therapeutic
86intervention.
I nflammatory myofibroblastic tumor (I MT; seeC hapter 24) is a distinctive lesion predominantly composed of
myofibroblastic cells with a variable admixture of inflammatory cells, including mature lymphocytes, histiocytes, plasma
cells, and eosinophils, and extracellular collagen. I MT is predominantly a soft tissue and visceral tumor that may occur in the
88,89mucosa of the upper aerodigestive tract. S ynonyms include inflammatory (myofibroblastic) pseudotumor, plasma cell
granuloma, plasma cell pseudotumor, and pseudosarcomatous (myofibroblastic) lesions or tumors. I MTs of the upper
aerodigestive tract present as solitary lesions. Evidence has shown anaplastic lymphoma kinase ( A L K) gene rearrangement
90,91and associated protein expression in I MTs. I n contrast to I MTs of children and young adults, which often contain clonal
cytogenetic rearrangements that activate the A L K receptor kinase gene in chromosome band 2p23, such rearrangements are
90,91uncommon in adults above 40 years of age with IMT.
Intraepithelial Precursor or Premalignant Lesions
Reactive changes of the mucosa of the upper aerodigestive tract may include hyperplasia, keratosis, and varying degrees of
architectural and cytologic atypia. Currently it is generally agreed that only those mucosal lesions exhibiting significant
dysplasia (i.e., moderate or severe dysplasia) should be considered premalignant, being associated with a relatively high
92-98propensity to progress to carcinoma.
D ysplasia is a potentially reversible (qualitative) alteration in the appearance of epithelial cells with an increased
likelihood to progress to S CC. S ynonyms include keratosis with atypia, atypia, mild dysplasia, moderate dysplasia, severe
dysplasia, squamous intraepithelial lesion, squamous intraepithelial neoplasia (S I N ), laryngeal intraepithelial neoplasia,
laryngeal intraepithelial lesion; simple hyperplasia, basal or parabasal hyperplasia, and atypical hyperplasia. S everal
classification schemes for precursor lesions have been proposed. The three generally most often used currently are the
World Health Organization (WHO) system, the S I N system, and the Ljubljana classification, commonly used in Europe. The
recommended terminology from the WHO includes mild, moderate, and severe dysplasia and CI S T(able 4B-3). The WHO
93system is used in this chapter.
TABLE 4B-3
Classification Schemes for Epithelial Precursor Lesions
WHO Classification* Squamous Intraepithelial Neoplasia Ljubljana Classification
Mild dysplasia SIN1 Basal/parabasal cell hyperplasia
Moderate dysplasia SIN2 Atypical hyperplasia
Severe dysplasia SIN3 Atypical hyperplasia
CIS SIN3 CIS
*Preferred classification scheme.
CIS, Carcinoma in situ; SIN, squamous intraepithelial neoplasia; WHO, World Health Organization.
I n general, the degree of dysplasia in the mucosa of the larynx is considered to increase in severity with increasing
cytologic and/or architectural abnormality and with the progression of such changes toward the surface of the mucosal
epithelium. This approach is analogous to that used in the oral cavity and uterine cervix. S quamous cell CI S is traditionally
92defined as atypia that occupies the full thickness of the mucosal epithelial layer. The classic form of CI S as seen in the
uterine cervix (i.e., a uniform mucosal proliferation of immature basaloid cells with no surface maturation) is uncommonly
97,98seen in the larynx. More common is dysplasia characterized by abnormal cellular keratinization, or dyskeratosis, and
99the presence of large pleomorphic cells with eosinophilic cytoplasm, with surface keratinization being frequent. This
100change has been referred to as keratinizing dysplasia. The grading of the keratinizing dysplasias includes keratinizing
mild dysplasia, keratinizing moderate dysplasia, and keratinizing severe dysplasia. The keratinizing moderate and severe
98dysplasias are reported to correlate with an increased incidence of subsequent invasive carcinoma. The distinction
between keratinizing moderate and severe dysplasia, although still used by many, may be subtle, often difficult, and
subjective, and some (proponents of the S I N system) would combine the two into a category of high-grade intraepithelial
97-99neoplasia, again analogous to the situation in the uterine cervix.
Clinically, laryngeal epithelial dysplasias are more common in men than in women and are generally limited to the adult
population with a mean age at diagnosis in the sixth decade of life. D ysplastic lesions may occur anywhere in the larynx but
are identified mainly along the true vocal cord. Typically, it is a unilateral lesion but may be bilateral in up to 30% of
100cases. The most frequent symptom is hoarseness.
Clinically, severe dysplasia or CI S may appear as a reddened mucosal patch (erythroplakia), a thickened whitish patch
(leukoplakia), or a mixture of the two pa erns (speckled leukoplakia). A lternatively, it may be clinically inapparent. I ts
diagnosis and differentiation from lesser degrees of atypia depend on biopsy interpretation. Etiologic causes may include
tobacco smoking (most common) and excessive alcohol use. The risk of development of dysplastic lesions increases with
duration of smoking and/or alcohol use. The role of HPV in the development of these lesions remains unproved.
Grossly, laryngeal dysplasia may be localized, circumscribed flat or papillary area with a white (leukoplakic), red
(erythroplakic), or gray appearance.
Histologic changes can be separated into architectural and cellular or maturation abnormalities. A rchitectural
abnormalities include the presence of elongated and irregular-appearing rete pegs extending downward into the submucosa.+
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Cellular abnormalities include nuclear pleomorphism; nuclear hyperchromasia with irregularities in the nuclear contour;
increase in nuclear size relative to the cytoplasm (increased nucleus to cytoplasm ratio); crowding of cells with loss of
polarity; abnormal keratosis (dyskeratosis); increased mitotic activity, involving the mid and upper (superficial) portions of
the surface epithelium and that may include atypical forms; and loss of maturation with increased cellularity in the
superficial epithelium. Prominent nucleoli may be present but are not unique to dysplasia and may be seen in a reactive or
reparative process.
A s previously indicated, the grading of intraepithelial dysplasia includes mild, moderate, and severe. Mild dysplasia
(grade I ) is limited to the lower portions or inner third of the epithelium (basal zone dysplasia). Moderate dysplasia (grade
I I ) involves up to two thirds of the thickness of the epithelium. S evere dysplasia (grade I I I ) involves from two thirds to
almost complete thickness of the epithelium.
Nonkeratinizing Dysplasia
The paradigm for grading epithelial dysplasia is the one used for (and is most common to) the uterine cervix, referred to as
“classic” or nonkeratinizing dysplasia. These lesions are characterized by absent keratosis and increasing gradations of
dysplasia including mild (grade I ), moderate (grade I I ), and severe (grade I I I ) with the la er representing full-thickness
replacement of the squamous epithelium by atypical, small, immature basaloid cells, referred to as CI S (Fig. 4B-6). This
grading scheme is reproducible and is clinically useful. However, the “classic” or nonkeratinizing dysplasia commonly seen
in the uterine cervix is uncommon in the upper aerodigestive tract, especially in the laryngeal glottis.
FIGURE 4B-6 Hypopharyngeal (nonkeratinizing) severe dysplasia or carcinoma in situ. Full-thickness
dysplasia is seen, including absence of cellular maturation cells, loss of cellular polarity, presence of
nuclear pleomorphism, and hyperchromasia occupying the entire thickness of the mucosal epithelial layer.
(From Fried M P 1996 The larynx: a multidisciplinary approach, 2nd ed. Mosby, New York, Fig. 40-26)
Keratinizing Dysplasia
100The majority of the upper aerodigestive tract lesions fall under the designation of keratinizing dysplasias. The criteria for
evaluating keratinizing dysplasias are less defined, and the diagnosis of severe keratinizing intraepithelial dysplasia remains
controversial. The definition of severe dysplasia in the se ing of keratosis, especially in the glo is, is broader than the highly
reproducible pa ern seen in the uterine cervix and includes a microscopically heterogenous group of lesions. I n the se ing
of keratinizing dysplasia where surface maturation is retained with only partial replacement of the epithelium by atypical
cells, severe dysplasia includes those lesions in which the epithelial alterations are so severe that a high probability would
exist for the progression to an invasive carcinoma if left untreated. S evere dysplasia shows the presence of aberrant cell
maturation with dyskeratotic cells and mitotic figures (with or without atypical forms) that often is limited to the basal zone
(Fig. 4B-7) without classically defined CI S characterized by full-thickness dysplasia. These alterations occur in the presence
of surface keratinization and often occur in association with architectural alterations of the surface epithelium to include
elongated, downward growing, and irregularly shaped rete pegs. I n the evaluation of upper aerodigestive tract dysplasia, the
presence of surface keratinization is not significant; however, finding dyskeratotic cells represents an important clue to the
presence of significant dysplasia.+
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FIGURE 4B-7 Keratinizing severe dysplasia of the larynx. The mucosal epithelium shows surface
keratinization with elongated rete pegs and maturational abnormality with immature-appearing cells
showing nuclear pleomorphism, nuclear hyperchromasia, and loss of polarity. Although the dysplastic cells
are limited to the basal zone with maturation of the upper two thirds of the surface epithelium, the extent
of architectural and cytomorphologic changes is diagnostic for severe dysplasia.
The histopathologic interpretation and grading of keratinizing dysplasias of the upper aerodigestive tract are imprecise
and subjective. I t should be noted that it is well accepted that invasive carcinoma may occur in the se ing of keratinizing
dysplasia in which the dysplastic changes are limited to the basal zone without classically defined CI S (i.e., without
fullthickness intraepithelial dysplasia). Given the complexities in the issues relating to upper aerodigestive tract intraepithelial
lesions, confusion and misunderstandings may occur between the clinician and the pathologist and may result in
inappropriate management of the patient. Using the definition of CI S as applied to the uterine cervix requires loss of
maturation of squamous epithelium with full-thickness intraepithelial dysplasia. Therefore, by this definition, the majority
of keratinizing severe dysplasias cannot be CI S , becausek eratosis requires maturation of the squamous epithelium.
Therefore the use of the specific term CI S in keratinizing dysplasias has been questioned and is likely inappropriate in this
se ing; a more appropriate designation is severe keratinizing dysplasia, with the understanding that such lesions have a
similar potential for invasion as classically defined CI S and, as such, are for all intents and purposes tantamount to
classically defined CIS.
The differential diagnosis for keratinizing dysplasias may include reactive epithelial changes, VC, and microinvasive
carcinoma. Reactive epithelial alterations lack the constellation of cellular abnormalities previously detailed relative to
keratinizing dysplasias. Epithelial hyperplasia (acanthosis) is a common finding and can be seen with or without keratosis,
without atypia, or in association with atypia. I n hyperplasia an irregular contour to the basal zone usually exists, and the
epithelium may protrude below adjacent epithelium, possibly suggesting microinvasive carcinoma. Epithelial hyperplasias
may be caused by an infectious agent (e.g., fungi, others), and fungal stains (e.g., Gomori methenamine silver [GMS ],
periodic acid–S chiff [PA S ]) may be useful to identify the causative microorganism. The presence of morphologic evidence of
dysplasia in association with keratinizing dysplasias allows for differentiation from VC. A diagnosis of microinvasive
carcinoma should be reserved for those examples in which definitive evidence exists of dissociated squamous cells at the
epithelial-stromal interface, with superficial invasion of the lamina propria.
Risk of Progression of Intraepithelial Dysplasia
The end point for the grading of dysplasia is to convey to the clinician what is the potential biologic behavior of a given
epithelial lesion. Keratotic epithelium without dysplasia carries a very low risk of developing subsequent carcinoma with
101reported incidences of from 1% to 5%. I n contrast, keratotic epithelium with dysplasia is associated with an increased risk
for the subsequent progression or development of premalignant or overtly carcinomatous changes varying from 11% to 18%
101of cases. This risk of malignant transformation represents an increase of three to five times when compared with
carcinoma arising in keratotic lesions without atypia. The clinical significance and natural history of laryngeal CI S have been
difficult to pin down precisely, and various studies have reported a rate of progression to invasive carcinoma varying from
102,1033.5% to 90%. D ifferences in criteria for diagnosis and patient selection probably contribute to this disparity in results.
Furthermore, it is important to remember that CI S often is not an isolated lesion and may be present near or adjacent to a
frankly invasive carcinoma. A ppropriate clinical and histologic sampling is therefore of extreme importance. I t is generally
thought that severe dysplasia or CI S , if left untreated, will progress to an invasive carcinoma in a significant number of
101cases, although perhaps not in every case. I n a review of the literature, Barnes cited the risk to progression to carcinoma
relative to upper aerodigestive tract moderate dysplasia of approximately 20%; for severe dysplasia, approximately 24%. This
difference is not statistically significant. Given the absence of statistical significance in progression to invasive carcinoma
between moderate dysplasia and severe dysplasia, utility may exist in employing the two-grade system currently in use for
uterine cervical dysplasias (Bethesda classification) for the keratinizing dysplasias of the upper aerodigestive tract to include
(1) low-grade squamous intraepithelial lesion or neoplasia for mild dysplasia and (2) high-grade squamous intraepithelial
lesion or neoplasia for moderate and severe dysplasias.
A nother important point to recognize is the clinical concern a ached to a diagnosis of severe keratinizing intraepithelial+
neoplasia. This clinical concern is due to the fact that severe dysplasia is often multifocal and frequently occurs adjacent to or
near synchronous foci of invasive carcinoma. Furthermore, this form of dysplasia has a rate of progression to invasive
carcinoma that is greater than that of “classic” CI S . A diagnosis of severe dysplasia requires therapeutic intervention, as well
as clinical evaluation of the entire upper aerodigestive tract to exclude the possible presence of additional foci of dysplasia or
carcinoma.
I n general, mild and moderate dysplasias are thought to be reversible alterations. Circumstantial evidence supports the
idea that preinvasive dysplasias are potentially reversible after cessation or removal of an instigating factor such as tobacco
use. The problems of predicting the malignant potential of a dysplastic lesion are greatest in cases of moderate dysplasia. I t
is virtually impossible to differentiate the moderately dysplastic lesions that are reversible from those that represent the
earliest forms of neoplastic transformation. Therefore a diagnosis of moderate dysplasia should engender enough concern to
the clinician to warrant close patient follow-up. Recurrence or persistence of this dysplasia may be indicative of malignant
transformation. The clinically abnormal lesions that show limited cytologic and maturation abnormalities, falling under the
designation of reactive atypias or hyperplastic lesions, represent reversible changes that rarely, if ever, progress to
carcinoma. These lesions are responsive to conservative management.
The treatment for laryngeal dysplasia typically follows a conservative approach, including vocal cord stripping or local but
101,103 104complete excision in localized cases. Radiotherapy has been used as well.
Microinvasive, Superficial, or “early” Invasive Squamous Cell Carcinoma
Microinvasive S CC is a cancer that infiltrates into the superficial compartment of the lamina propria. The concept of
97-99,105,106superficially invasive, or microinvasive, S CC is recognized in the larynx, as in the cervix. The definition of what
constitutes microinvasion varies in the literature and includes (1) the presence of sca ered malignant cells within the
submucosa just below the basement membrane; (2) the presence of malignant cells limited to 2 mm of invasion; (3) the
presence of malignant cells within 1 to 2 mm of the basement membrane without angioinvasion; (4) the presence of tongues
or discrete foci of malignant epithelium invading through the basement membrane; the preferred definition is that of (5)
invasive carcinoma extending into the stroma no more than 0.5 mm measured from the epithelial basement membrane and
107 107without angioinvasion. The presence of angioinvasion excludes a diagnosis of microinvasive carcinoma. Of note,
extension of the dysplastic process to involve the seromucinous glands is still considered as CI S and not invasive carcinoma.
Clinical manifestations and appearance are similar to those of CI S . I n the larynx, full cord mobility is present. A ny
dysfunction in vocal cord mobility (fixation) by definition means muscle invasion, which excludes a diagnosis of
microinvasive cancer.
Histologically, microinvasive carcinoma can occur in two unrelated phases. The first is the development from (and as a
continuum of) CI S . The second is invasion from an epithelium demonstrating no evidence of CI S . I n the upper aerodigestive
tract, particularly in the larynx, severe dysplasia (i.e., CI S ) is not a prerequisite for the development of invasive S CC F(ig.
4B8). S uch invasive carcinomas “drop off” or “drop down” from the basal cell layer with the overlying mucosa showing no
evidence of dysplasia.
FIGURE 4B-8 Invasive squamous cell carcinoma of the larynx. The invasive carcinoma is arising from
surface epithelium in which keratinizing dysplasia exists, limited to the basal zone without full-thickness
intraepithelial dysplasia.
I t may be difficult, especially in small biopsy specimens, to identify a focus of microscopic invasion (i.e., penetration
through the mucosal basement membrane into the subjacent stroma) in a predominantly intraepithelial carcinoma. The+
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basement membrane of an intraepithelial lesion may be obscured by inflammation; also, nests of carcinoma that invade via a
rounded pushing margin may still have basement membrane components (laminin and type I V collagen) identifiable
98,108immunohistochemically.
Features such as a desmoplastic stromal reaction, foreign-body reaction to keratin in the stroma (so-called keratin
granuloma) (Fig. 4B-9), and the presence of separate tiny clusters of (or single) neoplastic cells in the stroma are useful as
109evidence of superficial invasion. I t has been suggested that the clinical significance of microinvasion is similar to that of
97,110 110CIS or severe dysplasia and that the prognosis is excellent with appropriate therapy.
FIGURE 4B-9 The presence of a foreign body giant cell reaction to keratin (so-called keratin granuloma)
is useful as evidence of invasive carcinoma. A, Granuloma formation identified in proximity to the invasive
carcinoma is characterized by the presence of multinucleated giant cells and shows cytokeratin
immunoreactivity (B).
Microinvasive cancer is a biologically malignant lesion, potentially capable of gaining access to lymphatic or vascular
channels in the lamina propria, that may result in metastatic disease. For microinvasive carcinoma of the laryngeal glo is,
the clinical significance is similar to CI S or severe dysplasia, and with appropriate therapy (excision and/or radiotherapy)
progression of disease from a microinvasive to a more invasive carcinoma does not occur. This may be due to the earlier
clinical manifestations produced by glo ic cancers, leading to an earlier diagnosis of cancer before it has invaded into
deeper aspects of the larynx. Glo ic microinvasive cancers are generally not associated with metastatic disease because the
glo ic portion of the larynx has quantitatively fewer lymphovascular spaces as compared with the supraglo is and
subglottis.
Invasive Squamous Cell Carcinoma
S CC is by far the most common malignant neoplasm of the larynx. Cancer of the larynx is much more common in men than
in women, occurring most commonly in the fifth to seventh decades. The discrepancy in incidence between men and women
has recently decreased slightly, possibly because of the increased incidence of smoking among women. Fewer than 1% occur
in patients under 30 years of age, and S CC rarely may occur in the pediatric age group (first and second decades of life).
109,111,112S moking and alcohol consumption are considered highly significant etiologic factors in this disease. Evidence has
109,111,113-115suggested a possible role for HPV infection, r a s oncogene activation, and gastroesophageal reflux as well. The
majority of hypopharyngeal cancers occur in the piriform sinus, with carcinomas of the posterior wall occurring next most
116commonly, and primary postcricoid carcinomas being the rarest of hypopharyngeal carcinomas. A s with laryngeal
116cancers, men are more frequently affected than women, and 90% of patients report a history of tobacco use. Cancers of
the trachea are much more rare, but S CC is also the most common tracheal malignancy. I t is more common in men than in
women and most common in the fifth to seventh decades of life. I n order of involvement, tracheal carcinomas occur in the
lower third (60%) > upper third (30%) > middle third (10%).
The classic symptom of carcinomas of the vocal cord or supraglo ic larynx is hoarseness, or a muffled or altered voice.
104,117Pain, dysphagia, or hemoptysis may also occur. S ubglo ic carcinomas are more likely to produce stridor or airway
obstruction, even when not particularly large, because of the inflexibility imparted to the subglo ic space by the cricoid
104cartilage, the only circumferential cartilage in the respiratory tract. Piriform sinus cancers are, unfortunately, often large
and advanced when discovered because they tend to produce symptoms late. D ysphagia, otalgia, a neck mass resulting from
118lymph node disease, or general inanition are possible symptoms of hypopharyngeal cancer. Tracheal carcinomas tend to
produce stridor or wheezing when sufficient airway compromise develops.
Glo ic cancers are the most common laryngeal cancers, followed in incidence by supraglo ic cancers. Primary subglo ic
119carcinomas are rare. S upraglo ic tumors are more prone to extend across the midline than glo ic lesions. The laryngeal
ventricles appear to be a barrier to extension of carcinoma between the glo ic and supraglo ic compartments, resulting in
the successful use of horizontal supraglo ic laryngectomy to treat some supraglo ic cancers. Reports, however, indicate that
pathways exist for carcinomas to spread between these compartments, notably with spread from the glo is to the arytenoid
region posterior to and behind the ventricle, spread in the paraglo ic space near the thyroid cartilage lateral to the ventricle,
and extension to the anterior commissure area, with invasion of the anterior commissure tendon and/or the thyroid cartilage
120-122and spread inferiorly. I t is not surprising then, that large transglo ic tumors, involving both glo ic and supraglo ic
compartments, do occur. These tend to be aggressive neoplasms with a poor prognosis. Glo ic cancers extend subglo icallymore commonly than supraglottically; the conus elasticus acts as a rather imperfect barrier to the spread of tumor.
The gross appearance of invasive S CC is quite variable and includes ulcerated, flat, exophytic, verrucoid, or papillary
growths. Laryngeal S CCs may present grossly as exophytic shaggy-surfaced masses, with or without surface ulceration, or as
deeply invasive ulceroinfiltrative masses without a prominent surface mass (Fig. 4B-10).
FIGURE 4B-10 Squamous cell carcinoma of the larynx. A, Exophytic fungating tumor involving right true
vocal cord. B, Raised plaque-like supraglottic tumor with focal ulceration that crosses the midline. C,
Ulceroinfiltrative supraglottic tumor.
The histologic appearance of S CC of the larynx, hypopharynx, and trachea corresponds to that of S CCs in other sites (e.g.,
109oral cavity, lung, esophagus, skin) (Fig. 4B-11). Tumors may be keratinizing or nonkeratinizing, although most produce
recognizable intracellular or extracellular keratin, and vary from well to poorly differentiated. S evere dysplasia or CI S of the
surface epithelium may be a common component found in association with invasive S CC; however, this component need not
be present. For all types of S CC the presence of invasion is diagnostic of malignancy. I nvasion can be as single cells or small
irregular aggregates or can appear as large cords or cohesive aggregates. I n addition, a desmoplastic stromal response and
foreign body reaction to keratin in the stroma (so-called keratin granuloma) assist in identifying invasion (see Fig. 4B-9).
I nvasive cancer will efface the normal architecture and may be associated with lymphovascular invasion, neurotropism, and
invasion into muscle, bone, and cartilage. Once the cancer invades beyond a few millimeters or extends into muscle,
cartilage, or other soft tissue components outside the anatomic structure from which it originates, then the tumor is a higher
clinical stage neoplasm with the potential for more aggressive behavior.+
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FIGURE 4B-11 Squamous cell carcinoma of the larynx. A, Well-differentiated carcinoma. B, Moderately
differentiated carcinoma.
S ampling is a major issue in the evaluation of S CC of the upper aerodigestive tract. I n the absence of adequate
representative tissue including epithelial-stromal interface, one should be circumspect with the diagnosis of S CC. D iagnostic
pitfalls in the diagnosis of S CC include pseudoepitheliomatous hyperplasia, necrotizing sialometaplasia, juxtaoral organ of
Chievitz, and radiation atypia.
Patients with laryngeal or hypopharyngeal S CCs frequently undergo irradiation therapy; this induces morphologically
recognizable effects on the tumor and irradiated tissues. Fibrous obliteration of tumor and increased keratin production by
the neoplasm, as well as foreign-body giant cell and/or histiocytic reaction to keratin or other tumor debris, may be seen
after irradiation, together with dilatation of lymphatics and atypical mesenchymal cell nuclei in the host stromal tissue.
Atrophy of nonneoplastic seromucinous glands in the radiated field often occurs, with enlargement of glandular epithelial
nuclei. This appearance can simulate persistent small islands of carcinoma to the unwary observer. A ppreciation of the
normal lobular glandular architecture and structure may facilitate recognition of the structures as atrophic glands rather
than tumor.
Histologic Prognostic Indicators
A mong the histologic findings that may impact prognosis in head and neck S CC are (1) status of the surgical resection
margins, (2) tumor size, thickness, and location of the lesion; (3) pa ern of invasion; (4) involvement of lymphovascular
spaces; (5) invasion of soft tissue structures including nerves, bone, and cartilage; (6) nodal metastasis with or without
extranodal extension of tumor; (7) distant metastasis; (8) host response; (9) neovascularization; and (10) presence of multiple
malignancies. A rguably, the presence of nodal metastasis with extranodal extension of carcinoma represents the most
123important biologic predictor, associated with increased locoregional disease and distant metastasis. Efforts to a ach
prognostic significance to morphologic features, such as degree of differentiation, have met with varying degrees of
124-131success. D ata involving the morphologic pa ern at the advancing tumor front, D N A analysis, oncogenes such as p 5 3,
132-136and cyclin D 1 protein expression have shown promise in predicting the clinical behavior of laryngeal cancers. I t
would appear that evaluation based on multiple factors, such as tumor grade, stage, and size, D N A , and oncogene status, as
well as the general status of the patient, might most accurately give an indication of prognosis.
The prognosis for patients with a small laryngeal S CC discovered early is favorable. Overall, more than 60% of patients in
137the United S tates with laryngeal cancer are alive after 5 years, with 5-year disease-free rates as high as 90% being reported
138for T1 (small localized) carcinomas of the vocal cord. A s might be expected, survival decreases with advancing stage of
disease and the presence of lymph node metastases, especially with extranodal extension of the tumor. The staging system
recommended by the A merican J oint Commi ee on Cancer is outlined inT ables 4B-4 and 4B-5. S ubglo ic and
hypopharyngeal tumors generally have a worse prognosis, probably related to their generally more advanced stage at
diagnosis. S urgery and radiation therapy, alone or in combination, with or without adjunctive chemotherapy, have been used
116,119as treatment modalities in cases of cancer of the larynx and hypopharynx. More recently, cetuximab plus radiotherapy
has been shown to significantly improve overall survival at 5 years compared with radiotherapy alone for advanced
139locoregional head and neck SCC.
TABLE 4B-4
TNM Staging of Carcinoma of the Larynx
Primary Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
Supraglottis
T1 Tumor limited to one subsite of supraglottis with normal vocal cord mobility
T2 Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region outside the
supraglottis (e.g., mucosa of base of tongue, vallecula, medial wall of pyriform sinus) without fixation of the
larynxT3 Tumor limited to larynx with vocal cord fixation and/or invades any of the following: postcricoid area,
preepiglottic tissues, paraglottic space, and/or minor thyroid cartilage erosion (e.g., inner cortex)
T4a Moderately advanced local disease
Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues
of neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus)
T4b Very advanced local disease
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures
Glottis
T1 Tumor limited to the vocal cord(s) (may involve anterior or posterior commissure) with normal mobility
T1a Tumor limited to one vocal cord
T1b Tumor involves both vocal cords
T2 Tumor extends to supraglottis and/or subglottis, or with impaired vocal-cord mobility
T3 Tumor limited to the larynx with vocal cord fixation, and/or invades paraglottic space, and/or minor thyroid
cartilage erosion (e.g., inner cortex)
T4a Moderately advanced local disease
Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues
of neck, including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus)
T4b Very advanced local disease
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures
Subglottis
T1 Tumor limited to the subglottis
T2 Tumor extends to vocal cord(s) with normal or impaired mobility
T3 Tumor limited to larynx with vocal cord fixation
T4a Moderately advanced local disease
Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of
neck, including deep extrinsic muscles of the tongue, strap muscles, thyroid, or esophagus)
T4b Very advanced local disease
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures
Regional Lymph Nodes (N)*
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
N2 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 lymph nodes, none more than 6 cm in greatest dimension
N2a Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension
N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension
N3 Metastasis in a lymph node, more than 6 cm in greatest dimension
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
T1N1M0
T2N1M0T3N1M0
Stage T4aN0M0
IVA T4aN1M0
T1N2M0
T2N2M0
T3N2M0
T4aN2M0
Stage T4b Any N M0
IVB
Any T N3M0
Stage Any T Any N M1
IVC
*Note: Metastases at level VII are considered regional lymph node metastases.
Reproduced with permission of the American Joint Committee on Cancer (AJCC), Chicago, Ill. The original source for this
material is the AJCC Cancer Staging Manual, Seventh Edition (2010). Published by Springer-Verlag, New York (Available at
www.springeronline.com)
TABLE 4B-5
TNM Staging of Carcinoma of the Oropharynx and Hypopharynx
Primary Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
Oropharynx
T1 Tumor 2 cm or less in greatest dimension
T2 Tumor more than 2 cm but not more than 4 cm in greatest dimension
T3 Tumor more than 4 cm in greatest dimension or extension to lingual surface of epiglottis
T4a Moderately advanced local disease
Tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible*
T4b Very advanced local disease
Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or encases carotid
artery
Hypopharynx
T1 Tumor limited to one subsite of hypopharynx and/or 2 cm or less in greatest dimension
T2 Tumor invades more than one subsite of hypopharynx or an adjacent site, or measures more than 2 cm in
greatest dimension without fixation of hemilarynx
T3 Tumor more than 4 cm in greatest dimension or with fixation of hemilarynx or extension to esophagus
T4a Moderately advanced local disease
Tumor invades thyroid/cricoid cartilage hyoid bone, thyroid gland, or central compartment soft tissue†
T4b Very advanced local disease
Tumor invades prevertebral fascia, encases carotid artery, or invades mediastinal structures
‡Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
N2 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 lymph nodes, none more than 6 cm in greatest dimension
N2a Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension
N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension+
+
+
+
N3 Metastasis in a lymph node, more than 6 cm in greatest dimension
Distant Metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
Anatomic Stage/Prognostic Groups
Stage 0 Tis N0M0
Stage I T1N0M0
Stage II T2N0M0
Stage III T3N0M0
T1N1M0
T2N1M0
T3N1M0
Stage T4aN0M0
IVA
T4aN1M0
T1N2M0
T2N2M0
T3N2M0
T4aN2M0
Stage T4b Any N M0
IVB Any T N3M0
Stage Any T Any N M1
IVC
*Mucosal extension to lingual surface of epiglottis from primary tumors of the base of the tongue and vallecula does not
constitute invasion of larynx.
†Central compartment soft tissue includes prelaryngeal strap muscles and subcutaneous fat.
‡Metastases at level VII are considered regional lymph node metastases.
Reproduced with permission of the American Joint Committee on Cancer (AJCC), Chicago, Ill. The original source for this
material is the AJCC Cancer Staging Manual, Seventh Edition (2010). Published by Springer-Verlag, New York (Available at
www.springeronline.com)
Morphologic Subtypes of Squamous Cell Carcinoma
Papillary (Exophytic) Squamous Cell Carcinoma
S CCs (keratinizing and nonkeratinizing) of the upper aerodigestive tract (Table 4B-6) are characterized by exophytic or
papillary growth, clinically simulating the appearance of a benign papilloma or a VC, but, in contrast with the la er, the
neoplastic cells of the exophytic and papillary SCCs are cytologically malignant. These tumors have been termed exophytic or
26,140,141papillary S CCs. Papillary (exophytic) S CC represents an uncommon but distinct subtype of head and neck S CC.
The demographics are similar to those of conventional S CC, with the tendency to affect men more than women and
occurring in adults with a mean age in the seventh decade of life. Papillary S CCs arise in the larynx, oral cavity, oropharynx
and hypopharynx, and sinonasal tract. The larynx is the most common site. Within the larynx most of these carcinomas are
located in the supraglo is, followed by the glo is and rarely the subglo is. Laryngeal involvement includes hoarseness and
airway obstruction; less often, dysphagia and hemoptysis may occur. S moking and alcohol use have been linked to the
development of papillary S CC. HPV subtypes identified include 6, 11, 16, and 18. HPV (by in situ hybridization and
polymerase chain reaction) have been detected in papillary SCC, and preexisting papillomas have been reported in up to 34%
140of patients.
TABLE 4B-6
V ariants of S quamous C ell C arcinoma+
+
Verrucous carcinoma
Papillary squamous cell carcinoma
Spindle cell squamous carcinoma
Basaloid squamous cell carcinoma
Adenosquamous carcinoma
Lymphoepithelial-like carcinoma
Giant cell carcinoma
Papillary S CC is most often seen as a solitary lesion with an exophytic or papillary growth. Tumor size may range from
2 mm up to 4 cm. Histologically, papillary S CC has filiform growth with finger-like projections and identifiable fibrovascular
cores or a broad-based bulbous to exophytic growth with rounded projections resembling a cauliflower-like growth pa ern
in which fibrovascular cores may be seen (Fig. 4B-12). The squamous epithelium is cytologically malignant, and this
malignant epithelium identifies these tumors as carcinomas, separating them from papillomas. S urface keratinization is
generally limited and often absent. D efinitive invasion may be difficult to demonstrate in biopsy specimens, with the
carcinomatous epithelium suggesting an in situ process rather than invasive carcinoma. However, the extent of growth with
the formation of a clinically appreciable exophytic mass goes beyond the general concept of in situ carcinoma. These tumors
should be considered as being invasive, even in the absence of definitive stromal invasion.
FIGURE 4B-12 Exophytic (papillary) squamous cell carcinoma. A, Prominent exophytic and papillary
epithelial growth. B, The entire epithelium component is malignant.
Papillary S CCs usually arise de novo without identification of coexisting benign lesion such as a papilloma, although
association with precursor papilloma or occurrence in patients with a previous history of a papilloma at the site of the
papillary SCC has been reported.
The differential diagnosis of papillary and exophytic S CC includes laryngeal papillomatosis, conventional S CC, and VC
(Table 4B-7). Laryngeal papillomatosis is distinguished by its bland epithelial proliferation. Cytologic abnormalities may be
seen in laryngeal papillomatosis but tend to be focal when present, although they do not approach the level of dysplasia seen
in papillary S CC. VC is characterized by a verrucous growth pa ern with marked keratosis in layers or tiers, absent nuclear
atypia, absent mitotic activity beyond the basal layer, and a pushing rather than infiltrative pattern of invasion.
TABLE 4B-7
Clinicopathologic Features of Select Squamous Cell Carcinoma Variants
PSCC VC SCSC BSCC
Age, sex Seventh decade, M > F Sixth-seventh Sixth-eighth decades, Sixth-seventh decades, M > F
decades, M > F M > F
Site* Larynx > oral cavity, Oral cavity > Larynx—TVC > FVC, Hypopharynx (piriform sinus),
oropharynx, and larynx (glottis) supraglottis larynx (supraglottis), tonsil
hypopharynx
Symptoms Hoarseness and airway Oral—mass Hoarseness, airway Hoarseness, dysphagia, pain,
obstruction with or obstruction, neck mass
without dysphagia
pain
Larynx—
hoarseness
RF Tobacco and alcohol Tobacco (chewing, No known RF Tobacco and alcohol
smoking)
Viral HPV implicated HPV implicated No HPV implicated
etiology
Histology Filiform to papillary to Epithelial Malignant Invasive neoplasm
broad-based bulbous to proliferation undifferentiated predominantly composed of+
+
+
exophytic growth with with uniform spindle cell and pleomorphic basaloid cellsPSCC VC SCSC BSCC
fibrovascular cores; squamous pleomorphic with associated minor
squamous epithelium is cells without cellular squamous cell component
cytologically malignant; dysplastic proliferation and (epithelial dysplasia, abrupt
surface keratinization is features or the presence of a keratinization, carcinoma in
generally limited and mitoses; conventional situ, invasive carcinoma);
often absent; considered marked squamous cell variety of growth patterns,
as being invasive even in surface component including solid, lobular,
the absence of definitive keratinization (carcinoma in situ cribriform, cords, trabeculae,
stromal invasion; usually (“church- and/or invasive and gland-like or cystic
arise de novo but may be spire” SCC); may be growth; increased mitotic
associated with keratosis); entirely composed activity, comedonecrosis in
precursor papilloma or broad or of malignant center of neoplastic lobules;
occurrence at site of bulbous rete undifferentiated peripheral nuclear palisading
prior papilloma pegs with a spindle cells and basement membrane–like
pushing, not (cellular or material may be seen
infiltrative, hypocellular
margin collagenized)
without
differentiated
epithelial
componentIHC Positive for cytokeratins Positive for Positive for Consistently positive for
(IHC typically not cytokeratins cytokeratins in cytokeratins (AE1/3, 34βE12,
required for diagnosis) (IHC typically majority of cases CAM5.2); neuroendocrine
not required (approximately markers (i.e., chromogranin
for diagnosis) 60%) but may be and synaptophysin) are
negative in 40% of usually negative, but
cases; variable occasional cases may be
reactivity seen for positive; variable expression
p63; may also be of vimentin, NSE, S-100
positive for protein, and actins
vimentin, desmin,
actin
Treatment Surgery Surgery Surgery with or Surgery, ND, radiation, and
without adjunctive chemotherapy
radiotherapy
Spread Regional lymph nodes; Locally invasive; Metastasizes to Early dissemination to regional
distant metastasis is rare not metastatic regional lymph and distant lymph nodes,
(lung) nodes and lung lung, bone, skin, brain
Prognosis Similar to conventional SCC Excellent Dependent on stage Poor, often resulting in death
of similar stage although but overall within a year of diagnosis
may have an overall prognosis is poor
more favorable
prognosis than
comparable conventional
SCC
*Most common sites in the head and neck.
BSCC, Basaloid squamous cell carcinoma; FVC, false vocal cord; HPV, human papillomavirus; IHC, immunohistochemistry; ND,
neck dissection; NSE, neuron-specific enolase; PSCC, papillary squamous cell carcinoma; RF, potential risk factors; SCSC,
spindle cell squamous carcinoma; TVC, true vocal cord; VC, verrucous carcinoma.
S urgery is the treatment of choice for papillary S CC; adjunctive (radiation) therapy may be used. The majority of papillary
S CCs are low clinical stage (T2); their behavior overall is similar to that of conventional S CC of similar stage, although some
140,141authors report a better overall prognosis for papillary SCC than for conventional SCC when matched for T stage.
Verrucous Carcinoma
VC is a highly differentiated variant of S CC with locally destructive, but not metastatic, capabilities. VC can occur anywhere
in the upper aerodigestive tract. The most common sites in descending order are the oral cavity, larynx, nasal fossa, sinonasal
142,143 143-150tract, and nasopharynx. Laryngeal VC represents from 1% to 4% of all laryngeal carcinomas. The most
common site of occurrence in the larynx is the glo ic area (anterior true vocal cord); less common sites of occurrence include
the supraglo is, hypopharynx, and subglo is. Hoarseness is the most common complaint; less frequent symptoms include
airway obstruction, hemoptysis, dysphagia. The etiology of VC remains speculative and includes the use of tobacco products.
113,151,152Viral induction may be a factor in the development of VC. However, data are conflicting in the literature
concerning identification of HPV D N A by in situ hybridization techniques. S ome investigators either failed to identify HPV
153 154-157D N A in any oral cavity VC or identified HPV D N A in a very limited number of cases. Perhaps these discrepancies
relate to the difficulties in the interpretation of in situ hybridization studies. This may be complicated by problems of+
158nonspecific staining or sensitivity of detection, and it is unclear that VC was separated reliably from conventional S CC.
159,160Polymerase chain reaction analysis for the presence of HPV in the VCs has confirmed the presence of HPV D N A .
These studies suggest a direct pathogenetic role of HPV, rather than that of an innocent bystander, in the development of
VC. The active role of HPV may be as a promoter in the multistep process of carcinogenesis in squamous cells of the upper
161aerodigestive tract. D yson and colleagues showed that a protein product of HPV can bind the retinoblastoma gene
product, thereby removing the regulatory block on cell cycle progression from G1 to S.
I rrespective of site, the pathologic appearance of VC generally is the same. The gross appearance of VC is a tan or white,
warty, fungating or exophytic, firm to hard mass measuring up to 10 cm in diameter. I n general, the tumors have a broad
base. The histologic appearance of VC is that of a bland squamous cell proliferation with uniform cells lacking dysplastic
features (Fig. 4B-13). Orderly maturation is seen with retention of polarity. N o increased nucleus to cytoplasm ratio, nuclear
pleomorphism, or dyskeratosis is seen. Mitotic figures can be seen in the basal area but are not present elsewhere. I n
addition to the bland epithelial cell proliferation, marked surface keratinization (“church-spire” keratosis) exists, and,
characteristically, broad or bulbous rete pegs push downward into the stroma. I nvasive growth into the submucosa as
angulated, cohesive tumor nests or individual discohesive neoplastic cells is not a feature. A mixed chronic inflammatory cell
infiltrate composed of lymphocytes, plasma cells, and histiocytes may be prominent in the stroma. Viral-associated
cytopathic changes (koilocytosis) may be present. A n adequate biopsy for a diagnosis of VC should include ample epithelial
and stromal tissue. I n the absence of stroma, the biopsy should be considered as inadequate, and a definitive diagnosis of
VC should not be made.
FIGURE 4B-13 A, Verrucous carcinoma of the larynx, showing bulbous fronds with a pushing border and
associated dense chronic inflammatory infiltrate. B, The epithelium is bland, lacking cytologic atypia or
mitotic activity.
The diagnosis of VC does not usually require any special stains (i.e., histochemistry or immunohistochemistry). I n certain
se ings, a florid but bland epithelial proliferation may occur as a result of fungal infection, such as candidiasis. The fungal
forms are best seen by silver stains, such as GMS . The fungi should be present within the depths of the epithelial
proliferation and not limited to the surface keratin or most superficial epithelium.
VC must be differentiated from “conventional” types of S CC. Both clinically and histopathologically, many overlapping
findings may exist between these tumor types. The histologic differentiation of VC from a “conventional” type of carcinoma
is based on the presence or absence of cytologic abnormalities. A ny dysplastic features should exclude a diagnosis of VC.
Minimal dysplastic features are limited to the basal zone in VC. The epithelial dysplastic changes in conventional squamous
carcinoma may or may not be associated with keratosis or dyskeratosis. D yskeratosis can be seen in “conventional” S CC but
usually is not a feature of VC. I t has become apparent that VC is not always a “pure” lesion, and cases have been recognized
146,150,162-164wherein foci of conventional infiltrative SCC are present in lesions otherwise characteristic of classic VC. Such
“hybrid” or combined verrucous-squamous carcinomas have been noted in both oral and laryngeal sites. I n the larynx they
have been said to be more aggressive than pure VCs and to behave (and hence merit treatment) more like comparably
163staged conventional SCCs. Obviously, then, such foci should be sought and commented on in specimens of VC.
The pathologic diagnosis of VC may be extremely difficult and require multiple biopsies over several years before
identification of diagnostic features. Both clinicians and pathologists need to be aware of this fact. To this end, adequate
initial biopsy material is critical and should include a good epithelial-stromal interface. The pathologist should not
overinterpret a verrucoid lesion as a carcinoma without seeing the relationship of the lesion to the underlying stroma.
S imilarly, an adequate epithelial-stromal interface is required to exclude invasive carcinoma in the presence of dysplastic
squamous epithelial alterations.
144,165S urgical excision is the definitive diagnostic modality for VC. S ome literature supports the dogma that
radiotherapy is contraindicated in the treatment of VC because of the purported induction of anaplastic transformation.
However, many reasons exist to doubt the validity of radiation-induced anaplastic transformation of VC. S imilar
162,166transformations of VC occur after surgery or cryosurgery and even in the absence of any therapeutic intervention.+
+
+
144Batsakis and colleagues pointed out several factors that weigh against the association of radiation-induced
transformation including that the interval between radiotherapy and the high-grade malignancy may be extremely short
144(less than 8 months). A s detailed by Batsakis and colleagues the descriptions and illustrations of “anaplastic
transformation” of VCs are inadequate. A more likely scenario is that “host tumors” were not VCs but were conventional
squamous carcinomas that may not have been adequately sampled, thus precluding the identification of less differentiated
(“anaplastic”) foci that were a part of the neoplasm from its inception. S urgery remains the treatment of choice with local
167 167 168control in 85% of patients. The rate of local control with radiotherapy is less than 50%. Vidyasagar and colleagues
reported a series of 107 irradiated patients in which 31% of tumors recurred. They claim that these figures compare favorably
with a similar recurrence rate after surgery.
Spindle Cell Squamous Carcinoma (Sarcomatoid Carcinoma)
S pindle cell squamous carcinoma (S CS C) is composed of conventional S CC (in situ or invasive carcinoma) associated with a
malignant spindle-shaped and pleomorphic (epithelioid) stromal component. S CS C occurs throughout the upper
169-171aerodigestive tract mucosa but is most common in the larynx. I n the larynx the most common site of occurrence is the
true vocal cords; less often it may occur in the false vocal cords and supraglo is. S ymptoms include hoarseness, voice
changes, airway obstruction, and dysphagia. N o specific correlation exists with known risk factors (alcohol, tobacco, or
environment or occupation). SCSC has been reported in areas of prior irradiation.
The majority of tumors have a polypoid exophytic configuration, with either a broad base or a relatively narrow
172,173pedicle (Fig. 4B-14). Tumors of this la er type may autoamputate in whole or in part and be expectorated by the
172patient. Sessile and ulceroinfiltrative tumors occur more rarely.
FIGURE 4B-14 Spindle cell carcinoma of the larynx. A, Gross photograph of a polypoid tumor in the
arytenoid region. B, Whole-organ section of the same tumor, showing much of the tumor connected to the
larynx by a pedicle and a portion of the tumor with a broader base. The tumor is not deeply infiltrative.
(From Fried M P 1996 The larynx: a multidisciplinary approach, 2nd ed. Mosby, New York, Fig. 40-30)
The histologic features that define S CS C include a malignant undifferentiated spindle cell proliferation in the presence of
a differentiated squamous cell component that includes either intraepithelial dysplasia or CI S or frankly invasive S CC F(ig.
4B-15). A s such, not infrequently, the differentiated squamous cell component is scant to absent, and the tumor is composed
entirely of the spindle-shaped and pleomorphic (undifferentiated) component. The difficulty in finding and identifying the
squamous component may be related to the extensive surface ulceration that is frequently encountered. The polypoid
tumors are often extensively ulcerated, with surface fibrin deposition. The base of the polypoid tumor has been suggested as
173,174a productive location in which to search for and locate the conventional carcinomatous tissue. I n general, these are
hypercellular tumors composed of pleomorphic-appearing spindle and epithelioid cells with large, hyperchromatic nuclei,
increased nucleus to cytoplasm ratio, indistinct to prominent eosinophilic nucleoli, inconspicuous to ample eosinophilic to
amphophilic cytoplasm, increased mitotic activity (typical and atypical), and necrosis. The growth pa ern of S CS C may be
fascicular, storiform, or palisading, with or without an associated myxomatous stroma. I f the superficial epithelium is intact,
the malignant spindle cell component is not separated from the surface but can be seen intimately associated with the
surface epithelium. An intact surface epithelium may or may not be dysplastic.+
+
FIGURE 4B-15 Spindle cell squamous carcinoma. A, The combination of a differentiated squamous
epithelial component (in this figure infiltrating squamous carcinoma) and an intimately associated
malignant spindle and pleomorphic cell infiltrate is diagnostic of this neoplasm. B, Cytokeratin
immunoreactivity is present and usually is focal but may be negative.
I n some S CS Cs, the spindle cell proliferation may be sparsely cellular with marked fibrosis or collagenized stroma F(ig.
4B-16). I n these hypocellular S CS Cs, the surface epithelium may be intact without dysplasia, or a definitive S CC may not be
present. I n this situation, the diagnosis of malignancy may be extremely difficult. The hypocellular S CS C is still a polypoid
lesion, involving the superficial submucosal compartment, and the spindle or pleomorphic cell proliferation has atypical
nuclear features with increased mitotic activity that includes typical and atypical forms. The superficial localization of the
tumor and the presence of nuclear atypia assist in differentiating this tumor from mesenchymal neoplasms or reactive
proliferations, such as a predominantly myofibroblastic process. Heterologous elements, including bone and cartilage, can
be seen. These elements may show features of malignancy (heterologous chondrosarcomatous and osteosarcomatous foci).
FIGURE 4B-16 Spindle cell squamous carcinoma. This example has prominent collagenous stroma.
I mmunohistochemical evaluation may be helpful in the diagnosis of S CS C (seeF ig. 4B-15). The spindle cells are keratin
175positive in the majority of cases, but cytokeratin may be absent in up to 40% of cases. Other authors have identified a
similar staining pa ern for cytokeratin, ranging from 30% to 50% of cases of S CS C, depending on the antibody
170,176-181used. Therefore the absence of cytokeratin staining does not preclude a diagnosis of S CS C. Multiple keratins
should be used in the evaluation of S CS C including (but not necessarily limited to) cytokeratin A E1/A E3, CA M5.2,
cytokeratin 5/6, pan-keratin, and OS CA R to increase the possibility of identifying keratin-positive cells. Cytokeratin
immunoreactivity may be limited in extent. A marker of squamous cells and myoepithelial cells, p63, is a helpful adjunct
stain and should be used in conjunction with cytokeratins in the diagnosis of S CS Cs. S taining with p63 may vary from
diffuse and strong to focal sca ered moderately to strongly positive nuclei. I n the absence of epithelial differentiation by
immunohistochemical staining, a diagnosis of S CS C is suggested by the absence of immunoreactivity that may be specific
for another diagnosis, such as S -100 protein for a mucosal malignant melanoma or reactivity with mesenchymal markers
(e.g., desmin) that might be diagnostic of a sarcoma. However, potentially compounding the diagnostic problem is the
presence in some cases of immunoreactivity with markers that have traditionally been thought to be representative of
mesenchymal differentiation. Vimentin is present in virtually 100% of cases (personal experience). Vimentin and various
171,176,180-184myogenic markers (desmin, actins) have been reported in S CS C. I n a study of 26 S CS Cs of various upper
aerodigestive tract sites, 42% of the tumors were reactive with cytokeratin, 100% reactive with vimentin, and 42% reactive
179with the myogenic markers HHF-35 (pan-actin) and α-smooth muscle actin. Twenty-five percent coexpressed cytokeratin
179and actin. N akleh and colleagues thought that the presence of myogenic reactivity was indicative of myofibroblastic or
smooth muscle differentiation and not skeletal muscle differentiation. Ultrastructurally, S CS C usually shows evidence of
epithelial derivation, including desmosomes, tonofilaments, and macula adherens, and, on occasion, this may be the most
171,178,180reliable means of making the diagnosis. Other ultrastructural studies have shown that some of the spindled cells
demonstrate mesenchymal features (abundant dilated rough endoplasmic reticulum), some epithelial features (desmosomes
185and tonofilaments), and some both. These confusing findings may be explained by invoking the currently favored theory
of the histogenesis of this neoplasm: that it is an epithelial neoplasm, a variant of S CC, in which many of the constituent
neoplastic epithelial cells have undergone mesenchymal metaplasia, in some cases so complete as to result in the loss of+
+
+
+
+
169,172,173,185most, if not all, of their epithelial characteristics. The situation is analogous to that of so-called metaplastic or
matrix-producing carcinomas of the breast. The concept of the atypical spindle cells representing a reactive nonneoplastic
186 187stromal component, originally proposed by Lane and reiterated by Goellner and colleagues, is contradicted by the
174presence of metastases containing both spindled and carcinomatous components ; the finding of positive
188immunohistochemical staining for r a s oncogene p 2 1 in the spindled cells adds further evidence for the neoplastic nature
of these cells.
The three principal differential diagnoses to consider are sarcoma, bizarre postirradiation granulation tissue, and so-called
inflammatory myofibroblastic tumor. S arcomas may usually be differentiated from spindle cell carcinoma by the presence of
a recognizable carcinomatous component in the la er lesion. A n exception is the case of synovial sarcoma (see later
discussion). A much more difficult problem is encountered in the absence of a carcinomatous component on hematoxylin
and eosin microscopy. I n such a case, immunohistochemical and/or ultrastructural demonstration of epithelial
differentiation is helpful; however, rare sarcomas (e.g., synovial sarcoma) may show keratin positivity. Rare keratin-positive
189cells have been described in so-called malignant fibrous histiocytomas. S uch cases do not have carcinomatous areas on
hematoxylin and eosin microscopy, nor do they exhibit epithelial differentiation ultrastructurally, but, in the light of
potential sampling problems, some of these cases may well represent spindle cell (sarcomatoid) carcinomas. Bizarre, highly
atypical proliferative granulation tissue reactions can occur after irradiation and may closely mimic the sarcoma-like
190component of spindle cell carcinoma. S uch lesions do not possess a carcinomatous component, and the endothelial cells
190in such lesions share the atypicality of the other constituent mesenchymal cells. Rare cases of laryngeal inflammatory
88myofibroblastic tumor have been reported. These are benign myofibroblastic cell proliferations of spindled and stellate
cells, disposed in a generally loose arrangement and often associated with chronic inflammatory cells. The tumor cells are
bland to slightly atypical and do not feature severe pleomorphism, atypical mitoses, an associated component of
88conventional S CC, or keratin positivity of spindled cells. Furthermore, A LK immunostaining may be present in
inflammatory myofibroblastic tumor, a finding not identified in SCSC.
In general, SCSCs are more aggressive than conventional SCCs and are more radioresistant. Most current opinion suggests
172,173that this tumor is potentially lethal. S uperficial polypoid tumors and tumors located on the true vocal cord appear to
169,172,173,191have a better prognosis than extraglottic and deeply infiltrating lesions.
The anatomic location for S CS C affects prognosis. I n a comparison of spindle cell carcinomas of various upper
172aerodigestive tract sites, Batsakis and colleagues reported 70% mortality for sinonasal S CS C, as compared with 60% for
oral cavity S CS C, and 30% for laryngeal S CS C. I n addition, local recurrence and metastatic disease are common, the la er
192,193primarily to cervical lymph nodes and to lung. The histology of the metastatic deposits may include conventional SCC
192alone, spindle cell carcinoma alone, or both conventional and spindle cell squamous carcinoma. Histologic appearance
168,191and the proportion of conventional S CC are thought not to have a significant bearing on clinical outcome, although
194keratin immunopositivity of the spindle cell component has been reported to be adversely associated with survival.
Basaloid Squamous Cell Carcinoma
Basaloid S CC (BS CC) is a high-grade variant of S CC characterized by an invasive neoplasm composed of basaloid cells
intimately associated with either dysplastic squamous epithelium, in situ S CC, and/or invasive S CC. BS CC most often arises
195-200in the hypopharynx (piriform sinus), supraglo ic larynx, oral cavity, tongue, tonsil, and palate. Less frequently, the
201 199,202,203trachea and sinonasal tract may be involved. BS CC occurs more commonly in men than in women,
predominantly in the sixth to seventh decades of life. S ymptoms relative to laryngeal tumors include hoarseness, dysphagia,
200,204pain, or a neck mass. Etiologic factors include excessive alcohol and/or tobacco use. I n contrast to BS CC of the
oropharynx in which HPV may play an etiologic role, such an association has not been identified in BS CC of other
204a(nonoropharyngeal) sites, in which HPV16 is usually negative.
BS CCs are firm to hard, tan-white masses often with central necrosis, measuring up to 6.0 cm in greatest dimension.
I nfrequently, they may be exophytic. The histologic appearance is that of an infiltrating tumor arranged in a variety of
growth pa erns, all of which may be seen within any given tumor and include solid, lobular, cell nests, cribriform, cords,
trabeculae, and gland-like or cystic spaces. The tumor originates from the surface epithelium, which may show severe
dysplasia and/or direct continuity with the invasive carcinoma (Fig. 4B-17). Frequently, comedo necrosis is identified within
the center of the neoplastic lobules (see Fig. 4B-17). One of the distinctive cytologic features is the presence of a basaloid cell
component consisting of small, closely apposed cells with hyperchromatic nuclei, scanty cytoplasm, and marked mitotic
activity; large cells and pleomorphism may be seen (Fig. 4B-18). A nother important cytologic feature is the intimate
association with foci of squamous differentiation, whether dysplastic, in situ malignant, or invasive. I n addition, a neoplastic
spindle cell carcinomatous component may be identified in association with the basaloid squamous elements. The presence
of intercellular deposition of eosinophilic hyalin or mucohyalin material simulates the appearance of reduplicated basement
203membrane material associated with tumors of (minor) salivary gland origin. Rose e-like structures can be seen. BS CCs
are deeply invasive tumors with frequent invasion of soft tissue structures and neurotropism.FIGURE 4B-17 Basaloid squamous cell carcinoma. A, Invasive carcinoma with lobular growth pattern
and associated comedotype necrosis, foci of trabecular growth (upper right), and a focus of abrupt
keratinization (upper left). B, The carcinoma is predominantly composed of a basaloid cell proliferation
with limited but identifiable squamous differentiation.
FIGURE 4B-18 Basaloid squamous carcinoma. Nuclear pleomorphism and increased mitotic activity with
focal squamous pearls are seen.
Histochemical evaluation of BS CC does not demonstrate the presence of epithelial mucin. The basement membrane-like
material is PA S and alcian blue positive. I mmunohistochemistry shows consistent staining with cytokeratin, as well as with
199,200other epithelial markers, including epithelial membrane antigen and carcinoembryonic antigen. I mmunoreactivity
with p63 is present. The neuroendocrine markers chromogranin and synaptophysin are typically negative, although
205chromogranin has been reported in a minority of cases. Variable immunoreactivity is seen with vimentin, S -100 protein,
and actin. Electron microscopy shows the basaloid component to have desmosomes, rare tonofilaments, and loose stellate
195granules or replicated basal lamina within the cystic spaces.
206The differential diagnosis of BS CC is detailed inT able 4B-8. Hewan-Lowe and D ardick identified ultrastructural
features that assist in differentiating BS CC from adenoid cystic carcinoma. These authors compared the ultrastructural
features of three BS CC and three adenoid cystic carcinomas and found that the BS CC had features of S CC, including cell
groups with numerous and prominent tonofilament bundles, prominent desmosomes, and epithelial pearls. These features
206were not present in the adenoid cystic carcinomas. Features of glandular differentiation were exclusively identified in the
adenoid cystic carcinomas but not in the BS CC, including oligocilia and lumina (large lumina and smaller compressing
ones).
TABLE 4B-8
Basaloid Squamous Cell Carcinoma: Differential Diagnosis
BSCC AdCC SCUNC
Age, sex Sixth-seventh Fifth-seventh decades, no sex Sixth-seventh decades, M > F
decades, M > F predilection except for
submandibular tumors, which
are more common in women
Location Predilects to Major salivary glands and minor Uncommon in H&N: Larynx
hypopharynx (intraoral) salivary glands; may (supraglottis) is the most common
(piriform sinus), occur in other mucosal sites site; other H&N sites rare
larynx including sinonasal tract; rare
(supraglottis), in the larynx and hypopharynx
and oropharynx
(palatine tonsil)Histology: 1. Invasive with 1. Invasive with cribriform 1. Submucosal invasive tumor withBSCC AdCC SCUNC
1. Growth lobules with representing the most solid nests, sheets, or ribbons
2. Cytomorphology comedotype frequent pattern having a and absence of a fibrovascular
necrosis, solid, “Swiss cheese” appearance stroma
cribriform, of pseudocysts and true 2. Hypercellular tumor with
cords, glands; may show tubular hyperchromatic, pleomorphic,
trabeculae, and and solid patterns oval to spindle-shaped nuclei,
gland-like 2. Composed of abluminal increased nucleus to cytoplasm
2. Predominantly (myoepithelial) and luminal ratio, nondescript cytoplasm,
composed of (duct) cells: predominantly and indistinct cell borders;
pleomorphic, composed of isomorphic nuclear chromatin described as
hyperchromatic basaloid (abluminal) cells “salt and pepper” in appearance
basaloid cells with uniform angular to with absence of nucleoli; “crush”
with numerous oval, hyperchromatic nuclei, artifact is frequently present;
mitoses; absent to small nucleoli, confluent foci of necrosis and
squamous cell eosinophilic to clear- individual cell necrosis seen;
component appearing cytoplasm lacking abundant mitoses, including
(dysplasia, CIS, nuclear pleomorphism and atypical forms; nuclear molding
invasive SCC) mitotic activity; epithelial may be identified; neural-type
is the minor (duct) cells line true rosettes rarely may be present
component glandular spaces
characterized by the cells
with round nuclei and
eosinophilic-appearing
cytoplasm
Surface involvement Present in the form Absent Absent but may be ulcerated
of dysplasia or
CIS
Squamous Present but is the Absent Present but when found is limited in
differentiation minor component extent
and may be
found only focally
Neurotropism Yes Yes Yes
IHC Positive for Abluminal cells: positive for Positive for cytokeratin,
cytokeratins, cytokeratins, p63, S-100 chromogranin, synaptophysin,
EMA, and CEA; protein, calponin, SMA, NSE, Leu 7, NFP, EMA, CEA,
TTFneuroendocrine vimentin 1; calcitonin rarely is positive; may
markers Duct cells: positive for be p16 positive
(chromogranin cytokeratins, EMA, CEA;
and All cell types negative for
synaptophysin) neuroendocrine markers
are usually (chromogranin and
negative but synaptophysin)
occasionally may
be positive;
variable
expression can be
seen with
vimentin, NSE,
S100 protein, and
actin; may be p16
positive
HPV association In some cases* No In some cases†
Treatment Surgery, Surgery and radiotherapy Systemic chemotherapy and
radiotherapy, therapeutic irradiation
chemotherapy
Spread Metastasis frequent Metastasis (local or distant) Metastasis frequent (even at
often at uncommon: distant metastasis presentation) to regional lymph
presentation to occurs late in disease course to nodes and to liver, lung, bone, and
cervical lymph lungs, bone, brain, and liver brain
nodes and lung
Prognosis Dependent on Short-term prognosis is good, Poor:
clinical stage but but long-term prognosis is 16% 2-yr survival
overall poor; survival rates are as 5% 5-yr survival
considered to be follows:
poor 5 year, 71%-89%10 year, 29%-71%BSCC AdCC SCUNC
15 year, 29%-55%
*HPV-positive BSCC are more likely to occur in nonsmokers and alcohol abstainers, are less likely to have p53 mutations, and
are reported to show improved overall survival due to increased radiosensitivity.
†HPV-positivity in SCUNC does not alter poor prognosis.
AdCC, Adenoid cystic carcinoma; BSCC, Basaloid squamous cell carcinoma; CEA, carcinoembryonic antigen; CIS, carcinoma in
situ; EMA, epithelial membrane antigen; H&N, head and neck; HPV, human papillomavirus; IHC, immunohistochemistry; NFP,
neurofilament protein; NSE, neuro