Diagnostic Surgical Pathology of the Head and Neck E-Book
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This resource is the authoritative guide to problematic areas of the head and neck for the surgical pathologist. With particular emphasis placed on diagnostic problems and differential diagnosis in addition to coverage of more common diagnostically straightforward lesions, you’ll get the most complete diagnostic picture possible. The updated second edition features new coverage and a more user-friendly layout.
  • Features the most comprehensive collection of head and neck pathology specimens in one reference for comparison with your findings.
  • Covers rare as well as common diagnoses to help you identify even the most obscure disease entities.
  • Provides clinicopathologic correlations throughout to give you all the information you need to formulate a complete diagnostic report.
  • Emphasizes differential diagnosis and avoiding diagnostic pitfalls so you can overcome difficult diagnostic challenges.
  • Covers FNA cytology, molecular genetic techniques, and immunohistochemistry to present the most compete diagnostic picture possible.
  • Presents a brand-new chapter on specimen handling to ensure effective processing and reporting of head and neck specimens.
  • Features more than 1700 full-color illustrations that capture the pathologic and cytopathologic appearances of the full range of common and rare neoplastic and non-neoplastic lesions.



Publié par
Date de parution 07 avril 2009
Nombre de lectures 0
EAN13 9781437719512
Langue English
Poids de l'ouvrage 27 Mo

Informations légales : prix de location à la page 0,1150€. Cette information est donnée uniquement à titre indicatif conformément à la législation en vigueur.


Diagnostic Surgical Pathology of the Head and Neck
Second Edition

Douglas R. Gnepp, MD
Professor of Pathology, The Warren Alpert Medical School of Brown University
Senior Surgical Pathologist, Rhode Island Hospital, Providence, Rhode Island

Elsevier Inc., 2009
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
ISBN-13: 978-1-4160-2589-4
Copyright © 2009, 2001 by Saunders, an imprint of Elsevier Inc.
All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher.
Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone: (+1) 215 239 3804, fax: (+1) 215 239 3805, e-mail: healthpermissions@elsevier.com . You may also complete your request online via the Elsevier homepage ( http://www.elsevier.com ), by selecting “Customer Support” and then “Obtaining Permissions.”

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on his or her own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editor assumes any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book.
Library of Congress Cataloging-in-Publication Data
Diagnostic surgical pathology of the head and neck / [edited by] Douglas
R. Gnepp.—2nd ed.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-4160-2589-4 (alk. paper)
1. Head—Diseases—Diagnosis. 2. Neck—Diseases—Diagnosis.
3. Pathology, Surgical. I. Gnepp, Douglas R.
[DNLM: 1. Head and Neck Neoplasms. 2. Diagnostic Techniques, Surgical. 3. Head—pathology. 4. Head—surgery. 5. Neck—pathology.
6. Neck—surgery. WE 707 D536 2009]
RC936.D53 2009
ISBN: 978-1-4160-2589-4
Publishing Director: Linda Belfus
Acquisitions Editor: William Schmidt
Developmental Editor: Katie DeFrancesco
Design Direction: Louis Forgione
Printed in China.
Last digit is the print number: 9 8 7 6 5 4 3 2
To Diane, Ari, Stella, Ethan, and Gracie

Carl M. Allen, DDS, MSD, Professor and Director, Section of Oral and Maxillofacial Surgery and Pathology, College of Dentistry, The Ohio State University, Columbus, Ohio
10. Odontogenic Cysts and Tumors

Jerry E. Bouquot, DDS, MSD, Professor and Chair, Department of Diagnostic Sciences, University of Texas at Houston Dental Branch, Houston, Texas
4. Lesions of the Oral Cavity

Margaret S. Brandwein-Gensler, MD, Professor of Pathology and Otorhinolaryngology, Montefiore Medical Center–Moses Division, Albert Einstein College of Medicine, Bronx, New York
5. Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

John D. Crissman, MD, Former Professor and Chair, Department of Pathology, Former Dean, Wayne State University School of Medicine, Detroit, Michigan
1. Squamous Intraepithelial Neoplasia of the Upper Aerodigestive Tract

Douglas D. Damm, DDS, Professor, Division of Oral and Maxillofacial Pathology, University of Kentucky College of Dentistry, Lexington, Kentucky
10. Odontogenic Cysts and Tumors

Gustave L. Davis, MD, Clinical Professor of Pathology, Department of Pathology, Professor, Program in Applied Mathematics, Graduate School of Arts and Sciences, Yale University, New Haven, Connecticut
12. Ear: External, Middle, and Temporal Bone

Ronald A. DeLellis, MD, Pathologist-in-Chief, Lifespan AMC Pathology Laboratories, Rhode Island Hospital and The Miriam Hospital, Professor and Associate Chair of Pathology and Laboratory Medicine, The Warren Alpert Medical School of Brown University, Providence, Rhode Island
7. Thyroid and Parathyroid Glands

Samir K. El-Mofty, DMD, PhD, Professor, Department of Pathology and Immunology, Associate Professor, Department of Otolaryngology Head and Neck Surgery, Washington University School of Medicine, Attending Medical Staff, Barnes Jewish Hospital, St. Louis, Missouri
9. Bone Lesions

John Eveson, PhD, FDSRCPS, MRCPath, FRCPath, FDSRCS, FDSRCSE, Professor of Head and Neck Pathology, University of Bristol, Honorary Consultant in Oral Medicine and Pathology, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom
6. Salivary and Lacrimal Glands

Andrew L. Folpe, MD, Professor of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
8. Soft-Tissue Tumors of the Head and Neck

Nina Gale, MD, Professor of Pathology, Institute of Pathology Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
1. Squamous Intraepithelial Neoplasia of the Upper Aerodigestive Tract

Douglas R. Gnepp, MD, Professor of Pathology, The Warren Alpert Medical School of Brown University, Senior Surgical Pathologist, Rhode Island Hospital, Providence, Rhode Island
1. Squamous Intraepithelial Neoplasia of the Upper Aerodigestive Tract
5. Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea
6. Salivary and Lacrimal Glands
Appendix I . Head and Neck Tumors: TNM Staging
Appendix II . Guidelines for the Dissection of Head and Neck Specimens

Gerardo E. Guiter, MD, Assistant Professor of Pathology and Laboratory Medicine, Weill Cornell Medical College–Qatar, Doha, Qatar
15. Fine-Needle Aspiration Biopsy

John D. Henley, MD, Anatomic Pathologist, University of Cincinnati Medical Center, Cincinnati, Ohio
6. Salivary and Lacrimal Glands

Lester J. Layfield, MD, Professor and Head, Department of Anatomic Pathology, University of Utah School of Medicine, Huntsman Cancer Hospital, Salt Lake City, Utah
15. Fine-Needle Aspiration Biopsy

Pei Lin, MD, Associate Professor, Department of Hematopathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas
13. Hematopoietic Lesions

Mario A. Luna, MD * , Formerly Professor of Pathology, Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas
11. Cysts of the Neck, Unknown Primary Tumor, and Neck Dissection

Panna Mahadevia, MD, Associate Professor of Pathology, Montefiore Medical Center–Moses Division, Albert Einstein College of Medicine, Bronx, New York
5. Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

L. Jeffrey Medeiros, MD, Professor and Chair, Department of Hematopathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas
13. Hematopoietic Lesions

Susan Muller, DMD, Associate Professor, Department of Pathology and Laboratory Medicine, Department of Otolaryngology–Head and Neck Surgery, Emory University School of Medicine, Atlanta, Georgia
4. Lesions of the Oral Cavity

Brad W. Neville, DDS, Professor and Director, Division of Oral and Maxillofacial Pathology, Department of Stomatology, Medical University of South Carolina, College of Dental Medicine, Charleston, South Carolina
10. Odontogenic Cysts and Tumors

Hiromasa Nikai, DDS, PhD, Former Chair, Department of Oral Pathology, Hiroshima University School of Dentistry, Professor Emeritus, Hiroshima University, Hiroshima, Japan
4. Lesions of the Oral Cavit y

Yuri E. Nikiforov, MD, PhD, Professor, Department of Pathology, Director, Division of Molecular Anatomic Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
7. Thyroid and Parathyroid Glands

Bayardo Perez-Ordonez, MD, FRCPC, Associate Professor, Department of Pathology, University Health Network, Clinical Studies Resource Centre Member, Ontario Cancer Institute, Toronto, Ontario, Canada
3. Nonsquamous Lesions of the Nasal Cavity, Paranasal Sinuses, and Nasopharynx

Madeleine Pfaltz, MD, Pathologist, Kempf und Pfaltz, Histologissche Diagnostik, Zurich, Switzerland
11. Cysts of the Neck, Unknown Primary Tumor, and Neck Dissection

Latha Pisharodi, MD, Associate Professor, Department of Pathology, The Warren Alpert Medical School of Brown University, Director of Cytopathology, Rhode Island Hospital, Providence, Rhode Island
15. Fine-Needle Aspiration Biopsy

Manju L. Prasad, MD, Associate Professor, Department of Pathology, University of Massachusetts Memorial Medical Center and Medical School, Worcester, Massachusetts
3. Nonsquamous Lesions of the Nasal Cavity, Paranasal Sinuses, and Nasopharynx

Mary Richardson, DDS, MD, Professor, Department of Pathology and Laboratory Medicine, Vice Chair of Clinical Affairs, Director of Surgical Pathology, Division of Anatomic Pathology, Medical University of South Carolina, Charleston, South Carolina
2. Squamous Cell Carcinoma of the Upper Aerodigestive System

Wael A. Sakr, MD, Professor and Chair, Department of Pathology, Wayne State University School of Medicine, Department of Pathology, Harper Hospital, Detroit, Michigan
1. Squamous Intraepithelial Neoplasia of the Upper Aerodigestive Tract

Roderick H.W. Simpson, MB, MMed, FRCPath, Consultant Histopathologist, Department of Histopathology, Royal Devon and Exeter Hospital Foundation Trust, Exeter, United Kingdom
6. Salivary and Lacrimal Glands

Pieter J. Slootweg, MD, DMD, PhD, Professor, Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
2. Squamous Cell Carcinoma of the Upper Aerodigestive System
Appendix II . Guidelines for the Dissection of Head and Neck Specimens

Mark R. Wick, MD, Professor, Department of Pathology, University of Virginia School of Medicine, Pathologist, University of Virginia Medical Center, Charlottesville, Virginia
14. Cutaneous Tumors and Pseudotumors of the Head and Neck

* Deceased.
From an anatomic and pathologic perspective the region of the head and neck is one of the most complex areas of the body, with a variety of different organ systems and tissue types within its domain. The second edition of Diagnostic Surgical Pathology of the Head and Neck includes the numerous advances in head and neck pathology, particularly in the molecular characterization of many of the lesions arising in this region. The general organization of the text has remained unchanged. However, to minimize redundancy throughout the various chapters, I have integrated the precancerous lesions from all mucosal sites and the mucosal squamous carcinomas in separate chapters, and the nonsquamous cancers and other lesions on a regional basis into individual chapters. In addition, there are separate chapters covering bone and skin lesions that have a predilection for the head and neck, as well as a greatly expanded soft-tissue chapter. Instead of dedicating a chapter to molecular pathology, I have elected to incorporate the relevant molecular information within each chapter under the appropriate topics. Also, I have added a separate chapter on cytology and have integrated color pictures throughout this text; all photomicrographs are of hematoxylin-eosin stained glass slides except where otherwise indicated. The appendix on staging has been updated and a new appendix illustrating grossing techniques has been added. In addition, a list of abbreviations used in this text has been included to aid the reader.Lastly, in the salivary gland chapter, I have included lacrimal gland and sac lesions to better round out the text to make it more useful for the reader.
The purpose of this edition is the same as the previous publication: to provide a comprehensive textbook that covers the full range of surgical pathology, again emphasizing differential diagnosis and more problematic areas. My hope is that this text will help the surgical or oral pathologist when dealing with a difficult case, as well as providing an in-depth reference for the surgical or oral pathologist, head and neck or oral surgeon, general otolaryngologist or dentist, or anyone interested in reviewing head and neck pathology.

I would like to thank all the authors for their excellent contributions. It is with great sadness, however, that I would like to acknowledge the recent passing of one of the champions of our specialty and the coauthor of one of the chapters, Dr. Mario Luna. His memory will live on through his many outstanding scholarly publications and through his generosity, warmth, and kindness. I especially would like to express appreciation to my family for their understanding and patience: to my wife, Diane, and all my children, Ethan, Ari, and Stella who supported me throughout this project, I thank you.
Abbreviations Used in Text

ABC aneurysmal bone cyst
AC anaplastic carcinoma
ACC acinic cell carcinoma
AdCC adenoid cystic carcinoma
ADSC adenosquamous carcinoma
AFH angiomatoid fibrous histiocytoma
AFIP Armed Forces Institute of Pathology
AFX atypical fibroxanthoma
AgNOR argyrophilic nucleolar organizer regions
AIDS acquired immunodeficiency syndrome
AK alveolar keratosis
ALCL anaplastic large cell lymphoma
ALHE angiolymphoid hyperplasia with eosinophilia
ALT atypical lipomatous tumor
ANCAs antineutrophilic cytoplasmic antibodies
AOLP adult-onset laryngeal papillomatosis
APMET aggressive papillary middle ear tumor
ARM adult rhabdomyoma
ARMS alveolar rhabdomyosarcoma
ARPC AIDS-related parotid cyst
ASC adenoid squamous carcinoma
ASCC adenoid squamous cell carcinoma
ASPS alveolar soft-part sarcoma
BCA basal cell adenoma
BCAC basal cell adenocarcinoma
BFH benign fibrous histiocytoma
BLEL benign lymphoepithelial lesion
BMT benign mixed tumor
BSC basaloid squamous carcinoma
BSCC basaloid squamous cell carcinoma
Ca-ex-PA carcinoma ex pleomorphic adenoma
CAT cribriform adenocarcinoma of the tongue
cBFH cellular variant of benign fibrous histiocytoma
CCC clear cell carcinoma
CEA carcinoembryonic antigen
CIS carcinoma in situ
CK cytokeratin
CMV cytomegalovirus
COF cemento-ossifying fibroma
CT computed tomography
DEC ductal eccrine carcinoma
DFS desmoid-type fibromatosis
DFSP dermatofibrosarcoma protuberans
DL dedifferentiated liposarcoma
DLBCL diffuse large B-cell lymphoma
DSCC desmoplastic squamous cell carcinoma
DTE desmoplastic trichoepithelioma
EAF eosinophilic angiocentric fibrosis
EBV Epstein-Barr virus
ECS ectopic hamartomatous thymoma
ECT ectomesenchymal chondromyxoid tumor of the anterior tongue
EFT Ewing family of tumors
EGFR epidermal growth factor receptor
EH epithelioid hemangioendothelioma
EHT ectopic hamartomatous thymoma
ELS endolymphatic sac
EMA epithelial membrane antigen
EMC epithelial-myoepithelial carcinoma
EMP extramedullary plasmacytoma
ERMS embryonal rhabdomyosarcoma
ESMC extraskeletal myxoid chondrosarcoma
ES/PNET Ewing’s sarcoma/primitive neuroectodermal tumor
FCOD florid cemento-osseous dysplasia
FD fibrous dysplasia
FNA fine-needle aspiration
FRM fetal rhabdomyoma
FVPTC follicular variant of papillary thyroid carcinoma
GCF giant cell fibroblastoma
GCT giant cell tumor
GERD gastrointestinal reflux disease
GFAP glial fibrillary acidic protein
GMS Gomori methenamine silver
HCCC hyalinizing clear cell carcinoma
H&E hematoxylin and eosin
HHV human herpesvirus
HIV human immunodeficiency virus
HNSCC head and neck squamous cell carcinoma
HPC hemangiopericytoma
HPV human papillomavirus
HSV herpes simplex virus
HT Hashimoto’s thyroiditis
HTA hyalinizing trabecular adenoma
Ig immunoglobulin
IHC immunohistochemistry
IM infectious mononucleosis
IMFT inflammatory myofibroblastic tumor
ITAC intestinal-type adenocarcinoma
IVL intravascular lymphomatosis
JOLP juvenile-onset laryngeal papillomatosis
kD kilodalton
KFD Kikuchi-Fujimoto disease
KHE kaposiform hemiangioendothelioma
KS Kaposi’s sarcoma
LCC large cell carcinoma
LCG Langerhans cell granulomatosis
LCH Langerhans cell histiocytosis
LCS laryngeal chondrosarcoma
LE lupus erythematosus
LEC lymphoepithelial carcinoma
LESA lymphoepithelial sialadenitis
LGSDC low-grade salivary duct carcinoma
LMS leiomyosarcoma
LOH loss of heterozygosity
LOS laryngeal osteosarcoma
MAC microcystic adnexal carcinoma
MGCT malignant cutaneous granular cell tumor
MALT mucosa-associated lymphoid tissue
MC mesenchymal chondrosarcoma
MCs medullary carcinoma
MDNEC moderately differentiated neuroendocrine carcinoma
MEC mucoepidermoid carcinoma
MEN multiple endocrine neoplasia
MESA myoepithelial sialadenitis
MF mycosis fungoides
MFH malignant fibrous histiocytoma
MGC multinucleated giant cell
MM malignant melanoma
MPNST malignant peripheral nerve sheath tumor
MS myeloid sarcoma
MSI microsatellite instability
MSS monophasic synovial sarcoma
MTB Mycobacterium tuberculosis
Nd:YAG neodymium-yttrium-aluminum garnet
NEC neuroendocrine carcinoma
NF neurofibromatosis
NF-1 neurofibromatosis type 1
NHL non-Hodgkin’s lymphoma
NICO neuralgia-inducing cavitational osteonecrosis
NK natural killer
NOS not otherwise specified
NPC nasopharyngeal carcinoma
NPDC nasopalatine duct cyst
NSM necrotizing sialometaplasia
OFMT ossifying fibromyxoid tumor of soft parts
ONB olfactory neuroblastoma
PA pleomorphic adenoma
PAS periodic acid–Schiff
PBL plasmablastic lymphoma
PDNEC poorly differentiated neuroendocrine carcinoma
PDSS poorly differentiated synovial sarcoma
PEA papillary endovascular angioendothelioma
PEH papillary endothelial hyperplasia
PEN palisaded encapsulated neuroma
PFH plexiform fibrous histiocytoma
PL pleomorphic lipoma
PLGA polymorphous low-grade adenocarcinoma
PMTMCT phosphaturic mesenchymal tumor, mixed connective tissue type
PNCS primary neuroendocrine carcinoma of the skin
POF peripheral ossifying fibroma
PPAR peroxisome proliferator–activated receptor
PPT proliferating pilar tumor
PRM pleomorphic rhabdomyosarcoma
PsJOF psammomatoid juvenile ossifying fibroma
PSCC papillary squamous cell carcinoma
PT parathyroid
PTC papillary thyroid carcinoma
PTN parathyroid hormone
PVL proliferative verrucous leukoplakia
RA rheumatoid arthritis
RMS rhabdomyosarcoma
RPC relapsing polychondritis
SANS subacute necrotizing sialadenitis
SC sebaceous carcinoma
SCC squamous cell carcinoma
SCCIS squamous cell carcinoma in situ
SCEC small cell (neuro)endocrine carcinoma
SCL spindle cell lipoma
SDC salivary duct carcinoma
SEC superficial extending carcinoma
SFT solitary fibrous tumor
SHML sinus histiocytosis with massive lymphadenopathy
SIN squamous intraepithelial neoplasia
SL sebaceous lymphadenoma
SLN sentinel lymph node
SmCC small cell carcinoma
SND selective neck dissection
SNEC small cell neuroendocrine carcinoma
SNUC sinonasal undifferentiated carcinoma
SpCC spindle cell carcinoma
SS Sjögren’s syndrome
T 3 triiodothyronine
T 4 thyroxine
TCO tracheopathia chondro-osteoplastica
TCVPTC tall cell variant of papillary thyroid carcinoma
TDC thyroglossal duct cyst
TFL tumefactive fibroinflammatory lesion
TIA-1 T-cell intracellular antigen-1
TL tuberculoid leprosy
TrJOF trabecular juvenile ossifying fibroma
TSG tumor suppressor gene
TSH thyroid-stimulating hormone
TTF thyroid transcription factor
TUGSE traumatic ulcerative granuloma with stromal eosinophilia
UADT upper aerodigestive tract
VC verrucous carcinoma
vHL von Hippel-Lindau disease
WDL well-differentiated liposarcoma
WDNEC well-differentiated neuroendocrine carcinoma
WG Wegener’s granulomatosis
WHO World Health Organization
Table of Contents
Abbreviations Used in Text
Chapter 1: Squamous Intraepithelial Neoplasia of the Upper Aerodigestive Tract
Chapter 2: Squamous Cell Carcinoma of the Upper Aerodigestive System
Chapter 3: Nonsquamous Lesions of the Nasal Cavity, Paranasal Sinuses, and Nasopharynx
Chapter 4: Lesions of the Oral Cavity
Chapter 5: Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea
Chapter 6: Salivary and Lacrimal Glands
Chapter 7: Thyroid and Parathyroid Glands
Chapter 8: Soft-Tissue Tumors of the Head and Neck
Chapter 9: Bone Lesions
Chapter 10: Odontogenic Cysts and Tumors
Chapter 11: Cysts of the Neck, Unknown Primary Tumor, and Neck Dissection
Chapter 12: Ear: External, Middle, and Temporal Bone
Chapter 13: Hematopoietic Lesions
Chapter 14: Cutaneous Tumors and Pseudotumors of the Head and Neck
Chapter 15: Fine-Needle Aspiration Biopsy
Head and Neck Tumors: TNM Staging
Guidelines for the Dissection of Head and Neck Specimens
Chapter 1 Squamous Intraepithelial Neoplasia of the Upper Aerodigestive Tract

Wael A. Sakr

Nina Gale *
* Dr. Nina Gale only collaborated on the molecular sections of the chapter

Douglas R. Gnepp, John D. Crissman
The consistency and reproducibility of pathologic diagnosis of preinvasive neoplastic changes of the upper aerodigestive tract (UADT) continue to represent a challenging area for both surgical pathologists and their clinical colleagues responsible for managing these early lesions. There are several reasons for the difficulty:
• Although the criteria applied by pathologists to determine both the presence and the extent of dysplasia/ intraepithelial neoplasia are becoming more publicized through reports of task forces, publications, and websites, these criteria continue to have rather poor reproducibility among pathologists including those with expertise in this field.
• There is a need to increase awareness and familiarity with the significance of site-specific microscopic alterations concerning squamous mucosal changes as they affect areas such as the vocal cords and nasopharyngeal mucosa. The historical frame of criteria developed for uterine cervix is often inapplicable.
• The natural history of mucosal alterations in the oral cavity, nasopharynx, and larynx is directly related to their microscopic characteristics, namely, the presence and grade of dysplasia/intraepithelial neoplasia. Accordingly, it is critical that a reproducible classification system be applied to characterize these lesions and communicate the information to the clinical partner(s) in a consistent fashion.
This chapter discusses the early neoplastic changes within the UADT according to the traditional and somewhat arbitrary compartmentalization of this area into the oral cavity, the sinonasal tract, the oropharynx and nasopharynx, and the larynx. It is well recognized, however, that these sites form a functional and anatomic unit and, more importantly, share exposure to the same etiopathogenetic factors implicated in carcinogenesis and show the same spectrum of preinvasive changes associated with the development of squamous cell carcinoma, the most common malignancy of these anatomic sites. This review aims to offer a balanced representation of the current understanding of the pathology/pathobiology of preinvasive neoplasia of the UADT region with emphasis on accounting for the attempts to standardize the terms, definitions, and classifications of the pathologic and molecular changes associated with early neoplastic transformation. The chapter concludes with a summary of the mounting molecular genetic studies designed to correlate the expression of selected markers with the morphologic spectrum of neoplastic transformation.

The past decade has witnessed a remarkable growth in the body of literature addressing all aspects of intraepithelial and precursor lesions of the more common epithelial malignancies including those affecting the various locations of the anatomically complex UADT region. Similar to studies concerning other organ systems, the spectrum of interest reflected in published investigations of UADT precursors encompasses aspects of epidemiology and risk factors, clinical and pathologic classification, molecular genetic characteristics, and natural history and evolution of such lesions. 1 - 3
Squamous cell carcinoma (SCC) of the upper aerodigestive tract represents a major cancer burden, particularly in regions of the world where cigarette smoking and other forms of tobacco consumption continue to be prevalent. 4 The outlook for the incidence, morbidity, and mortality of UADT, lung, and other tobacco-associated malignancies is tightly linked to the trends of marketing and consumption of tobacco, mostly in the form of cigarette smoking. Future predictions for such diseases are also strongly linked to the trends of smoking assumed by teenagers and young adults in terms of the age at which they adopt the habit and the duration and severity of their consumption. Alcohol consumption is another recognized risk factor for the development of invasive SCC of the UADT with evidence to document a synergistic effect when the two risk factors are combined. 5 Increasing rates of smoking and drinking among women appears to gradually decrease the predominant male-to-female ratio traditionally associated with the demographics of this disease. 6 On the other hand, recent studies in certain populations with follow-up data indicate that lower consumption of tobacco and alcohol translates to lower rates of both the incidence and the mortality related to head and neck cancer. 7
Based on the premise of progression, proposing that intraepithelial neoplastic changes of the UADT epithelium are the likely precursors for invasive cancer, it is logical to attribute the risk of invasive disease and the development of preinvasive neoplastic changes to the same etiologic factors. 8
The traditional presentation of most patients with squamous neoplasia of the head and neck has been typically during the invasive phase of the disease, often with advanced tumors and with many patients with regional (and/or systemic) metastases at the time of diagnosis. 9 - 12 Accordingly, there are limited series of patients in which the histologic changes preceding squamous carcinoma have been sampled in a systematic approach and with documented follow-up. 13 - 15 This bleak picture is changing slowly in selected regions where educational and outreach efforts are enhanced. 14, 16
For decades, the main studies documenting the progression of squamous precursors to invasive cancer were observations established in the laryngeal glottis. 17, 18 Similar observations in the oral cavity were contributed primarily by the oral pathology literature. 19 - 21 Of concern is the notion that these two bodies of investigative literature have often used different terminology and histologic definitions for preinvasive/dysplastic lesions in these two anatomic locations of the UADT. In recent years, several reports reflecting the attempts of task forces and working groups to standardize the terminology based on reproducible criteria have been published. 22 - 26
There are clinical, experimental, and morphologic lines of evidence supporting the concept that SCC of the UADT arises from noninvasive lesions of the squamous mucosa. 27 - 29 These lesions encompass a histologic continuum between the normal mucosa at one end and high-grade dysplasia/carcinoma in situ (CIS) at the other, establishing a model of neoplastic progression. While these precursors are becoming better characterized, they continue to have the rather inconsistent criteria applied for both establishing pathologic diagnosis and, perhaps more challenging, assigning a grade for the intraepithelial neoplastic changes. 25, 30, 31 This continuum of preinvasive neoplasia is encountered in many other epithelia, including those of the lower respiratory tract and the cervix uteri. Increasing genetic abnormalities typically accompany worsening histologic grades in the UADT and other examples of preinvasive neoplastic progression. These observations support a model that envisions cancer progression as the phenotypic result of accumulation of genetic abnormalities.
From a historical perspective, the criteria used to establish the diagnosis of squamous intraepithelial neoplasia (SIN) in the UADT have been marred by extrapolation of histologic definitions based on the longer experience with intraepithelial neoplasia of the uterine cervix. 32 Although both anatomic sites are primarily lined by squamous mucosa, the most common site of cancer development in the cervix originates usually from metaplastic squamous mucosa. Typically, dysplasia/SIN arising in metaplastic squamous epithelium does not have the propensity to contain or form cytoplasmic or surface keratin, which is the norm for dysplasia/SIN arising in normally keratinized mucosa. Dysplasia/SIN arising in the head and neck mucosa, on the other hand, often encompass a component of epithelial hyperplasia, usually with prominent keratinization, a phenomenon that is uncommon in the uterine cervix.
Numerous classification systems have been proposed to characterize these early histologic changes in the UADT 33 - 36 ; more than 20 classifications can be found for such lesions in the larynx. 37 - 43 This complicates both the comparison of the gross and microscopic definitions in published series and the delineation of conclusions relating the morphologic terms to clinical behavior. The more recent Ljubljana and World Health Organization (WHO) classifications have been gaining more recognition, although the application of criteria by pathologists and the communication of the diagnostic terms to clinicians remain inconsistent. 22, 25, 30, 44
The characterization of preinvasive neoplastic lesions of the UADT, through clinical, morphologic, immunohistochemical, and, more recently, molecular means lays the premises for early detection and treatment of head and neck SCC (HNSCC). 45, 46 Furthermore, understanding and documenting the morphologic and molecular abnormalities associated with this progression are likely to offer insight into the biology of HNSCC, while identifying markers of transformation that may help develop surrogate clinical endpoints in chemoprevention clinical trials. 47, 48

Normal Anatomy

Sinonasal Tract
The anatomic variation in size, shape, and location of all paranasal sinuses is remarkable, including the possibility of one or more of these sinuses being underdeveloped or absent. The sinuses are lined with a mucous membrane that is continuous with the nasal mucosa and is histologically similar to that of the nasal cavity (pseudostratified, ciliated epithelium; Fig. 1-1 ). The epithelium and lamina propria of the sinuses are thinner than the nasal epithelium and lack a rich vascular plexus. The mucus formed in the sinuses is moved by the action of the cilia through the apertures to the nasal cavity.

Figure 1-1 Normal histology of the nasopharynx and paranasal sinuses. The lining of the paranasal sinuses, the roof of the nasopharynx, and the posterior nares is similar to that of the nasal cavity, with histologically pseudostratified ciliated epithelium lining these passages. The rest of the nasopharynx, approximately 60%, is lined by a nonkeratinized squamous epithelium with areas of transition between the two types as depicted.

Oral Cavity and Posterior Tongue
The oral cavity is lined mostly by a nonkeratinized, stratified squamous epithelium except for specialized regions where the epithelial lining becomes keratinized. The nonkeratinized mucosa includes, from the basement membrane to the surface, a stratum basale, a stratum spinosum (prickly), and a superficial layer. In the keratinized epithelium, a stratum granulosum and a keratinized (corneum) layer are present above the prickly layer. Cytologically, there is a progressive decrease in the nucleus-to-cytoplasm ratio, and a progressive increase in the accumulation of intracytoplasmic keratin filaments, marking the increased differentiation of this epithelium from the stratum basale to the stratum corneum. The stratum basale is constituted by cuboidal cells with a high nucleus- to-cytoplasm ratio, resting on the basement membrane 49 ( Fig. 1-2 A ). Molecular data show that they are the only cell type that expresses proliferation-associated antigens and the RNA component of telomerase within the normal mucosa 50 (see Fig. 1-2 B ). By replacing the committed cells that undergo terminal differentiation in the more superficial layers of the epithelium, these basal cells ensure the epithelium’s turnover and thus have the role of stem cells. 51 In keratinized epithelium, the superficial layer is entirely constituted by anucleated cells showing accumulation of intermediate filaments, whereas in nonkeratinized epithelium, small nuclei are still retained. Furthermore, in keratinized epithelium, an intermediate layer may be present between the keratin layer and the prickly layer, similar to the epidermis, characterized by large intracellular granules called stratum granulosum. Regional variations in the composition of the epithelium, including its degree of keratinization, reflect differences in the extent of mechanical stress during mastication, which in turn depends on the resiliency of the exposed areas. Thus, the squamous (masticatory) mucosa of the gingiva and hard palate, fastened to the underlying bone by heavy collagen bundles, not allowing it to stretch, is keratinized. The thickness of the stratum granulosum is also more pronounced in the hard palate. Areas of the oral cavity, such as the lips, soft palate, cheeks, and floor of the mouth, characterized by higher resiliency and subject to lesser mechanical stress, are lined by nonkeratinized mucosa ( Fig. 1-3 A ). Some individuals show an anatomic variant of this distribution, characterized by keratinization occurring in the malar mucosa, along a line starting from the labial commissure and running parallel to the occlusion line of the premolars and molars. This line is visible clinically as a white line and is designated linea alba.

Figure 1-2 Normal-appearing squamous mucosal lining of the upper aerodigestive tract. A , The normally nonkeratinizing epithelial lining is composed of the cuboidal cells of the stratum basale, with a relatively high nucleus-to-cytoplasm ratio, resting on the basement membrane. There is a progressive decrease in the nucleus-to-cytoplasm ratio and a progressive increase in the accumulation of intracytoplasmic keratin filaments toward the superficial layers of the lining. B , Histologically normal squamous mucosa immunostained for cellular proliferation. In the absence of reactive or neoplastic changes, markers signifying cellular proliferation are typically limited to the basal/parabasal layers of the stratum basale as evident by this immunohistochemical stain for monoclonal mouse antihuman Ki-67 antigen (MIB1).

Figure 1-3 Representative biopsy specimens from the floor of the mouth ( A ) and the dorsum of the tongue ( B ). In both samples, the architectural and cytologic features of maturation are preserved. In the normal physiologic status, the thickness of the squamous epithelial lining of the upper aerodigestive tract (reflecting the number of cell layers) shows marked variation depending on the anatomic region.
The structure of the interface with the underlying stroma also reflects the amount of mechanical stress to which the mucosa is subject. Thus, the buccal mucosa has prominent mucosal ridges, anchoring it to a heavily collagenized lamina propria. In contrast, areas protected from stress, such as the floor of the mouth, possess thinner and shallower rete ridges and a less collagenized lamina propria. 36
The histologic variations within the mucosal lining of the tongue are reflective of its function as a taste organ. In its posterior third, the lingual mucosa becomes enriched with lymphoid tissue, part of the mucosa-associated lymphoid tissue of the UADT. The degree of keratinization, thickness, presence of pigments, and degree of vascularization of the mucosa and its lamina propria all affect the color of the mucosa (see Fig. 1-3 B ). These attributes are of relevance when correlating the clinical appearance of mucosal lesions with their microscopic composition.
The oral cavity hosts minor salivary glands within its submucosa. The spectrum of intraepithelial neoplasia, including in situ carcinoma, can involve both the acini as well as the excretory ducts of minor salivary glands in a fashion that can mimic invasive carcinoma. 52

Anatomically, the pharynx is divided into three compartments: oropharynx, nasopharynx, and hypopharynx. Both the oropharynx and hypopharynx are lined by stratified, nonkeratinized squamous epithelium with the submucosal compartments containing seromucinous glands and aggregates of lymphoid tissue. The lining of the nasopharynx is approximately 60% stratified, nonkeratinized squamous epithelium with the other 40% being pseudostratified by ciliated, respiratory-type epithelium. The latter predominates in the posterior nares and in the roof of the posterior wall, whereas the remaining areas reveal an alternation of the two types of epithelia. Notably, at the transition between the two types, the mucosa assumes an intermediate or transitional appearance that may mimic intraepithelial neoplasia. 53 The low magnification appearance of the mucosa in these areas may assume a relatively disorganized architecture, referred to also as incomplete metaplasia, which may mimic true dysplasia ( Fig. 1-4 ). Microscopic evaluation on higher magnification typically reveals preserved maturation and lack of frank nuclear atypia, often coupled with the presence of a ciliated layer in the vicinity of these areas, allowing for a better appreciation of such mucosal variations ( Fig. 1-5 ). Similar features are observed at the transition between squamous and respiratory epithelia in the larynx in normal conditions 53 and during the process of squamous metaplasia in the bronchial ciliated epithelium in response to irritants. 54

Figure 1-4 Morphologic variation within the squamous mucosa lining. The intermediate or transitional areas of the mucosal lining between the pseudostratified ciliated and the nonkeratinized squamous epithelia in the pharynx may, on low magnification, give the impression of architectural disorganization (referred to also as incomplete metaplasia).

Figure 1-5 Morphologic variation within the squamous mucosa lining. The presence of a top ciliated layer within or adjacent to the transitional areas and careful evaluation including the use of higher magnification show such areas to have orderly maturation with no appreciable nuclear changes.

While the normal laryngeal mucosal lining also varies slightly in terms of thickness, similar to the case in the oral cavity, thick, keratinizing surface epithelial lining is restricted to the laryngeal glottis. It is believed that the thicker keratinized epithelium of the glottis helps to protect the mucosa from the repetitive mechanical trauma of phonation. The rest of the epithelial lining of the larynx changes according to the location and shows an alternation of ciliated, respiratory type, and squamous epithelia. The supraglottic compartment (extending from the tip of the epiglottis to the inferior border of the false vocal cord) shows respiratory type epithelium, which merges into squamous epithelium in the posterior surface of the epiglottis superiorly and, inferiorly, at the glottis (composed of the true vocal cords and the anterior commissure). Accordingly, the false vocal cords and the true vocal cords are lined by respiratory and squamous epithelia, respectively. The squamous epithelium merges into respiratory mucosa at the lower border of the true vocal cord, covering the subglottic larynx (the portion of larynx between the lower border of the true vocal cord and the first tracheal ring), and blends inferiorly into the respiratory epithelium of the trachea.
The respiratory epithelium is a ciliated, pseudostratified epithelium. Its basal layer is composed of basal cells connected to the basement membrane by hemidesmosomes, which do not reach to the lumen. They have a high nucleus-to-cytoplasm ratio and, as in squamous mucosa, represent the regenerative component of the epithelium. The differentiated cells extending toward the luminal surface are composed of ciliated, brush, and goblet cells, allowing mucociliary clearance. A minor component of the epithelium, detectable only by performing electron microscopy or special immunohistochemical stains, is constituted by small granular cells. These cells, which are morphologically similar to the basal cells by regular light microscopy, have neurosecretory granules and belong to the diffuse neuroendocrine system. 55 Similar to the pharynx, areas between the squamous and respiratory-type epithelia have a transitional appearance, characterized by progressive flattening of luminal cells, a progressively more elongated shape, and an arrangement parallel to the basement membrane. In approximately half of smokers, patches of metaplastic squamous mucosa are present in the supraglottic larynx. 56

Pathologic Features of Preneoplasia of the Upper Aerodigestive Tract
Two major mucosal alterations occur in response to carcinogenic exposures of the UADT: (1) thickened keratotic, hyperplastic mucosa with a dull or whitish gross appearance (clinical leukoplakia; Fig. 1-6 ) and (2) thin, friable atrophic mucosa with a red gross appearance (clinical erythroplakia; Fig. 1-7 ). It needs to be emphasized that the terms leukoplakia and erythroplakia are descriptive clinical terms referring to the appearance of the mucosa as a white ( leuko ) or red ( erythro ) patch, respectively. In recent years, it became recognized that variable combinations of the altered mucosa having an admixture of white and red appearance exist and have acquired the name of speckled lesion or speckled leukoplakia ( Fig. 1-8 ).

Figure 1-6 Leukoplakia. This term should not be used as a histologic or microscopic diagnosis. Clinically, it characterizes a mucosal surface with a white, keratotic appearance translating most often to a hyperplastic, histologically benign mucosa, that is, without squamous intraepithelial neoplasia.

Figure 1-7 Erythroplakia. Characteristically thinned, severely reddened, and congested mucosal surface with variably defined borders.

Figure 1-8 A and B , Speckled lesions. Variable combinations of a red mucosal surface and a white keratotic appearance, often with ill-defined borders between the two components.
In this section, we detail the clinical features of these lesions, including aspects of epidemiology, etiology, and gross appearance within the two major anatomic sites of the UADT, the oral cavity and the larynx. This is followed by a discussion of the microscopic criteria to determine the presence and the extent of histologic changes of dysplasia/SIN and finally a section summarizing the correlation between the histologic and clinical classifications (i.e., gross and microscopic features) and their risk of progression.

Clinical and Gross Mucosal Changes of Injury

The term leukoplakia, denoting white squamous mucosal patches, was coined by Schwimmer, 57 a Hungarian pathologist, in the second half of the 19th century. Currently, the WHO definition of leukoplakia is “[a] predominantly white lesion of the oral mucosa that cannot be characterized as any other definable lesion.” 58 This change represents a common type of the squamous mucosal response to some form of injury. 36 Leukoplakia is not a histologic term, and its use as a specific histopathologic entity should be strongly discouraged. The term leukoplakia has been used in older reports, including some addressing the malignant potential for progression into overt cancer, in isolation of histologic characterization of the clinically assigned diagnosis.
The clinical leukoplakia appearance results from an injury inducing epithelial hyperplasia, usually with prominent surface keratinization. 59 - 63 This appearance reflects changes in the thickness and/or composition of the epithelium (such as increased keratinization and parakeratosis) and/or in the lamina propria (such as fibrosis or increased vascularity), altering its translucence.
The thick hyperplastic lesions can develop in the course of inflammatory and, less commonly, carcinogenic injuries. 63, 64 In the latter, the resulting epithelial hyperplasia and surface keratin formation can be associated with variable degrees of cytoarchitectural alteration of dysplasia/SIN. 65 Only the extent of these, as carefully defined microscopically, can help predict the risk of progression to invasive cancer. 65 Several recent studies have emphasized that the preneoplastic nature of leukoplakia is attributed to the histologic characterization of the clinically identified white patch, namely, the identification of microscopic features of dysplasia/SIN. Some of these reports also correlated the clinical attributes with the histologic characteristics associated with the progression of these lesions to overt cancer. Leukoplakia therefore is a clinical diagnosis whose true nature can only be unveiled by microscopic examination. Particularly, the distinguishing feature of those leukoplakias that are truly preneoplastic, representing a small subset of all clinically diagnosed leukoplakias, is the presence of microscopic changes associated with dysplasia/SIN. 66

Erythroplakia is also a lesion with a distinct gross appearance; it presents as a red, hyperemia-appearing mucosal surface with variably distant borders. 66, 67 The term erythroplasia was first used by Qeyrat in 1911 to indicate a lesion of the glans penis with the appearance of an erythematous area and representing a premalignant process. 67 Erythroplakia used to be included in older reports with leukoplakia of the variegated or speckled type. The WHO, however, recognizes erythroplakia as an entity separate from leukoplakia, with distinctive clinical, pathologic features and defines it as a “fiery red patch that cannot be characterized clinically or pathologically as another definable lesion.” 58 This alteration invariably represents the result of UADT carcinogens, usually the effect of tobacco or alcohol. It is characterized by a thin or atrophic mucosa, usually with little or no histologic evidence of epithelial maturation, typically underlined by a lamina propria, which contains telangiectatic vessels often with chronic inflammation. The thin mucosa is usually composed of atypical cells without significant keratinization, resulting in weakened epithelial surface integrity, which is more susceptible to mechanical trauma.
Unlike leukoplakia, which is most often associated with formation of plaque raising the mucosal surface, erythroplakia is typically a depressed lesion below the level of the surrounding mucosa. 66 Erythroplakia is most commonly observed in thin squamous mucosa such as is found in the ventral tongue, floor of the mouth, palatine arc, and retromolar trigone. 67, 68 Erythroplakia usually represents at least high-grade dysplasia with a high progression rate to invasive cancer. The histologic changes of dysplasia/SIN in these thin mucosae are similar to those described in the classic dysplasia/CIS sequence of the uterine cervix. Not surprising is the frequent observance of concurrent invasive carcinoma in surgical specimens from mucosa with the clinical appearance of erythroplakia. 67, 68

Speckled Mucosa
After the recognition that essentially all erythroplakia and some leukoplakia represent intraepithelial neoplasia, commonly severe in the former and variable in the latter, the observation that admixtures of the two can coexist was made. 67 Terms such as erythroleukoplakia, leukoerythroplakia, erosive leukoplakia, speckled leukoplakia, and speckled erythroplakia have been used to describe the combined red and white areas of the oral mucosal changes. 69 - 72
Characterization of the significance of mucosal lesions with an admixture of red and white areas has evolved as it became evident that the erythroplakic component is the one that dictates the biological aggressiveness of these lesions because it is the component that is invariably associated with the histologic changes of severe dysplasia/CIS. Accordingly, speckled lesions have a prognosis more akin to their most ominous erythroplakic component. The observation that many of the speckled leukoplakias may have previously been classified as leukoplakias may explain why some observers in the past found such a high frequency of subsequent carcinoma in what was erroneously classified as pure leukoplakia. 73

Clinical Aspects of Preinvasive Neoplastic Lesions of the Oral Cavity
Over the past decade, there has been a dramatic increase in the development of potential oral cancer and precancer screening aids including brush biopsy cytology, light-based tissue reflectance detection systems (ViziLite Plus [Zila Pharmaceuticals Inc., Phoenix, AZ], MicroLux DL [AdDent Inc., Danbury, CT]), toluidine blue mucosal staining, and narrow-emission tissue fluorescence (VELscope [LED Dental Inc., White Rock, BC, Canada]). Each of these techniques may hold promise in selected clinical settings. Unfortunately, none, to date, have provided definitive evidence to suggest that they improve the sensitivity or specificity of oral cancer screening beyond conventional oral examination alone. The efficacy of these various techniques was recently reviewed by Lingen and colleagues. 74 Additional studies to determine the clinical utility of these techniques are necessary before they become a mainstream practice.

Oral Leukoplakia

The literature dealing with the spectrum of neoplastic changes in the mucosa of the oral cavity continues to expand. 69, 75 - 77 As previously mentioned, two major types of intraepithelial neoplastic changes are found in the oral cavity: thin erythroplakic mucosa with dysplasia/SIN and keratinizing hyperplastic (leukoplakic) mucosa, which may or may not have the histologic changes of dysplasia/SIN. Despite a resurgence of interest in the early detection and the potential for reversal of preinvasive changes by chemoprevention, there are persisting difficulties in terms of reproducibility of diagnoses, especially for hyperplastic keratinizing epithelium with minimal evidence of maturation abnormalities on histologic examination. 30, 78 These discrepancies are due to variability in the terminology and diagnostic criteria, especially in the keratinizing hyperplastic mucosal lesions. Unfortunately, few studies have addressed the prevalence of oral cavity dysplasia/SIN with documented histologic confirmation. 79 Only a fraction of the gross mucosal changes with a white leukoplakic mucosal appearance will contain histologic changes of dysplasia/SIN. 61, 79 These observations have been confirmed by several studies originating from different geographic areas where tobacco use is prevalent. 80

Prevalence and Incidence
Studies of clinical oral leukoplakia report a wide range of prevalence in the studied populations. This is related to population selection in terms of geography, age, gender, and so on, the criteria applied by examiners and their expertise, and, most importantly, the prevalence of habit-related risk factors, namely, tobacco use and alcohol consumption. Overall, the prevalence of leukoplakia varies between 0.6% and 10%, of which 0.2% to 1% was reported to harbor dysplasia/SIN on histologic examination. 80 - 82 The overlapping and variable terminology makes drawing conclusions from these studies difficult. Most studies were able to establish a higher prevalence of a variety of white oral lesions with the use of tobacco, smokeless tobacco, and alcohol. 81 This discrepancy further stresses the conceptual and biological difference existing between the term leukoplakia and the histologically defined terms of dysplasia and/or intraepithelial neoplasia. There are ongoing attempts to address the issues of variable terminology and clinical and histologic definitions of leukoplakia. 80
The peak age of incidence of oral leukoplakia is in the fifth to seventh decade. 65 Interestingly, the peak age at occurrence of dysplasia is the sixth decade, whereas the peak incidence of invasive cancer occurs a decade later. A similar time interval is present in the incidence of dysplasia versus invasive cancer in the cervix uteri 82 and the bronchus. 83 The presence of this time interval indirectly supports the precursor role of dysplasia.
Leukoplakia affects predominantly males. Percentages range from 54% ( n = 3256) 65 to 78% ( n = 710). 59

In parallel to the etiologic agents responsible for most head and neck squamous cell carcinomas (HNSCCs), smoking and alcohol abuse are the most established risk factors for clinical oral leukoplakia. 61 While this is true for populations in the Western world, additional consumption/exposures are contributing factors in other parts of the globe. In India, areca nut chewing produces a similar lesion characterized histologically by oral submucosal fibrosis, while qat chewing in Yemen appears to be the major risk factor for oral cancer and premalignant lesions. 58, 84 - 86 A number of heterogeneous clinical conditions including candidiasis, discoid lupus, lichen planus, and in situ and invasive squamous carcinoma can all appear clinically as a white patch ( Table 1-1 ). In addition, several distinct clinical conditions/infections have been shown to be associated with leukoplakia, often with an increased risk of oral cancer; some of these are briefly discussed. Risk factors associated with the progression of leukoplakia, including both clinical and pathologic ones (microscopic documentation of dysplasia/SIN), are listed in ( Table 1-2 ).
Table 1-1 Mimics of Leukoplakia Lichen planus Candidiasis Discoid lupus White sponge nevus Verruciform xanthoma Verruca Granular cell tumor Papillary hyperplasia secondary to ill-fitting dentures Morsicatio buccorum
Table 1-2 Risk Factors associated with Malignant Transformation of Leukoplakia
1 Long duration of leukoplakia
2 Gender (women are at greater risk than men)
3 Idiopathic leukoplakia (i.e., occurring in nonsmokers)
4 Presence of epithelial dysplasia
5 Location on the tongue or the floor of the mouth
6 Presence of Candida albicans
7 Nonhomogeneous leukoplakia defined as a white and red lesion (herein included in the class speckled mucosa)
The association of an increased risk of HNSCC with acquired immunodeficiency syndrome is controversial. A specific type of dysplasia, termed hairy leukoplakia, can occur in patients with human immunodeficiency virus and those with clinically established acquired immunodeficiency syndrome. 87 This dysplasia is characterized by a ballooning, ground-glass appearance of the cells in the upper half of the epithelium and intranuclear inclusions. It typically affects the lateral edges of the tongue 88 and is associated with a high incidence of human papillomavirus (HPV) and Epstein-Barr virus infection. 89 Most authors report that acquired immunodeficiency syndrome is associated with an increased incidence of malignancy, including cervical and anogenital squamous cell cancer, 90, 91 although some contest this finding. 92 The increased incidence of HNSCCs in patients with acquired immunodeficiency syndrome is uncertain. 93, 94 Of interest is the observation that the series that reported the highest incidence of transformation of leukoplakias to overt cancer (17.5%, with a follow-up of 7 years, vs. the 2.7%–6% figure in all other reports), came from the same institution reporting increased occurrence of hairy leukoplakia in patients with acquired immunodeficiency syndrome ( Table 1-3 ). 87 The presence of an association between HPV infection and SCC has been documented in small subsets of patients, who develop SCC in the absence of the usual predisposing factors of cigarette and alcohol use, in the setting of a particular type of preneoplastic lesion, namely, proliferative verrucous leukoplakia (PVL). 95

Table 1-3 Overall Progression Rate of Oral Leukoplakia to Invasive Cancer
Sideropenic dysphagia (Plummer-Vinson syndrome), a condition characterized by iron deficiency anemia with frequent associated autoimmune diseases, 96 affects the UADT with atrophy of the oral mucosa and a predisposition to the development of multiple oral carcinomas, predominantly in the posterior oropharynx. Esophageal dysphagia also typically occurs. 96
The premalignant potential of lichen planus is not accepted by all authors 97, 98 and not supported by recent molecular data that indicate that the percentage of loss of heterozygosity at several chromosomal sites in lichen planus is lower in this lesion than in simple hyperplasia. 99 In contrast, the occurrence of a distinct type of dysplasia that shares some histologic features with lichen planus, that is, hyperkeratosis, bandlike lymphocytic infiltrate, hypergranulosis, called lichenoid dysplasia and distinct from true lichen planus, is generally accepted. 88, 99, 100
Syphilis, now rarely seen in the industrialized world, may be associated with the development of leukoplakia, which may undergo malignant transformation. 58 Few cases of SCC of the lip arising in an atrophic epithelium in discoid lupus have been described. 58 Xeroderma pigmentosum, an autosomal recessive disease caused by defective DNA repair, is characterized by early-onset SCC, arising in the setting of actinic keratoses, which may involve the lips. Epidermolysis bullosa, an inherited disease affecting the skin and the oral mucosa, has been described to be associated with SCC of the tongue. 58
An increased incidence of SCC and associated premalignant lesions of the epidermis has been described in renal transplant recipients. 101

Sites of Occurrence
Thick white squamous mucosal patches are more common on the buccal gingival gutter (maxillary and mandibular sulci), followed by the palate and lips, alveolar ridge, and dorsal tongue. 65, 102 Leukoplakic changes occurring in these mucosal locations are often the result of numerous types of injuries. These changes are usually not associated with dysplasia/SIN; however, occasionally dysplasia/SIN may arise in these areas. On the other hand, leukoplakia affecting the thin mucosa of the ventral tongue, tonsil, retromolar trigone, and hypopharynx is usually the result of carcinogenic exposure and should be viewed with heightened suspicion for harboring dysplasia/SIN. 64, 65, 80, 88, 103 In men, 54% of combined cases of dysplasia and invasive cancer are in the floor of the mouth. Thus, leukoplakias at different sites have different risks of harboring significant pathologic alterations. 59 When all etiologies suspected to cause the gross appearance of leukoplakia are considered, the prevalence of those caused by carcinogens becomes exceedingly high, at approximately 25%, whereas the prevalence of leukoplakia attributed to tobacco use only is estimated to be 4.3%. 80

Clinical Subtypes
Many descriptive, clinical variants of leukoplakia have been described. These can be reduced to two main types: those with a uniformly white appearance and those with a variegated appearance, 58 designated, respectively, as homogeneous and speckled by some authors. 103 Others have subdivided the first type into leukoplakia simplex and verrucosa and designated the latter leukoplakia erosiva. 104 Several descriptive clinical variants are recognized within the homogeneous and nonhomogeneous groups. 58

Verrucous Hyperplasia
Verrucous hyperplasia, originally termed oral florid papillomatosis, 105 is a diagnosis that should be used only following microscopic evaluation. In addition to the oral cavity where it is most frequently seen, this lesion could be encountered in the sinuses, where it may be associated with schneiderian papillomas, which show evidence of keratinization, and in the larynx. 106 Verrucous hyperplasia was first described by Shear and Pindborg 105 in 1980. It is slightly more common in females and is most frequently found in the sixth to eighth decades. The gingival and alveolar mucosa are the most frequent sites of involvement, followed, in decreasing order, by buccal mucosa, tongue, floor of the mouth, lip, and palate. 106 In the initial report of Shear and Pindborg, 53% of patients had associated leukoplakia. In 29% of patients, there was associated verrucous carcinoma; in 66% of the patients, there was epithelial dysplasia; and in 10% of patients, there was a typical SCC. 105, 106 The major differential diagnosis is verrucous carcinoma as both lesions exhibit florid papillary and verrucoid growth, and some authors consider verrucous hyperplasia to represent a precursor of verrucous carcinoma. Suarez and colleagues 106 emphasized the exophytic growth pattern of verrucous hyperplasia contrasted to that of the downward, invasive growth exhibited by verrucous carcinoma. This differential clearly requires careful gross and microscopic correlation, frequently with submission of the entire lesion.

Proliferative Verrucous Leukoplakia
A particular form of oral leukoplakia, recently termed PVL, has been shown to have a higher tendency to progress to SCC. 83, 95, 106 - 108 The most common sites of occurrence for PVL are the buccal mucosa (63%), gingiva (56%), and tongue (47%) in females and the tongue (82%) and gingiva (45%) in males. The lesion is more prevalent in females (ratio of 4:1). Only 31% of patients had a history of tobacco use. 95 This aggressive form often starts as a unifocal lesion, predominantly in mandibular or alveolar locations and buccal mucosa, with gross appearance of a warty, somewhat papillary surface. The lesion tends to rapidly become multifocal with a propensity to harbor significant degrees of dysplastic epithelial alterations ( Fig. 1-9 ). Silverman and Gorsky 95 studied 54 patients with PVL, 17 of whom were included in the original report by Hansen and colleagues. 107 Seventy percent of patients developed carcinoma (mean, 7.7 years from initial diagnosis; range, 1–27 years); a second malignancy developed in another PVL site in 31.5% of the cases. In the final report by Hansen and colleagues, 107 87% of their patients developed SCC in a follow-up period that extended to 20 years in some patients. More than 40% of this cohort died of their tumors. If these data are combined with data from the Silverman and Gorsky series, the PVL-associated death rate is 50%. This entity is often diagnosed retrospectively, as the lesions are found to persist, become more numerous, and resist treatment.

Figure 1-9 Proliferative verrucous leukoplakia. Exuberant proliferation with thickening of the mucosal lining that typically harbors variable degrees of architectural and cytologic atypia. This lesion has a greater tendency to progress to squamous cell carcinoma.
Patients who are later diagnosed with PVL may present with hyperkeratosis and leukoplakic lesions described as homogeneous in nature. Over time, the lesions become exophytic and wartlike and begin to appear nodular. Erythematous regions also begin to emerge in the white plaques. Dysplasia often occurs late in the progression of this disease, placing importance on the treatment of hyperplastic lesions. With progression, additional white lesions, often bilateral, appear in PVL patients. Regional lymph node involvement and metastases may also be a late feature of PVL progression in patients developing SCC. These patients should be treated with an aggressive surgical approach; adding radiation has offered no additional survival benefit. 95 Recently, Brennan and colleagues 109 showed that leukoplakia with p53 mutations in cells near the surgical margin have a greater risk of localized recurrence than those that do not harbor mutations in this tumor suppressor gene (TSG). Possibility studying margin areas in PVL for p53 mutations may aid in treating this aggressive disease.
Hansen and colleagues 107 originally suggested 10 histologic stages in the continuum of PVL, which were reduced to four by Suarez and colleagues 106 : clinical flat leukoplakia, verrucous hyperplasia, verrucous carcinoma, and conventional SCC. PVL may have any of these stages as well as any combination of them during its clinical course.
Treatment of PVL has proven complicated, primarily owing to its propensity to recur at the treatment site and spread to additional areas in the oral cavity. Surgical excision, carbon dioxide laser treatment, cryosurgery, chemotherapy, and photodynamic therapy have all been used to treat PVL. Zakrzewska and colleagues 108 showed that the lowest recurrence rates were found with photodynamic therapy. This modality, however, is a recent addition to the battery of weapons used by the oncologist, and follow-up times for patients undergoing this treatment are shorter than those for other modalities. Thus, additional studies with a longer follow-up period will determine the true usefulness of this method of treatment. In all cases, rigorous follow-up is required for PVL patients with the continued biopsy of both old and new lesions. In many cases, several rounds of treatment may be required to contain the disease, although no treatments have proven effective curatively.

Oral Erythroplakia

Erythroplakia has often been mentioned in the context of discussing leukoplakia and/or premalignant lesions in general. 71 The tendency of oral erythroplakia to harbor/progress to oral cancer was suggested by Pindborg and colleagues 103 in a 1963 publication; this was followed by several reports by Mashberg and colleagues, 67, 110, 111 who emphasized that “persistent asymptomatic erythroplakia rather than leukoplakia in high risk sites of the oral cavity is the earliest and primary sign of oral carcinoma.” 110
It is likely that the lower prevalence of oral erythroplakia compared to oral leukoplakia has resulted in remarkably fewer publications defining the term and establishing its associated etiologic, clinical, and pathologic features. While the clinical identification of red mucosal changes in the oral cavity should raise the suspicion of advanced intraepithelial neoplasia and possibly invasive carcinoma, some non-neoplastic conditions can cause a similar appearance including infections, such as Candida albicans infections, tuberculosis, and histoplasmosis. 112

Prevalence and Incidence
Most of the studies with epidemiologic data concerning oral erythroplakia were conducted in India and Southeast Asia, indicating prevalence rates of 0.02% to 0.83%, 66, 113 with the majority occurring in older individuals (sixth and seventh decades). 68, 114 In a study investigating the incidence of in situ carcinoma, which is the microscopic manifestation of most oral erythroplakia, Bouquot and Ephros 115 reported only six newly diagnosed cases per 1,000,000 persons each year, translating to 1500 cases diagnosed annually in the United States. 66 Erythroplakia, however, is highly prevalent in patients with in situ and invasive oropharyngeal carcinoma (54% and 64%, respectively). 110

Tobacco use and alcohol consumption represent the most significant risk factors for the development of oral erythroplakia. 114 Among nonsmokers and nondrinkers, chewing betel quid has been reported as a risk factor for oral erythroplakia. The possible etiologic roles for infections caused by HPV and C. albicans have not been proven.

Sites of Occurrence
Oral erythroplakia affects, most commonly, the mucosal surfaces of the soft palate, the floor of the mouth, and the buccal mucosa. 114 Shafer and Waldron 68 reported gender-related differences in terms of the mucosal sites affected; these investigators indicated that the most common site of occurrence of erythroplakia in men was the floor of the mouth. In women, the combined mandibular alveolar mucosa, mandibular gingiva, and mandibular sulcus were most commonly affected. In men, this combined site was the least common site of occurrence. Erythroplakia does not usually affect the tongue. 58 Bouquot and Ephros 115 indicated that 50% of lesions diagnosed as oral erythroplakia measure less than 1 cm in greatest dimension, with the majority being less than 1.5 cm in diameter.

Clinical Aspects of Preinvasive Neoplastic Lesions of the Larynx
Perhaps more so than the oral cavity, the clinical and pathologic terms used to characterize lesions perceived or suspected to represent premalignant epithelial changes of the laryngeal mucosa and the vocal cords in particular have been inconsistent and confusing. Terms like simple leukoplakia, leukoplakia with dysplasia (of different grades), keratosis, keratosis with atypia, and risky epithelium have all been used or proposed to depict a wide range of mucosal changes with no clear distinction as to whether a term encompasses a clinical/gross appearance only, a microscopic alteration only, or a combination of both. 42, 116, 117 Some authors emphasize that while the term leukoplakia is a clinical term, keratosis should be strictly a microscopic diagnosis based on total replacement of superficial epithelial cells by keratin filaments and dissolution of the nuclei. 118 More recently, the term epithelial hyperplastic laryngeal lesion has been proposed. 119 Although the term hyperplasia is the one used, the classification is referred to as depicting dysplastic laryngeal lesions. 120 A more morphologically driven attempt by pathologists proposes to classify the spectrum of squamous lesions of the larynx into distinct categories ranging from reactive proliferation with epithelial hyperplasia (the authors also refer to it as keratosis) to atypical hyperplasia, dysplasia, CIS, and overt invasive cancer. 121
These inconsistencies persisted despite the emphasis by expert investigators that “adequate diagnosis, treatment and prognosis of particular pathologic entities of the laryngeal mucosa depend entirely on the histologic changes of the epithelium and that difficulties begin with the lack of uniformity and inconsistency of terminology.” 119 A major concern with some of the potentially well-designed and well-conducted studies with follow-up is the fact that the terms applied by the authors are not uniformly understood/accepted by other investigators and at best can only be poorly compared to other sets of definitions used by different groups conducting similar studies. 118, 122

Laryngeal Leukoplakia

In the literature, the mucosal appearances by the clinical observation of the larynx are not as well documented as they are in the oral cavity. Although both red and white mucosal alterations are recognized by laryngologists as abnormal, consensus as to their relative importance has not been achieved. Part of the summary of Workshop No. 2 of the Centennial Conference of Laryngeal Cancer includes the following: “The pathologists insisted in the majority that the appearance of a reddish, edematous, sometimes granular lesion is most characteristic of pure CIS. However, all of the laryngologists insisted that more often than that, this type of base for CIS had a whitish or keratotic covering, either thick, punctuate, thin, or even friable.” 36
Laryngologists use the term keratosis for thick white mucosal plaques and red for the thin erythema-appearing epithelial changes. 123, 124 The term keratosis with and without atypia has historical support and has been used for a number of years. 123 Keratosis usually refers to hyperplasia with prominent surface keratinization. It is the authors’ impression that most glottic mucosal changes are of the keratinizing hyperplasia variety and are analogous to oral leukoplakia with atypia. The presence of epithelial dysplasia/SIN is relatively uncommon in this anatomic site but represents the epithelial changes most likely to progress to invasive cancer. 125 Red thin mucosal alterations of the true cords are rare and correlate with the exceedingly rare classic CIS of the true cord. However, thin reddish changes occur in the supraglottis and adjacent mucosa with a speckled pattern or with white thickened plaques and are invariably associated with dysplasia/SIN/invasive carcinoma on biopsy and histologic examination.
Laryngeal leukoplakia was first described by Durant in 1880. This entity was further studied in the 1920s by Pierce 126 and Jackson. 127 The latter eloquently defined atypia in 1930, as the “mobilization of an army preparatory to invasion,” recognizing its malignant potential. Remarkably, this conclusion, later endorsed by James Ewing, was made at a time when the concept of preinvasive neoplasia was not widely recognized.
The premalignant potential of areas appearing as whitish in the larynx, variously called hyperkeratosis, leukoplakia, and pachyderma laryngis, has long been recognized. Their laryngoscopic appearance is heterogeneous: they may be flat or raised, their surface rough or smooth, and they may be adjacent to normal or inflamed mucosa. 42 Similar to oral leukoplakia, the clinical appearance of laryngeal leukoplakia is correlated histologically with the presence of hyperkeratosis; the microscopic rather than the clinical appearance of the lesion defines its malignant potential. As for oral leukoplakia, the clinical entity leukoplakia encompasses histologically heterogeneous lesions, ranging from simple hyperkeratosis to invasive carcinoma, as later discussed in detail. 42, 128 The presence and grade of dysplasia dictate its biological potential, that is, its probability if developing into overt invasive cancer.

The major carcinogens affecting the larynx and associated mucosal structures are cigarette smoke and alcohol. 129 Use of oral tobacco has not been incriminated as a cause of SCC in the larynx. Nutrition becomes an important element in the development of SCC in both the supraglottic larynx and the glottis. 130 The relative contribution of alcohol and tobacco in the development of laryngeal cancers is more than additive as the two carcinogens appear to potentiate each other in a multiplicative manner. 131
Auerbach and colleagues, 41 who had previously demonstrated a similar etiologic relationship with bronchial dysplasia, also firmly established the relationship between laryngeal dysplasia and cigarette smoke. Their seminal study, involving serial sections from the entire larynx, established that both the number of cell rows in the basal layer of the epithelium and the percentage of atypical nuclei increased with the number of cigarettes smoked per day.

Sites of Occurrence
These lesions have a striking predilection for males, with a male-to-female ratio ranging from 5:1 35 to 7:1 132 and 8:4. 39 Most lesions occur in the fifth to seventh decades, with a mean age of 52 132 to 59 39 years. A temporal gap exists between the occurrence of keratosis and CIS and invasive carcinoma, as for oral dysplasia. Miller and Fisher 133 observed that the peak age of incidence of CIS antedates that of SCC by 7 years: 55 versus 62. The existence of this gap indirectly supports the premalignant nature of dysplasia, analogous to oral leukoplakia and to other anatomic examples of premalignancy. 82 The majority of leukoplakia occurs in the true vocal cord: 33% in both, 35% in either left or right, 11% in both vocal cords and interarytenoid areas. 132

Laryngeal Erythroplakia
There is a scarcity of literature dealing with the epidemiologic and etiologic data available on laryngeal erythroplakia compared with those published on aspects of leukoplakia and hyperkeratotic lesions of the larynx. Accordingly, the significance of the red mucosal lesions found in the larynx is referenced in the discussion summarizing the clinicopathologic correlation and progression potential.

Histologic Definitions
A brief review of the current nomenclature to characterize morphologic changes of the lining of the UADT may be useful before the discussion of the histologic features of preinvasive lesions of these mucosal passages. 58, 134 The typical lining of the UADT is a mature, nonkeratinizing squamous epithelium in which the proliferative activity is limited under normal conditions to the basal and parabasal cell layers only. As indicated previously, the thickness of the squamous epithelium lining these passages, including areas within the same anatomic compartment such as the oral cavity, varies.

Squamous Metaplasia
Metaplasia describes the replacement of one type of specialized epithelium with another, that is, the replacement of ciliated, respiratory-type epithelium of the false vocal cord by squamous epithelium. It is a reversible process that may progress to overt dysplasia or revert to normal and may also be seen in association with inflammatory conditions. It differs from dysplasia in that it lacks any cytologic atypia.

In hyperplasia, there is an increase in thickness of the epithelium, secondary to an increase in one or more of its component layers (the basal layer, the prickly layer [acanthosis], or the superficial layer [hyper-/parakeratosis]), usually a combination of the former with one or two of the latter, without perturbations in maturation and without any accompanying cytologic atypia. Notably, minimal cell crowding and cytologic atypia may also occur in association with inflammation.
At least two histologic patterns of squamous hyperplasia without changes of intraepithelial neoplasia are recognized. One is the simple or flat hyperplasia in which the basement membrane remains well defined as a “line” separating the thickened epithelium from the underlying stroma ( Fig. 1-10 ). The other pattern is architecturally more complex, and, while it involves a degree of the epithelial thickening, the epithelial stromal interface in this pattern is less well defined and the proliferating epithelial “tongues” tend to anastomose, entrapping the stromal compartment ( Fig. 1-11 ). Such a pattern may be occasionally seen, particularly with small, tangentially sectioned biopsy specimens, causing differential diagnostic difficulty with neoplastic changes. Both the flat, architecturally simple hyperplasia and the more complex ones with a pseudoepitheliomatous pattern can accompany mucosal inflammation and exhibit reactive/atypical cytologic changes ( Fig. 1-12 ).

Figure 1-10 Simple or flat hyperplasia. The epithelial lining is thickened, usually due to a uniform expansion of the different layers, but particularly the basal and parabasal compartment. There is normal maturation with preserved nuclear orientation and lack of appreciable nuclear atypia. The architecture is relatively simple with the basement membrane forming a well-defined separation from the underlying stroma.

Figure 1-11 Pseudoepitheliomatous hyperplasia. This is an architecturally more complex hyperplasia. While it involves a degree of the epithelial thickening, the epithelium-stroma interface in this pattern is less well defined and the proliferating epithelial “tongues” tend to anastomose, entrapping the stromal compartment. This figure is somewhat tangentially oriented, accentuating the anastomotic tongues of the epithelium.

Figure 1-12 A and B , Hyperplasia secondary to mucosal inflammation. The latter can obscure the epithelium-stroma interface and cause reactive nuclear atypia or be largely confined to the underlying stroma with expansion of the basal/parabasal layers being the more significant epithelial change.

Dysplasia and Squamous Intraepithelial Neoplasia
These terms characterize architectural mucosal alterations that involve squamous epithelium of variable thickness with loss of maturation, orientation/polarity of the cell layers, and cytologic changes with nuclear atypia, pleomorphism, and increased mitotic activity. When histologically established, these changes have the biological potential of developing into overt cancer ( Table 1-4 ).
Table 1-4 Histologic Criteria Used in the Grading of Dysplasia Criterion Definition Cytologic atypia Increased nucleus-to-cytoplasm ratio, presence of nucleoli, hyperchromasia, pleomorphism Mitotic activity Number and level of mitoses within the mucosa; presence of abnormalities in the mitotic spindle, i.e., tripolar mitoses Abnormal maturation and polarity Reflected by the ratio between the differentiated component, composed of the prickly and squamous layers, and the undifferentiated component, composed of atypical cells. Also reflected by the occurrence of premature keratinization within the epithelium rather than at its luminal surface.

Mild Dysplasia
Cells with slightly abnormal cytologic features are present but limited to the lower third of the epithelium. Orderly maturation into prickly and squamous layers in the upper two thirds of the epithelium is preserved. Mitoses may be present but are limited to the basal layer and are of normal configuration; keratosis may be present ( Fig. 1-13 ).

Figure 1-13 A and B , Low-grade squamous intraepithelial neoplasia/mild dysplasia. The lower one third of the lining contains cells with enlarged, atypical nuclei and occasional mitotic figures; the upper layers show normal maturation. There is only minimal surface keratinization.

Moderate Dysplasia
Abnormal cells with atypical cytologic features occupy the lower two thirds of the mucosa. Cytologic atypia is more pronounced than in mild dysplasia; nucleoli tend to be prominent. Maturation is preserved in the upper third of the mucosa; normal-appearing mitoses may be found in the parabasal and intermediate layers ( Fig. 1-14 ).

Figure 1-14 A and B , Intermediate (grade 2) squamous intraepithelial neoplasia/moderate dysplasia. The abnormal architectural and cytologic changes of altered maturation, nuclear atypia, and mitosis are more established as they involve the lower two thirds of the lining, maintaining maturation only within the upper third of the mucosal lining. There is only minimal surface keratinization.

Severe Dysplasia
Atypical cells showing marked nuclear abnormalities and prominent mitotic activity occupy more than two thirds of the epithelium. They are not as crowded and, most importantly, not as cytologically atypical as in CIS. Maturation is preserved, as evidenced by focal superficial squamous maturation and focal preservation of intercellular bridges. Mitoses, including atypical ones, may extend to the upper third of the epithelium. Associated keratosis may be present ( Fig. 1-15 ).

Figure 1-15 A–C , High-grade squamous intraepithelial neoplasia/severe dysplasia (essentially nonkeratinizing). There are full-thickness architectural changes with loss of normal maturation and disarray of orientation. Cytologically, nuclear enlargement, pleomorphism, anaplasia, and increased mitotic activity are all evident.

High-Grade Keratinizing Dysplasia
Cells with high-grade cytologic features, similar to those found in CIS, occupy the lower two thirds of the mucosa; mitoses are frequent, including abnormal ones. Abnormal maturation is highlighted by the occurrence of single-cell keratinization or keratin pearl formation within the epithelium rather than at its luminal surface. However, in contrast to classic CIS, the uppermost component of the epithelium shows a prominent keratinized layer ( Fig. 1-16 ).

Figure 1-16 A–C , High-grade keratinizing dysplasia. Full-thickness abnormal architectural and cytologic changes of squamous intraepithelial neoplasia (SIN) can be associated with surface keratinization. The changes illustrated in these photomicrographs qualify for keratinizing high-grade SIN and can be encountered as a component of speckled mucosa. It is important to emphasize that the involvement of the lower two thirds or more is not a requirement for the diagnosis of high-grade keratinizing dysplasia in the vocal cords in particular. Significant nuclear anaplasia, albeit limited to the lower epithelial layers, in this location should trigger the diagnosis ( C ).

Carcinoma in Situ
Cells with frankly malignant cytologic features occupy the whole thickness of the epithelium; squamous differentiation is entirely absent. Abnormal cells have the cytologic hallmarks of malignancy, including a high nucleus-to-cytoplasm ratio, prominent single or multiple nucleoli, nuclear hyperchromasia, and pleomorphism. Mitotic figures, including atypical ones, are frequent and extend throughout the entire mucosa, including its upper third. By definition, the changes are limited to the epithelium; stromal invasion is absent. Typically, most CISs of the UADT are nonkeratinizing ( Fig. 1-17 A and B ), although keratinizing CIS can be encountered in the vocal cord or the oral cavity (see Fig. 1-17 C ).

Figure 1-17 Carcinoma in situ (CIS). The findings depict cells with high-grade cytologic features, similar to those found in classic CIS, occupying the full thickness of the epithelium with no apparent surface keratinization ( A and B ). In contrast, the less common form of CIS in the upper aerodigestive tract, namely, the keratinizing type, demonstrates the uppermost component of the epithelium to have a variably prominent keratinized layer with the lower two thirds of the mucosa containing mitotic figures, including abnormal ones ( C ).

Histologic Classification of Upper Aerodigestive Tract Preneoplastic Lesions
Microscopic grading of preneoplastic lesions of the UADT is of paramount importance biologically and clinically because the probability of malignant progression to invasive cancer of these lesions is dictated by their grade. This correlation, which is discussed more extensively later, highlights the importance of obtaining a biopsy sample of all suspect lesions and giving priority to microscopic over clinical examination.
The grading system, as described by the WHO, 58, 134 follows criteria similar to those accepted for other organs, particularly the cervix uteri. 32 Cervical preneoplastic lesions have been studied extensively and have represented for years a standard histologic model of squamous preneoplastic lesions. Thus, the grading criteria applied to the cervix have been extended to all other squamous preneoplastic lesions, including those of the UADT. This grading system relies on the extent of distribution of the abnormal cells within the epithelium. These are limited to the lower third of the epithelium in mild dysplasia and extend to about two thirds in moderate dysplasia and to more than two thirds of the epithelium in severe dysplasia. The difference between severe dysplasia and CIS is that, in CIS, the abnormal cells have a higher grade and frankly malignant cytologic features. In addition, in CIS, they involve the entire epithelium, including its most apical component and thus there is a complete lack of maturation/differentiation. Lesser-grade cytologic features and some maturation, however, characterize severe dysplasia. 58, 134 Several authors have stressed that the etiopathogenetic factors associated with dysplasia and SCC of the UADT (i.e., alcohol and smoking) and cervix (HPV infection) are different. 120 Furthermore, it has been pointed out that UADT dysplastic lesions may show unique morphologic features not seen in cervical dysplasia; that is, superficial maturation may be seen in association with high-grade cytologic features in the lower third or two thirds of the mucosa. Thus, the mere application of the criteria used for the cervix to the UADT preneoplastic lesions would result in an underassessment of their grade. 135, 136
Two main alternative classification schemes to the WHO system have been proposed by Crissman and colleagues 124, 125 and Kambic and colleagues. 35, 119, 120 They are both characterized by an emphasis on cytologic features rather than the relative ratio of abnormal to differentiated cellular components within the epithelium. The system advocated by Crissman and colleagues 136, 137 recognizes a category of keratinizing dysplasia to designate a lesion showing superficial keratinization in association with high-grade cytologic features in the remaining mucosa. In these authors’ experience, such lesions have a high incidence of local relapse, a high progression rate to invasive cancer, and a high content of aneuploidy. 119 Thus, they are included in a high-grade dysplasia group (SIN-laryngeal intraepithelial neoplasia III). 124, 125 These authors further stressed that abnormal differentiation was present in these lesions in the form of aberrant keratinization (dyskeratosis), represented by single-cell keratinization and keratin pearls, occurring in the midst of the epithelium. 125 Underreporting of keratinizing dysplasia and its difference from classic CIS were confirmed by others upon systematic review of laryngeal biopsy specimens. 138 The system advocated by Crissman and colleagues 124, 125 proposed the designation SIN (or laryngeal intraepithelial neoplasia) as an alternative to dysplasia. The proposed advantages of the designation intraepithelial neoplasia are many. This definition matches the currently used designation for the cervix uteri (cervical intraepithelial neoplasia), which has replaced the old designation of dysplasia and thus allows more standardized reporting of preneoplastic lesions across different anatomic sites. Furthermore, as intended by the authors, this designation is more clinically oriented and broader than dysplasia and allows the inclusion of nonmorphologic parameters, that is, molecular markers, in the grading system. Although biologically sound, this suggestion has not met with acceptance in routine clinical practice.
Kambic and colleagues 119, 120, 139 proposed for the larynx a distinction of dysplasia into simple, abnormal, atypical hyperplasia and CIS. In this classification, known as the Ljubljana classification, the emphasis is on cytologic features. Simple hyperplasia shows an increase in epithelial thickness secondary to an increase in the stratum spinosum, with no cellular atypia in the basal and parabasal layers. In abnormal hyperplasia, the basal or parabasal layers are increased, encompassing up to one half of the mucosal thickness, but their nuclei, although enlarged, lack significant cytologic atypia. The occurrence of significant nuclear atypia and dyskeratosis, associated with preservation of the overall epithelial architecture characterizes atypical hyperplasia. In CIS, cells with the cytologic features of malignancy occupy the majority of the epithelium, which has lost its regular stratification and shows very frequent mitoses. 119, 120, 139 The approximate correlation between the different classifications used for dysplasia is summarized in Table 1-5 . However, the Ljubljana and the WHO systems are not easily reducible one to the other, as demonstrated by large variation in the classification of lesions between the two groups. Thus, of 12 cases diagnosed as mild dysplasia by the WHO system, three were reclassified as simple, eight as abnormal, and one as atypical hyperplasia; of 19 cases of moderate dysplasia, two were reclassified as simple, 10 as abnormal, six as atypical hyperplasia, and one as CIS; of 14 cases of severe dysplasia, one was reclassified as simple, eight as atypical hyperplasia, and one as CIS. 140 Nine lesions were placed in a group of large-cell hyperplasia, a category not described in the original Ljubljana classification. 140 Like other multitiered grading systems, the WHO system, which is the most commonly used in pathologic practice, has high inter- and intraobserver variability. 19 Most observers think the morphologic distinction between severe dysplasia and CIS is difficult to establish and reproduce with consistency. 134 Furthermore, if these two lesions may potentially have a different progression risk to overt cancer, advocating such a difference would be difficult to ascertain because the morphologic distinction between them cannot currently be reproduced. 134
Table 1-5 Classification Schemes That Histologically Characterize Precursor and Related Lesions 2005 WHO Classification Squamous Intraepithelial Neoplasia Ljubljana Classification of Squamous Intraepithelial Lesions Squamous cell hyperplasia   Squamous cell (simple) hyperplasia Mild dysplasia SIN 1 Basal/parabasal cell hyperplasia * Moderate dysplasia SIN 2 Atypical hyperplasia † Severe dysplasia SIN 3 ‡ Atypical hyperplasia † Carcinoma in situ SIN 3 ‡ Carcinoma in situ
SIN, squamous intraepithelial neoplasia.
* Basal/parabasal cell hyperplasia may histologically resemble mild dysplasia, but the former is a conceptually benign lesion and the latter is the lower grade of precursor lesion.
† “Risky epithelium”: The analogy to moderate and severe dysplasia is approximate.
‡ The advocates of SIN combine severe dysplasia and carcinoma in situ.
These limitations currently justify simplifying preinvasive squamous neoplastic changes into two tiers: low-grade dysplasia (most authors would limit this category to mild dysplasia, while a few expand it to include moderate dysplasia) and high-grade dysplasia (including severe dysplasia and CIS and, for most investigators, moderate dysplasia). The importance of establishing a mutual understanding of this terminology between pathologists, surgeons, and oncologists can’t be overemphasized. Alternatively, a more reproducible way of grading dysplasia, possibly combining histologic and morphometric parameters together with immunohistochemical and molecular markers, needs to be developed that can be more precisely correlated with clinical outcome.

Classification of Intraepithelial Neoplasia
The histologic changes representing dysplasia/SIN in the UADT ( Table 1-6 ) encompass a continuum with two distinct appearances at the two opposite ends of this spectrum.
1 Hyperplastic squamous mucosa with prominent surface keratinization (leukoplakic appearance) has a rate of progression to a higher grade of dysplasia/SIN or invasive carcinoma proportional to the degree of cytoplasmic and nuclear atypia. In addition to the cytologic atypia, one factor not usually stressed as abnormal is the presence of premature keratinization, which is characterized by prominent cytoplasmic keratin formation in the lower or middle portion of the epithelium, either as focal (pearls) or diffuse cytoplasmic keratinization. A classification scheme defining grades of keratinizing dysplasia has been found to be predictive of the risk of persisting dysplasia/SIN and/or subsequent invasive cancer.
2 Thin or atrophic squamous mucosa with little or no cellular maturation and prominent nuclear atypia (erythroplakic appearance) invariably has a histologic diagnosis of the classic form of severe dysplasia/CIS as originally described in the uterine cervix. This classic form of intraepithelial neoplasia is uniformly recognized by the pathology community and has a high rate of transformation or progression to invasive cancer.
Table 1-6 Criteria Used for Diagnosing Dysplasia Architecture Cytology Irregular epithelial stratification Abnormal variation in nucleus size (anisonucleosis) Loss of polarity of basal cells Abnormal variation in nucleus shape (nuclear pleomorphism) Drop-shaped rete ridges Abnormal variation in cell size (anisocytosis) Increased number of mitotic figures Abnormal variation in cell shape (cellular pleomorphism) Abnormal superficial mitoses Increased nucleus-to-cytoplasm ratio Premature keratinization in single cells (dyskeratosis) Increased nucleus size Keratin pearls within rete pegs Atypical mitotic figures Increased number and size of nucleoli Hyperchromasia
Defining the histologic criteria for intraepithelial neoplasia remains relatively straightforward for the two ends of this histologic spectrum but is problematic when overlapping features of these extremes coexist. The two ends of the spectrum described in the previous sections, atrophic dysplasia/SIN and hyperplastic keratinizing dysplasia/SIN, are relatively easy to recognize, especially the former. However, an admixture of these two ends of the spectrum, that is, normal-thickness mucosa with a proliferation of immature basal-like cells in the lower regions of the epithelium and variable degrees of surface keratinization, is commonly underdiagnosed and may not be recognized as high-grade epithelial dysplasia/SIN. Any evidence of surface maturation in the uterine cervical SIN grading scheme results in a lower grade assigned. This is clearly not the case in intraepithelial neoplasia of the UADT mucosa. Surface keratinization is commonplace in UADT SIN and must be recognized as such. Epithelial hyperplasia with or without prominent surface keratinization will require a different set of guidelines than thin mucosa with little or no evidence of surface maturation. The remaining portion of this section of the chapter is devoted to expressing the rules that we have found helpful and our interpretation of the literature in supporting our conclusions. General guidelines to the important histopathologic features in gauging grades of SIN according to the WHO 47 are listed:
1 Loss of polarity of the basal cells
2 Proliferation of the basal cells
3 Increased nucleus-to-cytoplasm ratio
4 Epithelial hyperplasia with drop-shaped submucosal rete extension
5 Irregular epithelial stratification and cellular pleomorphism
6 Premature keratinization of single cells (dyskeratosis) or keratin pearls in the rete pegs
7 Increased mitotic figures and abnormally superficial mitoses
8 Presence of abnormal mitotic figures
9 Variation in nucleus size, shape, and hyperchromatism; increased nucleus size
10 Increased number and size of nucleoli
11 Abnormal variation in cell shape and size

Definition and Classification of Squamous Intraepithelial Neoplasia
Orderly or normal maturation with and without hyperplasia is defined by the relative relationship of basal and parabasal (immature and normal proliferating cells) to maturing keratinocytes of the intermediate zone and the superficial protective keratotic layers. The determination of hyperplasia that maintains normal maturation characteristics is often reversible when the offending agent is removed. Carcinogens result in genetic damage that, if not repaired, persists or progresses, and the resulting phenotypic expression of the damage is not always expressed by dysplasia/SIN in either hyperplastic or thin mucosa. When carcinogens result in altered phenotypic histologic expression, invariably abnormal maturation of the epithelium will result. In effect, genetic alterations produce an uncoupling of normal maturation, and these maturation abnormalities are invariably associated with nucleus cytologic aberrations. 131 Normal maturation results in an orderly mosaic-like pattern with similarly sized nuclei maintaining an equidistant relationship. The distance is defined by the gradual increase in cell cytoplasm volume (often with keratinization) and nucleus shrinkage and condensation as epithelial maturation develops during the cellular migration toward the epithelial surface. The nuclei gradually undergo either pyknosis or karyorrhexis as a final step in the maturation process. Concurrent with epithelial maturation is an increase in keratin intermediate filaments, which provide surface mechanical protection by the development of hyaline-keratin cytoplasmic bundles.
Nuclear pleomorphism, usually with hyperchromasia, is invariably associated with cellular disorganization with epithelial dysplasia characterized by the loss of normal cellular maturation. Abnormal maturation is commonly associated with the following:
1 Premature or early cytoplasmic keratinization (dyskeratosis) in the lower one third to two thirds of the epithelium, a common but not often stressed sign of dysplasia ( Fig. 1-18 A and B ).
2 Excessive cytoplasmic keratinization in all levels of the epithelium; another change that is seldom recognized as a significant maturation abnormality (see Fig. 1-18 C and D ).
3 Abnormal proliferation of immature cells in the lower and middle portions of the epithelium, but with evidence of surface maturation and keratinization. This may represent the most common expression of the hyperplastic form of epithelial dysplasia occurring in the UADT ( Fig. 1-19 ).
4 Loss of the normal development of cytoplasmic keratinization resulting in a thin epithelium with little or no evidence of cellular maturation ( Fig. 1-20 ). This form represents the classic form of CIS with immature or uncommitted cells constituting the full thickness of the nonproliferative, frequently atrophic epithelium and is associated with an erythroplakic mucosal appearance.

Figure 1-18 A – D , Abnormal intraepithelial keratinization (dyskeratosis). Premature individual cell keratinization ( A and B ), including the formation of keratin pearls ( C and D ) within the lower one third to two thirds of the epithelium, is a rather common but not often stressed sign of dysplasia. This phenomenon also includes the excessive cytoplasmic keratinization in all levels of the epithelium, another change that is seldom recognized as a significant maturation abnormality.

Figure 1-19 A and B , Abnormal proliferation of immature cells in the lower half of the epithelium. This alteration, as it is accompanied by evidence of surface maturation and keratinization, may represent the most common expression of the hyperplastic form of epithelial dysplasia occurring in the upper aerodigestive tract.

Figure 1-20 A and B , Complete loss of maturation and cytoplasmic keratinization. This more profound alteration results often in a thin epithelium, with little or no evidence of cellular maturation.

Histopathologic Classification of Squamous Intraepithelial Neoplasia
It is important to develop an objective system to define the degree of morphologic alterations with specific and perhaps reproducible criteria to help the clinician assessing the biological potential of a SIN lesion for persisting or progressing to invasive cancer.
The observations that seem most applicable to define degrees of abnormality or dysplasia/SIN include the following ( Table 1-7 ):
1 Hyperplasia . Classic CIS presenting grossly as erythroplakia is usually a thin mucosa without hyperplasia. Most dysplasia/SIN have a thickened hypercellular epithelium, which must be judged to have normal or abnormal maturation. This assessment is crucial in determining grade.
2 Keratinization . Most, but not all, hyperplastic epithelia have evidence of cytoplasmic keratin formation. Probably one of the most important issues in grading dysplasia/SIN of the UADT is recognizing that the development of cytoplasmic keratin near the surface invariably represents normal epithelium.
a Surface keratinization in the form of acellular keratin with or without parakeratosis is the usual form of keratinizing dysplasia/SIN. Generally, the proliferation of immature cells or abnormally sized nuclei into the upper epithelium defines this form of dysplasia/SIN.
b Cytoplasmic keratin in the upper portion of the epithelium signifies epithelial maturation, but similar to 2a, proliferation of abnormal cells into the upper epithelium defines dysplasia/SIN.
c Hyperkeratinization with excessive cytoplasmic keratin accumulation in the lower epithelium is also distinctly abnormal. Either diffuse accumulation of keratin with or without nuclear abnormalities is pathologic and represents high-grade dysplasia/SIN. Focal areas of keratin formation in the lower epithelium also represent a maturational abnormality and usually are associated with high-grade dysplasia/SIN.
3 Epithelial maturation . This observation is the most variable and the most difficult to define. It is an attempt to assess the nuclear and cytoplasmic volume (area) ratios with the development of keratinization evident in the expanding cytoplasm of the cells in the middle and especially the upper one third of the epithelium.
Table 1-7 Classification of Squamous Intraepithelial Neoplasia Classification Hyperplastic Form Atrophic Form Hyperplasia/keratosis
Thickened, hyperplastic epithelium
Rare mitosis confined to suprabasal layer
Normal maturation
Surface keratinization common
No nuclear pleomorphism
Thin mucosa
Normal mucosal maturation
No nuclear pleomorphism SIN I (low grade)
Epithelial hyperplasia
Increased mitoses common (1–2 per high-power field)
Three or more layers of basal-like cells
Minor nuclear pleomorphism
Some proliferation of basal-like cells
Increased mitoses (1–2 per high-power field)
Minor nuclear pleomorphism
Surface maturation still evident SIN II (high grade)
Epithelial hyperplasia
Mitoses in all layers common, including abnormal forms
Marked epithelial maturation abnormalities with immature basal-like cells constituting inner and middle one third or in combination with premature keratinization, including presence of pearls
Prominent nuclear pleomorphism
Increased chromatin staining
Proliferation of basal-like cells involving the full thickness
Prominent submucosal changes
Numerous mitoses at all levels; may have abnormal mitotic forms
Prominent nuclear pleomorphism
Little or no evidence of maturation or keratinization
SIN, squamous intraepithelial neoplasia.
Deviation from the expected pattern of maturation in hyperplastic epithelium can take many forms: (1) proliferation of basal-like cells to the surface above the suprabasal region; (2) extension of intermediate cells to the surface, especially without evidence of expansion of the cytoplasm, usually with evidence of keratin formation; (3) enlarged hyperchromatic nuclei in the outer epithelium; and (4) excessive cytoplasmic keratin formation in the lower epithelium.
In general, epithelial maturation is an orderly progression of basal cells to intermediate cells with expanding cytoplasm as the cells migrate toward the surface. The nuclei are initially small (basal cells), become larger (intermediate), and are gradually lost (keratinization). The nuclei always maintain a pattern of equidistance, with the distance between nuclei becoming greater as cytoplasmic volume increases. We refer to this nuclear pattern as mosaic, and it is critical in the histologic definition of normal maturation.
1 Mitoses . One could expect increased mitoses (zero to one per high-power field) in a hyperproliferative hyperplastic epithelium. In reactive hyperplastic processes, morphologically normal mitoses are confined to the basal/suprabasal layers of the epithelium, and the presence of mitoses above this level is pathologic. Abnormal mitoses invariably reflect neoplastic transformation.
2 Nuclear pleomorphism , for the purpose of this discussion, refers to variation in nucleus size, shape, and chromatin staining in adjacent cells. Normally, the nuclei become smaller as they migrate toward the surface with a predictable maturation process, eventually disappearing in hyperkeratosis or remaining as pyknotic remnants in parakeratosis. Mild nuclear pleomorphism can be seen in low-grade lesions, while appreciable variation in nucleus size, shape, and staining characteristics is invariably found in high-grade SIN.

Correlation between Clinical and Histologic Classifications
The histologic diagnoses of lesions presenting clinically as leukoplakia range from hyperplasia to invasive carcinoma. The surface keratin layer can be found over benign, mature squamous epithelium of the flat or pseudoepitheliomatous type ( Fig. 1-21 ) or mucosa with mild, moderate, or severe dysplasia corresponding to low, intermediate, and high-grade SIN ( Fig. 1-22 ).

Figure 1-21 Benign histologic correlate of clinical leukoplakia. The surface keratin layer corresponding to the white appearance extends over benign, mature squamous epithelium of the flat ( A ) or pseudoepitheliomatous ( B ) type.

Figure 1-22 Dysplastic histologic correlates of clinical leukoplakia. In contrast to the majority of clinically white, leukoplakic mucosal lesions, these three illustrations show the mucosa beneath the keratin layer to harbor changes of mild ( A ), moderate ( B ), or severe ( C ) keratinizing dysplasia corresponding to low-, intermediate-, and high-grade squamous intraepithelial neoplasia.
In the largest series of leukoplakias studied to date, of 3256 oral cases, Waldron and Schaefer 65 found histologic evidence of neoplastic changes (dysplasia or overt cancer) in 20% of the cases: 12.2% mild to moderate dysplasia, 4.5% severe dysplasia, and 3.1% invasive carcinoma. 65 The remaining 80% of the lesions had varying combinations of hyperorthokeratosis and acanthosis, without dysplasia. Similar percentages of dysplasia were found by Banoczy and Csiba 64 in a series of 500 cases, although their overall incidence of invasive carcinoma in leukoplakia was found to be 9.6%.
Gross mucosal changes of erythroplakia, on the other hand, translate almost invariably to high-grade dysplasia/in situ carcinoma of the nonkeratinizing type ( Fig. 1-23 ). Several authors have shown that lesions with a heterogeneous appearance with an alternation of white and red areas are at increased risk of harboring high-grade dysplasia ( Fig. 1-24 ) or invasive cancer compared with uniformly white lesions. It is not unusual for some of these lesions to harbor foci of microinvasive or early SCC ( Fig. 1-25 ).

Figure 1-23 Histologic correlate of clinical erythroplakia. Gross mucosal changes of erythroplakia translate almost invariably to high-grade dysplasia/in situ carcinoma of the nonkeratinizing type.

Figure 1-24 Histologic correlate of clinical mucosal changes of speckled mucosal lesions. With the presence of a red, erythroplakic component, the histology of such areas reveals high-grade dysplasia/in situ carcinoma. As depicted in Figure 1-25 , they can also harbor micro- or frankly invasive carcinoma.

Figure 1-25 A and B , Histologic correlate of clinical mucosal changes of speckled mucosal lesions. Complex surface epithelium with high-grade squamous intraepithelial neoplasia but with focal areas showing foci of early invasive squamous cell carcinoma.
Thus, Banoczy and Csiba 64 found the incidence of severe dysplasia/CIS to increase progressively, from 0.8% in leukoplakia simplex, to 6.6% in leukoplakia verrucosa, to 12% in leukoplakia erosiva. The incidence of mild-moderate dysplasia progressed, in the same lesions, from 17.5% to 28% to 35%, respectively. 64 However, lesions with the appearance of erythroplakia harbor the highest percentage of high-grade dysplasia and overt cancer. Schaefer and Waldron, 68 in a series of 65 oral cases, found that 9% of erythroplakias show low-grade dysplasia, 40% high-grade dysplasia, and 51% invasive SCC. 68 In the series of Mashberg and colleagues 111 ( n = 158), 89% of early asymptomatic invasive SCC cases and more than 93% of CIS cases had an erythroplakia component. SCC, compared with CIS, had a higher percentage of elevation (58% vs. 35%) and granular or rough surface (59% vs. 35%) and was more often indurated (10% vs. 0%; Table 1-8 ).

Table 1-8 Distribution of Dysplasia and Invasive Squamous Cell Carcinoma in Oral Leukoplakia and Erythroplakia

Clinicopathologic Studies

Oral Cavity
The recognition that these two major types of squamous mucosal response to injury represent two ends of a spectrum of gross and histologic appearance is an important step in understanding intraepithelial neoplasia. The major problem in developing a balanced set of rules to diagnose dysplasia/SIN of the UADT is that many examples combine features from both ends of the diagnostic spectrum. The most common mucosal reaction to any type of injury is characterized by epithelial proliferation and hyperkeratosis (clinical leukoplakia). This process may or may not be in response to carcinogenic injury. The frequency of clinical leukoplakia becoming neoplastic varies greatly. Establishing neoplasia is greatly dependent on the presence or absence of cellular atypia that reflects genetic changes, which can now be documented using a wide range of recently described molecular techniques. These observations regarding clinical mucosal appearance, their histologic correlates, and their clinical course are critical to our understanding of intraepithelial neoplasia and the progression to invasive carcinoma.
The observation that persisting erythroplakic or speckled mucosa is commonly associated with dysplasia/SIN is also critical in understanding the spectrum of SIN occurring in the UADT. This typical erythroplakic-appearing mucosa invariably has paucity (or absence) of surface maturation and a prominence of uncommitted basal-like cells with nuclear pleomorphism constituting the full thickness of the thin epithelium. Erythroplakic change is ominous and almost always represents high-grade SIN. In contrast, leukoplakia may or may not represent irreversible neoplastic injury. Neoplastic change can only be absolutely confirmed by the histologic changes of dysplasia/SIN.

In general, a review of the literature reveals numerous terms for what are interpreted as similar approaches for the grading of dysplasia/SIN. 123 - 125 We believe, as do others, 141 that the minor variations between keratosis without atypia and keratosis with mild atypia are difficult to separate with reproducible certainty and are likely to represent neoplastic transformation and should be viewed as a single entity. Although the subclassification of the epithelial dysplasia/SIN of the UADT into histologic grades analogous to other organ systems has not been well defined, there is a growing body of evidence demonstrating that various grading systems have biological significance in predicting the probability of progression. 125 One of the first classification systems was reported by Kleinsasser, 142 who separated abnormal laryngeal biopsies into three subgroups:
1 Grade 1, or simple hyperplasia, consists of hyperplasia with normal cell maturation. Only a small number of patients with this biopsy specimen interpretation progress to invasive cancer.
2 Grade 2 represents a small group of biopsy specimens that show atypical nuclei and disturbances of differentiation. For these patients, observation is recommended.
3 Grade 3, or precancerous epithelium, is referred to as CIS by some pathologists. The epithelium contains all the changes observed in SCC except invasion.
The division of the continuous spectrum of the histopathologic alterations defining SIN is, at best, arbitrary. Review of the literature supports this position. 39, 43, 123, 125, 128, 132, 133, 141 - 149 With 1268 biopsy specimens interpreted as keratosis without atypia or with mild atypia, 40 cases (3.2%) progress to invasive SCC. These observations are derived from a diverse group of studies, many of which are primarily clinically oriented, many with less than stringent histopathologic definitions. Nevertheless, the 3.2% is remarkably similar to the results of several of the smallest series with careful pathology review, resulting in a low frequency of progression to invasive cancer for these keratinizing hyperplastic epithelial alterations with little or no dysplasia/SIN. 43, 124, 132
The summary data reviewing the pertinent literature contain very few biopsy specimens graded as moderate atypia, and those classified as such have a frequency of progression to invasive carcinoma of 13.7%. This figure is not significantly different from the 15.3% reported for biopsies classified as severe atypia/CIS. We know that the classic atrophic forms of severe dysplasia/CIS are a relatively rare adjunct to invasive carcinomas or an isolated event. Our interpretation of these seemingly anomalous observations is that the small groups of intermediate SIN II (keratosis with moderate atypia) were biopsy specimens with some nuclear/cytoplasmic alterations but with prominent surface or epithelial keratinization and, as a result, were undergraded. 150 Although the frequency of DNA aneuploidy and, more importantly, the rate of progression to invasive cancer are similar for those intermediate lesions and high-grade SIN, the former group is commonly downgraded into a lower grade of dysplasia/SIN. 39, 142, 151, 152 This would account for the similar frequency of progression to invasive carcinoma between the historical groups of intermediate SIN and high-grade SIN categories. This observation is confirmed in the excellent study of Hellquist and colleagues 150 in which the dysplasia they called well differentiated had the highest rate of progression to invasive SCC. Their examples of this well-differentiated group of SIN demonstrate extensive cytoplasmic keratinization at all levels in the epithelium with little, if any, nuclear pleomorphism. In our experience, this lesion, characterized by extensive epithelial keratinization is often undergraded and represents an epithelial dysplasia with a high frequency of progression to invasive carcinoma.
The second important prognostic observation reported by Hellquist and colleagues 39 was that keratosis/SIN that persisted or recurred was ominous, an observation not commonly stressed in the clinical or pathology literature. High-grade dysplasia/SIN is usually characterized by proliferation of immature cells in the lower and middle layers and a degree of superficial keratinization. This morphologic profile is recognized by most experienced pathologists as a prominent feature of high-grade SIN because of the evidence of maturation as reflected by surface keratinization. Unfortunately, many of the clinicopathologic studies include pathology descriptions with little or no detail of the histologic criteria for classification of the epithelial alterations.

Malignant Progression of Upper Aerodigestive Tract Preneoplastic Lesions
The frequency with which clinical leukoplakia becomes neoplastic varies greatly depending on the study population, but a fivefold higher risk of neoplastic development has been calculated to be conservative. Causative agents include carcinogens such as tobacco and alcohol, friction on the mucosal surface, and microscopic organisms such as C. albicans . 73 It was recently proposed that the term leukoplakia be restricted in use to nondefinable lesions. 80 A diagnosis of leukoplakia should be made when a lesion cannot be diagnosed clinically as any other disease with a white appearance. Therefore, lesions that are excluded from this definition include tobacco-induced white lesions; hairy leukoplakias, now referred to as Greenspan lesions; and Candida -associated lesions that respond to treatment.

Oral Cavity
The overall incidence of progression to invasive SCC of premalignant lesions of the oral cavity ranges from 2.7% to 17.5% in the studies with the longest follow-up and with the largest numbers of patients. As stressed previously, the progression rate is related to the degree of dysplasia, and this in turn varies in relation to the site. Thus, Waldron and Schafer, 65 in a series of 3256 cases, found the incidence of dysplasia and CIS to be disproportionately high in the floor of the mouth (42.9% vs. an 8% overall incidence of leukoplakia), tongue (24% vs. a 6.8% overall incidence of leukoplakia), and lips (24% vs. an overall 10.3% incidence of leukoplakia). Thus, while all leukoplakias should be subject to histologic examination, both the presence of redness (erythroplakic component) and the occurrence in high-risk sites should be of clinical concern. The incidence of progression to invasive carcinoma is also related to the clinical type of leukoplakia, consistent with their different association with high-grade dysplasia. None of the cases of leukoplakia simplex ( n = 371) were found to progress to cancer, while 5.5% of leukoplakia verrucosa ( n = 183) and 25.9% of leukoplakia erosiva ( n = 116) progressed during a mean observation time of 9.8 years ( Table 1-9 ). 59

Table 1-9 Incidence of Dysplasia in Clinical Subtypes of Leukoplakia and Their Frequency of Progression to Squamous Cell Carcinoma
A higher risk of cancer in association with female sex has been reported by several authors: the overall incidence of malignant transformation in the series of Banoczy 59 is 8.8% in females versus 5.1% in males. In contrast, the male-to-female distribution of CIS and SCC was 3.2:1 and 1.9:1, respectively, in the whole series. An even higher difference in incidence was found for tongue cancers, 86.6% of which occurred in females. This site also showed a higher prevalence in the incidence of dysplasia among females. 59 A similar bias in malignant transformation of females versus males (58% vs. 42%) was observed by Silverman and colleagues. 63 The reasons for these gender-related differences are not known.
The etiologic role of tobacco use in the development of SCC of the oral cavity has been well established. However, several authors have shown that leukoplakia occurring in nonsmokers has an excess risk of developing into SCC compared with leukoplakia arising in smokers. 60, 63, 153 It is worth stressing that most oral cancers arise de novo, without an associated precancerous lesion.
While the association between leukoplakia, dysplasia, and the prospective development of cancer is firmly established, examination of overt cancer only discloses coexisting leukoplakia or CIS in a small subset of cases. A large retrospective study of oral and oropharyngeal cancers occurring over a span of 54 years in a small community in Minnesota addressed this issue retrospectively. Analysis of this set of 201 cases showed that only 7% of invasive cancers had adjacent CIS, while an additional 2% had severe epithelial dysplasia. 154 However, a limitation of this study is that it relied entirely on pathology reports and thus may have underestimated the percentage of dysplasia, secondary to sampling error and/or underreporting by the pathologist. In the same report, the authors show that cancers associated with leukoplakia are smaller and less invasive, and their histologic grade is lower than those without it. 153 Other authors had observed that the progression time from CIS into overt SCC is extremely variable. 155 These findings highlight that, although likely to include a preneoplastic phase, the natural history of SCC may show significant patient-to-patient variations.
A distinctive type of hyperplasia, PVL, has been described. 107, 108 This lesion was identified retrospectively and is characterized by a verrucous clinical appearance, an expanding and often multifocal growth pattern, and a high (up to 70%) rate of progression into invasive carcinoma. 95 The initial manifestation is usually that of simple hyperkeratosis. However, the lesion tends to recur and progress to dysplasia or invasive carcinoma, often in a multifocal distribution, retaining an exophytic-verrucous appearance, and thus the diagnosis can reliably be made only retrospectively. 107 There is a male-to-female ratio of 4:1; the mean age of occurrence is 62 years, and the most frequent sites are the gingiva and tongue. The histologic appearance is either that of simple hyperkeratosis, dysplasia, or verrucous carcinoma. 95, 107 Notably 69% of the patients have no history of tobacco exposure. 95 In contrast, 78% show evidence of HPV 16 infection, highlighting the possible transforming role of this virus in this setting. 156

The reported frequency of transformation of leukoplakia varies from 3.5% to 21%; the largest studies reported frequencies of 4.4% to 16% ( Tables 1-10 to 1-12 ). 157 - 160 As with oral dysplasia, the rate of progression to overt cancer increases with the degree of dysplasia. Thus, in the series of Blackwell and colleagues, 135 in which 62 leukoplakias were studied for a mean follow-up of 74 months, the rate of progression was 0/6 in the absence of dysplasia, 12% for mild dysplasia (3/26), 33% (5/15) for moderate dysplasia, and 33% for severe dysplasia/CIS (5/15). 135 Kambic and colleagues 35 found an overall incidence of SCC of 19% (17/88): 12 of 17 cases of high-grade dysplasia, three of 17 cases of low-grade dysplasia, and two of 17 cases of simple hyperplasia. The rate of recurrence is also related to the severity of dysplasia: 53% (9/17) for CIS and 18% (3/17) for moderate-severe dysplasia. 128 The progression rate of CIS to invasive carcinoma was found to be 63% in a group of 27 patients managed conservatively after a mean follow-up time of 9 months. 161 In the series of Gillis and colleagues, 162 progression to CIS or invasive carcinoma was observed in three of seven patients with keratosis and five of 12 cases of atypia with or without keratosis; progression to invasive SCC was observed in three of eight cases of CIS. Norris and Peale 43 used the same terminology and found that the incidence of progression was related to the presence of atypia: only one in 30 cases of keratosis without atypia progressed to SCC after 32 months. Of 86 cases of keratosis with atypia, 11 progressed, after an average of 22 months: five to SCC, four to CIS, and two to CIS with equivocal evidence of invasion. Hellquist and colleagues 39 found an overall incidence of progression to SCC of 8.7% ( n = 161). SCC developed in two of 98 (2%) patients with slight dysplasia, three of 24 (12%) with moderate dysplasia, and nine of 39 (23%) with severe dysplasia/CIS. Additionally, five of 98 cases with hyperplasia or mild dysplasia progressed to moderate or severe dysplasia; three of 24 cases with moderate dysplasia progressed to severe dysplasia. The mean follow-up time was not indicated, but more than 86% of patients had more than 2 years of follow-up and 57% more than 5 years. Crissman and colleagues 136 stressed that 36% of 25 patients with CIS had microinvasive carcinoma (see Fig. 1-25 ) and another three developed invasive carcinoma in 6 to 8 years. In a large series of patients followed from 1.5 to 12 years and classified according to the Ljubljana classification scheme, 0.7% of simple ( n = 380), 1% of abnormal ( n = 414), and 9.5% of atypical ( n = 105) hyperplasia cases progressed to invasive carcinoma (see Tables 1-10 to 1-12 ). 35
Table 1-10 Frequency of Progression of Laryngeal Leukoplakia and Dysplasia to Invasive Squamous Carcinoma Authors Total No. of Patients Percentage Progressing Sllamniku et al. 141 (1989) 921 6.7 Crissman et al. 136 (1988) 25 12 Bouquot et al. 157 (1991) 108 16 Lundgren and Olofsson 158 (1987) 232 13 Plch et al. 159 (1998) 227 4.4 McGavran et al. 160 (1960) 84 3.5 Miller and Fisher 133 (1971) 203 15.7 Blackwell et al. 135 (1995) 62 21 Norris and Peale 43 (1963) 116 10 Hellquist et al. 39 (1982) 161 8.7

Table 1-11 Incidence of Progression to Squamous Cell Carcinoma in Relation to Histology in Laryngeal Dysplasia

Table 1-12 Frequency of Progression to Invasive Squamous Carcinoma in the Larynx
Other investigators have stressed the importance of specific histologic parameters in predicting progression to invasive SCC. In particular, the occurrence of single-cell intraepithelial keratinization, 136 pleomorphism, mitotic activity, and mucosa-associated inflammation 135 has been found to confer an increased likelihood of progression to SCC. In the series of Crissman and colleagues, 136 dyskeratosis was further associated with an increased likelihood of recurrence.
Follow-up studies of dysplasia highlight that these lesions may recur not only in the same site but also in anatomically separate foci, as either CIS or invasive carcinoma. Thus, in the series of Gillis and colleagues, 162 13 of 57 patients treated with radiotherapy or surgery had a recurrence of CIS or invasive SCC developed de novo. In two of 42 patients, a second primary lesion occurred. These data highlight the presence of multiple foci of transformed cells within the UADT, stressing that the entire field is prone to develop cancer, as first described by Slaughter and colleagues. 163

Sinonasal Region and Nasopharynx

Clinical and Epidemiologic Aspects
There continues to be a relative scarcity of literature dealing with both the histologic definitions of preinvasive neoplasia of the upper respiratory portion of the UADT and the clinical evolution of these lesions. Traditionally, the few studies addressing intraepithelial neoplasia in the nasopharynx are in association with invasive carcinoma. The interest in preinvasive and invasive carcinomas has focused on investigating molecular or immunohistochemical alterations of the spectrum of neoplasia, which included the intraepithelial phase but concentrated mostly on the invasive tumor. In particular, studies of intraepithelial neoplasia of the nasopharynx are mostly associated with investigating the role of Epstein-Barr virus or other molecular changes in nasopharyngeal carcinoma. While these studies have, for the most part, investigated markers in the dysplastic epithelium adjacent to invasive carcinoma, 164 - 166 few recent reports have concentrated on characterizing the pure intraepithelial changes segregated from a large pool of invasive tumors. The difficulty in finding series with larger numbers of intraepithelial changes in isolation of invasive carcinoma appears to be related to the lack of clinical symptoms associated with this phase of neoplasia. Accordingly, studies designed to screen high-risk individuals have the potential for identifying such patients. In terms of etiologic factors, there is a reported association between exposure to wood manufacturing products and adenocarcinoma of the nasal cavity and paranasal sinuses. 167 However, identification of precursor mucosal changes is not documented for woodworkers. The spectrum of hyperplastic, metaplastic, and neoplastic changes within the nasal epithelial lining has been well described in workers exposed to nickel fumes. 168 In a longitudinal study designed to investigate the effects of reducing exposure to nickel fumes on nasal mucosal alterations, there was a reduction in dysplasia in workers who had lowered their exposure to nickel over the study period. Sinonasal papillomas, primarily inverted papilloma, can harbor areas of dysplasia/neoplasia. Barnes and Bedetti 169 reported dysplasia and CIS in 6% and 3%, respectively, in a series of 61 inverted papillomas. It is conceivable that these preinvasive changes are the precursors of invasive SCC, reported to be discovered in 4% to 6% of cases of resected papillomas. 170 In general, dysplastic changes are diagnosed using criteria similar to those used for other squamous mucosa.
In a recent review concerning the risks of malignancy in inverted papilloma of the nose and paranasal sinuses, von Buchwald and Bradley 171 suggest a rather poor understanding of the etiology of inverted papilloma or the factors responsible for malignant transformation; rates reported by these authors were 7.1% and 3.6% for synchronous and metachronous carcinomas, respectively. With almost all recurrences/transformations attributed to incomplete resection, there is a definitive need for long-term follow-up with biopsies if needed.

Pathologic Features and Differential Diagnosis
The clinical gross appearance of intraepithelial neoplasia in the nasopharynx is that of a bulging or thickened mucosa that is usually adjacent to an invasive malignancy.
The information on morphologic changes associated with dysplasia or CIS originating in the nasopharynx comes from studies investigating certain morphologic and mostly molecular aspects of invasive nasopharyngeal carcinoma. Pathmanathan and colleagues 172 reported 11 cases of isolated dysplasia or CIS originating from the nasopharynx from a pool of 1811 patients (0.6%). In this study, designed primarily to investigate the role of the Epstein-Barr virus in the pathogenesis of nasopharyngeal carcinoma, the authors described isolated preinvasive mucosal changes in a small fraction of cases identified via a large screening program. The alterations were described as thickened epithelium with loss of normal stratification and nuclear pleomorphism ( Fig. 1-26 ). These mucosal changes involve the full thickness of the nonkeratinizing surface epithelium. The dysplastic changes can also result in thinned epithelium with few cell layers, which exhibit both architectural and cytologic abnormalities similar to erythroplasia in the oral cavity.

Figure 1-26 A and B , In situ carcinoma of the nasopharynx. Obvious architectural abnormalities involving the full thickness of the (usually thicker but occasionally thinner) lining characterize carcinoma in situ of the nasopharyngeal mucosa. There are also marked cytologic alterations and a rich lymphocytic population in the submucosal stroma.
In a more recent report, Cheung and colleagues 173 identified nine cases of nasopharyngeal intraepithelial lesions in a biopsy screening study between 1996 and 2002. Histologically, the authors characterize these lesions as involving nonciliated epithelium with the epithelial cells showing mild to moderate nuclear atypia with enlarged vesicular nuclei, accentuated nuclear membranes, and prominent eosinophilic nucleoli. The nucleus-to-cytoplasm ratio was slightly increased, representing the lower end of the intraepithelial neoplastic spectrum as the authors also characterized the level of involvement of the lining to be within the lower one third or one half of the thickness. The higher-grade lesions involved the lower two thirds of the epithelial lining with demonstrable nuclear hyperchromasia and uniformly high nucleus-to-cytoplasm ratios. In both grades, the basement membrane was intact and the mosaic type of differentiation with generally preserved cellular polarity were maintained. The epithelial changes are associated with variable degrees of subepithelial lymphocyte exocytosis, focally disrupting the basement membrane. Marker studies showed increased expression of bcl-2 and p53 in high-grade lesions. A similar report was also published by Pak and colleagues, 174 who identified three intraepithelial neoplastic lesions of the nasopharynx in a 10-year study with two of the three cases subsequently progressing into invasive carcinoma in intervals of 40 to 48 months. The same group reported on the utility of using contact endoscopy to identify the atypical cells of a preinvasive lesion in the nasopharynx in a clinical setting, which may not be evident in a routine imaging examination.

Molecular and Biomarker Studies
Sheu and colleagues 175 studied the immunohistochemical expression of p53 and bcl-2 in normal, inflamed, dysplastic, and invasive nasopharyngeal carcinoma. The authors reported that 80% of the dysplastic epithelium adjacent to invasive nasopharyngeal carcinoma had detectable expression of p53 protein. They also found overexpression of p53 and increased expression of bcl-2 in the dysplastic epithelium. Both this study and the previously mentioned report by Pathmanathan and colleagues 172 have indirectly implicated dysplastic epithelium as the precursor of invasive carcinoma in the nasopharynx by virtue of the intermediate position that it occupies between normal mucosa and invasive carcinoma. In addition, the expression of the viral genome p53 and bcl-2 molecular markers in these areas of transition from normal to dysplasia to invasive cancer argues for these intermediate preinvasive mucosal changes leading to invasive carcinoma.

Intraoperative (Frozen-Section) Interpretation of Squamous Intraepithelial Neoplasia
One of the most frequent indications for intraoperative consultations for surgical procedures aimed at resecting SCC of the UADT is to ensure that the surgical margins of resections are free of tumor (invasive carcinoma for all margins and/or significant dysplastic/intraepithelial neoplastic changes for peripheral mucosal margins). The latter is an area that can be hampered by both technical and interpretation difficulties. We believe that both difficulties can be markedly alleviated if these samples are handled carefully and are evaluated microscopically, applying the same criteria used for routinely processed sections.
From a gross evaluation standpoint, it is important that mucosal margins are carefully inspected to define the shiny epithelial lining and ensure an “on-edge embedding that allows for well-oriented histology with minimal tangential sectioning (an artifact that can lead to a false impression of a lack of maturation and dysplastic changes). Equally important, inappropriate embedding can result in sections without a mucosal lining, precluding the ability to assess this compartment altogether.
Good-quality sections that are of appropriate thickness (3–5 μm) and are free of folds ( Fig. 1-27 ) are essential for accurate evaluation. It is important to keep in mind that frozen-section preparations often have a technique-related artifact of having nuclei appear larger, with a microscopic impression of a higher nucleus-to-cytoplasm ratio, leading to an overestimation of the presence of dysplastic changes ( Fig. 1-28 ). This phenomenon is likely to be more frequently encountered when assessing frozen sections of stratified epithelia including the UADT mucosa. Comparing the frozen-section slides to their routinely processed counterparts of the same tissue often confirms an epithelial lining within the normal histologic range (see Fig. 1-28 B ).

Figure 1-27 Squamous mucosal frozen-section preparation. Orientation and technical quality. Good-quality sections ( A ) that are of appropriate thickness (3–5 μm) and free of folds are essential for accurate evaluation of the mucosal lining and stromal compartment. B , Poor-quality frozen section.

Figure 1-28 Potential tendency for overinterpretation of dysplasia/squamous intraepithelial neoplasia in frozen-section preparation of squamous mucosa. The technical preparation of frozen sections tends to be associated with the artifact of having nuclei that appear larger with a microscopic impression of a higher nucleus-to-cytoplasm ratio leading to an overestimation of the presence of dysplastic changes. Comparing the frozen-section slides ( A ) with their routinely processed counterparts ( B ) of the same tissue often confirms an epithelial lining within the normal histologic range.
During frozen-section evaluation, a degree of reactive epithelial changes when significant inflammation is present should be allowed. The inflammation can also cause squamous metaplasia within the lining of normally glandular submucosal structures ( Fig. 1-29 ). One should also keep in mind that dysplasia may also involve submucosal glands.

Figure 1-29 A and B , Squamous metaplasia in submucosal glands. Frozen-section preparation. Radiation and current or resolving mucosal inflammation, among other factors, can cause squamous metaplasia within the lining of normally glandular submucosal structures. On occasion, if partially sectioned and accompanied by cytologic atypia, such structures can cause interpretational difficulty.
With these considerations in mind, determining the presence of dysplasia/SIN, particularly of the moderate to severe range, can be established on most well-prepared frozen-section slides of mucosal margins using the same architectural and cytologic criteria discussed earlier ( Fig. 1-30 ).

Figure 1-30 A–D , High-grade dysplasia/squamous intraepithelial neoplasia (SIN). Frozen-section preparations. When the frozen-section preparation is of acceptable orientation and quality of sectioning and staining, it is usually not difficult to determine the presence of dysplasia/SIN, particularly of the moderate to severe range in sections of the mucosal margins. The same architectural and cytologic criteria used for routine histology are applicable.
Finally, stromal inflammation and/or vascular and endothelial proliferation can lead to an erroneous impression of the presence of invasive tumor, particularly in thick frozen-section preparations ( Fig. 1-31 ).

Figure 1-31 A–C , Stromal reaction and vascular proliferation. The fibroconnective tissue stroma in these sections appears occupied by a darkly stained proliferative process that mimics on low magnification and particularly in thick frozen-section preparations invasive carcinoma, considering that the surface epithelium is also dysplastic. Closer inspection of this area, however, confirms the process to represent a rather florid vascular proliferation with endothelial hyperplasia.

Molecular Alterations in Carcinogenesis
SSC in the UADT develops during a long-term, multistep accumulation of nonlethal genetic changes in a single precursor cell, which leads to the evolution of a clonal population of transformed epithelial cells with a selective growth advantage. 176, 177 The first genetic model of tumor development was furnished for colorectal cancer. Its three basic principles also suit other epithelial tumors, including SCC UADT: (1) cancer develops as the result of inactivation of TSGs and/or activation of proto-oncogenes; (2) a sequence of genetic changes leads to the development of tumor phenotype; and (3) net accumulation of genetic changes finally determines the phenotype of malignancy, although the order of events during this process may vary. 177 A tumor progression model was additionally devised for SCC UADT in 1996 by Califano and colleagues. 176 They delineated a distinct pattern and potential timing of genetic alterations along a continuum of malignant transformation, together with morphologic changes.
However, despite these outstanding achievements in understanding head and neck carcinogenesis, the genetic events and their exact sequence underlying the progression from normal epithelium to invasive SCC UADT have not been entirely elucidated. From six to 10 independent genetic changes within a single cell have been estimated to be necessary for SCC UADT development. 178 Molecular changes are believed to be morphologically expressed as different grades of squamous intraepithelial lesions, from squamous cell hyperplasia to invasive cancer. The latency period between carcinogen exposure and appearance of malignancy may last up to 25 years. 179
Genetic changes of the squamous epithelium, ranging from mutation of a single nucleotide to numerical and structural alterations of entire chromosomes, are in the oral cavity, oro- and hypopharynx, and larynx causally related to a number of mutagens. They originate from the environment and specific lifestyle, that is, chemical carcinogens, physical agents and micro-organisms, while some DNA damage may be also induced spontaneously. 180 Initiation of precursor lesions in the previously mentioned regions is mainly related to recognized carcinogens from alcohol and tobacco, such as polycyclic aromatic hydrocarbons, nitrosamines, aldehydes, and aromatic amines. 181, 182 Interestingly, the difference in genetic and expression alterations in precursor lesions and SCC of the oral cavity, oro- and hypopharynx, and larynx suggests that the genetic profile is predominantly related to histopathologic grade rather than site of origin of the lesions. 183 It therefore seems reasonable to group and evaluate precursor lesions and overt cancers of these regions (excluding tonsils) together. The identification and characterization of the comprehensive specter of genetic aberrations in SCC development may not only elucidate the process of carcinogenesis but may also provide promising diagnostic tools for early detection, prevention, and assessment of cancer risk from precursor lesions.

Field Cancerization
The clinical concept of field cancerization originally proposed by Slaughter and colleagues 163 was formulated to explain carcinogenesis of multiple cancers and precursor lesions in the UADT, particularly in the oral cavity. The authors made the point that a primary tumor is encircled by precancerous lesions, and after resection of malignancy, second primaries may develop from the remaining altered epithelium. This hypothesis, therefore, suggested that lengthy exposure to carcinogens (tobacco use and alcohol consumption) lead to “condemned mucosa” containing many mutated cells, from which new (polyclonal) tumors independently arise. 188 The histologically based field cancerization concept has gradually been overtaken by the one established on molecular changes of the affected mucosa. The hypothesis, proposed by Bedi and colleagues 185 and Califano and colleagues, 185 - 187 advocates micrometastatic spreading or a monoclonal theory, which means that a precancerous field of mucosa may derive from an early genetic event that has undergone clonal expansion and lateral migration or expansion. Some other authors suggest that at least a proportion of second primary tumors in the UADT develop from a single contiguous genetically altered field and thus arise from a clonal origin. 188 - 190

Chromosomal Changes
The search for specific target areas in the genome, involved in development and progression of SCC UADT, was initially studied with conventional cytogenetic techniques, which enabled the detection of various chromosomal aberrations, such as chromosomal loss or gain, rearrangements (inversions and translocations), deletions, and amplifications. Classic cytogenetic studies of SCC UADT and of precursor lesions have been limited by multiple impediments, including low frequency of mitotic figures from direct preparations, suboptimal chromosome preparations, significant complexity of cytogenetic changes, and obstacles in single-cell preparations. 191 - 193 Nevertheless, karyotyping analyses, additionally supplemented by new techniques such as multicolor fluorescence in situ hybridization and spectral karyotyping have been adequately productive in the identification of key genomic regions involved in the development and progression of SCC UADT. Comparative genomic hybridization is a form of fluorescence in situ hybridization that comprehensively screens the genome for gains and losses of DNA segments across the entire genome in a single hybridization experiment, using either fresh or paraffin-embedded specimens. 194 - 196 Using comparative genomic hybridization, Brieger and colleagues 197 found that gains of genetic material on chromosomal arms 15q and 21q are early events in the development of SCC UADT, while gains on 3q, 8q, and 11q might later contribute to tumor progression.
Microsatellite markers, which are repeated sequences scattered throughout the genome that have revolutionarily made it possible to ascertain minimal regions of loss on particular chromosomal arms, 198 have been shown to be useful molecular indicators for detecting and establishing the behavior of precursor lesions. DNA ploidy, detecting by flow cytometry, image analysis, and molecular cytogenetic analyses such as metaphase and interphase fluorescence in situ hybridization assays is a widely studied genetic marker in the process of malignant progression in the UADT, in which genetically stable diploid cells are replaced by genetically unstable aneuploid cells. Measurement of DNA ploidy in oral, pharyngeal, and laryngeal precursor lesions has provided a view to anticipating their clinical behavior more objectively. 193, 199 - 201 Chromosomal aneuploidy was found to precede malignant transformation and increased progressively with the severity of lesions in both the frequency of affected cells and in the number of affected chromosomes. 180, 199 In laryngeal lesions, numerical chromosome aberrations, such as tetraploidization, have already been found in an initial stage of carcinogenesis (transition from hyperplasia to dysplasia). On the other hand, the acquisition of genetic instability, as evidenced by chromosome copy number imbalances and chromosome polyploidization, appears to be associated with progression to malignant growth. 201

Tumor Suppressor Gene Inactivation and Allelic Loss
Failure of growth inhibition is one of the most decisive changes in the process of carcinogenesis. Cell proliferation is controlled by the products of a TSG. Knudson 202 proposed a “two-hit hypothesis” in which the loss of TSGs in epithelial tumors may be produced by the mutation of one allele and loss of another, caused by some other mechanisms leading to a deficit of TSG products. Loss of genomic material in one of a pair of chromosomes is presented as loss of heterozygosity (LOH). LOH, which is revealed at chromosomal areas that are supposed to contain TSGs, might be related to the process of malignant alterations. 179, 203
The correlation of specific patterns of genetic changes during the process of carcinogenesis in the head and neck region is often limited by difficulties in obtaining tissue specimens from the same lesion over time. 204 Despite these serious obstacles, numerous studies of LOH patterns provide promising data to supplement the genetic model of SCC development in the oral cavity and larynx. 176, 186, 201, 204 - 208 The first, and later refined, progression model in carcinogenesis of the head and neck region is entirely based on LOH analyses. 176, 186 The most frequently altered chromosomal region in the genetic model of a precursor lesion is 9p21, where the p16 gene is located, followed by 3p21, 11q13, which contains the cyclin D 1 locus, and 17p13, where the p53 gene is located; 3p with at least three putative tumor suppressor loci, 13q21, 6p, and 8. Certain genetic events, such as 9p21 LOH, 3p LOH, and 17p13 have been found to be among the earliest events on the progression pathway. 184 Sanz-Ortega and colleagues 206 and Veltman and colleagues 209 reported similar results showing that laryngeal dysplasia correlates with LOH at 3p21, 5q21, 9p21, and 18q21 in early carcinogenesis. LOH at either 9p21 or 3p14 has also been identified in precursor oral lesions, and the presence of one or both of these alterations has been associated with SCC development, probably even with its initiation. 205
Alterations of the p53 gene, caused by allelic losses, point mutations, deletions, insertions, or inactivation through complex formation with viral proteins (e.g., HPV), abolish its function as a guardian of the genome. A cell’s ability to repair and undergo apoptosis due to DNA damage is impaired, ultimately leading to genomic instability. 47, 210 - 212 Approximately half of head and neck cancers contain a mutation at 17p13, where the p53 gene resides, frequently in the codons 238-248 hot spot region. 213 - 215 It has been suggested that the rate of mutations may be even higher when all 11 exons of the p53 gene are sequenced. 216 Loss of p53 function occurs in earlier phases of head and neck carcinogenesis, 176, 186, 217, 218 and consequent loss of p53 function results in progression from precursor lesions to overt SCC, which increases the likelihood of further genetic progression. 210, 212 Overexpression of the p53 protein is frequently but not always associated with gene mutation. The predictive value of the p53 overexpression in SCC UADT and precursor lesions remains controversial. 218 Gallo and colleagues 217 reported that simultaneous p53 and p16 INK4a alterations in precursor laryngeal lesions seem to have some malignant potential. On the contrary, the predictive value of p53 overexpression appears to be less pronounced in oral lesions. 218, 219 However, Homann and colleagues 218 reported interesting data in a prospective study of p53 overexpression in tumor distant epithelia (derived from a head and neck site adjacent to but away from the original tumor, that is, oropharyngeal mucosa with a laryngeal primary or hypopharyngeal mucosa with an oropharyngeal primary) of the head and neck cancer patients. They found that p53 overexpression in tumor distant epithelia could serve as a biomarker to identify those patients who are at high risk of developing a second primary cancer. 218

Microsatellite Instability
Microsatellite instability (MSI), characterized by simple insertions or deletions of base pairs, is associated with mutations in genes concerned with replication and DNA repair. MSI is a dominant mechanism in development in some epithelial tumors, such as hereditary nonpolyposis colon cancer, but is infrequently present in head and neck carcinogenesis. The proportion of high- and low-MSI SCC UADT was found to be 3% and 10%, respectively, but no mutation was identified in mismatch repair genes HLH1 and HSH2 . 220 MSI is therefore considered an infrequent event in head and neck carcinogenesis, but when it does occur, it shows some different characteristics compared with that in colorectal cancer. In addition, Ha and coworkers reported that MSI increases as epithelial changes in the head and neck region progress to overt cancer, ranging from 5.9% in hyperplastic lesions to 33% in invasive SCC. 45 However, the results of both studies are not completely comparable, as Ha and colleagues 45 studied MSI only with microsatellite markers related to regions where LOH is a predominant finding in SCC UADT and not with markers associated with regions characteristically changed in the hereditary nonpolyposis colon cancer (Bethesda markers). 220 The results of Glavac and colleagues 220 indicate the dominant role of the suppressor in comparison with the mutator pathway in the SCC carcinogenesis.

Proto-oncogene Amplification
Proto-oncogenes importantly participate in regulating cellular growth and proliferation. Different categories of oncogenes significantly contribute in the development of precursors and SCC UADT. Important members of the cell cycle regulators are cyclin D 1 and epidermal growth factor receptor (EGFR). Cyclin D 1 , located in the 11q13 chromosome region, has a central role in the cell cycle. It regulates the G 1 /S transition by phosphorylation and inactivation of the retinoblastoma gene, which is considered a key event in cell cycle control. Gene amplification and overexpression have been frequently described in SCC UADT and also in its precursor lesions. 221 - 223 Cyclin D 1 inhibitor, p16 gene, contributes to cell cycle control through decrease of Rb gene phosphorylation. Despite related but opposite functions of genes, gain of cyclin D 1 and loss of p16 are considered to be independent mechanisms in G 1 /S phase dysregulation. 224, 225 It is believed that constitutive activation of the cyclin D 1 pathway can reduce or overcome certain mitogen requirements for cell proliferation and thus contribute to oncogenic transformation. 47
Amplification of the chromosome 11q13 is a frequently detected event in SCC UADT development, observed in 30% to 50% of cases. 226 In addition to cyclin D 1 , several genes that have potential functional importance for head and neck tumorigenesis are frequently coamplified in this region, including the INT2 gene (a member of the fibroblast growth factor family), EMS1 , FGF4 , vascular endothelial growth factor-βετα, phosphatase-1a, and glutathione S-transferase p. INT2 gene amplification, in particular, has been detected as an early event in head and neck carcinogenesis, already present at the stage of dysplasia. These data provide evidence that gene amplification can also occur early in the UADT tumorigenesis process. 227
The EGFR affects cell division, migration, adhesion, differentiation, and apoptosis through a tyrosine kinase pathway. 228 Overexpression of EGFR was found to correlate with the severity of epithelial abnormalities, suggesting that its alteration is an early genetic event in head and neck cancer development. 229, 230

Telomerase Reactivation
The telomerase enzyme is a multisubunit enzyme complex. A telomerase catalytic subunit functions as a reverse transcriptase that can synthesize the telomeric ends at each cell division. 231 In normal tissue, the telomerase remains undetectable, with the exception of germ cells and stem cells of renewable tissues. 232 Several studies have confirmed that reactivation of telomerase is one of the most frequent events in human carcinogenesis, associated with cellular immortality, which contributes to the accumulation of genetic abnormalities and increase in genomic instability. 231, 233 Telomerase was found to be reactivated in 90% of malignant neoplasms, including SCC UADT. Furthermore, recent studies have suggested that telomerase reactivation is an early event in oral and laryngeal carcinogenesis, already detectable at the stage of precursor lesions (atypical hyperplasia or severe dysplasia). It has been proved that the presence and relative quantity of human telomerase reverse transcriptase mRNA, as well as human telomerase reverse transcriptase protein, increase progressively with the degree of squamous intraepithelial lesions in laryngeal and oral epithelium. 234 - 237 Nevertheless, other genetic changes appear to be necessary for progression of these epithelial changes to invasive SCC.

Genetic Progression Model
Califano and colleagues 176, 179, 186 related the entire spectrum of squamous intraepithelial lesions, ranging from squamous cell hyperplasia to CIS and invasive SCC, with a series of corresponding genetic alterations. They found a stepwise progression of allelic loss, which explains how precursor lesions can grow and spread. The authors advocate a hypothesis that a single cell with genetic changes and its daughter cells, with an additional accumulation of alterations, develop progressive phenotypic changes until they become malignant. This genetic progression model not only favors the idea of clonal expansion but it also delineates the limits to which clones of transformed cells can migrate. They proved that clonal epithelial populations, conferred with significant growth advantage, may migrate to distances of several centimeters. 186 Clonal genetic changes are present even in the earliest lesions. Thus, 30% of benign hyperplastic lesions express loss at 9p21 or 3p, and these events are presumed to be among the first steps in the progression to malignancy.
Identification of genetic alterations in precursor lesions also has prognostic significance. Progressing and nonprogressing cases of oral epithelial dysplasia show different LOH patterns with multiple allelic losses. Patients with LOH at 3p and/or 9p but at no other arms exhibit only a slight increase of 3.8-fold in relative risk of oral cancer development. In contrast, those patients with additional losses on 4q, 8q, 11q, or 17p, which appeared uncommon in nonprogressing cases, showed a 33-fold increase in relative risk of progression to cancer compared with cases that retained both of these arms. 204 A recently presented transcriptional progression model for head and neck cancer using array-based gene expression profiling characterizes the timing and nature of genetic events encompassing early and late stages of SCC UADT. Convincing evidence suggests that the majority of genetic alterations occur early in tumorigenesis because a group of 334 genes in premalignant lesions were significantly up- or down-regulated when compared with the normal control tissue, whereas only 23 genes were altered in a comparison of the premalignant with the malignant group. 183
In conclusion, understanding the fundamental molecular alterations in SCC UADT development might lead to application of additional treatment modalities for patients with this disease. The use of adenoviral vectors to restore p53 gene expression, demethylating agents to re-express p16 , anti-EGFR immunotherapy, and small-molecule kinase inhibitors is promising for possible treatment, although all these methods are still in various stages of testing and clinical trials. 211 Regrettably, at present, no single molecular biomarker can reliably predict the risk of cancer progression in different grades of squamous intraepithelial lesions in the head and neck region. Previous examinations of genetic events were more or less focused on the single-gene level. In contrast, a new array-based technology allows thousands of genes to be examined simultaneously, making a better understanding of the events characteristic of head and neck carcinogenesis possible. 238 Although several markers, including loss of chromosome regions 9p21-22 and 17p13, overexpression/amplification of 11q13, EGFR overexpression, telomerase reactivation, and aneuploid DNA content, generally signify an increased risk of malignant progression, 176 various treatment modalities for different grades of squamous intraepithelial lesions and their prognostication still mostly rely on clinical data, adequate biopsy specimens, and histopathologic findings. 34, 203

Molecular Markers of Dysplasia
Since the initial histologic characterization of premalignant conditions of the UADT, one of the major advances in this field has been the identification of the molecular alterations with which they are associated ( Table 1-13 ). 239 While biologically justified and crucial in reducing the variability intrinsic in a morphology-based system, 139 the inclusion of molecular markers has yet to find a role in the classification of dysplasia. Yet, understanding the molecular basis of progression for UADT preneoplastic lesions is invaluable in understanding the biology of SCC. Furthermore, it may be of clinical relevance if molecular markers of dysplasia are used as screening tools for early detection or as intermediate markers in chemoprevention trials. The prototype model of molecular alterations associated with preneoplastic progression is the colon, where sequential molecular alterations have first been described to occur alongside the morphologic progression from normal to cancer. 140 A similar accumulation of alterations has been described in the UADT to occur in increasing morphologic grades of dysplasia (see Table 1-13 ).
Table 1-13 Incidence of Molecular Alterations in Low-Grade and High-Grade Dysplasia   LGD HGD EGFR 170, 246 + ++ Mib-1/PCNA 49, 51, 245 + ++ p21 248 + + p53 239, 246, 247 9–67% 33–85% Aneuploidy 136 33% 100% Apoptosis 249 + ++ bcl-2 175 + ++
+, ++, focal and diffuse immunoreactivity, respectively; EGFR, epidermal growth factor receptor; HGD, high-grade dysplasia; LGD, low-grade dysplasia.
Molecular alterations occurring in preneoplastic lesions of the UADT belong to two main groups, reflecting abnormalities in either cellular differentiation or cell cycle control. Changes of the first group include those affecting the profile of keratin expression and were the first to be reported. In normal epithelium, low molecular weight keratins are expressed in the basal layer and high molecular weight keratins in the stratum spinosum. Abnormal cells express, regardless of their position, low molecular weight keratins, while high molecular weight keratins are expressed either in the uppermost keratinized layer or not at all in dysplasia. Thus, suprabasal expression of low molecular weight keratins such as CK19 has been proposed to constitute a marker of dysplasia, 19, 125 although this finding cannot reliably distinguish hyperplasia from true dysplasia. 49
The foremost alteration in cell cycle regulation occurring in dysplasia is the occurrence of an increased proliferative rate in association with increasing morphologic grades. This has traditionally been assessed by morphologic evaluation, that is, counting mitoses. However, more recently, the discovery of proliferating cell nuclear antigen and Ki-67 antigens, expressed exclusively by proliferating cells, has allowed an objective evaluation of the proliferative rate. 51, 240 - 243 By both methods, a continuum of increasing proliferative rates is seen in increasing grades of dysplasia. In contrast, the only population to show infrequent positivity in normal mucosa is the basal layer, compatible with its role as progenitor cell. 51, 240, 241 Interestingly, in simple mucosal hyperplasia, only the basal layer shows positive staining for proliferative antigens, setting it aside from true dysplasia, where the expression of this antigen extends to suprabasal cells. 49
Alterations in many molecules controlling the cell cycle are frequent in dysplasia and are likely responsible for its hyperproliferative state. A continuum of increasing positivity is observed in the rate of p53 positivity, as detected by immunohistochemistry in lesions of increasing histologic grades. 241, 244, 245 While negative in normal epithelium, p53 is found in 9.4% to 32% of low-grade and 33% to 50% of high-grade cases of dysplasia. 241, 245 Suprabasal expression of CK 19 and proliferating cell nuclear antigen is associated with positivity for p53 in the majority of cases of dysplasia, 49 highlighting the link existing between abnormal differentiation and cell cycle alterations. Alterations in the distribution of the cyclin kinase inhibitor p21 also occur. Whereas only the intermediate layer of the normal epithelium expresses this marker, the entire dysplastic epithelium shows positivity. 246
Increasing percentages of EGFR positivity are also seen, seemingly associated with the dysplastic component. 244 Increasing percentages of aneuploid populations are also observed in increasing grades, progressing from 33% of SIN I to 78% of SIN II and 100% of SIN III. 119
Apoptosis increases in parallel with the proliferative rate, as observed morphologically or by DNA in situ labeling techniques. 241, 247 The relevance of alterations in the apoptotic rate is highlighted by data showing a change in expression of the antiapoptotic protein bcl-2 (the target gene deregulated as a consequence of the 14;18 translocation occurring in most follicular lymphomas) in dysplasia. While normally found only in 37% of normal squamous mucosa, where its expression is restricted to the basal layer, its expression increases to 71% of dysplastic lesions and 80% of invasive ones in the nasopharynx. 248
Genetic studies of preneoplastic lesions for LOH have shown that increasing grades of dysplasia show accumulation of genetic deletions, compatible with the commonly accepted model envisioning cancer as the result of multiple genetic “hits.” The earliest and most common changes occur at sites 3p and 9p. The 9p locus harbors genes for the kinase inhibitors p16 and p19, which are frequently altered in HNSCC, as well as in malignancies from other sites. The 3p14 and 3p21 sites harbor several candidate TSGs, including the gene deleted in von Hippel-Lindau disease, the DNA mismatch repair enzyme hMLH1, affected in hereditary nonpolyposis colon cancer, the retinoic acid receptor βετα, and the fragile histidine triad ( FHIT ) gene. 249 While the identification of the specific suppressor gene(s) located at 3p14 and 3p21 whose loss is responsible for the development of cancer is still unresolved, the FHIT gene has recently been proposed to be a specific target of cigarette smoke carcinogens 171, 250, 251 and shown to behave as a TSG in vitro. 252 In a retrospective study correlating molecular alterations with progression to overt cancer, losses at 3p and 9p loci were the most common lesions both in nonprogressing and progressing premalignant lesions. However, they were virtually always present in progressing lesions, compatible with a model whereby they are necessary but not sufficient for malignant transformation. The occurrence of additional chromosomal losses was shown to confer a much higher risk of progression, comparable to losses at 3p and 9p alone. 253 These included chromosomal sites 4q, 8p, 11q, and notably 17p. 253, 254 Because this latter site is the locus of p53, these data are compatible with the histochemical data quoted previously, showing alterations in p53 as an important event in the progression of premalignant lesions. Overall, these data are compatible with a model envisioning loss of genetic material in chromosomes 3p and 9p loci as involved in initiation 253 and additional genetic losses, including p53, as involved in progression.
Changes in the basement membrane have also been described in dysplasia. Normal and hyperplastic mucosae are usually associated with a prominent and continuous basement membrane, as assessed by immunohistochemical staining with collagen type IV and laminin. The basement membrane is usually prominent and continuous in mild to moderate dysplasia; in contrast, in severe dysplasia/CIS, it is often thinned and discontinuous. However, some invasive cancers retain a continuous pattern of basement membrane staining, and thus this stain cannot be used to reliably discern noninvasive from invasive proliferations. 204
Dysplastic lesions of the nasopharynx have been shown to harbor clonal integration of the Epstein-Barr virus, in concordance with the accepted role that this virus plays in the development of nasopharyngeal carcinoma. 176 Expression of Epstein-Barr virus antigens has also been shown to occur focally in the basal layer of normal squamous mucosa of the tongue and to be augmented in oral leukoplakia occurring in patients with human immunodeficiency virus. 255

Biomarkers of Epithelial Maturation and Intraepithelial Maturation
Numerous investigators have diligently searched for markers of maturation or abnormal expression of markers indicative of loss of maturation. The resurgence of interest in chemoprevention and reversal of oral mucosal changes such as leukoplakia has resulted in attempts to identify biomarkers that can be used to monitor epithelial maturation. 256 One of the first markers to be carefully investigated was the expression of cytokeratins with the hope that expression of abnormal cytokeratins would signify abnormal epithelium. 242 Unfortunately, cytokeratins vary greatly within dysplastic epithelium as does the phenotypic expression (morphology) reflecting genetic alterations. 242 In general, simple or low molecular weight keratins are expressed in classic or atrophic forms of CIS but not in those demonstrating normal surface maturation with hematoxylin-eosin identifiable surface cytoplasmic keratin, usually of high molecular weight. 257 However, not all studies have been able to confirm these observations. 49, 258 Attempts to identify marker chromosome or genetic changes signaling neoplastic transformation have resulted in a number of important observations. Cell DNA content has repeatedly been increased or abnormal in the most severe dysplasia/SIN. Measurements confirming abnormal DNA content have been performed by image analysis. 151, 152 Almost all high-grade dysplasia/SIN lesions have abnormal DNA nuclear content. In addition, some dysplasia/SIN lesions with prominent keratinization are also aneuploid, despite having less obviously abnormal nuclear alterations. This seems a surprising observation from a morphologic perspective but reinforces what we have learned, namely, that excessive keratinization in an abnormal pattern also signifies expression of neoplastic change. Similar but more sophisticated observations documenting individual chromosomal polysomy in preinvasive epithelial changes have also been reported. 259 Subsequent molecule-oriented studies have identified a number of abnormalities in dysplasia/SIN; however, the most commonly reported analyzed gene products are overexpression of EGFR and the p53 oncogene. These studies have found increased EGFR expression with high grades of SIN. 260, 261 Both increased p53 gene product and p53 mutations have been identified in noninvasive SIN and have been noted to increase in invasive carcinomas. 210, 261 p53 gene product expression, measured by immunohistochemistry, is also increased in SIN adjacent to invasive cancers and is thought by some to represent a potential marker of recurrence when present in surgical margins. 43
Several recent studies provide strong evidence in support of augmenting traditional histopathologic examination with genetic testing. Mao and colleagues 205 correlated LOH in a significant number of oral leukoplakias at 9p21 and 3p14 with a greater probability of progression to HNSCC. This finding suggests the potential of microsatellite analysis in predicting cancer risk of oral leukoplakia. 262 Rosin and colleagues 204 also used this technique in studying the progression of oral lesions initially diagnosed as epithelial hyperplasia or mild/moderate dysplasia. They found that almost all lesions progressing to SCC exhibit LOH at these two sites. Five other regions (4q, 8p, 11q, 13q, and 17p) were examined. Loss of any of these additional chromosomes, in addition to 3p and/or 9p, provided better predictive value of developing SCC, with nearly 60% of the hyperplastic or dysplastic lesions exhibiting LOH at 3p and/or 9p, plus LOH at an additional site developing carcinoma. These data are preliminary, and additional prospective studies are necessary to better understand their importance. Because microsatellite analysis can be done noninvasively on exfoliative cells collected by scraping the lesion surface, this technique may provide additional data relevant to patient care.


1 Mithani SK, Mydlarz WK, Grumbine FL, et al. Molecular genetics of premalignant oral lesions. Oral Dis . 2007;13:126-133.
2 Ustundag E, Kaur AC, Boyaci Z, et al. Combined use of histopathology with touch smear cytology in biopsies of the larynx. Eur Arch Otorhinolaryngol . 2006;263:866-871.
3 Sadri M, McMahon J, Parker A. Laryngeal dysplasia: Aetiology and molecular biology. J Laryngol Otol . 2006;120:170-177.
4 Dobrossy L. Epidemiology of head and neck cancer: Magnitude of the problem. Cancer Metastasis Rev . 2005;24:9-17.
5 Taylor B, Rehm J. When risk factors combine: The interaction between alcohol and smoking for aerodigestive cancer, coronary heart disease, and traffic and fire injury. Addict Behav . 2006;31:1522-1535.
6 Hassan MA, Lund VJ, Howard DJ, et al. Are the demographics for squamous cell cancer in the head and neck changing in the United Kingdom? J Laryngol Otol . 2007;121:154-157.
7 Moriniere S. [Epidemiology of head and neck cancer]. Rev Prat . 2006;56:1637-1641.
8 Thomas G, Hashibe M, Jacob BJ, et al. Risk factors for multiple oral premalignant lesions. Int J Cancer . 2003;107:285-291.
9 Epstein JD, Knight TK, Epstein JB, et al. Cost of care for early- and late-stage oral and pharyngeal cancer in the California medicaid population. Head Neck . 2008;2:178-186.
10 Otoh EC, Johnson NW, Mandong BM, et al. Primary head and neck cancers in Jos, Nigeria: A re-visit. West Afr J Med . 2006;25:92-100.
11 Najeeb T. Clinicopathological presentation of tongue cancers and early cancer treatment. J Coll Physicians Surg Pak . 2006;16:179-182.
12 Brouha XD, Tromp DM, de Leeuw JR, et al. Laryngeal cancer patients: Analysis of patient delay at different tumor stages. Head Neck . 2005;27:289-295.
13 Day TA, Chi A, Neville B, et al. Prevention of head and neck cancer. Curr Oncol Rep . 2005;7:145-153.
14 Matthias C. [Early detection and prevention of carcinomas of the oral cavity and pharynx]. MMW Fortschr Med . 2005;147:53-55.
15 Sutthavong S, Jansisyanont P, Boonyopastham N. Oral health care in head and neck cancer. J Med Assoc Thai . 2005;88(Suppl 3):S339-S353.
16 Barzan L, Talamini R, Franchin G, et al. Changes in presentation and survival of head and neck carcinomas in Northeastern Italy, 1975–1998. Cancer . 2002;95:540-552.
17 Fiorella R, Di Nicola V, Resta L. Epidemiological and clinical relief on hyperplastic lesions of the larynx. Acta Otolaryngol Suppl . 1997;527:77-81.
18 Goldman NC. Problems in outpatients with laryngeal hyperplastic lesions. Acta Otolaryngol Suppl . 1997;527:70-73.
19 Abbey LM, Kaugars GE, Gunsolley JC, et al. Intraexaminer and interexaminer reliability in the diagnosis of oral epithelial dysplasia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 1995;80:188-191.
20 Colella G, De Luca F, Lanza A, et al. [The malignant transformation of leukoplakia of the oral cavity. A review of the literature and clinical case reports]. Minerva Stomatol . 1995;44:291-300.
21 Scala M, Moresco L, Comandini D, et al. [The role of the general practitioner and dentist in the early diagnosis of preneoplastic and neoplastic lesions of the oral cavity]. Minerva Stomatol . 1997;46:133-137.
22 Driemel O, Hertel K, Reichert TE, et al. [Current classification of precursor lesions of oral squamous cell carcinoma principles of the WHO classification 2005]. Mund Kiefer Gesichtschir . 2006;10:89-93.
23 Fischer DJ, Epstein JB, Morton THJr, et al. Reliability of histologic diagnosis of clinically normal intraoral tissue adjacent to clinically suspicious lesions in former upper aerodigestive tract cancer patients. Oral Oncol . 2005;41:489-496.
24 Fischer DJ, Epstein JB, Morton TH, et al. Interobserver reliability in the histopathologic diagnosis of oral pre-malignant and malignant lesions. J Oral Pathol Med . 2004;33:65-70.
25 Zerdoner D. The Ljubljana classification—its application to grading oral epithelial hyperplasia. J Craniomaxillofac Surg . 2003;31:75-79.
26 Nagy P. [The Ljubljana classification of epithelial hyperplastic laryngeal lesions]. Orv Hetil . 2003;144:2415-2417.
27 Holmstrup P, Vedtofte P, Reibel J, et al. Long-term treatment outcome of oral premalignant lesions. Oral Oncol . 2006;42:461-474.
28 Scully C, Sudbo J, Speight PM. Progress in determining the malignant potential of oral lesions. J Oral Pathol Med . 2003;32:251-256.
29 Nogami T, Kuyama K, Yamamoto H. Histopathological and immunohistochemical study of malignant transformation of oral leukoplakia, with special reference to apoptosis-related gene products and proliferative activity. Acta Otolaryngol . 2003;123:767-775.
30 Kujan O, Khattab A, Oliver RJ, et al. Why oral histopathology suffers inter-observer variability on grading oral epithelial dysplasia: An attempt to understand the sources of variation. Oral Oncol . 2007;43:224-231.
31 Warnakulasuriya S. Histological grading of oral epithelial dysplasia revisited. J Pathol . 2001;194:294-297.
32 Kurman R, Norris HJ, Wilkinson E. Atlas of Tumor Pathology. Tumors of the Cervix, Vagina, and Vulva. Washington, DC: Armed Forces Institute of Pathology, 1992;44-55.
33 van der Waal I, Axell T. Oral leukoplakia: A proposal for uniform reporting. Oral Oncol . 2002;38:521-526.
34 Gale N, Kambic V, Michaels L, et al. The Ljubljana classification: A practical strategy for the diagnosis of laryngeal precancerous lesions. Adv Anat Pathol . 2000;7:240-251.
35 Kambic V, Gale N, Ferluga D. Laryngeal hyperplastic lesions, follow-up study and application of lectins and anticytokeratins for their evaluation. Pathol Res Pract . 1992;188:1067-1077.
36 Kramer IR, Lucas RB, Pindborg JJ, et al. Definition of leukoplakia and related lesions: An aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol . 1978;46:518-539.
37 Ricci G, Molini E, Faralli M, et al. Retrospective study on precancerous laryngeal lesions: Long-term follow-up. Acta Otorhinolaryngol Ital . 2003;23:362-367.
38 Resta L, Colucci GA, Troia M, et al. Laryngeal intraepithelial neoplasia (LIN). An analytical morphometric approach. Pathol Res Pract . 1992;188:517-523.
39 Hellquist H, Lundgren J, Olofsson J. Hyperplasia, keratosis, dysplasia and carcinoma in situ of the vocal cords—a follow-up study. Clin Otolaryngol Allied Sci . 1982;7:11-27.
40 Neumann OG, Franz B. [Leukoplakias of the larynx (i. clinical and histological classification) (author’s transl)]. Laryngol Rhinol Otol (Stuttg) . 1977;56:828-831.
41 Auerbach O, Hammond EC, Garfinkel L. Histologic changes in the larynx in relation to smoking habits. Cancer . 1970;25:92-104.
42 Goodman ML. Keratosis (leukoplakia) of the larynx. Otolaryngol Clin North Am . 1984;17:179-183.
43 Norris CM, Peale AR. Keratosis of the larynx. J Laryngol Otol . 1963;77:635-647.
44 Barnes L, Eveson JW, Reichart P, Sidransky D, editors: Pathology and Genetics of Head and Neck Tumours. WHO Classification of Tumours, Vol. No. 9. 2005, WHO Press, Geneva: 430
45 Ha PK, Pilkington TA, Westra WH. Progression of microsatellite instability from premalignant lesions to tumors of the head and neck. Int J Cancer . 2002;102:615-617.
46 Hunter KD, Thurlow JK, Fleming J, et al. Divergent routes to oral cancer. Cancer Res . 2006;66:7405-7413.
47 Papadimitrakopoulou VA. Carcinogenesis of head and neck cancer and the role of chemoprevention in its reversal. Curr Opin Oncol . 2000;12:240-245.
48 Lippman SM, Sudbo J, Hong WK. Oral cancer prevention and the evolution of molecular-targeted drug development. J Clin Oncol . 2005;23:346-356.

Normal Anatomy
49 Coltrera MD, Zarbo RJ, Sakr WA, et al. Markers for dysplasia of the upper aerodigestive tract. Suprabasal expression of PCNA, p53, and CK19 in alcohol-fixed, embedded tissue. Am J Pathol . 1992;141:817-825.
50 Yashima K, Maitra A, Rogers BB, et al. Expression of the RNA 0component of telomerase during human development and differentiation. Cell Growth Differ . 1998;9:805-813.
51 Zidar N, Gale N, Cor A, et al. Expression of Ki-67 antigen and proliferative cell nuclear antigen in benign and malignant epithelial lesions of the larynx. J Laryngol Otol . 1996;110:440-445.
52 Browne RM, Potts AJ. Dysplasia in salivary gland ducts in sublingual leukoplakia and erythroplakia. Oral Surg Oral Med Oral Pathol . 1986;62:44-49.
53 Sternberg S. Histology for Pathologists. New York: Raven Press, 1992;451-455.
54 Nasiell M. Metaplasia and atypical metaplasia in the bronchial mucosa: A histopathological and cytopathological study. Acta Cytol . 1996;10:421-427.
55 Stiblar-Martincic D. Histology of laryngeal mucosa. Acta Otolaryngol Suppl . 1997;527:137-141.
56 Fechner R, Mills SE. Larynx and pharynx. In: Sternberg S, editor. Histopathology for the Pathologist . New York: LippincottRaven; 1996:443-455.

Clinical/Gross Mucosal Changes of Injury
57 Schwimmer E. Die idiopatisches scleimahaut plaques der mundhohle (leukoplakia buccalis). Arch Dermatol Syphilol . 1877;9:511-570.
58 WHO International Histological Classification of Tumors. In Pindborg J, Reichart PA, Smith CJ, et al, editors: Histologic Typing of Cancer and Precancer of the Oral Mucosa , 2nd ed, New York: Springer, 1997.
59 Banoczy J. Follow-up studies in oral leukoplakia. J Maxillofac Surg . 1977;5:69-75.
60 Einhorn J, Wersall J. Incidence of oral carcinoma in patients with leukoplakia of the oral mucosa. Cancer . 1967;20:2189-2193.
61 Shafer WG, Waldron CA. A clinical and histopathologic study of oral leukoplakia. Surg Gynecol Obstet . 1961;112:411-420.
62 Shklar G. Patterns of keratinization in oral leukoplakia. Arch Otolaryngol . 1968;87:400-404.
63 Silverman SJr, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer . 1984;53:563-568.
64 Banoczy J, Csiba A. Occurrence of epithelial dysplasia in oral leukoplakia. Analysis and follow-up study of 12 cases. Oral Surg Oral Med Oral Pathol . 1976;42:766-774.
65 Waldron CA, Shafer WG. Leukoplakia revisited. A clinicopathologic study of 3256 oral leukoplakias. Cancer . 1975;36:1386-1392.
66 Reichart PA, Philipsen HP. Oral erythroplakia—a review. Oral Oncol . 2005;41:551-561.
67 Mashberg A. Erythroplasia: The earliest sign of asymptomatic oral cancer. J Am Dent Assoc . 1978;96:615-620.
68 Shafer WG, Waldron CA. Erythroplakia of the oral cavity. Cancer . 1975;36:1021-1028.
69 Burkhardt A. [Premalignant changes in the mouth mucosa. Proposals for nomenclature by an international expert commission]. Pathologe . 1985;6:126-132.
70 Cawson RA, Langdon JD, Eveson JW. Erythroplasia (“erythroplakia”). In: Surgical Pathology of the Mouth and Jaws . London: Wright Publishing; 1996:180-182.
71 Lumerman H, Freedman P, Kerpel S. Oral epithelial dysplasia and the development of invasive squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 1995;79:321-329.
72 Seoane J, Varela-Centelles PI, Diz Dios P, et al. Experimental intervention study about recognition of erythroplakia by undergraduate dental students. Int Dent J . 1999;49:275-278.
73 van der Waal I, Schepman KP, van der Meij EH, et al. Oral leukoplakia: A clinicopathological review. Oral Oncol . 1997;33:291-301.

Clinical Aspects of Preinvasive Neoplastic Lesions of the Oral Cavity
74 Lingen MW, Kalmar JR, Karrison T, et al. Critical evaluation of diagnostic aids for the detection of oral cancer. Oral Oncol . 2008;44:10-22.
75 Brennan M, Migliorati CA, Lockhart PB, et al. Management of oral epithelial dysplasia: A review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 2007;103(Suppl 19):e11-e12.
76 Holmstrup P, Vedtofte P, Reibel J, et al. Oral premalignant lesions: Is a biopsy reliable? J Oral Pathol Med . 2007;36:262-266.
77 Marcus M, Maida CA, Freed JR, et al. Oral white patches in a national sample of medical HIV patients in the era of HAART. Community Dent Oral Epidemiol . 2005;33:99-106.
78 Brothwell DJ, Lewis DW, Bradley G, et al. Observer agreement in the grading of oral epithelial dysplasia. Community Dent Oral Epidemiol . 2003;31:300-305.
79 Schepman KP, van der Meij EH, Smeele LE, et al. Prevalence study of oral white lesions with special reference to a new definition of oral leucoplakia. Eur J Cancer B Oral Oncol . 1996;32B:416-419.
80 Axell T, Pindborg JJ, Smith CJ, et al. Oral white lesions with special reference to precancerous and tobacco-related lesions: Conclusions of an international symposium held in Uppsala, Sweden, May 18–21, 1994. International Collaborative Group on Oral White Lesions. J Oral Pathol Med . 1996;25:49-54.
81 Bokor-Bratic M. [Prevalence of oral leukoplakia]. Med Pregl . 2003;56:552-555.
82 Patten S. Diagnostic Cytopathology of the Uterine Cervix. Basel: Karger . 1978.
83 Saccomanno G, Archer VE, Auerbach O, et al. Development of carcinoma of the lung as reflected in exfoliated cells. Cancer . 1974;33:256-270.
84 Ali AA, Al-Sharabi AK, Aguirre JM. Histopathological changes in oral mucosa due to takhzeen al-qat: A study of 70 biopsies. J Oral Pathol Med . 2006;35:81-85.
85 Ali AA, Al-Sharabi AK, Aguirre JM, et al. A study of 342 oral keratotic white lesions induced by qat chewing among 2500 Yemeni. J Oral Pathol Med . 2004;33:368-372.
86 Sawair FA, Al-Mutwakel A, Al-Eryani K, et al. High relative frequency of oral squamous cell carcinoma in Yemen: Qat and tobacco chewing as its aetiological background. Int J Environ Health Res . 2007;17:185-195.
87 Greenspan D, Greenspan JS, Conant M, et al. Oral “hairy” leucoplakia in male homosexuals: Evidence of association with both papillomavirus and a herpes-group virus. Lancet . 1984;2:831-834.
88 Rosai J, editor. Rosai and Ackerman’s Surgical Pathology, 8th ed, Philadelphia: Mosby, 2004.
89 Adler-Storthz K, Ficarra G, Woods KV, et al. Prevalence of Epstein-Barr virus and human papillomavirus in oral mucosa of HIV-infected patients. J Oral Pathol Med . 1992;21:164-170.
90 Franceschi S, Dal Maso L, Arniani S, et al. Risk of cancer other than Kaposi’s sarcoma and non-Hodgkin’s lymphoma in persons with AIDS in Italy. Cancer and AIDS Registry Linkage Study. Br J Cancer . 1998;78:966-970.
91 Goedert JJ. The epidemiology of acquired immunodeficiency syndrome malignancies. Semin Oncol . 2000;27:390-401.
92 Beral V, Newton R. Overview of the epidemiology of immunodeficiency-associated cancers. J Natl Cancer Inst Monogr . 1998;23:1-6.
93 Barry B, Gehanno P. [Squamous cell carcinoma of the ENT organs in the course of the HIV infection]. Ann Otolaryngol Chir Cervicofac . 1999;116:149-153.
94 Singh B, Sabin S, Rofim O, et al. Alterations in head and neck cancer occurring in HIV-infected patients—results of a pilot, longitudinal, prospective study. Acta Oncol . 1999;38:1047-1050.
95 Silverman SJr, Gorsky M. Proliferative verrucous leukoplakia: A follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 1997;84:154-157.
96 Fenoglio-Preiser CM, editor. Gastrointestinal Pathology: An Atlas and Text, 2nd ed, New York: Lippincott—Raven, 1999.
97 Eisenberg E. Lichen planus and oral cancer: Is there a connection between the two? J Am Dent Assoc . 1992;123:104-108.
98 Eisenberg E, Krutchkoff DJ. Lichenoid lesions of oral mucosa. Diagnostic criteria and their importance in the alleged relationship to oral cancer. Oral Surg Oral Med Oral Pathol . 1992;73:699-704.
99 Zhang L, Cheng X, Li Y, et al. High frequency of allelic loss in dysplastic lichenoid lesions. Lab Invest . 2000;80:233-237.
100 Krutchkoff DJ, Eisenberg E. Lichenoid dysplasia: A distinct histopathologic entity. Oral Surg Oral Med Oral Pathol . 1985;60:308-315.
101 King GN, Healy CM, Glover MT, et al. Increased prevalence of dysplastic and malignant lip lesions in renal-transplant recipients. N Engl J Med . 1995;332:1052-1057.
102 Silverman SJr. Observations on the clinical characteristics and natural history of oral leukoplakia. J Am Dent Assoc . 1968;76:772-777.
103 Pindborg JJ, Renstrup G, Poulsen HE, et al. Studies in oral leukoplakias. V. Clinical and histologic signs of malignancy. Acta Odontol Scand . 1963;21:407-414.
104 Banoczy J. Oral leukoplakia and other white lesions of the oral mucosa related to dermatological disorders. J Cutan Pathol . 1983;10:238-256.
105 Shear M, Pindborg JJ. Verrucous hyperplasia of the oral mucosa. Cancer . 1980;46:1855-1862.
106 Suarez P, Batsakis JG, el-Naggar AK. Leukoplakia: Still a gallimaufry or is progress being made? A review. Adv Anat Pathol . 1998;5:137-155.
107 Hansen LS, Olson JA, Silverman SJr. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol . 1985;60:285-298.
108 Zakrzewska JM, Lopes V, Speight P, et al. Proliferative verrucous leukoplakia: A report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 1996;82:396-401.
109 Brennan JA, Mao L, Hruban RH, et al. Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck. N Engl J Med . 1995;332:429-435.
110 Mashberg A, Feldman LJ. Clinical criteria for identifying early oral and oropharyngeal carcinoma Erythroplasia revisited. Am J Surg . 1988;156:273-275.
111 Mashberg A, Morrissey JB, Garfinkel L. A study of the appearance of early asymptomatic oral squamous cell carcinoma. Cancer . 1973;32:1436-1445.
112 Shear M. Erythroplakia of the mouth. Int Dent J . 1972;22:460-473.
113 Hashibe M, Mathew B, Kuruvilla B, et al. Chewing tobacco, alcohol, and the risk of erythroplakia. Cancer Epidemiol Biomarkers Prev . 2000;9:639-645.
114 Scully C, Felix DH. Oral medicine—update for the dental practitioner: Red and pigmented lesions. Br Dent J . 2005;199:639-645.
115 Bouquot JE, Ephros H. Erythroplakia: The dangerous red mucosa. Pract Periodont Aesthet Dent . 1995;7:59-68.

Clinical Aspects of Preinvasive Neoplastic Lesions of the Larynx
116 Zhang H, Chen XM, Li ZH. [Clinical analysis of vocal cord leukoplakia in 32 cases]. Lin Chuang Er Bi Yan Hou Ke Za Zhi . 2000;14:22-23.
117 McLaren KM, Burnett RA, Goodlad JR, et al. Consistency of histopathological reporting of laryngeal dysplasia. The Scottish Pathology Consistency Group. Histopathology . 2000;37:460-463.
118 Frangez I, Gale N, Luzar B. The interpretation of leukoplakia in laryngeal pathology. Acta Otolaryngol Suppl . 1997;527:142-144.
119 Kambic V. Epithelial hyperplastic lesions—a challenging topic in laryngology. Acta Otolaryngol Suppl . 1997;527:7-11.
120 Hellquist H, Cardesa A, Gale N, et al. Criteria for grading in the Ljubljana classification of epithelial hyperplastic laryngeal lesions. A study by members of the Working Group on Epithelial Hyperplastic Laryngeal Lesions of the European Society of Pathology. Histopathology . 1999;34:226-233.
121 Koren R, Kristt D, Shvero J, et al. The spectrum of laryngeal neoplasia: The pathologist’s view. Pathol Res Pract . 2002;198:709-715.
122 Cupic H, Kruslin B, Belicza M. Epithelial hyperplastic lesions of the larynx in biopsy specimens. Acta Otolaryngol Suppl . 1997;527:103-104.
123 Crissman JD. Laryngeal keratosis and subsequent carcinoma. Head Neck Surg . 1979;1:386-391.
124 Crissman JD, Visscher DW, Sarkar FH. Premalignant lesions of the upper aerodigestive tract: Biomarkers of genetic alterations, proliferation, and differentiation. J Cell Biochem Suppl . 1993;17F:192-198.
125 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;13:5-16.
126 Pierce N. Leukoplakia laryngis. Ann Otol Rhinol Laryngol . 1920;29:301-308.
127 Jackson C. Cancer of the larynx: Is it preceded by a recognizable precancerous condition? Ann Surg . 1923;77:1-14.
128 Elman AJ, Goodman M, Wang CC, et al. In situ carcinoma of the vocal cords. Cancer . 1979;43:2422-2428.
129 Rothman K, Keller A. The effect of joint exposure to alcohol and tobacco on risk of cancer of the mouth and pharynx. J Chronic Dis . 1972;25:711-716.
130 Winn DM. Diet and nutrition in the etiology of oral cancer. Am J Clin Nutr . 1995;61:437S-445S.
131 Guenel P, Chastang JF, Luce D, et al. A study of the interaction of alcohol drinking and tobacco smoking among French cases of laryngeal cancer. J Epidemiol Community Health . 1988;42:350-354.
132 McGavran MH, Bauer WC, Ackerman LV. Sebaceous lymphadenoma of the parotid salivary gland. Cancer . 1960;13:1185-1187.
133 Miller AH, Fisher HR. Clues to the life history of carcinoma in situ of the larynx. Laryngoscope . 1971;81:1475-1480.

Histologic Definitions and Classification
134 Shanmugaratnam K, Sobin LH, editors. Histological Typing of Tumours of the Upper Respiratory Tract and Ear, 2nd ed, New York: Springer, 1991. WHO International Classification of Tumours
135 Blackwell KE, Fu YS, Calcaterra TC. Laryngeal dysplasia. A clinicopathologic study. Cancer . 1995;75:457-463.
136 Crissman JD, Zarbo RJ, Drozdowicz S, et al. Carcinoma in situ and microinvasive squamous carcinoma of the laryngeal glottis. Arch Otolaryngol Head Neck Surg . 1988;114:299-307.
137 Crissman JD. Laryngeal keratosis preceding laryngeal carcinoma. A report of four cases. Arch Otolaryngol . 1982;108:445-448.
138 Blackwell KE, Calcaterra TC, Fu YS. Laryngeal dysplasia: Epidemiology and treatment outcome. Ann Otol Rhinol Laryngol . 1995;104:596-602.
139 Kambic V, Gale N. Epithelial Hyperplastic Lesions of the Larynx. Amsterdam: Elsevier, 1995.
140 Michaels L. The Kambic-Gale method of assessment of epithelial hyperplastic lesions of the larynx in comparison with the dysplasia grade method. Acta Otolaryngol Suppl . 1997;527:17-20.
141 Sllamniku B, Bauer W, Painter C, et al. The transformation of laryngeal keratosis into invasive carcinoma. Am J Otolaryngol . 1989;10:42-54.
142 Kleinsasser O. Cancer of the larynx. A study of development and early growth. J Otolaryngol Soc Aust . 1968;2:8-12.
143 Doyle PJ, Flores A, Douglas GS. Carcinoma in situ of the larynx. Laryngoscope . 1977;87:310-316.
144 Gabriel CE, Jones DG. Hyperkeratosis of the larynx. J Laryngol Otol . 1973;87:129-134.
145 Gupta PC, Mehta FS, Daftary DK, et al. Incidence rates of oral cancer and natural history of oral precancerous lesions in a 10-year follow-up study of Indian villagers. Community Dent Oral Epidemiol . 1980;8:283-333.

Malignant Progression
146 Henry RC. The transformation of laryngeal leucoplakia to cancer. J Laryngol Otol . 1979;93:447-459.
147 Shibuya H, Amagasa T, Kan-Ichi S, et al. Leukoplakia-associated multiple carcinomas in patients with tongue carcinoma. Cancer . 1986;57:843-846.
148 Kambic V. Difficulties in management of vocal cord precancerous lesions. J Laryngol Otol . 1978;92:305-315.
149 Maran AG, Mackenzie IJ, Stanley RE. Carcinoma in situ of the larynx. Head Neck Surg . 1984;7:28-31.
150 Hellquist H, Olofsson J, Grontoft O. Carcinoma in situ and severe dysplasia of the vocal cords. A clinicopathological and photometric investigation. Acta Otolaryngol . 1981;92:543-555.
151 Crissman JD, Zarbo RJ. Quantitation of DNA ploidy in squamous intraepithelial neoplasia of the laryngeal glottis. Arch Otolaryngol Head Neck Surg . 1991;117:182-188.
152 Grontoft O, Hellquist H, Olofsson J, et al. The DNA content and nuclear size in normal, dysplastic and carcinomatous laryngeal epithelium. A spectrophotometric study. Acta Otolaryngol . 1978;86:473-479.
153 Roed-Petersen B. Cancer development in oral leukoplakia: Follow up of 331 patients. J Dent Res . 1971;50:711.
154 Bouquot JE, Weiland LH, Kurland LT. Leukoplakia and carcinoma in situ synchronously associated with invasive oral/oropharyngeal carcinoma in Rochester, Minn., 1935–1984. Oral Surg Oral Med Oral Pathol . 1988;65:199-207.
155 Ackerman LV, McGavran GM. Proliferating benign and malignant epithelial lesions of the oral cavity. J Oral Surg (Chic) . 1958;16:400-413.
156 Palefsky JM, Silverman SJr, Abdel-Salaam M, et al. Association between proliferative verrucous leukoplakia and infection with human papillomavirus type 16. J Oral Pathol Med . 1995;24:193-197.
157 Bouquot JE, Kurland LT, Weiland LH. Laryngeal keratosis and carcinoma in the Rochester, MN, population 1935–1984. Cancer Detect Prev . 1991;15:83-91.
158 Lundgren J, Olofsson J. Malignant tumours in patients with non-invasive squamous cell lesions of the vocal cords. Clin Otolaryngol Allied Sci . 1987;12:39-43.
159 Plch J, Pár I, Navrátilová I, et al. Long term follow-up study of laryngeal precancer. Auris Nasus Larynx . 1998;25:407-412.
160 McGavran MH, Bauer WC, Ogura JH. Isolated laryngeal keratosis. Its relations to carcinoma of the larynx based on a clinicopathologic study of 87 consecutive cases with long-term follow-up. Laryngoscope . 1960;70:932-951.
161 Hintz BL, Kagan AR, Nussbaum H, et al. A “watchful waiting” policy for in situ carcinoma of the vocal cords. Arch Otolaryngol . 1981;107:746-751.
162 Gillis TM, Incze J, Strong MS, et al. Natural history and management of keratosis, atypia, carcinoma-in situ, and microinvasive cancer of the larynx. Am J Surg . 1983;146:512-516.
163 Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer . 1953;5:963-968.
164 Bouvier G, Hergenhahn M, Polack A, et al. Characterization of macromolecular lignins as Epstein-Barr virus inducer in foodstuff associated with nasopharyngeal carcinoma risk. Carcinogenesis . 1995;16:1879-1885.
165 Hildesheim A, Levine PH. Etiology of nasopharyngeal carcinoma: A review. Epidemiol Rev . 1993;15:466-485.
166 Liebowitz D. Nasopharyngeal carcinoma: The Epstein-Barr virus association. Semin Oncol . 1994;21:376-381.
167 Boysen M, Voss R, Solberg LA. The nasal mucosa in softwood exposed furniture workers. Acta Otolaryngol . 1986;101:501-508.
168 Duffus JH. Epidemiology and the identification of metals as human carcinogens. Sci Prog . 1996;79:311-326.
169 Barnes L, Bedetti C. Oncocytic Schneiderian papilloma A reappraisal of cylindrical cell papilloma of the sinonasal tract. Hum Pathol . 1984;15:344-351.
170 Christensen WN, Smith RR. Schneiderian papillomas: A clinicopathologic study of 67 cases. Hum Pathol . 1986;17:393-400.
171 von Buchwald C, Bradley PJ. Risks of malignancy in inverted papilloma of the nose and paranasal sinuses. Curr Opin Otolaryngol Head Neck Surg . 2007;15:95-98.
172 Pathmanathan R, Prasad U, Sadler R, et al. Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N Engl J Med . 1995;333:693-698.
173 Cheung FMF, Pang SW, Yau TK, et al. Nasopharyngeal intraepithelial lesion: Latent Epstein-Barr virus infection with malignant potential. Histopathology . 2004;45:171-179.
174 Pak MW, To KF, Lo YMD, et al. Nasopharyngeal carcinoma in situ (NPCIS)—pathologic and clinical perspectives. Head Neck . 2002;24:989-995.
175 Sheu LF, Chen A, Meng CL, et al. Analysis of bcl-2 expression in normal, inflamed, dysplastic nasopharyngeal epithelia, and nasopharyngeal carcinoma: Association with p53 expression. Hum Pathol . 1997;28:556-562.

Molecular Alterations in Carcinogenesis
176 Califano J, van der Riet P, Westra W. Genetic progression model for head and neck cancer: Implications for field cancerization. Cancer Res . 1996;56:2488-2492.
177 Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell . 1990;61:759-767.
178 Renan MJ. How many mutations are required for tumorigenesis? Implications from human cancer data. Mol Carcinog . 1993;7:139-146.
179 Ha PK, Califano JA3rd. The molecular biology of laryngeal cancer. Otolaryngol Clin North Am . 2002;35:993-1012.
180 Bockmuhl U, Petersen I. DNA ploidy and chromosomal alterations in head and neck squamous cell carcinoma. Virchows Arch . 2002;441:541-550.
181 Forastiere A, Koch W, Trotti A. Head and neck cancer. N Engl J Med . 2001;345:1890-1900.
182 Trizna Z, Schantz S. Hereditary and environmental factors associated with risk and progression of head and neck cancer. Otolaryngol Clin North Am . 1992;25:1089-1103.
183 Ha PK, Benoit NE, Yochem R. A transcriptional progression model for head and neck cancer. Clin Cancer Res . 2003;9:3058-3064.
184 Almadori G, Bussu F, Cadoni G. Multistep laryngeal carcinogenesis helps our understanding of the field cancerization phenomenon: A review. Eur J Cancer . 2004;40:2383-2388.
185 Bedi GC, Westra WH, Gabrielson E. Multiple head and neck tumors: Evidence for a common clonal origin. Cancer Res . 1996;56:2481-2487.
186 Califano J, Westra WH, Meininger G. Genetic progression and clonal relationship of recurrent premalignant head and neck lesions. Clin Cancer Res . 2000;6:347-352.
187 Ha PK, Califano JA. The molecular biology of mucosal field cancerization of the head and neck. Oral Biol Med . 2003;14:363-369.
188 Scholes AG, Woolgar JA, Boyle MA. Synchronous oral carcinomas: Independent or common clonal origin? Cancer Res . 1998;58:2003-2006.
189 Tabor MP, Brakenhoff RH, Ruijter-Schippers HJ. Multiple head and neck tumors frequently originate from a single preneoplastic lesion. Am J Pathol . 2002;161:1051-1060.
190 Worsham MJ, Wolman SR. Common clonal origin of synchronous primary head and neck squamous cell carcinomas: Analysis by tumor karyotypes and fluorescence in situ hybridization. Hum Pathol . 1995;26:251-261.
191 Mertens F, Jin Y, Heim S, et al. Clonal structural chromosome aberrations in nonneoplastic cells of the skin and upper aerodigestive tract. Genes Chromosomes Cancer . 1992;4:235-240.
192 Teyssier J. The chromosomal analysis of human solid tumors. A triple challenge. Cancer Genet Cytogenet . 1989;37:103-125.
193 Voravud N, Shin DM, Ro JY. Increased polysomies of chromosomes 7 and 17 during head and neck multistage tumorigenesis. Cancer Res . 1993;53:2874-2883.
194 du Manoir S, Speicher MR, Joos S, et al. Detection of complete and partial chromosome gains and losses by comparative genomic in situ hybridization. Hum Genet . 1993;90:590-610.
195 Gollin SM. Chromosomal alterations in squamous cell carcinomas of the head and neck: Window to the biology of disease. Head Neck . 2001;23:238-253.
196 Kallioniemi OP, Kallioniemi A, Sudar D. Comparative genomic hybridization: A rapid new method for detecting and mapping DNA amplification in tumors. Semin Cancer Biol . 1993;4:41-46.
197 Brieger J, Jacob R, Riazimand HS. Chromosomal aberrations in premalignant and malignant squamous epithelium. Cancer Genet Cytogenet . 2003;144:148-155.
198 Field JK. Genomic instability in squamous cell carcinoma of the head and neck. Anticancer Res . 1996;16:2421-2431.
199 Ai H, Barrera JE, Meyers AD, et al. Chromosomal aneuploidy precedes morphological changes and supports multifocality in head and neck lesions. Laryngoscope . 2001;111:1853-1858.
200 Bracko M. Evaluation of DNA content in epithelial hyperplastic lesions of the larynx. Acta Otolaryngol Suppl . 1997;527:62-65.
201 Veltman JA, Bot FJ, Huynen FC. Chromosome instability as an indicator of malignant progression in laryngeal mucosa. J Clin Oncol . 2000;18:1644-1651.
202 Knudson AGJr. Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci U S A . 1971;68:820-823.
203 Reibel J. Prognosis of oral pre-malignant lesions: Significance of clinical, histopathological, and molecular biological characteristics. Crit Rev Oral Biol Med . 2003;14:47-62.
204 Rosin MP, Cheng X, Poh C, et al. Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res . 2000;6:357-362.
205 Mao L, Lee JS, Fan YH. Frequent microsatellite alterations at chromosomes 9p21 and 3p14 in oral premalignant lesions and their value in cancer risk assessment. Nat Med . 1996;2:682-685.
206 Sanz-Ortega J, Valor C, Saez MC. 3p21, 5q21, 9p21 and 17p13 allelic deletions accumulate in the dysplastic spectrum of laryngeal carcinogenesis and precede malignant transformation. Histol Histopathol . 2003;18:1053-1057.
207 Yoo WJ, Cho SH, Lee YS. Loss of heterozygosity on chromosomes 3p, 8p, 9p, and 17p in the progression of squamous cell carcinoma of the larynx. J Korean Med Sci . 2004;19:345-351.
208 Zhang L, Rosin MP. Loss of heterozygosity: A potential tool in management of oral premalignant lesions? J Oral Pathol Med . 2001;30:513-520.
209 Veltman JA, van Weert I, Aubele M. Specific steps in aneuploidization correlate with loss of heterozygosity of 9p21, 17p13 and 18q21 in the progression of pre-malignant laryngeal lesions. Int J Cancer . 2001;91:193-199.
210 Boyle JO, Hakim J, Koch W. The incidence of p53 mutations increases with progression of head and neck cancer. Cancer Res . 1993;53:4477-4480.
211 Hardisson D. Molecular pathogenesis of head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol . 2003;260:502-508.
212 Koch WM, Brennan JA, Zahurak M. p53 mutation and locoregional treatment failure in head and neck squamous cell carcinoma. J Natl Cancer Inst . 1996;88:1580-1586.
213 Hollstein M, Sidransky D, Vogelstein B, et al. p53 mutations in human cancers. Science . 1991;253:49-53.
214 Somers KD, Merrick MA, Lopez ME. Frequent p53 mutations in head and neck cancer. Cancer Res . 1992;52:5997-6000.
215 Wallace-Brodeur RR, Lowe SW. Clinical implications of p53 mutations. Cell Mol Life Sci . 1999;55:64-75.
216 Kropveld A, Rozemuller EH, Leppers FG. Sequencing analysis of RNA and DNA of exons 1 through 11 shows p53 gene alterations to be present in almost 100% of head and neck squamous cell cancers. Lab Invest . 1999;79:347-353.
217 Gallo O, Santucci M, Franchi A. Cumulative prognostic value of p16/CDKN2 and p53 oncoprotein expression in premalignant laryngeal lesions. J Natl Cancer Inst . 1997;89:1161-1163.
218 Homann N, Nees M, Conradt C. Overexpression of p53 in tumor-distant epithelia of head and neck cancer patients is associated with an increased incidence of second primary carcinoma. Clin Cancer Res . 2001;7:290-296.
219 Ogden GR, Chisholm DM, Morris AM, et al. Overexpression of p53 in normal oral mucosa of oral cancer patients does not necessarily predict further malignant disease. J Pathol . 1997;182:180-184.
220 Glavac D, Volavšek M, Potocnik U. Low microsatellite instability and high loss of heterozygosity rates indicate dominant role of the suppressor pathway in squamous cell carcinoma of head and neck and loss of heterozygosity of 11q14.3 correlates with tumor grade. Cancer Genet Cytogenet . 2003;146:27-32.
221 Izzo JG, Papadimitrakopoulou VA, Li XQ. Dysregulated cyclin D1 expression early in head and neck tumorigenesis: In vivo evidence for an association with subsequent gene amplification. Oncogene . 1998;17:2313-2322.
222 Jares P, Fernandez PL, Campo E. PRAD-1/cyclin D1 gene amplification correlates with messenger RNA overexpression and tumor progression in human laryngeal carcinomas. Cancer Res . 1994;54:4813-4817.
223 Volavšek M, Bracko M, Gale N. Distribution and prognostic significance of cell cycle proteins in squamous carcinoma of the larynx, hypopharynx and adjacent epithelial hyperplastic lesions. J Laryngol Otol . 2003;117:286-293.
224 Lai S, el-Naggar AK. Differential expression of key cell cycle genes (p16/cyclin D1/pRb) in head and neck squamous carcinomas. Lab Invest . 1999;79:255-260.
225 Okami K, Reed AL, Cairns P. Cyclin D1 amplification is independent of p16 inactivation in head and neck squamous cell carcinoma. Oncogene . 1999;18:3541-3545.
226 Williams ME, Gaffey MJ, Weiss LM. Chromosome 11Q13 amplification in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg . 1993;119:1238-1243.
227 Roh HJ, Shin DM, Lee JS. Visualization of the timing of gene amplification during multistep head and neck tumorigenesis. Cancer Res . 2000;60:6496-6502.
228 Geisler SA, Olshan AF. GSTM1, GSTT1, and the risk of squamous cell carcinoma of the head and neck: A mini-HuGE review. Am J Epidemiol . 2001;154:95-105.
229 Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res . 1993;53:3579-3584.
230 Grandis RJ, Tweardy DJ, Melhem MF. Asynchronous modulation of transforming growth factor alpha and epidermal growth factor receptor protein expression in progression of premalignant lesions to head and neck squamous cell carcinoma. Clin Cancer Res . 1998;4:13-20.
231 Meyerson M, Counter CM, Eaton EN. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell . 1997;90:785-795.
232 Dhaene K, Van Marck E, Parwaresch R. Telomeres, telomerase and cancer: An up-date. Virchows Arch . 2000;437:1-16.
233 Takakura M, Kyo S, Kanaya T. Cloning of human telomerase catalytic subunit (hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells. Cancer Res . 1999;59:551-557.
234 Luzar B, Poljak M, Gale N. Telomerase catalytic subunit in laryngeal carcinogenesis—an immunohistochemical study. Mod Pathol . 2005;18:406-411.
235 Luzar B, Poljak M, Marin IJ. Quantitative measurement of telomerase catalytic subunit (hTERT) mRNA in laryngeal squamous cell carcinomas. Anticancer Res . 2001;21:4011-4015.
236 Luzar B, Poljak M, Marin IJ. Human telomerase catalytic subunit gene re-expression is an early event in oral carcinogenesis. Histopathology . 2004;45:13-19.
237 Luzar B, Poljak M, Marin IJ, et al. Telomerase reactivation is an early event in laryngeal carcinogenesis. Mod Pathol . 2003;16:841-848.
238 Patel V, Leethanakul C, Gutkind JS. New approaches to the understanding of the molecular basis of oral cancer. Crit Rev Oral Biol Med . 2001;12:55-63.

Molecular Markers of Dysplasia and Epithelial Maturation
239 Munck-Wikland E, Kuylenstierna R, Lindholm J, Auer G. p53 immunostaining and image cytometry DNA analysis in precancerous and cancerous squamous epithelial lesions of the larynx. Head Neck . 1997;19:107-115.
240 Cattoretti G, Becker MH, Key G, et al. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol . 1992;168:357-363.
241 Gerdes J, Lemke H, Baisch H, et al. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol . 1984;133:1710-1715.
242 Lindberg K, Rheinwald JG. Suprabasal 40 kd keratin (K19) expression as an immunohistologic marker of premalignancy in oral epithelium. Am J Pathol . 1989;134:89-98.
243 Vogelesten B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal tumor development. N Engl J Med . 1988;319:525-532.
244 Gallo O, Franchi A, Chiarelli I, et al. Potential biomarkers in predicting progression of epithelial hyperplastic lesions of the larynx. Acta Otolaryngol Suppl . 1997;527:30-38.
245 Silvestri F, Bussani R, Pavletic N, et al. From epithelial dysplasia to squamous carcinoma of the head and neck region: Evolutive and prognostic histopathological markers. Acta Otolaryngol Suppl . 1997;527:49-51.
246 Gale N, Zidar N, Kambic V, et al. Epidermal growth factor receptor, c-erbB-2 and p53 overexpressions in epithelial hyperplastic lesions of the larynx. Acta Otolaryngol Suppl . 1997;527:105-110.
247 Nadal A, Campo E, Pinto J, et al. p53 expression in normal, dysplastic, and neoplastic laryngeal epithelium. Absence of a correlation with prognostic factors. J Pathol . 1995;175:181-188.
248 Cardesa A, Nadal A, Jares P, et al. Hyperplastic lesions of the larynx. Experience of the Barcelona group. Acta Otolaryngol Suppl . 1997;527:43-46.
249 Hellquist HB. Apoptosis in epithelial hyperplastic laryngeal lesions. Acta Otolaryngol Suppl . 1997;527:25-29.
250 Kok K, Naylor SL, Buys CH. Deletions of the short arm of chromosome 3 in solid tumors and the search for suppressor genes. Adv Cancer Res . 1997;71:27-92.
251 Tseng JE, Kemp BL, Khuri FR, et al. Loss of FHIT is frequent in stage I non-small cell lung cancer and in the lungs of chronic smokers. Cancer Res . 1999;59:4798-4803.
252 Sozzi G, Sard L, De Gregorio L, et al. Association between cigarette smoking and FHIT gene alterations in lung cancer. Cancer Res . 1997;57:2121-2123.
253 Nelson HH, Wiencke JK, Gunn L, et al. Chromosome 3p14 alterations in lung cancer: Evidence that FHIT exon deletion is a target of tobacco carcinogens and asbestos. Cancer Res . 1998;58:1804-1807.
254 Siprashvili Z, Sozzi G, Barnes LD, et al. Replacement of FHIT in cancer cells suppresses tumorigenicity. Proc Natl Acad Sci USA . 1997;94:13771-13776.
255 Sakr WA, Zarbo RJ, Jacobs JR, et al. Distribution of basement membrane in squamous cell carcinoma of the head and neck. Hum Pathol . 1987;18:1043-1050.
256 Lee JS, Lippman SM, Hong WK, et al. Determination of biomarkers for intermediate end points in chemoprevention trials. Cancer Res . 1992;52:2707s-2710s.
257 Smedts F, Ramaekers F, Robben H, et al. Changing patterns of keratin expression during progression of cervical intraepithelial neoplasia. Am J Pathol . 1990;136:657-668.
258 Ogden GR, Chisholm DM, Adi M, et al. Cytokeratin expression in oral cancer and its relationship to tumor differentiation. J Oral Pathol Med . 1993;22:82-86.
259 Hittelman WN, Voravud N, Shin DM, et al. Early genetic changes during upper aerodigestive tract tumorigenesis. J Cell Biochem Suppl . 1993;17F:233-236.
260 Miyaguchi M, Olofsson J, Hellquist HB. Immunohistochemical study of epidermal growth factor receptor in severe dysplasia and carcinoma in situ of the vocal cords. Acta Otolaryngol . 1991;111:149-152.
261 Shin DM, Ro JY, Hong WK, et al. Dysregulation of epidermal growth factor receptor expression in premalignant lesions during head and neck tumorigenesis. Cancer Res . 1994;54:3153-3159.
262 Mao L. Can molecular assessment improve classification of head and neck premalignancy? Clin Cancer Res . 2000;6:321-322.
Chapter 2 Squamous Cell Carcinoma of the Upper Aerodigestive System

Pieter J. Slootweg, Mary Richardson

Squamous cell carcinoma (SCC) of the upper aerodigestive tract (UADT) is the most common malignant neoplasm of the mucosal lining of the upper food and air passages. 1 In the Netherlands in 2000, 2400 new cases of head and neck cancer, mostly SCC, were registered as part of 69,000 new malignancies arising in a population of 15.9 million inhabitants. 2 Worldwide statistics cited 616,000 new cases in 2000. 3 It is evident that head and neck cancer, which carries an overall death risk of 54%, 3 represents a major health problem, and as the overwhelming majority of the tumors are SCCs, a large proportion of the workload of those working in a head and neck oncologic care setting will come from patients with this disease.

General Comments

Epidemiology and Risk Factors
Geographic variations in the occurrence of cancer have been recognized for many years. The estimates are not uniformly based on incidence data gathered by cancer registries but are also extrapolated from mortality data. With that caveat, it is likely that the gathered international information represents the relative cancer burden and site-specific patterns for many areas of the world. 4
Head and neck cancer is an important contributor to the worldwide cancer burden. Globally, head and neck cancer ranks as the sixth most common cancer. Among developing countries, head and neck cancer ranks third, and it is the fourth most common cancer in men worldwide. 3, 4 More than 90% of all UADT cancers are SCCs occurring in the fifth and sixth decades of life, with rates increasing with age. Furthermore, with a few exceptions, the incidence is higher in men than in women. 5 Pertinent epidemiologic data are briefly mentioned here for the various UADT sites.

The highest rates of lip cancer are in men from South Australia (13.5/100,000) and Canada (11/100,000 [Newfoundland fishermen]). 4, 6 The lowest rates occur in Asia (0.9/100,000). The incidence in the black population of the United States is very low to nil. 4 Lip cancer is uncommon in women. The risk of lip cancer seems to be decreasing. 4

Oral Cavity and Pharynx
Cancer of the oral cavity and pharynx consists of a diverse group of tumors with a large geographic variation. The most recent World Cancer Report finds that the most common head and neck cancer, namely, oral cancer, ranks 11th worldwide and cancer of the pharynx ranks 20th. 7 The largest contribution to the world total of oral cavity and pharynx cancers is from Southern Asia (34.6%), where they are mainly cancers of the mouth and tongue, and from China (15.7%), where they are mainly cancers of the nasopharynx. 3 Within the European community, oral cancer constitutes approximately 4.2% of all cancers. 8 The highest incidence among males (primary tumors of the pharynx) is reported from France (Bas-Rhin and Calvados), with annual rates of 40 per 100,000. 6, 8 The highest rates among women occur in parts of India. In India, however, the sex distribution of oral cancer is more equal. 6, 9
In their overview of the worldwide incidence of cancers, Parkin and colleagues 3 reported the female incidence of cancer of the mouth and pharynx to be the highest in Southern Asia and Melanesia. In the United States, cancer of the UADT represents approximately 4% of all malignancies. Oral cavity and pharynx cancers constitute approximately 50% of these UADT cancers. In the United States, it ranks seventh among blacks and 12th among whites. 6
Mapping of cancer mortality in the United States from 1950 to 1969 shows elevated rates among urban Northern males. This pattern was consistent with available major risk factors: tobacco use and drinking alcohol. Among females, mortality was highest in the rural South. The major risk identified was the long-standing use of smokeless tobacco products (snuff). Recent updates (1970–1989) among U.S. females reveal a decrease in the high-risk Southeast and several new high-risk areas along the Pacific and Florida coasts. 6
Tumors of the postcricoid region have historically been seen in Northern European women, especially those from rural Sweden, but also in those from the United Kingdom and Asia. 10, 11 In these regions, Plummer-Vinson syndrome (Paterson-Kelly syndrome, sideropenic dysphagia) was prevalent. 11, 12 The syndrome is characterized by dysphagia, glossitis, iron-deficiency anemia, cheilitis, and achlorhydria. Mucosal webs frequently develop along the anterior esophageal wall, and when carcinoma arises in these patients, the lesion is usually proximal to the web. Approximately 30% to 70% of patients with postcricoid carcinoma have Plummer-Vinson syndrome; however, only 3% to 10% of patients with Plummer-Vinson syndrome will develop carcinoma. The time of peak incidence of carcinoma occurs approximately 15 years after the onset of Plummer-Vinson syndrome. 11

Laryngeal cancer throughout the world has a higher incidence in men than in women. It occurs most frequently in the sixth and seventh decades of life. In the United States, the male-to-female ratio is 5:1, and this ratio is reasonably consistent worldwide. 13, 14 The incidence is higher among black residents than white residents in the same geographic region. 15 The highest incidence rates in men are reported for Southern Europe (annual incidence, 14.7/100,000), with Western Europe having the second highest rates (annual incidence, 11.4/100,000). 4 Coleman and colleagues 16 observed a three- to fourfold differential between Mediterranean and English populations that has remained constant over the past 20 years.
Tobacco use and alcohol consumption are strongly associated with laryngeal cancer. Users of dark tobacco have a higher risk of laryngeal cancer than users of light (flue-cured) tobacco. 17 In a large multicenter study evaluating alcohol consumption and tobacco use, the relative risk associated with cigarette smoking was approximately 10 for all subsites within the larynx and hypopharynx. The relative risk from alcohol was approximately 2, varied by site, and was highest for the epilarynx and hypopharynx. This study also found the combined exposure to alcohol and tobacco to be consistent with a multiplicative model. 18 A Latin American custom of drinking a nonalcoholic drink, mate, has been associated with an increased risk of laryngeal, oral, oropharyngeal, and esophageal cancers. In this era of global travel, mate has become available in all parts of the world. This drink is a tealike infusion of the herb Ilex paraguariensis (yerba mate). DeStefani and colleagues 19 hypothesized that a phenolic compound in the drink may act as a promoter. The exact mechanism is still uncertain. Mate drinking in the traditional manner should be considered one of the risk factors for cancer of the head and neck. 20, 21

Sinonasal Cavities
Cancer of the nasal and paranasal sinuses is infrequent. In the United States, the incidence is 0.75 per 100,000 persons. The most common site of occurrence is the maxillary sinus, which is affected twice as often as the nasal cavity. The least frequent areas involved are the ethmoid and sphenoid sinuses. The male-to-female ratio is 2:1. 22 The age at onset is approximately the sixth decade of life. Globally, these cancers are far more common in Japanese populations (incidence per 100,000, 2.6–2.2 for males and 1.4–1.2 for females) and certain African populations (2.5 in males and 1.8 in females). 23
Sinonasal cancers have a multifactorial etiology: sinonasal SCCs may develop from exposure to tobacco smoke, nickel, softwood dust, and mustard gas production, whereas adenocarcinomas may develop from exposure to hardwood, chrome pigment, and leather dust. 24 - 28 Another agent frequently cited as being involved with cancer of the nasal cavity is thorotrast. 22 Moreover, Epstein-Barr virus (EBV), well-known in the context of nasopharyngeal carcinoma (NPC), and human papillomavirus (HPV) appear to play a role in the pathogenesis of a variety of sinonasal carcinomas. 29 - 31

The epidemiology of NPC suggests the interaction of several variables: diet, viral agents, and genetic susceptibility. The endemic areas include Southern China and Northern Africa. The incidence in China increases from north to south, two to three per 100,000 to 25 to 40 per 100,000, respectively. 32 The consumption of salt-cured fish (Chinese style) has been implicated in studies of the Tanka culture, which has one of the highest incidences of NPC. Kadanos of Malaysia, Eskimos, and other Arctic region populations have high rates, approaching those of Southern China. Intermediate rates (3–6/100,000) are present in Southeast Asian peoples, including Thais, Vietnamese, Malays, and Filipinos. In North Africa, it appears that NPC is increased mainly in the Arab populations. In the United States, the incidence is low (0.7/100,000). 33 EBV has been found in all forms of NPC. 32, 34
Regarding age and gender, in all populations, the rates are higher in men than in women. Age distribution, however, does show variation between populations. In high-risk areas (e.g., Southern China), the peak age is between 45 and 54 years, with a decreasing incidence in older persons. In areas with low to moderate risk, an adolescent age peak has been noted. 32

SCC of the trachea has shown a strong male predominance of three times as many men as women. 35 There is a strong association with cigarette smoking. 36 Tracheal malignancy is most often seen (almost 50%), with adenoid cystic carcinoma being the second most frequent type found (25%). 35

Analytic Epidemiology
The study of the epidemiology of head and neck cancer has identified alcohol use and tobacco use as independent risk factors, and combined, they have a multiplicative risk. 1, 8, 17 Tobacco products such as cigarettes, cigars, snuff, and chews (e.g., betel quid, which consists of the leaf of the betel vine [ Piper betel ], areca nut, lime, and tobacco) are risk factors for head and neck cancer. 9, 21 Factors such as dietary deficiencies, after correcting for alcohol and tobacco use, particularly of vitamins A and C, iron, and certain trace elements, are thought to predispose to oral cancers. 9, 21 Other risks include previous irradiation; work in furniture, asbestos-related, and nickel industries; poor oral hygiene; and infection with the EBV. 1, 14 The association between either lichen planus or marijuana smoking and risk of oral cancer is still controversial. 37
Exposure to alcohol and tobacco affects various sites. With cigarette smoking, the gradient of the dose response and the magnitude of the risk show differences by gender and by primary site. Some studies have found women to have a greater risk than men per pack-year stratum. 8, 17 The subsites within the UADT that exhibit the greatest risk associated with alcohol exposure are the floor of the mouth, the hypopharynx, and the supraglottis. 38 Higher smoking-associated risk estimates have been reported for subsites of the larynx (glottis) and hypopharynx. Smokeless tobacco has a high risk for the oral cavity. 17 HPV has been associated with carcinomas arising in the palatine tonsils in a subset of young patients. Some studies have suggested this group of patients has better survival rates. 39
Case reports of head and neck cancer occurring within the first two decades of life are rare. Other patients with cancers in the first two decades may be individuals with genetic disorders or children with laryngeal papillomatosis. 40

Family occurrences of head and neck cancer have given credence to the role of inheritance in this particular neoplastic process. Few disorders have been associated with an increased incidence of head and neck cancers; laryngeal cancers have been described as part of the multiple cancers in Lynch II syndrome. 41
Bloom syndrome is an autosomal recessive disorder characterized by a high incidence of cancer at a young age. Twenty-eight of the initial 103 identified as Bloom syndrome patients developed cancer, and five of these cancers were head and neck carcinomas (one each of the epiglottis, pyriform sinus, and larynx and two of the base of the tongue; age range, 26–34 years). 42
Fanconi anemia is a recessively inherited disorder associated with increased risk of malignancies, including head and neck tumors. 43 The reported cases of carcinoma in this area include nine on the tongue (dorsal, lateral, and base), two on the pyriform sinus, one in the postcricoid area, and three on the gingiva and buccal mucosa. 44 Although the male-to-female ratio in Fanconi anemia is 2:1, the ratio is reversed among these patients with SCC. 44 Patients with Fanconi anemia are known to be susceptible to HPV-associated malignancies. HPV DNA has been demonstrated in specimens obtained from head and neck SCC in these patients. 45
Xeroderma pigmentosum is an autosomal recessive disease characterized by a DNA excision repair deficit. Damage to the chromosome is elicited by exposure to ultraviolet light. SCC on the anterior third of the tongue is frequent within the first two decades of life. These patients in the first two decades have an estimated 10,000 times greater frequency of tongue tumors than expected for that age group. SCC of the gingiva and palate also occurs with increased frequency in these patients. 46
Ataxia-telangiectasia is cytogenetically characterized by an increased number of spontaneously induced chromosomal aberrations. There are two separate clinical patterns of malignancy in these patients. In one of the reported clinical patterns of malignancy, the patients developed solid tumors, which included malignancies of the oral cavity within its spectrum. 47
An autosomally dominant disorder known as Li-Fraumeni syndrome is characterized by an early onset of a variety of tumors. Among these tumors, laryngeal carcinomas have been reported. These patients also have a high incidence of second primary tumors. 48
In the immunologically compromised population, which would include organ transplant recipients as well as patients with human immunodeficiency virus infection, there is known to be an increase in oral tumors. A report of increased oral SCC in patients infected with human immunodeficiency virus has been noted. 49 Those cases of head and neck cancer occurring in organ transplant recipients are predominantly seen along the vermilion border of the lip and are frequently associated with renal transplantation. 50

As outlined previously, the most important risk factors for SCC are alcohol and tobacco use, 1, 8, 51 - 54 but there is also increasing evidence that viruses are implicated in at least some cases of SCC. 1, 8, 55 - 57 The viruses that are considered to be of interest in this area are HPV, herpes simplex virus, and EBV. EBV has already been mentioned as being associated with NPCs, not only in the undifferentiated and nonkeratinizing tumors 58 but also in keratinizing SCCs. 59 Proof that herpes simplex virus is implicated in head and neck carcinogenesis is still lacking, although herpes simplex virus antigens have been observed in some oral cancers. 55 The role of HPV as a risk factor for SCC has gotten considerable support during the past years, 60 especially for nonkeratinizing SCC occurring in the tonsillar area 61 as well as in the sinonasal tract. 31 Meta-analyses of epidemiologic studies and multicenter case-control studies have confirmed HPV as an independent risk factor for oral cancer, with a range of odds ratios of 3.7 to 5.4. Tonsillar carcinomas appear to have the highest prevalence of HPV. HPV 16 is the most prevalent HPV type found in 84% of HPV DNA-positive tumors. Interestingly, patients with HPV 16–positive tumors seem to have a better overall and disease-specific survival rate compared with the HPV-negative group. Of the sinonasal carcinomas analyzed so far, 22% have been positive for any HPV type. 60
Recently, some evidence was presented that genetic predisposition also plays a role in the origin of SCC, 62, 63 although it has also been reported that environmental factors may contribute to familial aggregation of SCC. 64, 65 Possibly, it concerns the outcome of interplay between carcinogens and the ability to repair their damage. 66
Because cancer development implies damage to genetic material, it is important to analyze the genetic aberrations occurring in SCC and to try to relate these changes to the previously mentioned risk factors. Indeed, several investigations report multiple genetic abnormalities to be present in SCC, resulting in inappropriate activation of oncogenes or abrogation of tumor suppressor gene functions. 67 - 69 One of the most extensively investigated genetic abnormalities is that of the p53 gene. This gene serves as a control in cellular proliferation by coding for a protein that prevents cells with damaged DNA to proceed through the cell cycle, thus allowing time for DNA repair, or, if repair does not occur, causing apoptosis. 70 In this way, cells with abnormal DNA cannot proliferate, and the importance of a normally functioning p53 gene is exemplified by the observation that in many tumors, SCC included, p53 gene mutations are present. 71, 72
The significance of p53 dysfunction in SCC initiation and development is supported by its association with the epidemiologic risk factor of smoking; there is evidence that tobacco products may induce p53 gene mutations, 73 and an association between p53 gene mutations and smoking has been observed. 71, 72 Moreover, HPV-coded proteins may block the functions of the p53 protein, and therefore a causative role of HPV in SCC development also operates by disturbing the normal function of p53 protein. 74

Multiple Primary Tumors
As the entire mucosal lining of the UADT is exposed to the same carcinogenic agents, the occurrence of multiple primary tumors is not surprising and has indeed been documented extensively, their incidence varying from 10% to 35%, 75 - 80 whereas the risk of developing a second malignancy from treatment to death has been reported as 4% to 6% per year. 80, 81 In a prospective study, the development of a second primary tumor was the main cause of death. 82 Such tumors are considered synchronous if they are diagnosed at the same time as or within a 6-month period of identification of the primary lesion; if second cancers are diagnosed 6 months or more after the diagnosis of the primary cancers, they are metachronous neoplasms. 76
To qualify as multiple primary tumors, lesions must satisfy the following requirements: both lesions must be malignant as determined by histology, the lesions should be separated by normal-appearing mucosa (if the intervening mucosa demonstrates dysplasia, it is considered a multicentric primary 80 ), and the possibility that the second neoplasm represents metastasis should be excluded. 76 Those second primary cancers are observed not only in the UADT but also in the lungs, the latter especially in cases of laryngeal SCC 77, 78 or in other body sites. Two independent variables in head and neck carcinomas have been found to influence the occurrence of second metachronous cancer: anatomic site of the original primary tumor and age. 80 Second primary tumors in the head and neck area are more often seen when the first SCC is located in the oral cavity, oropharynx, or hypopharynx. 77 Within the oral cavity, patients with their primary tumor in the floor of the mouth, retromolar area, or lower alveolar process seem to be at greater risk of a second primary SCC than patients with tumors at other intraoral sites. 83 The oropharyngeal and hypopharyngeal sites associated with an increased frequency of second primary tumors are the base of the tongue (46%) and the pyriform sinus (34%), respectively. 83
Most second primary tumors are metachronous, although sometimes an unusually high proportion of synchronously occurring SCCs is found. 80 There also appears to be a genetic background for developing multiple SCCs of the UADT, as demonstrated by an increased sensitivity for mutagens in this group of patients. 84, 85 Second primary tumors adversely influence the prognosis of UADT SCC patients. Survival at 5 years for patients with a second cancer in the first 2 years was less than 50% and for those without a second primary, nearly 70%. 79 Prevention and detection of these second primary tumors may play the most important role in improving overall survival rates in the future. 78
Multiple primary tumors arising close to each other may have common genetic abnormalities indicating their derivation from a single precursor lesion that may occupy large mucosal areas. For these lesions, the designation second field tumor s has been proposed. 86

Local and Distant Metastasis
SCC of the UADT predominantly metastasizes to the lymph nodes of the neck, the site of the involved nodes being dependent on the localization of the primary tumor (see Chapter 11 ). 87 The adverse influence of metastatic neck node deposits on patient survival is firmly established, the prognosis being diminished approximately by half if lymph node metastases are present at presentation or during follow-up. 88 - 92 Prognosis further worsens if the tumor spreads beyond the lymph node into the soft tissues of the neck; this growth pattern is known as extracapsular spread. 88 - 90, 93 - 97 Whether microscopic extracapsular extension does have the same prognostic significance as gross extracapsular spread has been a controversial issue. 98 Recent studies, however, have indicated that the prognosis worsens in both situations. 99, 100 Extracapsular spread is only slightly correlated with nodal size; nodes less than 1 cm may already exhibit this feature. 94 Soft-tissue deposits in the neck appear to have the same prognostic significance as nodal metastasis with extracapsular spread. 100, 101
Not only extracapsular spread but also the presence of a desmoplastic stromal response in tumor-positive lymph nodes has been shown to worsen prognosis. 97 The prognostic significance of neck node disease justifies a very meticulous examination of neck dissection specimens, as a high incidence of micrometastases (<3 mm in size) has been found in patients without clinically manifest neck node disease. 102 However, one should realize that the prognostic significance of these tiny metastatic deposits has not yet been proven. 103, 104
Neck node disease also correlates with an increased risk of development of distant metastases. 105 - 108 Patients with disease in the neck had twice as many distant metastases as those without (13.6% vs. 6.9%), whereas the presence of extranodal spread meant a threefold increase in the incidence of distant metastases compared with patients without this feature (19.1% vs. 6.7%). 106 Originally, distant metastases defined as metastatic SCC at sites below the clavicle were considered rare. 109 However, since this report in the early 1920s, the occurrence of distant metastases of UADT SCC, predominantly occurring in the lungs, has been extensively demonstrated in clinical and autopsy studies ( Figs. 2-1 and 2-2 ). 110 - 112 As the lungs are also the most common site of second primary tumors in patients with UADT SCC, it has not always been possible to answer the question of whether a lung lesion is a second primary tumor or a metastasis from UADT SCC. 113, 114 Currently, molecular analysis of the various lesions offers the solution for this diagnostic problem. 115 - 118

Figure 2-1 Autopsy specimen. A tumor originating in the floor of the mouth has perforated the skin of the chin (this is not the mouth). Pleural nodules indicative of distant metastasis are present in both lungs.

Figure 2-2 Photomicrograph showing tumor in a thrombosed lung blood vessel as well as tumor growing elsewhere in the lung. In this way, head and neck tumors may spread to the lung.

Pathologic Features and Prognosis
A UADT SCC is a malignant epithelial tumor with squamous differentiation characterized by the formation of keratin or the presence of intercellular bridges or both. 119 This diagnosis is usually not difficult to make, the most significant diagnostic problem being very marked pseudoepitheliomatous hyperplasia of the mucosa, often overlying a granular cell tumor or an infectious process that may be mistaken for SCC. 120 However, when trying to infer data with prognostic significance from the histology, one enters an area replete with difficulties and uncertainties. In fact, tumor size and stage still represent the most significant prognostic factors for a patient with a UADT SCC, 121 and whether careful assessment of histomorphologic features adds anything of relevance to the prognosis other than at a statistical level is doubtful.
Nevertheless, for more than 80 years, pathologists have been trying to obtain information regarding prognosis by scrutinizing their histologic slides. When briefly reviewing this area, studies aimed at establishing associations between histology and survival as well as between histology and neck node disease are taken into account. Different approaches have been followed to obtain prognostically relevant data from histologic examination. The first attempts were made by Broders. 122 His classification system was based on the proportion of the neoplasm resembling normal squamous epithelium. Although some authors report histologic grade to have prognostic significance, 123 UADT SCC in most instances exhibits a heterogeneous cell population with differences in the degree of differentiation, which may lead to a high degree of intraobserver and interobserver differences in the histologic grading of a tumor. Furthermore, in practice, most UADT SCCs are graded as moderately differentiated, which may explain the poor correlation between patient outcome and histologic grading based on degree of differentiation. 124, 125 In an extensive multicenter study of more than 3000 patients, it was concluded that grading of UADT SCC, although a common practice, has not evolved as an important factor in treatment planning, this being due to the modest differences in survival rates between well and poorly differentiated tumors. 126
To obtain a more detailed morphologic evaluation of the growth potential of a UADT SCC, Jakobsson and colleagues 127 developed a multifactorial grading system, thereby paying attention not only to tumor features but also to the relationship of the tumor to the surrounding host tissue. This system has been used for SCC at various locations in the UADT with varying results, as reviewed by Anneroth and colleagues. 128 Some studies indicate that the value of this multifactorial grading system may improve when only the deeply invasive margins of the tumor are evaluated. 129 - 132 Tumor features that are assessed in this multifactorial grading system are degree of keratinization, nuclear pleomorphism, and number of mitotic figures. Features related to the tumor-host relationship are pattern of invasion, stage of invasion, and extent of peritumoral lymphoplasmacytic infiltration. Each assessed feature is scored from 1 to 4, and the scores for each morphologic feature are added together for a total malignancy score. 128
Because not all morphologic features are necessarily of equal prognostic importance, however, attention also has been paid to the importance of individual histologic parameters. The most important appears to be the pattern of invasion, tumors invading with pushing borders being less aggressive than tumors exhibiting diffuse spread with tiny strands or single cells ( Fig. 2-3 ). 129 - 141 Data on the specific significance of other parameters from the multifactorial grading system are less extensive. A grading system based on the presence or absence of keratin ( Fig. 2-4 ) as the only parameter to distinguish between well-differentiated and poorly differentiated cases was shown to make an independent statistically significant contribution to the prediction of prognosis. 133

Figure 2-3 A , Squamous cell carcinoma growing in large cohesive nests. B , Squamous cell carcinoma growing in tiny strands.

Figure 2-4 A , Squamous cell carcinoma with large keratin masses. B , Squamous cell carcinoma lacking extracellular keratin; only spinous differentiation can be observed.
When looking at the peritumoral lymphocytic infiltrate, one study mentions an inverse correlation between extent of infiltrate and incidence of neck node metastasis 138 ; no prognostic significance for this feature was found in other investigations. 136, 139 However, when analyzing the significance of individual cellular components, the number of T lymphocytes appeared to have some relevance. 142 The host’s reaction to an SCC may be visible not only as a peritumoral lymphocytic infiltrate but also as tumor-associated tissue eosinophilia, a feature of uncertain prognostic significance. 143, 144
Other histologic items that are not included in this multifactorial grading system 128 but nevertheless are considered to be prognostically important are tumor thickness, 129, 139, 141, 145 - 147 perineural growth ( Fig. 2-5 ), 129, 146, 148, 149 and vascular invasion ( Fig. 2-6 ). 137, 140, 150 The significance of the density of tumor vessels in the stroma adjacent to the tumor is controversial. 151 Concerning perineural invasion, one should be aware of the fact that in and around the oral cavity, intraneural and perineural epithelial structures are present that are not associated with malignant growth but probably are persisting epithelial embryologic structures. 152 - 154 Those structures are found at the medial surface of the mandible and are known as Chievitz’ organ, 153, 154 or they may be present in association with intrabony nerves, probably representing odontogenic epithelial nests ( Fig. 2-7 ), 152, 153 as well as in the anterior maxilla, probably representing a nasopalatine duct remnant. 153 The intimate relationship between these islands of epithelium and peripheral nerves could be erroneously interpreted to represent perineural and intraneural invasion. 153

Figure 2-5 Photomicrograph showing squamous cell carcinoma growing perineurally.

Figure 2-6 Photomicrograph showing squamous cell carcinoma with intravascular tumor embolus.

Figure 2-7 A , Odontogenic epithelial nests may be associated with nerves passing through the jaw bone. This feature should not be mistaken for perineural spread. B and C , Juxtaoral Chievitz’ organ. Note nests of epithelial cell rests with peripheral polarization of some of the basal cells ( B ) and areas with squamous differentiation ( C ). These nests should not be misinterpreted as malignant.
Aside from the evaluation of the aforementioned tumor features that could be prognostically significant, the pathologist contributes to an additional significant prognostic parameter by evaluating the completeness of the primary excision. 124 Almost all authors who have investigated the significance of tumor at the surgical margins agree that this finding is associated with an increase in local recurrence and mortality. Some authors observed this association only in patients with invasive tumor at the margins 155 - 157 ; others found the same negative influence in the event of tumor close to the margins (<5 mm) 137, 158, 159 or with patients having dysplasia or carcinoma in situ at the surgical margins. 160 - 164 Probably the negative influence of positive surgical margins is due, at least partly, to its close association with other tumor factors that have an adverse effect on prognosis, especially T stage. 165, 166 Also, anatomic tumor location and site of the involved margin, mucosal versus deep soft tissue and/or bone, may play a significant role and are worthy of inclusion in the surgical report. 167 In a series of small intraoral cancers, completeness of excision turned out to be the only factor of prognostic relevance, other histologic variables being irrelevant in predicting recurrence at the primary site. 168 In this study, definition of completeness of excision was dependent on tumor features. In the event of invasive growth in tiny nests and strands of tumor cells, the distance between individual tumor nests had to be less than the distance between the resection margin and the tumor nest closest to this margin. Thus, if the distance between tumor nests was greater than the margin-tumor distance, resection was considered not to be sufficiently radical, and hence the surgery was tabulated as incomplete. Sometimes, distance between the main tumor and separate nests can be large ( Fig. 2-8 ). This approach for margin analysis was validated in a larger study of almost 400 patients in which it was shown that the recurrence rate in the cases with positive margins was five times higher than in the cases with margins free of tumor or dysplasia, with recurrence at the primary site in cases of free margins being less than 5%. 169

Figure 2-8 Photomicrograph showing large distance between main tumor (MT) and separate nest (t). Such nests (t) may confound proper assessment of margin status when the line of resection runs between these nests and the main tumor, thus leaving tumor nests behind and nevertheless showing a free margin in the sections. Inset , Small nest of squamous cell carcinoma.
Intraoperative consultation for assessment of mucosal surface lesions at the surgical borders of a resection can be useful in differentiating inflammatory lesions and/or presence of neoplasia at the surgical margin. The procurement of surgical margins to be evaluated varies by institution (surgeon procured or pathologist procured) and type of tissue submitted (soft tissue, touch preparations of bony margins, curetting of bone marrow) or by specimen-based versus status postexcisional cavity biopsy specimen-based data. A negative surgical margin seen on frozen-section evaluation and confirmed on permanent-section evaluation does not ensure local control of disease but has been shown to enhance local control. 170 The criteria for a positive margin on frozen section is the same as discussed earlier. Others have proposed that the status of margin assessment should include other findings such as pattern of invasion, perineural invasion, and lack of lymphocytic response to more accurately guide and assess therapeutic intervention. 171
It is obvious from the foregoing that, when dealing with a UADT SCC specimen, the pathologist should pay attention to all tumor features that may assist the clinician in assessing the need for further treatment. Therefore, the pathology report should at least include data on tumor size and thickness, growth pattern, perineural and vasoinvasive growth, degree of differentiation, and evaluation of the margins, including tumor distance from the margins. If a neck dissection is included, the size, number, site, side relative to the primary tumor, and presence or absence of extracapsular spread should be stated because of prognostic significance. 172 A standard form as provided by the Royal College of Pathologists may be helpful and will facilitate computer-based analysis when performing retrospective studies. 173 Such guidelines and minimum data sets will produce reliable standardized data allowing prospective multicenter research projects. 174
In addition to studying conventional histopathologic aspects that could have prognostic significance, attempts have been made to obtain data with predictive value in other ways. Some authors have tried to obtain more objective data for features also assessed in routine histologic sections. This especially applies to the rate of proliferation or prognostic significance of p53 overexpression. Until now, these studies have provided no objective evidence of any association with patient outcome. 175, 176
The value of molecular markers in determining the prognosis for individual cases has not yet been demonstrated; consequently, none of the markers has gained any significance for daily practice to date. 177 - 179 Ongoing exploration of possible therapeutic markers among which are epidermal growth factor receptor and HER 2 may open new ways in the future. There is evidence that the presence of epidermal growth factor receptor may allow new chemotherapy options. 180
Detection of cells harboring p53 gene mutations in lymph nodes and at surgical margins has been reported to improve the prediction of local tumor recurrence by demonstrating the presence of tumor cells at sites judged to be tumor free by conventional histopathologic assessment, 181 but whether this method will improve patient survival is debatable. 169 Moreover, genetically altered cells found in histologically normal mucosal margins are not necessarily tumor cells. They could signify expanding fields of genetically altered preneoplastic cells as well. 86
More promising is the report that gene expression profiling in oral and oropharyngeal SCCs predicts whether neck node metastasis is present. 182

Site-Specific Features

The endodermally derived pharynx is traditionally divided into three functional and structural sections: the nasopharynx, the oropharynx, and the hypopharynx. The most cephalad of these divisions is a cuboidal structure, the nasopharynx. Anteriorly, the nasopharynx communicates with the nasal cavity via the choanae, laterally with the middle ears via the eustachian tubes, and inferiorly with the oropharynx. On the roof of the nasopharynx is the pharyngeal tonsil, which overlies the occipital bone and posterior portion of the body of the sphenoid bone. The floor of the nasopharynx is an imaginary horizontal line from the level of the palate to the posterior pharyngeal wall.
The distribution and frequency of occurrence of stratified squamous epithelium, intermediate (transitional) epithelium, and ciliated epithelium within the nasopharynx have been mapped and outlined by Ali 183 ; they appear to be fairly constant between the ages of 10 and 50 years.
One of the most important areas, from a pathologic standpoint, is the lateral wall of the nasopharynx. The lateral wall contains the site of the opening of the eustachian tube, which forms a triangular prominence, the torus tubarius. Rosenmüller’s fossa (pharyngeal recess, sinus of Morgagni, nasopharyngeal fossa) is a depression posterior to the torus tubarius. The fossa is formed by a herniation of the nasopharyngeal mucosa through a deficiency between the skull base and the most superior fibers of the superior constrictor muscle. The fossa overlies the foramen lacerum. Rosenmüller’s fossa is the most common site of origin for NPC. 184 - 186
An extensive network of lymphatics drains the nasopharynx. Those from the roof and posterior wall join in the midline, pass through the pharyngeal fascia, and drain to the right and left retropharyngeal lymph nodes (nodes of Rouvière). The other two chains frequently receiving drainage from the nasopharynx are the cervical chain and the spinal accessory nodes. A well-recognized initial presentation for NPC is a metastatic lymph node deposit within jugular or supraclavicular areas of the neck. 187 Presentation in the apex of the posterior triangle of the neck is a noteworthy characteristic of NPC. Other common sites of metastasis from the nasopharynx are the lymph nodes of the retropharyngeal space. 188

The etiology of NPC is a multifactorial interaction of race, genetics, environment, and EBV. 189 Reports of familial clusters suggest a genetic component. 189 - 191 Dietary factors have been proposed. Persons in southeast China who eat nitrosamine-rich salted fish (Chinese style) have one of the highest incidences of NPC, particularly the seafaring Tankas, for whom salted fish is a prominent dietary component. 192, 193 The dietary factors, however, have not explained the male-to-female ratio of 3:1 (which is seen in both endemic and nonendemic areas) or the ubiquitous association with EBV. 189, 194
The presence of EBV within the epithelial cells and not the lymphoid infiltrate has been demonstrated by various methodologies, including karyotyping, electron microscopy, in situ hybridization, polymerase chain reaction, and immunohistochemistry. 189, 195 - 199 High titers of immunoglobulin A antibodies to EBV-specific antigens, viral capsid antigen, and early antigen have been reported to correlate with tumor burden, relapse, and clinical progression. 189, 194

Clinical Features
NPC occurs in all age groups, most commonly in those 40 to 60 years old. It is most common in males, by a 3:1 ratio, in contrast to SCC of other head and neck sites, which has an even higher male incidence of 9:1. 194 In some intermediate- and low-risk areas, there is a bimodal age distribution, with peaks in the second and sixth decades. 200, 201 In the United States among blacks, the tumor has been reported to peak at 10 to 19 years of age. 202 In areas of Africa, NPC accounts for approximately 10% to 20% of childhood malignancies, 196 and in the Sudan, it is the most common pediatric cancer. 203 In the high incidence region of Southern China, however, NPC is only rarely seen in children. 196
The most common site of origin of NPC is on the lateral wall at Rosenmüller’s fossa. Patients may present with a variety of symptoms: serous otitis media, nasal obstruction, epistaxis, or cervical adenopathy commonly seen in the apex of the posterior cervical triangle (level 5, see Chapter 11 for description of levels).
The majority of patients (60%–72%) will present with unilateral or bilateral cervical adenopathy. 194 The site of the primary tumor may be occult.
More advanced disease is usually present if the patient’s symptoms include hearing loss, otalgia, headache, or evidence of cranial nerve involvement (10%–12% of cases). The cranial nerve involvement is easily explained by the proximity of the nasopharynx to the foramen lacerum and the contents of the most commonly involved region in NPC extension, the paranasopharyngeal space, which contains branches of the trigeminal nerve ( Fig. 2-9 ). 204, 205 In one computed tomography study of 262 patients with NPC, cranial nerve palsy of the third through the sixth cranial nerves had evidence of erosion of the base of the skull; however, erosion of the base of skull did not imply cranial nerve involvement. 206 Other presentations or evidence of relapse of tumor may be paraneoplastic syndromes such as hypertrophic osteoarthropathy syndrome (Pierre Marie syndrome), leukemoid reaction, and fever of unknown origin. 207

Figure 2-9 Schematic horizontal section through the nasopharynx (NP). a, adenoids; CA, carotid artery; E, eustachian tube; FL, foramen lacerum; FO, foramen ovale; LP, levator palati; PBF, pharyngobasilar fascia; PPS, parapharyngeal space; PTS, paratubal space; RF, Rosenmüller’s fossa; S, sphenoid sinus; TP, tensor palati; V, trigeminal ganglion.
One of the unique clinical features of NPC is the propensity for distant metastasis. At the time of presentation, 5% to 11% of patients have distant metastases. 208 During the course of the disease, 50% to 60% of patients develop distant metastases. 207 Autopsy series report the overall metastasis incidence to be 87%, with the common sites being bone, lung, and liver. 194, 209, 210 The natural history of disease progression is short, with 78% of metastases occurring within 18 months of the first symptoms. 194 After detection of systemic metastases, median survival is only approximately 6 months. 211 The frequency of distant metastatic sites for NPC as compared with those of other UADT SCCs is the following: bone (65% vs. 25% UADT SCC), liver (29% vs. 23% UADT SCC), and lung (18% vs. 84% UADT SCC). 207 Approximately 25% of patients with evidence of metastatic disease will have involvement of the bone marrow. 207
A number of different staging systems for NPC have been developed in different parts of the world. 185, 212 - 214 The most recent TNM classification by the American Joint Committee on Cancer 213 and Union International Contre le Cancer (International Union Against Cancer) 214 is customized for the unique behavior and therapeutic needs for NPC and can be found in Appendix I (“Head and Neck Tumors: TNM Staging”) . The original staging system proposed by Ho, developed in an area with one of the highest incidences of NPC, has undergone some modification, which has reduced the number of stages without reducing the accuracy of predicting prognosis. 215 Some advocate that the modified classification of this system shows a more even distribution of patients among stages, with a greater power of predicting prognosis, than other classification systems ( Table 2-1 ). 212 Unfortunately, there has not been one single generally accepted classification for comparison of treatments of NPC between centers.

Table 2-1 Ho’s Classification and Modified Ho’s Classification

Pathologic Features
NPC accounts for 3.7% of UADT tumors. 14 All forms of NPC are derived from the surface epithelium of the nasopharynx, having ultrastructural features such as tonofilaments and desmosomes of SCC. 216, 217 Tumors with glandular differentiation do not form part of the histologic spectrum of NPCs.
The most recent World Health Organization (WHO) classification has retained previous changes and added a new category of basaloid SCC (BSCC). 119 When comparing the last two revisions of the WHO classification with the first one, 218 - 220 there are significant alterations, as shown in Table 2-2 . 119, 218 - 220 The second edition of the WHO histologic typing of UADT tumors divides NPC into two broad histologic types: keratinizing SCCs and nonkeratinizing carcinomas. 219 This dichotomy is based on the observation that both nonkeratinizing types of NPC are associated with a positive EBV serology, marked propensity for cervical lymph node metastasis, and radiosensitivity. 221 Irrespective of their histologic subtypes, almost 100% of cases of NPC have demonstrable EBV-encoded small RNAs in the nuclei of their tumor cells, as demonstrated by in situ hybridization. 195, 208 The positive hybridization signal in keratinizing NPC, however, is less in proportion to that of malignant cells, usually limited to basal cells, than in other histologic types of NPC. 208
Table 2-2 Classification of Nasopharyngeal Carcinoma WHO (1978)
1 Squamous cell carcinoma (WHO type I)
2 Nonkeratinizing carcinoma (WHO type II)
3 Undifferentiated carcinoma (WHO type III) WHO (1991)
1 Squamous cell carcinoma
2 Nonkeratinizing carcinoma
a Differentiated nonkeratinizing carcinoma
b Undifferentiated carcinoma WHO (2005)
1 Squamous cell carcinoma
2 Nonkeratinizing carcinoma
a Differentiated nonkeratinizing carcinoma
b Undifferentiated carcinoma
3 Basaloid squamous cell carcinoma
WHO, World Health Organization.
Data from Shanmugaratnam K: Histological Typing of Tumours of the Upper Respiratory Tract and Ear, 2nd ed. Berlin: Springer, 1991, pp 28–33; Shanmugaratnam K: Histologic Typing of Upper Respiratory Tract Tumours. International Typing of Tumours, No. 19. Geneva: World Health Organization, 1978, pp 32–33; Chan JKC, Pilch BZ, Wenig BM, et al: Nasopharyngeal carcinoma. In Barnes L, Eveson JW, Reichart P, Sidransky D (eds): World Health Organization Classification of Tumours: Pathology and Genetics. Tumours of the Head and Neck. Lyon: IARC Press, 2005, pp 85–97.
Keratinizing NPC exhibits the features of a conventional SCC as occurs anywhere in the UADT. These keratinizing tumors (1) are infrequently seen in high-incidence areas (<5%), 189 (2) represent one fourth to one half of NPCs in low-incidence populations, 189 (3) are less often associated with lymph node or distant metastases, 192 (4) are usually not radiosensitive, 189 (5) occur primarily in adults, and (6) have been associated with cigarette smoking. 189, 222
The nonkeratinizing carcinoma group is subclassified into differentiated and undifferentiated subtypes. 119 As mentioned earlier, these two subclassified groups have overlapping histologic features and similar epidemiologic and biological characteristics (frequent lymph node involvement and distant metastases). NPC, nonkeratinizing, differentiated subtype, consists of cells in which squamous differentiation is not evident on light microscopy; these cells have distinct margins and usually form plexiform masses or, rarely, papillary structures. Some find this pavement-like arrangement of cells with well-defined borders reminiscent of urothelial transitional cell carcinoma, 223 and thus this type of NPC may mimic cylindrical cell carcinoma, an SCC type occurring in the sinonasal cavities and discussed under that heading.
Undifferentiated carcinoma consists of cells with scant cytoplasm, oval or round vesicular nuclei, and prominent nucleoli. The cell margins are indistinct, imparting a characteristic syncytial growth pattern, and the cells may be arranged in irregular masses or as loosely connected cells in a lymphoid stroma. 119 When associated with a lymphoid stroma, these tumors may be referred to as the lymphoepithelial type of undifferentiated carcinoma or as lymphoepithelioma, an entity discussed later.
The distinction between these three histologic types—SCC, nonkeratinizing carcinoma, differentiated subtype and undifferentiated subtype—is not always sharp. In one study, 26% of 363 NPCs examined had more than one histologic type. 217 In biopsy specimens with more than one histologic type, the tumor is classified by the predominant histologic type. 217 Some have found the demarcation between the subtypes of nonkeratinizing carcinoma to be the most problematic. 219, 224 A practical approach is to classify NPC as nonkeratinizing, differentiated subtype, if there is evidence of maturation (flattening or spindling) within the tumor cords. The distinction between the nonkeratinizing carcinoma differentiated subtype and the undifferentiated subtype may be more academic than real when considering prognosis; however, knowledge of the histologic features may prove useful when one is confronted with subsequent metastatic disease.

Differential Diagnosis
Keratinizing NPC should not give origin to differential diagnostic problems other than for SCC at other UADT sites. Nonkeratinizing NPC differentiated subtype may resemble, as already mentioned, cylindrical cell carcinoma of the paranasal sinuses. Further details on the differential diagnosis of the NPC undifferentiated type are mentioned when lymphoepithelioma is discussed.

Treatment and Prognosis
For treatment of NPC, irradiation is usually the first choice. The survival of NPC patients is influenced by age, sex, T and N stage, and histologic type; the nonkeratinizing, undifferentiated subtype is far more radiosensitive than keratinizing SCC. 223 For patients treated with radiotherapy, 5- and 10-year survival rates have been reported to be 58% and 47%, respectively. 225 The treatment modality for NPC is based on the histologic type, keratinizing versus nonkeratinizing carcinoma. The nonkeratinizing histologic types are radiosensitive. External beam–supervoltage radiotherapy is the standard treatment of locoregionally confined NPC. 189 The keratinizing types of NPC have a poor response to irradiation and are, therefore, more amenable to surgical resection. 223 Although improvements in radiation technique have occurred, both local control and distant failure remain problems. Neoadjuvant chemotherapy studies have shown NPC to be sensitive to preirradiation chemotherapy. 189
Several features have prognostic significance in NPC. Those features associated with a favorable outcome are (1) female gender, (2) age younger than 40 years at onset, and (3) lymphoepithelioma histology. 226 Those features associated with an unfavorable prognosis are (1) symptoms for more than 1 year, (2) keratinizing carcinoma histology, (3) positive lymph nodes in the lower neck, (4) cranial nerve involvement, and (5) distant metastases. 226 Those features not appearing to have an impact on prognosis are (1) unilateral or bilateral lymph nodes in the upper neck, (2) fixed nodes, and (3) involvement of bone at the skull base. 226 Tumor volume has also been shown to have prognostic significance. 227

Sinonasal Cavities
The sinonasal region is located in the mid-portion of the face and is composed of the centrally located paired nasal cavities surrounded by paired paranasal sinuses. The paranasal sinuses comprise the maxillary, frontal, ethmoidal, and sphenoidal sinuses. This maze of cavities abuts the base of the skull and lies adjacent to vital structures ( Fig. 2-10 ).

Figure 2-10 Sinus schematic with coronal ( A ) and transverse ( B ) sections. The arrows indicate pathways of tumor spread into adjacent structures and sinuses via the intricate sinonasal labyrinth.
The nasal cavity has a roof, floor, lateral wall, and septum. It is divided anteriorly into the nasal vestibule and posteriorly into the nasal antrum with turbinates. The nasal vestibule is bordered inferiorly by the palatine process of the maxilla and medially by the septal cartilage, and the superior and lateral walls are composed of the soft tissue of the nasal ala. The soft-tissue lining of the vestibule is an extension of integument, with its keratinizing stratified squamous epithelium and secondary appendages. This lining extends for approximately 1 to 2 cm from the external rim of the nose into the nares. Just beyond the limen nasi (which is a ridge across the roof of the nasal cavity formed by a border of the upper lateral cartilage) is roughly the location of the mucocutaneous junction. This junction demarcates the beginning of the respiratory mucosa of ectodermal origin, which is referred to as the schneiderian membrane. This membrane lines the nasal antrum with turbinates and paranasal sinuses. The superior, middle, and inferior turbinates (conchae), which have associated meatuses, hang into the nasal lumen along the lateral walls of the nasal cavity. The roof is formed by the cribriform plate, the sphenoid bone, and the frontal bone. Posteriorly, the conchae end approximately 1 cm anterior to the choanal orifice, which is a continuum of the posterior aspect of the nasal cavity into the anterior opening of the nasopharynx.
The ethmoid labyrinth in the adult is a completely pneumonized lattice of approximately three to 18 cells per side. The roof of the labyrinth is adjacent to the anterior cranial fossa. The lateral wall of the ethmoid sinus is the medial wall (lamina papyracea) of the orbit, and the medial wall of the ethmoid sinus forms the lateral wall of the nose and attachment for the middle turbinate. Because of the close proximity of the adjacent nasal passages and sinuses, the ethmoid sinus is the second most frequently involved sinus by tumor extension, after the maxillary sinus.
The maxillary sinus (antrum of Highmore) is the largest of the sinuses and encompasses the majority of the corpus of the maxilla. The walls of the maxillary sinus abutting the nasal cavity and orbit are thin, whereas those of the anterior and posterior walls are relatively thick. The apices of the premolars and molars of the maxilla protrude into the maxillary sinus and are covered by a thin plate of bone. The ostium from the maxillary sinus leads into an area within the middle meatus and is situated at the superior aspect of the maxillary sinus. The position of this ostium is unfavorable for drainage of the sinus while in an upright position.

Clinical Features
Malignancy of the sinonasal region represents 0.2% to 0.8% of all malignancies and approximately 3% of all those of the UADT. 22 SCC represents approximately 65% of the malignancies in the sinonasal region. 14, 228 The distribution of carcinoma by anatomic site is the maxillary sinus (55%–60%), nasal cavity (19%–35%), ethmoid sinus (9%–15%), nasal vestibule (4%), and frontal and sphenoid sinuses (1% each). 14, 229
The majority of the tumors in this region present in a late stage (T3 and T4), as the initial presenting signs are usually nonspecific. The nonspecific findings were noted to delay diagnoses from 3 to 14 months in one series. 230 Extent of tumor at the time of diagnosis best correlates with prognosis rather than degree of differentiation, with the exception of anaplastic carcinoma. 231
Regional metastases from sinonasal neoplasms are uncommon (9%–14% for SCC). 22 Metastasis from these tumors usually implies soft-tissue extension (antral tumors: cheek and soft palate; ethmoid tumors: medial canthal skin and nasopharyngeal extension). 22 The maxillary sinus drains primarily to the submandibular nodes. The lymphatic drainage of the ethmoid labyrinth is to the superior cervical nodes, and some drain directly posteriorly to the retropharyngeal nodes. 232 With recent advances in imaging, assessment of retropharyngeal lymph nodes is possible. 188
Although site-specific systems have been proposed, 233 the only internationally recognized staging system is for maxillary and ethmoid tumors. In 1938, Ohngren 234 proposed a theoretical plane from the medial canthus of the eye to the angle of the mandible, which created an anterior inferior infrastructure and a superior posterior suprastructure to the maxillary sinus area. This hypothetical division has clinical relevance because the anterior inferior tumors present early whereas the superior posterior tumors usually present after extensive tumor growth has occurred. The American Joint Committee on Cancer 213 and the Union International Contre le Cancer 214 have adopted a T classification for the maxillary sinus and ethmoid sinus, as noted in Appendix I .

Pathologic Features
In the histologic classification of the nasal cavity and paranasal sinuses, there is some confusing and controversial terminology. The majority of the carcinomas in this region are of the keratinizing squamous variety, but most of the controversial terminology revolves around the nonkeratinizing carcinomas. The synonyms for nonkeratinizing carcinoma include cylindrical cell carcinoma (Ringertz’ carcinoma), transitional cell carcinoma, and schneiderian carcinoma. Reference to cylindrical cell carcinoma can be found in the literature around 1900 as a histologic type of nasal carcinoma, but it was fully described by Ringertz 235 in 1938. The histologic description rendered by Ringertz described a sometimes papillary nonkeratinizing epithelial tumor that invaginated into the stroma. The invaginating epithelial growths had a palisading basal layer forming a crisp demarcation at the epithelium-stroma interface and forming a ribbon or garland-like pattern with central zones of necrosis.
In the American literature more than a decade earlier, Quick and Cutler 236 introduced the James Ewing term transitional cell carcinoma for a category of upper airway tumors that “exhibited transitional epithelial characteristics with cylindrical or cuboidal cells free of keratosis.” While investigating the effects of irradiation on tumors of the upper airway, Ewing found that patients with transitional cell carcinoma survived longer because the tumors were more radiosensitive than conventional SCCs; hence, justification for the entity. Ewing’s histologic description was similar to Ringertz’ description. Ewing, however, attributed the pattern of necrosis to the effects of irradiation on the tumor. Schneiderian carcinoma was also a term coined by James Ewing. This term referred to poorly differentiated carcinomas originating from the schneiderian membrane and was never clearly defined as an entity. 235, 237 The term is infrequently used.
The term transitional carcinoma was used by later investigators to describe malignant transformation in transitional papillomas of the nasal cavity. Transitional was chosen because of the histologic resemblance of the malignant epithelium to that of transitional epithelium of the urogenital tract. 238, 239 Also articles may be found that equate all three terms: transitional, schneiderian, and cylindrical cell carcinomas. 240
Clinical justification for the separate classification of cylindrical cell carcinoma and transitional cell carcinoma was proposed by Friedmann and Osborn 239 in 1982. They observed cylindrical cell carcinoma to have less tendency to spread via the lymphatics. Others, however, have reported cylindrical cell carcinoma to have a clinical course similar to that of conventional SCC. 228, 241, 242 The current WHO classification recognizes cylindrical cell carcinoma as a synonym for nonkeratinizing carcinoma. 243
In current American literature, the terms cylindrical cell carcinoma and transitional cell carcinoma are infrequently used. Some authors employ these designations to denote lesions also categorized as nonkeratinizing SCC of the nasal cavity and paranasal sinuses 244 or consider them to be just a subtype of SCC 245 ; others use the term cylindrical cell carcinoma to identify a variant of sinonasal SCC that may exhibit intracellular mucin production and sometimes has a growth pattern similar to a papilloma, making stromal invasion not immediately apparent. 246 To end this discussion on semantics and nosology, we advocate use of the WHO approach, recognizing cylindrical cell carcinoma as one of the synonyms of sinonasal nonkeratinizing SCC and recognizable by features as originally outlined by Ringertz: a papillary lesion composed of invaginating ribbons of pleomorphic nonkeratinizing cells that are mainly cylindrical and often arranged perpendicularly to the underlying basement membrane. The lesion invades with a pushing border, which makes stromal infiltration not immediately apparent when one is evaluating small biopsy specimens ( Fig. 2-11 ). The tumor may exhibit squamous metaplasia, which, if extensive, makes cylindrical cell carcinoma indistinguishable from conventional SCC.

Figure 2-11 A , Low-power micrograph of cylindrical cell carcinoma. The strands of polymorphic cells that make up the tumor show a well-defined interface with the adjacent stroma. B , At higher magnification, the polymorphous nature of the cells and the cylindrical aspect of basal and suprabasal cells are clearly shown.

Differential Diagnosis
Nonkeratinizing carcinoma, cylindrical cell type should not be confused with papillary SCC (PSCC), a lesion discussed more extensively in the section devoted to specific variants of SCC. Distinctive features are the lack of cylindrical cells in PSCC and the presence of papillary protrusions covered with an epithelial lining with the features of carcinoma in situ found in PSCC but absent in cylindrical cell carcinoma. Moreover, the histology of cylindrical cell carcinoma may mimic that of inverted papilloma. However, the presence of numerous microcysts in the multilayered epithelial ribbons in some parts of the material is valuable in confirming the diagnosis of inverted papilloma, whereas their absence in conjunction with cellular atypia should cause concern that the diagnosis might be SCC. 247

Treatment and Prognosis
For patients with carcinoma of the sinonasal area, the probability of surviving for 5 years is approximately 50%. 14 Within the nasal cavity, malignancy of the nasal vestibule and septum has a better prognosis, perhaps because of earlier diagnosis, 228, 248, 249 than in the remainder of the nasal cavity and paranasal sinuses. For patients with antral and ethmoidal disease, the probability of surviving 5 years is 48% and 68%, respectively. 229 The 5-year survival rate for patients with T2, T3, and T4 cancers of the antrum is 73%, 41%, and 15%, respectively. 230 There does not appear to be a significant correlation of survival rates with the patient’s sex or age at time of presentation. 230 Although multimodality therapy does not seem to change the 5-year survival rate, it appears to have improved the local control of tumor. 230 Factors limiting patient survival time are related to local recurrence, nodal metastasis, soft-tissue extension to the palate or nasopharynx, proptosis, and orbital symptoms, as metastases account for approximately 10% of deaths. 22, 250

Larynx and Hypopharynx
The hypopharynx and larynx are anatomically intimately associated and constitute the division point between the digestive tract and the lower respiratory tract. Owing to the nature of their anatomic proximity, accurate identification of a primary tumor site may be difficult; however, identification of the primary site has prognostic significance. Malignancy of the hypopharynx/larynx in the United States represents approximately 34% of all UADT cancers, the larynx being the most common at 28% and the hypopharynx representing 6.6% of UADT cancers. 14 Globally, tumors of the larynx are the second most common tumor of the respiratory tract and the 11th most common cancer in men. 15

The conically shaped hypopharynx is the most caudate portion of the endodermally derived pharynx. It communicates superiorly with the oropharynx and inferiorly with the larynx and esophagus. The superior border of the hypopharynx is an imaginary horizontal line drawn across at the level of the tip of the epiglottis. The inferior boundary is defined anteriorly by the aryepiglottic folds, which lead to the endolarynx, and posteriorly by the inlet to the cervical esophagus.
The hypopharynx is divided into three regions: the paired pyriform sinuses or recesses, the posterior pharyngeal wall, and the postcricoid region. The pyriform sinuses are bilaterally elongated, pear-shaped, three-walled gutters that open into the hypopharyngeal cavity and extend anteriorly and laterally on either side of the larynx. The borders of the pyriform sinus are formed superiorly by glossoepiglottic folds and medially by the hypopharyngeal surface of the aryepiglottic folds and the arytenoid and cricoid cartilages. The medial wall of the pyriform sinus is separated from the ventricle of the larynx and outer aspect of the cricoid cartilage by a thin submucosal layer of muscle. 251 The lateral wall of the pyriform sinus lies against the thyroid cartilage and blends into the posterior pharyngeal wall. Inferiorly, the pyriform sinus is in continuum with the entryway into the esophagus.
The posterior pharyngeal wall joins the lateral limits of the pyriform sinus and inferiorly, the cervical esophagus. The postcricoid region is a funnel-shaped area extending from the level of the arytenoid cartilages to the inferior border of the cricoid cartilage. Lateral borders of the postcricoid region blend with the pyriform sinus.
Stratified squamous epithelium lines the hypopharynx. The epithelium is nonkeratinizing; however, when subjected to chronic irritation, orthokeratinization or parakeratinization may be found. Within the submucosa are seromucinous glands, scattered lymphoid aggregates, and a rich anastomosing network of lymphatics.
In the United States and Canada, the frequency of involvement of the hypopharynx by cancer is the pyriform sinus (65%–85%), the posterior pharyngeal wall (10%–20%), and the postcricoid area (5%–15%). 252 Carcinoma of this region, with the exception of the postcricoid area, occurs predominantly in men and is associated with alcohol use and smoking.
Carcinomas of the hypopharynx generally have a poor prognosis, primarily because of a combination of unrestricted area for tumor growth, multifocality, and extensive lymphatic network. These tumors are notorious for submucosal spread beneath an intact mucosa, early lymph node metastasis, and a high rate of systemic metastases (20%–40%). 252 There appears to be no relationship between the degree of differentiation and the invasiveness of hypopharyngeal SCC, which means that its clinical aggressiveness cannot be explained by a higher percentage of poorly differentiated cancers at this site. 253 Some investigators have estimated the extent of submucosal spread to be anywhere from 1 to 0.5 cm for the pyriform sinus and postcricoid area, respectively. 254 This characteristic submucosal spread may not be accurately assessed clinically or by radiographic modalities (computed tomography or magnetic resonance imaging). 255, 256
Because of the paucity of early presenting symptoms, most patients present with advanced disease. In a study of 408 patients with tumors of the pyriform sinus, 67% had T3 or T4 lesions and 87% were stage III or IV at presentation. 255 Approximately one fourth of these patients will present with a mass in the neck and 70% will have lymph node disease at presentation. 255, 257 Upper and middle cervical nodes of levels II and III are most commonly involved. 258
Tumors of the pyriform sinus, particularly those involving the medial wall, frequently secondarily involve the larynx. 255, 259 The posterior hypopharyngeal wall tumors are usually exophytic and also frequently large at presentation (80% >5 cm). 252 Tumors of the posterior hypopharyngeal wall metastasize to upper and middle cervical nodes, and in more than 40% of patients, the retropharyngeal nodes are involved. 252
Carcinomas of the postcricoid area have shown a marked geographic variation in incidence. They are associated with Plummer-Vinson syndrome and nutritional deficiencies (see “Epidemiology and Risk Factors” section). Carcinoma of this area may extend inferiorly, involving the esophagus and trachea and thus necessitating the removal of a portion of the trachea. The lymphatics drain to the middle and lower cervical and paratracheal nodes. Eighteen percent will have bilateral cervical node metastases, and most local recurrences are due to unrecognized involvement of the paratracheal nodes. 252
The staging for the hypopharynx is primarily directed for tumors of the pyriform sinus. In the former TNM classification system, a 4- to 5-cm posterior pharyngeal wall tumor without laryngeal fixation would remain a T1 lesion. The lesion, however, would have a prognosis similar to a T3 lesion. 260 The most recent American Joint Committee on Cancer/Union International Contre le Cancer 213, 214 staging for hypopharyngeal cancer recognizes tumor size as an additional issue in staging, as is mentioned in Appendix I .

Treatment and Prognosis
Treatment for the hypopharynx is the combined use of radiation and surgery. The majority of lesions involve the pyriform sinus, and combined therapy is recommended, with the exception of T1 and T2 lesions (single-modality therapy). 255 In one large study of tumors of the pyriform sinus, the overall 5-year disease-free survival rate for combined therapy was 65.2%. 255 A decrease in survival rate after 2 years is primarily due to distant metastasis and to second primary malignancies. 10 The value of adjunctive chemotherapy in pyriform sinus malignancy is still unclear. 10

The larynx is divided traditionally into three subsites: supraglottic, glottic, and subglottic regions ( Fig. 2-12 ). Embryologically, the supraglottic region is derived from the third and fourth branchial arches (buccopharyngeal anlage), and the glottic and subglottic regions originate from the fifth branchial arch (laryngotracheal anlage). These two regions fuse somewhere at the level of the ventricle. 261

Figure 2-12 A , Midsagittal section of the larynx. Note fenestrations in lower aspect of the epiglottic cartilage. c, cricoid cartilage; e, epiglottis; HEM, hyoepiglottic membrane; PESP, pre-epiglottic space; PL, prelaryngeal (Delphian) lymph nodes; t, thyroid cartilage; TEL, thyroepiglottic ligament; THM, thyrohyoid membrane. B , Coronal section of the larynx. c, cricoid; Quad. m., quadrangular membrane; SBSP, subglottic space; SPSP, supraglottic space; t, thyroid cartilage; tg, thyroid gland; Vocal l, vocal ligament.
Because of the embryologic derivation and independent lymphatic circulation, there is a unique compartmentalization of the larynx. The supraglottic region extends from the tip of the epiglottis superiorly to the ventricle inferiorly and is one compartment. The glottic and subglottic regions make up the other compartment. The anatomic barriers have been demonstrated by dye studies and histology. 261 These anatomic barriers and the site of origin influence the growth and spread of laryngeal carcinoma. 262
Encompassed within the supraglottic area is the epiglottis (lingual and laryngeal aspects), the laryngeal aspect of the aryepiglottic folds, the arytenoids, the false vocal cords, and the ventricles. The supraglottic area has frequently been subdivided into the suprahyoid and infrahyoid areas. Those carcinomas in the suprahyoid area (tip of epiglottic rim of aryepiglottic folds and arytenoids) tend to have a worse prognosis than infrahyoid tumors and behave similarly to hypopharyngeal tumors. 252 The inferior border of the supraglottis is an imaginary horizontal line drawn across the apex of the ventricle. The supraglottic larynx lymphatics drain laterally and superiorly through the thyrohyoid membrane and drain into the subdigastric and superior jugular nodes.
The glottis includes the paired true vocal cords and the anterior and posterior commissure. Lymphatics of the true vocal cords are sparse to nonexistent. The anterior commissure tendon (Broyles’ ligament) is an important band of fibrous tissue that contains certain lymphatics and blood vessels and attaches to the thyroid cartilage devoid of the tumor-resistant perichondrium. 252 Tumors of the anterior commissure may grow upward to the epiglottis or may penetrate the thyroid cartilage, particularly if the thyroid cartilage has ossified. The inferior border of the glottic area is 1 cm below the apex of the ventricle. The subglottic area is from the lower edge of the glottis to the inferior aspect of the cricoid cartilage. The lymphatic drainage from these two areas is lateral and inferior through the cricothyroid membrane to the paratracheal nodes, deep cervical nodes, and prelaryngeal (Delphian) node.
Both lingual and superior portions of the laryngeal aspects of the epiglottis are covered by nonkeratinized stratified squamous epithelium. The stratified squamous epithelium on the inferior laryngeal aspect of the epiglottis merges with respiratory-type epithelium. Respiratory epithelium lines the false vocal cords, ventricle, and subglottis. The vibratory edge of the true vocal cord is lined by a nonkeratinizing stratified squamous epithelium. The interface between the ciliated columnar epithelium of the ventricle and the stratified squamous epithelium of the true vocal cord is often abrupt. There may be a transitional zone where the epithelium may appear disorganized and thickened and the cells may have enlarged basaloid features; however, mitotic figures are confined to the basal cell layer. 263 This transitional zone is a metaplastic area and should not be mistaken for dysplasia or carcinoma in situ ( Fig. 2-13 ).

Figure 2-13 A , Histologic section illustrating the transition between the respiratory epithelium, which lines the ventricle ( right ), and the squamous epithelium lining the true vocal cord ( left ). The epithelium present at the transitioning interface of these two types of epithelium is referred to as intermediate epithelium. B , Histologic section showing the presence of metaplastic ventricular epithelium ( left ) and an extensive area of intermediate epithelium ( right ). The transitional zone of intermediate epithelium has a slightly disordered appearance. These metaplastic zones may be misinterpreted as dysplasia.
A spatial subdivision within the larynx has been demonstrated through pathohistologic study of serial sections of the larynx (see Fig. 2-12 ). The majority of SCCs of the larynx have been observed to respect the limitations of the fibroelastic membranes and skeletal structures for an extended period of time. 264 This intralaryngeal compartmentalization has been the anatomic basis for various surgical procedures. 261 The first spatial area is known as the supraglottic space (not to be confused with the supraglottic region). This space extends from subjacent to the supraglottic mucosal surface to the quadrangular membrane and inferiorly to the lower edge of the vestibular ligaments and petiole. The space is bordered laterally by the quadrangular membrane and the laryngeal surface of the epiglottic cartilage.
The pre-epiglottic space is triangular and bounded superiorly by the hyoepiglottic ligament, anteriorly by the thyrohyoid membrane, and posteriorly by the epiglottis. There are foramina in the infrahyoid epiglottic cartilage that allow tumor spread from the laryngeal side of the epiglottis into this space and thus outside the larynx. This space communicates in its inferior aspect with the paraglottic space.
The paraglottic space is the largest connecting spatial structure within the laryngeal soft tissues. This space surrounds the whole of the ventricles lateral to the quadrangular membrane and medial to perichondrium of the thyroid cartilage and is limited inferiorly by the elastic conus and the cricothyroid membrane. Recently described are elastic and fibroelastic membranes that are subjacent to ventricular mucosa and in continuity with the elastic conus and quadrangular membrane, 265 thus providing a continuous elastic membrane that bridges the supraglottis and glottic areas. Lesions from the pyriform sinus may involve this space. Tumors entering this space have the potential to spread to the pre-epiglottic space; thus, a glottic or subglottic lesion could gain access to the supraglottic region.
Reinke’s space is of particular interest in that it is the smallest space to be described within the larynx and lies between the vocal cord fold epithelium and the vocal ligament. This region is composed of a few blood vessels and very poor lymphatic drainage. Its widest extent is in the craniocaudal direction in the middle third of the vocal folds. The space narrows toward the anterior commissure.
The subglottic space is the most inferior space. The upper boundary is made up of the vocal ligament and elastic conus (fibers from the vocal ligament), which reaches the lower edge of the cricoid cartilage and extends into the submucosal region of the trachea. With this information, it should be noted that there is no vertical separation of the lymphatic drainage of the larynx into the left and right sides, and, therefore, as clinically observed, contralateral metastasis may be seen.

Clinical Features
In discussing the spread of laryngeal carcinoma, it should be noted that traditionally the tumors have been divided by site: supraglottic, glottic, transglottic, and subglottic. The supraglottic tumors involve the false vocal cord, the ventricle, and the epiglottis (laryngeal or lingual aspects) and represent approximately 30% to 35% of laryngeal tumors. 266 These tumors have a marked propensity to spread to the pre-epiglottic space primarily through fenestrations within the epiglottic cartilage. Approximately 1% of these supraglottic tumors invade the glottis. Invasion of cartilage is exceedingly rare, restricted only to those cases in which the cartilage has undergone osseous metaplasia. The incidence of lymph node metastasis averages approximately 40%. The tumors are primarily treated by irradiation or laryngectomy.
Tumors of the glottic area are the most frequent, accounting for approximately 60% to 65% of laryngeal carcinomas. 266 Glottic tumors arise from the true vocal cords, primarily from the anterior third of the vocal cord, and frequently produce hoarseness. Because of early symptoms, tumors of the glottis may be found in an early stage. Five-year disease-free rates for T1 carcinomas (localized to the vocal cord) have been reported as high as 90%. 267 The degree of anterior commissure involvement appears to have prognostic significance, with patients with a progressively heavier involvement of the anterior commissure subsite having a progressively worse outcome. 268 The incidence of lymph node metastasis in T1 through T4 tumors is 1.9%, 16.7%, 25%, and 65%, respectively. 252 Lesions of the glottis tend to be localized for an extended period of time, primarily due to paucity of lymphatic vessels within Reinke’s space and the cartilaginous walls. Early cases are usually treated by irradiation. Surgical management can be used to salvage irradiation failures.
The concept of a transglottic lesion was first presented in 1961 by McGavran and colleagues. 269 The term transglottic does not refer to an anatomic site within the larynx but to a pattern of glottic tumor spread that crossed the laryngeal ventricle, therefore involving the supraglottis and glottis, and also with paraglottic space involvement. This particular pattern of involvement appeared to have an aggressive clinical course with a high incidence of lymph node metastasis (52%). 269 Transglottic carcinomas are treated primarily by laryngectomy and lymph node dissections. They represent less than 5% of all cases of laryngeal carcinoma. 266 With time and imprecise use, there has been deviation from the original 1961 concept of transglottic tumor (supraglottic/glottic as well as glottic/infraglottic). Therefore, it is better to specify tumor extension by recording the defined anatomic subsites involved and refrain from the term transglottic.
The infraglottic or subglottic tumors are also rare, representing less than 5% of all the cases. 266 Tumors included in this category are tumors that involve the region between the lower edge of the true vocal cord (where the squamous epithelium ends) and the first tracheal cartilage 270 or extending 1 cm below the edge of the true cord. 266 Other investigators have defined the subglottis as extending from the lower boundary of the glottis to the lower margin of the cricoid cartilage. 271 The tumors in this area frequently show extension into the trachea. Metastasis to cervical lymph nodes is approximately 15% to 20%, and the involvement of paratracheal lymph nodes is approximately 50%. Subglottic tumors are treated primarily by surgical excision and neck dissection, including the paratracheal lymph nodes.
The staging system for laryngeal carcinomas is mentioned in Appendix I . 213 Several suggestions for alteration of the TNM classification system have been proposed. 272, 273 It has been argued that there are embryologic, anatomic, functional, and oncologic reasons to divide the larynx into two main areas only, the supraglottis and the glottis (vocal folds), without any further subsites, and to abandon a separate group of subglottic tumors. 272 Moreover, it has been proposed that the T size of a tumor should not be assessed according to the extent of an anatomic region but should instead be measured in millimeters of greatest surface extent only. 272 Furthermore, the T2 category of vocal cord tumors should not contain those that lead to an inhibited mobility of the fold. All tumors with reduced vocal fold mobility or fixation should be classified as T3 or T4. 272 Finally, the N status should include number, size, site of metastasis, and presence of extracapsular spread. 272 Other investigators found that the addition of clinical information such as the presence and intensity of local symptoms attributable to the tumor, perilocal symptoms attributable to the inflammation surrounding the tumor at its primary site, extralocal symptoms due to interference of the tumor with normal function within the UADT or in the body as a whole, and distant symptoms implying that the tumor has spread beyond the primary locus to the TNM classification had an impact on prognostic estimations. 273

Treatment and Prognosis
In addition to the inverse relationship of primary tumor size with prognosis, lymph node metastasis is another extremely important prognostic factor in laryngeal cancer. 274 Both cervical metastasis and disease-free survival rates have been shown to be related to depth of invasion; for tumors with a thickness of 3.25 mm or greater, an elective neck dissection is recommended. 275
In advanced laryngeal carcinoma, cervical metastasis has been shown to be the most important prognostic variable for survival. A study with 159 patients (supraglottic, 97 patients; glottic, 60 patients; and subglottic, two patients) found disease-free survival rates to be 87% in patients with no regional metastasis, 82% in patients with one to two positive lymph nodes, and 33% in patients with three or more positive lymph nodes ( P < 0.001). 276 Risk of distant metastasis was 5% in node-negative patients and 36% in node-positive patients. Patients with three or more positive lymph nodes had decreased survival rates (at 48 months for node-negative patients, 68%; for patients with one to two nodes, 62%; and for patients with three or more nodes, 20%). Distant metastasis was found to be more common in patients with involvement of lower jugular and supraclavicular lymph nodes. 276
Extracapsular spread of carcinoma has significant impact on survival, a factor that is still ignored in the TNM staging, which does not include this issue as a separate item worthy of being recorded. 213 In one series of patients, extracapsular spread was present in 31% of N1 nodes and the 5-year survival rate of patients without extracapsular spread was 76%, whereas for patients with nodal metastases showing this phenomenon, it was only 17%. 274 The presence of extracapsular spread, no matter the size of the lymph node, should be included in the surgical pathology report. The prognostic significance of micrometastases is still being assessed. 103

Differential Diagnosis
One of the more problematic areas of diagnosis in the larynx is the evaluation of postirradiation persistence of SCC. Often dysplasia or atypia may be limited to the mucosa. Owing to the difficulty in distinguishing between tumor recurrence and postirradiation atypia, most pathologists would prefer to err on the side of conservatism. Pseudomalignant tissue reactions are well documented after irradiation or chemoradiation therapy. Full-thickness mucosal atypia that is histologically identical to dysplasia or carcinoma in situ may be observed. The distinction between benign and malignant can be very difficult with the diagnosis of malignancy based on stromal invasion. The histology of these radiation-induced lesions may show increased mitotic activity and even atypical mitotic figures. Grossly, the growths may be flat or broad-based polypoid lesions with ulceration and radiating vascular connective tissue. An indistinct border between the pleomorphic stromal cells and pleomorphic endothelial cells is a useful finding in radiation-induced atypia. The tinctorial quality of the cytoplasm may be gray-blue on hematoxylin-eosin–stained sections. Immunohistochemistry and flow cytometry findings are nonspecific. When the examiner is trying to make the distinction between recurrent tumor and tissue reaction, finding low-power granulation tissue architecture and similar degrees of cytologic atypia in both the endothelial cells and stroma aid in establishing the benign nature of the lesion. 277
Early cancer of the larynx is a term that has been used to describe malignant lesions limited to the mucosa similar to a variety of other sites, including the stomach, esophagus, cervix, and so on. 278 The early cancers of the larynx are usually located in the glottis. Unfortunately, the term has been used by clinicians and pathologists to convey different ideas. The clinical definition of early glottic cancer implies a Tcis or T1 lesion, with full chordal motility and no risk of neck metastasis. The pathologic definition describes a microscopically invasive carcinoma that transgresses the basement membrane but is confined to the lamina propria and has metastatic potential. 279 The pathologic description does not include extension into adjacent muscle or cartilage. Mucosal lesions of the glottis composed of carcinoma in situ with a microscopic focus of invasion or a superficial extending carcinoma (SEC; confined to the lamina propria) 280 represent early glottic cancer. Biologically, invasion is present, as is the potential for metastasis. 278

The trachea is a hollow tube beginning at the lower border of the cricoid cartilage at the level of the sixth cervical vertebra, extending inferiorly via the thoracic inlet to the mediastinum, and ending at the bifurcation into the left and right bronchi. The lining is a ciliated pseudostratified columnar epithelium. Within the underlying connective tissue are numerous minor seromucous glands. The walls are formed by hyaline cartilage rings that are incomplete posteriorly.
Neoplasms of the trachea are extremely rare. Malignancies of the trachea represent less than 0.2% of all malignancies within the respiratory tract and 0.04% of all malignant neoplasms. 281 Carcinoma is the most common malignant tumor occurring in the trachea and accounts for approximately 80% to 90% of all malignant tracheal neoplasms. 282, 283 Owing to the rarity of tracheal carcinomas, there is limited knowledge of these neoplasms.

Clinical Features
The most frequent tumor site within the trachea is not well established. Some reports have placed the most frequent site within 4 cm of the carina, 284 while others have reported that 40% to 45% of tumors are seen in the upper third of the trachea and only 30% to 35% in the lower third. 285 There are also reports of carcinoma developing in scars after tracheotomy. 286 The tumor growth is often sessile and obstructive in nature, producing asymmetric narrowing within the tracheal lumen. Approximately 10% of cases are shown to have a circumferential growth pattern. 283
Two histomorphologies, adenoid cystic carcinoma and SCC, constitute 75% to 85% of the carcinomas. 35, 283, 287 In the North American surgical literature, adenoid cystic carcinoma predominates, whereas in radiotherapy series, SCC is more common. 288

Treatment and Prognosis
A review of the literature containing 321 cases found a 5-year survival rate of approximately 25% for SCC and 80% for adenoid cystic carcinomas. 288 Approximately 17% to 40% of patients at the time of surgery for tracheal malignancies have tumor extension into the mediastinum. 283 The status of positive surgical margins and positive lymph nodes has an adverse effect on SCC. 287 In the Grillo and Mathiesen series, 287 35 patients had SCC. Thirteen patients died with cancer, and six of these 13 patients had positive nodes and four had invasive tumor at the surgical margins. In contrast, in the group of 22 patients alive without cancer, two had positive lymph nodes, one had invasive carcinoma, and six had carcinoma in situ at the surgical margins. Almost all these patients had postoperative irradiation. The treatment for tracheal malignancies has involved both surgical resection and irradiation. The current information suggests that surgery, with or without radiation, appears to be the most effective therapy. 287 In patients who cannot undergo surgery, curative radiation treatment may be given, resulting in overall 1-, 2-, and 5-year survival rates of 46%, 21%, and 8%, respectively. The dose of radiation appears to be of influence, with the 5-year survival rate decreasing from 12% for patients receiving doses greater than 56 Gy to 5% for lower doses. 289 Currently, no TNM classification exists for the trachea.


Clinical Features
SCC of the lip represents 10% to 45% of UADT SCCs in various series. 290 Most of these tumors occur in men. In contrast to cell carcinomas that are usually seen at the upper lip, the predilection site for SCC is the vermilion border of the lower lip, which is the mucosal strip between the mucocutaneous junction and the point of contact between the lips. 291 Sun exposure appears to represent the most significant etiologic factor. 292, 293 Clinically, these tumors manifest themselves either as exophytic or ulcerating lesions. Sometimes they are heavily keratinized, thus showing an irregular whitish-brown surface.
SCC of the lip is staged according to size: T1, tumors not exceeding 2 cm in diameter; T2, tumors more than 2 cm but not more than 4 cm; and T3, tumors larger than 4 cm. T4 tumors invade adjacent structures such as facial skin, mandibular bone, and tongue. 214

Treatment and Prognosis
Tumors are treated by surgery, irradiation, or a combination of both modalities. An overall survival rate of 83% has been reported: 87% for cases without metastasis as opposed to only 20% for cases with lymph node involvement. 293 The incidence of lymph node metastasis varied from 5% for T1 and T2 tumors to 67% for T3 and T4 tumors; submental or submandibular nodes are the ones involved. 290
The incidence of metastasis has also been related to tumor thickness, invasion pattern, and perineural invasion. 294 Perineural invasion may lead to tumor spread along the mental nerve into the mandible. This may become manifest by sensory disturbances and widening of the mandibular canal. 295 Therefore, radiographs of the mandible are mandatory in preoperative staging and during follow-up to detect this insidious way of spread shown by SCC of the lip. As intramandibular tumor spread may occur a considerable time after treatment of the lip, these patients may inadvertently be considered to have a primary intramandibular tumor ( Fig. 2-14 ).

Figure 2-14 Radiologic and macroscopic presentation of lip cancer showing perineural spread into the mandible. A , Radiograph showing bone loss in left premolar area. B , Occlusal view of specimen showing tumor lying buccally to the cuspid-premolar area. C , Surgical specimen sliced buccolingually to display tumor extension into the jaw and soft tissues.

Oral Cavity
Within the oral cavity, SCC may occur at various sites including the following: the maxillary and mandibular alveolar ridge, the floor of the mouth, the retromolar trigone, the tongue, the cheek, and the hard palate. Because site-specific characteristics and clinicopathologic features for each site vary, they are discussed separately for the various locations.

The tongue is subdivided into the mobile tongue, which belongs to the oral cavity, and the base of the tongue, which belongs to the oropharynx, the line demarcated by the circumvallate papillae separating both parts. 214 SCC of the tongue is the second most common malignant tumor of the oral cavity, surpassed only by that of the lip, and represents 25% of all intraoral cancers, two thirds of these being located at the mobile tongue. 290 SCC is most often located at the lateral border, from which it may extend into the adjacent floor of the mouth. SCC at the dorsal surface of the tongue is extremely rare and, if present, is most frequently a verrucous carcinoma. Most SCCs in the tongue grow as ulcerating, deeply invasive tumors, and their frequency of metastatic disease is the highest of all intraoral SCCs: 20% to 40% for T1 tumors, 40% for T2 tumors, and 75% for T3 tumors. 292 However, metastatic rates for the base of the tongue that belongs to the oropharynx are even higher: 70% for T1 cases. 292 The lymph nodes mostly involved are those that lie in the jugulodigastric area. 292

Pathologic Features
When examining surgical specimens from the mobile tongue with SCC, one should realize that the tumor may penetrate deeply into the tongue muscle, often by skipping uninvolved areas. Moreover, the possibility of perineural spread requires identification and histologic examination of the lingual nerve at the dorsal margin of the surgical specimen.
A lesion occurring at the dorsum of the tongue that may simulate SCC is the granular cell myoblastoma with its pseudoepitheliomatous hyperplasia of the covering epithelium. 120 Finding granular cells in the subepithelial stroma will allow proper classification.

Treatment and Prognosis
Tongue SCCs are staged according to their size and depending on spread beyond the tongue: T1, less than 2 cm; T2, greater than 2 to 4 cm; T3, greater than 4 cm; and T4 in the event of spread into the extrinsic tongue musculature such as the hyoglossus, styloglossus, genioglossus, and palatoglossus muscles. 214 The influence of size and stage on survival is as follows: Patients with T1N0 and T2N0 lesions have similar 3- and 5-year survival statistics (48% and 44% for the former and 56% and 44% for the latter group). 165 Patients with T3N0 cancer have a 50% rate of death due to cancer. 165 The T1N1 group have a 3-year survival rate of 80%, and the T2N1 group have a rate of 44%. 165 The T3N1 rate for 3-year tumor-free survival is 13%. These findings indicate that increasing size of the tumor by T stage and the presence of nodal disease both significantly decrease survival rates. 165 In more general terms, in other series, the 5-year survival rate ranges from 70% to 15% depending on the size of the tumor and the presence of nodal metastasis. 8, 292
T1 or T2 tumors may be cured by surgery or radiotherapy. More extensive lesions usually are treated using both modalities. Owing to the high incidence of nodal metastasis, treatment of tongue cancer includes either irradiation or surgery of the neck; the choice between these depends on the method chosen for treatment of the primary tumor. 8, 292 Tumor thickness in particular has a high predictive value for occult cervical metastasis and poor outcome, 296, 297 but its proper use in surgical pathology has been hampered by the lack of uniform or comparable study groups, diversity in measurement techniques, and cutoff values that vary, to date, from 3 to 10 mm. 298

Floor of the Mouth
The floor of the mouth is a horseshoe-shaped mucosal area between the lateral border of the tongue medially and the gingiva of the lower alveolar ridge laterally or, in its anterior part, ventrally. Dorsally, it extends to the left and right tonsillar areas. SCC at the floor of the mouth represents 9% of all UADT SCCs and 15% to 20% of oral cavity cancers, surpassed only by cancers of the lip and tongue. 290
Anteriorly in the floor of the mouth, ducts of the bilaterally located submandibular salivary glands open into the oral cavity. SCC at this site may obstruct salivary flow, leading to enlargement of these glands, which may simulate submandibular lymph node metastasis ( Fig. 2-15 ). This feature is possibly responsible for a 24% to 56% false-positive (clinically positive but histologically negative) error rate in assessing lymph nodes in patients with floor-of-the-mouth cancer. 299 Moreover, SCC may extend along these ducts. 300

Figure 2-15 Squamous cell carcinoma in the floor of the mouth at the orifice of the submandibular duct may cause obstruction and dilatation of the duct. A , Tumor present at the orifice. B , Tumor obstructing the duct at a more proximal level.
SCC of the floor of the mouth is staged similarly to SCC of the tongue; T1, T2, and T3 according to size and T4 when the tumor invades adjacent structures, either by horizontal spread to involve the mandibular bone or the lateral border of the tongue or by vertical growth into the deep muscles of the floor of the mouth.

Treatment and Prognosis
Approximately 9% to 30% of SCCs of the floor of the mouth are associated with occult metastatic disease. Metastasis to lymph nodes occurs in 9%, 29%, and 68% of T1, T2, and T3 cancers, respectively. 290 The submandibular lymph nodes represent the first echelon involved. The 5-year survival rate is also related to tumor size and drops from 90% to zero across the various tumor stages. 8, 290 One recent study mentions that in cancer of the floor of the mouth, the patients with the best 3-year tumor-free survival rates were those with cancer staged as T1N0 (70%) and T1N1 (62%), the relationship between T stage and survival being highly significant but the relationship between N status and survival not being significant. 165
Treatment of SCC of the floor of the mouth is mainly surgical, sometimes including a small rim of the mandibular alveolar bone if the tumor extends to less than 1 cm from the bone. If the tumor is fixed to the alveolar bone, treatment is the same as for tumors primarily occurring on the lower alveolar ridge; this is discussed elsewhere. Whether to treat the neck in cases of floor-of-the-mouth SCC without clinically manifested neck node disease is controversial. 290
At the floor of the mouth, the close association between the invading SCC and the sublingual gland may result in malignant squamous cells intermingled with mucus-containing cells ( Fig. 2-16 ). This should not lead to an inappropriate diagnosis of mucoepidermoid carcinoma but should be recognized as a site-related phenomenon.

Figure 2-16 By invading mucous glands, squamous cell carcinoma may mimic mucoepidermoid carcinoma.

The cheek is covered by the buccal mucosa, which extends from the retromolar trigone posteriorly to the lips anteriorly. Its upper and lower borders are formed by the junction with the buccal side of the maxillary and mandibular alveolar mucosa. SCC at this site accounts for 8% of oral cavity cancers. 292 The tumor may spread diffusely into the underlying tissues, initially without causing symptoms that cause the patient to seek medical advice. The tumor may penetrate into the cheek musculature or extend into the maxillary or mandibular bone when growing upward or downward.

Treatment and Prognosis
Tumors are staged according to size, and this staging has proved to be prognostically significant by a decrease in 5-year survival rates from 60% to 5% for T1 compared with T4 tumors. Lymph node metastases are observed in 10% of presenting patients; mostly they are located in the submandibular or upper cervical area. 292 It should, however, be emphasized that patients with SCC of the cheek have a worse stage-for-stage survival rate than do patients with other oral cavity sites. 301 Low stage and negative margins are not adequate predictors of local control. 301 Treatment consists of either surgery or radiotherapy or both, depending on the size of the lesions, and may sometimes include a full-thickness resection including mucosal lining as well as skin and intervening tissue layers. In T1 or T2 tumors without clinically detectable nodal metastasis, treatment of the neck is optional. In T3 and T4 tumors, it is required. 292

Alveolar Ridge
The mucosa covering the alveolar ridge of the upper and lower jaw is firmly attached to the underlying bone and, in dentate individuals, to the root surface of the teeth. In the lower jaw, it extends from the left to the right retromolar area, bordered lingually by the floor of the mouth and buccally by the buccal mucosa. In the upper jaw, its lateral border is the transition to the buccal mucosa; at its palatal side, no sharp anatomic border is present; the alveolar mucosa merges into the mucosal lining covering the hard palate. Dorsally the mucosal lining of the upper alveolar ridge is also bordered by the retromolar area.
SCC of the alveolar ridge constitutes from 7% to 18% of all intraoral cancers, including cancer of the lip. 252 Tumors at this site may be ulcerating or exophytic. As they occur at sites naturally firmly connected to bone, tumors at this location are always fixed to the bone. Radiographs are needed to assess the extent of bone involvement, which may be either by erosion, resorbing bone over a broad front, or penetration through haversian canals and marrow spaces, the former growth pattern known as expansive and the latter as infiltrative ( Fig. 2-17 ). 302 There are some indications that initially, when only the alveolar ridge is involved, SCC exhibits an expansive growth pattern, whereas the infiltrative pattern is associated with growth of the tumor into the basal bone, which is less easily resorbed. 303 The variation in patterns of bone involvement have until now not be shown to have any relationship with metastatic rate or other established clinicopathologic parameters. However, recognizing the variation in bone involvement by tumor is necessary to correlate histologic findings with preoperative radiographs. In cases with an expansive growth pattern, the radiographs will give a reliable picture of the extent of bone involvement, whereas in cases with an infiltrative pattern of bone involvement, the real tumor size will be underestimated as the tumor penetrates bone with an initially undisturbed architecture.

Figure 2-17 A , Squamous cell carcinoma destroying mandibular bone by erosion. The marrow spaces of the mandible are still uninvolved. B , Squamous cell carcinoma showing diffuse invasion of the mandibular bone and the perimandibular periosteum.
In cases of dentate patients, tumor may invade the periodontal ligament space, causing loose teeth ( Fig. 2-18 ). Gingival bleeding also may occur. As these symptoms also may be seen in cases of inflammatory periodontal disease, SCC of the alveolar ridge may be confused with this affliction, causing delay in diagnosis. This occurs especially in cases in which the tumor is located at the inner side of the gingiva in the mucosal area that faces the tooth surface while leaving the outer gingival surface uninvolved, giving the impression of a healthy gingival margin while the carcinoma is lurking in an invisible site ( Fig. 2-19 ).

Figure 2-18 A , Surgical specimen of squamous cell carcinoma occurring at the maxillary gingiva. B , Radiograph of the same specimen showing periodontal bone loss around the first premolar tooth, which indicates tumor growth in the periodontal ligament space.

Figure 2-19 Photomicrograph showing squamous cell carcinoma growing in a periodontal pocket and underneath an apparently healthy gingiva. In this way, the tumor may remain unnoticed for some time.
Histologically, SCC invading the periodontal ligament spaces should not be confused with gingival mucosal lining exhibiting pseudoepitheliomatous hyperplasia ( Fig. 2-20 ). Moreover, one should keep in mind that the gingival tissues may contain numerous intraepithelial nests and strands, either dental lamina rests or tangentially cut, elongated rete pegs extending from the overlying epithelium ( Fig. 2-21 ). These structures may mimic intragingival subepithelial tumor extension but can be recognized because they lack cytonuclear atypia. On the other hand, intragingival tumor extension may be mistaken for non-neoplastic intragingival epithelial structures.

Figure 2-20 The epithelium that lines the gingival pocket may show reactive hyperplasia. These changes should not be interpreted as neoplastic.

Figure 2-21 Photomicrograph showing odontogenic epithelial nests underneath normal gingival mucosa. This situation should not be mistaken for submucosal tumor extension.
In the upper jaw, SCC may penetrate through the bone into the maxillary sinus, followed by spread into this paranasal cavity. Owing to concomitant edematous thickening of the antral mucosal lining or even polyp formation, the actual tumor size may be overestimated when the extent of tumor involvement of the jaw is assessed in the radiographs ( Fig. 2-22 ). In the lower jaw, tumor may not only spread into the body of the mandible but also may exhibit perimandibular spread. As this growth pattern may not be apparent on radiographs, the size of the tumor may be underestimated ( Fig. 2-23 ).

Figure 2-22 A , Surgical specimen of a squamous cell carcinoma of the upper alveolar ridge. The tumor has eroded away the maxillary bone. In the antral mucosal lining, polyp formation ( middle top ) has occurred. B , Hematoxylin-eosin–stained slide of the same specimen. The polypoid, non-neoplastic changes in the antral mucosa are clearly visible.

Figure 2-23 A , Radiograph showing a reduction in the height of the mandibular bone in the left premolar area due to squamous cell carcinoma in the same area. B , On histologic examination, the tumor can be seen not only to have hollowed out the alveolar ridge but also to have spread alongside the lingual periosteum. This latter mode of spread cannot be detected in the radiograph.

Treatment and Prognosis
SCC of the lower alveolar ridge is second to SCC of the tongue in its frequency of lymph node metastasis; an average of 30% is mentioned; the nodes mostly involved are the submandibular and upper jugular nodes. 292 Owing to this high frequency of metastasis, elective treatment of the neck should be considered for patients with primary tumors that overlie the symphysis, are moderately or poorly differentiated, or display radiographic or histologic evidence of mandibular invasion. 304 The 5-year survival rate varies from 70% to 30% depending on the T stage. 8 Staging is done based on tumor size for T1 to T3 stages, just as for the other sites. Staging a tumor as T4 requires demonstration of tumor growth through the cortical bone into the medullary cavity; merely superficial erosion of the cortical bone and some periosteal remodeling do not justify classification as T4 ( Fig. 2-24 ).

Figure 2-24 A , The tumor merely touches the mandible by growing into the gingiva. Although these tumors clinically may be adherent to the mandible, actual bone involvement is not present. B , Squamous cell carcinoma taking the periodontal ligament space as an entrance to grow deeply into the jaw and spreading in the cancellous bone.
Treatment of alveolar ridge SCC is by surgery. In the maxilla, this usually means a total or subtotal hemimaxillectomy. In the lower jaw, a mandibulectomy should be performed, usually in combination with some type of neck-node dissection. 292 In the past few years, many articles have been published concerning the feasibility of jaw bone–preserving surgery. The common opinion is that in patients with SCC of the lower alveolar ridge, a complete resection of the jaw is not necessary, provided that sufficient mandibular bone is uninvolved to enable the surgeon to remain at a safe distance from the tumor. 305 Evidence-based guidelines on what constitutes sufficient mandibular bone, however, are not available. In cases of atrophic edentulous jaws, this will almost always be impossible. If the tumor involves dentate jaw areas, a rim mandibulectomy may be performed. 292, 305 It should be stressed, however, that the decision to perform a rim mandibulectomy needs to be based on a very thorough assessment of the extent of bone involvement by tumor, which includes technically superb radiographs, including the use of intraoral dental films.
It has been reported that in the case of tumors involving bone by expansive growth, radiographs are quite reliable in indicating the real extent of bone loss due to tumor. 302 However, in cases of more diffuse tumor spread in cancellous bone, the radiographs may not be in accordance with the histologic extent of bone involvement by tumor, and sometimes additional surgery to obtain free bone margins will be necessary. Also, spread along the inferior alveolar nerve may give origin to tumor at the margins, and, therefore, histologic examination of this nerve at the ventral and dorsal bone margins is required. 306 - 308 In cases of more extended mandibulectomies, these nerve ends are situated at the mental foramen ventrally and the mandibular foramen dorsally. When more limited surgery is performed, the cut nerve ends should be identified within the mandibular canal.
In cases of previous irradiation, radiation-induced bone changes that allow diffuse tumor spread within the mandible make any preoperative assessment of bone involvement by tumor unreliable; in these instances, bone-preserving surgery, therefore, is not possible. 309
Although the majority of SCCs have been reported to invade the jaw at the occlusal ridge, at least in the mandibles not previously irradiated, 309 it has also been observed that the route of entry by which the tumor invades the jaw is dependent on the tumor’s position relative to the bony surface and that in addition to growth into the periodontal ligament, penetration of the lingual and the buccal cortical plates may occur (see Fig. 2-24 ) 302 ; this finding implies that not only horizontal rim mandibulectomies but also sagittal or oblique osteotomy planes may be chosen to perform bone-preserving surgery. 305, 310 The ultimate decision on how to handle an SCC approaching or involving the mandible should be based on a combination of imaging techniques and good clinical judgment. 311
Overall mean survival time and 5-year survival rate for SCC at the lower alveolar ridge was 56.6 months and 44%, respectively. Higher stage was associated with a lower survival rate, as were positive surgical margins. 312

Retromolar Trigone
The retromolar trigone or retromolar area consists of a triangular mucosal surface that lines the ventral surface of the ascending mandibular ramus. It is bordered ventrocaudally by the gingiva posterior to the last molar tooth in the mandible, mostly the third, and ventrocranially by the mucosa covering the maxillary tuberosity; its lateral and medial bor ders are respectively the buccal mucosa and the anterior tonsillar pillar. As tumors of the retromolar area are predominantly classified together with those occurring in one of the adjacent mucosal areas, no data on frequency of involvement of this site are available.

Clinical Features
Tumors of the retromolar trigone do not differ substantially from those of the lower alveolar ridge in clinical behavior and type of metastases. They may spread into the buccal mucosa but more often spread into the tonsillar area. Moreover, tumors involving the retromolar area may penetrate deep into the parapharyngeal soft tissue and exhibit spread along lingual and mandibular nerves, sometimes as distant as the site where both nerves join to enter the base of the skull. Lateral growth of SCC at this site involves the medial side of the ascending mandibular ramus ( Fig. 2-25 ). Occult metastases were found in 64% of clinically N0 necks for SCC at this site. 313

Figure 2-25 Schematic drawing showing the spread that may be taken by squamous cell carcinoma of the retromolar trigone. Growth may be submucosally toward the soft palate or infratemporal space in a cranial direction or laterally toward the parapharyngeal space and the large vessels of the neck.

Treatment and Differential Diagnosis
Treatment will usually be surgical, followed by irradiation for more extensive tumors. 292 It should also be noted that SCC at the retromolar trigone may mimic ameloblastoma by pronounced palisading of the carcinoma cells at the tumor-stroma interface and the development of intercellular edema in the tumor nests. This point is more extensively discussed elsewhere (see “Other Unusual Features and Diagnostic Pitfalls in Squamous Cell Carcinomas” section).

Hard Palate
The mucosal lining covering the hard palate is enclosed laterally and ventrally within the horseshoe-shaped upper alveolar ridge mucosa, from which it cannot be demarcated because both consist of mucosa firmly attached to underlying bony tissue. Dorsally, the hard palate mucosa is bordered by the mucosal surface of the soft palate that belongs to the oropharynx.

Clinical Features
Incidence data for palatal SCC range from a low of 0.8% to a high of 62% of oral SCC, the latter figure being from countries where people smoke cigarettes with the burning end within the mouth. This habit of “reverse smoking” has been reported from South India, the Philippines, Sardinia, Jamaica, Venezuela, Colombia, Panama, and some islands of the South Caribbean. 314 In an area in India where the habit of smoking cigars with the lighted end inside the mouth is prevalent, palatal cancer accounts for 45% of all oral cancers. 315 Reverse smoking is done to keep the ashes from falling in food or on clothes and to extend the burning time of the cigar or cigarette. 314 Incidence data include cases from the soft and hard palates, one fourth of SCCs being located in the hard palate and the remaining ones occurring in the soft palate or uvula. 290

Treatment and Prognosis
Tumors of the hard palate behave as tumors of the upper alveolar ridge and are staged and treated accordingly; surgery is the preferred treatment modality. Elective treatment of the neck generally is not required except in cases with more extensive tumors. 8

The oropharynx is situated between the nasopharynx cranially and the hypopharynx caudally. It is subdivided into the following anatomic regions: base of the tongue, tonsil and tonsillar fossa, soft palate, and posterior pharyngeal wall. Incidence data on SCC for the various subsites within the oropharynx are not available. Taken together, oropharyngeal SCC equals cancer of the lip in frequency of occurrence. 292

Base of the Tongue
Anteriorly, a line demarcated by the circumvallate papillae separates the base of the tongue from the mobile tongue. Posteriorly, it ends at the base of the epiglottis. The lateral borders are both sulci glossopalatini, the tonsils, and the tonsillar fossae as well as the faucial pillars.

Clinical Features
An SCC at the base of the tongue may attain considerable size before being recognized, with pain and dysphagia being the most frequent presenting symptoms. Staging is done based on size for stages 1 through 3 as for the other previously mentioned locations. Tumors are classified as stage 4 when they invade mandibular bone, soft tissues of the neck, or extrinsic tongue muscles. Tumors located laterally may spread into the retromolar trigone, anterior faucial pillar, and tonsil. Medially situated tumors invade the extrinsic tongue musculature and may extend posteriorly to the epiglottis and pre-epiglottic space.

Treatment and Prognosis
Treatment is mostly by a combination of surgery and irradiation. As SCC of the base of the tongue has a high frequency of neck node metastasis, for as many as 70% with T1 tumors, elective treatment of the neck is indicated. 292 The metastases are mostly located in upper and middle cervical nodes. Contralateral or bilateral nodal metastases occur in 20% to 30% of cases. 252 The prognosis for SCC occurring at the base of the tongue varies from a 65% to 30% 5-year survival rate, depending on tumor stage. 316

Tonsillar Area and Soft Palate
The tonsillar area is bordered by the anterior and posterior faucial pillar and glossopalatine sulcus. Cranially, this area is continuous with the inferior surface of the soft palate. Tumors in this area may involve the faucial pillars, the tonsillar area proper, and the soft palate. Tumors arising at different sites in this area may vary in their clinical aspects and behavior. In cases of SCC of the tonsil, the tumor usually exhibits deep penetration into underlying tissues or may extend into the base of the tongue or the lateral pharyngeal wall. Moreover, the tumor is notorious for its tendency to grow submucosally in a cranial direction into the nasopharynx, which may not be recognized at preoperative tumor staging. Tumors of the faucial pillars and the soft palate tend to grow more superficially, involving large mucosal areas without penetrating deeply.

Pathologic Features
Histologically, these lesions exhibit severe epithelial dysplasia or carcinoma in situ in which invasive growth occurs multifocally. In the palate, the invading SCC may penetrate into the seromucinous palatal glands, and in this way, the tumor may mimic mucoepidermoid carcinoma histologically (see Fig. 2-16 ).
A lesion occurring at the soft and hard palates that may simulate SCC clinically and histopathologically is necrotizing sialometaplasia. 317 The lobular architecture of the squamous epithelial islands and necrotic remnants of salivary gland tissue are distinctive features helpful in distinguishing this lesion from SCC.

Treatment and Prognosis
Tumor staging in this area is not different from staging in other sites: T1, T2, or T3 depending on size and T4 when the tumor invades mandibular bone or soft tissues of the neck such as the parapharyngeal space, 213, 214 a site also at risk of SCC of the retromolar area.
The different behaviors of tumors of the tonsillar area proper and of the faucial pillars and soft palate are also demonstrated by a lower frequency of metastasis shown by tumors at the latter site. 290 The lymph nodes most frequently involved are the cervical ones. 87 Sometimes these metastases exhibit cystic degeneration ( Fig. 2-26 ), and, in cases of a yet undiscovered oropharyngeal primary SCC, these metastases may be mistaken for branchiogenic carcinoma. 318, 319 From analysis of a series of 136 cases of cystic SCC in the neck, it was concluded that in most of these cases, the origin of the primary site was in faucial or lingual tonsillar crypt epithelium. None of these cases was a branchiogenic carcinoma. 320

Figure 2-26 A , Photomicrograph showing a cystic tumor in a neck node. B , Higher magnification showing the pleomorphic epithelium lining the cysts. This presentation of metastatic tumor suggests the oropharynx as the primary site.
Treatment of tonsillar and faucial or palatal SCC is surgery or irradiation for small lesions and a combination of both modalities for larger ones. In a recent meta-analysis, it was shown that irradiation with surgical treatment of the neck is the preferred method for treating these patients. 321 The prognosis for SCC in the tonsillar area and the palate varies from an approximately 90% to a 20% 5-year survival rate, depending on tumor stage. 292

Pharyngeal Wall
The superior border of the pharyngeal wall is at the level of the soft palate; the lower border is at the level of the vallecula. Tumors at this site usually have attained a large size before being discovered, as they are relatively symptom free, which may be responsible for the fact that 60% to 80% of the tumors at this site are T3 or T4. 252 Tumors may extend cranially into the nasopharynx, posteriorly into the prevertebral fascia, and caudally into the hypopharynx and pyriform sinuses. Neck node metastasis is present in 50% to 60% of cases, sometimes bilaterally in cases of tumor at or near the midline. 252 Treatment usually is by irradiation because surgery is technically difficult in this area and includes the neck nodes. Local control varies from 71% to 37%, depending on tumor stage. 292
Squamous Cell Carcinoma: Unusual Variants

Verrucous Carcinoma

Clinical Features
Verrucous carcinoma (VC) is defined as a warty variant of SCC characterized by a predominantly exophytic overgrowth of well-differentiated keratinizing epithelium with locally aggressive pushing margins. 119 Since its first description by Ackerman 322 in 1948, this tumor has been the subject of a continuous debate concerning diagnostic features and mode of treatment. 323 - 327
Its occurrence originally was related to the use of chewing tobacco or snuff, although this was never substantiated by controlled epidemiologic investigations. Moreover, HPV appears to be of etiologic significance, 328 although not supported universally. 329
VC predominantly occurs in older people, the majority of cases being observed in individuals in their sixth decade or later, and has a higher incidence in males. 330 The sites in the head and neck area at which VC does occur are the oral cavity (56%) and the larynx (35%). 326 Within the oral cavity, buccal mucosa and gingiva are the most frequently involved sites. 322 VC is a rare oral carcinoma with an annual incidence rate of one to three cases for every million persons. 331 When occurring in the larynx, the second most frequently involved head and neck site, the vocal cords are the preferred location. 324 VC may also arise, in order of decreasing frequency, in the nasal fossa, sinonasal tract, and nasopharynx.
Clinically, the tumor manifests as a broadly implanted papillary, nonulcerating soft-tissue mass lacking induration and exhibiting a red, white, or red and white surface, depending on the amount of surface keratinization. 324 It often occupies large surface areas ( Fig. 2-27 ). When located in the vicinity of the jaw, radiographs may reveal erosion of bony tissue.

Figure 2-27 Verrucous carcinoma occupying a large portion of the surface of the right cheek and corner of the mouth. The lesion exhibits a heavily keratinized and irregular surface.

Pathologic Features
Histologically, VC is broadly based and invasive, with plump papillary invaginations of thickened and infolding epithelium that lack the usual cytologic criteria of malignancy. 325 Mitoses are rare, and, when observed, they are located in a suprabasal position immediately above the basal cell layer where they normally occur, a feature that may be helpful in recognizing VC. Clefts within the infolding epithelium may contain cellular debris and keratin plugs, but keratin may also be absent.
At the junction between the normal epithelium and the lesion, VC normally exhibits an abrupt transition ( Fig. 2-28 A ). The histology of this border zone has been described in detail by Jacobson and Shear, 323 who noted that in VC, the inwardly projecting epithelial folds often cause a margin of normal epithelium to retract down with them into the underlying connective tissue, a feature that may be helpful in distinguishing VC from reactive inflammatory epithelial hyperplasia (see Fig. 2-28 B ). The stroma adjacent to the tumor almost always exhibits a chronic lymphoplasmacytic infiltrate. When the surgical specimen contains bone, osteoclasts may be present at the bony surface, indicating resorption due to tumor invasion. Sometimes, keratin masses in the stroma may evoke a foreign-body giant-cell reaction. Perineural invasion and vascular invasion are not features of a VC. Sometimes lesions with the overall morphology of a VC may contain areas of ordinary SCC of varying grade. 323, 325, 327, 332 For these lesions, which accounted for 20% in a series of 104 VC cases, the designation hybrid tumor has been used. 327, 333 These hybrid tumors did not have any distinctive clinical characteristics but were shown to have a higher tendency to recur locally: six of 20 (30%) for hybrid tumors versus 15 of 84 (17.9%) for VC in its strictest sense. 327 The quantity of SCC within a VC required for a lesion to qualify as a hybrid tumor has not been defined. In line with the axiom that the course of a tumor is determined by its less differentiated component, a wise approach is to diagnose all VCs with areas of SCC as a hybrid tumor and to treat them as SCC. 333

Figure 2-28 Photomicrograph showing the junction of verrucous carcinoma with normal epithelium. The difference between the blunt epithelial invagination of the tumor ( left ) and the sharply pointed rete pegs of the adjacent epithelium ( right ) are clearly visible ( A ). Often, the adjacent normal epithelium is drawn downward by the infolding epithelial processes of the verrucous carcinoma ( B ).

Differential Diagnosis
Histologically, VC has to be distinguished from reactive inflammatory epithelial hyperplasia, squamous papilloma, conventional SCC, and PSCC. 119, 325, 330 Lack of cellular atypia serves to rule out conventional SCC and PSCC, the latter lesion to be discussed more extensively under that specific heading (see “Papillary Squamous Cell Carcinoma” ). 334 Distinguishing VC from squamous papilloma and reactive inflammatory epithelial hyperplasia may be more problematic. Determining the DNA content by nuclear cytometry on Feulgen-stained histologic sections has been reported to be diagnostically useful in detecting cells with abnormal DNA content in VC; this finding may be helpful in differentiating VC from benign lesions. 335 Recording nuclear size with image analysis has been suggested to be helpful in differentiating VC from squamous papilloma, as the cells in VC are, in general, larger (>300 μυm) than those in papillomas (<250 μυm). 336
Moreover, compared with VC, squamous papillomas typically have a more complex exophytic, branching growth pattern, frequently with minimal keratin production. The latter feature is in contrast with VC, which usually shows extensive keratinization.
The major problem is to distinguish between reactive inflammatory epithelial hyperplasia and VC, as both are composed of thickened epithelium lacking cellular atypia and a stromal component densely infiltrated by lymphocytes and plasma cells. It may be helpful to realize that in reactive inflammatory hyperplasia, the rete pegs in most instances form an anastomosing network and exhibit slender extensions, whereas in VC, the rete pegs are broader and blunt. 330 Moreover, suprabasal mitoses typically seen in VC are absent in inflammatory epithelial hyperplasia. Nevertheless, excluding or confirming VC usually requires close cooperation between clinician and pathologist.
Other real or purported entities that may give origin to diagnostic confusion are verrucous hyperplasia 332, 337 - 339 and proliferative verrucous leukoplakia. 339, 340 Verrucous hyperplasia was described first by Shear and Pindborg 337 in 1980 as a lesion resembling VC both clinically and histologically, but different from VC in exhibiting an exophytic growth pattern without submucosal invasion in contrast with the endophytic broad-based invasive growth pattern shown by VC. Therefore, in verrucous hyperplasia, the lesion lies above the level determined by a connecting line drawn between the border between the lesion and the uninvolved epithelium at either side, whereas in VC, the bulk of the lesion lies below such a line. However, this feature may be difficult to evaluate. Moreover, parts of an individual lesion may be situated above the level of the normal mucosa and other parts below, and, therefore, the view has been proposed that verrucous hyperplasia and VC are in fact one and the same lesion. 325, 330, 332, 338, 339 Possibly the site of occurrence determines whether a VC grows predominantly exophytically or endophytically. This assumption was inferred from a comparative study in which it was shown that exophytic verrucous proliferations occurred in a small proportion of cases (26%) on mucosal areas tightly bound down to underlying bone, the so-called mucoperiosteum (alveolar process and palate), whereas the endophytic verrucous proliferations did so in a larger proportion of cases (53%). 332 These site-related differences in growth pattern of verrucous proliferations may be explained as follows: An exophytic lesion may form when a loosely textured lamina propria is able to follow the extensive epithelial folding that occurs when, in a localized area, epithelium proliferates in a horizontal as well as a vertical direction. In contrast, if the supporting tissue is tightly bound to the periosteum, as in cases occurring at the palate or alveolar process, the epithelial rete pegs cannot heap up into an exophytic mass but proliferate in a downward direction. In this way, the presence of an endophytic or an exophytic growth pattern of the verrucous lesion is a result of the different texture of the supporting connective tissue and thus site dependent.
Alternatively, verrucous hyperplasia could be a precursor lesion that may progress to either VC or conventional SCC. 341 Irrespective of whether one considers verrucous hyperplasia to be an entity in its own right, a superficially growing form of VC, or a preneoplastic lesion, the lesion has to be removed entirely by surgical excision, going through a tissue level deep enough to ensure complete removal. As this approach is adequate for VC as well, discussion on where to put verrucous hyperplasia is somewhat academic.
The diagnosis of VC or verrucous hyperplasia should never be used for epithelial lesions combining a verrucous architecture with cytonuclear atypia or architectural disturbances compatible with dysplasia as both VC and verrucous hyperplasia are composed of cells without the usual cytologic criteria of malignancy. Those cases have to be put diagnostically somewhere in the spectrum of epithelial dysplasia depending on the severity of the cytologic and architectural aberrations.
Proliferative verrucous leukoplakia is a lesion first described by Hansen and colleagues. 340 The lesion begins as a simple hyperkeratosis that in time becomes exophytic and wartlike, and, finally, malignant degeneration into SCC may occur. Some stages in this continuum may be histologically similar to VC, and one has to rely on clinical data, especially a long history of flat thickened keratoses that have changed in clinical appearance by becoming more exophytic. 339 - 343

Treatment and Prognosis
Most authors mention surgery as the most effective mode of treatment for VC. 325, 344, 345 If one combines several studies on treatment of VC, the initial control rate for radiation treatment of VC of the oral cavity was 59% with a final salvage rate of almost 80%, and it was concluded that radiation as well as surgery can be used to treat VC but that, because of superior cure rates, surgical therapy should remain the mainstay of treatment. 341 Ferlito and colleagues 346 collected 148 cases of VC from the head and neck treated primarily with irradiation, the majority of which exhibited a treatment failure (persistence/recurrence), the overall local control rate being 64 of 148 (43.2%), which they consider ample support for the theory that irradiation is far less effective than surgery because VC, although not radioresistant, is less radiosensitive than conventional SCC. Nevertheless, radiotherapy is recommended for cases of laryngeal VC that cannot be resected with preservation of laryngeal function. 347 For oral cavity cases, surgery remains the preferred mode of treatment. 326
As the VC does not give origin to neck node metastasis, neck dissection does not form part of the treatment of VC. 119, 325, 327 However, one should exclude coexistent conventional SCC by extensive histologic sampling from any case of surgically excised VC to be sure that there is no risk of neck node metastasis. These hybrid tumors have been shown to have a higher tendency to recur locally. 327
In the past, radiotherapy was considered to be strictly contraindicated as treatment of VC because of the supposed risk of transformation of VC to a far more aggressively behaving SCC, the so-called anaplastic transformation. 348 - 350 However, critical analysis of these data has shown that radiation therapy probably plays no role in this malignant transformation of VC, as it has also been shown to occur independently of the treatment employed. 325, 327, 330, 351
VC is notorious for its association with other UADT mucosal (pre-)malignancies. These lesions may be part of the VC or may occur elsewhere in the mucosal lining of the UADT either synchronously or metachronously. 322 - 324, 327, 332, 338 Because of the frequent association of VC with metachronous and synchronous UADT SCC that may be as high as 37%, 327, 332 every patient with VC must be considered at high risk and be subjected to close follow-up.

Spindle Cell Carcinoma
Spindle cell carcinoma (SpCC), also called pseudosarcoma, sarcomatoid SCC, “collision” tumor, or sarcomatoid carcinoma, is a biphasic tumor composed of SCC cells and pleomorphic spindle-shaped cells. 352 Since its original description, several theories have been forwarded regarding the significance of the pleomorphic cells. 353, 354 These cells represent either non-neoplastic bizarre stromal areas, metaplastically altered SCC cells, or cells of a separate mesenchymal neoplasm that forms a collision tumor with the SCC component, for which the term carcinosarcoma is employed. Currently, there is ample evidence that SCC cells can exhibit differentiation toward cells with a mesenchymal phenotype. Therefore, they have to be considered a variant of SCC in which the pleomorphic component originates through dedifferentiation of the SCC component. 353 - 360 Molecular pathology has recently provided convincing proof of an evolution of the sarcomatoid component from the conventional one. 360 Metastasis is to the cervical lymph nodes; the deposits may exhibit conventional SCC, SpCC, or both together. 355, 357, 361, 362

Clinical Features
An SpCC typically occurs in the oral cavity and the larynx 355, 362 ; less frequently, it may arise in the sinonasal area and pharynx. Concerning age and sex, no differences between SpCC and conventional SCC have been reported. Similar to conventional SCC, there is a strong association with a history of cigarette smoking. Macroscopically, SpCC may be a polypoid tissue mass or a fungating or ulcerated lesion not different from conventional SCC ( Fig. 2-29 ). 359

Figure 2-29 Autopsy specimen. Spindle cell carcinoma presenting itself as a large polypoid mass in the right pyriform sinus.

Pathologic Features
Histologically, SpCC typically exhibits areas of SCC and areas of pleomorphic spindle cells. The former component may be very scant or limited to noninvasive areas of epithelial dysplasia or carcinoma in situ located at the surface of the tumor, and its identification may require extensive sampling for histologic examination. Often the overlying epithelium may be ulcerated, and, because of this, the squamous component may not be seen; rarely, the tumor may be composed entirely of a spindle cell proliferation. The pleomorphic spindle cells usually form the bulk of the lesion; they are arranged in fascicles or whorls. Storiform or giant cell areas may also be present. Moreover, foci of osteoblastic or chondroblastic differentiation (both benign and malignant) sometimes are observed. 355, 359, 362, 363 There may be sharp borders between SCC areas and the spindle cell component, but a gradual transition, with SCC cells “dropping off” from the epithelial nests or overlying squamous epithelium into the pleomorphic spindle cell areas, frequently may also be observed. 352, 359
Ultrastructural examination may reveal epithelial features such as desmosomes or tonofilaments in the spindle cells. 356, 359 More easy to employ is immunohistochemistry, by which expression of epithelial markers can be analyzed ( Fig. 2-30 ). The most sensitive and reliable epithelial markers to be used for demonstration of the epithelial phenotype are keratin (AE1/AE3), K1, K18, and epithelial membrane antigen. 359 Moreover, double-labeling has indicated keratin and vimentin in individual spindle cells, 356 thereby illustrating the versatility of the intermediate filament phenotype. Recently, p63 has been reported as a useful marker for SpCC. 364

Figure 2-30 Spindle cell carcinoma. A , Hematoxylin-eosin–stained section showing pure population of pleomorphic spindle cells. B , Nuclear positivity for p63 reveals carcinomatous character of the spindle cells. C and D , Development of atypical bone and cartilage in spindle cell carcinoma, thus mimicking osteosarcoma or chondrosarcoma.
As SpCCs may, in their spindle cell component, exhibit not only vimentin expression but also other mesenchymal filaments, especially myogenic markers, positivity for this marker does not rule out a diagnosis of SpCC. 359 Even the absence of keratin positivity cannot be considered evidence against a diagnosis of SpCC, as this may be due to loss of reactivity for antikeratin antibodies due to fixation or embedding procedures or to a phenotypic change of the tumor cells. Tumors purely composed of pleomorphic spindle cells without any expression of keratin have been observed to recur as conventional SCC and serve to illustrate the profound divergence in differentiation morphologically as well as immunohistochemically shown by SCC cells. 357
Sometimes SpCC exhibits acantholysis; in this way, spaces lined by pleomorphic cells are formed that may mimic angiosarcoma ( Fig. 2-31 ). At other body sites, the label pseudoangiosarcomatous carcinoma has been used for lesions with this histomorphology. 365 It must also be mentioned that conventional SCC sometimes contains myxoid areas with enlarged stromal cells exhibiting swollen vesicular nuclei, sometimes showing mitoses. However, these cells are dispersed among a non-neoplastic background and not densely packed in whorls of fascicles as in SpCC, which identifies them as part of a stromal reaction. Therefore, in these cases, a diagnosis of SpCC does not apply. Moreover, the observation that stromal fibroblasts as well as endothelial cells may both show these atypical changes may be helpful in distinguishing between SpCC and SCC with atypical stromal features ( Fig. 2-32 ).

Figure 2-31 Spindle cell carcinoma exhibits pronounced acantholysis. Covering squamous epithelium lacks atypical features.

Figure 2-32 Squamous cell carcinoma with bizarre fibroblastic and bizarre endothelial stromal cells. The atypia in fibrous tissue and endothelium serve to rule out spindle cell carcinoma.

Differential Diagnosis
When SCC and spindle cells are both observed, the diagnosis of SpCC is easily made. In the absence of the SCC component, diagnosis is more difficult because in these instances, one has to distinguish between the so-called monophasic SpCC and a possible medley of mesenchymal spindle cell lesions, either benign or malignant, such as various types of spindle cell sarcomas and nodular fasciitis. 353
Nodular fasciitis may exhibit mitotic figures, but they are not atypical; moreover, no cellular pleomorphism is present. Therefore, discerning this lesion from SpCC should not be too problematic. Distinguishing between monophasic SpCC and spindle cell sarcomas such as fibrosarcoma and leiomyosarcoma may be more difficult. However, sarcomas in the head and neck area located at mucosal surfaces are extremely rare, and, when they do occur, an intervening fibrous layer usually separates the lesion from the overlying epithelium. In the case of SpCC, just as in conventional SCC, the tumor is either ulcerating or directly abutting onto the overlying epithelium without an intervening uninvolved stroma. Occasionally, the spindle cells of the tumor may “stream off”or drop off from the overlying squamous epithelium. This latter feature may be helpful in making the appropriate diagnosis. However, if SpCC occurs intraosseously, 366 its distinction from sarcomas with a spindle cell appearance may be extremely difficult or even impossible if immunohistochemistry or electron microscopy fail to reveal epithelial characteristics ( Fig. 2-33 ).

Figure 2-33 Photomicrographs showing an intraosseous spindle cell carcinoma. A , Pure spindle cell component. B , Positivity for keratin indicating epithelial character. C , Positivity for desmin that should not be mistaken as an indication for a sarcoma with myogenic differentiation.
When occurring in the larynx, the differential diagnosis of SpCC also includes the recently recognized benign proliferative lesion that has been labeled inflammatory myofibroblastic tumor. This lesion shares a lot of overlapping features with SpCC, such as clinical presentation as a polypoid or pedunculated mass and histologic features such as spindle cells displaying mitotic figures lying in a myxoid or fibrous stroma; its differentiation from SpCC may prove to be extremely difficult. Key features assisting in differentiating SpCC from the inflammatory myofibroblastic tumor are the absence of dysplastic or carcinomatous epithelial components, lack of dropping off from the overlying squamous epithelium, and no atypical mitotic figures. 367
Sometimes, UADT mucosal melanomas may present as polypoid masses composed of pleomorphic spindle cells. When keeping this possibility in mind, immunohistochemistry with the appropriate antibodies (e.g., S-100, HMB45) serves to confirm or rule out this diagnosis if melanin is not found in the primary tumor. For a more extensive discussion of the histologic features of nodular fasciitis, inflammatory myofibroblastic tumor of the larynx, melanoma, and spindle cell sarcoma that may be helpful in the differential diagnosis, the reader is referred to their descriptions elsewhere in this book. For practical purposes, it is advisable to consider a pleomorphic spindle cell lesion occurring at the mucosal surfaces at the UADT to be an SpCC. 353
This discussion on SpCC and its differential diagnosis is finalized by remarking that SpCC sometimes may assume the appearance of an innocuous granulation tissue polyp. Sometimes SpCC may exhibit a very edematous or densely collagenous stroma with only dispersed, slightly pleomorphic spindle cells and an ulcerated surface, and therefore the true neoplastic nature of the lesion is easily overlooked. Only after several recurrences, the lesion may reveal the more characteristic appearance of an SpCC ( Fig. 2-34 ). The converse situation, granulation tissue mimicking SpCC, may occur after ionizing-radiation exposure. After radiation exposure, bizarre granulation tissue–containing pleomorphic spindle cells and atypical mitotic figures may develop that should not be misinterpreted as tumor recurrences displaying the histomorphology of SpCC 277 ; this was discussed previously in the section on laryngeal SCC. Combined chemoradiation therapy frequently shows similar findings but with a greater degree of mucosal and submucosal glandular atypia and distortion.

Figure 2-34 A , Photomicrograph showing spindle cell carcinoma masquerading as an innocuous granulation polyp. B , In the recurrent lesion, the real nature of the lesion became apparent.
An SpCC should not be confused with the so-called teratocarcinosarcoma. 368, 369 This neoplasm typically occurs in the nasal cavity and the paranasal sinuses, sites at which SpCC rarely occurs, and is characterized by an extremely diverse histologic pattern with mature and immature glands, benign squamous and malignant poorly differentiated epithelia, and rhabdomyosarcomatous, chondrosarcomatous, and neuroepithelial differentiation ( Fig. 2-35 ). Although this tumor is considered by some authors to be part of the spectrum exhibited by SpCC, 353 its far more complex histology and different predilection site make its classification as a distinct entity separate from SpCC more appropriate.

Figure 2-35 A , Photomicrograph showing a variety of patterns in teratocarcinosarcoma. In the mesenchymal component, osteoid is present. B , In the epithelial areas, rosette formation indicates neuroectodermal differentiation.

Treatment and Prognosis
Treatment of SpCC is the same as for conventional SCC. Batsakis and colleagues 370 reviewed the lethality of SpCC in the head and neck and correlated their findings by anatomic site. Sixty percent of 53 patients with tumors of the oral cavity died within 1 month to 6 years, 77% of 13 patients with tumors of the sinonasal tract died within 6 months to 2.5 years, and 34% of 65 patients with tumors of the larynx died within 4 months to 2 years. Polypoid glottic tumors appeared to have the most favorable prognosis (90% 3-year survival rate), whereas patients with supraglottic, hypopharyngeal, sinonasal, and oral SpCCs did poorly regardless of their tumor’s gross appearance. Batsakis and colleagues 370 concluded that SpCCs manifest a biologic behavior that is more aggressive than most conventional SCCs. However, in a series of early-stage (T1–T2) glottic tumors, patients with SpCC treated with irradiation had control rates similar to those of irradiated patients with disease of similar volume with the more typical SCC. 371

Basaloid Squamous Cell Carcinoma
Basaloid squamous cell carcinoma (BSCC; synonyms include basaloid carcinoma and adenoid cystic-like carcinoma) is a rare histologic variant of SCC. It was first characterized in the UADT in 1986 by Wain and colleagues. 372 Although identical basaloid tumors have been described in a variety of body sites, 373, 374 including the trachea, esophagus, 375, 376 lung, 377 and anal region, this variant has a marked predilection for the base of the tongue, supraglottic larynx, and hypopharynx (pyriform sinus). Although still controversial, clinically, it is considered an aggressive tumor with a propensity for regional lymph nodal (80%) and systemic (60%) metastases. 372

Clinical Features
Since the original report of UADT BSCC, more than 100 cases have appeared in the English literature. The tumor is mucosa-based, and the most common sites still remain the base of the tongue, hypopharynx (pyriform sinus), and supraglottic larynx. 372, 376, 378 - 394 Among the most common complaints at patient presentation are a neck mass, dysphagia, hoarseness, weight loss, otalgia, sore throat, cough, and hemoptysis. This tumor has a high prevalence in the older population, with a median age of 63 years (range, 27–88 years); a male predominance (82%), and presentation at a high stage (stage III–IV). 391
The aggressive biological nature of BSCC is manifested by frequent lymph node metastasis (64%) and distant metastasis (44%) to lung, liver, bones, brain, and skin; frequent local recurrence; and a mortality rate of 38% (at 17-month median follow-up). 391 The justification for distinction of this variant of SCC appears to be at least twofold: (1) recognition of the tumor’s tendency to present at a high clinical stage (stage III and IV, although the sites of predilection may significantly contribute to this feature) and (2) prevention of the diagnostic confusion of this variant with another entity having a different prognosis (e.g., adenoid cystic carcinoma) or requiring a different treatment modality (neuroendocrine carcinoma).
BSCC may be related to tobacco and alcohol abuse and possibly other risk factors. In a review of 90 reported cases, 42 of the 90 patients were known to have smoked tobacco or consumed alcohol or both. 391 There has also been one case of BSCC arising in a patient after radiotherapy for a previous neoplasm. 387 Second primary tumors have also been reported in patients with BSCC. 388, 392, 394
The macroscopic descriptions of BSCC have been those of an exophytic mass 382, 388, 389 as well as a flat lesion 383, 387 with central ulceration and marginal submucosal induration. 389 The size of the lesions has ranged from 1 to 6 cm. 391 A tendency for prominent deep and lateral submucosal soft-tissue infiltration has been noted. 388, 395

Pathologic Features
As the name implies, this tumor is biphasic with distinct histologic findings. Perhaps the most salient feature of this tumor is the intimate and often abrupt association of the basaloid component with the squamous component ( Fig. 2-36 A and B ). The basaloid component of the tumor is defined by four features: (1) solid growth of cells in a lobular configuration, closely apposed to the surface mucosa; (2) small, crowded cells with scant cytoplasm; (3) dark, hyperchromatic nuclei without nucleoli; and (4) small cystic spaces containing material resembling mucin that stains with periodic acid–Schiff or Alcian blue (see Fig. 2-36 C and D ). Ancillary features include small and large foci of necrosis within central areas of tumor lobules (comedonecrosis; see Fig. 2-36 E ) and hyalinization of the stroma, often in association with microcyst formation ( Fig. 2-37 ; and see Fig. 2-36 E ). Wain and colleagues 372 required the associated squamous component to be among the following: invasive SCC that usually has a superficial location (usually well or moderately differentiated), overlying surface epithelium with dysplasia (usually severe dysplasia or carcinoma in situ; Fig. 2-38 ), or focal squamous differentiation within basaloid tumor islands. Criteria used to identify the squamous epithelium required the presence of two or more of the following: (1) individual cell keratinization, (2) intercellular bridging, (3) keratin pearl formation, and (4) cells arranged in a mosaic pattern.

Figure 2-36 A , Photomicrograph of basaloid squamous cell carcinoma with a brisk transition from small basaloid tumor cells to polygonal keratinizing squamous cells. B , Note the focal prominent peripheral palisading of the basaloid cells, central hyaline-like material, and adjacent eosinophilic keratinized cells. C , Basaloid tumor cells of basaloid squamous cell carcinoma illustrating nuclear pleomorphism, scant cytoplasm, and slight basal cell palisading. D , Section of basaloid squamous cell carcinoma within a background of myxoid-appearing stroma. E , Photomicrograph demonstrating comedonecrosis with a focus of dystrophic microcalcification identified within an island of basaloid squamous cell carcinoma. F , An island of basaloid squamous cell carcinoma illustrating nuclear pleomorphism and prominent hyalinization of stroma (hyalinosis), which is frequently associated with microcyst formation.

Figure 2-37 Photomicrograph of basaloid squamous cell carcinoma showing prominent spherical hyalinized stroma (hyalinosis) with the beginnings of microcyst formation.

Figure 2-38 Photomicrograph of a basaloid squamous cell carcinoma with the overlying mucosa demonstrating carcinoma in situ, as shown in inset .
Since the initial description, other histologic features have been described. Among these are a prominent festoon, cribriform, pseudoglandular, or trabecular growth pattern of the basaloid cells 66, 368, 377 ; individual cell necrosis; large vesicular nuclei; nucleoli; prominent mitotic activity, 378, 396 with some containing abnormal mitotic figures 376 ; and a focal spindle cell component. 383
Perineural invasion has not been a consistent finding. 376, 381, 383, 391 Moreover, lymphovascular infiltration has been observed in four of nine cases (44.4%). 376 Nodal metastases may show either basaloid cells, basaloid cells with conventional SCC, or the presence of only conventional SCC. In two series, extracapsular extension within the lymph node metastasis was present in more than 50% of the patients with nodal involvement. 383, 391
Ultrastructurally, the basaloid cells were described as polygonal and the chromatin was finely dispersed within pale nuclei. The cytoplasm was found to contain desmosomes, rare tonofilaments, and free ribosomes. On electron microscopy of the cystlike spaces identified on light microscopy, they were found to be lined with basement membrane material and filled with loose stellate granules or replicated basal lamina arranged in parallel stacks or globular masses. Squamous components contained well-formed desmosomes and clumps of tonofilaments. None of the following were observed: neurosecretory granules, myofilaments with dense bodies, secretory granules, cytoplasmic organization, or cellular polarity. 372
Immunohistochemical staining features were investigated in 40 cases of BSCC reported by Banks and colleagues. 378 Their findings were as follows: 100% keratin staining with 34βεταE12 antibody, 79% with an AE1/AE3, 83% for low-molecular-weight keratin 8/18 (CAM 5.2), 83% for epithelial membrane antigen, 53% for carcinoembryonic antigen, 39% for S-100 protein; 75% stained diffusely but weakly with neuron-specific enolase. None of the tumors were positive for chromogranin, synaptophysin, muscle-specific actin, or glial-fibrillary acid protein.
The keratin staining pattern in general has been observed to be limited to the cells with eosinophilic cytoplasm. The basaloid cells specifically have shown weak to absent staining. 376, 378 The carcinoembryonic antigen has been found to be limited primarily to the squamous component of the tumor, but rare ductal cell staining has been observed. 376 Staining for actin has also had variable reports of positivity. 376, 378, 385 Barnes and colleagues 395 summarized their immunohistochemical findings in a series of 15 patients as follows: reactivity for cytokeratin, epithelial membrane antigen, carcinoembryonic antigen, and vimentin (vimentin immunostaining being displayed as a delicate perinuclear ring or perinuclear dot and being found only in the basaloid cells but not in the squamous component). Positivity is focally observed for S-100 protein, muscle-specific actin, and collagen IV.
Two studies have evaluated the DNA ploidy of BSCC. In one report, it was concluded that patients with an aneuploid BSCC had a better survival rate than those with a diploid BSCC. 376 However, in another study, the better survival rate for aneuploid BSCC tumors could not be confirmed: patients with aneuploid and diploid tumors both had unfavorable outcomes manifested by local recurrence or distant metastasis or both. 391

Differential Diagnosis
Because of the heterogeneous nature of BSCC, there is potential for diagnostic error. Biopsy specimens not representative of the whole lesion may be devoid of the biphenotypic expression required to make the correct diagnosis. Absence of the squamous component may suggest the diagnosis of a sinonasal undifferentiated carcinoma, nonkeratinizing SCC, adenoid cystic carcinoma, or neuroendocrine carcinoma, 396 whereas the possibility of a basal cell adenocarcinoma also should be taken into account. 397
Differentiating BSCC from sinonasal undifferentiated carcinoma may be a diagnostic challenge. It is a very anaplastic neoplasm that rarely shows evidence of squamous differentiation. 398 Sinonasal undifferentiated carcinoma is composed of cells with a high nucleus-to-cytoplasm ratio that grows in confluent sheets with prominent individual cell and broad zones of necrosis. In contrast, BSCC shows abrupt keratinization, tubular growth patterns, and prominent redundant eosinophilic basement membrane globules in many tumor cells (hyalinosis). 399
Nonkeratinizing SCC may enter into the differential diagnosis of BSCC, especially in the sinonasal tract. Generally, nonkeratinizing SCC lacks the comedonecrosis pattern and abrupt keratinization in basaloid cells, which is very characteristic of BSCC. The cells of nonkeratinizing SCC are often fusiform or polygonal but, as the name implies, do not typically exhibit keratinization. Nonkeratinizing SCC also lacks the nuclear hyperchromasia, single-cell necrosis, and prominent mitotic activity seen in BSCC.
Adenoid cystic carcinoma of the solid variant is the major consideration in the differential diagnosis. Both tumors may have areas with a cribriform growth pattern. Among the most useful distinguishing characteristics of BSCC from adenoid cystic carcinoma is that BSCC has continuity with overlying epithelium, which has carcinoma in situ, severe dysplasia, or SCC. Other helpful characteristics include BSCC having greater nuclear pleomorphism, evidence of squamous differentiation, prominent necrosis, and frequent mitotic figures, all features not typically seen in adenoid cystic carcinoma. 400 The clinical features separating these two neoplasms are fairly distinct. Adenoid cystic carcinoma rarely presents with frequent lymph node metastasis and has a longer, more protracted course than BSCC. BSCC also has a different site of predilection than adenoid cystic carcinoma, as indicated earlier. The immunohistochemical staining patterns of adenoid cystic carcinoma and BSCC may have some utility in separating these two neoplasms in small biopsy specimens. Carcinoembryonic antigen shows ductal positivity in adenoid cystic carcinoma while being limited primarily to the squamous component in BSCC. S-100 is not particularly useful in distinguishing these two neoplasms. Also, muscle-specific actin has been found to be positive in approximately 60% of the cases of adenoid cystic carcinoma that have a cribriform pattern. 376 In one series, no BSCC with a cribriform pattern reacted with muscle-specific actin. 378 Recent studies have found p63 to be a useful marker for distinguishing adenoid cystic carcinoma from BSCC. p63 will diffusely stain the basal cells and not the keratinized areas of BSCC; in contrast, p63 stains the peripheral layer cells in adenoid cystic carcinoma. The one caveat is that p63 staining results may overlap for the solid variant of adenoid cystic carcinoma and BSCC. 401, 402
Another consideration in the differential diagnosis is small cell (neuroendocrine) carcinoma (SCEC), which is composed, on histologic examination, of sheets of small hyperchromatic cells showing nuclear molding and may occur in the same sites. 403 This tumor lacks stromal mucin or pseudoglandular cribriform patterns and rarely is connected to the surface mucosa. 404 Immunohistochemistry may be useful in differentiating BSCC from SCEC. Neuron-specific enolase may be positive in both tumors; however, unlike SCEC, BSCC lacks positivity for chromogranin and synaptophysin. 372 Positivity for chromogranin or synaptophysin would exclude BSCC. 378, 404 The keratin staining patterns are different in these two neoplasms as well; SCEC frequently shows a globular-appearing perinuclear staining pattern that is not observed in BSCC. 404 It has also been reported that BSCC reacts with the high-molecular-weight cytokeratin antibody 34E12, which failed to show any reactivity with SCEC. 405 Ultrastructurally, BSCC lacks neuroendocrine differentiation. SCEC, even poorly differentiated, frequently contains dense core granules, supporting this line of differentiation.
Basal cell adenocarcinoma can be distinguished from BSCC by its predominant location in major salivary gland tissue, a site where BSCC does not occur, and far less aggressiveness, which is exemplified by a blander histology. 397
Metastatic basal cell carcinoma of the skin, although uncommon, may enter the differential diagnosis when the initial presentation is a lymph node metastasis. 406 - 408 The frequency of metastatic basal cell carcinoma in large series ranges from 0.0028% to 0.55%. 407, 408 The size of the basal cell carcinoma has also been correlated with metastasis (3 cm in diameter had a 1.9% incidence of metastasis). 408 In most cases of metastatic basal cell carcinoma, the primary tumor is present when the metastasis is detected 406 or the patient has a history of frequent recurrence. 406 Clinical detection of a skin lesion and biopsy confirmation of a primary tumor should aid in resolving this dilemma. The histologic features of basal cell carcinoma of skin do not demonstrate the degree of atypia, pleomorphism, or prominent necrosis characteristically seen in BSCC. Finally, it should be kept in mind that BSCC occurring at other sites, such as the lung, may metastasize to the neck nodes.

Treatment and Prognosis
There has been some question of the proposed aggressive nature of BSCC. The nebulous symptoms associated with the sites of predilection for this SCC variant may contribute to the perceived advanced stage at presentation. Banks and colleagues, 378 thought that, stage for stage, the BSCC treatment and behavior were similar to those of conventional SCC. Luna and colleagues, 387 in their series of nine patients, compared age, sex, clinical stage, site, date of diagnosis, and treatment of BSCCs to those of patients with conventional SCC. Although the series was small and the results need confirmation, they found the biological behavior of BSCC similar to that of conventional SCC. Another report had come to a similar conclusion. 383 In the series by Coppola and colleagues, 381 the basaloid component represented 50% to 80% of the tumor for each case. They suggested that perhaps the percentage of basaloid component in tumors may correlate with prognosis and explain conflicts in results. The treatment still remains primarily radical surgery in combination with radiotherapy or chemotherapy. Owing to the fact that more than 50% of the cases present with lymph node metastasis at the time of diagnosis, systemic adjunctive chemotherapy should be investigated. 409 Because of these clinical and histologic features, BSCC should be recognized as a distinct variant of SCC.

Adenoid Squamous Cell Carcinoma
In 1947, Lever 410 first described a variant of SCC of the skin that he called adenoacanthoma. He postulated that the tumor arose from the eccrine sweat ducts and glands. The tumor was composed of a combination of glandular and squamous differentiation. Several years later, Lever modified his concept, and others concurred that the gland-like spaces were the result of acantholysis of solid nests of SCC. 411, 412 Muller and colleagues 412 suggested the name adenoid squamous cell carcinoma (ASCC) to avoid confusion with adenoacanthoma of the endometrium. Other synonyms include pseudoglandular SCC, acantholytic SCC, and SCC with gland-like features. 413 - 417
The largest series on ASCC of skin observed that this variant of SCC presented most often as an ulcer or nodule on sun-exposed areas of the head and neck region, predominantly in elderly men. 413 There was often an associated adenoid actinic keratosis, and therefore sun exposure was considered an important factor. Approximately 2% to 3% of these patients with lesions greater than 2 cm had evidence of deep invasion with metastasis, both lymph node and visceral. 413 A later series with 55 cutaneous cases of ASCC in 49 patients found that 19% of the patients died of metastatic or recurrent disease. This clinical behavior was somewhat more aggressive than conventional SCC of the skin, and prognosis seemed to correlate with lesion size; a size greater than 1.5 cm would portend an unfavorable course. 417

Clinical Features
A recent review of the literature of ASCC collected 26 cases involving the oral cavity and one in the nasopharynx. Twenty-two of the cases were described on the vermilion border of the upper or lower lip, with the lower lip being the most common oral site of occurrence, accounting for 17 of 26 cases. 418 The mean age at occurrence was 54.5 years (range, 41–75 years). Tumor size, when reported, was 2 cm or smaller. One patient with a lip lesion was immunocompromised. 418 The largest single series of oral ASCC 419 contained 15 cases of the lip with a mean patient age of 56.1 years (range, 41–57 years) and a male predominance. All 15 patients were alive and disease free after 27.6 months of follow-up. Just more than one third of these patients developed a subsequent lesion on the vermilion area of the lip several years after diagnosis of the initial lesion.
In contrast to ASCC of the skin and lip, cases involving mucosal surfaces of the head and neck devoid of sun exposure may behave more aggressively. The first reported intraoral case was in 1977 420 and involved a lesion of the posterior lateral aspect of the tongue in a 61-year-old man. The tumor recurred 4 months after treatment, and the patient died of sepsis 8 months after the initial diagnosis. That same year, Takagi and colleagues 421 reported two cases. Both patients experienced local recurrence and died of their disease (38 and 46 months after diagnosis). The other cases are at the floor of the mouth 418 and the nasopharynx. 422 Both patients were male and aged 42 and 58 years, respectively, with no evidence of disease. Others have observed cases in the supraglottic larynx, 423 the hypopharynx, and the sinonasal tract. 424

Pathologic Features
ASCC is included in the WHO classification of upper respiratory tract tumors under the designation acantholytic SCC and defined as an SCC in which pseudoglandular spaces or lumina result from acantholysis of tumor cells. 119 On gross examination, the majority of these lesions appear as ulcerations, hyperkeratotic surfaces, or exophytic, wart-like lesions and range in size from 0.4 to 12 cm. 417
Microscopically, the tumor is characterized by a lobular growth pattern of keratinizing SCC that shows central regions containing rounded spaces (pseudoglandular alveolar areas that are lined with a basal layer of polygonal cells with the central lumina containing detached dyskeratotic acantholytic neoplastic cells, “glassy” keratinocytes; Figs. 2-39 and 2-40 ). 414 Prominent keratin pearl formation is usually present ( Fig. 2-41 ). In some instances, this acantholysis is sufficient to mimic a neoplastic angiomatous proliferation, 425, 426 similar to the one observed in SpCC. 365 No true glandular formations are seen. No intracellular mucin is present in these lesions. ASCC may exhibit limited focal communication between the submucosal or dermal tumor and the overlying surface epithelium. 412, 417 Numerous sections may be required to demonstrate this relationship.

Figure 2-39 Invasive adenoid squamous cell carcinoma showing extensive acantholysis creating the pseudoglandular structures.

Figure 2-40 Histologic section of adenoid squamous cell carcinoma showing pseudoglandular formation lined by a basilar layer of polygonal cells containing a central lumen of detached “glassy” keratinocytes.

Figure 2-41 Photomicrograph showing adenoid squamous cell carcinoma with prominent keratin pearl formation and pseudoglandular alveolar areas.
Specific cytologic features, 427 histochemical staining characteristics, 413 and ultrastructure 422 of this variant have been reported. Immunohistochemistry has demonstrated these tumors to be positive for cytokeratins (AE1/AE3) and epithelial membrane antigen and negative for carcinoembryonic antigen, S-100, CD34, and factor VIII–related antigen. 417, 425 The ultrastructural findings have supported the squamous origin with a few hemidesmosomes and attached tonofilaments and no glandular features (e.g., intracytoplasmic microvilli, secretory granules). 422

Differential Diagnosis
The differential diagnosis includes adenosquamous carcinoma (ASC), the next variant of SCC to be discussed, and mucoepidermoid carcinoma. On morphology alone, the presence of abundant keratin pearl formation and lack of mucocytes may eliminate mucoepidermoid carcinoma. The absence of intracytoplasmic mucin and no true glandular component (adenocarcinoma) separates this lesion from ASC. 424

Treatment and Prognosis
The clinical behavior described in the WHO classification is that of a low-grade malignancy. Others have concluded, however, that ASC within the head and neck region has a worse prognosis than conventional SCC, although the numbers of patients reported until now are too small to support this assumption. 422, 424, 428 Treatment of these lesions is similar to treatment of conventional SCC. 428

Adenosquamous Carcinoma
ASC is a rare and controversial neoplasm that, as the name implies, possesses histomorphologic features of an adenocarcinoma and SCC. It has been described in a variety of body sites, including the uterine cervix, lung, and pancreas. 429 - 431 ASC in the upper respiratory tract was defined in 1968 by Gerughty and colleagues 432 in a series of 10 patients. This investigation showed the neoplasm to be extremely aggressive, with 80% of the patients having proven metastasis.

Clinical Features
Approximately 100 cases of ASC in the upper respiratory tract have been reported in the English-language literature. 432 - 442 More than 50 unreported cases of oral ASC are present in the files of the Armed Forces Institute of Pathology (Dr. Gary Ellis, personal communication, 1996). Eighty-five percent of Armed Forces Institute of Pathology cases arose from the tongue, the floor of the mouth, and the tonsillar-palatine region. 443 The most common site of the cases in the literature is the larynx (in decreasing frequency: supraglottic, transglottic, glottic region) of which there are 20 reported cases. 433 Other reported sites include the nose and paranasal sinuses, 432, 434, 435 tongue, 432 maxillary alveolus, 436 floor of the mouth, 432 upper lip, 437 nasopharynx, 437 oropharynx, 437 and hypopharynx. 437 - 441
There is a marked male predominance. The most frequent age at occurrence is the sixth and seventh decades of life (age range, 39–76 years). Symptoms are similar to those of SCC occurring in their respective sites. In the reported laryngeal cases, the male-to-female ratio is 19:1, and the average patient age is 60.8 years; 25% had cervical lymph node metastasis, and the 5-year survival rate was 22% (two of nine patients). 433
The etiology has not been defined. Unfortunately, in many reports, tumor staging was not included and, therefore, direct comparisons by site, stage, and treatment are difficult. Evidence of the aggressive biological nature of ASC is best supported with the reported occurrence of lymph node metastasis (25%–80%), 432, 433 distant metastatic sites including the lung, liver, bone marrow, kidney, adrenal gland, and colon, 433, 440 and the 5-year survival rates of 25% 432 and 22%. 433 Owing to the lack of staging information in the reported cases, however, no comparison with 5-year survival rates of SCC can be made.
In the series by Gerughty and colleagues 432 (three tongue, two floor of the mouth, two nose, and three larynx tumors), the tumor size ranged from 0.2 to 1.0 cm, half of the cases had perineural invasion, 80% of the cases had cervical lymph node metastasis, and the 5-year survival rate was 25%. In another study, 21 cases of mucoepidermoid carcinoma/ASC involving the larynx and hypopharynx were evaluated. 438 Nine of the 21 cases were deemed compatible with the description of Gerughty and colleagues of ASC. In nine patients (patients per stage: I, two; II, two; III, three; IV, two), the rate of metastasis was 33% and the 3-year survival rate by actuarial methods was 53%. These ASCs did not appear to act as aggressively as those described by Gerughty and colleagues. Other associated findings described for ASC have been pulmonary lymphangitic carcinomatosis 440 and possibly a radiation-induced lesion. 442 ASC may be included in some classifications of salivary gland neoplasms 443 or as a variant of SCC 430 and historically but inaccurately under mucoepidermoid carcinoma. 444

Pathologic Features
The gross description of these lesions has been of an erythroplakic, ulcerated area to a polypoid broad-based mass. 432, 441 Tumor size has ranged from 0.2 to 5 cm. The histologic criteria defined by Gerughty and colleagues 432 required a neoplasm to be composed of an admixture or separate areas of SCC and adenocarcinoma. Four basic components were observed: ductal carcinoma in situ, adenocarcinoma, SCC, and a mixed carcinoma. The squamous epithelium required two or more of the following features: (1) intercellular bridging, (2) keratin pearl formation, (3) parakeratotic differentiation, (4) individual cell keratinization, and (5) cellular arrangements showing pavement or mosaic patterns ( Figs. 2-42 to 2-45 ). The glandular epithelium required the demonstration of intracytoplasmic sialomucin by (preferably) high iron diamine–Alcian blue or periodic acid–Schiff stain retention after diastase digestion and Mayer’s mucicarmine. The tumor cells were of three basic types: basaloid, squamous, and undifferentiated. All cell types were represented in the tumors even though one cell type may have predominated.

Figure 2-42 A , Low-power view of an adenosquamous carcinoma, demonstrating surface squamous cell carcinoma transitioning to a deeply invasive adenocarcinoma. B , Close-up of the infiltrating atypical ductal structures.

Figure 2-43 A , Photomicrograph showing an area of squamous differentiation within an adenosquamous cell carcinoma. B , Presence of adenocarcinoma component within an adenosquamous cell carcinoma.

Figure 2-44 A section of adenosquamous cell carcinoma illustrating adenocarcinoma with well-formed ductal structures and no mucocytes.

Figure 2-45 Adenosquamous cell carcinoma with duct carcinoma in situ formation.
Since the description of Gerughty and colleagues, 432 some modifications have been made. First, the strict requirement for intracytoplasmic mucin has not been a requisite for some examiners to make this diagnosis. 443 This is reflected in the WHO classification description of ASC. 119 The adenocarcinoma component has well-formed ductal structures usually without mucocytes. In the vast majority of cases, overlying mucosa has a carcinoma in situ or superficial SCC. The deeply invasive submucosal aspect of the tumors frequently displays transformation from SCC to adenocarcinoma. 445 Reports in the literature have suggested this arrangement by reporting the initial biopsy containing SCC and subsequent resection showing ASC. 433, 440
The histogenesis of ASC is debatable. Gerughty and colleagues 432 considered the neoplasm to be from totipotential cells from the excretory duct of minor salivary glands. Other investigators have included the mucosal lining of the upper respiratory tract as a source. 444 The original series cited the presence of the ductal carcinoma in situ preceding the fully developed characteristic ASC, the presence of intracytoplasmic mucin, and the prominence of ductal components in nodal metastasis as grounds for supporting a glandular origin. 432
Immunocytochemistry studies have shown positive staining for the high-molecular-weight cytokeratins (LKL1) in both the squamous and glandular components. All glandular components stained positive for carcinoembryonic antigen and low-molecular-weight cytokeratins (19KD) while the squamous component was negative for both. 437

Differential Diagnosis
The differential diagnosis of ASC includes ASCC, mucoepidermoid carcinoma, nonkeratinizing SCC, and necrotizing sialometaplasia.
The first entity in the differential diagnosis is ASCC, which is exceedingly rare in this region and considered to be of nonglandular origin. This tumor is, as previously discussed, a variant of SCC with pseudoglandular formations or an alveolar appearance because of central acantholysis. There is no intracytoplasmic mucin production in these tumors or well-formed areas of ductal adenocarcinoma.
Distinguishing ASC from mucoepidermoid carcinoma is more difficult. Both neoplasms may be of ductal or surface mucosa origin and share some similar cell types. Mucoepidermoid carcinoma does not usually exhibit anaplastic nuclear features and is not associated with carcinoma in situ of the overlying mucosa. ASC, in contrast to mucoepidermoid carcinoma (1) has a tendency for demonstrable intercellular bridges, (2) demonstrates keratin pearl formation and dyskeratosis, and (3) has distinct areas of adenocarcinoma. 437
The third differential diagnosis, nonkeratinizing SCC, may have rare mucin-containing pseudoglandular structures; however, no areas of definitive adenocarcinoma or keratinization typically are present. 437 This lesion is more extensively discussed in the section on sinonasal carcinoma.
The fourth differential diagnosis is that of a benign entity, necrotizing sialometaplasia, which may be confused with mucoepidermoid carcinoma or SCC. This lesion is most frequently associated with minor salivary or seromucinous glands. The overlying surface is usually ulcerated. Within the subjacent minor glands, there may be intraductal proliferation of metaplastic squamous cells, partial necrosis of salivary seromucinous glands, and vascular proliferation. The overall lobular configuration of the lesion is an important distinguishing characteristic. 446 Necrotizing sialometaplasia is discussed in more detail in Chapter 6 (“Salivary and Lacrimal Glands”). Coexistence of ASC with a salivary gland tumor has also been observed. 447

Treatment and Prognosis
ASC is considered to have an aggressive behavior in comparison to standard SCC and mucoepidermoid carcinoma. 432, 447 - 450 As mentioned earlier, owing to limited numbers for comparison, it is difficult to determine whether the aggressiveness is site related 443 or inherent to the tumor. 432, 448, 449 The primary mode of recommended treatment is surgical. 441, 449 Radiation alone overall has had poor results, 433, 450 with a rare exception. 439 Radiation combined with radical surgery, however, has been reported to improve local control. 439

Papillary Squamous Cell Carcinoma
In a 1988 article discussing squamous papillary neoplasms of the UADT, Crissman and colleagues 451 proposed the term papillary carcinoma for a rare variant of SCC. This lesion, named papillary squamous cell carcinoma (PSCC) in the current WHO classification, 117 has also been described in other parts of the body such as the skin, 452 uterine cervix, 453 conjunctiva of the eye, 454 and thymus. 455 Within the UADT, PSCC has been mentioned as making up part of the histologic spectrum shown by the clinical entity proliferative verrucous leukoplakia, 334, 339, 340 a condition more extensively discussed in the context of VC.
In the study on papillary neoplasia in the adult UADT, Crissman and colleagues 451 presented six cases of PSCC. These patients were an average age of 63.3 years, with the age at onset of disease ranging from 46 to 79 years, and did not have a history of recurrent papillomatosis. The architectural features were those of an exophytic neoplasm with a papillary configuration. The epithelium lining the fibrovascular cores showed either carcinoma in situ or pronounced cellular pleomorphism with surface keratinization. Lesions without an invasive component were called noninvasive papillary carcinoma to distinguish them from invasive papillary carcinoma that had foci of SCC in association with the superficial papillary component. The invasion was usually found within the vascular cores or in the base of the stalks. Five of the six patients were male; three lesions were present in the larynx, one in the nasopharynx, one in the pyriform sinus, and one in the oropharynx. 444 Data on HPV involvement vary. 451, 456

Clinical Features
In a series of 104 laryngeal cases identified in the files of the Otorhinolaryngic Head and Neck Pathology Tumor Registry of the Armed Forces Institute of Pathology, there were 25 females and 79 males, aged 27 to 89 years, with a mean age at presentation of 60.7 years. Clinical presentation was generally hoarseness. A large number of patients were smokers or consumed alcohol, or both. Tumor size varied from 0.3 to 6 cm in greatest dimension, and the larger tumors were frequently associated with vocal cord impairment or fixation. 457 Another preferred site of PSCC is the sinonasal tract. 456

Pathologic Features
The histologic features of PSCC are a papillary display of fibrovascular cores lined with markedly dysplastic epithelium of normal or increased thickness. The malignant-appearing squamous epithelium may be composed entirely of immature basal-like cells or have prominent nuclear and cellular pleomorphism in the lower portion of the epithelium with varying degrees of surface keratinization. 451 If no stromal invasion of the atypical epithelium is observed, lesions should be called atypical papillary hyperplasia or PSCC in situ. 458 Frequently, squamous neoplasms with papillary components contain predominantly noninvasive areas, and it may require extensive histologic sampling to find areas of invasion. 341, 451, 456, 457
Two histologic patterns have been identified in PSCC: papillary-frond or broad-based exophytic growth ( Figs. 2-46 and 2-47 ). The papillary pattern consisted of multiple, thin, delicate filiform, finger-like papillary projections. The papillae contained a delicate fibrovascular core surrounded by the neoplastic epithelium. Tangential sectioning would yield commonly one or occasionally a number of central fibrovascular cores, but would appear more like a bunch of celery cut across the stalk. The exophytic pattern consisted of a broad-based, bulbous to exophytic growth of the squamous epithelium. The projections were rounded and cauliflower-like in growth pattern. Tangential sectioning would yield a number of central fibrovascular cores, but the outer aspect was lobular, not papillary (see Figs. 2-46 and 2-47 ). 450 Whether this subdivision is reproducible and of any value has been questioned. 459

Figure 2-46 Papillary squamous cell carcinoma. A and B , Papillary frond-like type. Note delicate finger-like extensions of tumor extending up from and along the surface, composed of dysplastic epithelium lining pencilate, fibrovascular cores. C , Dysplastic epithelium extending into adjacent seromucinous gland duct. D , A small focus of invasive squamous carcinoma from an adjacent area that extends almost down to the cartilage.

Figure 2-47 Papillary squamous cell carcinoma, broad-based exophytic growth type ( A, B , and D ). Note polypoid, broad-based exophytic growth with complex fibrovascular cores lined, at least focally, by dysplastic epithelium ( C ). Areas of invasion were noted in this biopsy specimen in two of the biopsy fragments ( E and F , arrowheads ).

Differential Diagnosis
The growth pattern of this neoplasm evokes a clinical and histologic differential diagnosis ranging from solitary papilloma to VC. Applying the criterion of invasion to diagnose PSCC simplifies the diagnostic process when considering a solitary papilloma with atypia. The diagnosis of PSCC in situ in contrast to papilloma requires the epithelium to be severely dysplastic or carcinoma in situ, not just focal areas of atypia. PSCC is not associated with recurrent papillomatosis or inverting papillomas. 341, 451 The history of a recurrent adult or juvenile papillomatosis with marked dysplasia having a rapid rate of recurrence has been well documented. Malignant transformation in these lesions, however, is very rare. 460 - 462 Moreover, PSCCs occur in older patients.
VC is another differential diagnostic consideration. The fronded fibrovascular-based epithelial growth pattern as well as the presence of significant cytologic atypia distinguishes PSCC from the bland cytologic character of VC. VC has a more sessile base with a confluent downward “pushing border” rather than features of an infiltrative cell process 341 and is usually associated with a greater degree of hyperkeratosis.
Finally, PSCC has to be distinguished from nonkeratinizing or cylindrical cell carcinoma, this latter lesion being characterized by ribbons of cylindrical epidermoid cells and lacking the papillae covered with a layer of epidermoid cells exhibiting severe atypia and disturbed maturation (for more detail, see the “Sinonasal Cavities” section).

Treatment and Prognosis
In the series of 104 laryngeal PSCCs mentioned before, patients were treated with excisional biopsy, vocal cord stripping, and laryngectomy in conjunction with radiation. Eighty-seven patients had no evidence of disease at the time of last follow-up. Of the 92 patients with an exophytic pattern, 10 died with widely metastatic disease and seven died with locally recurrent disease. Four of 12 patients with the papillary pattern developed local recurrence, but none died of the disease. The authors conclude that the group of papillary and exophytic SCCs generally has a better prognosis than usual SCCs and that the papillary histologic variant appears to have an even better prognosis than the exophytic type. 457

Lymphoepithelioma, also called lymphoepithelial carcinoma, is a histologic variant of SCC that was first reported by Regaud and Reverchon 463 and independently by Schmincke. 464 At present, it is defined by the occurrence of a distinctive intermingling of undifferentiated carcinoma cells with a prominent lymphoid stroma. 119 Lymphoepithelioma mainly occurs in the nasopharynx; occasionally, tumors with the same histomorphologic features have been described in the oropharynx (Waldeyer’s ring region), salivary glands, tonsils, tongue, soft palate, uvula, floor of the mouth, sinonasal tract, larynx, trachea, hypopharynx, lung, thymus, stomach, skin, breast, uterine cervix, vagina, and urinary bladder under a variety of terms: undifferentiated carcinoma of nasopharyngeal type, undifferentiated carcinoma with lymphoid stroma, lymphoepithelioma, lymphoepithelium-like carcinoma, and lymphoepithelial carcinoma. In contrast to lymphoepithelioma of the nasopharynx, lymphoepithelioma arising at these other sites, with the exception of the major salivary glands, does not exhibit a close association with EBV except in Chinese patients. 195, 208, 465 - 469
As the majority of cases of lymphoepithelioma involve the nasopharynx, clinical, epidemiologic, and other data are mainly based on tumor series at this location, and therefore discussion of these characteristics is based on lymphoepithelioma in the nasopharynx unless explicitly stated otherwise; lymphoepithelioma of the salivary glands is discussed in Chapter 6 .

Clinical Features
Lymphoepithelioma has its highest worldwide incidence in the people of Southeast China, Southeast Asia, the Arctic regions, and Malaysia. 470 - 472 Regions of occurrence have been designated as high incidence (e.g., South China province of Kwantung and Hong Kong), intermediate incidence (e.g., North Africa), and low incidence (e.g., Europe and the United States). Lymphoepithelioma represents the majority of nasopharyngeal cancer cases in regions where nasopharyngeal cancer is endemic. 194 In the United States, where nasopharyngeal cancer represents only 0.2% of all cancers, 60% of these are lymphoepitheliomas. 223 In contrast, in Chinese regions where nasopharyngeal cancer represents 18% to 25% of all cancers, lymphoepithelioma accounts for more than 90% of these. 59, 223 Moreover, lymphoepithelioma is the most common type of nasopharyngeal cancer in young people (>90%). 196 Other features specific for lymphoepithelioma are occurrence at a younger age than other head and neck SCCs, absence of a strong alcohol or tobacco etiologic relationship, lack of substantial risk for a second primary tumor (1.3%), 183 and a very high rate of systemic dissemination. 194
Similar to nasopharyngeal cancer in general, lymphoepithelioma usually arises on the lateral or posterosuperior wall of the nasopharynx. The clinical appearance of the tumor may be exophytic, infiltrative, or ulcerative. Dickson 185 found the gross appearance of tumor in the nasopharynx to be exophytic in 74.2% of lesions, infiltrative in 14.4% of lesions, and ulcerative in 6.7% of lesions; in 4.8%, the appearance of the lesion was not well documented.

Pathologic Features
Microscopically, lymphoepithelioma is composed of cells containing large, round or oval, vesicular nuclei with a smooth, thin nuclear membrane and one to three prominent eosinophilic nucleoli. 473 The borders of the amphophilic cytoplasm are indistinct ( Fig. 2-48 A ). Frequently, spindle-shaped tumor cells with hyperchromatic nuclei are present. 217 The associated infiltrate is mixed and composed of T lymphocytes and may contain plasma cells, follicular dendritic cells, or abundant eosinophils. 226 Individual tumor cells may be surrounded by the mixed infiltrate, resembling Hodgkin’s disease. 474 The presence of noncaseating granulomas negative for acid-fast bacilli, sarcoid-like granulomas, and localized amyloid has been reported in the adjacent stroma. 224

Figure 2-48 A , Photomicrograph of nasopharyngeal carcinoma (lymphoepithelioma) illustrating brisk mitotic activity, the indistinct cytoplasmic borders, vesicular nuclei, and prominent nucleoli. Note the epithelium is infiltrated by the mixed inflammatory background. B , Photomicrograph of lymphoepithelioma with a syncytial growth pattern of the epithelium within a background of lymphocytes. C , Photomicrograph demonstrates the sinusoidal pattern of spread of a lymphoepithelioma metastatic to a lymph node. D , Photomicrograph showing lymphoepithelioma. Inset , Same tumor subjected to in situ hybridization for detecting Epstein-Barr virus RNA transcripts. Nuclear positivity is clearly visible.
Historically, but inaccurately, lymphoepitheliomas were subdivided into two histologic types: Regaud type (clusters, nests, or aggregates of neoplastic epithelial cells with lymphoid elements) and Schmincke type (dispersed tumor cells forming a syncytial net beneath an inflammatory infiltrate; see Fig. 2-48 B ). 194, 475, 476 These two types were essentially descriptions of two growth patterns of an undifferentiated carcinoma. Familiarity with these variations in the histomorphology of undifferentiated carcinoma is useful, particularly when the examiner is confronted with a small biopsy of the primary tumor or is evaluating a metastatic deposit in a cervical lymph node with an occult primary tumor (see Fig. 2-48 C ). Designation of lymphoepithelioma as a Regaud or a Schmincke type does not have prognostic significance.
Various histologic findings are reported to have an impact on the prognosis. The presence of a high density of follicular dendritic cells (S-100 positive) 477 and eosinophils 478 has been associated with a good prognosis. The presence of a spindle-cell phenotype or cordlike arrangement and increased nuclear anaplasia has been reported to indicate a poor prognosis. 224
Confirming the presence of the EBV within tumor cells of diagnostic tissue has proven to be useful. The expression of EBV-encoded RNA-1 detected by in situ hybridization technique in primary lymphoepithelioma and in metastatic cells of lymphoepithelioma has been found to be helpful in specimens in which this diagnosis is suspected (see Fig. 2-48 D ). 208 Others have used polymerase chain reaction for detecting EBV in paraffin-embedded tissue and tissue from fine-needle aspiration in patients with unknown primary tumors. 198, 199 The usefulness of tumor ploidy determination remains controversial. 226

Differential Diagnosis
Because of the frequently inconspicuous epithelial nature of undifferentiated carcinoma including lymphoepithelioma and because its most common presentation is metastases to cervical lymph nodes, the differential diagnosis is diverse. Included in the differential diagnosis are Hodgkin’s disease, large cell lymphoma, lymphoid hyperplasia, melanoma, and sinonasal undifferentiated carcinoma.
Hodgkin’s disease as a differential diagnosis presents the most deceptive pitfall, particularly if the initial histologic diagnosis is based on a cervical lymph node in a young patient with adenopathy. 473, 479 Lymph nodes containing undifferentiated carcinoma exhibit varying degrees of nodal replacement by tumor. Capsular fibrosis and dense bands of collagen entrapping discohesive tumor cells are histologic findings that may be common to Hodgkin’s disease and lymphoepithelioma. 473, 474, 479 The carcinoma cells may have vesicular nuclei with prominent eosinophilic nucleoli suggestive of the mononuclear variants of Reed-Sternberg cells. 474 Immunohistochemical stains are very helpful in this dilemma. The undifferentiated carcinoma cells will be positive for cytokeratin and negative for leukocyte common antigen, LeuM1, L26, and UCHL1. 474
Undifferentiated carcinoma is morphologically easily mistaken for large cell lymphoma ( Fig. 2-49 ). Again, the immunohistochemical stains for cytokeratins (AE1/AE3) can be useful. The majority (97%) 480 of nasopharyngeal cancers will be positive for cytokeratins, with the caveat that cytokeratin positivity has been reported in rare lymphomas. 481 Leukocyte common antigen positivity in undifferentiated carcinoma has not yet been reported in the epithelial component.

Figure 2-49 Note the poorly differentiated carcinoma cells of lymphoepithelioma mimicking a lymphoma.
Lymphoid hyperplasia is a common finding in nasopharyngeal biopsy specimens and should be included in the differential diagnosis of the lymphoepithelioma type of undifferentiated carcinoma when nasopharyngeal lymphoid hyperplasia accompanies cervical adenopathy in a patient who tests positive for human immunodeficiency virus type 1. 482 Cytokeratin stains again should resolve this question. An increased incidence of lymphoepithelioma in patients with acquired immunodeficiency syndrome has not been observed. 483
Melanoma is rare in the nasopharynx. The nuclear features of undifferentiated carcinoma and melanoma may be similar. The immunohistochemical staining patterns for undifferentiated carcinoma are the reverse for melanoma. In undifferentiated carcinoma, HMB45 and S-100 are negative while cytokeratin is positive. 224
Sinonasal undifferentiated carcinoma is similar histomorphologically to lymphoepithelioma. Cells of sinonasal undifferentiated carcinoma, however, are smaller, are frequently associated with large areas of necrosis, do not usually contain spindle-shaped cells, are not associated with a positive serology for EBV, and are frequently positive by immunohistochemical staining for neural markers (e.g., neuron-specific enolase). 224

Treatment and Prognosis
Treatment and prognosis were examined previously under the discussion of NPC (see “Nasopharynx” section).

Other Unusual Features and Diagnostic Pitfalls in Squamous Cell Carcinomas
SCC variants such as SpCC, VC, and other entities discussed previously are not rare and have obtained recognition as specific subtypes of UADT SCC. There are, however, other less frequently observed morphologic variants of SCC that have gained less attention. The first to be discussed is the so-called desmoplastic SCC (DSCC). 484 Clinically, this lesion presents itself as a firm submucosal mass. Histologic examination demonstrates a fibrous lesion in which clumps of vesiculated nuclei are observed. Immunohistochemistry of these latter cells demonstrates cytoplasmic positivity for keratin ( Fig. 2-50 ). Ultrastructural examination also reveals epithelial features such as tonofilaments and desmosomes. Because of the preponderance of fibrous tissue, the lesion may be mistaken for a benign spindle cell lesion, such as proliferative myositis or nodular fasciitis. 484 If DSCC invades bone, extensive bony remodeling may occur, leading to a histomorphology suggesting fibrous dysplasia with the invading tumor being present as only tiny strands ( Fig. 2-51 ).

Figure 2-50 A , Photomicrograph showing desmoplastic epidermoid carcinoma; pleomorphic epithelial cells are present in tiny nests, surrounded by a prominent fibrous stroma. B , Staining with antikeratin antibody serves to highlight the neoplastic epithelium.

Figure 2-51 A , Photomicrograph showing fibro-osseous tissue resembling fibrous dysplasia. Only a few epithelial nests are present in this area from a squamous cell carcinoma that invades bone and has evoked an osteoblastic reaction. B , By immunohistochemical staining for keratin, the invading epithelial nests are more clearly displayed.
A DSCC should not be confused with SpCC because, in that SCC type, the malignant nature is obvious and the lesion exhibits sarcomatous features, whereas in DSCC, the major part of the lesion consists of desmoplastic stroma simulating a benign mesenchymal proliferation. As only two cases of DSCC have been reported, one in the right lateral aspect of the posterior mobile tongue and the other in the right base of the tongue, 484 it is not known whether this SCC subtype behaves differently from conventional SCC. In the gingiva, DSCC may be confused with odontogenic epithelial nests, a feature mentioned in the discussion of alveolar ridge SCC.
Another SCC variant not widely recognized is SEC, primarily occurring in the larynx and hypopharynx. 280 SEC is a poorly or moderately differentiated infiltrating SCC showing an entirely or predominantly superficial type of growth. Despite its intramucosal site, lymph node metastases may be present. 280 SEC is notorious for its association with multiple synchronous and metachronous neoplasms in the UADT. SEC should not be confused with microinvasive SCC. The latter lesion is basically an intraepithelial lesion with tiny foci of penetration through the epithelial basement membrane, whereas SEC occupies the mucosal lining extending to underlying glands or muscle; in other words, the entire lamina propria is involved. To date, the prognostic significance of distinguishing between conventional SCC and SEC is unclear. 280
SCCs may also mimic odontogenic epithelial tumors, in particular the acanthomatous ameloblastoma, by exhibiting palisading of the basal cell layer facing the stroma and by showing epithelial spindle cell areas with extensive intercellular edema that display an abrupt transition to distinctly circumscribed keratin pearls ( Fig. 2-52 ). The lack of reverse polarization of the nucleus from the basement membrane within the palisaded layer and no evidence of collagen condensation in the subjacent connective tissue should aid in preventing the erroneous diagnosis of ameloblastoma for a lesion that is an SCC. (Refer to Chapter 10 [“Odontogenic Cysts and Tumors”] for more detail.) For some unknown reasons, SCCs that mimic some microscopic features of ameloblastomas are frequently observed in the retromolar area.

Figure 2-52 Sometimes squamous cell carcinoma may mimic ameloblastoma by acantholysis and peripheral palisading.
Poorly differentiated SCC may exhibit a nodular growth pattern with intervening fibrous bands, thus simulating malignant lymphoma. Occasional cells with eosinophilic cytoplasm and cells arranged in clusters will reveal the epithelial nature of such a lesion, and immunohistochemistry with appropriately selected markers (broad-spectrum keratin and panleukocytic markers) will confirm the diagnosis of poorly differentiated SCC ( Fig. 2-53 ). Moreover, poorly differentiated SCC may invade an overlying uninvolved epithelial lining and in this way mimic the intraepithelial extension of a malignant melanoma ( Fig. 2-54 ). Also in this case, individual cells or cell clusters showing more classic SCC features can be found as evidence against a diagnosis of malignant melanoma. However, in small biopsy specimens, the unwary observer may be led astray by this growth pattern. Immunohistochemistry can also be helpful in this situation, with broad-spectrum keratin staining being positive in the former and S-100 and HMB45 staining positive in the latter.

Figure 2-53 Low-power photomicrograph showing large tumor areas with intervening fibrous septa mimicking malignant lymphoma. Inset , At high power, clusters of cells with eosinophilic cytoplasm indicate the epithelial nature of this lesion.

Figure 2-54 A , Photomicrograph showing poorly differentiated squamous cell cancer invading overlying healthy epithelium, thus mimicking melanoma. B , Elsewhere, the tumor surrounds a squamous epithelial nest that represents squamous metaplasia in salivary tissue; this should not be mistaken for squamous differentiation of the tumor cells.
If SCC exhibits extensive acantholysis, lumina occur lined with cells with pleomorphic nuclei, a growth pattern closely mimicking angiosarcoma. This feature may occur in SpCC 365 as well as in ASSC, 425 but angiosarcoma-like areas may also be part of more conventional SCC. Immunohistochemistry will reveal that the pleomorphic cells lining the lumina are positive for keratin and negative for endothelial markers, thus confirming their epithelial nature ( Fig. 2-55 ).

Figure 2-55 A , Low-power photomicrograph showing blood lakes surrounded by pleomorphic cells. B , At higher magnification, the nuclear pleomorphism of the cells that cover fibrous stalks is clearly visible. C , Keratin immunohistochemistry reveals the epithelial nature of the cells that line the blood lakes. D , Factor VIII immunohistochemistry only stains the endothelial cells that line the vessels in the fibrous stalks. This histologic and immunohistochemical picture is typical of pseudoangiosarcomatous squamous cell carcinoma with blood lakes originating through acantholysis and intratumoral hemorrhage.

Concluding Remarks
SCC is the most common head and neck malignancy. Usually, the diagnosis is easily made, although there are diagnostic pitfalls, as mentioned previously. The major diagnostic responsibility for the pathologist dealing with head and neck specimens coming from patients with this tumor is the identification of either macroscopic or microscopic features having prognostic significance and necessitating additional treatment. An adequate anatomic knowledge of the various head and neck sites from which tumor resection specimens are obtained is required in performing this task. 485 A histologic section can be sent anywhere for additional consultation; however, overlooking macroscopic features because of lack of anatomic expertise may cause irreparable loss of clinically relevant information and thus have a negative impact on optimal patient care.


1 Forastiere A, Koch W, Trotti A, et al. Head and neck cancer. N Engl J Med . 2001;345:1890-1900.
2 Visser O, Sieslingh S, van Dijck JAAM, editors. Cancer in the Netherlands 1999/2000. Eleventh Report of the Netherlands Cancer Registry. Utrecht: Vereniging van Integrale Kankercentra, 2003.
3 Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur J Cancer . 2001;37(Suppl 8):S4-S66.

Epidemiology and Risk Factors
4 Muir CS, Nectoux J. International patterns of cancer. In: Schottenfeld D, Fraumeni JF, editors. Cancer Epidemiology and Prevention . 2nd ed. New York: Oxford University Press; 1996:141-167.
5 Parkin DM, Muir CS, Whelan SW, editors. Cancer Incidence in Five Continents . IARC Sci., Vol VI; 1992, International Agency for Research on Cancer, Lyon, Publ. No. 120
6 Blot WJ, McLaughlin JK, Devesa SS, et al. Cancers of the oral cavity and pharynx. In: Schottenfeld D, Fraumeni JF, editors. Cancer Epidemiology and Prevention . 2nd ed. New York: Oxford University Press; 1996:666-680.
7 Stewart BW, Kliehues P, editors. World Cancer Report, WHO International Agency for Research on Cancer. Lyon: IARC Press, 2003.
8 Boyle P, Macfarlane GJ, Blot WJ, et al. Review. European School of Oncology advisory report to the European Commission for the Europe Against Cancer Programme: Oral carcinogenesis in Europe. Eur J Cancer . 1995;31B:75-85.
9 Paterson IC, Eveson JW, Prime SS. Molecular changes in oral cancer may reflect aetiology and ethnic origin. Eur J Cancer . 1996;32B:150-153.
10 Elias MM, Hilgers FJM, Keus RB, et al. Carcinoma of the pyriform sinus: A retrospective analysis of treatment results over a 20-year period. Clin Otolaryngol . 1995;20:249-253.
11 Hoffman RM, Jaffe PE. Plummer-Vinson syndrome. A case report and literature review. Arch Intern Med . 1995;155:2008-2011.
12 Ferguson MM, Dagg JH. Nutritional disorders. In: Jones JH, Mason DK, editors. Oral Manifestations of Systemic Diseases . Philadelphia: WB Saunders; 1980:211-228.
13 Austin DF, Reynold P. Laryngeal cancer. In: Schottenfeld D, Fraumeni JF, editors. Cancer Epidemiology and Prevention . 2nd ed. New York: Oxford University Press; 1996:618-636.
14 Muir C, Weiland L. Upper aerodigestive tract cancers. Cancer . 1995;75:147-153.
15 Cattaruzza MS, Maisonneuve P, Boyle P. Epidemiology of laryngeal cancer. Eur J Cancer . 1996;32B:293-305.
16 Coleman MP, Estève J, Damiecki J, et al. Trends in cancer incidence and mortality, IARC Sci. Publ.; 1993, International Agency for Research in Cancer, Lyon, No. 121
17 Spitz MR. Epidemiology and risk factors for head and neck cancer. Semin Oncol . 1994;21:281-288.
18 Tuyns AJ, Esteve J, Raymond L, et al. Cancer of the larynx/hypopharynx, tobacco and alcohol. IARC International Case Control Study in Turin and Varese (Italy), Zaragoza and Navarra (Spain), Geneva (Switzerland) and Calvados (France). Int J Cancer . 1988;41:483-491.
19 DeStefani E, Correa D, Oreggia F. Risk factors for laryngeal cancer. Cancer . 1987;60:308-309.
20 Goldenberg D, Golz A, Joachims HZ. The beverage mate: A risk factor for cancer of the head and neck. Head Neck . 2003;25:595-601.
21 Goldenberg D, Lee J, Koch WM, et al. Habitual risk factors for head and neck cancer. Otolaryngol Head Neck Surg . 2004;131:986-993.
22 Osguthorpe JD. Sinus neoplasia. Arch Otolaryngol Head Neck Surg . 1994;120:19-25.
23 Muir CS, Nectoux J. Descriptive epidemiology of malignant neoplasms of nose, nasal cavities, middle ear and accessory sinuses. Clin Otolaryngol . 1980;5:195-211.
24 Doll R, Morgan IG, Speizer FE. Cancer of the lung and sinuses in nickel workers. Br J Cancer . 1970;24:623-632.
25 Vaughan TL, Davis S. Wood dust exposure and squamous cell cancers of the upper respiratory tract. Am J Epidemiol . 1991;133:560-564.
26 Merler E, Baldasseroni A, Laria R, et al. On the causal association between exposure to leather dust and nasal cancer: Further evidence from a case-control study. Br J Indust Med . 1986;43:91-95.
27 Davies JM, Easton DF, Birdstrup PL. Mortality from respiratory cancer and other causes in United Kingdom chromate production workers. Br J Indust Med . 1991;48:299-313.
28 Wada S, Miyanishi P, Nishimoto Y. –Mustard gas as a cause of neoplasia in man. Lancet . 1968;1:1161-1163.
29 Leung SI, Yuen ST, Chung LP, et al. Epstein-Barr virus is present in a wide histological spectrum of sinonasal carcinomas. Am J Surg Pathol . 1995;19:994-1001.
30 Katori H, Nozawa A, Tsukuda M. Markers of malignant transformation of sinonasal inverted papilloma. Eur J Surg Oncol . 2005;31:905-911.
31 El-Mofty SK, Lu DW. Prevalence of high-risk human papillomavirus DNA in nonkeratinizing (cylindrical cell) carcinoma of the sinonasal tract. A distinct clinicopathologic and molecular disease entity. Am J Surg Pathol . 2005;29:1367-1372.
32 Yu MC, Henderson BE. Nasopharyngeal Cancer. In: Schottenfeld D, Fraumeni JF, editors. Cancer Epidemiology and Prevention . 2nd ed. New York: Oxford University Press; 1996:603-618.
33 Lee JT, Ko CY. Has survival improved for nasopharyngeal carcinoma in the United States? Otolaryngol Head Neck Surg . 2005;132:303-308.
34 Wei WI, Sham JST. Nasopharyngeal carcinoma. Lancet . 2005;365:2041-2054.
35 Webb BD, Walsh GL, Roberts DB, et al. Primary tracheal malignant neoplasms. The University of Texas MD Anderson Cancer Center experience. J Am Coll Surg . 2006;202:237-246.
36 Baraka ME. Malignant tumours of the trachea. Ann R Col Surg Engl . 1984;66:27-29.
37 Boyle P, Macfarlane GJ, Zheng T, et al. Recent advances in epidemiology of head and neck cancer. Curr Opin Oncol . 1992;4:471-477.
38 Blot WJ, McLaughlin JK, Winn DM, et al. Smoking and drinking in relation to oral pharyngeal cancer. Cancer Res . 1988;48:3282-3287.
39 Fakhry C, Gillison M. Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol . 2006;24:2606-2611.
40 Gindhart TD, Johnston WH, Chism SE, et al. Carcinoma of the larynx in childhood. Cancer . 1980;46:1683-1687.
41 Trizna Z, Schantz SP. Hereditary and environmental factors associated with risk and progression of head and neck cancer. Otolaryngol Clin North Am . 1992;25:1089-1103.
42 Berkower AS, Biller HF. Head and neck cancer associated with Bloom’s syndrome. Laryngoscope . 1988;98:746-748.
43 Snow DG, Campbell JB, Smallman LA. Fanconi’s anaemia and post-cricoid carcinoma. J Laryngol Otol . 1991;105:125-127.
44 Lustig JP, Lugassy G, Neder A, et al. Head and neck carcinoma in Fanconi’s anaemia: Report of a case and review of the literature. Eur J Cancer . 1995;31B:68-72.
45 Szentirmay Z, Polus K, Tamas L, et al. Human papillomavirus in head and neck cancer: Molecular biology and clinicopathological correlations. Cancer Metastasis Rev . 2005;24:19-34.
46 Patton LL, Valdez IH. Xeroderma pigmentosum: Review and report of a case. Oral Surg Oral Med Oral Pathol . 1991;71:297-300.
47 Hecht F, Hecht BK. Cancer in ataxia-telangiectasia patients. Cancer Genet Cytogenet . 1990;46:9-12.
48 Gardner GM, Steiniger JR. Family cancer syndrome: A study of the kindred of a man with osteogenic sarcoma of the mandible. Laryngoscope . 1990;100:1259-1263.
49 Flaitz CM, Nichols CM, Adler-Storthz K, et al. Intraoral squamous cell carcinoma in human immunodeficiency virus infection. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 1995;80:55-62.
50 Mullen DL, Silverberg SG, Penn I, et al. Squamous cell carcinoma of the skin and lip in renal homograft recipients. Cancer . 1976;37:729-734.

51 Elwood JM, Pearson JCG, Skippen DH, et al. Alcohol, smoking, social and occupational factors in the etiology of cancer of the oral cavity, pharynx and larynx. Int J Cancer . 1984;34:603-612.
52 Brugere J, Guenel P, Leclerc A, et al. Differential effects of tobacco and alcohol in cancer of the larynx, pharynx and mouth. Cancer . 1986;57:391-395.
53 Macfarlane GJ, Zheng T, Marshall JR, et al. Alcohol, tobacco, diet and the risk of oral cancer: A pooled analysis of three case-control studies. Eur J Cancer . 1995;31B:181-187.
54 Scully C. Oral precancer. Preventive and medical approaches to management. Eur J Cancer B Oral Oncol . 1995;31B:16-26.
55 Scully C. Viruses and oral squamous carcinoma. Eur J Cancer . 1992;28B:57-59.
56 Yeudall WA. Human papillomaviruses and oral neoplasia. Eur J Cancer . 1992;28B:61-66.
57 Brachman DG. Molecular biology of head and neck cancer. Semin Oncol . 1994;21:320-329.
58 Hording U, Nielsen HW, Albeck H, et al. Nasopharyngeal carcinoma: Histopathological types and association with Epstein-Barr virus. Eur J Cancer . 1993;29B:137-139.
59 Pathmanathan R, Prasad U, Chandrika G, et al. Undifferentiated, nonkeratinizing and squamous cell carcinoma of the nasopharynx. Variants of Epstein-Barr virus–infected neoplasia. Am J Pathol . 1995;146:1355-1367.
60 Syrjanen S. Human papillomavirus (HPV) in head and neck cancer. J Clin Virol . 2005;32(Suppl 1):S59-S66.
61 El-Mofty S, Lu DW. Prevalence of human papillomavirus type 16 DNA in squamous cell carcinoma of the palatine tonsil, and not the oral cavity, in young patients. A distinct clinicopathologic and molecular disease entity. Am J Surg Pathol . 2003;27:1463-1470.
62 de Vries N, Drexhage HA, de Waal LP, et al. Human leukocyte antigens and immunoglobulin allotypes in head and neck cancer patients with and without multiple primary tumors. Cancer . 1987;60:957-961.
63 Jefferies S, Foulkes WC. Review: Genetic mechanisms in squamous cell carcinoma of the head and neck. Oral Oncol . 2001;37:115-126.
64 Goldstein AM, Blot JW, Greenberg RS, et al. Familial risk in oral and pharyngeal cancer. Eur J Cancer . 1994;30B:319-322.
65 Cloos J, Reid CBA, Snow GB, et al. Review. Mutagen sensitivity: Enhanced risk assessment of squamous cell carcinoma. Eur J Cancer . 1996;32B:367-372.
66 Scully C, Field JK, Tanzawa H. Genetic aberrations in oral or head and neck squamous cell carcinoma (SCHNN): 1. Carcinogen metabolism, DNA repair and cell cycle control. Oral Oncol . 2000;36:256-263.
67 Scully C, Field JK, Tanzawa H. Genetic aberrations in oral or head and neck squamous cell carcinoma 2. Chromosomal aberrations. Oral Oncol . 2000;36:311-327.
68 Schantz SP. Carcinogenesis, markers, staging and prognosis of head and neck cancer. Curr Opin Oncol . 1993;5:483-490.
69 Kim MM, Califano JA. Mini-review: Molecular pathology of head and neck cancer. Int J Cancer . 2004;112:545-553.
70 Hunter KD, Parkinson EK, Harrison PR. Profiling early head and neck cancer. Nat Rev Cancer . 2005;5:127-135.
71 Field JK, Pavelic ZP, Spandidos DA, et al. The role of the p53 tumor suppressor gene in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg . 1993;119:1118-1122.
72 Brennan JA, Boyle JO, Koch WM, et al. Association between cigarette smoking and mutation of the p53 gene in squamous cell carcinoma of the head and neck. N Engl J Med . 1995;332:712-717.
73 Denissenko MF, Pao A, Tang M, et al. Preferential formation of benzo(a)pyrene adducts at lung cancer mutational hot spots in p53. Science . 1996;274:430-432.
74 Hafkamp HC, Speel EJM, Haesevoets A, et al. A subset of head and neck squamous cell carcinomas exhibits integration of HPV 16/18 and overexpression of p16 INK4A and p53 in the absence of mutations in p53 exons 5–8. Int J Cancer . 2003;107:394-400.

Multiple Primary Tumors
75 Slaughter DP, Southwick HW, Smejhel W. Field cancerization in oral stratified epithelium. Cancer . 1953;6:963-968.
76 Gluckman JL, Crissman JD, Donegan JO. Multicentric squamous cell carcinoma of the upper aerodigestive tract. Head Neck Surg . 1980;3:90-96.
77 Haughey BH, Arfken CL, Gates GA, et al. Meta-analysis of second malignant tumors in head and neck cancer: The case for an endoscopic screening protocol. Ann Otol Rhinol Laryngol . 1992;101:105-112.
78 Terhaard CJ, Hordijk GJ, van den Broek P, et al. T3 laryngeal cancer: A retrospective study of the Dutch Head and Neck Oncology Cooperative Group: Study design and general results. Clin Otolaryngol . 1992;17:393-402.
79 Day GL, Blot WJ, Shore RE, et al. Second cancers following oral and pharyngeal cancer: Patient’s characteristics and survival patterns. Eur J Cancer . 1994;30B:381-386.
80 Schwartz LH, Ozsahin M, Zhang GN, et al. Synchronous and metachronous head and neck carcinomas. Cancer . 1994;74:1933-1938.
81 Lippman SM, Spitz M, Trizna Z, et al. Epidemiology, biology, and chemoprevention of aerodigestive cancer. Cancer . 1994;74:2719-2725.
82 Dhooge IJ, de Vos M, van Cauwenberge PB. Multiple primary malignant tumors in head and neck cancer. The case for an endoscopic screening protocol. Ann Otol Rhinol Laryngol . 1992;101:105-112.
83 Jovanovic A, van der Tol IGH, Kostense PJ, et al. Second respiratory and upper digestive tract cancer following oral squamous cell carcinoma. Eur J Cancer . 1994;30B:225-229.
84 Schantz SP, Spitz MR, Hsu TC. Mutagen sensitivity in patients with head and neck cancers: A biologic marker for risk of multiple primary malignancies. J Natl Cancer Inst . 1990;82:1773-1775.
85 Gallo O, Bianchi S, Giovannucci ML, et al. p53 oncoprotein overexpression correlates with mutagen-induced chromosome fragility in head and neck cancer patients with multiple malignancies. Br J Cancer . 1995;71:1008-1012.
86 Braakhuis BJM, Leemans CR, Brakenhoff RH. Review. Expanding fields of genetically altered cells in head and neck squamous carcinogenesis. Semin Cancer Biol . 2005;15:113-120.

Local and Distant Metastases
87 Shah JP. Patterns of cervical lymph node metastasis from squamous carcinomas of the upper aerodigestive tract. Am J Surg . 1990;160:405-409.
88 Shah JP, Cendon RA, Farr HW, et al. Carcinoma of the oral cavity. Factors affecting treatment failure at the primary site and neck. Am J Surg . 1976;132:504-507.
89 Snow GB, Annyas AA, van Slooten EA, et al. Prognostic factors of neck node metastasis. Clin Otolaryngol . 1982;7:185-192.
90 Leemans CR, Tiwari RM, van der Waal I, et al. The efficacy of comprehensive neck dissection with or without postoperative radiotherapy in nodal metastases of squamous cell carcinoma of the upper respiratory and digestive tracts. Laryngoscope . 1990;100:1194-1198.
91 Shah JP. Cervical lymph node metastasis-diagnostic, therapeutic, and prognostic implications. Oncology . 1990;4:61-69.
92 Jones AS, Phillips DE, Helliwell TR, et al. Occult lymph node metastases in head and neck squamous carcinoma. Eur Arch Otorhinolaryngol . 1993;250:446-449.
93 Johnson JT, Myers EN, Bedetti CD, et al. Cervical lymph node metastases incidence and implications of extracapsular carcinoma. Arch Otolaryngol . 1985;111:534-537.
94 Carter RL, Bliss JM, Soo KC, et al. Radical neck dissections for squamous carcinomas: Pathological findings and their clinical implications with particular reference to transcapsular spread. Int J Radiat Oncol Biol Phys . 1987;13:825-832.
95 Brasilino de Carvalho M. Quantitative analysis of the extent of extracapsular invasion and its prognostic significance: A prospective study of 170 cases of carcinoma of the larynx and hypopharynx. Head Neck . 1998;20:16-21.
96 Richard JM, Sancho-Garnier H, Micheau C, et al. Prognostic factors in cervical lymph node metastasis in upper respiratory and digestive tract carcinomas: Study of 1713 cases during a 15-year period. Laryngoscope . 1987;97:97-101.
97 Olsen KD, Caruso M, Foote RL, et al. Primary head and neck cancersHistopathologic predictors of recurrence after neck dissections in patients with lymph node involvement. Arch Otolaryngol Head Neck Surg . 1994;120:1370-1374.
98 Ferlito A, Rinaldo A, Devaney KO, et al. Review: Prognostic significance of microscopic and macroscopic extracapsular spread from metastatic tumor in the cervical lymph nodes. Oral Oncol . 2002;38:747-751.
99 Woolgar JA, Rogers SN, Lowe D, et al. Cervical lymph node metastasis in oral cancer: The importance of even microscopic extracapsular spread. Oral Oncol . 2003;39:130-137.
100 Jose J, Coatesworth AP, Johnston C, et al. Cervical node metastases in squamous cell carcinoma of the upper aerodigestive tract: The significance of extracapsular spread and soft tissue deposits. Head Neck . 2003;25:451-456.
101 Jose J, Moor JW, Coatesworth AP, et al. Soft tissue deposits in neck dissections of patients with head and neck squamous cell carcinoma. Prospective analysis of prevalence, survival, and its implications. Arch Otolaryngol Head Neck Surg . 2004;130:157-160.
102 van den Brekel MWM, van der Waal I, Meijer CJLM, et al. The incidence of micrometastases in neck dissection specimens obtained from elective neck dissections. Laryngoscope . 1996;106:987-991.
103 Ferlito A, Devaney KO, Rinaldo A, et al. Clinicopathological consultation. Micrometastases. Have they an impact on prognosis? Ann Otol Rhinol Laryngol . 1999;108:1185-1999.
104 Woolgar JA. Micrometastasis in oral/oropharyngeal squamous cell carcinoma: Incidence, histopathological features and clinical implications. Br J Oral Maxillofac Surg . 1999;37:181-186.
105 Vikram B, Strong EW, Shah JP, et al. Failure at distant sites following multimodality treatment for advanced head and neck cancer. Head Neck Surg . 1984;6:730-733.
106 Leemans CR, Tiwari R, Nauta JJP, et al. Regional lymph node involvement and its significance in the development of distant metastases in head and neck carcinoma. Cancer . 1993;71:452-456.
107 Calhoun KH, Fulmer P, Weiss R, et al. Distant metastases from head and neck squamous cell carcinomas. Laryngoscope . 1994;104:1199-1205.
108 Genden EM, Ferlito A, Bradley PJ, et al. Review. Neck disease and distant metastases. Oral Oncol . 2003;39:207-212.
109 Crile GW. Carcinoma of the jaws, tongue, cheek and lips. Surg Gynecol Obstet . 1923;36:159-184.
110 Slootweg PJ, Hordijk GJ, Koole R. Autopsy findings in patients with head and neck squamous cell cancer and their therapeutic relevance. Eur J Cancer . 1996;32B:413-415.
111 Nishijima W, Takooda S, Tokita N, et al. Analyses of distant metastases in squamous cell carcinoma of the head and neck and lesions above the clavicle at autopsy. Arch Otolaryngol Head Neck Surg . 1993;119:65-68.
112 Grätz KW, Makek M. Fernmetastasen und Zweitkarzinome bei Mundhöhlenkarzinomen. Dtsch Z Mund Kiefer Gesichts Chir . 1990;14:5-11.
113 Slootweg PJ, Rutgers DH, Wils IS. DNA ploidy analysis of squamous cell head and neck cancer to identify distant metastasis from second primary. Head Neck . 1992;14:464-466.
114 Slootweg PJ, Giessen MCA, Rutgers DH, et al. DNA heterogeneity in metastasizing squamous cell head and neck cancer. J Craniomaxillofac Surg . 1993;21:348-350.
115 Leong PP, Rezai B, Koch WM, et al. Distinguishing second primary tumors from lung metastases in patients with head and neck squamous cell carcinoma. J Natl Cancer Inst . 1998;90:972-977.
116 van Oijen MGCT, Leppers Vd Straat FGJ, Tilanus MGJ, et al. The origins of multiple squamous cell carcinomas in the aerodigestive tract. Cancer . 2000;88:884-893.
117 Talbot SG, Estilo C, Maghami E, et al. Gene expression profiling allows distinction between primary and metastatic squamous cell carcinomas in the lung. Cancer Res . 2005;65:3063-3071.
118 Geurts TW, Nederlof PM, van den Brekel MWM, et al. Pulmonary squamous cell carcinoma following head and neck squamous cell carcinoma: Metastasis or second primary. Clin Cancer Res . 2005;11:6608-6614.

Pathologic Features and Prognosis
119 Barnes L, Eveson JW, Reichart P, et al, editors. World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of the Head and Neck. Lyon: IARC Press, 2005.
120 Kershisnik M, Batsakis JG, Mackay B. Pathology consultation. Granular cell tumors. Ann Otol Rhinol Laryngol . 1994;103:416-419.
121 Platz H, Fries R, Hudec M. Retrospective DÖSAK study on carcinomas of the oral cavity: Results and consequences. J Maxillofac Surg . 1985;13:147-153.
122 Broders AC. Carcinoma of the mouth: Types and degrees of malignancy. Am J Roentgenol Rad Ther Nucl Med . 1927;17:90-93.
123 Arthur K, Farr HW. Prognostic significance of histologic grade in epidermoid carcinoma of the mouth and pharynx. Am J Surg . 1972;124:489-492.
124 Zarbo RJ, Crissman JD. The surgical pathology of head and neck cancer. Semin Oncol . 1988;15:10-19.
125 Kearsley JH, Thomas S. Prognostic markers in cancer of the head and neck region. Anticancer Drugs . 1993;4:419-429.
126 Roland NJ, Caslin AW, Nash J, et al. Value of grading squamous cell carcinoma of the head and neck. Head Neck . 1992;14:224-229.
127 Jakobsson PÅ, Eneroth CM, Killander D, et al. Histologic classification and grading of malignancy in carcinoma of the larynx. Acta Radiol Ther Phys Biol . 1973;12:1-8.
128 Anneroth G, Batsakis J, Luna M. Review of the literature and a recommended system of malignancy grading in oral squamous cell carcinomas. Scand J Dent Res . 1987;95:229-249.
129 Borges AM, Shrikhande SS, Ganesh B. Surgical pathology of squamous carcinoma of the oral cavity: Its impact on management. Semin Surg Oncol . 1989;5:310-317.
130 Bryne M, Koppang HS, Lilleng R, et al. New malignancy grading is a better prognostic indicator than Broders’ grading in oral squamous cell carcinomas. J Oral Pathol Med . 1989;18:432-437.
131 Odell EW, Jani P, Sheriff M, et al. The prognostic value of individual histologic grading parameters in small lingual squamous cell carcinomas. The importance of pattern of invasion. Cancer . 1994;74:789-794.
132 Welkoborsky HJ, Hinni M, Dienes HP, et al. Predicting recurrence and survival in patients with laryngeal cancer by means of DNA cytometry, tumor front grading and proliferation markers. Ann Otol Rhinol Laryngol . 1995;104:503-510.
133 Wiernik G, Millard PR, Haybittle JL. The predictive value of histological classification into degrees of differentiation of squamous cell carcinoma of the larynx and hypopharynx compared with the survival of patients. Histopathology . 1991;19:411-417.
134 Truelson JM, Fisher SG, Beals TE, et al. DNA content and histologic growth pattern correlate with prognosis in patients with advanced squamous cell carcinoma of the larynx. Cancer . 1992;70:56-62.
135 Umeda M, Yokoo S, Take Y, et al. Lymph node metastasis in squamous cell carcinoma of the oral cavity: Correlation between histologic features and the prevalence of metastasis. Head Neck . 1992;14:263-272.
136 Horiuchi K, Mishima K, Ohsawa M, et al. Prognostic factors for well-differentiated squamous cell carcinoma in the oral cavity with emphasis on immunohistochemical evaluation. J Surg Oncol . 1993;53:92-96.
137 Ravasz LA, Hordijk GJ, Slootweg PJ, et al. Uni- and multivariate analysis of eight indications for post-operative radiotherapy and their significance for local-regional cure in advanced head and neck cancer. J Laryngol Otol . 1993;107:437-440.
138 Kirita T, Okabe S, Izumo T, et al. Risk factors for the postoperative local recurrence of tongue carcinoma. J Oral Maxillofac Surg . 1994;52:149-154.
139 Slootweg PJ, de Pagter M, de Weger RA, et al. Lymphocytes at tumor margins in patients with head and neck cancer. Relationship with tumor size, HLA molecules and metastasis. Int J Oral Maxillofac Surg . 1994;23:286-289.
140 Resnick MJM, Uhlman D, Niehans GA, et al. Cervical lymph node status and survival in laryngeal carcinoma: Prognostic factors. Ann Otol Rhinol Laryngol . 1995;104:685-694.
141 Rasgon BM, Cruz RM, Hilsinger RL, et al. Relation of lymph node metastasis to histopathologic appearance in oral cavity and oropharyngeal carcinoma: A case series and literature review. Laryngoscope . 1989;99:1103-1110.
142 Hirota J, Ueta E, Osaki T, et al. Immunohistologic study of mononuclear infiltrates in oral squamous carcinomas. Head Neck Surg . 1990;12:118-125.
143 Thompson AC, Brailley PJ, Griffin NR. Tumor-associated tissue eosinophilia and long-term prognosis for carcinoma of the larynx. Am J Surg . 1994;168:469-471.
144 Sassler AM, McClatchey KD, Wolf GT. Eosinophilic infiltration in advanced laryngeal squamous cell carcinoma. Laryngoscope . 1995;105:413-416.
145 Howaldt HP, Frenz M, Pitz H. Proposal for a modified T-classification for oral cancer. J Craniomaxillofac Surg . 1992;21:96-101.
146 Woolgar JA, Scott J. Prediction of cervical lymph node metastasis in squamous cell carcinoma of the tongue/floor of mouth. Head Neck . 1995;17:463-472.
147 O’Brien CJ, Lauer CS, Fredricks S, et al. Tumor thickness influences prognosis of T1 and T2 oral cavity cancer—but what thickness. Head Neck . 2002;25:937-945.
148 McMahon J, O’Brien CJ, Pathak I, et al. Influence of condition of surgical margins on local recurrence and disease-specific survival in oral and oropharyngeal cancer. Br J Oral Maxillofac Surg . 2003;41:224-231.
149 Rahima B, Shingaki S, Nagata M, et al. Prognostic significance of perineural invasion in oral and oropharyngeal carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 2004;97:423-431.
150 Close LG, Brown PM, Vuitch MF, et al. Microvascular invasion and survival in cancer of the oral cavity and oropharynx. Arch Otolaryngol Head Neck Surg . 1989;115:1304-1309.
151 Hannen EJ, Riediger D. The quantification of angiogenesis in relation to metastasis in oral cancer: A review. Int J Oral Maxillofac Surg . 2004;33:2-7.
152 Jensen JL, Wuerker RB, Correll RW, et al. Epithelial islands associated with mandibular nerves. Report of two cases in the walls of mandibular cysts. Oral Surg Oral Med Oral Pathol . 1979;48:226-230.
153 Wysocki GP, Wright BA. Intraneural and perineural epithelial structures. Head Neck Surg . 1981;4:69-71.
154 Pantanowitz L, Balogh K. Significance of the juxtaoral organ (of Chievitz). Head Neck . 2003;25:400-405.
155 Scholl P, Byers RM, Batsakis JG, et al. Microscopic cut-through of cancer in the surgical treatment of squamous carcinoma of the tongue. Prognostic and therapeutic implications. Am J Surg . 1986;152:354-360.
156 Jones AS. Prognosis in mouth cancer: Tumour factors. Eur J Cancer . 1994;30B:8-15.
157 Wenig BL, Berry BW. Management of patients with positive surgical margins after vertical hemilaryngectomy. Arch Otolaryngol Head Neck Surg . 1995;121:172-175.
158 Bradford CR, Wolf GT, Fisher SG, et al. Prognostic importance of surgical margins in advanced laryngeal squamous carcinoma. Head Neck . 1996;18:11-16.
159 Spiro RH, Guillamondegui O, Paulino AF, et al. Pattern of invasion and margin assessment in patients with oral tongue cancer. Head Neck . 1999;21:408-413.
160 Bauer WC, Lesinski SG, Ogura JH. The significance of positive margins in hemilaryngectomy specimens. Laryngoscope . 1975;85:1-13.
161 Looser KG, Shah JP, Strong EW. The significance of “positive” margins in surgically resected epidermoid carcinomas. Head Neck Surg . 1978;1:107-111.
162 Chen TY, Emrich LJ, Driscoll DL. The clinical significance of pathological findings in surgically resected margins of the primary tumor in head and neck carcinoma. Int J Radiat Oncol Biol Phys . 1987;13:833-837.
163 Loree TR, Strong EW. Significance of positive margins in oral cavity squamous carcinoma. Am J Surg . 1990;160:410-414.
164 Weijers M, Snow GB, Bezemer PD, et al. The clinical relevance of epithelial dysplasia in the surgical margins of tongue and floor of mouth squamous cell carcinoma. An analysis of 37 patients. J Oral Pathol Med . 2002;31:11-15.
165 Brennan CT, Sessions DG, Spitznagel EL, et al. Surgical pathology of cancer of the oral cavity and oropharynx. Laryngoscope . 1991;101:1175-1197.
166 Ravasz LA, Slootweg PJ, Hordijk GJ, et al. The status of the resection margin as a prognostic factor in the treatment of head and neck carcinoma. J Craniomaxillofac Surg . 1991;19:314-318.
167 Woolgar JA, Triantafyllou A. A histological appraisal of surgical margins in oral and oropharyngeal cancer resection specimens. Oral Oncol . 2005;41:1034-1043.
168 van Es RJJ, Amerongen NV, Slootweg PJ, et al. Resection margin as a predictor of recurrence at the primary site for T1 and T2 cancers. Evaluation of histopathologic variables. Arch Otolaryngol Head Neck Surg . 1996;122:521-525.
169 Slootweg PJ, Hordijk GJ, Schade Y, et al. Treatment failure and margin status in head and neck cancer. A critical view on the potential value of molecular pathology. Oral Oncol . 2002;38:500-503.
170 Batsakis JG. Surgical excision margins: A pathologist’s perspective. Adv Anat Pathol . 1999;6:140-148.
171 Brandwein-Gensler M, Teixeira MS, Lewis CM, et al. Oral squamous cell carcinoma: Histologic risk assessment, but not margin status is strongly predictive of local disease-free and overall survival. Am J Surg Pathol . 2005;29:167-178.
172 Brekel MWMvan den, Snow GB. Assessment of lymph node metastases in the neck. Eur J Cancer . 1994;30B:88-92.
173 www.rcpath.org .
174 Woolgar JA. Review. Histopathological prognosticators in oral and oropharyngeal squamous cell carcinoma. Oral Oncol . 2006;42:229-239.
175 Partridge M, Gaballah K, Huang X. Molecular markers for diagnosis and prognosis. Cancer Metastasis Rev . 2005;24:71-85.
176 Nylander K, Dabelsteen E, Hall PA. The p53 molecule and its prognostic role in squamous cell carcinomas of the head and neck. J Oral Pathol Med . 2000;29:413-425.
177 Quon H, Liu FF, Cummings BJ. Potential molecular prognostic markers in head and neck squamous cell carcinomas. Head Neck . 2001;23:147-159.
178 Nagpal JK, Das BR. Oral cancer: Reviewing the present understanding of its molecular mechanism and exploring the future directions for its effective management. Oral Oncol . 2003;39:213-221.
179 Friedlander PL. The use of genetic markers in the clinical care of patients with head and neck cancer. Arch Otolaryngol Head Neck Surg . 2003;129:363-366.
180 Willmore-Payne C, Holden JA, Layfield LJ. Detection of EGFR- and HER2-activating mutations in squamous cell carcinoma involving the head and neck. Mod Pathol . 2006;19:634-640.
181 Brennan JA, Mao L, Hruban RH, et al. Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck. N Engl J Med . 1995;332:429-435.
182 Roepman P, Wessels LF, Kettelarij N, et al. An expression profile for diagnosis of lymph node metastases from primary head and neck squamous cell carcinomas. Nat Genet . 2005;37:182-186.

183 Ali MY. Distribution and Character of the Squamous Epithelium in the Human Nasopharynx, UICC Monograph Series, Vol 1; 1967, Munksgaard, Copenhagen, 138-141
184 Loh LE, Chee TS, John AB. The anatomy of the fossa of Rosenmuller. Singapore Med J . 1991;32:154-155.
185 Dickson RI. Nasopharyngeal carcinoma. An evaluation of 209 patients. Laryngoscope . 1981;91:333-354.
186 Ho JHC. An epidemiologic and clinical study of nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys . 1978;4:183-197.
187 Lindberg RD. Distribution of cervical lymph node metastasis of oral and oropharyngeal carcinomas. Cancer . 1972;29:1446-1449.
188 McLaughlin MP, Mendenhall WM, Mancuso AA, et al. Retropharyngeal adenopathy as a predictor of outcome in squamous cell carcinoma of the head and neck. Head Neck . 1995;17:190-198.
189 Fandi A, Cvitkovic E. Biology and treatment of nasopharyngeal cancer. Curr Opin Oncol . 1995;7:255-263.
190 Bloom S. Cancer of the nasopharynx. Laryngoscope . 1961;71:1207-1260.
191 Coffin CM, Rich SS, Dehner LP. Familial aggregation of nasopharyngeal carcinoma and other malignancies. A clinicopathologic description. Cancer . 1991;68:1323-1328.
192 Ho HC. Nasopharyngeal carcinoma in Hong Kong, Muir CS, Shanmugaratnam K, editors, UICC Monograph Series, Cancer of the Nasopharynx, Vol. 1; 1967, Munksgaard, Copenhagen, 58-63
193 Ho HC. Cancer of the nasopharynx, Harris RJC, editor, Panel II, Ninth International Cancer Congress, UICC Monograph Series, Vol 10; 1967, Springer, Berlin, 110-116
194 Cvitkovic E, Bachouchi M, Armand JP. Nasopharyngeal carcinoma. Biology, natural history, and therapeutic implications. Hematol Oncol Clin North Am . 1991;5:821-838.
195 Vasef MA, Ferlito A, Weiss LM. Clinicopathological consultation. Nasopharyngeal carcinoma, with emphasis on its relationship to Epstein-Barr virus. Ann Otol Rhinol Laryngol . 1997;106:348-356.
196 Hawkins EP, Krischer JP, Smith BE, et al. Nasopharyngeal carcinoma in children: A retrospective review and demonstration of Epstein-Barr viral genomes in tumor cell cytoplasm: A report of the Pediatric Oncology Group. Hum Pathol . 1990;21:805-810.
197 Choi PHK, Suen MWM, 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.
198 Feinmesser R, Miyazakai I, Cheung R, et al. Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissue obtained by fine-needle aspiration. N Engl J Med . 1992;326:17-21.
199 Feinmesser R, Feinmesser M, Freeman JL, et al. Detection of occult nasopharyngeal primary tumours by means of in situ hybridization. J Laryngol Otol . 1992;106:345-348.
200 Easton J, Levine P, Connely R, et al. Studies on nasopharyngeal carcinoma in the United States: A model for international comparisons. Comp Immunol Microbiol Infect Dis . 1979;2:221-228.
201 Easton J, Levine P, Hyams V. Nasopharyngeal carcinoma in the United States. Arch Otolaryngol . 1980;106:88-91.
202 Greene M, Fraumeni J, Hoover R. Nasopharyngeal cancer among young people in the United States: Racial variation by cell type. J Natl Cancer Inst . 1977;58:1267-1271.
203 Hidayatalla A, Malik MO, El Hadi AE, et al. Studies on nasopharyngeal carcinoma in the Sudan. I. Epidemiology and aetiology. Eur J Cancer Clin Oncol . 1983;19:705-710.
204 Su C-Y, Lui C-C. Perineural invasion of the trigeminal nerve in patients with nasopharyngeal carcinoma. Cancer . 1996;78:2063-2069.
205 Werner-Wasik M, Winkler P, Uri A, et al. Nasopharyngeal carcinoma in children. Med Pediatr Oncol . 1996;26:352-358.
206 Sham JT, Cheung YK, Choy D, et al. Cranial nerve involvement and base of the skull erosion in nasopharyngeal carcinoma. Cancer . 1991;68:422-426.
207 Cvitkovic E, Bachouchi M, Boussen H, et al. Leukemoid reaction, bone marrow invasion, fever of unknown origin, and metastatic pattern in the natural history of advanced undifferentiated carcinoma of nasopharyngeal type: A review of 255 consecutive cases. J Clin Oncol . 1993;11:2434-2442.
208 Tsai ST, Jin YT, Su IJ. Expression of EBER1 in primary and metastatic nasopharyngeal carcinoma tissues using in situ hybridization. A correlation with WHO histologic subtypes. Cancer . 1996;77:231-236.
209 Derigs P. Lymphoepitheliales Carcinom des Rachens mit Metastasen. Virchows Arch . 1923;244:1-7.
210 Ahmad A, Stefani S. Distant metastases of nasopharyngeal carcinoma. A study of 256 male patients. J Surg Oncol . 1986;33:194-197.
211 Vikram B, Mishra UB, Strong EW, et al. Patterns of failure in carcinomas of the nasopharynx: Failure at distant sites. Head Neck Surg . 1986;8:276-279.
212 Teo PM, Leung SF, Yu P, et al. A comparison of the Ho’s, International Union Against Cancer, and American Joint Committee stage classifications for nasopharyngeal carcinoma. Cancer . 1991;67:434-439.
213 Greene FL, Page DL, Fritz AG, et al. American Joint Committee on Cancer. In Cancer Staging Manual . New York: Springer; 2002.
214 Sobin LH, Wittekind C. TNM: Classification of Malignant Tumours, 6th ed. New York: John Wiley and Sons, 2002.
215 Teo PM, Tsao SY, Ho JH, et al. A proposed modification of the Ho stage-classification for nasopharyngeal carcinoma. Radiother Oncol . 1991;21:11-23.
216 Svoboda D, Kirchner F, Shanmugaratnam K. Ultrastructure of nasopharyngeal carcinoma in American and Chinese patients. Exp Mol Pathol . 1965;4:189-204.
217 Shanmugaratnam K, Chan SH, de The G, et al. Histopathology of nasopharyngeal carcinoma. Correlations with epidemiology, survival rates, and other biological characteristics. Cancer . 1979;44:1029-1044.
218 Shanmugaratnam K. Histologic Typing of Upper Respiratory Tract Tumours. International Typing of Tumours, No. 19. Geneva: World Health Organization, 1978;32-33.
219 Shanmugaratnam K, Sobin LH. The World Health Organization Histological Classification of Tumours of the Upper Respiratory Tract and Ear. Cancer . 1993;71:2689-2697.
220 Chan JKC, Pilch BZ, Wenig BM, et al. Nasopharyngeal carcinoma. In: Barnes L, Eveson JW, Reichart P, Sidransky D, editors. World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of the Head and Neck . Lyon: IARC Press; 2005:85-97.
221 Skinner DW, Haslett Van CA, et al. Nasopharyngeal carcinoma: Modes of presentation. Ann Otol Rhinol Laryngol . 1991;100:549-551.
222 Zhu K, Levine RS, Brann EA, et al. A population-based case-control study of the relationship between cigarette smoking and nasopharyngeal cancer (United States). Cancer Causes Control . 1995;6:507-512.
223 Kapadia SB, Janecka IP. Nasopharyngeal carcinoma, Myers EN, Bluestone CD, Brackmann DE, Kranse CJ, editors, Advances in Otolaryngology—Head and Neck Surgery, Vol 9, 1995, Mosby, St. Louis, 247-261.
224 McGuire LJ, Lee JCK. The histopathologic diagnosis of nasopharyngeal carcinoma. Ear Nose Throat J . 1990;69:229-236.
225 Bailet JW, Mark RJ, Abemayor E, et al. Nasopharyngeal carcinoma: Treatment results with primary radiation therapy. Laryngoscope . 1992;102:965-972.
226 Barnes L, Kapadia SB. The biology and pathology of selected skull base tumors. J Neurol Oncol . 1994;20:213-240.
227 Sze WM, Lee AW, Yau TK, et al. Primary tumor volume of nasopharyngeal carcinoma: Prognostic significance for local control. Int J Radiat Oncol Biol Phys . 2004;59:21-27.

Sinonasal Cavities
228 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.
229 Roush GC. Epidemiology of cancer of the nose and paranasal sinuses: Current concepts. Head Neck Surg . 1979;2:3-11.
230 Sisson GASr, Toriumi DM, Atiyah RA. Paranasal sinus malignancy: A comprehensive update. Laryngoscope . 1989;99:143-150.
231 Mundy EA, Neiders ME, Sako K, et al. Maxillary sinus cancer: A study of 33 cases. J Oral Pathol . 1985;14:27-36.
232 Rice DH. Benign and malignant tumors of the ethmoid sinus. Otolaryngol Clin North Am . 1985;18:113-124.
233 Wang CC. Treatment of carcinoma of the nasal vestibule by irradiation. Cancer . 1976;38:100-106.
234 Ohngren LS. Malignant tumors of the maxilloethmoidal region. Acta Otolaryngol Suppl . 1938;19:1-476.
235 Ringertz N. Pathology of malignant tumours arising in the nasal and paranasal cavities and maxilla. Acta Otolaryngol Suppl . 1938;27:95-157.
236 Quick D, Cutler M. Radiation reaction of metastatic squamous cell carcinoma in cervical lymph nodes. AJR Am J Roentgenol . 1925;14:529-540.
237 Geschikter CF. Tumors of the nasal and paranasal cavities. Am J Cancer . 1935;2:637-660.
238 Osborn DA. Nature and behavior of transitional tumors in the upper respiratory tract. Cancer . 1970;25:50-60.
239 Friedmann I, Osborn DA. Carcinoma of the surface epithelium (including ameloblastoma). In: Friedmann I, editor. Pathology of Granulomas and Neoplasms of the Nose and Paranasal Sinuses . Edinburgh: Churchill Livingstone; 1982:118-132.
240 Manivel C, Wick MR, Dehner LP. Transitional (cylindric) cell carcinoma with endodermal sinus tumor-like features of the nasopharynx and paranasal sinuses. Arch Pathol Lab Med . 1986;110:198-202.
241 Michaels L. Malignant neoplasms of surface epithelium. In: Michaels L, Hellquist HB, editors. Ear, Nose and Throat Histopathology . 2nd ed. Berlin: Springer; 2001:189-191.
242 Hellquist HB. Tumours of the surface epithelium. In: Hellquist HB, editor. Pathology of the Nose and Paranasal Sinuses . London: Butterworth; 1990:89-92.
243 Pilch BZ, Bouquot J, Thompson LDR. Squamous cell carcinoma. In: Barnes L, Eveson JW, Reichart P, Sidransky D, editors. World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of the Head and Neck . Lyon: IARC; 2005:15-17.
244 Wenig BM. Neoplasms of the nasal cavity and paranasal sinuses. In: Wenig BM, editor. Atlas of Head and Neck Pathology . Philadelphia: WB Saunders; 1993:57-58.
245 Mills SE, Gaffey MJ, Frierson HF. Tumors of the upper respiratory tract and ear. In: Atlas of Tumor Pathology, 3rd Series, No. 26 . Washington, DC: Armed Forces Institute of Pathology; 2000:56.
246 Rosai J. Respiratory tract. In: Rosai J, editor. Rosai and Ackerman’s Surgical Pathology . 9th ed. St Louis: Mosby; 2004:310.
247 Michaels L, Young M. Histogenesis of papillomas of the nose and paranasal sinuses. Arch Pathol Lab Med . 1995;119:821-826.
248 Patel P, Tiwari R, Karim ABM, et al. Squamous cell carcinoma of the nasal vestibule. J Laryngol Otol . 1992;106:332-336.
249 Fradis M, Podoshin L, Gertner R, et al. Squamous cell carcinoma of the nasal septum mucosa. Ear Nose Throat J . 1993;72:217-221.
250 Kraus DH, Sterman BM, Levine HL, et al. Factors influencing survival in ethmoid sinus cancer. Arch Otolaryngol Head Neck Surg . 1992;118:367-372.

Larynx and Hypopharynx
251 Del Regato JAM, Spjut HJ, Cox JD, editors, Ackerman and Del Regato’s Cancer. Diagnosis, Treatment, and Prognosis, 6th ed. 1985, Mosby, St. Louis, 346.
252 Barnes L, Johnson JT. Pathologic and clinical considerations in the evaluation of major head and neck specimens resected for cancer. Pathol Annu . 1986;21:173-250.
253 Michaels L, Hellquist HB. Squamous cell carcinoma of the hypopharynx. In Ear, Nose and Throat Histopathology , 2nd ed, London: Springer Verlag; 2001:448-451.
254 Harrison DFN. Pathology of hypopharyngeal cancer in relation to surgical management. J Laryngol Otol . 1970;84:349-367.
255 Spector JG, Sessions DG, Emami B, et al. Squamous cell carcinoma of the pyriform sinus: A nonrandomized comparison of therapeutic modalities and long-term results. Laryngoscope . 1995;105:397-406.
256 Thabet HM, Sessions DG, Gado MH, et al. Comparison of clinical evaluation and computed tomographic diagnostic accuracy for tumors of the larynx and hypopharynx. Laryngoscope . 1996;106:589-594.
257 Jones AS, Wilde A, McRae RD, et al. The treatment of early squamous cell carcinoma of the piriform fossa. Clin Otolaryngol . 1994;19:485-490.
258 Jones AS, Roland NJ, Field JK, et al. The level of cervical lymph node metastases: Their prognostic relevance and relationship with head and neck squamous carcinoma primary sites. Clin Otolaryngol . 1994;19:63-69.
259 Kirchner J, Owen J. Five hundred cancers of the larynx and pyriform sinus. Laryngoscope . 1977;87:1288-1303.
260 Million R, Cassiss N. Management of head and neck cancer. A multidisciplinary approach. Philadelphia: JB Lippincott, 1994;431-497.
261 Myers EN, Alvi A. Management of carcinoma of the supraglottic larynx: Evolution, current concepts, and future trends. Laryngoscope . 1996;106:559-567.
262 Pressman J, Simon M, Moncel C. Anatomical studies related to the dissemination of cancer of the larynx. Trans Am Acad Ophthalmol Otolaryngol . 1960;64:628-638.
263 Fechner RE, Mills SE, Sternberg S, editor. Histology for Pathologists, 1992, Raven Press, New York, 443-455.
264 Olofsson J, van Nostrand AWP. Growth and spread of laryngeal and hypopharyngeal carcinoma with reflections on the effect of pre-operative irradiation. 139 cases studied by whole organ sectioning. Acta Otolaryngol (Stockh) . 1973;308(Suppl):1-84.
265 Beitler JJ, Mahadevia PS, Silver CE, et al. New barriers to ventricular invasion in paraglottic laryngeal cancer. Cancer . 1994;73:2648-2652.
266 Rosai J. Respiratory tract. In: Rosai J, editor. Rosai and Ackerman’s Surgical Pathology . 9th ed. St Louis: Mosby; 2004:342-343.
267 Wang CC. Head and neck neoplasms. In: Mansfield CM, editor. Therapeutic Radiology: New Directions in Therapy . New Hyde Park, NY: Medical Examination Publishing; 1983:144-169.
268 Rucci L, Gammarota L, Gallo O. Carcinoma of the anterior commissure of the larynx. 2. Proposal of a new staging system. Ann Otol Rhinol Laryngol . 1996;105:391-396.
269 McGavran MH, Bauer WC, Ogura JH. The incidence of cervical lymph node metastasis from epidermoid carcinoma of the larynx and their relationship to certain characteristics of the primary tumor. A study based on the clinical and pathological findings for 96 patients treated by primary en bloc laryngectomy and radical neck dissection. Cancer . 1961;14:55-66.
270 Stell PM, Gregory I, Watt J. Morphology of the human larynx. II. The subglottis. Clin Otolaryngol . 1980;5:389-395.
271 Gnepp D, Barnes L, Crissman J, et al. Association of directors of anatomic and surgical pathology. Recommendations for the reporting of larynx specimens containing laryngeal neoplasms. Virchows Arch . 1997;431:155-157.
272 Kleinsasser O. Revision of classification of laryngeal cancer. Is it long overdue? (Proposals for an improved TN-classification.). J Laryngol Otol . 1992;106:197-204.
273 Piccirillo JF, Wells CK, Sasaki CT, et al. New clinical severity staging system for cancer of the larynx. Five-year survival rates. Ann Otol Rhinol Laryngol . 1994;103:83-92.
274 Hirabayashi H, Koshii K, Uno K, et al. Extracapsular spread of squamous cell carcinoma in neck lymph nodes: Prognostic factor of laryngeal cancer. Laryngoscope . 1991;101:502-506.
275 Yilmaz T, Hosal AS, Gedikoglu G, et al. Prognostic significance of depth of invasion in cancer of the larynx. Laryngoscope . 1998;108:764-768.
276 Moe K, Wolf GT, Fisher SG, et al. Regional metastases in patients with advanced laryngeal cancer. Arch Otolaryngol Head Neck Surg . 1996;122:644-648.
277 Weidner N, Askin FB, Berthrong M, et al. Bizarre (pseudo malignant) granulation-tissue reactions following ionizing-radiation exposure. Cancer . 1987;59:1509-1514.
278 Ferlito A, Carbone A, DeSanto LW, et al. Clinicopathological consultation. “Early” cancer of the larynx: The concept as defined by clinicians, pathologists, and biologists. Ann Otol Rhinol Laryngol . 1996;105:245-246.
279 Ferlito A. The natural history of early vocal cord cancer. Acta Otolaryngol (Stockh) . 1995;115:345-347.
280 Carbone A, Volpe R. Superficial extending carcinoma (SEC) of the larynx and hypopharynx. Pathol Res Pract . 1992;188:729-735.

281 McCarthy MJ, Rosado-de-Christensen ML. Tumors of the trachea. J Thorac Imag . 1995;10:180-198.
282 Gilbert JGJr, Mazzarella LA, Feit LA. Primary tracheal tumors in the infant and adult. Arch Otolaryngol . 1953;58:1-9.
283 Houston HE, Payne WS, Harrison EGJr, et al. Primary cancers of the trachea. Arch Surg . 1969;99:132-140.
284 Manninen MP, Paakkala TA, Pukander JS, et al. Diagnosis of tracheal carcinoma at chest radiography. Acta Radiol . 1992;33:546-547.
285 Morency G, Chalaoui J, Samson S, et al. Malignant neoplasms of the trachea. J Can Assoc Radiol . 1989;40:198-200.
286 Theegarten D, Freitag L. Scar carcinoma of the trachea after tracheotomy. Case report and review of the literature. Respiration . 1993;60:250-253.
287 Grillo HC, Mathiesen DJ. Primary tracheal tumors: Treatment and results. Ann Thorac Surg . 1990;49:69-77.
288 Gelder CM, Hetzel MR. Primary tracheal tumours: A national survey. Thorax . 1993;48:688-692.
289 Mornex F, Coquard R, Danhier S, et al. Role of radiation therapy in the treatment of primary tracheal carcinoma. Int J Radiat Oncol Biol Phys . 1998;41:299-305.

290 Barnes L, Verbin RS, Guggenheimer J. Cancer of the oral cavity and oropharynx. In: Barnes L, editor. Surgical Pathology of the Head and Neck . 2nd ed. New York: Marcel Dekker; 2001:369-438.
291 Luna-Ortiz K, Güemes-Meza A, Villavicencio-Valencia V, et al. Lip cancer experience in Mexico. An 11-year retrospective study. Oral Oncol . 2004;40:992-999.
292 Schantz SP, Harrison LB, Hong WK. Cancer of the head and neck. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: Principles and Practice of Oncology . 4th ed. Philadelphia: JB Lippincott; 1993:574-672.
293 Antoniades DZ, Styanidis K, Papanayotou P, et al. Squamous cell carcinoma of the lips in a northern Greek population. Evaluation of prognostic factors on 5-year survival rate-I. Eur J Cancer . 1995;31B:340-345.
294 Rodolico V, Barresi E, di Lorenzo R, et al. Lymph node metastasis in lower lip squamous cell carcinoma in relation to tumour size, histologic variables and p27 kip1 expression. Oral Oncol . 2004;40:92-98.
295 Bagatin M, Orihovac Z, Mohammed AM. Perineural invasion by carcinoma of the lower lip. J Craniomaxillofac Surg . 1995;23:155-159.

Oral Cavity and Oropharynx
296 Yuen APW, Lam KY, Lam LK, et al. Prognostic factors of clinically stage I and II oral tongue carcinoma–A comparative study of stage, thickness, shape, growth pattern, invasive front malignancy grading, Martinez-Gimeno score, and pathologic features. Head Neck . 2002;24:513-520.
297 O-charoenrat PO, Pillai G, Patel S, et al. Tumour thickness predicts cervical nodal metastases and survival in early oral tongue cancer. Oral Oncol . 2003;39:386-390.
298 Pentenero M, Gandolfo S, Carozzo M. Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma. A review of the literature. Head Neck . 2005;27:1080-1091.
299 Diaz EM, Holsinger FC, Zuniga ER, et al. Squamous cell carcinoma of the buccal mucosa. One institution’s experience with 119 previously untreated patients. Head Neck . 2003;25:267-273.
300 Daley TD, Lovas JGL, Peters E, et al. Salivary duct involvement in oral epithelial dysplasia and squamous cell carcinoma. Oral Surg Oral Med Oral Pathol . 1996;81:186-192.
301 Sieczka E, Datta R, Singh A, et al. Cancer of the buccal mucosa: Are margins and T-stage accurate predictors of local control? Am J Otolaryngol . 2001;22:395-399.
302 Slootweg PJ, Müller H. Mandibular invasion by oral squamous cell carcinoma. J Craniomaxillofac Surg . 1989;17:69-74.
303 Brown JS, Browne RM. Factors influencing the patterns of invasion of the mandible by oral squamous cell carcinoma. Int J Oral Maxillofac Surg . 1995;24:417-426.
304 Eicker SA, Overholt SM, El-Naggar AK. Lower gingival carcinoma. Clinical and pathologic determinants of regional metastases. Arch Otolaryngol Head Neck Surg . 1996;122:634-638.
305 Müller H, Slootweg PJ. Mandibular invasion by oral squamous cell carcinoma. Clinical aspects. J Craniomaxillofac Surg . 1990;18:80-84.
306 Southam JC. The extension of squamous carcinoma along the inferior dental neurovascular bundle. Br J Oral Surg . 1970;7:137-145.
307 McGregor AD, MacDonald DG. Patterns of spread of squamous cell carcinoma within the mandible. Head Neck Surg . 1989;11:457-461.
308 O’Brien CJ, Carter RL, Soo KC, et al. Invasion of the mandible by squamous carcinomas of the oral cavity and oropharynx. Head Neck Surg . 1986;8:247-256.
309 McGregor AD, MacDonald DG. Routes of entry of squamous cell carcinoma to the mandible. Head Neck Surg . 1988;10:294-301.
310 Brown JS, Lowe D, Kalavrezos N, et al. Patterns of invasion and routes of tumor entry into the mandible by oral squamous cell carcinoma. Head Neck . 2002;24:370-383.
311 Cleary KR, Batsakis JG. Pathology consultation. Oral squamous cell carcinoma and the mandible. Ann Otol Rhinol Laryngol . 1995;104:977-979.
312 de Vicente JC, Recio OR, Pendas SL, et al. Oral squamous cell carcinoma of the mandibular region: A survival study. Head Neck . 2001;23:536-543.
313 Antoniades K, Lazaridis N, Vahtsevanos K, et al. Treatment of squamous cell carcinoma of the anterior faucial pillar-retromolar trigone. Oral Oncol . 2003;39:680-686.
314 Quigley LF, Cobb CM, Schoenfeld S, et al. Reverse smoking and its oral consequences in Caribbean and South American peoples. J Am Dent Assoc . 1964;69:427-442.
315 Reddy DG, Rao VK. Cancer of the palate in coastal Andhra due to smoking cigars with the burning end inside the mouth. Indian J Med Sci . 1957;11:791-798.
316 Zhen W, Karnell LH, Hoffman HT, et al. The national cancer data base on squamous cell carcinoma of the base of the tongue. Head Neck . 2004;26:660-674.
317 Abrams AM, Melrose RJ, Howell FV. Necrotizing sialometaplasia. A disease simulating malignancy. Cancer . 1973;32:130-135.
318 Micheau C, Cachin MY, Caillon B. Cystic metastases in the neck revealing occult carcinoma of the tonsil. A report of six cases. Cancer . 1974;33:228-233.
319 Compagno J, Hyams VJ, Safavian M. Does branchiogenic carcinoma really exist? Arch Pathol Lab Med . 1976;100:311-314.
320 Thompson LDR, Heffner DK. The clinical importance of cystic squamous cell carcinomas in the neck. A study of 136 cases. Cancer . 1998;82:944-956.
321 Parsons JT, Mendenhall WM, Stringer SP, et al. Squamous cell carcinoma of the oropharynx. Surgery, radiation therapy, or both. Cancer . 2002;94:2967-2980.

Verrucous Carcinoma
322 Ackerman LV. Verrucous carcinoma of the oral cavity. Surgery . 1948;23:670-678.
323 Jacobson S, Shear M. Verrucous carcinoma of the mouth. J Oral Pathol . 1972;1:66-75.
324 Ferlito A, Recher G. Ackerman’s tumor (verrucous carcinoma) of the larynx. A clinicopathologic study of 77 cases. Cancer . 1980;46:1617-1630.
325 Batsakis JG, Hybels R, Crissman JD, et al. The pathology of head and neck tumors: Verrucous carcinoma. Head Neck Surg . 1982;5:29-38.
326 Koch BB, Trask DK, Hoffman HT, et al. National survey of head and neck verrucous carcinoma. Patterns of presentation, care and outcome. Cancer . 2001;92:110-120.
327 Medina JE, Dichtel MAJW, Luna MA. Verrucous squamous carcinomas of the oral cavity. Arch Otolaryngol . 1984;110:437-440.
328 Fliss DM, Noble-Topham SE, McLachlin CM, et al. Laryngeal verrucous carcinoma: A clinicopathologic study and detection of human papillomavirus using polymerase chain reaction. Laryngoscope . 1994;104:146-152.
329 Johnson TL, Plieth DA, Crissman JD, et al. HPV detection by polymerase chain reaction (PCR) in verrucous lesions of the upper aerodigestive tract. Mod Pathol . 1991;4:461-465.
330 Luna MA, Tortoledo ME. Verrucous carcinoma. In: Gnepp DR, editor. Pathology of the Head and Neck . New York: Churchill Livingstone; 1988:497-515.
331 Bouquot JE. Oral verrucous carcinoma: Incidence in two US populations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 1998;86:318-324.
332 Slootweg PJ, Müller H. Verrucous hyperplasia or verrucous carcinoma. An analysis of 27 patients. J Oral Maxillofac Surg . 1983;11:13-19.
333 Orvidas LJ, Kerry DK, Lewis JE, et al. Verrucous carcinoma of the larynx. Head Neck . 1998;20:197-203.
334 Ishiyama A, Eversole LR, Ross DA, et al. Papillary squamous neoplasms of the head and neck. Laryngoscope . 1994;104:1446-1452.
335 Ferlito A, Antonutto G, Silvestri F. Histological appearances and nuclear DNA content of verrucous squamous cell carcinoma of the larynx. ORL J Otorhinolaryngol Relat Spec . 1976;38:65-85.
336 Cooper JR, Hellquist HB, Michaels L. Image analysis in the discrimination of verrucous carcinoma and squamous papilloma. J Pathol . 1992;166:383-387.
337 Shear M, Pindborg JJ. Verrucous hyperplasia of the oral mucosa. Cancer . 1980;46:1855-1862.
338 Arendorf TM, Aldred MJ. Verrucous carcinoma and verrucous hyperplasia. J Dent Assoc South Africa . 1982;37:529-532.
339 Murrah VA, Batsakis JG. Proliferative verrucous leukoplakia and verrucous hyperplasia. Ann Otol Rhinol Laryngol . 1994;103:660-663.
340 Hansen LS, Olson JA, Silverman S. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol . 1985;60:285-298.
341 Crissman JD, Gnepp DR, Goodman ML, et al. Preinvasive lesions of the upper aerodigestive tract: Histologic definitions and clinical implications (a symposium). Pathol Annu . 1987;22:311-352.
342 Zakrewska JM, Lopes V, Speight P, et al. Proliferative verrucous leukoplakia A report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 1996;82:396-401.
343 Batsakis JG, Suarez P, El-Naggar AK. Review. Proliferative verrucous leukoplakia and its related lesions. Oral Oncol . 1999;35:354-359.
344 Hagen P, Lyons GD, Haindel C. Verrucous carcinoma of the larynx: Role of human papillomavirus, radiation, and surgery. Laryngoscope . 1993;103:253-257.
345 Demian SDE, Bushkin FL, Echeverria RA. Perineural invasion and anaplastic transformation of verrucous carcinoma. Cancer . 1973;32:395-401.
346 Ferlito A, Rinaldo A, Mannara GM. Review article. Is primary radiotherapy an appropriate option for the treatment of verrucous carcinoma of the head and neck? J Laryngol Otol . 1998;112:132-139.
347 McCaffrey TV, Witte M, Ferguson MT. Verrucous carcinoma of the larynx. Ann Otol Rhinol Laryngol . 1998;107:391-395.
348 Perez CA, Kraus FT, Evans JC, et al. Anaplastic transformation in verrucous carcinoma of the oral cavity after radiation therapy. Radiology . 1966;86:108-115.
349 van Nostrand AWP, Olofsson J. Verrucous carcinoma of the larynx. A clinical and pathologic study of 10 cases. Cancer . 1972;30:691-702.
350 Edström S, Johansson SL, Lindström J, et al. Verrucous squamous cell carcinoma of the larynx. Evidence for increased metastatic potential after irradiation. Otolaryngol Head Neck Surg . 1987;97:381-384.
351 Tharp MEII, Shidnia H. Radiotherapy in the treatment of verrucous carcinoma of the head and neck. Laryngoscope . 1995;105:391-396.

Spindle Cell Carcinoma
352 Batsakis JG, Suarez P. Sarcomatoid carcinomas of the upper aerodigestive tracts. Adv Anat Pathol . 2000;5:282-293.
353 Nappi O, Wick MR. Sarcomatoid neoplasms of the respiratory tract. Semin Diagn Pathol . 1993;10:137-147.
354 Wick MR, Swanson PE. Carcinosarcomas: Current perspectives and a historical review of nosological concepts. Semin Diagn Pathol . 1993;10:118-127.
355 Ellis GL, Corio RL. Spindle cell carcinoma of the oral cavity. A clinicopathologic assessment of fifty-nine cases. Oral Surg Oral Med Oral Pathol . 1980;50:523-534.
356 Zarbo RJ, Crissman JD, Venkat H, et al. Spindle-cell carcinoma of the upper aerodigestive tract mucosa. An immunohistologic and ultrastructural study of 18 biphasic tumors and comparison with seven monophasic spindle-cell tumors. Am J Surg Pathol . 1986;10:741-743.
357 Slootweg PJ, Roholl PJM, Müller H, et al. Spindle-cell carcinoma of the oral cavity and larynx. Immunohistochemical aspects. J Craniomaxillofac Surg . 1989;17:234-236.
358 Takata T, Ito H, Ogawa J, et al. Spindle cell squamous carcinoma of the oral region. An immunohistochemical and ultrastructural study on the histogenesis and differential diagnoses with a clinicopathological analysis of six cases. Virchows Arch . 1991;419:177-182.
359 Thompson L, Wieneke JA, Miettinen M, et al. Spindle cell (sarcomatoid) carcinoma of the larynx. A clinicopathologic study of 187 cases. Am J Surg Pathol . 2002;26:153-170.
360 Choi HR, Sturgis EM, Rosenthal DI, et al. Sarcomatoid carcinoma of the head and neck. Molecular evidence for evolution and progression from conventional squamous cell carcinomas. Am J Surg Pathol . 2003;27:1216-1220.
361 Staley CJ, Ujiki GT, Yokoo H. “Pseudocarcinoma” of the larynx. Independent metastasis of carcinomatous and sarcomatous elements. Arch Otolaryngol . 1971;94:458-465.
362 Lambert PR, Ward PH, Berci G. Pseudosarcoma of the larynx. A comprehensive analysis. Arch Otolaryngol . 1980;106:700-708.
363 Marioni G, Altavilla G, Marino F, et al. Case report. Squamous cell carcinoma of the larynx with osteosarcoma-like stromal metaplasia. Acta Otolaryngol . 2004;124:870-873.
364 Lewis JSJr, Ritter JH, El-Mofty S. Alternative epithelial markers in sarcomatoid carcinomas of the head and neck, lung, and bladder—p63, MOC-31, and TTF-1. Mod Pathol . 2005;18:1471-1481.
365 Banerjee SS, Eyden BP, Wells S, et al. Pseudoangiosarcomatous carcinoma: A clinicopathological study of seven cases. Histopathology . 1992;21:13-23.
366 Petri WH, Auclair PA, Branham GB, et al. Intraosseous tumor of the maxilla. J Oral Maxillofac Surg . 1985;43:726-734.
367 Wenig BM, Devaney K, Bisceglia M. Inflammatory myofibroblastic tumor of the larynx. A clinicopathologic study of eight cases simulating a malignant spindle cell neoplasm. Cancer . 1995;76:2217-2229.
368 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.
369 Fernandez PL, Cardesa A, Alos L, et al. Sinonasal teratocarcinosarcoma: An unusual neoplasm. Pathol Res Pract . 1995;191:166-171.
370 Batsakis JG, Rice DH, Howard DR. The pathology of head and neck tumors: Spindle cell lesions (sarcomatoid carcinomas, nodular fasciitis and fibrosarcoma) of the aerodigestive tracts, part 14. Head Neck Surg . 1984;4:499. –413
371 Ballo MT, Garden AS, El-Naggar AK, et al. Radiation therapy for early stage (T1-T2) sarcomatoid carcinoma of true vocal cords: Outcomes and patterns of failure. Laryngoscope . 1998;108:760-763.

Basaloid Squamous Cell Carcinoma
372 Wain SL, Kie R, Vollmer RT, et al. Basaloid squamous carcinoma of the tongue, hypopharynx, and larynx: Report of 10 cases. Hum Pathol . 1986;17:1158-1166.
373 Dougherty BG, Evans HL. Carcinoma of the anal canal: A study of 79 cases. J Clin Pathol . 1985;83:159-164.
374 Ferry JA, Scully RE. “Adenoid cystic” carcinoma and adenoid basal carcinoma of the uterine cervix: A study of 38 cases. Am J Surg Pathol . 1988;12:134-144.
375 Epstein JI, Sears DL, Tucker RS, et al. Carcinoma of the esophagus with adenoid cystic differentiation. Cancer . 1984;53:1131-1136.
376 Tsang WYW, Chan JKC, Lee KC, et al. Basaloid-squamous carcinoma of the upper aerodigestive tract and so-called adenoid cystic carcinoma of the oesophagus: The same tumour type? Histopathology . 1991;19:35-46.
377 Brambilla E, Moro D, Veale D, et al. Basal cell (basaloid) carcinoma of the lung: A new morphologic and phenotypic entity with separate prognostic significance. Hum Pathol . 1992;23:993-1003.
378 Banks ER, Frierson HF, Mills SE, et al. Basaloid squamous cell carcinoma of the head and neck. Am J Surg Pathol . 1992;16:939-946.
379 Cadier MA, Kelly SA, Parkhouse N, et al. Basaloid squamous carcinoma of the buccal cavity. Head Neck . 1992;14:387-391.
380 Campman SC, Gandour-Edwards RF, Sykes JM. Basaloid squamous carcinoma of the head and neck. Arch Pathol Lab Med . 1994;118:1229-1232.
381 Coppola D, Catalano E, Tang CK, et al. Basaloid squamous cell carcinoma of floor of mouth. Cancer . 1993;72:2299-2305.
382 Gartlan MR, Goetz SP, Graham SM. Basaloid-squamous carcinoma (BSCC) of the larynx. Arch Otolaryngol Head Neck Surg . 1992;118:998-1001.
383 Ereno C, Lopez JI, Sanchez JM, et al. Basaloid-squamous cell carcinoma of the larynx and hypopharynx. A clinicopathologic study of 7 cases. Pathol Res Pract . 1994;190:186-193.
384 Hellquist HB, Dahl F, Karlsson MG, et al. Basaloid squamous cell carcinoma of the palate. Histopathology . 1994;25:178-180.
385 Klijanienko J, El-Naggar A, Ponzio-Prion A, et al. Basaloid squamous carcinoma of the head and neck. Immunohistochemical comparison with adenoid cystic carcinoma and squamous cell carcinoma. Arch Otolaryngol Head Neck Surg . 1993;119:887-890.
386 Lovejoy HM, Matthews BL. Basaloid-squamous carcinoma of the palate. Otolaryngol Head Neck Surg . 1992;106:159-162.
387 Luna MA, El Naggar A, Parichatikanond P, et al. Basaloid squamous carcinoma of the upper aerodigestive tract. Cancer . 1990;66:537-542.
388 McKay MJ, Bilous AM. Basaloid-squamous carcinoma of the hypopharynx. Cancer . 1989;63:2528-2531.
389 Muller S, Barnes L. Basaloid squamous cell carcinoma of the head and neck with a spindle cell component. Arch Pathol Lab Med . 1995;119:181-182.
390 O’Malley BWJr. Pathologic quiz case 2: Basaloid-squamous carcinoma of the right pyriform sinus. Arch Otolaryngol Head Neck Surg . 1992;118:212-215.
391 Raslan WF, Barnes L, Krause JR, et al. Basaloid squamous cell carcinoma of the head and neck: A clinicopathologic and flow cytometric study of 10 new cases with review of the English literature. Am J Otolaryngol . 1994;15:204-211.
392 Seidman JD, Berman JJ, Yost BA, et al. Basaloid squamous carcinoma of the hypopharynx and larynx associated with second primary tumors. Cancer . 1991;68:1545-1549.
393 Shvili Y, Talmi YP, Gal R, et al. Basaloid-squamous carcinoma of larynx metastatic to the skin of the nasal tip. J Craniomaxillofac Surg . 1990;18:322-324.
394 Wan SK, Chan JKC, Tse KC. Basaloid-squamous carcinoma of the nasal cavity. J Laryngol Otol . 1992;106:370-371.
395 Barnes L, Ferlito A, Altavilla G, et al. Clinicopathological consultation. Basaloid squamous cell carcinoma of the head and neck. Clinicopathological features and differential diagnosis. Ann Otol Rhinol Laryngol . 1996;105:75-82.
396 Batsakis J, El-Naggar A. Basaloid-squamous carcinomas of the upper aerodigestive tracts. Ann Otol Rhinol Laryngol . 1989;98:919-920.
397 Ferlito A, Rinaldo A, Altavilla G, et al. Basaloid squamous cell carcinoma of the larynx and hypopharynx. Ann Otol Rhinol Laryngol . 1997;106:1024-1035.
398 Ejaz A, Wenig BM. Sinonasal undifferentiated carcinoma. Clinical and pathologic features and a discussion on classification, cellular differentiation and a differential diagnosis. Adv Anat Pathol . 2005;12:134-143.
399 Wieneke JA, Thompson LDR, Wenig BM. Basaloid squamous cell carcinoma of the sinonasal tract. Cancer . 1999;85:841-854.
400 Van der Wal JE, Snow GB, Karim ABMF, et al. Adenoid cystic carcinoma of the palate with squamous metaplasia or basaloid-squamous carcinoma? Report of a case. J Oral Pathol Med . 1994;23:461-464.
401 Emanuel P, Wang B, Wu M, et al. p63 immunohistochemistry in the distinction of adenoid cystic carcinoma from basaloid squamous cell carcinoma. Mod Pathol . 2005;18:645-650.
402 Burstein DE, Nagi C, Kohtz, et al. Immunodetection of GLUT1, p63 and phospho-histone H1 in invasive head and neck squamous carcinoma: Correlation of immunohistochemical staining patterns with keratinization. Histopathology . 2006;48:717-722.
403 Gnepp DR, Wick MR. Small cell carcinoma of the major salivary glands: An immunohistochemical study. Cancer . 1990;66:185-192.
404 Gnepp DR. Small cell neuroendocrine carcinoma of the larynx. A critical review of the literature. ORL J Otorhinolaryngol Relat Spec . 1991;53:210-219.
405 Morice WG, Ferreiro JA. Distinction of basaloid squamous cell carcinoma from adenoid cystic and small cell undifferentiated carcinoma by immunohistochemistry. Hum Pathol . 1998;29:609-612.
406 Farmer ER, Helwig EB. Metastatic basal cell carcinoma: A clinicopathologic study of seventeen cases. Cancer . 1980;46:748-757.
407 Tavin E, Persky MS, Jacobs J. Metastatic basal cell carcinoma of the head and neck. Laryngoscope . 1995;105:814-817.
408 Snow SN, Sahl W, Lo JS. Metastatic basal cell carcinoma. Cancer . 1994;73:328-335.
409 Larner JM, Malcolm RH, Mills SE, et al. Radiotherapy for basaloid squamous cell carcinoma of the head and neck. Head Neck . 1993;15:249-252.

Adenoid Squamous Cell Carcinoma
410 Lever WF. Adenoacanthoma of sweat glands. Carcinoma of sweat glands with glandular and epidermal elements; Report of four cases. Arch Dermatol Syphilol . 1947;56:157-171.
411 Lever WF. Histopathology of the Skin. Philadelphia: JB Lippincott, 1954;480-481.
412 Muller SA, Wilhelmy CMJr, Harrison EGJr, et al. Adenoid squamous cell carcinoma (adenoacanthoma of Lever). Report of seven cases and review. Arch Dermatol . 1964;89:589-597.
413 Johnson WC, Helwig EB. Adenoid squamous cell carcinoma (adenoacanthoma). A clinicopathologic study of 155 patients. Cancer . 1966;19:1639-1650.
414 Wansker BA, Smith JGJr, Okansky S. Adenoacanthoma-dyskeratotic squamous cell carcinoma with tubular and alveolar formations. Arch Dermatol . 1957;75:96-104.
415 Lever WF. Histopathology of the Skin, 4th ed, Philadelphia: JB Lippincott; 1967:511-512.
416 Eusebi V, Lamovec J, Cattani MG, et al. Acantholytic variant of squamous cell carcinoma of the breast. Am J Surg Pathol . 1986;10:855-861.
417 Nappi O, Pettinato G, Wick MR. Adenoid (acantholytic) squamous cell carcinoma of the skin. J Cutan Pathol . 1989;16:114-121.
418 Jones AC, Freedman PD, Kerpel SM. Oral adenoid squamous cell carcinoma: A report of three cases and review of the literature. J Oral Maxillofac Surg . 1993;51:676-681.
419 Jacoway JR, Nelson JF, Boyers RC. Adenoid squamous cell carcinoma (adenoacanthoma) of the oral labial mucosa. A clinicopathologic study of fifteen cases. Oral Surg Oral Med Oral Pathol . 1971;32:444-449.
420 Goldman RL, Klein HZ, Sung M. Adenoid squamous cell carcinoma of the oral cavity. Report of the first case arising in the tongue. Arch Otolaryngol . 1977;103:496-498.
421 Takagi M, Sakota Y, Takayama S, et al. Adenoid squamous cell carcinoma of the oral mucosa. Cancer . 1977;40:2250-2255.
422 Zaatari GS, Santoianni RA. Adenoid squamous cell carcinoma of the nasopharynx and neck region. Arch Pathol Lab Med . 1986;110:542-546.
423 Hertenstein JC, Fechner RE. Acantholytic squamous cell carcinoma. Arch Otolaryngol Head Neck Surg . 1986;112:780-782.
424 Batsakis JG, Huser J. Squamous carcinomas with gland like (adenoid) features. Ann Otol Rhinol Laryngol . 1990;99:87-88.
425 Nappi O, Wick MR, Pettinato G, et al. Pseudovascular adenoid squamous cell carcinoma of the skin. A neoplasm that may be mistaken for angiosarcoma. Am J Surg Pathol . 1992;16:429-438.
426 Zidar N, Gale N, Zupevc A, et al. Pseudovascular adenoid squamous-cell carcinoma of the oral cavity-A report of two cases. J Clin Pathol . 2006;59:1206-1208.
427 Dodd LG. Fine-needle aspiration cytology of adenoid (acantholytic) squamous-cell carcinoma. Diag Cytopathol . 1995;12:168-172.
428 Ferlito A, Devaney KO, Rinaldo A, et al. Clinicopathological consultation. Mucosal adenoid squamous cell carcinoma of the head and neck. Ann Otol Rhinol Laryngol . 1996;105:409-413.

Adenosquamous Carcinoma
429 Gluckmann A, Cherry CP. Incidence, histology, and response to radiation of mixed carcinomas (adenoacanthomas) of the uterine cervix. Cancer . 1956;9:971-979.
430 Cihak RW, Kawashima T, Steer A. Adenoacanthoma (adenosquamous carcinoma) of the pancreas. Cancer . 1972;29:1133-1140.
431 Naunheim KS, Taylor JR, Skosey C, et al. Adenosquamous lung carcinoma, clinical characteristics, treatment and prognosis. Ann Thorac Surg . 1987;44:462-466.
432 Gerughty RM, Hennigar GR, Brown FM. Adenosquamous carcinoma of the nasal, oral and laryngeal cavities. Cancer . 1968;22:1140-1155.
433 Fujino K, Ito J, Kanaji M, et al. Adenosquamous carcinoma of the larynx. Am J Otolaryngol . 1995;16:115-118.
434 Minic AJ, Stajcic Z. Adenosquamous carcinoma of the inferior turbinate: A case report. J Oral Maxillofac Surg . 1994;52:764-767.
435 Ogawa T. A clinicopathological study of adenocarcinomas of the nasal cavity and paranasal sinuses. Nippon Jibiinkoka Gakkai Kaiho . 1989;92:317-333.
436 Napier SS, Gormley JS, Newlands C, et al. Adenosquamous carcinoma. A rare neoplasm with an aggressive course. Oral Surg Oral Med Oral Pathol . 1995;79:607-611.
437 Martinez-Madrigal F, Baden E, Casiraghi O, et al. Oral and pharyngeal adenosquamous carcinoma, a report of four cases with immunohistochemical studies. Eur Arch Otorhinolaryngol . 1991;248:255-258.
438 Damiani JM, Damiani KK, Hauck K, et al. Mucoepidermoid-adenosquamous carcinoma of the larynx and hypopharynx: A report of 21 cases and a review of the literature. Otolaryngol Head Neck Surg . 1981;89:235-243.
439 Aden KK, Adams GL, Niehans G, et al. Adenosquamous carcinoma of the larynx and hypopharynx with five new case presentations. Trans Am Laryngol Assoc . 1988;109:216-221.
440 Zieske LA, Myers EN, Brown BM. Pulmonary lymphangitic carcinomatosis from hypopharyngeal adenosquamous carcinoma. Head Neck Surg . 1988;10:195-198.
441 Sanderson RJ, Rivron RP, Wallace WA. Adenosquamous carcinoma of the hypopharynx. J Laryngol Otol . 1991;105:678-680.
442 Siar CH, Ng KH. Adenosquamous carcinoma of the floor of the mouth and lower alveolus: A radiation-induced lesion? Oral Surg Oral Med Oral Pathol . 1987;63:216-220.
443 Ellis GL, Auclair PL, Gnepp DR, et al. Other malignant epithelial neoplasms. In: Ellis GL, Auclair PL, Gnepp DR, editors. Surgical Pathology of the Salivary Glands . Philadelphia: WB Saunders; 1991:455-459.
444 Hyams VJ, Batsakis JG, Michaels L. Tumors of the upper respiratory tract and ear, Atlas of Tumor Pathology, 1988, Armed Forces Institute of Pathology, Washington, DC, 104-107, 2nd series, no. 25
445 Batsakis JG, Luna MA, El-Naggar AK. Pathology consultation: Nonsquamous carcinomas of the larynx. Ann Otol Rhinol Laryngol . 1992;101:1024-1026.
446 Fechner RE. Necrotizing sialometaplasia: A source of confusion with carcinoma of the palate. Am J Clin Pathol . 1977;67:315-317.
447 Sanner JR. Combined adenosquamous carcinoma and ductal adenoma of the hard and soft palate: Report of a case. J Oral Surg . 1979;37:331-334.
448 Ferlito A. A pathologic and clinical study of adenosquamous carcinoma of the larynx: Report of four cases and review of the literature. Acta Otorhinolaryngol Belg . 1976;30:379-389.
449 El-Jabbour JN, Ferlito A, Friedmann I. Adenosquamous carcinoma. In: Ferlito A, editor. Neoplasms of the Larynx . Edinburgh: Churchill Livingstone; 1993:249-251.
450 Izumi K, Mnakajima T, Maeda T, et al. Adenosquamous carcinoma of the tongue. Report of a case with histochemical, immunohistochemical, and ultra-structural study and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 1998;85:178-184.

Papillary Squamous Cell Carcinoma
451 Crissman JD, Kessis T, Shah KV, et al. Squamous papillary neoplasia of the adult upper aerodigestive tract. Hum Pathol . 1988;19:1387-1396.
452 Landman G, Taylor RM, Friedman KJ. Cutaneous papillary squamous cell carcinoma. A report of two cases. J Cutan Pathol . 1990;17:105-110.
453 Randall ME, Andersen WA, Mills SE. Papillary squamous cell carcinoma of uterine cervix: A clinicopathologic study of nine cases. Int J Gynecol Pathol . 1986;5:1-10.
454 Li WW, Pettit TH, Zakka KA. Intraocular invasion by papillary squamous cell carcinoma of the conjunctiva. Am J Ophthalmol . 1980;90:697-701.
455 Leong AS, Brown JH. Malignant transformation in a thymic cyst. Am J Surg Pathol . 1984;8:471-475.
456 Suarez PA, Adler-Storthz K, Luna MA, et al. Papillary squamous cell carcinomas of the upper aerodigestive tract: A clinicopathologic and molecular study. Head Neck . 2000;22:360-368.
457 Thompson LDR, Wenig BM, Heffner DK, et al. Exophytic and papillary squamous cell carcinomas of the larynx. A clinicopathologic series of 104 cases. Otolaryngol Head Neck Surg . 1999;120:718-724.
458 Cardesa A, Zidar N, Nadal A, et al. Papillary squamous cell carcinoma. In: Tumors of the Hypopharynx, Larynx and Trachea. WHO Classification. Tumours of the Head and Neck . Lyon: IARC Press; 2005:126.
459 Batsakis JG, Suarez P. Papillary squamous carcinoma: Will the real one please stand up. Adv Anat Pathol . 2000;7:2-8.
460 Altmann F, Basek M, Stout AP. Papillomas of the larynx with intraepithelial anaplastic changes. Arch Otolaryngol . 1986;11:423-429.
461 Lindeberg H, Oster S, Oxlund I, et al. Laryngeal papillomas: Classification and course. Clin Otolaryngol . 1986;11:423-429.
462 Quick CA, Foucar E, Dehner LP. Frequency and significance of epithelial atypia in laryngeal papillomatosis. Laryngoscope . 1979;89:550-560.

463 Regaud C, Reverchon L. Sur un cas d’epithelioma epidermoide developpe dans le massif maxillaire superieure etendu aux ligaments de la face, aux cavites buccale, nasale et orbitaire ainsi que aux ganglions du cou gueri par la radiotherapie. Rev Laryngol Otol Rhinol (Bord) . 1921;42:369-378.
464 Schmincke A. Ueber lympho-epitheliale geschwülste. Ziegler Beitr Pathol Anat Allg Pathol . 1921;68:161-170.
465 Frank DK, Cheron F, Cho H, et al. Nonnasopharyngeal lymphoepitheliomas (undifferentiated carcinomas) of the upper aerodigestive tract. Ann Otol Rhinol Laryngol . 1995;104:305-310.
466 Iezzoni JC, Gaffey MJ, Weiss LM. The role of Epstein-Barr virus in lymphoepithelioma-like carcinomas. Am J Clin Pathol . 1995;103:308-315.
467 MacMillan C, Kapadia SB, Finkelstein SD, et al. Lymphoepithelial carcinoma of the larynx and hypopharynx: Study of eight cases with relationship to Epstein-Barr virus and p53 gene alterations, and review of the literature. Hum Pathol . 1996;27:1172-1179.
468 Weiss LM, Gaffey MJ, Shibata D. Lymphoepithelioma-like carcinoma and its relationship to Epstein-Barr virus. Am J Clin Pathol . 1991;96:156-158.
469 Ferlito A, Weiss CM, Rinaldo A, et al. Clinicopathological consultation: Lymphoepithelial carcinoma of the larynx, hypopharynx and trachea. Ann Otol Rhinol Laryngol . 1997;106:437-444.
470 Clifford P. On the epidemiology of nasopharyngeal carcinoma. Int J Cancer . 1970;5:287-309.
471 De-The G. Epidemiological evidence implicating the Epstein-Barr virus in Burkitt’s lymphoma and nasopharyngeal carcinoma etiology, IARC Sci., 1978, IARC, Lyon, 285-299, Publ. No. 20
472 Lanier A, Bender T, Talbot M, et al. Nasopharyngeal carcinoma in Alaskan Eskimos, Indians and Aleuts. Cancer . 1980;46:2100-2106.
473 Giffler RF, Gillespie JJ, Ayala AG, et al. Lymphoepithelioma in cervical lymph nodes of children and young adults. Am J Surg Pathol . 1977;1:293-301.
474 Zarate-Osorno A, Jaffe ES, Medeiros LJ. Metastatic nasopharyngeal carcinoma initially presenting as cervical lymphadenopathy. A report of two cases that resembled Hodgkin’s disease. Arch Pathol Lab Med . 1992;116:862-865.
475 Cappell DF. Lymphoepithelioma of the nasopharynx and tonsils. J Pathol Bact . 1934;39:49-64.
476 Scofield HH. Epidermoid carcinoma of the nasal and pharyngeal regions: A statistical and morphological analysis of two hundred and fourteen cases. Georgetown University, 1952. MS thesis
477 Nomori H, Watanabe S, Nakajima T, et al. Histiocytes in nasopharyngeal carcinoma in relation to prognosis. Cancer . 1986;57:100-105.
478 Looi LM. Tumour-associated tissue eosinophilia in nasopharyngeal carcinoma: A pathologic study of 422 primary and 138 metastatic tumors. Cancer . 1987;59:466-470.
479 Carbone A, Micheau C. Pitfalls in microscopic diagnosis of undifferentiated carcinoma of nasopharyngeal type (lymphoepithelioma). Cancer . 1982;50:1344-1351.
480 Sugimoto T, Hashimoto H, Enjoli M. Nasopharyngeal carcinoma and malignant lymphomas: An immunohistochemical analysis of 74 cases. Laryngoscope . 1990;100:742-748.
481 Frierson HF, Bellafiore FJ, Gaffney MJ, et al. Cytokeratin in anaplastic cell large cell lymphoma. Mod Pathol . 1994;7:317-321.
482 Shahab I, Osborne B, Butler J. Nasopharyngeal lymphoid tissue masses in patients with human immunodeficiency virus-1. Cancer . 1994;74:3083-3088.
483 Melbye M, Cote TR, West D, et al. Nasopharyngeal carcinoma: An EBV-associated tumour not significantly influenced by HIV-induced immunosuppression. Br J Cancer . 1996;73:995-997.

Unusual Features in Epidermoid Carcinoma
484 Norris CM, Mustoe TA, Ross JS, et al. Desmoplastic squamous cell carcinoma of the tongue simulating myositis or fasciitis. Head Neck Surg . 1986;9:51-55.

Concluding Remarks
485 Slootweg PJ. Complex head and neck specimens and neck dissection. How to handle them. Best Practice No. 182. J Clin Pathol . 2005;58:243-248.
Chapter 3 Nonsquamous Lesions of the Nasal Cavity, Paranasal Sinuses, and Nasopharynx

Manju L. Prasad, Bayardo Perez-Ordonez

Anatomy and Histology

Nasal Cavity
The nose is a complex organ formed by two components: the external and the internal nose. The external nose is triangular, with a wide base that contains two external openings, the nares or nostrils, separated by the columella. Inside the aperture of each nostril is a dilated area covered by skin known as the vestibule.
The internal nose is divided by the septum into right and left nasal cavities or fossae. Posteriorly, it communicates with the nasopharynx through the choana. Each cavity is divided into four parts: superior (roof), inferior (floor), lateral, and medial walls. The superior wall is formed anteriorly by the cribriform plate of the ethmoid bone, which separates the nasal cavity from the anterior cranial fossa. The posterior portion of the roof is formed by the body of the sphenoid bone. The floor constitutes the largest portion of the nasal cavity and is formed by the palatine process of the maxillary bone and the horizontal plate of the palatine bone. The superior, middle, and inferior turbinates with their corresponding meatuses are located in the lateral wall, which is formed by the nasal portion of the maxillary bone, the perpendicular plate of the palatine bone, and the ethmoidal labyrinth, which separates the nasal cavity from the orbit. 1 - 3 The middle turbinate may occasionally be pneumatized.
Histologically, the nasal vestibule is covered by skin and is composed of keratinizing squamous epithelium and subcutaneous tissue with numerous hair follicles, sebaceous glands, and sweat glands. The squamous epithelium from the vestibule changes to ciliated pseudostratified (respiratory-type) epithelium, which covers the entire nasal cavity with the exception of a small portion of the posterior roof. The latter is lined with the olfactory epithelium. 4 The submucosa contains seromucinous glands and numerous thick muscularized blood vessels that resemble erectile tissue and are especially prominent in the turbinates. The olfactory epithelium consists of several types of cells: bipolar spindle cells with myelinated and nonmyelinated axons traversing the cribriform plate, columnar sustentacular cells, round basal cells, and serous glands (Bowman’s glands) in the lamina propria. 0040, 1

Paranasal Sinuses
The largest of the paranasal sinuses are the maxillary sinuses. These triangular cavities are located in the body of each maxilla. The base is formed by the lateral wall of the nasal cavity and the apex projects into the zygoma. Each sinus has a superior wall or roof, an inferior wall or floor, and posterior, medial, and anterolateral walls. The roof forms the floor of the orbit, whereas the floor is formed by the alveolar and palatine processes of the maxilla. The posterior wall relates to the infratemporal space and the pterygopalatine fossa. The anterior wall is the facial surface of the maxilla.
The ethmoid sinuses are formed by the frontal, maxillary, lacrimal, sphenoidal, and palatine bones. They are located in the ethmoidal labyrinth and consist of numerous air-filled cells divided into anterior, middle, and posterior groups according to their relation to the labyrinth. The frontal sinuses are located in the vertical portion of the frontal bone with only a thin plate of bone separating them from the anterior cranial fossa and both orbits. The ostium of the frontal sinus opens into the anterior part of the medial meatus. The sphenoid sinuses are located within the sphenoid bone and are related to numerous vital structures in the cranial cavity; the internal carotid arteries are located laterally, whereas the optic chiasm and the hypophysis are located posteriorly.
The paranasal sinuses are lined with ciliated pseudostratified respiratory-type epithelium interspersed with goblet cells similar to the nasal cavities. This epithelium is also known as schneiderian epithelium and is ectodermal in origin, unlike the endodermally derived mucosa of the nasopharynx. The mucous membrane in the sinuses is thinner and less vascular than that of the nasal cavity. The seromucinous glands are also more sparse and are largely concentrated at the ostium of the maxillary sinus.

The pharynx is divided into three parts: nasopharynx, oropharynx, and hypopharynx. The nasopharynx is the portion of the pharynx that lies behind the nasal cavity and above the soft palate. It has anterior, posterior, and lateral walls. The anterior wall communicates with the nasal cavity through the choana. The posterior wall is continuous with the roof of the nasal cavity and includes the roof of the nasopharynx anteriorly and a posterior portion located against the base of the skull and the body of the sphenoid. The posterior wall extends inferiorly to the free border of the soft palate where the oropharynx begins. The lateral walls contain the ostia of the eustachian tubes, which are surrounded by cartilaginous elevations called the torus tubarius. Posterior to this prominence there is a depression called Rosenmüller’s fossa. 5, 6
Approximately 60% of the nasopharyngeal mucosa is lined with stratified squamous epithelium of endodermal origin. These areas include the lower half of the anterior and posterior walls and the anterior half of the lateral walls. Ciliated pseudostratified respiratory-type epithelium covers the areas around the nasal choanae and the roof of the posterior wall. The remainder of the nasopharynx contains irregular patches of squamous and ciliated epithelium. There are also areas with an intermediate or transitional-type epithelium. The submucosa contains seromucinous glands, which can undergo oncocytic metaplasia, especially in older individuals. 7 Bilateral oncocytic cysts and melanotic oncocytic metaplasia arising from these glands have been described. 8, 9 A prominent lymphoid component with germinal centers is also present beneath the mucosa. These lymphoid elements can be present within the mucosal epithelium, forming the so-called lymphoepithelium. 5, 6

Inflammatory Disorders

Rhinitis and Sinusitis
Rhinitis and sinusitis are the most common disorders of the sinonasal tract. Most cases are viral in origin, but they can be complicated by superimposed bacterial infections. Most examples are the result of adenoviruses, echoviruses, or rhinoviruses. Recently, cytomegalovirus has been reported as a cause of sinusitis in patients infected with human immunodeficiency virus (HIV). 10 Developmental anomalies that also may cause chronic sinusitis in children include hypoplasia of the maxillary sinuses, concha bullosa, a deviated uncinate process, and so-called Haller’s cells. 11 Complications of rhinosinusitis include secondary bacterial infection with extension into adjacent structures causing pharyngotonsillitis. In addition, chronic allergic rhinitis plays a significant role in the genesis of inflammatory pseudopolyps. The treatment of acute rhinitis and sinusitis is symptomatic. Chronic sinusitis may be medically managed with topical nasal steroids and antibiotics. Patients who have failed medical management may benefit from surgical intervention in the form of nasal lavage, the creation of a nasoantral window, or, more recently, functional endoscopic nasal surgery. 11 Chronic sinusitis is also a component of Kartagener’s syndrome. This syndrome also includes bronchiectasis and situs inversus and is due to a defective ciliary cytoskeleton lacking dynein arms. 12 - 14 Occasionally, pathologists will be asked to perform ultrastructural assessment of nasal biopsies in cases suspicious of Kartagener’s syndrome.

Mucous Impaction

Clinical Features
Mucous impaction is an uncommon inflammatory lesion that has also been called inspissated mucus or snotoma. 15 It is most commonly seen in children and young adults with a long-standing history of chronic rhinosinusitis of any etiology. It is a pseudoneoplastic process resulting from the impaction of a large amount of mucus within the maxillary antrum. This mucous mass produces opacification of the antrum, usually without sinus wall destruction or invasion. However, rare cases, similar to a mucocele, may present with pressure erosion and destruction of bone.

Pathologic Features
Grossly, the mass has a translucent appearance and a gray to pink color. Microscopically, it consists of mucus containing numerous neutrophils, lymphocytes, and plasma cells admixed with desquamated respiratory-type epithelium.

Differential Diagnosis
The differential diagnosis of mucous impaction includes myxoma, well-differentiated mucinous adenocarcinoma, and embryonal rhabdomyosarcoma. The typical clinical history, the lack of destruction or invasion of the maxillary bone, the presence of degenerating inflammatory cells, and the absence of neoplastic cells should argue against the diagnosis of a neoplasm.

Treatment and Prognosis
This is a pseudoneoplastic condition with an excellent prognosis. The treatment of choice is removal of the impacted mucus with treatment of the underlying inflammatory process. Rarely, laryngeal stridor may occur due to impacted nasal/nasopharyngeal mucous secretions in the larynx. 16

Sinonasal Inflammatory Polyps

Clinical Features
Sinonasal inflammatory polyps are nonneoplastic proliferations of the sinonasal mucosa composed of epithelial and stromal elements. The pathogenesis of these lesions is uncertain; however, mucosal edema and inflammation, cytokine secretion, and collagen synthesis stimulated by eosinophils have all been implicated. 17, 18 They have been divided into inflammatory nasal and antrochoanal polyps.
Inflammatory polyps are most often seen in adults with a long-standing history of chronic rhinitis accompanied by allergy, asthma, aspirin intolerance, or diabetes mellitus. They are multiple and often present as bilateral masses arising from the lateral nasal wall. Symptoms at presentation include nasal obstruction, rhinorrhea, and headaches. Radiologic studies usually reveal a soft-tissue mass with air-fluid levels occupying the nasal cavity or paranasal sinuses. Large inflammatory polyps can destroy bone and extend into the nasopharynx, orbit, and cranial cavity. 19 - 21 Inflammatory nasal polyps develop in approximately 20% of children with cystic fibrosis, and in some, they may be the initial clinical manifestation of the disease. Children with inflammatory nasal polyps should be investigated for cystic fibrosis.
Unlike inflammatory polyps, polyps of the antrochoanal type are more frequently seen in children, 22, 23 although this finding has not been reproduced in other studies. 24 These lesions arise in the maxillary antrum and secondarily extend into the nasal cavity. 25 Approximately 90% are solitary. They are the least common nasal polyps. 24, 26

Pathologic Features
Inflammatory polyps can measure up to several centimeters in diameter and have a myxoid or gelatinous appearance. Most have a broad stalk. Histologically, they are lined with respiratory epithelium with a variably thickened basement membrane. 27 The epithelium often exhibits some degree of squamous metaplasia. In some cases, this metaplastic epithelium shows a degree of atypia suggestive of dysplasia. 28 The stroma is abundant and highly edematous or myxoid and contains a mixed inflammatory infiltrate composed of eosinophils, lymphocytes, and plasma cells ( Fig. 3-1 A ). Sometimes Charcot-Leyden crystals associated with abundant eosinophils may be seen. In cases associated with infection, neutrophils may be present in large numbers. Epstein-Barr virus (EBV) genome has been demonstrated in mucosal lymphocytes of Chinese patients with nasal polyposis. 29 The stroma contains a variable number of fibroblasts and blood vessels. Typically, inflammatory polyps do not contain seromucinous glands. Secondary changes include surface ulceration, fibrosis, infarction, granulation tissue, deposition of a dense amyloid-like material, cartilaginous or osseous metaplasia, glandular hyperplasia, and, sometimes, granuloma formation. Polyps associated with cystic fibrosis contain fewer eosinophils and lack basement membrane thickening and submucosal hyalinization (see Fig. 3-1 B ). 30 The mucin in cystic fibrosis is acidic and stains blue or purple with Alcian blue/periodic acid–Schiff stain, in contrast to inflammatory polyps of the usual type, which contain neutral mucin that stains pink/magenta.

Figure 3-1 A , Inflammatory polyp showing thickened basement membrane, edematous stroma, and a mixed inflammatory infiltrate comprised predominantly of eosinophils and plasma cells. B , Inflammatory polyp in cystic fibrosis. Note the lack of thickening of the glandular basement membrane.
Antrochoanal polyps exhibit a long fibrous stalk. Histologically, they lack the thick basement membrane and the prominent inflammatory infiltrate of inflammatory polyps. 0310, 22 The stroma is variable but tends to be fibrotic and contains large vascular spaces with scant glandular elements. 24

Differential Diagnosis
Many polyps contain spindle or polygonal stromal cells with slightly hyperchromatic nuclei. However, in some cases, the number and the degree of atypia seen in these fibroblasts ( Fig. 3-2 ) are sufficient to raise the possibility of a malignant tumor. 32, 33 In most cases, the differential diagnosis elicited is an embryonal rhabdomyosarcoma. The typical clinical history, the presence of a heavy inflammatory infiltrate, the lack of hypercellularity, and the absence of mitotic activity argue against this diagnosis. The atypical stromal cells are preferentially concentrated in the subepithelial region and in the vicinity of blood vessels. These atypical cells are immunoreactive to actin, suggesting a myofibroblastic derivation, and closely resemble radiation fibroblasts.

Figure 3-2 Atypical fibroblast in an inflammatory polyp. The nucleus is hyperchromatic, but there is no associated hypercellularity or mitotic activity.
Other lesions that should be separated from sinonasal polyps are nasopharyngeal angiofibroma, schneiderian papilloma, and squamous cell carcinoma. Nasopharyngeal angiofibroma contains stromal myofibroblasts with a spindle or stellate shape admixed with thick abnormal vessels not seen in polyps. Nasal polyps also lack the thick fibrovascular papillary cores, the inverted growth pattern, the oncocytic epithelium, and the intraepithelial microcysts of schneiderian papillomas. The degree of atypia or invasion seen in squamous cell carcinoma is also absent.

Treatment and Prognosis
The treatment of sinonasal polyps is surgical resection. Identification and treatment of etiologic factors are necessary to prevent recurrences. Antrochoanal polyps may also recur if the stalk is not completely resected.

Myospherulosis is a rare iatrogenic pseudomycotic lesion occurring in the nasal cavity, paranasal sinuses, middle ear, and soft tissues. 34 - 36 Typically, patients with myospherulosis have a history of surgery followed by packing of the nasal cavity with petrolatum-based ointment before the development of a nasal mass. 34, 36 Histologically, there is a prominent fibrous and chronic inflammatory reaction with foreign body–type giant cells surrounding pseudocystic spaces. These spaces contain saclike structures with a thick dark wall ( Fig. 3-3 ) and are referred to as parent bodies with enclosed fungus-like endobodies or spherules that are simply degenerating erythrocytes. Fungal infections can be ruled out with a methenamine silver stain. 34

Figure 3-3 Myospherulosis of the sinonasal tract. Irregular cystic space containing larger parent bodies, which are enveloping smaller spherules or endobodies.
(Courtesy of Dr. Bruce Wenig, Beth Israel Medical Center, New York, NY.)

Granulomatous Diseases

Tuberculosis in the upper respiratory mucosa is usually a manifestation of disseminated disease. 37, 38 The most common presentation is that of an ulcer or a polyp involving the septum and the inferior turbinate. In some cases, septal perforation can be seen. Microscopically, there are numerous poorly formed granulomas. Caseous necrosis is relatively infrequent, and it is rare to find microorganisms in an acid-fast stain. The differential diagnosis of tuberculosis in the sinonasal tract includes other granulomatous diseases and Wegener’s granulomatosis. The diagnosis is made by clinicopathologic correlation and cultures. The treatment consists of multiagent chemotherapy including a combination of isoniazid, rifampicin, streptomycin, and ethambutol.

Sarcoidosis is a multisystemic disorder that most often affects the lung and mediastinal lymph nodes. Rarely, it also involves the upper respiratory tract, including the nasal cavity and paranasal sinuses. 39 - 41 Grossly, the nasal mucosa is dry and crusty and is involved by yellow submucosal nodules. Histologically, the mucosa reveals numerous noncaseating epithelioid and giant cell granulomas. Stains for acid-fast bacilli are negative, and there is no vasculitis or necrosis. 40 The differential diagnosis includes other granulomatous diseases, especially cholesterol granulomas, tuberculosis, leprosy, and Wegener’s granulomatosis. Virtually all patients with sinonasal sarcoidosis have pulmonary and hilar nodal involvement. 42 The treatment of sarcoidosis depends on the clinical manifestations of the disease and sites involved. Oral prednisone is usually the drug of choice. Chlorambucil may also be used when corticosteroids fail or are contraindicated.


Clinical and Pathologic Features
Leprosy is a slowly progressive disease caused by Mycobacterium leprae . The infection affects the skin and peripheral nerves and results in disabling deformities. This infection has largely disappeared in the United States and most of Europe but still affects millions of people in underdeveloped countries. Leprosy is a disease with clinicopathologic manifestations determined by the host’s cellular immune response. Two clinical forms of the disease occur, depending on whether the host is capable of mounting a T cell–mediated immune response or is anergic. Those with an immune response develop tuberculoid leprosy. Anergy results in lepromatous leprosy.
M. leprae is transmitted from person to person via aerosols that originated from lesions in the upper respiratory tract. The vast majority of the lesions observed in the nasal cavity are of the lepromatous type and consist of large numbers of macrophages filled with massive quantities of acid-fast bacilli. 43, 44 Fibroblasts, neutrophils, eosinophils, and plasma cells can also be present. Occasionally, some of these cells are seen along nerves that show Schwann cells containing large numbers of bacilli. The bacilli may also be found within endothelial cells and fibroblasts, mucous glands and ducts, and vascular lumens. The bacilli are highlighted with the Fite-Faraco modification of the Ziehl-Nielsen stain.

Differential Diagnosis
The main differential diagnosis of tuberculoid leprosy includes sarcoidosis, tuberculosis, certain fungal infections, and Wegener’s granulomatosis. All these latter entities have significantly different epidemiologic findings, clinical manifestations, and serologic and microbiological tests that should allow their distinction from tuberculoid leprosy. Rhinoscleroma may resemble lepromatous leprosy, but in leprosy, the Fite-Faraco stain should demonstrate the presence of large numbers of acid-fast organisms.

Treatment and Prognosis
Dapsone, rifampin, clofazimine, and ethionamide are the main drugs used to treat leprosy. Adequate treatment requires the use of most of these drugs for several years. Supportive care is also important in reducing morbidity and injuries leading to blindness and mutilation. The prognosis depends on clinical stage of the disease, type of disease, availability of effective drugs, adherence to treatment, and supportive care measures.


Clinical Features
Rhinoscleroma is a chronic granulomatous disease that is endemic in parts of Central and South America, North and Central Africa, and certain areas of Eastern Europe. 45 - 48 It is uncommon in North America. 49 Rhinoscleroma is caused by the gram-negative rod Klebsiella rhinoscleromatis and affects primarily the nasal cavity and nasopharynx. 50, 51 Involvement of the lip, oropharynx, and palate is also common. In severe cases, the infection causes bone destruction and nasal obstruction with extension into the paranasal sinuses, orbit, middle ear, larynx, and tracheobronchial tree. Clinically, rhinoscleroma is characterized by three phases: rhinitic, florid, and fibrotic. The initial symptoms resemble a common cold, but in fully developed disease, there are also dysphonia, aphonia, and anosmia. Clinically, anesthesia of the soft palate and hypertrophy of the uvula should suggest the diagnosis of rhinoscleroma. In advanced cases, the destruction of the nasal cartilage with the formation of nodules causes a severe deformity referred to as Hebra’s nose. 48 Recently, rhinoscleroma has been described as an opportunistic infection in HIV-affected individuals. 52

Pathologic Features
Pathologically, rhinoscleroma is also characterized by three phases: rhinitis or catarrhal, florid or granulomatous, and fibrotic. In the catarrhal phase, the tissue changes are nonspecific and consist of abundant neutrophils, cellular debris, and granulation tissue. In the granulomatous phase, rhinoscleroma is characterized by pseudoepitheliomatous hyperplasia of the overlying mucosa and a dense chronic inflammatory infiltrate composed of lymphocytes, plasma cells with numerous Russell’s bodies, and large macrophages with clear vacuolated cytoplasm. These macrophages are referred to as Mikulicz cells. The microorganisms are present within the cytoplasm of these macrophages and can be demonstrated by a Warthin-Starry silver stain, a Giemsa stain, or a Gram stain. In inconclusive cases, the bacteria can be identified in 1- to 2 mm–thick sections stained with toluidine blue. In the final fibrotic phase, there are variable degrees of fibrosis and the Mikulicz cells are absent or are difficult to identify.

Differential Diagnosis
The differential diagnosis of rhinoscleroma includes leprosy, sarcoidosis, tuberculosis, mycotic infections, and sinonasal sinus histiocytosis with massive lymphadenopathy ([SHML] Rosai-Dorfman disease). Clinicopathologic features, special stains, and microbiologic cultures are helpful in excluding other granulomatous infections. In leprosy, the organisms are acid fast and can be demonstrated by the Fite-Faraco stain. Rhinoscleroma lacks the large atypical cells with emperipolesis that show positive S-100 protein immunostaining, seen in SHML.

Treatment and Prognosis
The initial treatment of rhinoscleroma consists of prolonged antibiotic therapy using doxycycline, ciprofloxacin, ceforanide, rifampicin, or streptomycin. Antibiotic therapy is generally effective. Surgery and laser ablation of tissue deformities caused by fibrous masses in the late fibrous phase of rhinoscleroma may be considered. However, these corrective procedures can only be used after the patient is clinically and histologically free of disease, and cultures have been negative.

Fungal Diseases

Clinical Features
Sinonasal mycotic disease can be clinically classified as acute fulminant/invasive sinusitis, chronic noninvasive/chronic indolent, “fungus ball” or mycetoma, and allergic. 53, 54 According to a recent review, the most common fungal sinusitis is allergic. 54 Occasionally, the histologic distinction between invasive fungal disease and a fungus ball or mycetoma is difficult or impossible and the distinction needs to be made on clinical and radiologic grounds. The histologic diagnosis of sinonasal mycotic infections often requires a heightened suspicion. In chronic noninvasive fungal infections, the mucosa shows a nonspecific inflammatory reaction and often the use of Gomori methenamine silver and periodic acid–Schiff stains is required to identify the hyphae. Chronic noninvasive infections have been associated with Aspergillus spp, 55 Pseudallescheria boydii , 56 Bipolaris spp, 57 Sporothrix schenckii , 58 Schizophylum commune , 59 and, rarely, Mucor. 60
Acute fulminant or angioinvasive fungal infections are common in immunocompromised hosts, particularly those with HIV infection and those with hematologic malignancies. 0620, 59 Acute fungal infections are characterized by acute inflammation, tissue necrosis, and numerous hyphae invading blood vessels ( Fig. 3-4 ). Mucormycosis (phycomycosis) is usually seen in association with poorly controlled diabetes mellitus, although it can also be seen in noncompromised hosts. 63 It is an aggressive infection that can quickly extend into soft tissues, orbit, and brain. Recognition is based on the identification of broad nonseptate hyphae. Other fungi capable of causing invasive fungal sinusitis include Aspergillus , 64 - 66 Candida spp, 67 cryptococcosis, 68 Curvularia lunata , 69 P. boydii , 62 and Alternaria spp. 70

Figure 3-4 A , Invasive aspergillosis with tissue necrosis and vascular thrombosis. B , Gomori methenamine silver stain demonstrating branching, septated hyphae with vascular invasion typical of invasive Aspergillus .
Allergic fungal sinusitis is a noninvasive fungal pansinusitis that occurs in immunocompetent individuals with a long-standing history of atopy, elevated levels of total immunoglobulin E, and peripheral eosinophilia. 71 Initially, this condition was attributed to infection with Aspergillus spp because of the presence of dichotomous fungal hyphae and the histologic similarities to allergic bronchopulmonary aspergillosis. 72 Subsequent studies, however, have demonstrated that nearly 80% of cases of allergic fungal sinusitis are due to members of the Dematiaceae family, with the most common genus being Bipolaris followed by Curvularia, Exerohilum, Alternaria , and Cladosporium . 0740, 71
Rhinosporidiosis is a chronic, superficial, mucocutaneous infection primarily involving the nasal cavities, nasopharynx, and oral cavity. 75 This infection, initially thought to be caused by Rhinosporidium seeberi , now seems to be caused by the waterborne organism cyanobacterium Microcystis aeruginosa . 76 It is endemic in India and Sri Lanka, where 90% of all infections occur. Rarely, cases are seen in the United States. 77 Clinically, the lesions are seen as friable polyps or papillomas.

Pathologic Features
Histologically, allergic fungal sinusitis consists of abundant pale eosinophilic or basophilic allergic mucin with a laminated appearance. The mucin contains numerous eosinophils, plasma cells, and lymphocytes admixed with cellular debris, sloughed respiratory epithelial cells, and edematous respiratory mucosa. Charcot-Leyden crystals with clusters of degenerated eosinophils are constant microscopic features. Fungal hyphae with dichotomous 45-degree branching and rare yeast forms are identified with Gomori methenamine silver or Fontana-Masson stain. 72, 74 No fungal balls or invasion of bone or mucosa is present. Because of morphologic similarities of the fungi causing allergic fungal sinusitis, cultures are mandatory for the exact identification of the organism responsible. Fungus balls are characterized by the presence of large numbers of noninvasive fungal colonies with pale centers. 54
Microscopically, rhinosporidiosis is characterized by hyperplastic respiratory or squamous epithelium accompanied by a lymphoplasmacytic infiltrate. The subepithelial stroma contains numerous cysts or sporangia ranging in size from 100 to 300 µm with thick walls ( Fig. 3-5 ). The sporangia contain numerous endospores with a characteristic arrangement of immature and mature forms. The immature forms are small, whereas the mature forms are larger and contain eosinophilic cytoplasmic globules. The diagnosis rests on the identification of these structures in the surgical material or by smear preparations. 78

Figure 3-5 Rhinosporidiosis is characterized by hyperplastic papillary epithelium ( A ) with a prominent submucosal chronic inflammatory infiltrate ( B ) and sporangia containing numerous endospores ( C ).
Recently, Tadros and colleagues 79 described a case of fungal infection involving the right maxillary sinus in a 33-year-old woman with sickle cell disease caused by Scedosporium apiospermum . This is an additional case of hyalohyphomycosis, an emerging mycosis in immunodeficient individuals caused by nonpigmented septate hyphae that closely resemble P. boydii . Recognition of this infection is important because Scedosporium spp are resistant to the most commonly used antimycotic agents, such as amphotericin B.

Differential Diagnosis
The differential diagnosis of fungal infections in the sinonasal tract includes a large number of non-neoplastic and neoplastic diseases. Sinonasal tuberculosis is generally accompanied by pulmonary disease and a positive skin test. Microscopically, there are large numbers of granulomas with caseous necrosis that are not seen in fungal infections. Gomori methenamine silver and acid-fast stains are helpful in revealing the responsible organism. Wegener’s granulomatosis may be difficult to exclude based on morphologic grounds alone because vasculitis may be a focal finding in nasal biopsies. However, most patients with Wegener’s granulomatosis also have renal manifestations and serologic cytoplasmic antineutrophilic and myeloperoxidase antibodies. Sinonasal T-cell or natural killer–cell lymphomas may present with extensive tissue destruction with a polymorphous infiltrate involving the sinonasal tract. They also reveal the presence of an atypical lymphoid infiltrate not seen in sinonasal mycotic infections. Silver and periodic acid–Schiff stains may demonstrate the fungal organisms. Acute fulminant fungal infections may present with similar clinical features to those of idiopathic midline destructive disease, a controversial disorder of doubtful existence.

Treatment and Prognosis
The treatment and prognosis of sinonasal fungal disease vary depending on the type of infection, causative organisms, and underlying medical conditions. 80, 81 The treatment of most noninvasive fungal disease usually consists of sinusotomy and curettage of all necrotic and diseased tissue. The invasive forms, especially opportunistic mycosis associated with diabetes mellitus or immunosuppression, require radical surgical débridement and intravenous amphotericin B. In those affected by mucormycosis, surgery has an important role in removing devitalized tissues because the vascular thrombosis present in necrotic tissues interferes with the delivery of amphotericin B. Surgery is also the mainstay in the treatment of chromoblastomycosis because the fungus shows little response to amphotericin B or flucytosine chemotherapy. Amphotericin B plays a major role in the treatment of invasive aspergillosis, mucormycosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, paracoccidioidomycosis, and phaeohyphomycosis. Miconazole is the drug of choice in the treatment of P. boydii . 81 Surgical resection is the primary treatment of rhinosporidiosis, whereas chemotherapy may play a role in the management of multiple recurrences. In some infections, such as blastomycosis, the role of surgery is more limited and is used only to establish a definitive diagnosis and to drain accumulations of pus.
The treatment of allergic fungal sinusitis varies according to clinical features and extent of disease. 80 The prognosis of noninvasive fungal infections in the sinonasal tract is excellent. The invasive forms have a guarded prognosis. In the case of mucormycosis, the most important determinant of survival is the underlying disorder. Patients with no underlying disease had a survival rate of approximately 75%, whereas those with leukemia or renal disease had a survival rate of 20%. 80 Adequate chemotherapy is also important in patient outcome; the addition of amphotericin B in the management of diabetic patients with mucormycosis has increased the survival rate from 37% to 79%.

Non-Neoplastic Lesions, Including Cysts and Hamartomas

Necrotizing Sialometaplasia
Necrotizing sialometaplasia is rare in the sinonasal tract. This process is characterized by necrosis of the nasal seromucinous glands with secondary squamous metaplasia. It is usually seen after surgery or trauma in the sinonasal region. 82, 83 The metaplastic squamous cells may show focal nuclear atypia, but there is overall maintenance of the lobular acinar architecture and the individual acini maintain smooth contours. 84 The main significance of necrotizing sialometaplasia is its recognition and separation from squamous cell carcinoma and mucoepidermoid carcinoma. These tumors have a more infiltrative appearance, and, in the case of mucoepidermoid carcinoma, variable numbers of mucous and intermediate cells can also be identified. Rare cases may recur 85 or can obscure an underlying squamous cell carcinoma. 86

Mufarrij and colleagues 87 reported a case of localized amyloidosis in the sinonasal tract. The patient had no evidence of systemic disease. The morphologic appearance and stains were typical of localized amyloidosis at other sites.

Paranasal Sinus Mucocele

Clinical Features
Paranasal mucoceles are chronic, non-neoplastic cystic lesions secondary to obstruction of the sinus outlet. 88, 89 They occur more frequently in the ethmoid sinuses and frontal sinus region (90%) and less commonly in the maxillary and sphenoid regions. In most instances, the blockage is secondary to an inflammatory or allergic process, although cystic fibrosis, trauma, or neoplastic processes have also been implicated. 90 - 92 The symptoms associated with these lesions vary depending on the location, size, and degree of extension into adjacent structures and include facial pain and swelling, proptosis, rhinorrhea, and nasal obstruction. 93 Radiologically, there is opacification of the affected sinus; in long-standing cases, erosion with destruction or sclerosis of the adjacent bone can also be present. 91, 94 - 96

Pathologic Features
The gross appearance is characterized by a cyst filled with a mucoid or gelatinous secretion. Microscopically, the cysts are lined with flattened pseudostratified ciliated columnar epithelium accompanied by secondary changes such as fibrosis, granulation tissue, and recent and remote hemorrhage with cholesterol granulomas. In some instances, the epithelium exhibits a variable degree of squamous metaplasia. Sinus mucoceles have been divided into two groups: internal and external types. In the internal type, the cyst herniates into the submucosal tissues of the bony wall of the sinuses, whereas in the external type the cyst extends into the cranial cavity or subcutaneous tissues.

Differential Diagnosis
The clinical, radiologic, and pathologic features can closely simulate those of a neoplasm. The pathologic diagnosis of sinus mucocele should be closely correlated with the clinical history and radiologic and surgical findings. The characteristic clinical and radiologic findings and the absence of tumor cells in pathologic material should exclude the possibility of a neoplasm.

Treatment and Prognosis
The treatment of mucocele consists of surgical relief of the sinus obstruction and decompression of the mucocele. This may be accomplished by endoscopic surgery or by removal of the medial maxillary wall.

Respiratory Epithelial Adenomatoid Hamartoma

Clinical Features
Respiratory epithelial adenomatoid hamartoma is a rare lesion characterized by an adenomatoid proliferation of respiratory ciliated cells occurring in the nasal cavity, sinuses, and nasopharynx.
This glandular process is derived from the schneiderian or surface nasopharyngeal epithelium, not from seromucinous glands. Most patients are males in the fifth or sixth decade of life. In the study by Wenig and Heffner, 97 there were 27 males and four females with a median age of 58 years. The symptoms at presentation are nonspecific and include rhinosinusitis, allergies, nasal obstruction, stuffiness, septum deviation, and epistaxis. At physical examination, the lesion appears as a polypoid mass most commonly arising in the posterior septum. Involvement of the lateral wall, middle meatus, and inferior turbinate is less common.

Pathologic Features
Under low-power examination, these lesions have a polypoid appearance. They are characterized by a benign proliferation of hamartomatous glands lined with ciliated respiratory epithelium, and surrounded by a thick, eosinophilic, hyalinized basement membrane ( Fig. 3-6 ). 97 The glands are round or oval and vary in size from small to large with a dilated appearance. The glandular lumina contains mucinous or amorphous material. Often the glandular lining is in direct contiguity with the surface epithelium, which occasionally reveals mucous metaplasia. The stroma surrounding glands is often edematous and contains a mixed inflammatory infiltrate resembling the stroma of inflammatory polyps. Infrequently the larger glands may be intermixed with bland, smaller, uniform glands, which, on rare occasions, may compose the entire lesion (see Fig. 3-6 C and D ).

Figure 3-6 Respiratory epithelial adenomatoid hamartoma. A and B , The lesion consists of a proliferation of hamartomatous glands lined with ciliated columnar epithelium that is continuous with the surface. The glands can be large ( A and B ) or small ( C and D ). C , Small gland proliferation may mimic infiltrating well-differentiated adenocarcinoma. Note the lack of atypia, back-to-back cribriform pattern, and desmoplastic stromal reaction. D , High power demonstrates glandular epithelium with no cytologic atypia.

Differential Diagnosis
The most important differential diagnosis is a well-differentiated adenocarcinoma. Respiratory epithelial adenomatoid hamartoma does not have the complex glandular growth with a back-to-back cribriform pattern and lacks the infiltrative growth and desmoplastic stroma of well-differentiated adenocarcinomas. Sinonasal adenocarcinomas exhibit aggressive growth with invasion of bone and soft tissues, which is not seen in respiratory epithelial adenomatoid hamartoma. These lesions may also be misdiagnosed as schneiderian papilloma. However, respiratory hamartomas are not lined with squamous or cylindrical epithelium with intraepithelial mucous cysts, as is the case with papillomas.

Treatment and Prognosis
Respiratory epithelial adenomatoid hamartoma is a benign condition with no risk of recurrence, persistence, or progression. The treatment should be conservative local excision or polypectomy.

Nasal Chondromesenchymal Hamartoma

Clinical Features
Nasal chondromesenchymal hamartoma is a rare tumor-like lesion of the nasal cavity composed of chondroid, stromal, and cystic areas. 98 This lesion has morphologic similarities to the so-called chondromesenchymal hamartoma of the chest wall. The lesion may present within weeks of birth and usually by 3 months of age, although older children and adults may be affected. The oldest patient reported in the literature was 69 years of age. 99 The lesion has a predilection for male children. The most common presentation is that of a nasal mass, often accompanied by respiratory difficulty. The septum and middle turbinate are reported to be common sites of origin. The mean size in the series by McDermott and colleagues 98 was 3.6 cm; however, Ozolek and colleagues 99 reported a mass that was 8 cm. Involvement of paranasal sinuses and erosion of the cribriform plate with extension into the cranial cavity are frequent computed tomographic findings.

Pathologic Features
The lesions are composed of irregular islands of mature hyaline and fibrocartilage that give it a lobulated appearance ( Fig 3-7 ). The cartilaginous nodules are surrounded by bland spindle cells. The stromal component may be loose and myxoid or dense and fibrocollagenous. The cystic areas may be composed of blood-filled cystic spaces reminiscent of aneurysmal bone cyst or of microcysts within the myxoid areas. Osteoclast-like multinucleated giant cells may be present at least focally. Uncommon findings are hemorrhagic spaces suggestive of aneurysmal bone cyst, “chicken-wire” calcifications, fibro-osseous areas with immature woven bone suggestive of fibrous dysplasia, perivascular hyalinization, and mitotic activity. Some of the cartilaginous nodules may be lined with respiratory epithelium. One of the cases reported by Ozolek and colleagues 99 also showed glandular epithelial and adipose tissue components. Immunohistochemistry shows that the stromal spindle cells express smooth muscle actin and the chondroid cells express S-100 protein.

Figure 3-7 Nasal chondromesenchymal hamartoma. A , Chronically inflamed sinus mucosa overlying nodules of eosinophilic matrix and cellular areas interspersed with bony trabeculae. B , Bony trabeculae with chondromyxoid nodules. C , Alternating hypercellular and hypocellular myxoid nodules. D , Osteoclast-like giant cells and bone within hypercellular and hypocellular eosinophilic nodules.
(Courtesy of Dr. John A. Ozolek, University of Pittsburgh Medical Center, Pittsburgh, PA.)

Differential Diagnosis
The main differential diagnoses of nasal chondromesenchymal hamartoma are cartilaginous neoplasms of the sinonasal tract. Awareness of this lesion, the patient’s age, and the presence of noncartilaginous elements admixed with the cartilage nodules in their characteristic architecture should exclude a primary cartilaginous neoplasm.

Treatment and Prognosis
The treatment of nasal mesenchymal hamartomas is surgical resection. Complete resection is difficult and often necessitates a combined intranasal-neurosurgical approach. Erosion of the adjacent bone with intracranial extension was seen in one of the cases reported by McDermott and colleagues, 98 while two of their seven patients had residual disease. Additional surgical resections are indicated in those patients with continued growth of the residual mass. No recurrences or deaths due to this lesion have been reported.

Glial Heterotopia and Encephalocele

Clinical Features
Glial heterotopia represents a congenital displacement of neuroglial tissue and is considered a variant of encephalocele rather than a true neoplasm. 100, 101 Generally, it presents at birth or within the first few years of life. The most common locations are the subcutaneous tissues of the nose (60% extranasal), nasal cavity (30% intranasal), and, less frequently, the ethmoid sinus, palate, middle ear, tonsils, and pharyngeal area. Dumbell-shaped lesions with involvement of the subcutaneous tissues and subjacent nasal cavity (extranasal and intranasal) may be seen. Radiologic studies are indicated to exclude communication with the cranial cavity. 1030, 100
Encephalocele is a developmental anomaly closely related to glial heterotopia. When located in the nasal cavity, encephalocele is virtually indistinguishable from glial heterotopia. 100, 102 By definition, encephalocele maintains a connection with the central nervous system via a defect in the cribriform plate. Meningitis can be a serious complication. Before any biopsy is attempted in children with a mass in the upper nasal cavity or the base of the external nose, communication with the central nervous system should be excluded.

Pathologic Features
Microscopically, glial heterotopia is composed of a mixture of mature astrocytes, gemistocytic astrocytes, glial fibers, and fibrovascular connective tissue. Neuronal elements are usually absent or scant, although on rare occasions they can be abundant. 104 In long-standing lesions, the degree of fibrosis may obscure the true nature of the lesion. Immunohistochemical stains for glial fibrillary acidic protein and S-100 protein can be helpful in confirming the diagnosis. 105 Microscopically, encephaloceles consist of a mixture of neural and glial tissues. 101 - 103, 106

Differential Diagnosis
The differential diagnosis of glial heterotopia includes typical encephalocele, nasal teratomas, and a true glioma. The lack of communication with the cranial cavity will exclude an encephalocele, and the absence of tissues other than glial elements should exclude teratoma. True gliomas complicating glial heterotopia have been described. 107, 108
The differential diagnosis of encephalocele includes glial heterotopia, nasal teratoma, and also a true glioma. The characteristic clinical and radiologic findings should distinguish this lesion from other developmental anomalies and cystic teratomas.

Treatment and Prognosis
The prognosis for children with encephalocele and nasal glial heterotopia is excellent after resection. In the case of glial heterotopia, simple excision is sufficient. In encephalocele, a craniotomy and repair of the craniofacial defect are required. Recurrences of glial heterotopia are due to incomplete resection.

Dermoid Cyst
Dermoid cyst is a non-neoplastic lesion that probably represents another developmental anomaly related to the midline closure of the face. 103 It is most frequently found as a mass in the midline of the bridge of the nose of infants, but may also present as a fistula. It may also be found in the nasopharynx, where the term hairy polyps has been used. Most cases show erosion of the underlying nasal bones. Microscopically, dermoid cysts are lined with keratinizing squamous epithelium and frequently contain hair follicles and sebaceous glands in the cyst wall. No neural elements are present. Bacterial contamination and cyst rupture may cause a prominent inflammatory reaction in the adjacent soft tissues. These lesions should be distinguished from cystic teratomas; the characteristic clinical and radiologic features of dermoid cyst and the absence of other tissues including those of endodermal origin are helpful in making this distinction. Treatment is complete resection, including excision of any discharging fistulous tract. 109

Tornwaldt’s Cyst
Tornwaldt’s cyst is a developmental cyst lined with ciliated respiratory epithelium, usually located in the midline, in the posterosuperior wall of nasopharynx surrounded by the adenoids. It can become infected and present as a mass or may be discovered incidentally upon radiologic imaging. 110 With the advent of head and neck magnetic resonance imaging, its existence appears to be more common than previously thought. 111 The patients are usually 15 to 30 years of age and may be of either sex. Surgery is the treatment of choice in symptomatic cases.

Lymphoid Hyperplasia
Clinically significant lymphoid hyperplasia in the sinonasal region and nasopharynx is relatively uncommon. 112 Rimarenko and Schwartz 113 described an example of this condition that simulated a nasal polyp. The histopathologic appearance of lymphoid hyperplasia in the sinonasal tract is similar to that seen in lymph nodes ( Fig. 3-8 A ). It is characterized by the presence of secondary germinal centers composed of a mixture of tingible-body macrophages, small cleaved lymphocytes, large noncleaved cells, and large transformed lymphocytes admixed with plasma cells and numerous mitotic figures (see Fig. 3-8 B ). The presence of a monomorphic cellular infiltrate and cytologic atypia should be viewed with suspicion. Care should be taken to exclude a neoplasm with a prominent lymphoid infiltrate or a lymphoepithelioma-type carcinoma, particularly in the nasopharynx. Rarely, Castleman disease or angiolymphoid hyperplasia can also present as a nasopharyngeal polypoid tumor. 114 Rare cases of plasma cell granuloma and inflammatory pseudotumors have also been reported in this location. 115 - 117

Figure 3-8 A , Lymphoid hyperplasia of the nasopharynx. There is formation of secondary germinal centers with prominent mantle zones. B , Reactive germinal center with numerous transformed follicular center cells, a high mitotic rate, and numerous tingible body macrophages. Note the presence of dark and pale areas.
Recently there have been reports of HIV-infected patients presenting with nasal obstruction, epistaxis, hearing loss, and sore throat due to enlarged nasopharyngeal and palatine tonsils. 118, 119 The nasopharyngeal biopsy and tonsillectomy specimens in this group of patients reveal moderate to marked follicular and interfollicular hyperplasia, with attenuated or partially lost mantle zones. Some cases have monocytoid B-cell hyperplasia and interfollicular zone expansion by aggregates of immunoblasts and plasma cells. Additional findings were infiltration of the germinal centers by small lymphocytes, resulting in fragmentation of the hyperplastic germinal center, a phenomenon known as follicle lysis, and follicular involution resulting in prominence of blood vessels accompanied with infiltration by sheets of plasma cells and immunoblasts. 118, 119 Wenig and colleagues 119 described the presence of multinucleated giant cells immunoreactive for CD68 and S-100 protein containing HIV p24 protein clustered adjacent to the surface squamous epithelium. The constellation of these morphologic findings was considered virtually diagnostic of HIV infection by these authors. 119

Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman Disease)

Clinical Features
SHML is a rare idiopathic disorder of histiocytes that presents primarily with massive enlargement of cervical lymph nodes 120, 121 ; however, extranodal disease with involvement of the nasal cavity, orbit, and other head and neck sites is common. 122 - 124 The mean age at onset is approximately 20 years, and mild upper respiratory infection often precedes the development of cervical lymphadenopathy. Involvement of the sinonasal tract is often accompanied by nodal disease or extranodal lesions in other head and neck sites. In approximately 20% of cases of sinonasal SHML, the upper aerodigestive passages are the only sites of disease. Laboratory manifestations include anemia, red-cell autoantibodies, elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. 123, 124

Pathologic Features
Sinonasal SHML presents as nasal polyps or nodules with partial obstruction of the nasal cavity and is histologically characterized by a diffuse polymorphic infiltrate composed of numerous plasma cells, often with abundant Russell’s bodies, small lymphocytes, polymorphs, eosinophils, and characteristic histiocytes with large vesicular nuclei, sometimes showing mild pleomorphism and small but distinct nucleoli ( Fig. 3-9 A ). The cytoplasm of these histiocytes is abundant and clear or eosinophilic and often contains numerous intact lymphocytes, many of them within vacuoles. This phenomenon has been referred to as emperipolesis or lymphophagocytosis. Plasma cells, polymorphs, and erythrocytes can also be seen within these histiocytes. Fibrosis can be a prominent finding in extranodal disease and may hamper the recognition of the characteristic histiocytes of SHML. Lymphoid aggregates resembling a lymph node are also commonly seen in the nasal mucosa. S-100 protein (see Fig. 3-9 B ), CD68, and Mac-387 antibodies are expressed by these cells. 1260, 122

Figure 3-9 A , Sinonasal Rosai-Dorfman disease. A mixed inflammatory cell infiltrate containing large histiocytes with vesicular nuclei ( inset ). B , The histiocytes are characteristically S-100 protein positive, whereas the phagocytosed intracytoplasmic inflammatory cells are negative.

Differential Diagnosis
The differential diagnosis of SHML includes rhinoscleroma, leprosy, Langerhans cell granulomatosis, and non-Hodgkin’s lymphoma (NHL). Separation of SHML from these entities is based on recognition of its characteristic morphologic features and the immunohistochemical profile of the histiocytes. The S-100 protein–positive, atypical, large histiocytes showing emperipolesis are the hallmark of SHML and are absent in rhinoscleroma, leprosy, and NHL. The foamy histiocytes of rhinoscleroma contain gram-negative rods consistent with Klebsiella rhinoscleroma. Histiocytes in leprosy may show cytoplasmic acid-fast bacilli. Langerhans cell granulomatosis is a clonal proliferation of neoplastic histiocytes that express S-100 protein and CD1a and contain the typical Birbeck granules demonstrated by electron microscopy. Histiocytes in SHML are negative for CD1a and Birbeck granules.

Treatment and Prognosis
There is no systematic treatment study of SHML. 127 In general, SHML follows a benign clinical course 123 ; in one study, five of nine patients with sinonasal SHML experienced recurrences of their lesion and four had persistent disease when last seen. 122 Most patients undergo complete surgical resection of their masses. However, patients with systemic manifestations or respiratory obstruction may need systemic therapy. In a literature review of all sites involved by SHML, Komp 127 states that a combination of vinca alkaloid, alkylating agents, and corticosteroids appears to be the most effective. Radiotherapy did not appear to be particularly effective. The responses with these agents appeared to be worse than with malignant lymphomas. It is imperative that the correct diagnosis be made so that complete removal of the mass is pursued.

Wegener’s Granulomatosis

Clinical Features
Wegener’s granulomatosis is a systemic vasculitis and necrotizing granulomatosis with involvement of the upper and lower respiratory tracts and kidneys. 128, 129 Wegener’s granulomatosis was grouped in the past with lymphomatoid granulomatosis, polymorphic reticulosis, idiopathic midline destructive disease, and a host of infectious processes under the vague clinical terms of midfacial necrotizing lesion and lethal midline granuloma.
Clinically, patients with involvement of the upper respiratory tract usually present with sinusitis, rhinorrhea, headache, nasal obstruction, anosmia, sinus pain, and, less often, otitis media and mastoiditis due to involvement of the eustachian tube. 130, 131 In most patients, there are also pulmonary or renal manifestations. 130 Classic or cytoplasmic antineutrophilic cytoplasmic antibodies (ANCAs) directed against neutrophilic proteinase 3 are present in the serum of most patients; a minority have antibodies against myeloperoxidase or (peri)nuclear ANCAs, whereas others lack these antibodies altogether. 132, 133 The presence of these antibodies and their titers appear to be related to levels of disease activity.

Pathologic Features
The diagnosis of Wegener’s granulomatosis using biopsy specimens of the head and neck is frequently difficult and inconclusive. The pathologic features to look for in these specimens are mucosal ulceration, acute and chronic inflammation, vasculitis, necrosis, and granulomatosis. The inflammation in Wegener’s granulomatosis is generally mixed acute and chronic, with neutrophils aggregating in small clusters and microabscesses ( Fig. 3-10 ). Lymphocytes and plasma cells are usually abundant, and eosinophils are frequently seen. This inflammatory reaction may mask the underlying blood vessels and vasculitis. The necrotizing vasculitis involves arterioles and small arteries and veins. All stages of vasculitis may be present, ranging from acute to granulomatous to healed. The acute stage is characterized by patchy fibrinoid necrosis of the vessel wall accompanied by a prominent neutrophilic infiltrate. The inflammation and necrosis may involve part or the entire circumference of the affected vessel. Extravasated red blood cells, fibrin thrombi, and swollen endothelial cells are often seen. Multinucleated giant cells and histiocytes are present in granulomatous vasculitis. Healed vasculitis is characterized by concentric fibrosis surrounding an endothelium-lined vascular lumen. Frequently, recognition of involved blood vessels is difficult; in these instances, the use of elastic stains is helpful to identify the fragmented elastic remnants.

Figure 3-10 Wegener’s granulomatosis. Invasion of blood vessels by a mixed inflammatory infiltrate composed of neutrophils, eosinophils, lymphocytes, and macrophages. A giant cell is also present.
Coagulative necrosis is invariably present in Wegener’s granulomatosis, but its detection in head and neck biopsy specimens depends on tissue sampling and biopsy sample size. Usually it is patchy in distribution and may have a “geographic” appearance, with a prominent rim of palisaded epithelioid and spindle-shaped macrophages. Giant cells are also often present around the necrotic areas. A pathologic change not frequently recognized is the presence of microscopic foci of extravascular necrosis characterized by degenerated collagen with a clumped or granular appearance or fibrinoid degeneration. 131
Giant cells unassociated with granulomas are typically present, but they tend to aggregate around areas of necrosis or are scattered in an edematous stroma. The granulomas in Wegener’s granulomatosis are poorly formed, and most often consist of loose aggregates of mononuclear and multinucleated macrophages ( Fig. 3-11 ). The giant cells and granulomas can be found within the vessel wall, adjacent to the vessel, or distant from the affected vessels.

Figure 3-11 Wegener’s granulomatosis. Poorly formed granuloma with numerous macrophages, small lymphocytes, and eosinophils.
The utility of head and neck biopsies in establishing the diagnosis of Wegener’s granulomatosis depends on a constellation of clinical and histopathologic findings. Devaney and colleagues 130 proposed the following criteria for the diagnosis of Wegener’s granulomatosis using head and neck biopsy specimens: (1) The finding of necrosis, vasculitis, and granulomatous inflammation is diagnostic if the patient has involvement of lung, kidney, or both; (2) if two of these microscopic features are present, the biopsy sample is considered diagnostic only if both the kidney and the lung are involved, and if only one site is involved, the biopsy specimen is considered probable; (3) if only one of the three microscopic features is present, the biopsy specimen is considered suggestive if both lung and kidney are affected and suspicious if only one site is involved; (4) if none of the microscopic features are present, the biopsy specimen is considered nonspecific even if there is clinical involvement of lung and kidney. In general, the diagnosis of Wegener’s granulomatosis based on head and neck biopsies requires a careful correlation of clinical, serologic, microbiologic, and pathologic data. The less the clinical support is for Wegener’s granulomatosis, the greater the number of pathologic findings needed to make a diagnosis. 128

Differential Diagnosis
The differential diagnosis of Wegener’s granulomatosis includes infectious processes, Churg-Strauss syndrome, and sinonasal lymphoma. The diagnosis of aggressive sinonasal infections resides in close clinicopathologic correlation and the identification of an infectious agent in microbiologic cultures or biopsy material. Sinonasal infections generally do not have concurrent pulmonary and renal involvement and lack serum ANCAs. Although the mucosa of the oral cavity, sinonasal tract, and nasopharynx can be inflamed and ulcerated, it is rare to find the extensive cartilage and bone destruction associated with sinonasal lymphoma. Sinonasal lymphoma should not have pulmonary or renal disease and also lacks perinuclear ANCAs. In difficult cases, immunophenotyping and molecular pathology studies should be used to exclude the diagnosis of NHL.

Treatment and Prognosis
The prognosis of patients with Wegener’s granulomatosis largely depends on the extent of the disease and the treatment employed. Patients with the limited form of the disease may have only nasal and pulmonary involvement without glomerulonephritis or systemic involvement. A combined regimen of cyclophosphamide and prednisone is generally used for at least 1 year. Azathioprine has also been used as an alternative or adjunct to cyclophosphamide.

Eosinophilic Angiocentric Fibrosis

Clinical Features
Eosinophilic angiocentric fibrosis (EAF) of the sinonasal tract is an exceedingly rare condition characterized by progressive submucosal perivascular fibrosis of unknown etiology. 134 - 138 Occasional cases have been associated with granuloma faciale, 135 and Loane and colleagues 139 described it in a patient with Wegener’s granulomatosis. EAF predominantly affects women, with a female-to-male ratio of 4:1. Age at presentation has ranged from 19 to 79 years, with a mean age of 50. Most patients present with a history of long-standing and progressive nasal obstruction accompanied by discharge. Pain and epistaxis have been reported. Physical examination reveals mucosal thickening or a mass with narrowing of the nasal passages. The septum and lateral nasal wall are most commonly affected, but involvement of the maxillary sinus, facial or orbital soft tissues, or subglottis can be seen.

Pathologic Features
Morphologically, EAF is characterized by a variable and evolving mixture of a rich polymorphic cellular inflammatory infiltrate, non-necrotizing eosinophilic vasculitis, and fibrosis. The eosinophilic vasculitis affects submucosal capillaries and venules. The inflammatory infiltrate is composed of numerous eosinophils, with variable numbers of B and T lymphocytes, plasma cells, neutrophils, and macrophages. The fibrosis consists of a distinctive perivascular concentric fibrosis with an “onion-skin” appearance ( Fig. 3-12 ). In later stages of the disease, whorls of collagen and reticulin fibers are seen. Typically, the inflammatory infiltrate and the vasculitis become sparser as the fibrosis increases in density.

Figure 3-12 Eosinophilic angiocentric fibrosis showing arterioles and small vessels nearly obliterated by perivascular concentric (onion-skin) fibrosis. The inflammatory infiltrate is lymphoplasmacytic admixed with eosinophils.

Differential Diagnosis
The differential diagnosis of sinonasal EAF includes Wegener’s granulomatosis, Churg-Strauss syndrome, granuloma faciale, and infection. Perivascular fibrosis is not a typical finding in Wegener’s granulomatosis; furthermore, giant cells, necrosis, and increased serum ANCAs are not seen in EAF. Churg-Strauss syndrome has fibrinoid necrosis and granulomas that are absent in EAF. Granuloma faciale is almost always seen in the face, more commonly affects males, and exhibits prominent vasculitis without concentric perivascular fibrosis. Mucosal ulceration, geographic or fibrinoid necrosis, thrombosis, giant cells, and granulomas are not microscopic features of EAF.

Treatment and Prognosis
Surgical resection with relief of the nasal obstruction is the treatment of choice in EAF, although recurrences are extremely common and multiple excisions are frequently required. The efficacy of steroids and cytotoxic drugs in the management of EAF remains largely unknown.

Idiopathic Midline Destructive Disease
Idiopathic midline destructive disease was the term proposed by Tsokos and colleagues 140 in 1982 for a locally destructive process involving the upper respiratory tract. The patients presented with pansinusitis and destructive lesions involving the nasal septum, bone, and, less frequently, skin. The destructive process sometimes extended into the orbit, nasopharynx, larynx, and trachea. None of the patients described by Tsokos and colleagues 140 had systemic disease, and there was no evidence of an infectious process by culture or special stains. However, since the advent of immunohistochemistry and molecular diagnosis, the existence of idiopathic midline destructive disease as a distinctive clinicopathologic entity has become controversial. The majority of the purported cases of idiopathic midline destructive disease seem to represent extranodal NHL or Wegener’s granulomatosis. Indeed, some authors have suggested that idiopathic midline destructive disease as a histologic entity should be abandoned, although as a clinical descriptive term, it may still be useful. 141, 142
Midline nasal destruction may be caused by aggressive infections, vasculitis, or neoplastic processes, particularly NHL in the sinonasal tract. Midline nasal destruction in cocaine abusers should also be recognized because of its better prognosis with more conservative treatment measures. 143 Because the histopathologic features of nasal destruction in cocaine abuse are not specific, the diagnosis rests heavily on a good clinical history and the identification of cocaine abuse. Patients presenting with extensive midline destruction should undergo a careful work-up with clinicopathologic correlation, serologic studies, microbiology cultures, and biopsies with adequate ancillary studies, including immunohistochemistry, flow cytometry, and gene rearrangement.


Epithelial Tumors

Schneiderian Papillomas

Clinical Features
Sinonasal or schneiderian papillomas are benign neoplasms of the respiratory mucosa or schneiderian mucosa lining the nasal cavity and paranasal sinuses. Although there are no reliable data to estimate the incidence of schneiderian papillomas in the general population, they are relatively common. They accounted for 25% of nasal tumors seen in the Institute of Laryngology and Otology in London, 144 and Vrabec 145 and Suh and colleagues 146 reported large series of 101 and 57 cases of inverted papilloma, respectively, in 25- and 30-year study periods. These lesions have been designated by many names, reflecting dissimilar microscopic appearances; however, they are now classified in three histologic groups: fungiform (exophytic or everted) papillomas, inverted (squamous) papillomas, and cylindrical cell (oncocytic) papillomas. 147 - 149 Schneiderian papillomas have been regarded as variants of a single entity; however, Michaels and Young 148 and Michaels 150 have recently contradicted this concept and regarded these lesions as three separate entities. In a review of 191 cases, they did not find intermediate forms. They regard everted and cylindrical cell types as true papillomas, whereas inverted papilloma is seen as a mucosal polyp with extensive squamous metaplasia. No known etiologic or risk factors were associated with the development of schneiderian papillomas in the past; however, in recent years, human papillomavirus DNA has been detected in the exophytic and inverted types using in situ hybridization and polymerase chain reaction. 151 - 153 Human papillomavirus 6/11 has been the most common type detected. 154 No association has been found between human papillomavirus and cylindrical cell papillomas. 154, 155
Sinonasal papillomas occur in a wide age range, but most cases are seen in patients between 30 and 60 years of age. 1570, 147 They are uncommon in children. Males are affected at least twice as often as females. 1580, 145 Symptoms at presentation include unilateral nasal obstruction and stuffiness and less commonly epistaxis, facial pain, and purulent discharge. Proptosis may be associated with extensive bone erosion, sometimes seen in inverted papillomas. Involvement of the middle ear and mastoid has been rarely described. 159 In general, papillomas are unilateral 1600, 144 ; however, they are often multifocal and, more rarely, bilateral.

Pathologic Features
All three types of schneiderian papillomas exhibit certain overlapping architectural and cytologic features, and several authors have described lesions with exophytic and endophytic components. 1610, 156 Exophytic papillomas constituted approximately 50% of the sinonasal tract papillomas reported by Hyams. 147 They are almost exclusively found in the nasal septum. 147, 162 Histologically, these lesions exhibit an exophytic pattern and are composed of papillary fronds with a thin central core of fibrovascular tissue ( Fig. 3-13 ). The surface of the papilloma is lined with a thick nonkeratinizing squamous epithelium also referred to as transitional epithelium. 160 The lining may contain intraepithelial mucous cysts and, less frequently, ciliated respiratory epithelium with small numbers of goblet cells. 147 Unlike inverted papillomas, fungiform papillomas do not contain large glycogenated squamous cells. Surface keratinization with formation of a granular cell layer, a chronic inflammatory infiltrate, atypia, and mitotic activity are uncommon. 147

Figure 3-13 A , Exophytic or fungiform papilloma characterized by fibrovascular cores of variable size lined with thick squamous epithelium. B , The squamous epithelium is well differentiated with no atypia, keratinization, or mitotic activity.
In many authors’ experiences, inverted papilloma is the most common type of schneiderian papilloma. 146, 148, 156, 158, 160 - 162 Most tumors are confined to the lateral nasal wall and sinuses. 1610, 146 The maxillary sinus is most commonly affected, but involvement of ethmoid or sphenoid sinuses may also be seen. Under low-power examination, inverted papillomas have an endophytic growth pattern with invaginations of the surface epithelium into the underlying stroma ( Fig. 3-14 ). This pattern gives the tumors a lobulated appearance. The neoplastic epithelium has a variable appearance and mostly consists of a markedly thickened layer of nonkeratinizing squamous epithelium overlying a thick basement membrane. The surface of the epithelial lining may be covered by a layer of ciliated respiratory epithelium, which often merges with a transitional-type epithelium ( Fig. 3-15 ). The presence of numerous mucous cells with intraepithelial mucous cysts is also a common feature. 146, 157, 160, 162, 163 The squamous component may contain areas with large clear cells with abundant cytoplasmic glycogen and rarely may demonstrate a moderate degree of atypia. 147 Mitotic figures may be seen; however, they are usually few and are limited to the basal and parabasal layers. 147, 157, 161, 162 The stroma varies from fibrous to myxomatous. Chronic inflammation is more frequently seen in inverted papillomas than in exophytic papillomas and occasionally may closely resemble inflammatory polyps. Surface keratinization is uncommon; however, when present, the possibility of a squamous cell carcinoma should be excluded. 146, 147, 156, 162

Figure 3-14 Nasal papilloma, inverted type. Note the lobulated appearance with formation of deep clefts.

Figure 3-15 Inverted papilloma. Extension of neoplastic epithelium into seromucinous glands. This pattern of involvement is responsible for recurrences after a limited resection.
The least common type of schneiderian papilloma is the cylindrical cell or so-called oncocytic schneiderian papilloma. 147, 148, 164, 165 The anatomic location and gross pathologic features of cylindrical cell papillomas are similar to those of inverted papillomas. Microscopically, they are lined with a multilayered epithelial proliferation of tall columnar cells with eosinophilic, granular cytoplasm ( Fig. 3-16 A ). Scattered mucous cells with intraepithelial mucous cysts are also commonly seen (see Fig. 3-16 B ). Architecturally, they too resemble inverted papillomas due to their endophytic growth pattern. The surface of these papillomas can also be lined with respiratory-type epithelium, and frequently they also have a nonkeratinizing transitional cell component.

Figure 3-16 Cylindrical cell (oncocytic) papilloma ( A ) with characteristic intraepithelial cysts ( B ).

Differential Diagnosis
Several lesions may be confused or need to be separated from schneiderian papillomas. Occasionally, inverted or cylindrical cell papillomas may be misdiagnosed as inflammatory polyps. Although inflammatory polyps may show squamous metaplasia, they do not have the thick nonkeratinizing squamous epithelium seen in inverted papillomas. In contrast to schneiderian papillomas, inflammatory polyps have thick hyalinized basement membranes, prominent seromucinous glands, and stromal inflammatory cell infiltrates. They do not have an inverted growth pattern, intraepithelial pseudocysts and neutrophils, or the oncocytic epithelium of cylindrical cell papillomas. Rhinosporidiosis may imitate the intraepithelial pseudocysts of cylindrical cell papillomas; however, papillomas do not have the degree of inflammation associated with rhinosporidiosis; the cysts are smaller and are intraepithelial rather than submucosal; and, more importantly, the cysts do not contain microorganisms.
The differential diagnosis of cylindrical cell papilloma should also include low-grade sinonasal papillary adenocarcinoma. Low-grade adenocarcinoma is composed of infiltrative small acini and cribriform structures not seen in cylindrical cell papilloma. The surface epithelium in adenocarcinoma may be normal, whereas in papilloma, it is thickened by the neoplastic cells. Schneiderian papilloma should also be separated from nonkeratinizing squamous cell carcinoma. The degree of cytologic atypia seen in carcinomas is usually not seen in papilloma uncomplicated by concurrent carcinoma. Attention to other features such as inverted pattern, invasive nests, and desmoplastic stroma is necessary to establish a definitive diagnosis.

Treatment and Prognosis
Most clinicians agree that the treatment of choice of schneiderian papillomas is surgical resection; however, there is no general agreement on the extent or type of surgery required. Most authors agree that recurrence of papillomas is a reflection of incomplete removal and recommend complete resection through a lateral rhinotomy incision with medial maxillectomy as adequate treatment. 145, 158, 166, 167 In selected patients with limited disease 168 or in those who refuse radical treatment, a more conservative approach using endoscopic removal may be recommended as an alternative. The recurrence rate with this approach has been as high as 17%. 145, 158 Patients with invasion of the skull base may require craniofacial resection. 158 Radiotherapy is primarily used as adjuvant therapy in tumors with associated carcinoma. 160
The historical recurrence rate of all histologic types has ranged from 4% to 74%, 146, 147, 157, 160, 161, 166, 169 with multiple recurrences in many patients. Today there is almost universal agreement that this high recurrence rate is probably due to incomplete resection since papillomas have the tendency to spread widely along the respiratory mucosa through cylindrical cell or squamous metaplasia. A conservative resection such as polypectomy does not eliminate microscopic disease and has been associated with high recurrence rates. 1610, 146 The recurrence rate for inverted and cylindrical cell papillomas has been reduced to approximately 5% with lateral rhinotomy and medial maxillectomy. 1660, 145
The prognosis of schneiderian papillomas of all histologic type without in situ or invasive carcinoma is excellent. As previously discussed, the local recurrence rate depends heavily on the initial surgical approach. Several large studies 145, 147, 158, 161 found no deaths directly caused by schneiderian papillomas. In situ or invasive squamous cell carcinoma occurs in approximately 5% to 14% of patients with sinonasal papillomas ( Fig. 3-17 ). 145 - 147, 160, 166, 167 This complication is almost exclusively seen in the inverted or cylindrical cell types. Fungiform papillomas do not have malignant potential. The carcinoma may be seen as part of a papilloma or it may present as a recurrence after resection of a benign lesion. Most of the carcinomas are of the squamous type; however, sarcomatoid carcinoma, clear cell carcinoma, high-grade mucoepidermoid carcinoma, and sinonasal undifferentiated carcinoma (SNUC) can also be seen. 156 - 158, 170, 171 Manivel and colleagues 172 described two cases with endodermal sinus tumor-like features. There are no histologic features that predict recurrences or malignant transformation.

Figure 3-17 Carcinoma in situ arising in a squamous papilloma. There is significant cytologic atypia with nuclear pleomorphism and human papillomavirus effects in the dysplastic epithelium.

Salivary Gland–Type Tumors

Clinical Features
Tumors of the salivary gland type reportedly constitute 4% to 8% of neoplasms of the sinonasal tract. 173 - 177 These tumors arise from the seromucinous glands of the nasal cavity and paranasal sinuses and the overlying surface epithelium. 174, 178 The clinical features of sinonasal salivary gland–type tumors are nonspecific, and most patients with malignant tumors present with clinical stages T3 and T4. 173, 175, 179, 180

Pathologic Features
The pathologic features of these lesions are essentially similar to those of major and minor salivary glands with the notable exceptions of Warthin’s tumor and pure sebaceous lesions that have not been reported in this location 176 ; most other major histologic variants of salivary gland–type neoplasms have been described in this region, including benign ( Fig. 3-18 ) and malignant mixed tumors ( Fig. 3-19 ), 1820, 176 oncocytomas, 183, 184 myoepithelioma, 185 - 187 myoepithelial carcinoma, 188 adenoid cystic carcinoma ( Fig. 3-20 ), 174, 175, 179, 189 mucoepidermoid carcinoma ( Fig. 3-21 ), 177 acinic cell carcinoma, 190 - 192 basal cell adenocarcinoma, 193 polymorphous low-grade adenocarcinoma, 194 - 196 epithelial-myoepithelial carcinoma, 197 salivary duct carcinoma ( Fig. 3-22 ), and clear cell carcinoma. 177 The most common histologic types are adenoid cystic carcinoma and mixed tumor. 1770, 173 An unusual case of a nasal pleomorphic adenoma with skeletal muscle differentiation has been described by Lam and colleagues. 198

Figure 3-18 Mixed tumor of the maxillary sinus with sebaceous differentiation.

Figure 3-19 Recurrent malignant mixed tumor of the maxillary sinus. The tumor is destroying the lateral and medial walls and the floor of the maxilla.

Figure 3-20 Adenoid cystic carcinoma of the nasal cavity. The tumor exhibits a mixture of dilated tubules and cribriform areas with a focal solid growth pattern.

Figure 3-21 Low-grade mucoepidermoid carcinoma of the ethmoid sinus. A , The tumor has a cystic appearance. B , Note the mixture of mucus, intermediate, and squamous cells.

Figure 3-22 Salivary duct carcinoma of the maxillary sinus. The tumor shows the typical well-defined nests with central comedonecrosis.
Dehner and colleagues 199 described a peculiar lesion that they designated salivary gland anlage tumor or congenital pleomorphic adenoma. This lesion is characteristically located in the midline of the nasopharynx of newborns. Its congenital nature and histologic similarity to the normally developing salivary gland have led some authors to suggest that the salivary gland anlage tumor may be a tumor-like hamartomatous lesion. 200 The tumor is polypoid in appearance, and, although benign, it may cause respiratory and feeding problems, including acute airway obstruction due to its location. Imaging studies show a well-defined mass. Microscopically, the tumor is well circumscribed and is covered by an intact squamous mucosa, which appears to be in direct continuity with branching ductlike structures and cystic or solid squamous cell nests within the substance of the lesion. These epithelial structures compartmentalize multiple solid nodules of ovoid and spindle cells with bland cytologic features ( Fig. 3-23 ). 201 Immunohistochemical and ultrastructural studies have demonstrated a variable degree of myoepithelial differentiation within these nodules. 199, 201 Simple surgical excision is curative. 202

Figure 3-23 Salivary gland anlage tumor. A , The tumor is composed of cellular nodules with spindle cells and cystic ductlike structures with squamous epithelium. B , Cystic ductlike structures lined with benign squamous epithelium surrounded by myxoid stroma.
(Courtesy of Dr. Rebecca Thomas, Temple University, Philadelphia, PA.)

Differential Diagnosis
The diagnosis of salivary gland tumors in the sinonasal tract rests in awareness of their occurrence in this location and recognition of their typical morphologic features. The main differential diagnoses of malignant salivary gland tumors are well-differentiated sinonasal adenocarcinoma and intestinal-type adenocarcinoma.

Treatment and Prognosis
The treatment of salivary gland–type neoplasms in the sinonasal tract is complete surgical resection. The surgical approach employed, the extent of the surgery, and, ultimately, the prognosis depend on the location and structures involved by the tumor and its histologic type. 173 The reported 5-year survival rate for malignant salivary gland tumors in the sinonasal tract has varied from 40% to 63%, 173 - 175, 179 with adenoid cystic carcinoma being the most difficult to control owing to its advanced clinical stage at diagnosis and frequent involvement of surgical resection margins. Postoperative radiotherapy significantly improves local control. 1790, 173

By definition, these are nonsalivary gland–type adenocarcinomas. According to the World Health Organization, 203 sinonasal adenocarcinomas are classified as intestinal and nonintestinal types. The latter are further divided into low- grade and high-grade tumors.

Intestinal-Type Adenocarcinoma

Clinical Features
The intestinal-type adenocarcinoma (ITAC) is the second most common glandular malignancy of the sinonasal region after adenoid cystic carcinoma and is composed of cells mimicking normal, adenomatous, or carcinomatous intestinal mucosa. 171, 204 - 209 Approximately 85% of patients affected are male; the age at presentation has ranged from 23 to 84 years, with a mean of 50 to 64 years. The ethmoid sinus is the most commonly involved site (40%), followed by the nasal cavity and the maxillary antrum. Advanced tumors may involve the skull base extensively. Symptoms at presentation include nasal obstruction, epistaxis, facial pain, and the presence of a growing mass.
Intestinal-type sinonasal adenocarcinoma has a strong association with long-term exposure to fine hardwood dusts in the woodworking industry. 210 In such populations, the incidence approaches 1000 times that of the general public. 211 - 213 Approximately 20% of ITAC cases occur in patients with industrial wood dust exposure. Smoking and exposure to leather dust and nickel have also been incriminated. 205, 214 Although the morphologic features are similar, there seems to be clinical and prognostic differences between those cases arising in woodworkers and nonoccupational cases. Barnes 205 reported 17 cases of sporadic ITAC and compared them with published cases of ITAC arising in woodworkers and found that tumors related to industrial dust exposure occur predominantly in men (85%–95%) and show a striking predilection for the ethmoid sinus. Sporadic tumors frequently affect women and often arise in the maxillary antrum (20%–50%).

Pathologic Features
These neoplasms recapitulate the entire range of appearances assumed by normal and neoplastic large and small intestinal mucosa. At the well-differentiated end of the spectrum are tumors that resemble normal intestinal mucosa ( Fig. 3-24 ) replete with goblet, resorptive, Paneth, and argentaffin cells, along with well-formed villi and a muscularis mucosae. 206 Although it is tempting to label such proliferations benign heterotopias, they are aggressive, invasive lesions. The papillary tumors consist of elongated fronds lined with stratified columnar goblet cells suggestive of intestinal villous or tubular adenoma ( Fig. 3-25 ). Papillary tumors may be invasive or intramucosal.

Figure 3-24 Well-differentiated intestinal-type adenocarcinoma of the sinonasal tract simulating small intestinal mucosa.

Figure 3-25 Well-differentiated intestinal-type adenocarcinoma of the sinonasal tract with the appearance of a colonic adenoma.
The most common form of sinonasal ITAC resembles conventional colonic adenocarcinoma ( Fig. 3-26 ). In this variant, the neoplastic glands are lined with pleomorphic columnar cells arranged in a back-to-back pattern, vary in size, and widely invade the underlying stroma. Intracellular mucin is present focally, but goblet cells are not prominent. In less differentiated tumors, solid sheets of tumor cells may be present with only focal glandular lumina formation. Completing the analogy to intestinal neoplasms are the less frequent mucinous tumors. The predominant pattern in this variant consists of large glands distended with mucin or pools of extracellular mucin ( Fig. 3-27 ) with small clusters of neoplastic cells floating in it. Signet-ring cells form a minor component or, rarely, are predominant. Barnes 205 divided these tumors into five morphologic types: papillary, colonic, solid, mucinous, and mixed, the last displaying an admixture of the preceding morphologies. Kleinsasser and Schroeder 204 divided ITACs into papillary-tubular cylindrical cell type (grades I, II, and III corresponding to Barnes’ papillary, colonic, and solid), alveolar goblet cell type, signet-ring cell type (both corresponding to Barnes’ mucinous), and transitional (mixed) type. The resemblance of ITAC to normal and neoplastic intestinal epithelium is not limited to the light microscopic appearance. Ultrastructural studies have confirmed the presence of resorptive, goblet, Paneth, and argentaffin cells identical to their intestinal counterparts, and intestinal-type hormones have been documented immunocytochemically. 215 These tumors are positive for CK20, CDX2, and villin but, unlike colonic carcinoma, show variable expression of CK7 ( Fig. 3-28 ). 216, 217 Focal expression of chromogranin and other neuroendocrine markers may be observed. We have also seen rare examples of sinonasal adenocarcinomas with clear cytoplasm and subnuclear vacuoles imitating an endometrioid carcinoma with a secretory pattern ( Fig. 3-29 ).

Figure 3-26 Moderately differentiated intestinal-type adenocarcinoma. Morphologically, this tumor is similar to a colorectal carcinoma of the usual type.

Figure 3-27 Well-differentiated mucinous adenocarcinoma.

Figure 3-28 Intestinal-type adenocarcinoma with strong and diffuse expression of cytokeratin 7 ( A ), cytokeratin 20 ( B ), CDX2 (nuclear) ( C ), and villin ( D ).

Figure 3-29 Intestinal-type adenocarcinoma of the sinonasal tract with clear cytoplasm resembling secretory-type endometrium.

Differential Diagnosis
The rare low-grade tumors resembling normal intestinal mucosa and papillary carcinomas resembling villous adenoma can easily be recognized as primary nasal lesions because intestinal epithelium with this histology is not capable of metastasis. There are no morphologic features or immunocytochemical markers to distinguish primary nasal conventional or mucinous adenocarcinoma from a metastatic colonic carcinoma. Sinonasal ITACs express CK20, CDX2, and villin similar to colonic carcinoma and variably express CK7. 217 Interestingly, in contrast to colonic carcinomas, molecular pathology studies show infrequent K-ras, p53 , and mismatch repair gene ( hMLH1, hMSH2 ) mutations in sinonasal adenocarcinomas. 218 APC and β-catenin gene mutations have not been documented. 219 In a review of 82 tumors metastatic to the nose and paranasal sinuses, five were primary in the gastrointestinal tract. 220, 221 In some patients, the sinonasal lesion was the initial clinical manifestation of disease. Barium radiographic studies should be performed in patients with sinonasal tumors resembling colorectal carcinomas.

Treatment and Prognosis
The treatment of ITAC is surgical resection with or without radiation, depending on the extent of disease. 211, 222 Lateral rhinotomy with partial maxillectomy or exenteration of the ethmoid sinus or nasal cavity is the approach of choice, depending on the tumor location and extent. Patients with more advanced disease often require radical maxillectomy. External beam radiation alone has been employed as single-modality treatment, but a high incidence of local failure has been reported with this approach. 2140, 208 The role of adjuvant chemotherapy is unclear.
Intestinal-type sinonasal adenocarcinomas are aggressive neoplasms. In a review of 213 cases from the literature, Barnes 205 found that 53% of patients had developed local recurrences, 8% (range, 0%–22%) cervical lymph node metastases, 13% (range, 0%–29%) distant metastases, and 60% had died of their disease. Death usually results from uncontrollable local disease with intracranial extension or exsanguination. Tumors related to industrial wood dust exposure reportedly have a slightly better prognosis than tumors arising sporadically. Barnes found a 50% survival rate at 5 years in the first group, whereas the latter had a 20% to 40% survival rate at 5 years. Aggressive tumors may be associated with p53 overexpression. 219
Although all forms of intestinal-type neoplasia in the sinonasal region are at least locally aggressive, recent studies suggest the prognostic implications of histologic subtyping. Well-differentiated ITACs (papillary type) have an indolent course, while poorly differentiated (solid types) and mucinous adenocarcinomas have poorer survival rates. 204, 205, 207, 216

Nonintestinal-Type Adenocarcinoma
These are divided into low-grade and high-grade tumors. The high-grade tumors have a marked male predilection, with an average age at presentation of 59 years, and tend to involve the maxillary sinus. The tumor cells are markedly atypical and pleomorphic and show frequent mitoses, necrosis, and a predominantly solid growth pattern. The prognosis is very poor, with 20% survival at 3 years. 192

Low-Grade Adenocarcinoma

Clinical Features
Low-grade sinonasal adenocarcinomas are rare neoplasms with no sex predilection. 192, 223 Most cases arise in middle-aged adults with a median age of 54 years. The mean age for the cases reported as nasopharyngeal papillary adenocarcinoma was 37 years. 223 They also occur in children and the elderly (age range, 9–75 years). The nasal cavity is the most frequently involved site, followed by the ethmoid and maxillary sinuses. There is no known association with carcinogens. At presentation, most patients complain of nasal obstruction and epistaxis. Pain is uncommon. The most common site of involvement is the nasal cavity, followed by the ethmoid sinus.

Pathologic Features
Low-grade sinonasal adenocarcinomas are morphologically a heterogeneous group of tumors. In some, the architectural and cytologic uniformity frequently leads to a misdiagnosis of adenoma or papilloma. The majority of cases consist of small glands lined with a single layer of uniform cuboidal or columnar cells (seromucinous carcinoma). The neoplastic glands have a back-to-back arrangement without intervening stroma. Some glands are cystically dilated or slitlike with epithelial tufts ( Fig. 3-30 ), and others contain well-formed papillae ( Fig. 3-31 ). Nucleus size varies from case to case but tends to be uniform within a given lesion. Mitotic figures are generally rare. Most tumors contain both intracellular and extracellular mucin. Origin from surface mucosa may be seen. Some neoplasms included in this group consist of cells with basophilic cytoplasm arranged in small, acinus-like nests. 192 These lesions closely resemble acinar cell carcinomas of salivary gland type ( Fig. 3-32 ) and probably should be regarded as such and be separated from the other nonsalivary tumors in this group.

Figure 3-30 A , Low-grade sinonasal adenocarcinoma. The tumor is composed of infiltrative glands with a slitlike shape admixed with normal mucosa. B , Low-grade sinonasal adenocarcinoma. The papillary tufts are composed of cuboidal cells without significant pleomorphism.

Figure 3-31 A , Well-differentiated papillary sinonasal adenocarcinoma with complex branching papillae. B , The tumor is composed of tall, eosinophilic cells with a low nucleus-to-cytoplasm ratio, delicate fibrovascular cores with thin capillaries, and intraepithelial cysts.

Figure 3-32 Well-differentiated papillary sinonasal adenocarcinoma containing basophilic cells with cytoplasmic vacuoles closely resembling those of acinic cell carcinoma.
Nasopharyngeal papillary adenocarcinoma shows papillary and glandular growth patterns. The papillae exhibit arborization and hyalinized fibrovascular cores. The glands have a crowded appearance with a cribriform pattern. The epithelial cells lining these structures are columnar or pseudostratified. They possess eosinophilic cytoplasm and round to oval nuclei with optically clear chromatin. Moderate nuclear pleomorphism is present, but mitotic figures are uncommon. Psammoma bodies and focal necrosis are occasionally seen.

Differential Diagnosis
Low-grade sinonasal adenocarcinoma must be distinguished from ITAC because of the more aggressive clinical course of the latter. Distinction is usually straightforward, given the nuclear stratification and intestinal appearance of the latter neoplasms. In addition, intestinal-type tumors are cytologically more pleomorphic than low-grade adenocarcinomas, with the exception of rare nasal neoplasms resembling normal intestinal mucosa. Oncocytic schneiderian papillomas may also be confused with low-grade adenocarcinoma. Heffner and colleagues 192 listed the following differentiation features: (1) stratified epithelium in papillomas as opposed to single-layered cells in adenocarcinoma, (2) true glandular lumina in adenocarcinoma, and (3) more abundant myxomatous stroma in papillomas. The complex papillary pattern, vesicular nuclei, and focal psammoma bodies seen in some low-grade nasopharyngeal adenocarcinomas may mimic a metastatic papillary carcinoma of the thyroid gland 224 ; however, nasopharyngeal carcinomas lack positivity with thyroglobulin antibodies.

Treatment and Prognosis
Patients with low-grade carcinoma have a good prognosis. Most patients have localized disease at presentation and do not require radical surgical procedures for complete resection of their tumors. The value of radiotherapy is unknown. Recurrences developed in as many as 30% of the cases reported by Heffner and colleagues 192 but did not indicate intractable disease. After a median follow-up of 6 years, 78% of patients were disease free. Death from disease was seen in two cases and was due to local invasion rather than to metastases. None of the nine patients with low-grade nasopharyngeal papillary adenocarcinoma reported by Wenig and colleagues 223 developed metastases, although one tumor recurred locally after radiation therapy.

Small Cell Neuroendocrine Carcinoma

Clinical Features
Carcinomas with morphologic features indistinguishable from small cell carcinoma of the lung occasionally arise in the nasal cavity and paranasal sinuses. 225 - 228 An origin in the minor salivary gland has been proposed for these neoplasms. 226 The age at presentation has ranged from 26 to 77 years with a mean age of approximately 51 years. The most common symptom at presentation is epistaxis followed by exophthalmos and nasal obstruction. Some of these tumors may have elevated hormonal levels; Kameya and colleagues 229 described increased levels of adrenocorticotropin and calcitonin in two of their patients. Almost invariably the tumors are at an advanced clinical stage with involvement of multiple sinuses ( Fig. 3-33 ).

Figure 3-33 Sinonasal small cell carcinoma. This lesion is destroying the anterior wall of the left maxilla and involving the nasal cavity and the maxillary and ethmoid sinuses.

Pathologic Features
The tumor has the typical features of pulmonary oat cell carcinomas. Small cell neuroendocrine carcinomas (SNECs) are composed of sheets ( Fig. 3-34 ) and nests of small- to intermediate-size cells with a high nucleus-to-cytoplasm ratio, hyperchromatic nuclei with absent or inconspicuous nucleoli, and frequent mitotic figures ( Fig. 3-35 ). Nuclear molding and the DNA incrustation in vascular walls (Azzopardi phenomenon) can be seen. A peculiar glomeruloid vascular proliferation has also been described in neuroendocrine tumors of the sinonasal tract and other locations. 230

Figure 3-34 Sinonasal small cell carcinoma. The tumor cells are arranged in irregular sheets of variable size and lack the nested pattern seen in most olfactory neuroblastomas. Densely basophilic DNA material is also present.

Figure 3-35 Sinonasal small cell carcinoma. The tumor cells exhibit cytologic features similar to those of their pulmonary counterparts. The cells have a high nucleus-to-cytoplasm ratio with oval nuclei containing stippled chromatin. Nucleoli are inconspicuous and the mitotic rate is high.
Immunohistochemical studies in a limited number of SNECs suggest that they are almost invariably positive for keratins ( Fig. 3-36 ) with variable expression of neuron-specific enolase, chromogranin, and synaptophysin. 225 As in similar tumors in the lung, CD56 expression may be helpful. Unlike Merkel cell carcinomas, these tumors appear to be negative for cytokeratin (CK) 20. 231 Dense-core granules have been identified ultrastructurally. 2320, 228

Figure 3-36 Keratin immunostaining in sinonasal small cell carcinoma. The tumor is diffusely positive for AE1:AE3. This pattern differs from the focal or patchy expression seen in olfactory neuroblastoma.
An unusual small cell undifferentiated neoplasm with some features of small cell undifferentiated carcinoma, but also showing divergent mesenchymal differentiation, has been described in the sinonasal region after radiation therapy for bilateral retinoblastoma. 233, 234

Differential Diagnosis
The differential diagnosis of SNEC in the sinonasal tract includes olfactory neuroblastoma (ONB), SNUC, poorly differentiated and basaloid squamous cell carcinomas (BSCCs), malignant lymphoma, and, rarely, Ewing’s sarcoma or primitive neuroectodermal tumors (ES/PNET). This distinction may be difficult in some cases, but the combination of clinical, morphologic, immunohistochemical, and ultrastructural studies should allow a definitive diagnosis in most instances ( Table 3-1 ). Sinonasal SNEC should be distinguished from ONB because the latter has a better prognosis. The cells of ONB are arranged in a lobular pattern and exhibit moderate amounts of cytoplasm, round nuclei, a low nucleus-to-cytoplasm ratio, and low mitotic activity. Necrosis is uncommon. In contrast, SNEC lacks lobular architecture, fibrovascular septa, and neurofibrillary stroma and does not contain neurofibrillary rosettes. The cells of SNEC have scant cytoplasm, a high nucleus-to-cytoplasm ratio, round or oval dense hyperchromatic nuclei, and numerous mitotic figures and apoptotic cells accompanied by extensive areas of necrosis. Immunohistochemically, SNEC lacks the S-100 positive cells seen at the periphery of the cell nests of ONB and is negative for neurofilament. The expression of keratin in ONB is uncommon and when present is patchy or limited to areas with glandlike or olfactory differentiation, in contrast to the diffuse staining seen in SNEC (see Fig. 3-36 ).

Table 3-1 Ancillary Studies and Differential Diagnosis of Neuroendocrine and “Small Round Blue Cell” Tumors of the Sinonasal Tract
BSCC of the sinonasal tract 235 can be difficult to differentiate from SNEC. 236 Both neoplasms are composed of small pleomorphic cells with a high nucleus-to-cytoplasm ratio, inconspicuous nucleoli, high mitotic activity, and extensive areas of necrosis. However, SNEC does not have the well-defined tumor lobules with peripheral nuclear palisading, smooth contours, and hyaline basal lamina seen in BSCC. No evidence of squamous differentiation has been reported in SNEC, whereas in situ and invasive squamous cell carcinomas or tumor islands with abrupt keratinization are almost always found in BSCC. BSCC may express neuron-specific enolase, 237 but unlike SNEC, is negative for synaptophysin and chromogranin.

Treatment and Prognosis
SNECs are aggressive epithelial tumors with a high local and distant failure rate despite multimodal therapy. Given the poor prognosis associated with these tumors, there is need for a multidisciplinary treatment approach combining surgery, radiotherapy, and chemotherapy. Surgery with adjuvant chemotherapy with a platinum-base regimen may be used in a curative attempt in patients with limited local disease. A platinum-based chemotherapeutic regimen similar to the one used for pulmonary small cell carcinomas may be used for control of systemic relapses. Galanis and colleagues 238 reported a 72% response rate in 22 patients with extrapulmonary small cell carcinomas of all sites treated with a platinum-base regimen; however, the median duration of response was only 8.5 months. Owing to the poor long-term survival rate and the poor results obtained with surgery, radiotherapy may be an alternative for palliation in those patients with locally advanced disease.
Regardless of the therapy employed, the long-term prognosis for sinonasal SNEC remains poor. Of 12 cases reported by several authors, 226 - 229, 239 eight patients (67%) had died of disease and only three (25%) were alive with no evidence of disease. In a study of extrapulmonary small cell carcinomas from the Mayo Clinic, 238 the median survival of 14 patients with primary head and neck tumors was only 14.5 months. This group included seven cases involving the paranasal sinuses. It has been stated that the biological behavior of these tumors differs from that of their pulmonary counterparts in that aggressive local disease, rather than systemic dissemination, appears to dominate the clinical picture 226 - 228, 239 ; however, cervical lymph node and pulmonary metastases occur in a significant number of patients. 225, 238

Carcinoid Tumor
Carcinoid tumors of the sinonasal tract are extremely uncommon, with only isolated case reports. 240, 241 Siwersson and Kindblom 240 described a carcinoid tumor of the nasal cavity followed by a typical carcinoid tumor in the lung. These lesions showed the trabecular and organoid architecture typical of carcinoid tumors in other organs; however, the tumor cells in both had an oncocytic cytoplasm closely resembling that of oncocytomas of minor salivary gland origin. 240, 241 One of these cases had low mitotic activity and at least focal areas of marked cytologic atypia. 240 The differential diagnosis of these uncommon lesions includes oncocytoma; in fact, it is recommended that any oncocytic lesion in this region be investigated for neuroendocrine differentiation.
McCluggage and colleagues 242 reported a widely invasive neoplasm with amphicrine differentiation. The tumor was composed of large cohesive cells with an organoid arrangement and small glandular spaces. There were areas composed of goblet cells with abundant intracellular mucin. Immunohistochemistry and electron microscopy demonstrated neuroendocrine differentiation. The overall appearance of the tumor was reminiscent of a goblet cell carcinoid of the appendix.

Sinonasal Undifferentiated Carcinoma

Clinical Features
SNUC is a highly aggressive, undifferentiated anaplastic carcinoma, without obvious squamous or glandular differentiation. 243 - 247 This tumor is a distinct clinicopathologic entity and needs to be distinguished from other poorly differentiated carcinomas. Although earlier reports suggested a role for EBV in the pathogenesis of SNUC, 248, 249 recent studies in morphologically well-defined cases have not shown the EBV genome in SNUC. 250, 251 Loss of the retinoblastoma tumor suppressor gene function has been implicated in their pathogenesis. 252
The age range at presentation is broad, with both young adults and the elderly being affected. The median age is reported to be in the sixth decade (53–58 years). There is a male predominance (2–3:1), and an association with smoking has been reported. 245, 250, 251, 253 Symptoms are related to an extensively infiltrative and destructive sinonasal mass. Involvement of the nasal cavity, maxillary antrum, ethmoid sinus, sphenoid sinus, frontal sinus, nasopharynx, orbit, and cranial cavity is frequent. 244, 247, 253, 254

Pathologic Features
SNUCs consist of nests, trabeculae, ribbons, and sheets of medium-size polygonal cells, often with an organoid appearance ( Fig. 3-37 ). The nuclei are round to oval, slightly to moderately pleomorphic, and hyperchromatic. The chromatin varies from diffuse to coarsely granular, and the nucleoli are typically prominent ( Fig. 3-38 ). Most cells have small to moderate amounts of eosinophilic cytoplasm. Mitotic figures are numerous, and vascular invasion is extensive. Individual cell necrosis, and central comedo-type necrosis of cell nests are common (see Fig. 3-37 ). Squamous and glandular differentiation is absent, by definition; however, focal squamous differentiation has been reported in two cases. 255 Occasional sinonasal undifferentiated carcinomas may be associated with severe dysplasia or carcinoma in situ of the overlying surface mucosa. Immunocytochemical stains for pan-cytokeratin and simple keratins, including CK7, CK8, and CK19, are positive in all cases. 256 Keratin 4, CK5/6, and CK14 are negative. 256 The tumors are variably positive for epithelial membrane antigen, neuron-specific enolase, CD99, p5, and p63. The tumors are negative for carcinoembryonic antigen, S-100 protein, chromogranin, and synaptophysin. 250 Electron- microscopic studies document rare dense-core granules in individual cells. 243, 246

Figure 3-37 Sinonasal undifferentiated carcinoma. The tumor shows a nested pattern with central comedonecrosis and vascular invasion.

Figure 3-38 Sinonasal undifferentiated carcinoma. The cells are large and possess eosinophilic cytoplasm with a vesicular nucleus. Nucleoli are prominent.

Differential Diagnosis
Differential diagnostic considerations for SNUC include poorly differentiated squamous cell carcinoma and adenocarcinoma, undifferentiated nasopharyngeal carcinoma, ONB (grades III–IV), large cell lymphoma, and malignant melanoma. 232, 251, 256, 257 A first-line immunohistochemical diagnostic panel may include pan-cytokeratin, S-100, CD45, and CD30. If the tumor is cytokeratin positive and negative for all other markers, the differentiation from various carcinomas may be possible with careful morphologic examination. Areas of spindling of tumor cells with maturation of tumor cords are characteristic of the differentiated type of nonkeratinizing nasopharyngeal carcinoma and are not found in SNUC ( Table 3-2 ).
Table 3-2 Differential Diagnosis of Sinonasal Undifferentiated Carcinoma Tumor Morphology Immunohistochemistry SNUC Lobular architecture, extensive necrosis, and vascular invasion; uniformly large nucleus with prominent nucleolus pan-CK + (diffusely and strongly), CK5/6 −, EBV −, neuroendocrine markers −, lymphoid markers −, melanocytic markers − SCC, nonkeratinizing, poorly differentiated Frequent association with in situ SCC; cohesive, pushing, and infiltrative growth pattern; intercellular bridges; pleomorphic nuclei pan-CK + (diffusely and strongly), CK5/6 +, EBV −, neuroendocrine markers −, lymphoid markers −, melanocytic markers − Adenocarcinoma, poorly differentiated Focal glandular differentiation, focal mucin CEA +, pan-CK + (diffusely and strongly), CK5/6 −, EBV −, neuroendocrine markers −, lymphoid markers −, melanocytic markers − Nasopharyngeal carcinoma (lymphoepithelioma type) Discohesive single cells or syncytial sheets, prominent lymphoplasmacytic infiltrate, absence of necrosis, spindle cells, and vesicular nuclei EBV +, pan-CK + (diffusely and strongly), CK5/6 +, neuroendocrine markers −, lymphoid markers −, melanocytic markers − Olfactory neuroblastoma, grade IV Nested architecture, neurofibrillary background −/+, junctional activity/epitheliotropism + pan-CK −/+; at least focal S-100 +; sustentacular cells, NF +; chromogranin +, synaptophysin + Large cell lymphoma Discohesive tumor cells Lymphoid markers +, EBV +/−, pan-CK −, neuroendocrine markers −, melanocytic markers − Malignant melanoma Pigment +, junctional activity/epitheliotropism +, moderate amount of amphophilic cytoplasm S-100 +, melanocytic markers +, pan-CK −, neuroendocrine markers −, lymphoid markers −, EBV −
−/+, equivocal; CEA, carcinoembryonic antigen; CK, cytokeratin; EBV, Epstein-Barr virus; NF, neurofilament; SCC, squamous cell carcinoma; SNUC, sinonasal undifferentiated carcinoma.

Treatment and Prognosis
The prognosis of SNUC is poor. Complete surgical resection usually cannot be achieved, and until recently, irradiation and chemotherapy have been of little value. Recent studies have shown an improved response to cisplatin-based chemotherapy and bone marrow transplantation. 246, 258 The median survival ranges from 4 to 18 months, with more than 80% of the patients dying of the disease in 5 years. 2510, 245

Neuroectodermal Tumors


Clinical Features
Paragangliomas have been reported as primary tumors in the nasopharynx, nasal cavity, and paranasal sinuses ( Fig. 3-39 ) 259 - 262 or as secondary lesions extending from a carotid body or jugulotympanic or vagal paraganglioma. 261, 263 Most reported cases have occurred in females with a wide age range. Paragangliomas are most commonly seen as polypoid or exophytic masses in the middle or inferior turbinate. They have also been described in the posterior ethmoidal area, lateral and posterior pharyngeal walls, and posterior choana.

Figure 3-39 Paraganglioma of the left ethmoid sinus.

Pathologic Features and Differential Diagnosis
The recognition of paragangliomas in the sinonasal tract is mainly based on the awareness of their occurrence in this region. The microscopic characteristics are similar to those of paragangliomas in other head and neck locations ( Fig. 3-40 ). Paragangliomas may show significant nuclear pleomorphism; however, they are not mitotically active. The differential diagnosis includes ONB, pituitary adenoma, malignant melanoma, and poorly differentiated carcinoma. The cell nests of paraganglioma and ONB are surrounded by S-100–positive sustentacular cells; however, the chief cells of paraganglioma have more abundant cytoplasm and large vesicular nuclei that often exhibit prominent nucleoli and pseudonucleoli. Paragangliomas do not exhibit neurofibrillary background or rosettes characteristic of ONBs. Pituitary adenomas may be distinguished from paragangliomas based on smaller tumor cell size and the immunohistochemical expression of specific pituitary hormones. Although the differential diagnosis of paraganglioma in the sinonasal tract includes malignant melanoma, these neoplasms are easily distinguishable. Melanomas are diffusely positive for S-100 and melanocytic differentiation markers (HMB-45, MART1/A103, tyrosinase) and are negative for keratins, synaptophysin, and chromogranin. Electron microscopy in paragangliomas may demonstrate the presence of large numbers of dense core neuroendocrine granules, which should not be confused with melanosomes. Poorly differentiated carcinomas of the sinonasal tract usually reveal mitotic activity, necrosis, more nuclear pleomorphism, and a more infiltrative growth pattern than paragangliomas and do not stain for neuroendocrine markers.

Figure 3-40 Paraganglioma of the ethmoid sinus. The tumor cells are large and possess abundant eosinophilic cytoplasm. Note the presence of intranuclear pseudoinclusions. The original diagnosis in this case was malignant melanoma due to the presence of S-100–positive sustentacular cells.

Treatment and Prognosis
Sinonasal paragangliomas generally behave in a benign fashion. However, rare cases of malignant paraganglioma of the nasal cavity have been described. 264, 265 The latter appear to be aggressive neoplasms characterized by the development of multiple local recurrences and brain metastases. The treatment of sinonasal paragangliomas is complete surgical resection, if possible. In recurrent or malignant tumors, surgical debulking and radiotherapy may provide long-term local control.

Malignant Melanoma

Clinical Features
Primary malignant melanoma of the sinonasal tract constitutes approximately 1% of all melanomas. 266 - 270 In the material reviewed by Friedmann and Osborn 271 at the Institute of Laryngology and Otology in London, melanomas represented 5% of all sinonasal tumors and were the second most common malignancy (23%) in that region. The nasal cavity is more frequently affected than the paranasal sinuses. In the nasal cavity, involvement of the anterior septum, inferior turbinate, and middle turbinate is most common. The maxillary antrum, followed by the ethmoid sinuses, are the most frequently involved paranasal sinuses. 272 - 274 Primary melanomas of the frontal and sphenoid sinuses and the nasopharynx are extremely rare. There is no sex or race predilection, and 80% of the patients are older than 50 years of age with median age in the seventh decade. 275, 276 Symptoms at presentation are nonspecific and are related to the location of the tumor; they include nasal obstruction, epistaxis, facial pain, and sometimes melanorrhea or black mucus discharge. Symptoms may be present for a few weeks, several months, or even several years. 275, 276

Pathologic Features
Sinonasal melanomas are frequently polypoid or sessile nodules of tan-pink or brown- black color, depending on the absence or presence of pigment ( Fig. 3-41 ). The polyps are 2 to 3 cm in size; however, larger tumors involving several paranasal sinuses and extending into the skull base are not uncommon. Mucosal ulceration, hemorrhage, and necrosis are frequent. Histologically, melanomas have a varied cytologic appearance. 2760, 266 Most are composed of large epithelioid cells with abundant eosinophilic cytoplasm with round nuclei showing prominent eosinophilic nucleoli and/or spindle cells ( Fig. 3-42 A and B ). Approximately 30% to 40% of the tumors are composed of undifferentiated small round blue cells resembling lymphoma or other small round blue cell tumors (see Fig. 3-42 C ). Tumors may show plasmacytoid, rhabdoid, or large, pleomorphic, multinucleated, bizarre giant cells and rarely clear or vacuolated cells (see Fig. 3-42 D ). Frequently, an admixture of several morphologic tumor cell types is present. Tumor cells usually exhibit significant nuclear pleomorphism and numerous mitotic figures including atypical forms. Approximately 80% of tumors have cytoplasmic pigment. The neoplastic cells are arranged in an array of architectural patterns: solid, organoid, trabecular, alveolar, or any combination of these patterns. Spindle cell tumors may resemble high-grade sarcomas. Extensively necrotic tumors may show a pseudopapillary (peritheliomatous) architecture due to the preservation of perivascular tumor cells ( Fig. 3-43 ). 275, 276 Vascular and neural invasion is frequent. Junctional activity or pagetoid changes and cellular nests or theques may be identified in the adjacent nonulcerated epithelium in more than 70% of tumors, if diligently searched. However, unlike the cutaneous and oral melanoma, sinonasal melanoma does not present as pure in situ preinvasive or intraepithelial tumors. 276 All sinonasal melanomas are invasive, with 60% incidence of infiltration into deep tissues (e.g., bone, cartilage, and/or skeletal muscle). Desmoplastic variants are exceedingly rare. We have seen only one desmoplastic melanoma arising in the nasal vestibule in a background of solar elastosis. 277 Melanomas are usually positive for vimentin, S-100 (95%), HMB-45 (98%), and other melanocytic markers (tyrosinase, MART1/A103, microphthalmia transcription marker). In amelanotic tumors, the use of these stains may be helpful in establishing a definitive diagnosis. 278

Figure 3-41 Pigmented melanoma of the nasal cavity presenting as a sessile, dark tan nodule.

Figure 3-42 A , Sinonasal melanoma with epithelioid tumor cells showing marked nuclear atypia and pleomorphism, large nuclei with prominent nucleoli, moderate to abundant amphophilic cytoplasm, and mitoses. B , Spindle cell sinonasal melanoma involving the overlying respiratory mucosa. C , Melanoma with small, round, undifferentiated cells mimicking lymphoma but the pigment ( center right ) is a giveaway. D , Sinonasal melanoma with vacuolated tumor cells.

Figure 3-43 A , Amelanotic melanoma growing in solid sheets underneath an intact respiratory mucosa. B , Sinonasal melanoma with pseudopapillary architecture. C , In situ melanoma involving the respiratory mucosa. Note the subepithelial pigment. D , Immunohistochemistry with antityrosinase antibody (T311) showing in situ and subepithelial tumor cells, and with antimicrophthalmia transcription factor showing positive nuclear expression in undifferentiated tumor cells ( E ) (same tumor as in Fig. 3-42 C ).

Differential Diagnosis
The differential diagnosis of sinonasal malignant melanoma varies according to the cellular morphology and predominant architecture of the primary tumor. In lesions with epithelioid or spindle cell patterns, or both, the possibilities of a poorly differentiated carcinoma, sarcomatoid carcinoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, and other sarcomas should be excluded. Tumors comprising small undifferentiated cells (small round blue cells) need to be distinguished from lymphoma, rhabdomyosarcoma, ES/PNET, ONB, and SNEC. The presence of melanin pigment and junctional activity accompanied by immunohistochemistry with an appropriate panel of antibodies is of great value in establishing a definitive diagnosis. Melanomas are negative for CK, lymphoid, and myogenic markers. Metastatic melanoma to the sinonasal area may rarely be seen in association with stage IV widely disseminated cutaneous melanoma. Clinical history and in situ melanoma in the respiratory mucosa may help distinguish primary from secondary sinonasal melanoma.

Treatment and Prognosis
Clinical staging and histologic microstaging are independent predictors of survival. 2800, 269 The most frequently used clinical staging is independent of tumor size and takes into account the presence of metastasis to the regional lymph nodes and distant sites ( Table 3-3 ). The vast majority (80%–85%) of sinonasal melanomas are localized (N0M0) at presentation, and less than 10% have regional lymph node and distant metastasis. 269, 275, 278, 280 However, during the course of disease, 40% to 50% of the patients develop distant metastasis. 278, 280 Tumors with distant metastasis (stage III) or deep-tissue invasion (level III) have a poor prognosis. The presence of undifferentiated tumor cells comprising more than 25% of the tumor or pseudopapillary or sarcomatoid architecture reduces survival significantly compared with tumors without these features. In one study, vascular invasion was a significant predictor of disease progression (i.e., local recurrence, nodal metastasis, distant metastasis, and poor disease-specific survival). 280 The predictors of poor survival are summarized in Table 3-3 . Complete surgical resection is the treatment of choice. Radiotherapy and chemotherapy are of little value. In a study of 28 cases treated with radiotherapy alone, the reported local control rate was 79%; however, the 5-year survival rate was only 25%. 281 Malignant melanoma of the sinonasal tract is an aggressive disease with a 60% to 80% local recurrence rate, median survival of 2 to 3 years, and 5-year disease-specific survival varying from 10% to 47%. 268, 271, 273, 275, 276, 280, 282 Metastases to the lung, brain, and liver are common. 2830, 272 Interestingly, long-term survival has been reported in a small number of patients.
Table 3-3 Predictors of Poor Prognosis Clinical
Higher clinical stage 269, 280
Stage I: N0M0 (T any )
Stage II: N1M0 (T any )
Stage III: M1 (T any N any )
Tumors >3 cm in size and/or involving multiple anatomic sites 275
Recurrences 275 Pathologic
Higher microstage 279
Level I: Pure melanoma in situ without invasion or with microinvasion only
Level II: Invasion into lamina propria
Level III: Invasion into deep tissue (bone, cartilage, skeletal muscle)
Undifferentiated cells * comprising >25% of the tumor 275, 279
Pseudopapillary or sarcomatoid † architecture 275, 279
Necrosis 280
Vascular invasion 280
* Undifferentiated tumor cells were either small round blue cells resembling lymphoma or markedly pleomorphic, large, bizarre multinucleated giant cells.
† Sarcomatoid architecture resembling high-grade spindle or pleomorphic sarcoma.

Olfactory Neuroblastoma

Clinical Features
ONB was first described by Berger and colleagues 284 in 1924. Since then, it has been described and referred to by numerous terms: esthesioneuroblastoma, esthesioneuroepithelioma, esthesioneurocytoma, and olfactory placode tumor. 285, 286 ONB is an uncommon tumor and makes up approximately 10% of all nonsquamous malignancies in the nasal cavities and paranasal sinuses. 287 These tumors arise almost exclusively in the olfactory neuroepithelium in the superior portion of the nasal cavity. The putative cell of origin is a basal reserve cell, the olfactory stem cell that gives rise to both neuronal and epithelial (sustentacular) cells. 288 There is no race or gender predilection. ONB is seen in a broad age range (11 to older than 90 years) with bimodal peaks at 15 and 50 years. However, most cases present in the third and fourth decades, 289 - 295 The main presenting symptoms are nasal obstruction, epistaxis, and anosmia. Myers and colleagues 296 reported a case with invasion of the oral cavity and inappropriate antidiuretic hormone secretion. ONBs are slow-growing tumors, and symptoms may be present for a variable duration of time. Clinical and radiologic examination usually demonstrates a polypoid mass high in the nasal cavity, often extending into the paranasal sinuses. The classic radiologic image is that of a dumbbell-shaped mass in the superior nasal cavity with extension into the intracranial cavity across the cribriform plate.
In 1976, Kadish and colleagues 297 proposed a staging system for these neoplasms ( Table 3-4 ). Most tumors are in stage B and C at presentation with less than 10% with nodal and distant metastases ( Fig. 3-44 ). 288, 295

Table 3-4 Staging and Grading of Olfactory Neuroblastoma

Figure 3-44 Olfactory neuroblastoma involving the left nasal cavity and maxillary sinus.

Pathologic Features
Under low-power magnification, most ONBs consist of well-circumscribed cell nests and lobules separated by fibrovascular stroma ( Fig. 3-45 A ). The lobules may coalesce and interconnect, forming sheets of cells with a prominent capillary network. Approximately 60% to 70% of tumors have a variable amount of fibrillary stroma (see Fig. 3-45 B ), although in some cases, this may be focal ( Fig. 3-46 A ). Rosettes are also typical (see Fig. 3-45 C ), but like the fibrillary stroma may be absent. Homer Wright rosettes, also called pseudorosettes, are annular arrays of cells surrounding central zones of fibrils. They are most common in well-differentiated cases that contain a prominent fibrillary background. Less commonly, Flexner-Wintersteiner rosettes may be noted. Flexner-Wintersteiner rosettes are glandlike structures indicative of olfactory differentiation. 286, 298 The neoplastic cells are small or medium size and have pale eosinophilic cytoplasm with indistinct borders. The nuclei are round, somewhat vesicular, with fine “salt-and-pepper” chromatin and absent or inconspicuous nucleoli. Most cases show no or only mild to moderate nuclear pleomorphism (see Fig. 3-45 D ) 299 and a low mitotic rate. Necrosis is uncommon and is generally seen in poorly differentiated tumors with high mitotic counts. 286, 299 Pagetoid extension of tumor cells in the adjacent respiratory epithelium and mucosal glands may sometimes be seen ( Fig. 3-47 ). Divergent differentiation (e.g., glandular differentiation [see Fig. 3-46 B ]), squamous or myogenic differentiation, 300 and melanin pigment have been described. 301 Maturation to ganglioneuroblastoma is rarely seen in ONB. 302

Figure 3-45 A , Typical low-power appearance of olfactory neuroblastoma. The tumor is composed of well-defined nests of round cells separated by fibrovascular septa. B , Olfactory neuroblastoma showing abundant neurofibrillary stroma with small cells containing round hyperchromatic nuclei. This morphologic appearance is closely reminiscent of a pediatric neuroblastoma. C , Olfactory neuroblastoma with extensive rosette formation. D , Moderate nuclear pleomorphism is found in this olfactory neuroblastoma.

Figure 3-46 A , Poorly differentiated olfactory neuroblastoma (ONB) with sheets of neoplastic cells and focal neurofibrillary stroma. B , ONB with glandular differentiation. The glandular component is considered evidence of true olfactory differentiation by some authors and is usually immunoreactive for keratins.

Figure 3-47 A , Pagetoid involvement of submucous glands by tumor cells in olfactory neuroblastoma. B , Immunohistochemistry with pan-cytokeratin showing tumor cells (negative) between the basement membrane and the epithelium (positive) of submucous glands.
Immunohistochemical studies have shown that the cells of ONBs express neuron-specific enolase, CD56, synaptophysin ( Fig. 3-48 A ), and chromogranin. The periphery of the cell nests shows S-100 protein–positive (see Fig. 3-48 B ) spindle or stellate cells (sustentacular cells), which may be sparse in poorly differentiated, high-grade ONBs. Neurofilament protein and class III beta-tubulin are seen within the cytoplasm and fibrillary matrix. 302 ONBs are usually negative for CK; however, focal immunoreactivity may be found in approximately 20% to 25% of tumors, 3030, 290 generally in areas with epithelial differentiation (see Fig. 3-48 C ).

Figure 3-48 A , Diffuse expression of synaptophysin in a typical olfactory neuroblastoma. B , Sustentacular cells expressing S-100 at the periphery of the cell nests. C , Olfactory neuroblastoma with glandular differentiation immunoreactive for keratin.
Ultrastructurally, the fibrils in the fibrillary matrix correspond to tangles of neuronal cell processes. 232, 286, 304, 305 True olfactory differentiation is characterized by cylindrical cells with thin apical microvilli and a bulbous tip or olfactory vesicle containing a few dense-core granules. 286, 298
Hyams and colleagues 299 introduced a four-tier histologic grading system with the most well-differentiated tumors at one end and the most anaplastic, poorly differentiated, highly mitotic and necrotic tumors at the other end of the system (see Table 3-4 ). The low-grade (grades I–II) tumors have better a 5-year survival rate compared with high-grade (grades III–IV) tumors. The majority of ONBs are low grade and well differentiated (52%–60%). 288, 306 However, all histologic grades can metastasize.
Recently, the chromosomal translocation t(11;22) (q24;q12) with fusion of the EWS/FLI1 genes, typical of Ewing’s sarcoma or peripheral neuroectodermal tumor, was reported in two cell lines obtained from metastatic ONB and six primary ONBs. 307, 308 However, immunohistochemical studies (CD99, O13) failed to detect the protein product of the MIC-2 gene in ONB. 288, 309 We did not find EWS/FLI gene fusion messenger RNA in a series of well-characterized ONBs. 310 Wild-type p53 overexpression appears to be a late event in the progression of ONB. 311

Differential Diagnosis
The differential diagnosis of ONBs includes other neuroendocrine and small cell lesions of the sinonasal tract (see Table 3-1 ). Although ONB and sinonasal SNEC share certain morphologic features in addition to expression of neuroendocrine and epithelial markers, they should be differentiated because of significant prognostic differences. True sinonasal SNEC resembles small cell carcinoma of the lung. The degree of mitotic activity and the extensive areas of necrosis present in SNEC are not seen in most ONBs. SNECs do not exhibit cell nests surrounded by S-100–positive cells. Keratin expression in ONB is absent or limited to foci of glandlike or olfactory differentiation, whereas SNEC is diffusely positive. Ordonez and Mackay 286 proposed the separation of ONBs into two groups: classic neuroblastoma and neuroendocrine carcinoma. However, the clinical and biological value of this classification scheme remains unsettled. 285, 299, 302, 304, 312 We discourage the use of the term neuroendocrine carcinoma for lesions that fulfill the diagnostic criteria for ONB. The term, used in this context, fosters confusion with SNEC and has not been proven to be of clinical value. 302, 313
Olfactory neuroblastomas should also be distinguished from rhabdomyosarcoma. Rhabdomyosarcoma is one of the most common sinonasal malignant tumors in children, 314 - 316 but is also encountered in adults. 317 - 319 In adults, the solid variant of alveolar rhabdomyosarcoma may pose a significant diagnostic problem ( Figs. 3-49 and 3-50 ). The nests of alveolar rhabdomyosarcoma may resemble the characteristic nests of ONB. The use of a panel of immunostains should be extremely helpful in establishing the correct diagnosis. Rhabdomyosarcoma expresses muscle-specific actin, sarcomeric actin, desmin, myogenin, myoglobin, and myoD1 ( Figs. 3-50 and 3-51 ). Nuclear markers of skeletal muscle differentiation (e.g., myogenin) are especially useful when tumor cells are undifferentiated rather than cytoplasmic markers (e.g., myoglobin), which work best when tumor cells have abundant cytoplasm. The characteristic gene fusion transcript PAX3/PAX7-FKHR seems to be a useful molecular diagnostic tool; however, it is less sensitive than myogenin in the detection of rhabdomyosarcoma. 320 Rhabdomyosarcomas are usually negative for neuroendocrine markers and do not possess S-100–positive cells at the periphery of the tumor nests. However, rare rhabdomyosarcomas may stain for CD56, CD57, synaptophysin, chromogranin, and keratin. 320A Therefore, myogenic markers (desmin and myogenin) should be added to the immunohistochemical battery of stains for all small round blue cell tumors. ONBs are negative for myogenic markers. This differential diagnosis is critical as the prognosis of rhabdomyosarcoma in adults is dismal, despite multimodal therapy. For a more detailed description of rhabdomyosarcoma, please refer to Chapter 8 (“Soft-Tissue Tumors”) in this book.

Figure 3-49 Solid variant of alveolar rhabdomyosarcoma involving the lateral nasal wall. The tumor cells are small and raise the traditional differential diagnosis of small round blue cell tumors.

Figure 3-50 Alveolar rhabdomyosarcoma with nuclear expression of myogenin.

Figure 3-51 Desmin ( A ) and MyoD1 ( B ) are strongly positive in this alveolar rhabdomyosarcoma.
Malignant sinonasal melanoma, predominantly composed of small cells, may be confused with ONB. However, the degree of cytologic atypia and pleomorphism generally seen in melanoma is uncommon in ONB. Moreover, the immunophenotypes of these lesions are different. ONBs are diffusely positive for neuroendocrine markers, which are absent in melanomas. The characteristic location of the S-100–positive cells in ONB should also be helpful in making this distinction. The small undifferentiated cells of teratocarcinoma may resemble the cells of ONB 321, 322 ; however, the lack of nesting coupled with the presence of other epithelial and mesenchymal elements should point to the correct diagnosis. Sinonasal pituitary adenomas should also be considered in the differential diagnosis of ONB, but the lack of fibrillary background and the expression of keratin and specific pituitary hormones in pituitary adenomas indicate the correct diagnosis.
The distinction of sinonasal ES/PNET from grade III/IV ONB, particularly in small endoscopic biopsy specimens, can be extremely difficult. Although the phenotypes of these two distinct neoplasms are characteristic, they may have overlapping expression of vimentin, neuron-specific enolase, S-100, keratin, synaptophysin, and CD56. 323 - 325 Confirmation of the diagnosis with an extensive immunohistochemical panel or molecular genetics is almost mandatory given the differences in management and prognosis of these neoplasms. Periodic acid–Schiff staining usually demonstrates cytoplasmic glycogen in ES/PNET, and the diagnosis can be confirmed by their characteristic membranous staining for CD99 and nuclear expression of FLI1. FLI1 expression has not been studied in ONBs; however, they are negative for CD99 and lack the t(11;22) seen in most ES/PNET. 309, 310, 324, 326 - 329 Chapter 8 (“Soft-Tissue Tumors”) describes the characteristics of ES/PNET in greater detail.

Treatment and Prognosis
Complete surgical resection, if feasible, and adjuvant radiotherapy is the treatment of choice for ONBs. 288, 291, 292, 302 Local recurrence was seen in 29% to 38%, and nodal and distant metastasis developed in 16% to 46%. 288, 302 Recurrence or metastases may develop as late as 21 years after initial diagnosis; therefore, long-term follow-up is necessary. Combination chemotherapy with proton beam irradiation and peripheral blood stem cell transplantation in advanced or recurrent disease has shown promising results. 285, 294 The prognosis of ONB depends to a certain extent on the clinical stage, although the clinical behavior is often unpredictable. Histologic grading into low grade (Hyam’s grades I–II) and high grade (Hyam’s grades III–IV), a proliferative index (poor prognosis if >10%), and the presence or absence of S-100–positive sustentacular cells (minimal or absent: poor prognosis) are additional prognostically relevant factors. 295, 302 Wild-type p53 overexpression tends to correlate with local aggressive behavior and the development of metastasis. 311
Soft-Tissue Tumors
Soft-tissue tumors are rare in the sinonasal region. We describe only those lesions that are restricted to or seen with some frequency in the nasal cavity and the paranasal sinuses. For a more detailed description of various soft-tissue tumors, the reader is re- ferred to Chapter 8 in this book, dedicated to soft-tissue tumors.

Vascular Tumors

Lobular Capillary Hemangioma

Clinical Features
Lobular capillary hemangioma (pyogenic granuloma) is a distinctive vascular lesion most commonly seen in the fourth and fifth decades of life. It frequently affects pregnant females or males younger than 18 years of age. 330 - 332 There is no sex difference after 40 years of age. Injury and hormonal factors seem to play a role in their etiology. The predominant sites of involvement are the anterior portion of the nasal septum (Little’s area) and the tip of the turbinates. The most common clinical symptoms are epistaxis and nasal obstruction. Lesions arising in pregnant females often undergo spontaneous regression after delivery.

Pathologic Features
Grossly, lobular capillary hemangiomas are red or blue nodules or polypoid masses with smooth contours measuring up to 2 cm in diameter. Microscopically, they are composed of small, uniform vascular channels with a lobular architecture, often surrounding a larger central vessel (feeder vessel). The individual capillaries vary from solid nests of plump endothelial cells without lumina to large vessels lined with prominent endothelial cells showing mitotic activity. Intravascular papillary endothelial hyperplasia (tufting) may be seen. The endothelium is surrounded by pericytes and stromal cells. The stroma may be fibromyxoid. Secondary changes include mucosal ulceration with marked acute inflammation and a variable infiltrate of lymphocytes and plasma cells (pyogenic granuloma). 332

Differential Diagnosis
Perhaps the most clinically important lesions that need to be distinguished from a lobular capillary hemangioma are nasopharyngeal angiofibroma, glomangiopericytoma (sinonasal hemangiopericytoma), and angiosarcoma. The thick abnormal blood vessels and spindle or stellate fibroblasts of angiofibroma are significantly different from the small capillary-size vessels with a lobular pattern seen in hemangiomas. The nuclear atypia and infiltrative pattern that characterize angiosarcoma are also absent in a hemangioma. Glomangiopericytomas (sinonasal hemangiopericytomas) are larger and more cellular lesions than hemangiomas. They have an attenuated endothelial lining surrounded by a somewhat uniform population of plump to spindled cells, in contrast to the more prominent endothelial cells and the array of capillary-size blood vessels with the lobular architecture of a hemangioma. The capillaries in granulation tissue are frequently arranged perpendicular to the surface and lack the lobular architecture of a hemangioma.

Treatment and Prognosis
Hemangiomas are benign lesions, are treated by simple surgical resection, and only rarely recur. The pregnancy-related hemangiomas may regress after the termination of pregnancy.

Other Hemangiomas
Cavernous and venous hemangiomas are also found in this region. Cavernous hemangiomas tend to occur more frequently in adult men and are most often located in the lateral wall and may be intraosseous. Venous hemangiomas are uncommon and appear to preferentially involve the anterior nasal septum. Histologically, they are similar to their soft-tissue counterparts. Cavernous hemangiomas are composed of large, dilated, thin-walled blood vessels lined with flat, inactive endothelial cells and have a fibrous stroma. Venous hemangiomas have large, thick-walled blood vessels. Intraosseous cavernous hemangiomas can produce extensive bone destruction, thus simulating a malignant lesion 333 ; however, they lack the cytologic atypia and anastomosing vessels seen in angiosarcoma. Hemangiomas are usually cured by simple excision; in some cases of the cavernous type, embolization can be of benefit to control bleeding and facilitate resection. 333


Clinical Features
Angiofibromas are uncommon and constitute less than 1% of all head and neck tumors. They occur exclusively in young males between 10 and 25 years of age. Well-documented examples have been described in younger children (juvenile nasopharyngeal angiofibroma) and middle-aged patients; however, the tumor’s existence in females is disputed. Hyams 334 described no female patients among 150 cases reviewed at the Armed Forces Institute of Pathology. Angiofibromas arise in a fibrovascular nidus in the posterolateral wall of the roof of the nasal cavity where the sphenoidal process of the palatine bone meets the horizontal ala of the vomer and the pterygoid process and present predominantly and initially as a nasopharynx mass. The most common presenting symptoms are unilateral nasal obstruction and epistaxis. Extensive infiltration of adjacent structures (e.g., nasal cavities and maxillary sinuses, skull base, orbit, pterygoid region, temporal and infratemporal fossa, and middle cranial cavity) may cause facial swelling, diplopia, proptosis, headache, anosmia, and pain. More than one half of the patients have had symptoms for more than 1 year before diagnosis. The diagnosis of angiofibroma should be considered in any male younger than 30 years of age who presents with a nasopharyngeal mass.
Angiofibromas possess androgen, testosterone, and dihydrotestosterone receptors 335, 336 and basic fibroblast growth factor. 337, 338 This may explain their association with puberty in young males. The stromal and endothelial cells express activating transforming growth factor β 1, 339 but only the stromal cells express β-catenin and activating β-catenin gene mutation, suggesting that the stromal cells may be the neoplastic component of the tumor. 340 An association with familial adenomatous polyposis has been reported. 341 Estrogen and progesterone receptor expression is variable. 336, 342 On plain radiographs, the growing mass causes bowing of the posterior wall of the maxillary sinus. Selective carotid arteriogram demonstrates a typical and highly diagnostic vascular pattern (“blush”), which delineates the tumor and helps in presurgical embolization of the tumor ( Fig. 3-52 A ). Using computed tomography scans and magnetic resonance imaging, the tumors are staged I to IV, depending on their extent: stage I is limited to the nasopharynx; stage II involves the nasal cavities and paranasal sinuses without bone destruction; stage III invades the pterygopalatine, infratemporal, orbital, or parasellar regions; and stage IV shows intracranial infiltration. 343

Figure 3-52 A , Angiography demonstrating the typical irregular vascularity of a nasopharyngeal angiofibroma. B , Surgical specimen of an angiofibroma showing its lobular and markedly fibrous appearance.

Pathologic Features
Grossly, angiofibromas are well-circumscribed, lobulated, tan to purple-red masses measuring up to 6 cm in size but may be larger (see Fig. 3-52 B ). The cut surface has a fibrous appearance. Often, blood vessels can be seen near the base of resection. Ulceration, necrosis, and cystic spaces are distinctly uncommon.
Histologically, these tumors are characterized by the presence of a collagenized vascular stroma containing numerous, irregularly shaped (staghorn) blood vessels ( Fig. 3-53 ) lacking elastic fibers in their wall. 331, 344 - 346 The amount of collagen present in the stroma varies from fine to coarse strands embedded in a myxoid stroma to a dense, acellular collagenous tissue. The stroma contains spindle- or stellate-shaped myofibroblasts with plump nuclei and numerous mast cells (see Fig. 3-53 ). Occasional multinucleated stromal cells and ganglion-like cells similar to those seen in proliferative myositis can be encountered. Mitotic figures can also be seen, but they are uncommon. The shape and distribution of the blood vessels and stroma are variable within angiofibromas. The periphery of the lesion contains numerous small, capillary-like vessels lined with a single layer of endothelial cells with little fibrous tissue, whereas larger vessels with thick muscular walls surrounded by dense collagenous tissue are found in the center of the tumor. They are immunoreactive for vimentin and β-catenin, with occasional expression of smooth muscle actin ( Fig. 3-54 ). 3470, 340 Ultrastructurally, the stromal cells contain intranuclear inclusions, actin filaments, dense bodies, numerous pinocytotic vesicles, and dilated rough endoplasmic reticulum consistent with their fibroblastic/myofibroblastic nature. 347, 348

Figure 3-53 Nasopharyngeal angiofibroma with abundant interstitial collagen and characteristic stellate stromal cells ( A ) and with central blood vessel with thick wall and relatively hypocellular stroma ( B ). C , Solid portion of angiofibroma with collagenized stroma and thin collapsed blood vessels. D , Angiofibroma with edematous stroma, inflammatory cells, and thin-walled capillary-type blood vessels resembling granulation tissue.

Figure 3-54 Immunohistochemistry of angiofibroma showing strong nuclear immunoreactivity for β-catenin ( A ). B , CD31 demonstrating the large numbers of non-neoplastic endothelial cells. C , Smooth muscle actin showing the variable thickness of the blood vessels in nasopharyngeal angiofibroma.

Differential Diagnosis
The preoperative diagnosis of nasopharyngeal angiofibroma can be difficult. The diagnosis is based on clinical and radiologic findings. In fact, because of the characteristic radiologic appearance of angiofibroma, biopsy before definitive treatment is often unnecessary. These tumors should be distinguished from lobular capillary hemangioma, a distinction that can be extremely difficult in superficial biopsy material; however, the distinctive location of angiofibroma and its larger size and extension into adjacent structures make this differentiation possible. The differential diagnosis of nasopharyngeal angiofibroma also includes other vascular lesions such as glomangiopericytoma (sinonasal hemangiopericytoma), solitary fibrous tumor, and angiosarcoma, but the characteristic age, sex, and tumor location should strongly favor the diagnosis of angiofibroma. Furthermore, the thick blood vessels and the stellate stromal myofibroblasts seen in angiofibroma are not features of any of these neoplasms.

Treatment and Prognosis
Angiofibroma is a locally aggressive tumor and the prognosis depends on its local extent or stage. Surgical removal is the treatment of choice for resectable tumors. The recurrence rate is approximately 20% and is probably due to incomplete resection in extensive, high-stage tumors. Recurrences tend to occur within 1 to 2 years of surgery. Disease with intracranial extension has a higher frequency of recurrence. With recent advances in imaging and interventional neuroradiology, the recurrence rate has decreased considerably. Radiotherapy, hormone therapy, or chemotherapy may be employed for unresectable or recurrent disease 345, 349 ; however, sarcomatous transformation has been reported after radiotherapy. 350, 351 Preoperative embolization reduces the risk of intraoperative hemorrhage and incomplete tumor removal. Spontaneous regression as well as rare metastasis have been reported. 352, 353 The prognosis for a patient with angiofibroma is excellent; the mortality rate varies from 0% to 9% and is related to uncontrollable hemorrhage and intracranial extension.

Glomangiopericytoma (Sinonasal-Type Hemangiopericytoma, Hemangiopericytoma-like Tumor)
The sinonasal-type hemangiopericytoma, hemangiopericytoma-like tumor, and glomus tumor have been classified as glomangiopericytoma in the new World Health Organization classification of tumors. 354 Their association with hemangiopericytomas of soft tissues remains controversial. Most authors regard these lesions as related but separate entities and have used the term hemangiopericytoma-like tumors to refer to the nasal tumors. 355, 356 They appear to arise from a modified perivascular myoid cell. Their morphologic and immunophenotypic similarity to glomus tumor accounts for their renaming as glomangiopericytoma. 357, 358

Clinical Features
This uncommon soft-tissue neoplasm can arise at any site in the head and neck region, but the submucosal regions in the nasal cavity and the paranasal sinuses are the most frequent sites of involvement. Most patients are middle-aged or elderly adults, although tumors may be seen in a wide age range (5–86 years). There appears to be no race or sex predilection. The most common clinical symptoms are nasal obstruction and epistaxis. Physical and radiologic examinations reveal the presence of a polypoid mass high in the nasal cavity or a mass involving the paranasal sinuses with secondary extension into the nasal cavity. 359, 360 Folpe and colleagues 361 included two sinonasal hemangiopericytoma-like tumors of the ethmoid sinus in their series of osteomalacia-associated mesenchymal tumors. Both patients were men aged 21 and 46 years and had tumor-associated osteomalacia, phosphaturia, and hypophosphatemia for more than 2 years.

Pathologic Features
Grossly, the tumors are polypoid, measuring from less than 1 cm to 8 cm (average, 3 cm). Histologically, they resemble hemangiopericytomas in other locations. 362 Under low-power magnification, these tumors are well circumscribed and unencapsulated and have a uniform cellular appearance. Blood vessels range from small capillaries to sinusoidal spaces with a staghorn shape, often showing hyalinized walls ( Fig. 3-55 ). Necrosis and hemorrhage are generally absent. The tumor cells are tightly packed with little intervening collagen and may show a solid, fascicular, whorled, or storiform architecture. They have a monotonous appearance with round to oval shape and indistinct cytoplasm. The nuclei are regular and bland, varying from small and dark to somewhat vesicular ( Fig. 3-56 ). Nucleoli are inconspicuous. Mitoses are generally absent or fewer than three per 10 high-power fields. Some tumors may have myxoid or lipomatous areas. 363 Reticulin stains show reticulin fibers encircling individual pericytes. Immunostains are helpful in excluding other lesions with a hemangiopericytoma-like pattern. Factor VIII-RA, Ulex europaeus , and CD34 highlight the endothelium but are negative in the tumor cells ( Fig. 3-57 A ). Tumor cells consistently express vimentin and frequently express smooth muscle actin (see Fig. 3-57 B ), muscle-specific actin, fibroblastic growth factor-2, vascular endothelial growth factor, and factor XIIIa. 3640, 357 Electron microscopy reveals basal lamina enveloping individual tumor cells. 365

Figure 3-55 Glomangiopericytoma. A staghorn-shaped blood vessel is present in the center of the field. Note the uniform cellularity of the tumor.

Figure 3-56 Glomangiopericytoma. The tumor is quite cellular and uniform, but no significant cytologic atypia is present.

Figure 3-57 Immunohistochemistry of glomangiopericytoma. A , CD34 highlighting endothelial cells. Unlike solitary fibrous tumor, the neoplastic cells are negative. B , Tumor cells show diffuse and strong staining for smooth muscle actin.

Differential Diagnosis
Solitary fibrous tumor is the most difficult lesion to distinguish from glomangiopericytoma. Fortunately, this distinction is mostly of academic interest, given the excellent prognosis associated with both lesions. Glomangiopericytomas have a homogeneously cellular architecture, in contrast to the more varied appearance of solitary fibrous tumor, which exhibits hypercellular and hypocellular areas with abundant collagen. CD34 and bcl-2 are consistently expressed in solitary fibrous tumor but not in hemangiopericytoma. The expression of CD99 by solitary fibrous tumor may also help in the differential diagnosis of these entities. 366, 367 This distinction may be impossible in small specimens, and it is likely that many cases of glomangiopericytomas found in the literature in fact represent unrecognized solitary fibrous tumors. Sinonasal hemangiopericytomas do not express desmin and cytokeratin, which may help to differentiate smooth muscle tumor from synovial sarcoma.

Treatment and Prognosis
Most glomangiopericytomas behave in an indolent fashion and have an excellent prognosis after total surgical resection. 355, 360, 365, 368 However, recurrences are reported in 30% to 40% of cases, even after several years, and may be related to incomplete resection. Metastases are rare but well documented and are usually seen in the lung. 369, 370 Thus, these tumors are considered of borderline or low malignant potential. Features of aggressive behavior appear to be large size, bone invasion, marked pleomorphism, necrosis, increased mitosis (more than four per 10 high-power fields), and proliferative index (>10%). 358, 371

Other Vascular Lesions
Intravascular papillary endothelial hyperplasia (Masson’s tumor, Masson’s hemangioma) is a reactive pseudoneoplastic proliferation of endothelial cells associated with thrombosis of benign vascular lesions that may simulate angiosarcoma. 372 Rare cases have been described in the nasal cavity and paranasal sinuses. 330, 373 Histologically, intravascular papillary endothelial hyperplasia is characterized by dilated vascular spaces containing endothelium-lined papillary fronds with a variable amount of stroma ( Fig. 3-58 ). The stroma consists of a mixture of fibrin, red blood cells, and hypocellular hyaline material. The hyperplastic endothelial cells may have prominent but uniform nuclei with occasional mitotic activity. Thrombosis is usually present, and frank anaplasia or necrosis, unlike in angiosarcomas, is always absent.

Figure 3-58 Papillary endothelial hyperplasia (Masson’s tumor). Note the ectatic blood vessels with thin papillae containing hyalinized cores.
Rare cases of glomus tumor, angiomatosis, and hemangioendothelioma have been described in the sinonasal tract. 331, 374 Angiomatosis can be widespread and multifocal, but it is not a malignant lesion. The vascular channels of angiomatosis are lined with flat endothelium with no cytologic atypia. 331


Clinical Features
Primary angiosarcomas of the sinonasal tract are exceedingly rare tumors documented by a few case reports. 317, 331, 375 - 378 Association with radiation and vinyl chloride exposure has been reported. 379, 380 The maxillary sinus appears to be the most frequently involved region. The age at presentation is broad, but most reported cases are found in the sixth or seventh decade of life. 3780, 331 Symptoms at presentation are nonspecific and include unilateral nasal obstruction, epistaxis, purulent rhinorrhea, and proptosis in widely invasive tumors. These tumors have a tendency to present as bleeding polypoid masses or less commonly as ill-defined nodules. Angiosarcomas of the sinonasal tract exhibit histologic features similar to those of angiosarcomas in other locations and are characterized by the presence of freely anastomosing “gaping” vascular channels dissecting the underlying stroma ( Fig. 3-59 ). The neoplastic vessels are lined with atypical endothelial cells with “hobnail” nuclei and epithelial tufts ( Fig. 3-60 ). The individual tumor cells can be spindle-, polygonal-, or epithelioid-shaped with plump cytoplasm, hyperchromatic nuclei, and increased mitotic activity. They can be classified as low grade or high grade based on their overall appearance. Solid areas, necrosis, and hemorrhage may be prominent in high-grade tumors. The tumor cells express endothelial markers (e.g., CD31, CD34, factor VIII–related antigen, and Ulex europaeus ), which aid in the diagnosis. The differential diagnosis in this location includes hemangioma, glomangiopericytoma, solitary fibrous tumor, other soft-tissue sarcomas, and sarcomatoid carcinoma. Benign lesions that should be kept in mind when considering a diagnosis of angiosarcoma are an antrochoanal polyp with a prominent vascular component and papillary endothelial hyperplasia. 373 Unlike hemangiomas and other benign vascular lesions, low-grade angiosarcomas reveal the presence of infiltrative interconnecting vascular channels lined with atypical endothelial cells. Angiosarcomas also lack the lobular architecture seen in hemangiomas. Glomangiopericytoma and solitary fibrous tumor do not have the infiltrative pattern or the cytologic atypia seen in angiosarcoma.

Figure 3-59 Well-differentiated angiosarcoma involving the nasal septum. The tumor is dissecting the normal collagen and is associated with a moderate lymphocytic infiltrate.

Figure 3-60 This angiosarcoma shows only mild to moderate cytologic atypia. The endothelium has a hobnail appearance.
In contrast to angiosarcomas in other locations, primary sinonasal angiosarcomas tend to be low grade and have a lower incidence of local recurrences and metastases. Combined radical surgical resection followed by radiotherapy is the treatment of choice for sinonasal angiosarcomas, 376, 378 although small lesions can be treated by surgery alone. 331 The prognosis of angiosarcoma in the sinonasal tract is variable. The literature review by Bankaci and colleagues 376 revealed that five of 11 patients had no evidence of disease, three had local recurrences controlled by additional therapy, and three were alive with disease or had died with recurrences. One patient reported by Aust and colleagues 378 and another reported by Kimura and colleagues 375 were alive with no evidence of disease.

Kaposi’s Sarcoma and Bacillary Angiomatosis
Kaposi’s sarcoma of the sinonasal tract is extremely rare and is usually a manifestation of advanced disease in HIV-infected patients, although it may rarely arise in patients without HIV infection. 381 The histologic appearance is similar to that of Kaposi’s sarcoma in other locations ( Fig. 3-61 ). The immunohistochemical detection of HHV-8 protein expression helps differentiate them from morphologically similar lesions (e.g., pyogenic granuloma and bacillary angiomatosis). 382

Figure 3-61 Kaposi’s sarcoma of the nasal septum. The tumor is composed of spindle cells and contains numerous extravasated erythrocytes.
Bacillary angiomatosis is a vasoproliferative lesion caused by Rochalimaea henselae infection in immunosuppressed individuals, particularly those with HIV infection. 383, 384 Like Kaposi’s sarcoma, bacillary angiomatosis is also more common in the oral mucosa. A case involving the nasal cavity was described by Batsakis and Ro. 384 Histologically, bacillary angiomatosis resembles pyogenic granuloma; however, the endothelial cells are often larger and polygonal and may have some cytologic atypia. Numerous neutrophils are often present admixed with leukocytoclastic debris and a basophilic granular material. This material corresponds to large numbers of bacteria, easily demonstrable with Warthin-Starry or Steiner’s silver stains. 383

Fibrous and Fibrohistiocytic Tumors

Fibromas are uncommon benign lesions most frequently found in the nasal septum or vestibule. 385 The typical appearance is that of a small, raised nodule usually measuring less than 1 cm. Microscopically, they are composed of small spindle cells with bland cytologic features embedded in dense collagenous tissue. Fibromas are distinguished from aggressive fibrous lesions because of their small size and typical hypocellular appearance. They are treated by simple excision.

Benign Fibrous Histiocytoma
The nasal cavity and paranasal sinuses are rare sites for benign fibrous histiocytoma. 386 Symptoms at presentation are nonspecific. They are most often seen as tan to yellow nodules or polyps. Histologically, they show a mixture of spindle-shaped fibroblastic and myofibroblastic cells admixed with histiocytes arranged in a typical fascicular and storiform pattern. Often multinucleated giant cells, foamy and epithelioid histiocytes, hemosiderin-laden macrophages, lymphocytes, and plasma cells are present throughout the tumor. The stroma is variable and can be highly sclerotic with abundant collagen or focally myxoid. Benign fibrous histiocytoma should be distinguished from desmoid tumor (fibromatosis), malignant fibrous histiocytoma, and fibrosarcoma. These lesions differ from benign fibrous histiocytoma in their lack of histiocytes, multinucleated giant cells, and foam cells and show infiltration, cellular atypia, and nuclear pleomorphism. The treatment is complete surgical excision.

Myxoma and Fibromyxoma

Clinical Features
Myxomas of the craniofacial bones are rare neoplasms with well-defined clinicopathologic characteristics. 387 - 389 They affect the mandible more frequently than the maxilla (odontogenic myxoma). Most cases occur in children and young adults in the second and third decades of life, although they may also be seen in older individuals. 389 - 393 There is no gender predilection. 394 The most common presentation is that of a painless facial or nasal deformity. Other symptoms include nasal obstruction, exophthalmos, facial pain, and loose teeth. Radiologically, myxomas are seen as expansile unilocular or multilocular radiolucent masses involving the posterior or condylar regions of the mandible or the zygomatic process or alveolar bone of the maxilla. Extragnathic involvement is rare.

Pathologic Features
Grossly, myxomas are unencapsulated, although well demarcated. The consistency is variable, depending on the amount of collagen within the tumor and has been described as firm to gelatinous with a tan-yellow color. Myxomas are hypocellular tumors ( Fig. 3-62 A ) composed of slender spindle or stellate cells with inconspicuous cytoplasm and benign-appearing nuclei (see Fig. 3-62 B ). The chromatin is dense with no visible nucleoli. The tumor cells are embedded in an abundant myxoid or mucous background. 388, 389, 395, 396 A fibrous stroma may be found in some lesions, and when this stroma is relatively abundant, many authors use the term fibromyxoma. Unlike other myxomatous neoplasms, myxomas exhibit a poorly developed vascular network with only occasional thin capillary-type vessels within their stroma. Myxomas may extensively invade bone and adjacent soft tissues. The invasive edges of myxomas are broad pushing rather than infiltrative (see Fig. 3-62 A ).

Figure 3-62 A , Craniofacial myxoma compressing and pushing cortical bone. B , Small stellate cells embedded in a basophilic matrix in a typical myxoma. Note the absence of blood vessels.
The immunophenotype of craniofacial myxomas has not been widely studied. The tumor cells express vimentin and laminin. 397, 398 Muscle-specific actin, smooth muscle actin, desmin, CD31, CD34, collagen IV, and S-100 have been shown to be negative. Electron microscopy of myxomas has shown features of embryonic mesenchymal fibroblasts. The tumor cells exhibit scanty cytoplasm with a paucity of organelles.

Differential Diagnosis
The differential diagnosis of myxomas in the sinonasal tract is limited and includes other odontogenic tumors, benign peripheral nerve tumors, myxoid liposarcoma, and rhabdomyosarcoma. Odontogenic tumors are basically excluded by the absence of odontogenic epithelium in adequately sampled lesions. Although peripheral nerve tumors may reveal hypocellular areas with myxoid background, the tumor cells are plumper than the spindle and stellate cells of myxomas. In addition, nuclear palisading and S-100 are absent in myxomas. Malignant myxoid neoplasms exhibit increased cellularity and marked cellular atypia that significantly differ from the characteristic hypocellular appearance and bland cytologic features of myxomas. Normal dental follicle or developing dental papilla ( Fig. 3-63 ) in the lower maxilla can simulate myxoma, a problem compounded by the rare presence of small, inconspicuous nests of odontogenic epithelium in myxoma. The smooth periphery of the dental papilla or follicle focally covered by odontogenic epithelium helps exclude myxoma. In difficult cases, history and radiographic studies will help with this differential diagnosis.

Figure 3-63 A–C , Dental papilla with prominent myxoid stroma and a small focus of residual odontogenic epithelium on the smooth surface (see detail in C ); the focal presence of residual surface epithelium ( A and C , upper left ) helps differentiate this from a true myxoma. D , Dental follicle with myxoid stroma. The small clusters of odontogenic epithelium frequently help distinguish it from myxoma; however, myxoma may occasionally contain similar-appearing small odontogenic nests.

Treatment and Prognosis
Myxomas are benign tumors with an excellent long-term prognosis with no metastases and no tumor-related deaths. Nonetheless, myxomas have the capability of destroying bone and infiltrating soft tissues and the cranial cavity. 388, 389 The initial treatment should be aggressive because limited resections increase the chances of local recurrences and are associated with a high local recurrence rate. Three of the six patients reported by Fu and Perzin 388 developed local recurrences. The treatment of craniofacial myxomas is surgical and should be complete resection with wide margins of normal tissue. Often this requires subtotal or radical maxillectomy. 388, 389, 392, 393
Recently, we saw a malignant myxoid neoplasm with hypercellularity and cytologic atypia closely resembling a so-called myxofibrosarcoma of soft tissues ( Fig. 3-64 ). 397 The tumor developed multiple local recurrences with invasion of the cranial cavity, causing the patient’s death 5 years after initial resection.

Figure 3-64 Hypercellular areas of a low-grade sarcoma composed of plump spindle cells surrounded by a myxoid matrix. This case could be classified as myxofibrosarcoma. The patient died 5 years after initial resection with uncontrollable local disease.

Other Fibrous and Fibrohistiocytic Tumors (Fibromatosis [Desmoid Tumor], Solitary Fibrous Tumor, Fibrosarcoma, and Malignant Fibrous Histiocytoma)
Most fibrous tumors involve the soft tissues of the neck; however, involvement of the nasal cavity and paranasal sinuses may be seen rarely. 385 Symptoms at presentation are nonspecific and usually related to the presence of a mass, often accompanied by pain or tenderness.
Gnepp and colleagues 399 described 25 cases of fibromatosis in the sinonasal area. The maxillary sinus was the site most commonly affected, followed by the nasal cavity. Solitary fibrous tumors are reported in the nasal cavity and the paranasal sinuses. In two small series, the age ranged from 24 to 64 years, and there was no sex predilection. 400, 401
Fibrosarcoma, like most soft-tissue sarcomas, is uncommon in the sinonasal tract. 402, 403 Heffner and Gnepp 404 reported that most fibrosarcomas in the sinonasal tract are low-grade malignancies with sparse mitotic activity. Sinonasal fibrosarcomas exhibit a good long-term prognosis. The metastatic rate is low when compared with their counterparts in other locations 4040, 317 ; however, local recurrences are common and represent the most common cause of death in these patients. The recognition of the malignant nature of these tumors is often difficult, and it is possible that the high recurrence rate is due to incomplete removal. Fifteen of the 67 (22%) patients reported by Heffner and Gnepp 404 and only one of 13 cases (8%) reported by Fu and Perzin 386 died of the disease. Male sex, mitotic rate higher than four mitotic figures per 50 high-power fields, high histologic grade, and local failure are poor prognostic indicators. 402, 404
Malignant fibrous histiocytoma may be rarely seen in the sinonasal region. 317, 386, 405, 406 It shows no sex predilection, and most patients are in the sixth or seventh decade of life. At presentation, the tumors show advanced disease with extensive bone destruction and involvement of more than one anatomic compartment.
The low-grade fibrous tumors need to be differentiated from glomangiopericytoma (hemangiopericytoma-like tumors) in the sinonasal region. Malignant fibrous histiocytoma should be distinguished from sarcomatoid carcinomas, other high-grade sarcomas, particularly osteosarcoma, and spindle cell melanoma. These tumors are analogous to their soft-tissue counterparts and are discussed in greater detail in Chapter 8 in this book.

Muscle Tumors

Smooth Muscle Tumors
The sinonasal tract is a rare site for smooth muscle neoplasms. Leiomyomas, 407, 408 leiomyoblastomas, 409 and leiomyosarcomas have been reported in this location. 408 Leiomyosarcomas in the sinonasal tract are clinically similar to other sarcomas in this region, 317, 408, 410, 411 and their morphologic features are also similar to those of their soft-tissue counterparts ( Fig. 3-65 ). 412 The reader is referred to Chapter 8 in this book for a more exhaustive discussion of pathologic features and differential diagnosis. Leiomyosarcomas are aggressive neoplasms characterized by local recurrences and less commonly by distant metastases. However, tumors limited to the nasal cavity appear to have a better outcome. 408, 411 Seven of nine patients reported by Kuruvilla and colleagues 411 with small lesions were alive without disease after follow-up periods ranging from 9 months to 9 years. In the review by Dropkin and colleagues, 410 five of 14 patients had developed metastases. The treatment of sinonasal leiomyosarcomas is complete resection. The role of radiotherapy is controversial. 408, 410

Figure 3-65 Postradiation high-grade leiomyosarcoma. The tumor cells reveal an epithelioid appearance.

Skeletal Muscle Tumors
Rhabdomyomas are rare benign neoplasms of striated muscle. These tumors have a predilection for the head and neck area, but their occurrence in the nasopharynx is distinctly uncommon. 314, 413 For greater detail, the reader is referred to chapters and monographs devoted to soft-tissue tumors. In contrast to rhabdomyoma, rhabdomyosarcoma is one of the most common sinonasal malignant tumors in children, 314 - 316 although occasional tumors are also encountered in adults. 317 - 319 They need to be differentiated from other small round blue cell tumors in the sinonasal region, including ONBs (see Table 3-1 ). Rhabdomyosarcoma is discussed in detail in Chapter 8 in this book.

Peripheral Nerve Sheath Tumors
Schwannomas, neurofibromas, plexiform neurofibromas, and malignant peripheral nerve sheath tumors are encountered rarely in the nasal cavity and paranasal sinuses. 414 - 419 Sinonasal peripheral nerve sheath tumors affect males and females equally. The age at presentation ranges from 16 to 75 years. The median age in the series by Hasegawa and colleagues 420 was 52 years, whereas Robitaille and colleagues 421 reported a mean age of 28.8 years in their literature review. Most cases have not been associated with von Recklinghausen’s disease, although some have been seen in this clinical setting. 421 The symptoms at presentation are variable and depend on tumor location. Patients with lesions primarily located in the nasal cavity usually have nasal obstruction and epistaxis, whereas those with tumors arising in the sinuses present with headaches and facial swelling. Radiologic studies show fullness of the involved sinus ( Fig. 3-66 A ) and, not uncommonly, extensive bone destruction with extension into the skull base. It is imsportant to remember that these radiologic features are not necessarily an indication of malignancy. 4210, 417

Figure 3-66 A , Schwannoma involving the left nasal cavity and maxillary sinus. B , Typical Verocay body in a sinonasal schwannoma.
The histologic features of schwannomas and neurofibromas in this location do not differ histologically or ultrastructurally from lesions arising in other locations (see Fig. 3-66 B ). As in other locations, nuclear atypia may be present; it is not an indication of aggressive behavior. Most malignant peripheral nerve sheath tumors are poorly differentiated hypercellular lesions and are composed of spindle cells with hyperchromatic nuclei with frequent mitotic figures and necrosis. 4150, 404 Some cases have shown rhabdomyoblastic differentiation and have been designated malignant triton tumors. 404, 419 Fernandez and colleagues 416 reported a case of a malignant epithelioid schwannoma that elicited the differential diagnosis of malignant melanoma. The differential diagnosis includes other spindle cell neoplasms (refer to Chapter 8 in this book).
Schwannomas and neurofibromas are benign lesions that only rarely develop local recurrences and have an excellent prognosis. 4210, 414 Seven of eight benign tumors reported by Perzin and colleagues 414 showed no recurrences, and one recurrent lesion showed no radiologic evidence of progression. None of the four tumors with follow-up described by Hasegawa and colleagues 420 recurred after piecemeal resection only. The prognosis of malignant peripheral tumors in the sinonasal tract is more guarded and depends on the extent of disease, completeness of resection, use of adjuvant therapy, and grade of the tumor. In the combined experience of Perzin and colleagues, Robitaille and colleagues, and Fernandez and colleagues, three of six patients with malignant tumors had died of disease, one was alive with recurrent tumor, one had no recurrences, and one was lost to follow-up. 4210, 414 Four additional patients described in different reports 415, 418, 419, 422 were alive 3, 3, 11, and 3 years after treatment. Three of these patients received adjuvant radiotherapy after surgical resection. Most recurrences are seen within the first year after diagnosis.

Adipose Tissue Tumors
Although adipose tissue neoplasms represent one of the most common lesions of soft tissue, lipoma and liposarcoma are extremely uncommon in the sinonasal tract. 423 A myxoid liposarcoma arising in a 67-year-old woman was described by Fu and Perzin 423 in their review of nonepithelial neoplasms of the sinonasal tract. This lesion recurred locally, invaded the middle cranial fossa, and caused the patient’s death.
Tumors of bone and cartilage may rarely arise in the maxilla and nasal cartilage. Chondrosarcoma, osteosarcoma, and other benign osteoid and cartilage-producing tumors have been reported involving the nasal cavities and paranasal sinuses. Chordomas of the skull base, when extensive, may involve the nasopharynx. These tumors are discussed in detail in Chapter 9 in this book.

Miscellaneous Tumors


Clinical Features
Approximately 3% of all meningiomas secondarily involve the sinonasal tract 424 ; however, there are rare primary nasal or paranasal tumors ( Fig. 3-67 ). 425 - 428 As in other locations, there is a female predilection. Unlike primary intracranial lesions, a disproportionate number of tumors have been reported in younger patients. The mean age in the review by Ho 426 was 28 years. The most common symptoms are nasal obstruction, epistaxis, and exophthalmos. Some lesions may simulate a nasal polyp. The sphenoid sinus is the most common site of involvement.

Figure 3-67 Invasive meningioma of the maxillary sinus. The tumor has a solid appearance and invades bone and the antrum.

Pathologic Features
Most meningiomas in the sinonasal tract are of the meningothelial or transitional type and rarely the fibroblastic type. 4300, 425 They consist of tumor cells with a syncytial appearance arranged in whorls, sheets, or broad bands with variable numbers of psammoma bodies. The cytoplasm is moderate to abundant with indistinct cell membranes ( Fig. 3-68 ). The nuclei tend to be uniform with little pleomorphism and may exhibit nuclear pseudoinclusions. Bone invasion is frequent. Cases with mitotic activity and frank malignant histologic features have been described. 427, 428 Sadar and colleagues 428 reported a case of angioblastic meningioma, which nowadays would have been classified as malignant hemangiopericytoma.

Figure 3-68 A , Meningioma involving sinus mucosa. B , Typical meningothelial whorls are present.

Differential Diagnosis
The differential diagnosis of meningioma in the sinonasal tract includes poorly differentiated carcinoma, malignant melanoma, and ONB. Identification of the typical cytologic features of meningioma, the absence of fibrillary stroma, the lack of significant cellular atypia and necrosis, and the lack of staining for keratins, S-100, HMB-45, and neuroendocrine markers, but expression of epithelial membrane antigen are helpful in establishing a definitive diagnosis.

Treatment and Prognosis
Meningiomas are benign tumors, and complete local resection is curative. In the 19 cases reviewed by Ho, 426 no recurrences or deaths due to tumor were found. Nonetheless, they may exhibit recurrences and aggressive local behavior, and, occasionally, owing to their location, complete resection may be difficult to achieve. 425 Two cases of frankly malignant sinonasal meningiomas causing patient death were described by Sadar and colleagues. 428 Meningiomas do not seem to respond well to radiotherapy; however, postoperative irradiation may be used as adjuvant therapy in incompletely resected tumors.

Sinonasal Ameloblastoma
Primary sinonasal ameloblastomas are extremely rare with a dearth of case reports. The largest series reported consists of 24 cases seen at the Armed Forces Institute of Pathology during a period of 30 years. 431 Most patients are males, and the mean age at diagnosis is 59.7 years. The most common symptom is that of a rapidly enlarging mass in the maxillary sinus or nasal cavity. Approximately one third of patients have sinusitis or epistaxis. The histopathologic appearance of sinonasal ameloblastomas is similar to that of their gnathic counterparts, which are discussed in detail in Chapter 10 (“Odontogenic Cysts and Tumors”). By far the most common is the plexiform type characterized by a network of anastomosing cords of odontogenic epithelium surrounded by a loose, myxomatous, reticulum-like stroma.
The main differential diagnoses of sinonasal ameloblastoma are nasal extension of a gnathic tumor and craniopharyngioma. Before establishing the diagnosis of a primary sinonasal ameloblastoma, the presence of a gnathic lesion should be excluded. Ameloblastomas lack the cyst formation, degenerative changes, calcifications, and cholesterol clefts of craniopharyngioma. The latter typically involves the nasopharynx or sinuses through downward extension from a suprasellar location. Rarely, sinonasal ameloblastoma may simulate a basal cell adenoma or adenocarcinoma. Reverse polarization of the nuclei typical of ameloblastoma is not observed in basal cell tumors. The prognosis is excellent after complete surgical resection; however, local recurrences are seen in approximately 20% of patients, and some may have multiple recurrences.

Ectopic Pituitary Adenoma

Clinical Features
Involvement of the sinonasal region by extension from a large intrasellar pituitary adenoma is more common than ectopic pituitary adenomas. Ectopic pituitary adenomas are believed to arise in the remnants of embryonic adenohypophysis along the path of the developing Rathke’s cleft. These embryonic remnants are known to contain all the hormone-producing cells found in the normal gland. 432 These lesions are generally considered to arise from the pharyngeal pituitary gland. The so-called pharyngeal pituitary gland is found in the body of the sphenoid bone in more than 90% of adults in autopsy studies. 433 Not surprisingly, sphenoid sinus and bone are the most common locations of ectopic pituitary adenomas. 434, 435 Women are affected twice as often as males, and more than 58% of patients have evidence of hormone hyperactivity (e.g., Cushing’s disease, acromegaly, hyperthyroidism, or hyperparathyroidism). 436 Patients with nonfunctional ectopic pituitary adenomas may present with nasal obstruction, headaches, and epistaxis. 432, 434 Some lesions present as nasal polyps. 437

Pathologic Features
Most of these lesions display a histologic appearance similar to those located in the sella turcica. 432 They are unencapsulated but well circumscribed and have an endocrine architecture with nests, ribbons, trabeculae, papillae, and rosettes surrounded by a delicate vascular network ( Fig. 3-69 A ). Most are of the chromophobe cell type. 432 - 435 The nuclei are usually bland; however, some pleomorphism may be seen as is characteristic of neuroendocrine tumors, and should not deter one from the diagnosis of adenoma. There are no mitoses and no necrosis except in infarcted tumors. By immunohistochemistry, the tumors express cytokeratin and the usual neuroendocrine markers. Specific pituitary hormones, most frequently prolactin or growth hormone, may be demonstrated (see Fig. 3-69 B – D ). 438

Figure 3-69 A , Ectopic pituitary adenoma underlying respiratory epithelium. The tumor has an organoid architecture and is composed of round cells with no cytologic atypia. B , The tumor shows diffuse strong expression of chromogranin, α-subunit of glycoprotein hormones ( C ), and focal staining with prolactin ( D ).

Differential Diagnosis
Sinonasal pituitary adenomas should be distinguished from pituitary adenomas extending from the sella turcica, ONB, paraganglioma, carcinoid tumor, neuroendocrine and sinonasal undifferentiated carcinomas, lymphoma, and ES/PNET. Awareness of the existence of pituitary adenoma in ectopic locations and clinicopathologic correlation, particularly endocrine function and radiologic studies, are essential in arriving at a correct diagnosis. Immunohistochemical stains including hormonal markers of pituitary adenomas are necessary to establish a definitive diagnosis. Although pituitary adenomas may show some significant nuclear atypia, they do not have the degree of cellular pleomorphism, mitotic activity, and necrosis that characterize SNEC and sinonasal undifferentiated carcinoma. They can be distinguished from ONB by the absence of fibrillary stroma and by their consistent expression of keratin and specific pituitary hormones.

Treatment and Prognosis
Complete surgical removal is the treatment of choice; however, in large invasive lesions, this goal may not be achieved. For incompletely resected tumors, postoperative irradiation is indicated. 434, 437 Dopamine agonist drugs such as bromocriptine are effective in reducing the size of pituitary adenomas, especially prolactinomas. Malignant transformation is rarely reported. 439 The prognosis is generally good. Lloyd and colleagues 435 reported that four of 11 patients were cured by surgery alone or surgery followed by radiotherapy. Four patients died less than 1 year after surgery of unrelated causes or due to hormonal insufficiency. All three patients reported by Luk and colleagues 437 were alive after surgery alone or surgery followed by radiotherapy.

Craniopharyngiomas are complex benign epithelial neoplasms most commonly seen in the sellar and third ventricle regions. Their proposed origin is the obliterated craniopharyngeal duct of Rathke’s pouch, although origin from misplaced odontogenic epithelium has also been proposed. 440 Rarely, craniopharyngiomas arise in the nasopharynx and extend to the nasal cavity and the sphenoid and ethmoid sinuses. 441 - 443 Fewer than 50 infrasellar craniopharyngiomas are reported in the literature, with only two cases reported to involve the maxillary sinus. 444 The microscopic appearance is similar to that of sellar adamantinomatous craniopharyngiomas with their epithelial lobules, peripheral palisading, and internally loose epithelial cells reminiscent of stellate reticulum. Most lesions also have squamous metaplasia and cysts filled with keratin. These lesions are extremely uncommon in this location and should not be confused with a well-differentiated squamous cell carcinoma. A high index of suspicion is necessary to make the diagnosis if one is ever faced with this lesion.

Sinonasal Germ Cell Tumors
Rarely, the sinonasal tract and the nasopharynx are the sites for teratomas and other germ cell tumors. Most of the reported cases have occurred in children and are often congenital, 445 - 449 but they have also been described in older adults, especially the sinonasal yolk sac tumor and teratocarcinoma. 450
Teratomas in the sinonasal tract and nasopharynx are composed of a mixture of ectodermal, mesodermal, and endodermal elements and may be classified as mature and immature teratomas as in gonadal lesions. 451, 452 Most cases reported in children have been mature teratomas. 447, 448 Mature teratomas tend to be cystic, whereas immature teratomas may be solid or solid and cystic. Immature teratomas generally contain immature neural elements admixed with other immature and mature tissues and may demonstrate focally increased mitotic activity.
Sinonasal yolk sac tumors involving the nasopharynx have also been reported in children and adults. 4530, 446 These are aggressive neoplasms characterized by the presence of Schiller-Duval bodies admixed with papillae, tubules, microcysts and macrocysts, and sheets of primitive cells with a myxomatous background and deposits of eosinophilic basement membrane material as well as periodic acid–Schiff–positive hyaline droplets. Immunohistochemically, the tumor cells are positive for α-fetoprotein. 446, 447 In the case reported by Byard and colleagues, 446 the tumor appeared 3 years after excision of a congenital mature teratoma in a child. Petrovich and colleagues 450 reported a case of a left nasal malignant teratoma in a 63-year-old man that seems to represent an immature teratoma with papillary areas reminiscent of a yolk sac tumor.
The differential diagnosis of germ cell tumors in the sinonasal region and nasopharynx is complex and depends on the tissues seen in the surgical material. Mature teratoma should be distinguished from nasal glioma or meningocele. The latter entities probably represent developmental defects of the craniofacial skeleton and do not contain elements other than glia and neurons. The intrinsic difficulty of distinguishing immature cell elements in a teratoma from malignancy is well recognized. Olfactory neuroblastoma and rhabdomyosarcoma may resemble the neuroepithelium or the mesenchyme of immature teratoma but lack other neoplastic elements. Extensive sampling and identification of tissues arising from all three germ layers are key to the diagnosis of teratoma. A sinonasal yolk sac tumor should be separated from poorly differentiated adenocarcinoma. A yolk sac tumor can be distinguished by the array of architectural patterns present in the tumor and the characteristic Schiller-Duval bodies in addition to positive staining for α-fetoprotein. The prognosis of teratomas in children, even immature teratomas, is extremely favorable after complete surgical resection, and they generally do not require adjuvant chemotherapy or radiotherapy. Therefore, immature teratomas must be distinguished from teratocarcinoma. Unlike teratocarcinoma, an immature teratoma does not show cellular atypia. It is important to recognize areas of the yolk sac because these tumors are aggressive and require adjuvant cisplatin-based chemotherapy for adequate management.

Teratocarcinoma (Malignant Teratoma, Blastoma, Teratoid Carcinosarcoma)

Clinical Features
This unique neoplasm is extremely uncommon. It shows a male predominance and affects adults with an age range of 18 to 79 years and a mean age of 60 years. 454 - 457 The symptoms at presentation include nasal obstruction, epistaxis, pain, and proptosis. Radiologic studies generally show a nasal mass with bone destruction and extension into the ethmoidal or maxillary sinus.
Nasal blastomas are rare malignant neoplasms with controversial morphology and histogenesis. The relationship of nasal blastoma with and its differentiation from teratocarcinoma and carcinosarcoma of the sinonasal tract are still controversial; they probably represent the same pathologic entities. The new World Health Organization classification of head and neck tumors uses nasal blastoma as a synonym for teratocarcinoma. 458 There have been only isolated reports of these lesions. 459 - 461

Pathologic Features
Grossly, the tumors may be polypoid, friable, and hemorrhagic. 454, 456 Histologically, they are characterized by a heterogeneous combination of epithelial and mesenchymal elements. The epithelial components are composed of a mixture of clear cell, nonkeratinizing epithelium ( Fig. 3-70 A ), squamous epithelium without clear cell elements, squamous cell carcinoma, and benign, atypical, or clearly malignant glandular elements. Immature neuroepithelial tissue (see Fig. 3-70 B ) resembling ONB with rosette formation, ganglion cells, and glial differentiation are also present. 462 The mesenchymal tissues also have a variable appearance with areas of nonspecific myxomatous tissue, cellular areas of benign and malignant-appearing fibroblasts, and smooth muscle cells. 454 - 456 Rhabdomyoblastic and chondroblastic differentiation with areas of rhabdomyosarcoma, chondrosarcoma, or fetal cartilage may be seen. 463 Primitive epithelial and mesenchymal elements resembling fetal lung have been reported. The epithelial component consists of poorly developed glands and squamous epithelium. The stroma is formed by a variable mixture of malignant myxoid, chondromyxoid, fibrous, and muscular tissues. 459, 460 Unlike gonadal or extragonadal germ cell tumors, there are no areas of seminoma, yolk sac tumor, or choriocarcinoma. 457

Figure 3-70 Teratocarcinosarcoma containing a well-defined nest of benign-looking squamous epithelium with clear cytoplasm (A) and primitive neuroepithelium with numerous rosettes and pigmentation (B) .
(Courtesy of Dr. Bruce Wenig, Beth Israel Medical Center, New York, NY.)
The immunohistochemical findings are dependent on the areas studied. 455, 462 The primitive neuroepithelial tissue may be positive for CD99 (O13/MIC2), neuron-specific enolase, synaptophysin, and chromogranin. Keratin and rarely α-fetoprotein may also be seen in the neuroepithelial component. S-100 and glial fibrillary acidic protein are expressed by those areas with glial differentiation. Epithelial membrane antigen and keratin are seen in the epithelial elements. Desmin and myoglobulin are positive in areas with rhabdomyoblastic differentiation. Based on immunohistochemical and ultrastructural findings, Shimazaki and colleagues 463 suggested that teratocarcinomas may be neuroectodermal tumors with divergent differentiation.

Differential Diagnosis
The distinction of teratocarcinomas from nasal blastomas and malignant teratomas is tenuous and controversial. These tumors are regarded by some authors as similar, if not related, entities. 454, 455 It is likely that most of the reported cases of malignant or immature teratomas in adults represent examples of teratocarcinomas. 452 Clinically, they are distinguished from teratomas by the older age at first occurrence and morphologically by the absence of ectodermal and endodermal components. The differential diagnosis of teratocarcinoma is broad and includes squamous cell carcinoma, sarcomatoid carcinoma, adenocarcinoma, ONB, craniopharyngioma, and other sarcomas. The histologic complexity of teratocarcinoma and the presence of mixed epithelial and mesenchymal elements should suggest the diagnosis. A definitive diagnosis may not be possible in small biopsy specimens.

Treatment and Prognosis
The average survival time is less than 2 years. Approximately 67% of patients with adequate follow-up developed uncontrollable local recurrences and 35% developed metastases to cervical nodes. Some patients have prolonged survival periods. 454, 456

Alveolar Soft Part Sarcoma
A few cases of alveolar soft part sarcoma involving the nasal cavity and maxillary sinus have been reported in female patients aged 15 to 53 years. 464 - 466 The morphology is similar to their soft-tissue counterparts and is discussed in detail in Chapter 8 . The prognosis is poor due to the extensive vasoinvasive nature of these tumors.

Postradiation Sarcoma
Therapeutic radiation of primary lesions of the head and neck can rarely be complicated by the development of secondary sarcomas 467 - 469 in the sinonasal tract. The interval from radiation treatment to the development of the secondary malignancies has ranged from 3.5 to 30 years, 469 with a median latency period of 10 years. 467, 468 Clinically, most patients present with nasal obstruction, epistaxis, and facial pain. The histology is similar to postradiation sarcomas in other locations.

Lymphoplasmacytic Tumors
Chapter 13 (“Hematopoietic Lesions”) is entirely devoted to lymphomas and related entities. The following is only a very brief description of the most common hematolymphoid lesions in the sinonasal region.

Malignant Non-Hodgkin’s Lymphoma
Primary sinonasal and nasopharyngeal NHLs are uncommon in North America. However, a Danish study published in 1997 showed that NHL was the second most common malignant tumor in the sinonasal region, with squamous cell carcinoma being the most common (14% vs. 46%, respectively). 470 The majority of sinonasal lymphomas are the B-cell type, the most common histologic type being diffuse large B-cell (large cell immunoblastic) lymphoma. 471 - 475 In Asia and Latin America, the extranodal T-/natural killer cell (T-/NK cell) lymphoma of the nasal type is the most common lymphoma. 473, 476 Diffuse small noncleaved, Burkitt’s and non-Burkitt’s lymphomas are frequent in the nasopharynx of children. 4780, 475 Small lymphocytic, small cleaved cell, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, and mantle cell lymphoma have been described in this location, although they are distinctly uncommon. 4750, 472
The clinical symptoms at presentation are nonspecific and consist of nasal obstruction, epistaxis, rhinorrhea, and the presence of a mass. 471 - 474 The mean age at presentation has ranged from 59 to 70 years, with the vast majority of patients in their sixth or seventh decade of life, except for the diffuse small noncleaved Burkitt’s and non-Burkitt’s lymphomas that affect children. Patients with diffuse large B-cell lymphomas are generally a decade older than other patients. There is a slight male preponderance (1.2:1). 473, 476 Most tumors are locally advanced at presentation, with frequent bone destruction and extension into the adjacent sinuses, nasopharynx, or palate. The septal cartilage or palatal bone may be perforated, and proptosis may be seen in tumors invading the orbit.
The diagnosis and classification of lymphomas in the sinonasal region are based on the same parameters used in nodal lymphomas. An adequate biopsy specimen with good cell preservation is of utmost importance. The differential diagnosis of NHL includes small round blue cell tumors (e.g., sinonasal undifferentiated carcinoma, small cell carcinoma, ONB, rhabdomyosarcoma, malignant melanoma, and nasopharyngeal carcinoma; see Table 3-1 ). Close attention to architectural and cytologic details and the use of an immunohistochemical panel that includes epithelial, lymphoid, myogenic, and melanocytic markers are necessary to establish a definitive diagnosis.

Sinonasal T-Cell/Natural Killer Cell Lymphoma (Angiocentric Lymphoma, Polymorphic Reticulosis)
Numerous terms have been used to describe the clinical and pathologic features of extranodal T-/NK cell lymphoma (e.g., lethal midline granuloma, 479, 480 midline malignant reticulosis, 481 lymphomatoid granulomatosis, angiocentric peripheral T-cell lymphoma, 482, 483 and angiocentric lymphoproliferative lesion 484 ). Recent studies indicate that these tumors represent a distinctive group of malignant lymphomas with a T-/NK cell phenotype. 479, 485 - 489 Polymorphic reticulosis should be avoided as a diagnostic term, and an effort should be made to establish a precise pathologic diagnosis with the help of immunohistochemical and molecular pathology studies.
T-/NK cell sinonasal lymphoma is most commonly seen in Asia, and an increased incidence has also been described in Latin American countries such as Mexico, Guatemala, and Peru. 476, 490 - 492 The tumor has a strong association with EBV infection, and the presence of EBV-encoded RNA-1, EBV-encoded RNA-2, and, less commonly, LMP-1 has been identified in the neoplastic lymphoid cells. 479, 493 - 496 Mutations of the EBV-LMP-1 gene have been found in 26% of T-/NK cell sinonasal lymphomas in Mexico City; however, this study also found a similar proportion of mutations in reactive tonsils of healthy control subjects. 497 Sinonasal T-/NK cell lymphoma in this study was most commonly associated with EBV strain A. 497

Clinical Features
Sinonasal T-/NK cell lymphomas are most frequently seen in males, with a male-to-female ratio of 2 to 3:1. The age at presentation ranges from 13 to 80 years, with a mean age of approximately 45 years in most series. 483, 487, 492, 498, 499 Common symptoms are nasal obstruction, epistaxis, rhinorrhea, and the presence of an ulcerated nasal mass, frequently with extension to paranasal sinuses and palate. Bone destruction may also be present with perforation of the palate and nasal septum. Approximately 50% to 60% of patients have localized disease at presentation, and 25% may have involvement of cervical lymph nodes, skin, bone marrow, spleen, liver, or other extranodal sites. 4990, 483

Pathologic Features
Nasal or nasopharyngeal T-/NK cell lymphomas exhibit a broad morphologic spectrum, the hallmark being the presence of a polymorphic cellular infiltrate composed of atypical lymphoid cells admixed with a variable number of plasma cells, small lymphocytes, histiocytes, eosinophils, and neutrophils. The atypical cells vary in number, cell size, and cytologic atypia. In some cases, the neoplastic lymphoid cells are small to intermediate in size and possess dark, twisted hyperchromatic nuclei with irregular contours ( Fig. 3-71 ). In other cases, the cells are large with abundant pale to clear cytoplasm and exhibit large nuclei with prominent nucleoli ( Fig. 3-72 ). Giemsa-stained cytologic preparations from involved lymph nodes or peripheral blood have revealed azurophilic cytoplasmic granules. 500 The distribution of the neoplastic cells in the tissue is irregular and may vary from field to field, and in some instances they may be obscured by the reactive inflammatory cells. Most cases show prominent angiocentricity with infiltration and destruction of the vessel wall ( Fig. 3-73 ). Although this feature is characteristic of T-/NK cell lymphomas, it is not required for the diagnosis. Necrosis is almost invariably present in all cases of sinonasal T-/NK cell lymphoma, and recently it was proposed that the extensive apoptosis seen in these neoplasms is due to the cytolytic effects of cytolytic granular proteins perforin, T-cell intracellular antigen-1, and granzymes. 5020, 497 Often, it has a zonal distribution and is accompanied by extensive mucosal ulceration and destruction of cartilage or bone. The presence of granulomas and multinucleated giant cells is not a feature of these tumors.

Figure 3-71 Sinonasal T/NK-cell lymphoma. The lymphoma cells are small to intermediate size with irregular hyperchromatic nuclei. Plasma cells are also present.

Figure 3-72 Sinonasal T-/natural killer cell lymphoma. The lymphoma cells exhibit moderate amounts of pale eosinophilic cytoplasm, markedly atypical nuclei, numerous mitotic figures, and frequent apoptotic cells.

Figure 3-73 Sinonasal T-/natural killer cell lymphoma. The neoplastic cells are invading and destroying the wall of an arteriole (angiocentric pattern). There is extensive necrosis.
The immunophenotype of T-/NK cell lymphomas is characteristic. The tumor cells are positive for the NK cell marker CD56 (neural cell adhesion molecule; Fig. 3-74 A ) but are generally negative for other NK cell markers such as CD57 and CD16. 503, 504 They are also positive for CD2, CD45RO, and CD43. CD3 is negative in frozen tissue sections, but it may be seen in the tumor cell cytoplasm in paraffin-embedded tissues (see Fig. 3-74 B ). 482, 499, 505, 506 CD4, CD5, CD7, CD8, βF1, and TRCδ are generally negative, although occasional tumors may show expression of some of these T-cell markers. 479, 482, 486, 487, 499, 503 Tumor cells are positive for EBV (see Fig. 3-74 C ). As expected, all B-cell markers are negative. Staining for granzyme B, an antibody-detecting cytoplasmic cytotoxic granule, and the expression of perforin and T-cell intracellular antigen-1 appear to be specific for these tumors (see Fig. 3-74 D ). 497, 499 Most gene rearrangement studies have shown a germline configuration for the T-cell receptor-α, -β, -γ, and -δ genes, 471 although some cases have demonstrated rearrangement of some of these genes. 486, 495, 503, 505

Figure 3-74 Sinonasal T-/natural killer cell lymphoma showing strong staining for CD56 ( A ), cytoplasmic CD3 ( B ), Epstein-Barr virus by in situ hybridization ( C ), and T-cell intracellular antigen-1 ( D ).

Differential Diagnosis
The differential diagnosis of nasal T-/NK cell lymphomas includes sinonasal infections, especially fungal infections, Wegener’s granulomatosis, and other NHLs. The diagnosis of these neoplasms requires a high index of suspicion and rests on a combination of clinicopathologic findings, microbiologic cultures, characteristic immunophenotype, and, when necessary, molecular pathology analysis. The presence of a polymorphic lymphoid infiltrate with variable degrees of cytologic atypia, angioinvasion, and necrosis should strongly suggest a diagnosis of sinonasal T-/NK cell lymphoma, especially in patients with no serum ANCAs and no evidence of pulmonary or renal abnormalities.

Treatment and Prognosis
Traditionally, the prognosis of sinonasal T-/NK cell lymphomas has been poor, with death due to disease within 2 years of diagnosis. 481, 507 - 509 Recent studies suggest, however, that patients with localized disease may respond well to aggressive radiotherapy or combined chemotherapy, or both. In the study by Liang and colleagues, 498 78% of patients with stage I to II disease had a 78% response, although their disease-free survival rate at 5 years was only 60%. The 5-year survival rate for patients with stage III to IV disease was 17%. The 5-year and 15-year survival rates reported by Strickler and colleagues 489 were 63% and 50%, respectively, whereas Ho and colleagues 483 reported a 5-year survival rate of 64% in patients with polymorphic reticulosis. Most studies indicate that radiotherapy with or without chemotherapy is superior to chemotherapy alone as the initial treatment for sinonasal T-/NK cell lymphomas. 4990, 489 The combination of cyclophosphamide, doxorubicin, vincristine, and prednisone has been the most commonly used chemotherapy regimen. Patients with recurrent disease may be treated with combined therapy or chemotherapy alone. Involvement of the central nervous system, skin, or lung or systemic involvement is common in patients who fail therapy. A hemophagocytic syndrome is a common complication that adversely affects survival.

Extramedullary Plasmacytoma
Extramedullary plasmacytoma is discussed in detail in Chapter 13 . These tumors are uncommon, representing 5.7% of all plasmacytomas. 510 Approximately 90% of them occur in the head and neck, the sinonasal tract being involved in approximately 75% of these cases. Sinonasal plasmacytomas most commonly affect males in their sixth and seventh decades of life. 510 - 512 The symptoms at presentation are nonspecific and include unilateral nasal obstruction, rhinorrhea, epistaxis, and facial pain. The finding of Bence-Jones protein in urine is distinctly uncommon in the absence of disseminated disease.
Extramedullary plasmacytomas are composed of plasma cells with a diffuse pattern of infiltration and variable degrees of differentiation ( Fig. 3-75 ). In well-differentiated tumors, the neoplastic cells closely resemble mature plasma cells, although occasional mitotic figures can be seen. In moderately or poorly differentiated neoplasms, the cells are more pleomorphic and show a significant degree of atypia with frequent mitotic figures, large vesicular nuclei with coarse chromatin, and often prominent nucleoli ( Fig. 3-76 A ). Binucleated atypical plasma cells are common in poorly differentiated lesions. The high-grade tumors may closely resemble immunoblastic large cell lymphomas. Most lesions show a monotypic pattern of staining, usually for καππα light chain (see Fig. 3-76 B ). Poorly differentiated lesions should be differentiated from immunoblastic large cell lymphoma, granulocytic sarcoma, malignant melanoma, and poorly differentiated carcinomas. The systematic use of an antibody panel including keratins, epithelial membrane antigen, lymphoid markers and immunoglobulins, S-100, and HMB-45 should be useful in establishing a definite diagnosis.

Figure 3-75 Well-differentiated plasmacytoma involving the nasal cavity. Sheets of plasma cells are seen beneath the squamous mucosa.

Figure 3-76 Plasmacytoma with moderate degree of nuclear pleomorphism ( A ) and λ light chain restriction ( B ).
Extramedullary plasmacytomas are radiosensitive. Large lesions may require surgical debulking. These tumors may follow one of several clinical courses. Most patients have localized disease and are cured by surgery and radiotherapy. In a second group, the disease may recur locally after initial therapy but can be controlled with a good long-term prognosis. A third group will succumb to local tumor recurrences or to disseminated disease. Classic multiple myeloma develops in 30% to 50% of patients sometimes decades after the initial diagnosis. The 5-year survival rate has ranged from 30% to 70%. 510, 512

Metastatic Tumors

Clinical Features
Metastatic involvement of the sinonasal tract is rare. 513, 514 The most common malignancies that secondarily involve the sinonasal tract are the kidney, lung, and breast. 513 Other tumors that may occasionally metastasize to the nasal cavity and sinuses are malignant melanoma and carcinomas of the thyroid, pancreas, prostate, stomach, colon and rectum, testis, and adrenal gland. In most instances, metastases to the sinonasal tract are a manifestation of disseminated disease; however, sinonasal metastasis has been the initial presentation of carcinomas of the gastrointestinal tract, lung, liver, kidney, and thyroid. 220, 224, 515 - 517

Pathologic Features
Renal cell carcinoma in the sinonasal tract maintains its characteristic morphology of medium-size or large clear cells arranged in nests or sheets surrounded by thin-walled blood vessels ( Fig. 3-77 ). Unlike the clear cells of carcinomas of other sites, the cytoplasm in renal cell carcinoma does not have a vacuolated, granular, or pale eosinophilic appearance; instead, it is truly clear and often appears empty under light microscopy. The main differential diagnoses of renal cell carcinoma in the sinonasal tract are mucoepidermoid carcinoma and acinic cell carcinoma. In most instances, adequate sampling will solve this quandary because these neoplasms are only rarely entirely composed of clear cells. 518 Renal cell carcinoma does not contain the typical epidermoid or intermediate cells of mucoepidermoid carcinoma. The presence of mucous cells or intracytoplasmic mucin is also helpful in establishing the correct diagnosis. Clear cells are seen in only 6% of acinic cell carcinomas. 510 The presence of other cell types, particularly acinar cells with their characteristic periodic acid–Schiff diastase–resistant granules, should exclude the diagnosis of metastatic renal cell carcinoma. Some myoepithelial tumors may show clear cells. However, the absence of the highly vascular pattern typical of renal cell carcinoma and expression of myoepithelial markers should point toward the myoepithelial origin of the tumor. The morphology and immunohistochemical profile of tumors of salivary gland origin are described in greater detail in Chapter 6 (“Salivary and Lacrimal Glands”) in this book.

Figure 3-77 Renal cell carcinoma, clear cell type, metastatic to the nasal cavity.
There are no reliable morphologic features that allow distinction between metastatic colorectal carcinoma and moderately differentiated sinonasal ITAC. Immunohistochemistry is of no significant help as both tumors have the immunophenotype of intestinal cells and express CK20, CDX2, and villin. 217 In this situation, correlation with medical history and clinical findings, including colonoscopy, is necessary to establish the correct diagnosis. Well-differentiated ITAC and low-grade papillary adenocarcinoma are, in most cases, primary sinonasal tumors because these lesions resemble normal intestinal mucosa or villous adenomas, and intestinal lesions with this morphology do not have metastatic potential. Close attention to morphologic findings and correlation with clinical findings are necessary to exclude a metastatic neoplasm.
The main differential diagnosis of other metastatic adenocarcinomas such as those of the lung, breast, thyroid, pancreas, prostate, and stomach is mainly a poorly differentiated sinonasal intestinal-type adenocarcinoma. In this setting, the use of antibodies against thyroglobulin, prostate specific antigen, thyroid transcription factor-1, and surfactant apoprotein may be useful to exclude metastasis from those sites.
Metastatic involvement of the sinonasal tract is, in most cases, evidence of advanced disease and is associated with a dismal prognosis. 513 Two thirds of patients generally die within 1 year of diagnosis and less than 10% survive 5 years. Given the bleak prognosis of these patients and the disseminated nature of their disease, radical treatment does not appear to be warranted. However, palliative treatment with radiotherapy with or without surgery may help to control local disease and pain. Radiotherapy with or without surgery has also been reported to prolong life in some cases.

We dedicate this chapter to the memory of Dr. Andrew G. Huvos, our mentor in head and neck pathology. He is deeply missed.


Anatomy and Histology
1 Barnes L, Johnson JT. Pathologic and clinical considerations in the evaluation of major head and neck specimens resected for cancer. Pathol Annu . 1986;21:175-250.
2 Walike JW. Anatomy of the nasal cavities. Otolaryngol Clin North Am . 1973;6:609-621.
3 Wenig BM. Nasal cavity and paranasal sinuses. In: Wenig BM, editor. Atlas of Head and Neck Pathology . Philadelphia: WB Saunders; 1993:3-95.
4 Nakashima T, Kimmelman CP, Snow GB. Structure of the human fetal and adult olfactory neuroepithelium. Arch Otolaryngol . 1984;110:641-646.
5 Wenig BM. Anatomy and histology of the oral cavity, nasopharynx, and neck. In: Wenig BM, editor. Atlas of Head and Neck Pathology . Philadelphia: WB Saunders; 1993:101-102.
6 Mills SE, Fechner RE. Larynx and pharynx. In: Sternberg SS, editor. Histology for Pathologists . New York: Raven Press; 1997:391-403.
7 Erlandson RA. Oncocytes in the nasopharynx. Arch Otolaryngol . 1977;103:175-178.
8 Benke TT, Zitsch RP, Nashelsky MB. Bilateral oncocytic cysts of the nasopharynx. Otolaryngol Head Neck Surg . 1995;112:321-324.
9 Shek TWH, Lu ISC, Nichols JM, et al. Melanotic oncocytic metaplasia of the nasopharynx. Histopathology . 1996;26:273-275.

Rhinitis and Sinusitis
10 Marks SC, Upadhyay S, Crane L. Cytomegalovirus sinusitis: A new manifestation of AIDS. Arch Otolaryngol Head Neck Surg . 1996;122:789-791.
11 Milczuk HA, Dalley RW, Wessbacher FW, et al. Nasal and paranasal sinus abnormalities in children with chronic sinusitis. Laryngoscope . 1993;103:247-252.
12 Zamboni L. Clinical relevance of evaluation of sperm and ova. In: Kraus FT, Damjanov I, editors. Pathology of Reproductive Failure . Baltimore: Williams & Wilkins; 1991:10-31.
13 Robson AM, Smallman LA, Gregory J, et al. Ciliary ultrastructure in nasal brushings. Cytopathology . 1993;4:149-159.
14 Armengot M, Juan G, Barona R, et al. Immotile cilia syndrome: Nasal mucociliary function and nasal ciliary abnormalities. Rhinology . 1994;32:109-111.

Mucous Impaction
15 Hyams VJ. Unusual tumors and lesions. In: Gnepp DR, editor. Pathology of the Head and Neck: Contemporary Issues in Surgical Pathology . New York: Churchill Livingstone; 1988:459-495.
16 Dingle AF, Douglas-Jones AG. Airway obstruction with stridor due to nasal secretions. J Laryngol Otol . 1995;109:331-334.

Sinonasal Inflammatory Polyps
17 Jankowski R. Eosinophils in the pathophysiology of nasal polyps. Acta Otolaryngol (Stockh) . 1996;116:160-163.
18 Petruson B, Hansson HA, Petruson K. Insulin-like growth factor I is a possible pathogenic mechanism in nasal polyps. Acta Otolaryngol (Stockh) . 1988;106:156-160.
19 Hao SP, Chang C-N, Chen H-C. Transtubal nasal polyposis masquerading as a skull base malignancy. Otolaryngol Head Neck Surg . 1996;115:556-559.
20 Winestock DP, Bartlett PC, Sondheimer FK. Benign nasal polyps causing bone destruction in the nasal cavity and paranasal sinuses. Laryngoscope . 1978;88:675-679.
21 Yazbak PA, Phillips JM, Ball PA, et al. Benign nasal polyposis presenting as an intracranial mass: Case report. Surg Neurol . 1991;36:380-383.
22 Heck WE, Hallberg OE, Williams HL. Antrochoanal polyp. Arch Otolaryngol . 1950;52:538-548.
23 Ryan RE, Neel HB. Antrochoanal polyps. J Otolaryngol . 1979;8:344-346.
24 Cook PR, Davis WE, McDonald R, et al. Antrochoanal polyposis: A review of 33 cases. Ear Nose Throat J . 1993;72:401-410.
25 Berg O, Carenfelt C, Silversward C. Origin of the choanal polyp. Arch Otolaryngol Head Neck Surg . 1988;114:1270-1271.
26 Chen JM, Scholoss MD, Azouz ME. Antrochoanal polyp: A 10-year retrospective study in the pediatric population with a review of the literature. J Otolaryngol . 1989;18:160-172.
27 Tos M, Morgensen C. Mucous glands in nasal polyps. Arch Otolaryngol . 1977;103:407-413.
28 Baird AR, Hilmi O, White PS, et al. Epithelial atypia and squamous metaplasia in nasal polyps. J Laryngol Otol . 1998;112:755-757.
29 Tao Q, Srivastava G, Dickens P, et al. Detection of Epstein-Barr virus-infected mucosal lymphocytes in nasal polyps. Am J Pathol . 1996;143:1111-1118.
30 Oppenheimer EH, Rosenstein BJ. Differential diagnosis of nasal polyps in cystic fibrosis and atopy. Lab Invest . 1979;40:445-449.
31 Batsakis JG, Sneige N. Choanal and angiomatous polyps of the sinonasal tract. Ann Otol Rhinol Laryngol . 1992;101:623-625.
32 Batsakis JG. Stromal cell atypia in sinonasal polyposis. Ann Otol Rhinol Laryngol . 1986;95:321-322.
33 Compagno J, Hyams VJ, Lepore ML. Nasal polyposis with stromal atypia: Review of follow-up study of 14 cases. Arch Pathol Lab Med . 1976;100:224-226.

34 Rosai J. The nature of myospherulosis of the upper respiratory tract. Am J Clin Pathol . 1978;69:475-481.
35 Shimada K, Kobayashi S, Yamadori I, et al. Myospherulosis in Japan: A report of two cases and an immunohistochemical investigation. Am J Surg Pathol . 1988;12:427-432.
36 Kyriakos M. Myospherulosis of the paranasal sinuses, nose, and middle ear: A possible iatrogenic disease. Am J Clin Pathol . 1977;67:118-130.

Granulomatous Diseases
37 Lecointre F, Marandas P, Micheau C, et al. Tuberculosis of the mucosa of the naso-pharynx: A clinical study of 37 cases seen at the Gustave-Roussy institute between 1961 and 1978. Ann Otolaryngol Chir Cervicofac . 1980;97:423-433.
38 Waldman SR, Levine HL, Sebek BA, et al. Nasal tuberculosis: A forgotten entity. Laryngoscope . 1981;91:11-16.
39 McCaffrey TV, McDonald TJ. Sarcoidosis of the nose and paranasal sinuses. Laryngoscope . 1983;93:1281-1284.
40 Coup AJ, Hopper IP. Granulomatous lesions in nasal biopsies. Histopathology . 1980;4:293-308.
41 Krespi YP, Kuriloff DB, Aner M. Sarcoidosis of the sinonasal tract: A new staging system. Otolaryngol Head Neck Surg . 1995;112:221-227.
42 Postma D, Fry TL, Malenbaum BT. The nose, minor salivary glands and sarcoidosis. Arch Otolaryngol . 1984;110:28-30.
43 McDougall AC, Rees RJL, Weddell AGM, et al. The histopathology of lepromatous leprosy in the nose. J Pathol . 1975;115:215-226.
44 Pollack JD, Pincus RL, Lucente FE. Leprosy of the head and neck. Otolaryngol Head Neck Surg . 1987;97:93-96.
45 Wabinga HR, Wamukota W, Mugerwa JW. Scleroma in Uganda: A review of 85 cases. East Afr Med J . 1993;70:186-188.
46 Sherif M, Eissa S, Bakry MW. Scleroma (rhinoscleroma): An immuno- logic and histopathologic study. J Egypt Soc Parasitol . 1986;16:293-301.
47 Sedano HO, Roman CB, Koutlas IG. Respiratory scleroma: A clinicopathologic and ultrastructural study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 1996;81:665-671.
48 Schwartz DA, Geyer SJ. Klebsiella and rhinoscleroma. In: Connor DH, Chandler FW, Schwartz DA, et al, editors. Pathology of Infectious Diseases . Stamford, CT: Appleton & Lange; 1997:589-595.
49 Andraca R, Edson RS, Kern EB. Rhinoscleroma: A growing concern in the United States? Mayo Clinic experience. Mayo Clin Proc . 1993;68:1151-1157.
50 Batsakis JG, El-Naggar AK. Rhinoscleroma and rhinosporidiosis. Ann Otol Rhinol Laryngol . 1992;101:879-882.
51 Berger SA, Pollock AA, Richmond AS. Isolation of Klebsiella rhinoscleroma in a general hospital. Am J Clin Pathol . 1977;67:499-502.
52 Paul C, Pialoux G, Dupont B, et al. Infection due to Klebsiella rhinoscleromatis in two patients infected with human immunodeficiency virus. Clin Infect Dis . 1993;16:441-442.

Fungal Diseases
53 Brandwein M. Histopathology of sinonasal fungal disease. Otolaryngol Clin North Am . 1993;26:949-981.
54 Taxy JB. Paranasal fungal sinusitis; contributions of histopathology to diagnosis. A report of 60 cases and literature review. Am J Surg Pathol . 2006;30:713-720.
55 Stammberger HR, Jakse R, Beaufort F. Aspergillosis of the paranasal sinuses. X-ray diagnosis, histopathology and clinical aspects. Ann Otol Rhinol Laryngol . 1984;93:251-256.
56 Watters GW, Milford CA. Isolated sphenoid sinusitis due to Pseudallescheria boydii . J Laryngol Otol . 1993;107:344-346.
57 Rao A, Forgan-Smith R, Miller S, et al. Phaeohyphomycosis of the nasal sinuses caused by Bipolaris species. Pathology . 1989;21:280-281.
58 Zieske LA, Kopke RD, Hamill R. Dematiaceous fungal sinusitis. Otolaryngol Head Neck Surg . 1991;105:567-577.
59 Rosenthal J, Katz R, Du Bois DB, et al. Chronic maxillary sinusitis associated with the mushroom Schizophylum commune in a patient with aids. Clin Infect Dis . 1992;14:46-48.
60 Henderson LT, Robbins KT, Weitzner S, et al. Benign Mucor colonization (fungus ball) associated with chronic sinusitis. South Med J . 1988;81:846-850.
61 Grigg AP, Phillips P, Durham S, et al. Recurrent Pseudallescheria boydii sinusitis in acute leukemia. Scand J Infect Dis . 1993;25:263-267.
62 Meyer RD, Gaultier CR, Yamashita JT, et al. Fungal sinusitis in patients with AIDS: Report of 4 cases and review of the literature. Medicine (Baltimore) . 1994;73:69-78.
63 Del Valle Zapico A, Rubio Suarez A, Mellado Encinas P, et al. Mucormycosis of the sphenoid sinus in an otherwise healthy patient: Case report and literature review. J Laryngol Otol . 1996;110:471-473.
64 Lansford BK, Bower CM, Seibert RW. Invasive fungal sinusitis in the immunocompromised pediatric patient. Ear Nose Throat J . 1995;74:566-573.
65 Drakos PE, Nagler A, Or R, et al. Invasive fungal sinusitis in patients undergoing bone marrow transplantation. Bone Marrow Transplant . 1993;12:203-208.
66 McGill TJ, Simpson G, Healy GB. Fulminant aspergillosis of the nose and paranasal sinuses: A new clinical entity. Laryngoscope . 1980;90:748-754.
67 Kriesel JD, Adderson EE, Gooch WM, et al. Invasive sinonasal disease due to Scopulariopsis candida : Case report and review of scopulariopsosis. Clin Infect Dis . 1994;19:317-319.
68 Choi SS, Lawson W, Bottone E, et al. Cryptococcal sinusitis: A case report and review of literature. Otolaryngol Head Neck Surg . 1988;99:414-418.
69 Ismail Y, Johnson RH, Wells MV, et al. Invasive sinusitis with intracranial extension caused by Curvularia lunata . Arch Intern Med . 1993;153:1604-1606.
70 Valenstein P, Schell WA. Primary intranasal Fusarium infection: Potential for confusion with rhinocerebral zygomycosis. Arch Pathol Lab Med . 1986;110:751-754.
71 Torres C, Ro JY, El-Naggar AK, et al. Allergic fungal sinusitis: A clinicopathologic study of 16 cases. Hum Pathol . 1996;27:793-799.
72 Katzenstein AL, Sale SR, Greenberger PA. Pathologic findings in allergic aspergillus sinusitis: A newly recognized form of sinusitis. Am J Surg Pathol . 1983;7:439-443.
73 Corey JP, Delsuphe KG, Ferguson BJ. Allergic fungal sinusitis: Allergic, infectious, or both? Otolaryngol Head Neck Surg . 1995;113:110-119.
74 Friedman GC, Hartwick RW, Ro JY, et al. Allergic fungal sinusitis: Report of three cases associated with dematiaceous fungi. Am J Clin Pathol . 1991;96:368-372.
75 Watts JC, Chandler FW. Rhinosporidiosis. In: Connor DH, Chandler FW, Schwartz DA, et al, editors. Pathology of Infectious Diseases . Stamford, CT: Appleton & Lange; 1997:1085-1088.
76 Ahluwalia KB, Maheshwari N, Deka RC. Rhinosporidiosis: A study that resolves etiologic controversies. Am J Rhinology . 1997;11:479-483.
77 Gaines JJ, Clay JR, Chandler FW, et al. Rhinosporidiosis: Three domestic cases. South Med J . 1996;89:65-67.
78 Kamal MM, Luley AS, Mundhada SG, et al. Rhinosporidiosis: Diagnosis by scrape cytology. Acta Cytol . 1995;39:931-935.
79 Tadros TS, Workowski KA, Siegel RJ, et al. Pathology of hyalohyphomycosis by Scedosporium apiospermum ( Pseudallescheria boydii ): An emerging mycosis. Hum Pathol . 1998;29:1266-1272.
80 Blitzer A, Lawson W. Fungal infections of the nose and paranasal sinuses: Part I. Otolaryngol Clin North Am . 1993;26:1007-1035.
81 Lawson W, Blitzer A. Fungal infections of the nose and paranasal sinuses: II. Otolaryngol Clin North Am . 1998;26:1037-1068.

Necrotizing Sialometaplasia
82 Brannon RB, Fowler CB, Hartman KS. Necrotizing sialometaplasia: A clinicopathologic study of sixty-nine cases and review of the literature. Oral Surg Oral Med Oral Pathol . 1991;72:317-325.
83 Johnston WH. Necrotizing sialometaplasia involving the mucous glands of the nasal cavity. Hum Pathol . 1977;8:589-592.
84 Wenig BM, Devaney K, Wenig BL. Pseudoneoplastic lesions of the oropharynx and larynx simulating cancer. Pathol Annu . 1995;30:143-187.
85 Close LG, Cowan DF. Recurrent necrotizing sialometaplasia of the nasal cavity. Otolaryngol Head Neck Surg . 1985;93:422-425.
86 Franchi A, Gallo O, Santucci M. Pathologic quiz case 1. Necrotizing sialometaplasia obscuring recurrent well-differentiated squamous cell carcinoma of the maxillary sinus. Arch Otolaryngol Head Neck Surg . 1995;121:584-586.

87 Mufarrij AA, Busaba NY, Zaytoun GM, et al. Primary localized amyloidosis of the nose and paranasal sinuses: A case report with immunohistochemical observations and a review of the literature. Am J Surg Pathol . 1990;14:379-383.

Paranasal Sinus Mucocele
88 Natvig K, Larssen TE. Mucocele of the paranasal sinuses: A retrospective and histological study. J Laryngol Otol . 1978;92:1075-1082.
89 Feldman M, Lowry LD, Rao VM, et al. Mucoceles of the paranasal sinuses. Trans Pa Acad Ophthalmol Otolaryngol . 1987;39:614-617.
90 Schaeffer BT, Som PM, Sacher M, et al. Coexistence of a nasal mucoepidermoid carcinoma and sphenoid mucoceles: CT diagnosis and treatment implications. J Comput Assist Tomogr . 1985;9:803-805.
91 Crain MR, Dolan KD, Maves MD. Maxillary sinus mucocele. Ann Otol Rhinol Laryngol . 1990;99:321-322.
92 Tunkel DE, Naclerio RM, Baroody FM, et al. Bilateral maxillary sinus mucocele in an infant with cystic fibrosis. Otolaryngol Head Neck Surg . 1994;111:116-120.
93 Delfini R, Missori P, Iannetti G, et al. Mucoceles of the paranasal sinuses with intracranial and intraorbital extension: Report of 28 cases. Neurosurgery . 1993;32:901-906.
94 Hashim AS, Asakura T, Awa H, et al. Giant mucocele of paranasal sinuses. Surg Neurol . 1985;23:69-74.
95 Hesselink JR, Weber AL, New PF, et al. Evaluation of mucoceles of the paranasal sinuses with computed tomography. Radiology . 1979;133:397-400.
96 Weissman JL, Curtin HD, Eibling DE. Double mucocele of the paranasal sinuses. AJNR Am J Neuroradiol . 1994;15:1263-1264.

Respiratory Epithelial Adenomatoid Hamartoma
97 Wenig BM, Heffner DK. Respiratory epithelial adenomatoid hamartomas of the sinonasal tract and nasopharynx: A clinicopathologic study of 31 cases. Ann Otol Rhinol Laryngol . 1995;104:639-645.

Nasal Chondromesenchymal Hamartoma
98 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.
99 Ozolek JA, Carrau R, Barnes EL, Hunt JA. Nasal chondromesenchymal hamartoma in older children and adults. Series and immunohistochemical analysis. Arch Pathol Lab Med . 2005;129:1444-1450.

Glial Heterotopia, Encephalocele, and Dermoid Cyst
100 Yeoh GP, Bale PM, de Silva M. Nasal cerebral heterotopia: The so-called nasal glioma or sequestered encephalocele and its variants. Pediatr Pathol . 1989;9:531-549.
101 Karma P, Rasanen O, Karja J. Nasal gliomas: A review and report of two cases. Laryngoscope . 1977;87:1169-1179.
102 Zinreich SJ, Borders JC, Eisele DW, et al. The utility of magnetic resonance imaging in the diagnosis of intranasal meningoencephaloceles. Arch Otolaryngol Head Neck Surg . 1992;118:1253-1256.
103 Stoll W, Nieschalk M. Kongenitale Fehlbildungen des pranasalen Raumes: Gliome, Fisteln, Epidermoidzysten. Laryngorhinootologie . 1996;75:739-744.
104 Mirra SS, Pearl GS, Hoffman JC, et al. Nasal “glioma” with prominent neuronal component: Report of a case. Arch Pathol Lab Med . 1981;105:540-541.
105 Theaker JM, Fletcher CD. Heterotopic glial nodules: A light microscopic and immunohistochemical study. Histopathology . 1991;18:255-260.
106 Kane AM, Lore JJr. Meningoencephalocele of the paranasal sinuses. Laryngoscope . 1975;85:2087-2091.
107 Chan JK, Lau WH. Nasal astrocytoma or nasal glial heterotopia? Arch Pathol Lab Med . 1989;113:943-945.
108 Bossen EH, Hudson WR. Oligodendroglioma arising in heterotopic brain tissue of the soft palate and nasopharynx. Am J Surg Pathol . 1987;11:571-574.
109 Gnepp DR. Teratoid neoplasms of the head and neck. In: Barnes L, editor. Surgical Pathology of the Head and Neck . New York: Marcel Dekker; 1985:1411-1433.

Tornwaldt’s Cyst
110 Biurrun O, Olmo A, Barcelo X, et al. Thornwaldt’s cyst. The experience of a decade. An Otorrinolaringol Ibero Am . 1992;19:179-189.
111 Battino RA, Khangure MS. Is that another Thornwaldt’s cyst on M.R.I.? Australas Radiol . 1990;34:19-23.

Lymphoid Hyperplasia
112 Mabry RL. Lymphoid pseudotumor of the nasopharynx and larynx. J Laryngol Otol . 1967;81:441-443.
113 Rimarenko S, Schwartz IS. Polypoid nasal pseudolymphoma. Am J Clin Pathol . 1985;83:507-509.
114 Chen TC, Kuo T. Castleman’s disease presenting as a pedunculated nasopharyngeal tumour simulating angiofibroma. Histopathology . 1993;23:485-488.
115 Seider MJ, Cleary KR, van Tassel P, et al. Plasma cell granuloma of the nasal cavity treated by radiation therapy. Cancer . 1991;67:929-932.
116 Muzaffar M, Hussain SI, Chughtai A. Plasma cell granuloma: Maxillary sinuses. J Laryngol Otol . 1994;108:357-358.
117 Som PM, Brandwein MS, Maldjian C, et al. Inflammatory pseudotumor of the maxillary sinus: CT and MRI findings in six cases. AJR Am J Roentgenol . 1994;163:689-692.
118 Shahab I, Osborne BM, Butler JJ. Nasopharyngeal lymphoid tissue masses in patients with human immunodeficiency virus-1: Histologic findings and clinical correlation. Cancer . 1995;74:3083-3088.
119 Wenig BM, Thompson LDR, Frankel SS, et al. Lymphoid changes of the nasopharyngeal and palatine tonsils that are indicative of human immunodeficiency virus infection: A clinicopathologic study of 12 cases. Am J Surg Pathol . 1996;20:572-587.

Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman Disease)
120 Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: A newly recognized benign clinicopathologic entity. Arch Pathol . 1969;87:63-70.
121 Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: A pseudolymphomatous benign disorder: Analysis of 34 cases. Cancer . 1972;30:1174-1188.
122 Wenig BM, Abbondanzo SL, Childers EL, et al. Extranodal sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) of the head and neck. Hum Pathol . 1993;24:483-492.
123 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.
124 Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: Ear, nose, and throat manifestations. Arch Otolaryngol . 1978;104:687-693.
125 Eisen RN, Buckley PJ, Rosai J. Immunophenotypic characterization of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). Semin Diagn Pathol . 1990;7:74-82.
126 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.
127 Komp DM. The treatment of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). Semin Diagn Pathol . 1990;7:83-86.

Wegener’s Granulomatosis
128 Colby TV, Tazelaar HD, Specks U, et al. Nasal biopsy in Wegener’s granulomatosis. Hum Pathol . 1991;22:101-104.
129 Gaudin PB, Askin FB, Falk RJ, et al. The pathologic spectrum of pulmonary lesions in patients with anti-neutrophil cytoplasmic autoantibodies specific for anti-proteinase 3 and anti-myeloperoxidase. Am J Clin Pathol . 1995;104:7-16.
130 Devaney KO, Travis WD, Hoffman G, et al. Interpretation of head and neck biopsies in Wegener’s granulomatosis: A pathologic study of 126 biopsies in 70 patients. Am J Surg Pathol . 1990;14:555-564.
131 Del Buono EA, Flint A. Diagnostic usefulness of nasal biopsy in Wegener’s granulomatosis. Hum Pathol . 1991;22:107-110.
132 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.
133 Batsakis JG, El-Naggar AK. Wegener’s granulomatosis and antineutrophil cytoplasmic autoantibodies. Ann Otol Rhinol Laryngol . 1993;102:906-908.

Eosinophilic Angiocentric Fibrosis
134 Roberts PF, McCann BG. Eosinophilic angiocentric fibrosis of the upper respiratory tract: A mucosal variant of granuloma faciale? A report of three cases. Histopathology . 1985;9:1217-1225.
135 Altemani AM, Pilch BZ, Sakano E, et al. Eosinophilic angiocentric fibrosis of the nasal cavity. Mod Pathol . 1997;10:391-393.
136 Thompson LD, Heffner DK. Sinonasal tract eosinophilic angiocentric fibrosis. A report of three cases. Am J Clin Pathol . 2001;115:243-248.
137 Paun S, Lund VJ, Gallimore A. Nasal fibrosis: Long-term follow up of four cases of eosinophilic angiocentric fibrosis. J Laryngol Otol . 2005;119:119-124.
138 Onder S, Sungur A. Eosinophilic angiocentric fibrosis: An unusual entity of the sinonasal tract. Arch Pathol Lab Med . 2004;128:90-91.
139 Loane J, Jaramillo M, Young HA, Kerr KM. Eosinophilic angiocentric fibrosis and Wegener’s granulomatosis: A case report and literature review. J Clin Pathol . 2001;54:640-641.

Idiopathic Midline Destructive Disease
140 Tsokos M, Fauci AS, Costa J. Idiopathic midline destructive disease (IMDD). A subgroup of patients with the “midline granuloma” syndrome. Am J Clin Pathol . 1982;77:162-168.
141 Heffner DK. Idiopathic midline destructive disease [letter]. Ann Otol Rhinol Laryngol . 1995;104:258.
142 Rodrigo JP, Suarez C, Rinaldo A, et al. Idiopathic midline destructive disease: Fact or fiction. Oral Oncol . 2005;41:340-348.
143 Sercarz JA, Strasnick B, Newman A, et al. Midline nasal destruction in cocaine abusers. Otolaryngol Head Neck Surg . 1991;105:694-701.

Schneiderian Papillomas
144 Friedmann I, Osborn DA. Papillomas of the nose and sinuses. In: Pathology of Granulomas and Neoplasms of the Nose and Paranasal Sinuses . Edinburgh: Churchill Livingstone; 1982:104-116.
145 Vrabec DP. The inverted schneiderian papilloma: A 25-year study. Laryngoscope . 1994;104:582-605.
146 Suh KW, Facer GW, Devine KD, et al. Inverting papilloma of the nose and paranasal sinuses. Laryngoscope . 1977;87:35-46.
147 Hyams VJ. Papillomas of the nasal cavity and paranasal sinuses: A clinicopathological study of 315 cases. Ann Otol Rhinol Laryngol . 1971;80:192-206.
148 Michaels L, Young M. Histogenesis of papillomas of the nose and paranasal sinuses. Arch Pathol Lab Med . 1995;119:821-826.
149 Shanmugaratnam K, Sobin LH. Histological typing of tumors of the upper respiratory tract and ear, World Health Organization. International Histological Classification of Tumours, 2nd ed, 1991, Springer-Verlag, Berlin.
150 Michaels L. Benign mucosal tumors of the nose and paranasal sinuses. Semin Diagn Pathol . 1996;13:113-117.
151 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 the polymerase chain reaction. Hum Pathol . 1991;22:550-556.
152 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.
153 McLachlin CM, Kandel RA, Colgan TJ, et al. Prevalence of human papillomavirus in sinonasal papillomas: A study using polym-erase chain reaction and in situ hybridization. Mod Pathol . 1992;5:406-409.
154 Gaffey MJ, Frierson HFJr, Weiss LM, et al. Human papillomavirus and Epstein-Barr virus in sinonasal schneiderian papillomas. An in situ hybridization and polymerase chain reaction study. Am J Clin Pathol . 1996;106:475-482.
155 Sarkar FH, Visscher DW, Kintanar EB, et al. Sinonasal schneiderian papillomas: Human papillomavirus typing by polymerase chain reaction. Mod Pathol . 1992;5:329-332.
156 Lasser A, Rothfeld PR, Shapiro RS. Epithelial papilloma and squamous cell carcinoma of the nasal cavity and paranasal sinuses: A clinicopathological study. Cancer . 1976;38:2503-2510.
157 Vrabec DP. The inverted schneiderian papilloma: A clinical and pathological study. Laryngoscope . 1975;85:186-220.
158 Lawson W, Ho BT, Shaari CM, et al. Inverted papilloma: A report of 112 cases. Laryngoscope . 1995;105:282-288.
159 Seshul MJ, Eby TL, Crowe DR, et al. Nasal inverted papilloma with involvement of middle ear and mastoid. Arch Otolaryngol Head Neck Surg . 1995;121:1045-1048.
160 Snyder RN, Perzin KH. Papillomatosis of nasal cavity and paranasal sinuses (inverted papilloma, squamous papilloma): A clinicopathologic study. Cancer . 1972;30:668-690.
161 Ridolfi RL, Lieberman PH, Erlandson RA, et al. Schneiderian papillomas: A clinicopathologic study of 30 cases. Am J Surg Pathol . 1977;1:43-53.
162 Nielsen PL, Buchwald C, Nielsen LH, et al. Inverted papilloma of the nasal cavity: Pathological aspects in a follow-up study. Laryngoscope . 1991;101:1094-1101.
163 Katenkamp D, Stiller D, Kuttner K. Inverted papillomas of nasal cavity and paranasal sinuses: Ultrastructural investigations on epithelial-stromal interface. Virchows Arch . 1982;397:215-226.
164 Barnes L, Bedetti C. Oncocytic schneiderian papilloma: A reappraisal of cylindrical cell papilloma of the sinonasal tract. Hum Pathol . 1984;15:344-351.
165 Bawa R, Allen GC, Ramadan HH. Cylindrical cell papilloma of the nasal cavity. Ear Nose Throat J . 1995;74:179-181.
166 Calcaterra TC, Thompson JW, Paglia DE. Inverting papillomas of the nose and paranasal sinuses. Laryngoscope . 1980;90:53-60.
167 Myers EN, Schramm VLJr, Barnes ELJr. Management of inverted papilloma of the nose and paranasal sinuses. Laryngoscope . 1981;91:2071-2084.
168 Sham CL, Woo JKS, van Hasselt CA. Endoscopic resection of inverted papilloma of the nose and paranasal sinuses. J Laryngol Otol . 1998;112:758-764.
169 Harrison D, Lund VJ. Papillomas of the nasal cavity and paranasal sinuses. In: Tumours of the Upper Jaw . Edinburgh: Churchill Livingstone; 1993:73-80.
170 Kapadia SB, Barnes L, Pelzman K, et al. Carcinoma ex oncocytic schneiderian (cylindrical cell) papilloma. Am J Otolaryngol . 1993;14:332-338.
171 Walter P, Stebler S, Schaffer P, et al. Cylindrical epithelioma of nasal cavities and accessory sinuses. Anatomoclinical study of 26 cases. Ann Anat Pathol (Paris) . 1976;21:463-476.
172 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.

Salivary Gland–Type Tumors
173 Miller RH, Calcaterra TC. Adenoid cystic carcinoma of the nose, paranasal sinuses and palate. Arch Otolaryngol . 1980;106:424-426.
174 Manning JT, Batsakis JG. Salivary-type neoplasms of the sinonasal tract. Ann Otol Rhinol Laryngol . 1991;100:691-694.
175 Goepfert H, Luna MA, Lindberg RD, et al. Malignant salivary gland tumors of the paranasal sinuses and nasal cavity. Arch Otolaryngol . 1983;109:662-668.
176 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.
177 Heffner DK. Sinonasal and laryngeal salivary gland lesions. In: Ellis GL, Auclair PL, Gnepp DR, editors. Surgical Pathology of the Salivary Glands . Philadelphia: WB Saunders; 1991:544-559.
178 Gnepp DR, Heffner DK. Mucosal origin of sinonasal tract adenomatous neoplasms. Mod Pathol . 1989;2:365-371.
179 Tran L, Sidrys J, Horton D, et al. Malignant salivary gland tumors of the paranasal sinuses and nasal cavity. A UCLA experience. Am J Clin Oncol . 1989;12:387-392.
180 Spiro RH, Koss LG, Hajdu SI, et al. Tumors of minor salivary origin: A clinicopathologic study of 492 cases. Cancer . 1973;31:117-129.
181 Cho KJ, El-Naggar AK, Mahanupab P, et al. Carcinoma ex-pleomorphic adenoma of the nasal cavity: A report of two cases. J Laryngol Otol . 1995;109:677-679.
182 Compagno J, Wong RT. Intranasal mixed tumors (pleomorphic adenomas): A clinicopathologic study of 40 cases. Am J Clin Pathol . 1977;68:213-218.
183 DiMaio SJ, DiMaio VJ, DiMaio TM, et al. Oncocytic carcinoma of the nasal cavity. South Med J . 1980;73:803-806.
184 Chui RT, Liao SY, Bosworth H. Recurrent oncocytoma of the ethmoid sinus with orbital invasion. Otolaryngol Head Neck Surg . 1985;93:267-270.
185 Begin LR, Rochon L, Frenkiel S. Spindle cell myoepithelioma of the nasal cavity. Am J Surg Pathol . 1991;15:184-190.
186 Begin LR, Black MJ. Salivary-type myxoid myoepithelioma of the sinonasal tract: A potential diagnostic pitfall. Histopathology . 1993;23:283-285.
187 Alos L, Cardesa A, Bombi JA, et al. Myoepithelial tumors of salivary glands: A clinicopathologic, immunohistochemical, ultrastructural, and flow-cytometric study. Semin Diagn Pathol . 1996;13:138-147.
188 Graadt Van Roggen JF, Baatenburg-De Jong RJ, Verschuur HP, et al. Myoepithelial carcinoma (malignant myoepithelioma): First report of an occurrence in the maxillary sinus. Histopathology . 1998;32:239-241.
189 Ralfa S. Mucous gland tumors of paranasal sinuses. Cancer . 1969;24:683-691.
190 Ordonez NG, Batsakis JG. Acinic cell carcinoma of the nasal cavity: Electron-optic and immunohistochemical observations. J Laryngol Otol . 1986;100:345-349.
191 Perzin KH, Cantor JO, Johannessen JV. Acinic cell carcinoma arising in nasal cavity: Report of a case with ultrastructural observations. Cancer . 1981;47:1818-1822.
192 Heffner DK, Hyams VJ, Hauck KW, et al. Low-grade adenocarcinoma of the nasal cavity and paranasal sinuses. Cancer . 1982;50:312-322.
193 Fonseca I, Soares J. Basal cell adenocarcinoma of minor salivary and seromucous glands of the head and neck region. Semin Diagn Pathol . 1996;13:128-137.
194 Dardick I, van Nostrand P. Polymorphous low-grade adenocarcinoma: A case report with ultrastructural findings. Oral Surg Oral Med Oral Pathol . 1988;66:459-465.
195 Lloreta J, Serrano S, Corominas JM, et al. Polymorphous low-grade adenocarcinoma arising in the nasal cavities with an associated undifferentiated carcinoma. Ultrastruct Pathol . 1995;19:365-370.
196 Kleinsasser O. Terminal tubulus adenocarcinoma of the nasal seromucous glands: A specific entity. Arch Otorhinolaryngol . 1985;241:183-193.
197 Michal M, Sklalova A, Simpson RHW, et al. Clear cell myoepithelioma of the salivary gland. Histopathology . 1996;28:309-315.
198 Lam PWY, Chan JKC, Sin VC. Nasal pleomorphic adenoma with skeletal muscle differentiation: Potential misdiagnosis as rhabdomyosarcoma. Hum Pathol . 1997;28:1299-1302.
199 Dehner LP, Valbuena L, Perez-Atayde A, et al. Salivary gland anlage tumor (“congenital pleomorphic adenoma”). A clinicopathologic, immunohistochemical and ultrastructural study of nine cases. Am J Surg Pathol . 1994;18:25-36.
200 Boccon-Gibod LA, Grangeponte MC, Boucheron S, et al. Salivary gland anlage tumor of the nasopharynx: A clinicopathologic and immunohistochemical study of three cases. Pediatr Pathol Lab Med . 1996;16:973-983.
201 Cohen EG, Yoder M, Thomas RM, et al. Congenital salivary gland anlage tumor of the nasopharynx. Pediatrics . 2003;112:66-69.
202 Herrmann BW, Dehner LP, Lieu JE. Congenital salivary gland anlage tumor: A case series and review of literature. Int J Pediatr Otorhinolaryngol . 2005;69:149-156.

203 Franchi A, Santucci M, Wenig BM. Adenocarcinoma—nasal cavity and paranasal sinuses. In: Barnes L, Eveson JW, Reichart P, Sidransky D, editors. World Health Organization Classification of Tumours: Pathology & Genetics—Head and Neck Tumours . Lyon, France: IARC Press; 2005:20-23.

Intestinal-Type Adenocarcinoma
204 Kleinsasser O, Schroeder H-G. Adenocarcinomas of the inner nose after exposure to wood dust. Morphological findings and relationships between histopathology and clinical behavior in 79 cases. Arch Otolaryngol . 1988;245:1-15.
205 Barnes L. Intestinal-type adenocarcinoma of the nasal cavity and paranasal sinuses. Am J Surg Pathol . 1986;10:192-202.
206 Mills SE, Fechner RE, Cantrell RW. Aggressive sinonasal lesion resembling normal intestinal mucosa. Am J Surg Pathol . 1982;6:803-809.
207 Franquemont DW, Fechner RE, Mills SE. Histologic classification of sinonasal intestinal-type adenocarcinoma. Am J Surg Pathol . 1991;15:368-375.
208 Sanchez-Casis G, Devine KD, Welland LH. Nasal adenocarcinomas that closely simulate colonic carcinomas. Cancer . 1971;28:714-720.
209 Gamez-Araujo JJ, Ayala AG, Guillamondegui O. Mucinous adenocarcinoma of nose and paranasal sinuses. Cancer . 1975;36:1100-1105.
210 Elwood JM. Wood exposure and smoking: Association with cancer of the nasal cavity and paranasal sinuses in British Columbia. CMAJ . 1981;124:1573-1577.
211 Klintenberg C, Olofsson J, Hellquist H, et al. Adenocarcinoma of the ethmoid sinuses: A review of 28 cases with special reference to wood dust exposure. Cancer . 1984;54:482-488.
212 Ironside P, Matthews J. Adenocarcinoma of the nose and paranasal sinuses in woodworkers in the state of Victoria, Australia. Cancer . 1975;36:1115-1121.
213 Moran CA, Wenig BM, Mullick FG. Primary adenocarcinoma of the nasal cavity and paranasal sinuses. Ear Nose Throat J . 1995;70:821-828.
214 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.
215 McKinney CD, Mills SE, Franquemont DW. Sinonasal intestinal-type adenocarcinoma: Immunohistochemical profile and comparison with colonic adenocarcinoma. Mod Pathol . 1995;8:421-425.
216 Franchi A, Gallo O, Santucci M. Clinical relevance of the histological classification of sinonasal intestinal-type adenocarcinomas. Hum Pathol . 1999;30:1140-1145.
217 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.
218 Wu TT, Barnes L, Bakker A, et al. K-ras-2 and p53 genotyping of intestinal-type adenocarcinoma of the nasal cavity and paranasal sinuses. Mod Pathol . 1996;9:199-204.
219 Yom SS, Rashid A, Rosenthal DI, et al. Genetic analysis of sinonasal adenocarcinoma phenotypes: Distinct alterations of histogenetic significance. Mod Pathol . 2005;18:315-319.
220 Bernstein JM, Montgomery WW, Balogh K. Metastatic tumors to the maxilla, nose, and paranasal sinuses. Laryngoscope . 1966;76:621-650.
221 Gillmore JR, Gillespie CA, Hudson WR. Adenocarcinoma of the nose and paranasal sinuses. Ear Nose Throat J . 1987;66:120-123.
222 Alessi DM, Trapp TK, Fu YS, et al. Nonsalivary sinonasal adenocarcinoma. Arch Otolaryngol Head Neck Surg . 1988;114:996-999.

Nonintestinal Type Adenocarcinoma
223 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.
224 Cinberg JZ, Solomon MP, Ozbardacki G. Thyroid carcinoma and secondary malignancy of the sinonasal tract. Arch Otolaryngol . 1980;106:239-241.

Small Cell Neuroendocrine Carcinoma
225 Perez-Ordonez B, Caruana SM, Huvos AG, et al. Small cell neuroendocrine carcinoma of the nasal cavity and paranasal sinuses. Hum Pathol . 1998;29:826-832.
226 Koss LG, Spiro RH, Hajdu S. Small cell (oat cell) carcinoma of minor salivary gland origin. Cancer . 1972;30:737-741.
227 Rejowski JE, Campanella RS, Block LJ. Small cell carcinoma of the nose and paranasal sinuses. Otolaryngol Head Neck Surg . 1982;90:516-517.
228 Weiss MD, deFries HO, Taxy JB, et al. Primary small cell carcinoma of the paranasal sinuses. Arch Otolaryngol . 1983;109:341-343.
229 Kameya T, Shimosato Y, Adachi I, et al. Neuroendocrine carcinoma of the paranasal sinus: A morphological and endocrinological study. Cancer . 1980;45:330-339.
230 Gaudin PB, Rosai J. Florid vascular proliferation associated with neural and neuroendocrine neoplasms: A diagnostic clue and potential pitfall. Am J Surg Pathol . 1995;19:642-652.
231 Chan JKC, Suster S, Wenig BM, et al. Cytokeratin 20 immunoreactivity distinguishes Merkel cell (primary cutaneous) neuroendocrine carcinomas and salivary gland small cell carcinomas from small cell carcinomas of various sites. Am J Surg Pathol . 1997;21:226-234.
232 Kyung-Whan M. Usefulness of electron microscopy in the diagnosis of small round cell tumors of the sinonasal region. Ultrastruct Pathol . 1995;19:347-363.
233 Saw D, Chan JK, Jagirdar J, et al. Sinonasal small cell neoplasm developing after radiation therapy for retinoblastoma: An immunohistologic, ultrastructural, and cytogenetic study. Hum Pathol . 1992;23:896-899.
234 Frierson HF, Ross GW, Stewart FM, et al. Unusual sinonasal small-cell neoplasms following radiotherapy for bilateral retinoblastomas. Am J Surg Pathol . 1989;13:947-954.
235 Wan SK, Chan JK, Tse KC. Basaloid-squamous carcinoma of the nasal cavity. J Laryngol Otol . 1992;106:370-371.
236 Mills SE. Neuroendocrine tumors of the head and neck: A selected review with emphasis on terminology. Endocr Pathol . 1996;7:329-343.
237 Banks ER, Frierson HF, Mills SE, et al. Basaloid squamous cell carcinoma of the head and neck: A clinicopathologic and immunohistochemical study of 40 cases. Am J Surg Pathol . 1992;16:939-946.
238 Galanis E, Frytak S, Lloyd RV. Extrapulmonary small cell carcinoma. Cancer . 1997;79:1729-1736.
239 Raychowdhuri RN. Oat-cell carcinoma and paranasal sinuses. J Laryngol Otol . 1965;79:253-255.

Carcinoid Tumor
240 Siwersson U, Kindblom LG. Oncocytic carcinoid of the nasal cavity and carcinoid of the lung in a child. Pathol Res Pract . 1984;178:562-569.
241 Perdigou JB, Pages M, Le Bodic MF, et al. Tumeur oncocytarie avec granulations neuro-secretoires de la muqueuse nasale. Arch Anat Cytol Path . 1981;29:75-78.
242 McCluggage WG, Napier SS, Primrose WJ, et al. Sinonasal neuroendocrine carcinoma exhibiting amphicrine differentiation. Histopathology . 1995;27:79-82.

Sinonasal Undifferentiated Carcinoma
243 Frierson HF, Mills SE, Fechner RE, et al. Sinonasal undifferentiated carcinoma. Am J Surg Pathol . 1986;10:771-779.
244 Pitman KT, Lassen LF. Pathologic quiz case 2. Sinonasal undifferentiated carcinoma (SNUC). Arch Otolaryngol Head Neck Surg . 1995;121:1201-1203.
245 Frierson HFJr, 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 Deutsch B, Levine PA, Stewart M, et al. Sinonasal undifferentiated carcinoma: A ray of hope. Otolaryngol Head Neck Surg . 1993;108:697-700.
247 Helliwell TR, Yeoh LH, Stell PM. Anaplastic carcinoma of the nose and paranasal sinuses: A light microscopy, immunohistochemistry and clinical correlation. Cancer . 1986;58:2038-2045.
248 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.
249 Lopategui JR, Gaffey MJ, Frierson HFJr, 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.
250 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.
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 Greger V, Schirmacher P, Bohl J, et al. Possible involvement of the retinoblastoma gene in undifferentiated sinonasal carcinoma. Cancer . 1990;66:1954-1959.
253 Gallo O, Graziani P, Fini-Storchi O. Undifferentiated carcinoma of the nose and paranasal sinuses. Otolaryngol Head Neck Surg . 1995;72:588-595.
254 Ascaso FJ, Adiego MI, Garcia J, et al. Sinonasal undifferentiated carcinoma invading the orbit. Eur J Ophthalmol . 1994;4:234-236.
255 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.
256 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 patter. Am J Surg Pathol . 2002;26:1597-1604.
257 Mills SE, Fechner RE. “Undifferentiated” neoplasms of the sinonasal region: Differential diagnosis based on clinical, light microscopic, immunohistochemical, and ultrastructural features. Semin Diagn Pathol . 1989;6:316-328.
258 Hewan-Lowe K, Dardick I. Ultrastructural distinction of basaloid-squamous carcinoma and adenoid cystic carcinoma. Ultrastruct Pathol . 1995;19:371-381.

259 Ueda N, Yoshida A, Fukunishi R, et al. Nonchromaffin paraganglioma in the nose and paranasal sinuses. Acta Pathol Jpn . 1985;35:489-495.
260 Himelfarb MZ, Ostrzega NL, Samuel J, et al. Paraganglioma of the nasal cavity. Laryngoscope . 1983;93:350-352.
261 Lack EE, Cubilla AL, Woodruff JM. Paragangliomas of the head and neck region: A pathologic study of tumors from 71 patients. Hum Pathol . 1979;10:191-218.
262 Parisier SC, Sinclair GM. Glomus tumor of the nasal cavity. Laryngoscope . 1968;78:2013-2024.
263 Lack EE, Cubilla AL, Woodruff JM, et al. Paragangliomas of the head and neck region: A clinicopathologic study of 69 patients. Cancer . 1977;39:397-409.
264 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.
265 Branham GH, Gnepp DR, O’McMenomey S, et al. Malignant paraganglioma: A case report and literature review. Otolaryngol Head Neck Surg . 1989;101:99-103.

Malignant Melanoma
266 Franquemont DW, Mills SE. Sinonasal malignant melanoma: A clinicopathologic and immunohistochemical study of 14 cases. Am J Clin Pathol . 1991;96:689-697.
267 Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: A summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer . 1998;83:1664-1678.
268 Guzzo M, Grandi C, Licitra L, et al. Mucosal malignant melanoma of head and neck: Forty-eight cases treated at Istituto Nazionale Tumori of Milan. Eur J Surg Oncol . 1993;19:316-319.
269 Shah JP, Huvos AG, Strong EW. Mucosal melanomas of the head and neck. Am J Surg . 1977;134:531-535.
270 Barton RT. Mucosal melanomas of the head and neck. Laryngoscope . 1975;85:93-99.
271 Friedmann I, Osborn DA. Melanotic tumours of the nose and sinuses. In: Pathology of Granulomas and Neoplasms of the Nose and Paranasal Sinuses . Edinburgh: Churchill Livingstone; 1982:162-172.
272 Kingdom TT, Kaplan MJ. Mucosal melanoma of the nasal cavity and paranasal sinuses. Head Neck . 1995;17:184-189.
273 Lund VL. Malignant melanoma of the nasal cavity and paranasal sinuses. J Laryngol Otol . 1982;96:347-355.
274 Lund VL. Malignant melanoma of the nasal cavity and paranasal sinuses. Ear Nose Throat J . 1993;72:285-290.
275 Thompson LDR, Wieneke JA, Miettinen M. Sinonasal tract melanomas: A clinicopathologic study of 115 cases with a proposed staging system. Am J Surg Pathol . 2003;27:594-611.
276 Prasad ML, Busam KJ, Patel SG, et al. Clinicopathologic differences in malignant melanoma arising in oral squamous and sinonasal respiratory mucosa of the upper aerodigestive tract. Arch Pathol Lab Med . 2003;127:997-1002.
277 Prasad ML, Patel SG, Busam KJ. Primary mucosal desmoplastic melanoma of the head and neck. Head Neck . 2004;26:373. –337
278 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.
279 Prasad ML, Patel SG, Huvos AG, et al. Primary mucosal melanoma of the head and neck: A proposal for microstaging localized, stage I (node negative) tumors. Cancer . 2004;100:1657-1664.
280 Patel SG, Prasad ML, Escrig M, et al. Primary mucosal malignant melanoma of the head and neck. Head Neck . 2002;24:247-257.
281 Raben A, Pfister D, Harrison LB. Radiation therapy and chemotherapy in the management of cancers of the nasal cavity and paranasal sinuses. In: Kraus DH, Levine HL, editors. Nasal Neoplasia . New York: Thieme; 1997:183-212.
282 Thompson AC, Morgan DA, Bradley PJ. Malignant melanoma of the nasal cavity and paranasal sinuses. Clin Otolaryngol . 1993;18:34-36.
283 Robertson DM, Hungerford JL, McCartney A. Malignant melanomas of the conjunctiva, nasal cavity, and paranasal sinuses. Am J Ophthalmol . 1989;108:440-442.

Olfactory Neuroblastoma
284 Berger L, Luc G, Richard D. L’esthesioneuroepitheliome olfactif. Bull Assoc Etude Cancer . 1924;13:410-421.
285 Bhattacharyya N, Thornton AF, Joseph MP, et al. Successful treatment of esthesioneuroblastoma and neuroendocrine carcinoma with combined chemotherapy and proton radiation. Arch Otolaryngol Head Neck Surg . 1997;123:34-40.
286 Ordonez NG, Mackay B. Neuroendocrine tumors of the nasal cavity. Pathol Annu . 1993;28:77-111.
287 Spiro JD, Soo KC, Spiro RH. Nonsquamous cell malignant neoplasms of the nasal cavities and paranasal sinuses. Head Neck . 1995;17:114-118.
288 Dulguerov P, Allal AK, Calcaterra TC. Esthesioneuroblastoma: A meta-analysis and review. Lancet Oncol . 2001;2:683-690.
289 Hutter RVP, Lewis JS, Foote FWJ, et al. Esthesioneuroblastoma: A clinical and pathologic study. Am J Surg . 1963;106:748-753.
290 Perez-Ordonez B, Huvos AG. Olfactory neuroblastoma and sinonasal small cell neuroendocrine carcinoma: Immunohistochemical features and differential diagnosis. Mod Pathol . 1997;10:116A.
291 Dulguerov P, Calcaterra TC. Esthesioneuroblastoma: The UCLA experience 1970–1990. Laryngoscope . 1992;102:843-849.
292 Mills SE, Frierson HF. Olfactory neuroblastoma: A clinicopathologic study of 21 cases. Am J Surg Pathol . 1985;9:317-327.
293 Shah JP, Feghali J. Esthesioneuroblastoma. Am J Surg . 1981;142:456-458.
294 Mishima Y, Nagasaki E, Terui Y, et al. Combination chemotherapy (cyclophosphamide, doxorubicin, and vincristine with continuous-infusion cisplatin and etoposide) and radiotherapy with stem cell support can be beneficial for adolescents and adults with esthesioneuroblastoma. Cancer . 2004;101:437-444.
295 Ingeholm P, Theilgaard SA, Buchwald C, et al. Esthesioneuroblastoma: A Danish clinicopathological study of 40 consecutive cases. APMIS . 2002;110:639-645.
296 Myers SL, Hardy DA, Weibe CB, et al. Olfactory neuroblastoma invading the oral cavity in a patient with inappropriate antidiuretic hormone secretion. Oral Surg Oral Med Oral Pathol . 1994;77:645-650.
297 Kadish S, Goodman M, Wang CC. Olfactory neuroblastoma: A clinical analysis of 17 cases. Cancer . 1976;37:1571-1576.
298 Griego JE, Mackay B, Ordonez NG, et al. Olfactory neuroblastoma: A case report. Ultrastruct Pathol . 1996;20:399-406.
299 Hyams VJ, Batsakis JG, Michaels L, editors, Tumors of the upper respiratory tract and ear: Neuroectodermal lesions. Atlas of Tumor Pathology, 1988, Armed Forces Institute of Pathology, Washington, DC, 226-257, 2nd series
300 Miller DC, Goodman ML, Pilch BZ, et al. Mixed olfactory neuroblastoma and carcinoma: A report of two cases. Cancer . 1984;54:2019-2028.
301 Curtis JL, Rubinstein LJ. Pigmented example of melanotic neuroepithelial neoplasm. Cancer . 1982;49:2136-2143.
302 Hirose T, Scheithauer BW, Lopes MBS, et al. Olfactory neuroblastoma: An immunohistochemical, ultrastructural, and flow cytometric study. Cancer . 1995;76:4-19.
303 Frierson HF, Ross GW, Mills SE, et al. Olfactory neuroblastoma. Am J Clin Pathol . 1990;94:547-553.
304 Taxy JB, Bharani NK, Mills SE, et al. The spectrum of olfactory neural tumors: A light-microscopic immunohistochemical and ultrastructural analysis. Am J Surg Pathol . 1986;10:687-695.
305 Kahn LB. Esthesioneuroblastoma: A light and electron microscopic study. Hum Pathol . 1974;5:364-371.
306 Constantinidis J, Steinhart H, Koch M, et al. Olfactory neuroblastoma: The University of Erlangen-Nuremberg experience 1975–2000. Otolaryngol Head Neck Surg . 2004;130:567-574.
307 Sorensen PHB, Wu JK, Berean KW, et al. Olfactory neuroblastoma is a peripheral primitive neuroectodermal tumor related to Ewing sarcoma. Proc Natl Acad Sci U S A . 1996;93:1038-1043.
308 Whang-Peng J, Freter CE, Knutsen T, et al. Translocation t(11;22) in ONB. Cancer Genet Cytogenet . 1987;29:155-157.
309 Nelson RS, Perlman EJ, Askin FB. Is esthesioneuroblastoma a peripheral neuroectodermal tumor? Hum Pathol . 1995;26:639-641.
310 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.
311 Papadaki H, Kounelis S, Kapadia SB, et al. Relationship of p53 gene alterations with tumor progression and recurrence in olfactory neuroblastoma. Am J Surg Pathol . 1996;20:715-721.
312 Chaudhry MR, Akhtar S, Kim DS. Neuroendocrine carcinoma of the ethmoid sinus. Eur Arch Otorhinolaryngol . 1994;251:461-463.
313 Eden BV, Debo RF, Larner JM, et al. Esthesioneuroblastoma: Long-term outcome and patterns of failure. The University of Virginia experience. Cancer . 1994;73:2556-2562.
314 Fu YS, Perzin KH. Nonepithelial tumors of the nasal cavity, paranasal sinuses, and nasopharynx: A clinicopathologic study. V. skeletal muscle tumors (rhabdomyoma and rhabdomyosarcoma). Cancer . 1976;37:364-376.
315 Newton WAJr, Soule EH, Hamoudi AB, et al. Histopathology of childhood sarcomas. Intergroup rhabdomyosarcoma studies I and II: Clinicopathologic correlation. J Clin Oncol . 1988;6:67-75.
316 Horn RC, Enterline HT. Rhabdomyosarcoma: A clinicopathological study and classification of 39 cases. Cancer . 1958;11:181-199.
317 Sercarz JA, Mark RJ, Tran L, et al. Sarcomas of the nasal cavity and paranasal sinuses. Ann Otol Rhinol Laryngol . 1994;103:699-704.
318 Suzuki M, Kobayashi Y, Harada Y, et al. Rhabdomyosarcoma of the maxillary sinus: A case report. J Laryngol Otol . 1984;98:405-415.
319 El-Naggar AK, Batsakis JG, Ordonez NG, et al. Rhabdomyosarcoma of the adult head and neck: A clinicopathological and DNA ploidy study. J Laryngol Otol . 1993;107:716-720.
320 Hostein I, Andraud-Fregeville M, Guillou L, et al. Rhabdomyosarcoma: Value of myogenin expression analysis and molecular testing in diagnosing the alveolar subtype. Cancer . 2004;101:2817-2824.
Yasuda T, Perry K, Nelson M, et al: Alveolar rhabdomyosarcoma of the head and neck region in older adults: Genetic characterization and review of the literature. Hum Pathol (in press).
321 Chang KC, Jin YT, Chen RMY, et al. Mixed olfactory neuroblastoma and craniopharyngioma: An unusual pathologic finding. Histopathology . 1997;30:378-382.
322 Naresh KN, Pai SA. Foci resembling olfactory neuroblastoma and craniopharyngioma are seen in sinonasal teratocarcinosarcomas. Histopathology . 1998;32:84.
323 Liu Q, Ohshima K, Sumie A, et al. Nasal CD56 positive small round cell tumors. Differential diagnosis of hematological, neurogenic, and myogenic neoplasms. Virchows Arch . 2001;438:271-279.
324 Devaney K, Wenig BM, Abbondanzo SL. Olfactory neuroblastoma and other round cell lesions of the sinonasal region. Mod Pathol . 1996;9:658-663.
325 Folpe AL, Goldblum JR, Rubin BP, et al. Morphologic and immunophenotypic diversity in Ewing family tumors: A study of 66 genetically confirmed cases. Am J Surg Pathol . 2005;29:1025-1033.
326 Cope JU, Tsokos M, Miller RW. Ewing sarcoma and sinonasal neuroectodermal tumors as second malignant tumors after retinoblastoma and other neoplasms. Med Pediatr Oncol . 2001;36:290-294.
327 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.
328 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.
329 Szymas J, Wolf G, Kowalczyk D, et al. Olfactory neuroblastoma: Detection of genomic imbalances by comparative genomic hybridization. Acta Neurochir (Wien ) . 1997;139:839-844.

Lobular Capillary Hemangioma
330 Heffner DK. Problems in pediatric otorhinolaryngic pathology: II. Vascular tumors and lesions of the sinonasal tract and nasopharynx. Int J Pediatr Otorhinolaryngol . 1983;5:125-138.
331 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.
332 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;4:470-479.
333 Kim HJ, Kim JH, Hwang EG. Bone erosion caused by sinonasal cavernous hemangioma: CT findings in two patients. AJNR Am J Neuroradiol . 1995;16:1176-1178.

334 Hyams VJ. Tumors of the upper respiratory tract: Vascular tumors, Hyams VJ, Batsakis JG, Michaels L, editors, Atlas of Tumor Pathology, 1986, Armed Forces Institute of Pathology, Washington, DC, 130-145, 2nd series.
335 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.
336 Lee DA, Rao BR, Meyer JS, et al. Hormonal receptor determination in juvenile nasopharyngeal angiofibromas. Cancer . 1980;46:547-551.
337 Schiff M, Gonzalez AM, Ong M, et al. Juvenile nasopharyngeal angiofibroma contain an angiogenic growth factor: Basic FGF. Laryngoscope . 1992;102:940-945.
338 Nagai MA, Butugan O, Logullo A, et al. Expression of growth factors, proto-oncogenes, and p53 in nasopharyngeal angiofibromas. Laryngoscope . 1996;106:190-195.
339 Dillard DG, Cohen C, Muller S, et al. Immunolocalization of activated transforming growth factor beta1 in juvenile nasopharyngeal angiofibroma. Arch Otolaryngol Head Neck Surg . 2000;126:723-725.
340 Abraham SC, Montgomery EA, Giardiello FM, et al. Frequent beta-catenin mutations in juvenile nasopharyngeal angiofibromas. Am J Pathol . 2001;158:1073-1078.
341 Giardiello FM, Hamilton SR, Krush AJ, et al. Nasopharyngeal angiofibroma in patients with familial adenomatous polyposis. Gastroenterology . 1993;105:1550-1552.
342 Saylam G, Yucel OT, Sungur A, et al. Proliferation, angiogenesis and hormonal markers in juvenile nasopharyngeal angiofibroma. Int J Pediatr Otorhinolaryngol . 2006;70:227-234.
343 Chandler JR, Goulding R, Moskowitz L, et al. Nasopharyngeal angiofibromas: Staging and management. Ann Otol Rhinol Laryngol . 1984;93:322-329.
344 Sternberg SS. Pathology of juvenile nasopharyngeal angiofibroma: A lesion of adolescent males. Cancer . 1954;7:15-28.
345 Neel HB, Whicker JH, Devine KD, et al. Juvenile angiofibroma. Review of 120 cases. Am J Surg . 1973;126:547-556.
346 Beham A, Fletcher CDM, Kainz J, et al. Nasopharyngeal angiofibroma: An immunohistochemical study of 32 cases. Virchows Arch . 1993;423:281-285.
347 Beham A, Kainz J, Stammberger HR, et al. Immunohistochemical and electron microscopical characterization of stromal cells in nasopharyngeal angiofibromas. Eur Arch Otorhinolaryngol . 1997;254:196-199.
348 Taxy JB. Juvenile nasopharyngeal angiofibroma. An ultrastructural study. Cancer . 1977;39:1044-1054.
349 Goepfert H, Cangi A, Lee Y-Y. Chemotherapy for aggressive juvenile nasopharyngeal angiofibroma. Arch Otolaryngol . 1985;111:285-289.
350 Spagnolo DV, Papadimitriou JM, Archer M. Postirradiation malignant fibrous histiocytoma arising in juvenile nasopharyngeal angiofibroma and producing alpha-1-antitrypsin. Histopathology . 1984;8:339-352.
351 Chen KTK, Bauer FW. Sarcomatous transformation of nasopharyngeal angiofibroma. Cancer . 1982;49:369-371.
352 Dohar JE, Duvall AJ3rd. Spontaneous regression of juvenile nasopharyngeal angiofibroma. Ann Otol Rhinol Laryngol . 1992;101:469-471.
353 Hormia M, Koskinen O. Metastasizing nasopharyngeal angiofibroma: A case report. Arch Otolaryngol . 1969;89:107-110.

Glomangiopericytoma (Sinonasal Hemangiopericytoma)
354 Thompson LDR, Fanburg-Smith JC, Wenig BM. Borderline and low malignant potential tumours of soft tissue. In: Barnes L, Eveson JW, Reichart P, Sidransky D, editors. World Health Organization Classification of Tumours: Pathology & Genetics—Head and Neck Tumours . Lyon, France: IARC Press; 2005:43-45.
355 Compagno J, Hyams VJ. Hemangiopericytoma-like intranasal tumors: A clinicopathologic study of 23 cases. Am J Clin Pathol . 1976;66:672-683.
356 Compagno J. Hemangiopericytoma-like tumors of the nasal cavity: A comparison with hemangiopericytoma of soft tissues. Laryngoscope . 1978;88:460-469.
357 Tse LL, Chan JK. Sinonasal haemangiopericytoma-like tumour: A sinonasal glomus tumour or a haemangiopericytoma? Histopathology . 2002;40:510-517.
358 Thompson LDR, 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.
359 Abdel-Fattah HM, Adams GL, Wick MR. Hemangiopericytoma of the maxillary sinus and skull base. Head Neck . 1990;12:77-83.
360 Chawla OP, Oswal VH. Haemangiopericytoma of the nose and paranasal sinuses. J Laryngol Otol . 1987;101:729-737.
361 Folpe AL, Fanburg-Smith JC, Billings SD, et al. Most osteomalacia- associated mesenchymal tumors are a single histopathologic entity: An analysis of 32 cases and a comprehensive review of the literature. Am J Surg Pathol . 2004;28:1-30.
362 Purdy Stout A, Murray MR. Hemangiopericytoma: A vascular tumor featuring Zimmermann’s pericytes. Ann Surg . 1942;116:26-33.
363 Nielsen GP, Dickersin GR, Provenzal JM, et al. Lipomatous hemangiopericytoma: A histologic, ultrastructural and immunohistochemical study of a unique variant of hemangiopericytoma. Am J Surg Pathol . 1995;19:748-756.
364 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.
365 Eichhorn JH, Dickersin 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.
366 Mentzel T, Bainbridge TC, Katenkamp D. Solitary fibrous tumour: Clinicopathological, immunohistochemical, and ultrastructural analysis of 12 cases arising in soft tissues, nasal cavity and nasopharynx, urinary bladder and prostate. Virchows Arch . 1997;430:445-453.
367 Chilosi M, Facchetti F, Dei Tos AP, et al. Bcl-2 expression in pleural and extrapleural solitary fibrous tumours. J Pathol . 1997;181:362-367.
368 El-Naggar AK, Batsakis JG, Garcia GM, et al. Sinonasal hemangiopericytomas: A clinicopathologic and DNA content study. Arch Otolaryngol Head Neck Surg . 1992;118:134-137.
369 Billings KR, Fu YS, Calcaterra TC, et al. Hemangiopericytoma of the head and neck. Am J Otolaryngol . 2000;21:238-243.
370 Catalano PJ, Brandwein M, Shah DK, et al. Sinonasal hemangiopericytomas: A clinicopathologic and immunohistochemical study of seven cases. Head Neck . 1996;18:42-53.
371 Kowalski PJ, Paulino AF. Proliferation index as a prognostic marker in hemangiopericytoma of the head and neck. Head Neck . 2001;23:492-496.

Other Vascular Lesions
372 Kuo TT, Sayers CP, Rosai J. Masson’s “vegetans intravascular hemangioendothelioma”: A lesion often mistaken for angiosarcoma. Study of seventeen cases located in the skin and soft tissues. Cancer . 1976;38:1227-1236.
373 Stern Y, Braslavsky D, Segal K, et al. Intravascular papillary endothelial hyperplasia in the maxillary sinus: A benign lesion that may be mistaken for angiosarcoma. Arch Otolaryngol Head Neck Surg . 1991;117:1182-1184.
374 Dass AA, Saleem Y. Hemangioendothelioma of the maxillary sinus. Otolaryngol Head Neck Surg . 1995;112:735-737.

375 Kimura Y, Tanaka S, Furukawa M. Angiosarcoma of the nasal cavity. J Laryngol Otol . 1992;106:368-369.
376 Bankaci M, Myers EN, Barnes L, et al. Angiosarcoma of the maxillary sinus: Literature review and case report. Head Neck Surg . 1979;1:274-280.
377 Degos R, Labayle J, Belaich S, et al. Nasal angiosarcoma. Ann Dermatol Syphiligr (Paris) . 1971;98:406-407.
378 Aust MR, Olsen KD, Meland NB, et al. Angiosarcomas of the head and neck: Clinical and pathologic characteristics. Ann Otol Rhinol Laryngol . 1997;106:943-951.
379 Narula AA, Vallis MP, el-Silimy OE, et al. Radiation induced angiosarcomas of the nasopharynx. Eur J Surg Oncol . 1986;12:147-152.
380 Williamson IG, Ramsden RT. Angiosarcoma of maxillary antrum-association with vinyl chloride exposure. J Laryngol Otol . 1988;102:464-467.

Kaposi’s Sarcoma and Bacillary Angiomatosis
381 Gnepp DR, Chandler W, Hyams VJ. Primary Kaposi’s sarcoma of the head and neck. Ann Intern Med . 1984;100:107-114.
382 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.
383 Le Boit 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.
384 Batsakis JG, Ro JY. Bacillary angiomatosis. Ann Otol Rhinol Laryngol . 1995;104:668-672.

385 Fu YS, Perzin KH. Nonepithelial tumors of the nasal cavity, paranasal sinuses, and nasopharynx. a clinicopathologic study: VI. fibrous tissue tumors (fibroma, fibromatosis, fibrosarcoma). Cancer . 1976;37:2912-2928.

Benign Fibrous Histiocytoma
386 Perzin KH, Fu YS. Non-epithelial tumors of the nasal cavity, paranasal sinuses and nasopharynx: A clinico-pathologic study. XI. Fibrous histiocytomas. Cancer . 1980;45:2616-2626.

Myxoma and Fibromyxoma
387 Ghosh BC, Huvos AG, Gerold FP, et al. Myxoma of the jaw bones. Cancer . 1973;31:237-240.
388 Fu Y-S, Perzin KH. Non-epithelial tumors of the nasal cavity, paranasal sinuses and nasopharynx: A clinico-pathologic study. Cancer . 1977;39:195-203.
389 Heffner DK. Problems in pediatric otorhinolaryngic pathology. I. Sinonasal and nasopharyngeal tumors and masses with myxoid features. Int J Pediatr Otorhinolaryngol . 1983;5:77-91.
390 Hayes DK, Madsen JM, Simpson R, et al. Myxomas of the maxilla in infants and children. Otolaryngol Head Neck Surg . 1991;105:464-468.
391 Canalis RF, Smith GA, Konrad HR. Myxomas of the head and neck. Arch Otolaryngol Head Neck Surg . 1976;102:300-305.
392 Gregor RT, Loftus-Coll B. Myxoma of the paranasal sinuses. J Laryngol Otol . 1994;108:679-681.
393 Stout AP. Myxoma, the tumor of primitive mesenchyme. Ann Surg . 1948;127:706-719.
394 Simon EN, Merkx MA, Vuhahula E, et al. Odontogenic myxoma: A clinicopathological study of 33 cases. Int J Oral Maxillofac Surg . 2004;33:333-337.
395 Oliver DS, DiNardo LJ, Monahan M, et al. Pathologic Quiz Case 2. Odontogenic fibromyxoma. Arch Otolaryngol Head Neck Surg . 1995;121:805-807.
396 Harrison D, Lund VJ, editors, Mesenchymal malignancy Tumours of the Upper Jaw, 1993, Churchill Livingstone, Edinburgh, 135-156
397 Perez-Ordonez B, Shah JP, Huvos AG. Myxomas and fibromyxosarcoma of craniofacial bones. A study of 5 cases [abstract]. In: Proceedings of the 4th International Conference on Head and Neck Cancer . Canada: Toronto; 1996:235.
398 Moshiri S, Oda D, Worthington P, et al. Odontogenic myxoma: Histochemical and ultrastructural study. J Oral Pathol Med . 1992;21:401-403.

Other Fibrous and Fibrohistiocytic Tumors
399 Gnepp DR, Henley J, Weiss SW, et al. Desmoid fibromatosis of the sinonasal tract and nasopharynx: A clinicopathologic study of 25 cases. Cancer . 1996;78:2572-2579.
400 Witkin GB, Rosai J. Solitary fibrous tumor of the upper respiratory tract: A report of six cases. Am J Surg Pathol . 1991;15:842-848.
401 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.
402 Koka V, Vericel R, Lartigau E, et al. Sarcomas of nasal cavity and paranasal sinuses: Chondrosarcoma, osteosarcoma and fibrosarcoma. J Laryngol Otol . 1994;108:947-953.
403 Frankenthaler R, Ayala AG, Hartwick RW, et al. Fibrosarcoma of the head and neck. Laryngoscope . 1990;100:799-802.
404 Heffner DK, Gnepp DR. Sinonasal fibrosarcomas, malignant schwannomas, and “triton” tumors: A clinicopathologic study of 67 cases. Cancer . 1992;70:1089-1101.
405 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.
406 Tanaka T, Saito R, Kajiwara M, et al. Fibrous histiocytoma of the nasal cavity and maxillary sinus. Acta Pathol Jpn . 1982;32:657-669.

Muscle Tumors
407 Harcourt JP, Gallimore AP. Leiomyoma of the paranasal sinuses. J Laryngol Otol . 1993;107:740-741.
408 Fu YS, Perzin KH. Nonepithelial tumors of the nasal cavity, paranasal sinuses, and nasopharynx: A clinicopathologic study. IV. Smooth muscle tumors (leiomyoma, leiomyosarcoma). Cancer . 1975;35:1300-1308.
409 Papavasiliou A, Michaels L. Unusual leiomyoma of the nose (leiomyoblastoma). Report of a case. J Laryngol Otol . 1981;95:1281-1286.
410 Dropkin LR, Tang CK, Williams JR. Leiomyosarcoma of the nasal cavity and paranasal sinuses. Ann Otol Rhinol Laryngol . 1976;85:399-403.
411 Kuruvilla 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.
412 Weiss SW, Goldblum JR, editors, Leiomyosarcoma Enzinger and Weiss’s Soft Tissue Tumors, 4th ed, 2001, Mosby-Year Book, St. Louis, 727-746.
413 Kapadia SB, Meis JM, Frisman DM, et al. Adult rhabdomyoma of the head and neck: A clinicopathologic and immunophenotypic study. Hum Pathol . 1993;24:608-617.

Peripheral Nerve Sheath Tumors
414 Perzin KH, Panyu H, Wechter S. Nonepithelial tumors of the nasal cavity, paranasal sinuses and nasopharynx: A clinicopathologic study. XII: Schwann cell tumors (neurilemoma, neurofibroma, malignant schwannoma). Cancer . 1982;50:2193-2202.
415 Nagayama I, Nishimura T, Furukawa M. Malignant schwannoma arising in a paranasal sinus. J Laryngol Otol . 1993;107:146-148.
416 Fernandez PL, Cardesa A, Bombi JA, et al. Malignant sinonasal epithelioid schwannoma. Virchows Arch . 1993;423:401-405.
417 Hillstrom RP, Zarbo RJ, Jacobs JR. Nerve sheath tumors of the paranasal sinuses: Electron microscopy and histopathologic diagnosis. Otolaryngol Head Neck Surg . 1990;102:257-263.
418 Younis RT, Gross CW, Lazar RH. Schwannomas of the paranasal sinuses: Case report and clinicopathologic analysis. Arch Otolaryngol Head Neck Surg . 1991;117:677-680.
419 Shajrawi I, Podoshin L, Fradis M, et al. Malignant triton tumor of the nose and paranasal sinuses: A case study. Hum Pathol . 1989;20:811-814.
420 Hasegawa SL, Mentzel T, Fletcher CDM. Schwannomas of the sinonasal tract and nasopharynx. Mod Pathol . 1997;10:777-784.
421 Robitaille Y, Seemayer TA, El Deiry A. Peripheral nerve tumors involving paranasal sinuses: A case report and review of the literature. Cancer . 1975;35:1254-1258.
422 Hoffman DF, Everts EC, Smith JD, et al. Malignant nerve sheath tumors of the head and neck. Otolaryngol Head Neck Surg . 1988;99:309-314.

Adipose Tissue Tumors
423 Fu YS, Perzin KH. Non-epithelial tumors of the nasal cavity, paranasal sinuses and nasopharynx: A clinicopathologic study: VIII. Adipose tissue tumors (lipoma and liposarcoma). Cancer . 1977;40:1314-1317.

424 Farr HW, Gray GF, Vrana M, et al. Extracranial meningioma. J Surg Oncol . 1973;4:411-420.
425 Perzin KH, Pushparaj N. Nonepithelial tumors of the nasal cavity, paranasal sinuses, and nasopharynx: A clinicopathologic study. XIII: Meningiomas. Cancer . 1984;54:1860-1869.
426 Ho KL. Primary meningioma of the nasal cavity and paranasal sinuses. Cancer . 1980;46:1442-1447.
427 Taxy JB. Meningioma of the paranasal sinuses: A report of two cases. Am J Surg Pathol . 1990;14:82-86.
428 Sadar ES, Conomy JP, Benjamin SP, et al. Meningiomas of the paranasal sinuses, benign and malignant. Neurosurgery . 1979;4:227-232.
429 Kershisnik M, Callender DL, Batsakis JG. Extracranial, extraspinal meningiomas of the head and neck. Ann Otol Rhinol Laryngol . 1993;102:967-970.
430 Leyva WH, Gnepp DR. Pathologic quiz case 2. Meningioma. Arch Otolaryngol Head Neck Surg . 1987;113:206-209.

Sinonasal Ameloblastoma
431 Schafer DR, Thompson LDR, Smith BC, et al. Primary ameloblastoma of the sinonasal tract: A clinicopathologic study of 24 cases. Cancer . 1998;82:667-674.

Ectopic Pituitary Adenoma
432 Asa SL, editor, Tumors of the pituitary gland: Pituitary adenomas. Atlas of Tumor Pathology, 1998, Armed Forces Institute of Pathology, Washington, DC, 47-147 3rd series
433 Lloyd RV. Ectopic pituitary adenomas. In: Lloyd RV, editor. Major Problems in Pathology: Surgical Pathology of the Pituitary Gland (Major Problems in Pathology, Vol. 27) . Philadelphia: WB Saunders; 1993:116-120.
434 Langford L, Batsakis JG. Pituitary gland involvement of the sinonasal tract. Ann Otol Rhinol Laryngol . 1995;104:167-169.
435 Lloyd RV, Chandler WF, Kovacs K, et al. Ectopic pituitary adenomas with normal anterior pituitary glands. Am J Surg Pathol . 1986;10:546-552.
436 Pasquini E, Faustini-Fustini M, Sciarretta V, et al. Ectopic TSH-secreting pituitary adenoma of the vomerosphenoidal junction. Eur J Endocrinol . 2003;148:253-257.
437 Luk SC, Chan JKC, Chow SM, et al. Pituitary adenoma presenting as sinonasal tumor: Pitfalls in diagnosis. Hum Pathol . 1996;27:605-609.
438 Matsushita H, Matsuya S, Endo Y, et al. A prolactin producing tumor originated in the sphenoid sinus. Acta Pathol Jpn . 1984;34:103-109.
439 Hosaka N, Kitajiri S, Hiraumi H, et al. Ectopic pituitary adenoma with malignant transformation. Am J Surg Pathol . 2002;26:1078-1082.

440 Burger PC, Scheithauer BW, editors, Tumors of the central nervous system: Craniopharyngiomas. Atlas of Tumor Pathology, 1994, Armed Forces Institute of Pathology, Washington, DC, 349-354, 3rd series
441 Byrne MN, Sessions DG. Nasopharyngeal craniopharyngioma: Case report and literature review. Ann Otol Rhinol Laryngol . 1990;99:633-639.
442 Akimura T, Kameda H, Abiko S, et al. Infrasellar craniopharyngioma. Neuroradiology . 1989;31:180-183.
443 Falavigna A, Kraemer JL. Infrasellar craniopharyngioma: Case report. Arq Neuropsiquiatr . 2001;59:424-430.
444 Ahsan F, Rashid H, Chapman A, et al. Infrasellar craniopharyngioma presenting as epistaxis, excised via Denker’s medial maxillectomy approach. J Laryngol Otol . 2004;118:895-898.

Sinonasal Germ Cell Tumors
445 Gonzalez-Crussi F, editor. Extragonadal teratomas: Teratomas of the head (extracranial) Atlas of Tumor Pathology, 1982, Armed Forces Institute of Pathology. Washington, DC, 109-117, 2nd series
446 Byard RW, Smith CR, Chan HSL. Endodermal sinus tumor of the nasopharynx and previous mature congenital teratoma. Pediatr Pathol . 1991;11:297-302.
447 Lack EE. Extragonadal germ cell tumors of the head and neck region. Review of 16 cases. Hum Pathol . 1985;16:56-64.
448 Byard RW, Jimenez CL, Carpenter BF, et al. Congenital teratomas of the neck and nasopharynx: A clinicopathologic study of 18 cases. J Pediatr Child Health . 1990;26:12-16.
449 Guarisco JL, Butcher RB. Congenital cystic teratoma of the maxillary sinus. Otolaryngol Head Neck Surg . 1990;103:1035-1038.
450 Petrovich Z, Wollman J, Acquarelli M, et al. Malignant teratoma of the nasal cavity. J Surg Oncol . 1977;9:21-28.
451 Ulbright TM. Neoplasms of the testis. In: Bostwick DG, Eble JN, editors. Urologic Surgical Pathology . St. Louis: Mosby-Year Book; 1997:566-645.
452 Batsakis JG, El-Naggar AK, Luna MA. Teratomas of the head and neck with emphasis on malignancy. Ann Otol Rhinol Laryngol . 1995;104:496-500.
453 Gabris K, Orosz M, Suba Z. The effects on teeth of radiotherapy for nasal endodermal sinus tumor (yolk sac tumor) in childhood. Int J Oral Maxillofac Surg . 2001;30:356-358.

454 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.
455 Fernandez PL, Cardesa A, Alos L, et al. Sinonasal teratocarcinosarcoma: An unusual neoplasm. Pathol Res Pract . 1995;191:166-171.
456 Shanmugaratnam K, Kunaratnam N, Chia KB, et al. Teratoid carcinosarcoma of the paranasal sinuses. Pathology . 1983;15:413-419.
457 Luna MA. Critical commentary to “sinonasal teratocarcinoma.”. Pathol Res Pract . 1995:191. –172
458 Cardesa A, Luna MA. Germ cell tumours. In: Barnes L, Eveson JW, Reichart P, Sidransky D, editors. World Health Organization Classification of Tumours: Pathology & Genetics—Head and Neck Tumours . Lyon, France: IARC; 2005:76-79.
459 Patterson SD, Ballard RW. Nasal blastoma: A light and electron microscopic study. Ultrastruct Pathol . 1980;1:487-494.
460 Meinecke R, Bauer F, Skouras J, et al. Blastomatous tumors of the respiratory tract. Cancer . 1976;38:818-823.
461 Shindo ML, Stanley RBJr, Kiyabu MT. Carcinosarcoma of the nasal cavity and paranasal sinuses. Head Neck . 1990;12:516-519.
462 Pai SA, Naresh KN, Masih K, et al. Teratocarcinosarcoma of the paranasal sinuses: A clinicopathologic and immunohistochemical study. Hum Pathol . 1998;29:718-722.
463 Shimazaki H, Aida S, Tamai S, et al. Sinonasal teratocarcinosarcoma: Ultrastructural and immunohistochemical evidence of neuroectodermal origin. Ultrastruct Pathol . 2000;24:115-122.

Alveolar Soft Part Sarcoma
464 Chatterji P, Purohit GN, Ramdev IN, et al. Alveolar soft part sarcoma of the nasal cavity and paranasal sinuses. J Laryngol Otol . 1977;91:1003-1008.
465 Rubinstein MI, Drake AF, McClatchey KD. Alveolar soft part sarcoma of the nasal cavity: Report of a case and a review of the literature. Laryngoscope . 1988;98:1246-1250.
466 Barbareschi M, Ferrero S, Ottaviani F. Alveolar soft part sarcoma of the nasal cavity. Pathologica . 1988;80:363-370.

Postradiation Sarcoma
467 Coia LR, Fazekas JT, Kramer S. Postirradiation sarcoma of the head and neck: A report of three late sarcomas following therapeutic irradiation for primary malignancies of the paranasal sinus, nasal cavity, and larynx. Cancer . 1980;46:1982-1985.
468 Maisel RH, Manivel JC, Porto DP, et al. Postirradiation sarcomas of the head and neck. Ear Nose Throat J . 1989;68:684-701.
469 Huvos AG, Woodard HQ, Cahan WG, et al. Postirradiation osteogenic sarcoma of bone and soft tissues: A clinicopathologic study of 66 patients. Cancer . 1985;55:1244-1255.

Malignant Non-Hodgkin’s Lymphoma
470 Harbo G, Grau C, Bundgaard T, et al. Cancer of the nasal cavity and paranasal sinuses. A clinicopathological study of 277 patients. Acta Oncol . 1997;36:45-50.
471 Tran LM, Mark R, Fu YS, et al. Primary non-Hodgkin’s lymphomas of the paranasal sinuses and nasal cavity: A report of 18 cases with stage IE disease. Am J Clin Oncol . 1992;15:222-225.
472 Kapadia SB, Barnes L, Deutsch M. Non-Hodgkin’s lymphoma of the nose and paranasal sinuses: A study of 17 cases. Head Neck Surg . 1981;3:490. –439
473 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.
474 Frierson HFJr, Mills SE, Innes DJJr. Non-Hodgkin’s lymphomas of the sinonasal region: Histologic subtypes and their clinicopathologic features. Am J Clin Pathol . 1984;81:721-727.
475 Fu YS, Perzin KH. Nonepithelial tumors of the nasal cavity, paranasal sinuses and nasopharynx: A clinicopathologic study. X. Malignant lymphomas. Cancer . 1979;43:611-621.
476 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.
477 Kristensen S. Immunoblastic sarcoma of the nasal cavity. Arch Otorhinolaryngol . 1984;240:227-230.
478 Harrinson D, Lund VJ, editors, Lymphoreticular tissue neoplasia and destructive lesions Tumours of the Upper Jaw, 1993, Churchill Livingstone, Edinburgh, 265-281

Sinonasal T-/Natural Killer Cell Lymphoma
479 Lippman SM, Grogan TM, Speir CM, et al. Lethal midline granuloma with a novel T-cell phenotype as found in peripheral T-cell lymphoma. Cancer . 1987;59:936-939.
480 Gaulard P, Henni T, Marolleau J-P, et al. Lethal midline granuloma (polymorphic reticulosis) and lymphomatoid granulomatosis. Evidence for a monoclonal T-cell lymphoproliferative disorder. Cancer . 1988;62:705-710.
481 Kassel SH, Echevarria RA, Guzzo FP. Midline malignant reticulosis (so-called lethal midline granuloma). Cancer . 1969;23:920-935.
482 Ferry JA, Sklar J, Zukerberg LR, et al. Nasal lymphoma: A clinicopathologic study with immunophenotypic and genotypic analysis. Am J Surg Pathol . 1991;15:268-279.
483 Ho FC, Choy D, Loke SL, et al. Polymorphic reticulosis and conventional lymphomas of the nose and upper aerodigestive tract: A clinicopathologic study of 70 cases, and immunophenotypic studies of 16 cases. Hum Pathol . 1990;21:1041-1050.
484 Medeiros LJ, Jaffe ES, Chen YY, et al. Localization of Epstein-Barr viral genomes in angiocentric immunoproliferative lesions. Am J Surg Pathol . 1992;16:439-447.
485 Jaffe ES, Chan JKC, Su I-J, 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;20:102-111.
486 Suzumiya J, Takeshita M, Kimura N, et al. Expression of adult and fetal natural killer cell markers in sinonasal lymphomas. Blood . 1994;83:2255-2260.
487 Chan JK, Ng CS, Lau WH, et al. Most nasal/nasopharyngeal lymphomas are peripheral T-cell neoplasms. Am J Surg Pathol . 1987;11:418-429.
488 Tsang WYW, Chan JKC, Ng CS, et al. Utility of a paraffin section-reactive CD56 antibody (123C3) for characterization and diagnosis of lymphomas. Am J Surg Pathol . 1996;20:202-210.
489 Strickler JG, Meneses MF, Habermann TM, et al. Polymorphic reticulosis: A reappraisal. Hum Pathol . 1994;25:659-665.
490 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.
491 Aviles A, Rodriguez L, Guzman R, et al. Angiocentric T-cell lymphoma of the nose, paranasal sinuses and hard palate. Hematol Oncol . 1992;10:141-147.
492 van de Rijn M, Bhargava V, Molina-Kirsch H, et al. Extranodal head and neck lymphomas in Guatemala: High frequency of Epstein-Barr virus-associated sinonasal lymphomas. Hum Pathol . 1997;28:834-839.
493 Chan JK, Yip TT, Tsang WY, et al. Detection of Epstein-Barr viral RNA in malignant lymphomas of the upper aerodigestive tract. Am J Surg Pathol . 1994;18:938-946.
494 Kanavaros P, Briere J, Lescs MC, et al. Epstein-Barr virus in non-Hodgkin’s lymphomas of the upper respiratory tract: Association with sinonasal localization and expression of NK and/or T-cell antigens by tumor cells. J Pathol . 1996;178:297-302.
495 Luzi P, Leoncini L, Funto I, et al. Epstein-Barr virus infection in sinonasal non-Hodgkin’s lymphomas. Virchows Arch . 1995;425:121-125.
496 Ott G, Kalla J, Ott M, et al. The Epstein-Barr virus in malignant non-Hodgkin’s lymphoma of the upper aerodigestive tract. Diagn Mol Pathol . 1997;6:134-139.
497 Elenitoba-Johnson KSJ, Zarate-Osorno A, Meneses A, et al. Cytotoxic granular expression, Epstein-Barr virus strain type, and latent membrane protein-1 oncogene deletions in nasal T-cell lymphocyte/natural killer cell lymphomas from Mexico. Mod Pathol . 1998;11:754-761.
498 Liang R, Tood D, Chan TK, et al. Nasal lymphoma: A retrospective analysis of 60 cases. Cancer . 1990;66:2205-2209.
499 Van Gorp J, de Bruin PC, Sie-Go DMDS, et al. Nasal T-cell lymphoma: A clinicopathological and immunophenotypic analysis of 13 cases. Histopathology . 1995;27:139-148.
500 Aozasa K, Ohsawa M, Tomita Y, et al. Polymorphic reticulosis is a neoplasm of large granular lymphocytes with CD3+ phenotype. Cancer . 1995;75:894-901.
501 Ng CS, Lo STH, Chan JKC, et al. CD56+ putative natural killer cell lymphomas: Production of cytolytic effectors and related proteins mediating tumor cell apoptosis. Hum Pathol . 1997;28:1276-1282.
502 Oshima 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.
503 Harabuchi Y, Imai S, Wakashima J, et al. Nasal T-cell lymphoma casually associated with Epstein-Barr virus. Clinicopathologic, phenotypic, and genotypic studies. Cancer . 1996;77:2137-2149.
504 Petrella T, Delfau-Larue M-H, Caillot D, et al. Nasopharyngeal lymphomas: Further evidence for a natural killer cell origin. Hum Pathol . 1996;27:827-833.
505 Chiang AKS, Srivastava G, Lau PWF, et al. Differences in T-cell-receptor gene rearrangement and transcription in nasal lymphomas of natural killer and T-cell types: Implications on cellular origin. Hum Pathol . 1996;27:701-707.
506 Chott A, Rappersberger K, Scholossarek W, et al. Peripheral T cell lymphoma presenting primarily as lethal midline granuloma. Hum Pathol . 1988;19:1093-1101.
507 Crissman JD, Weiss MA, Gluckman J. Midline granuloma syndrome: A clinicopathologic study of 13 patients. Am J Surg Pathol . 1982;6:335-346.
508 Wong KF, Chan JKC, Ng CS, et al. CD56 (NKH1)-positive hematolymphoid malignancies: An aggressive neoplasm featuring frequent cutaneous/mucosal involvement, cytoplasmic azurophilic granules, and angiocentricity. Hum Pathol . 1992;23:798-804.
509 Ratech H, Burke JS, Blayney DW, et al. A clinicopathologic study of malignant lymphomas of the nose, paranasal sinuses, and hard palate, including cases of lethal midline granuloma. Cancer . 1989;64:2525-2531.

Extramedullary Plasmacytoma
510 Castro EB, Lewis JS, Strong EW. Plasmacytoma of paranasal sinuses and nasal cavity. Arch Otolaryngol . 1973;97:326-329.
511 Fu YS, Perzin KH. Nonepithelial tumors of the nasal cavity, paranasal sinuses and nasopharynx. A clinicopathologic study. IX. Plasmacytomas. Cancer . 1978;42:2399-2406.
512 Kapadia SB, Desai U, Cheng VS. Extramedullary plasmacytoma of the head and neck: A clinicopathologic study of 20 cases. Medicine . 1982;61:317-329.

Metastatic Tumors
513 Harrinson D, Lund VJ, editors, Nonepidermoid epithelial neoplasms. Tumours of the Upper Jaw, 1993, Churchill Livingstone, Edinburgh, 124-134.
514 Friedmann I, Osborn DA, editors. Metastatic tumours of the nose and sinuses. Pathology of Granulomas and Neoplasms of the Nose and Paranasal Sinuses, 1982, Churchill Livingstone, Edinburgh, 300-303
515 Frigy AF. Pathologic quiz case 2: Metastatic hepatocellular carcinoma of the nasal cavity. Arch Otolaryngol . 1984;110:624-627.
516 Yamasoba T, Kikuchi S, Sugasawa M, et al. Occult follicular carcinoma metastasizing to the sinonasal tract. ORL J Otorhinolaryngol Relat Spec . 1994;56:239-243.
517 Cinberg JZ, Terrife D. Follicular adenocarcinoma of the thyroid in the maxillary sinus. Otolaryngol Head Neck Surg . 1980;88:157-158.
518 Ellis GL. Clear cell neoplasms in salivary glands: Clearly a diagnostic challenge. Ann Diagn Pathol . 1998;2:61-78.
Chapter 4 Lesions of the Oral Cavity

Jerry E. Bouquot, Susan Muller, Hiromasa Nikai

Fibrous, Fibrohistiocytic, and Fibrovascular Lesions
The majority of soft-tissue masses of the mouth are hyperplastic inflammatory responses to local, usually chronic, trauma or infection. 1 - 14 These benign reactive lesions result from the proliferation of one or more components of the normal connective tissue stroma and are sometimes unique to the mouth because of their origin from periodontal or odontogenic tissues. Reactive lesions are much more common in the mouth than in other parts of the body, presumably because of the close proximity of the mucosa to hard, often sharp, teeth and prosthetic appliances. Found in the mouths of 3% of adults, these lesions collectively represent more than 80% of biopsied oral masses. 1, 2, 7
Also included in this first section are benign neoplastic lesions with fibrous proliferation as a major characteristic. Look-alike fibrous tumors of peripheral nerves and smooth muscle are discussed separately in this chapter under the sections relating to benign nerve tumors and benign muscle tumors. Altogether, neoplastic fibrous lesions are much less common than inflammatory hyperplasias of the mouth; they are also more likely to represent a localized manifestation of a systemic process or syndrome. 9, 11

Irritation Fibroma and Localized Fibrous Hyperplasia
The irritation fibroma, or traumatic fibroma, is a common submucosal response to trauma from teeth or dental prostheses and was first reported in 1846 as fibrous polyp and polypus. 15 It is universally understood that the use of the term fibroma is not intended in this case to convey neoplastic origin, as is the usual intent of its use for fibrous tumors in other anatomic sites. Found in 1.2% of adults ( Table 4-1 ), this inflammatory hyperplasia is the most common oral mucosal mass submitted for biopsy and is usually composed of types I and III collagen. 1, 11 Gingival lesions are also common, although at that location, they probably result from chronic infection rather than trauma. 16 A number of variations on the theme of inflammatory fibrous hyperplasia are mentioned in the following discussion.

Table 4-1 Prevalence Rates for Selected Oral Mucosal Masses and Surface Alterations in U.S. Adults

Clinical Features
The irritation fibroma has a slight male predilection and can occur at any age, but usually a biopsy is performed in the fourth through sixth decades of life. It is extremely rare during the first decade. Patients with multiple fibromas may represent cases of familial fibromatosis, fibrotic papillary hyperplasia of the palate, tuberous sclerosis, or multiple hamartoma syndrome (Cowden disease). 9, 11 Those with a generalized fibrous overgrowth of the gingival tissues are said to have fibrous gingival hyperplasia or gingival fibromatosis, which is discussed elsewhere in this chapter.
In the mouth, buccal, labial, and lateral tongue sites account for 71% of all fibromas. 2 The mass may be sessile or pedunculated and usually reaches its maximum size within a few months ( Fig. 4-1A ). It seldom exceeds 1.5 cm in size, and once fully formed, it remains indefinitely. 11, 17 It is an asymptomatic, moderately firm, immovable mass with a surface coloration that is most often normal but may show pallor from decreased vascularity, whiteness from thickened surface keratin, or ulceration from recurring trauma.

Figure 4-1 A , Pedunculated irritation fibroma of the left tongue. B , Leaf-shaped fibroma of the hard palate has been forced by an overlying denture to enlarge laterally and remain flat. C , Epulis fissuratum of the left maxillary vestibule presents as a redundant, linear fold of tissue ( arrow points to groove where denture usually seats).
A fibroma beneath a denture has no room to expand uniformly in all directions and so develops as a flat, pancake-shaped mass with small surface papules along the outer edges. 17 This leaf-shaped fibroma may be associated with an underlying cupped-out area of bony erosion (see Fig. 4-1 B ).
Another unique variant of denture-related fibroma, the epulis fissuratum (epulis means “mass on the gingiva”) is an irregular, linear, fibrous hyperplasia occurring in the mucosal vestibule or sulcus adjacent to the alveolar ridge, where the edge of a loose-fitting denture chronically pounds into the tissue. 1, 17 - 19 The mass runs parallel to the edge of the denture (see Fig. 4-1 C ). Eventually, three or more “waves” of fibrous redundant tissue may be seen, with deep grooves between them. The superior edges of these masses may have a line of papules or secondary growths, perhaps explaining why the lesion was first reported in 1858 as “mamillated epulis.” 20 The lesion accounts for approximately 3% of submitted oral biopsy samples and is usually found in persons 40 to 50 years of age. 18

Pathologic Features and Differential Diagnosis
The irritation fibroma is composed of a dense and minimally cellular stroma of collagen fibers arranged randomly or organized into interlacing fascicles ( Fig. 4-2A and B ). The stromal cells are bipolar fibroblasts with plump nuclei and fibrocytes with thin, elongated nuclei and minimal cytoplasm. As with keloids of the skin, the mucosal fibroma may be remarkably avascular, but areas of necrosis are not seen unless associated with overlying mucosal ulceration. Keloids do not, moreover, occur in the mouth.

Figure 4-2 A , The irritation fibroma is usually pedunculated, covered by a somewhat hyperplastic epithelium, and composed of dense collagenic tissue, sometimes with a few dilated veins. B , Thick collagen bundles are irregularly arranged, with few visible blood vessels. C , The epulis is more edematous and shows a more severe chronic inflammatory cell infiltration. This example also demonstrated extreme elongation of the surface epithelium (pseudoepitheliomatous hyperplasia). Transected tips of rete processes appear as independent islands of invading epithelium ( inset ).
Usually scattered, mature capillaries are found, and often a few of these are dilated. In cases resulting from the slow fibrosis of granulation tissue or pyogenic granuloma, focal areas of edema and neovascularity may be seen in the midportion or lower third of the mass. Occasional lesions may still contain residual granulation tissue, prompting some pathologists to prefer the term fibrotic pyogenic granuloma. Such lesions may be indistinguishable from the angiofibroma of tuberous sclerosis. Also, occasional fibrous masses have unusually large, sometimes multinucleated fibroblasts. These masses represent a giant cell fibroma, which is described later.
The lesion fibrosis typically extends to the overlying stratified squamous epithelium but may be separated from it by a thin layer of normal fibrovascular connective tissue. Although usually nonencapsulated, some lesions show a pseudoencapsulation and may, therefore,