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.

Subjects

Books
Savoirs
Medicine
VIH
Intraepithelial neoplasia
Keratocyst
Hodgkin's lymphoma
Journal of Clinical Pathology
Oncology
Ulceration
Follicular thyroid cancer
Odontogenic
Thyroid nodule
Benignity
Branchial cleft cyst
Mouth
Tissue typing
Dentigerous cyst
Verrucous carcinoma
AIDS
Papillary thyroid cancer
Pyogenic granuloma
MALT lymphoma
Dysplasia
Ameloblastoma
Hyperkeratosis
Neck dissection
Guideline
Adenoid cystic carcinoma
Neoplasm
Chondrosarcoma
Dermatofibrosarcoma protuberans
Carcinoma in situ
Digestive disease
Differential diagnosis
Leukoplakia
Thyroglossal cyst
Head and neck cancer
Basal cell carcinoma
Hashimoto's thyroiditis
Paget's disease of bone
Laryngitis
Physician assistant
Nasal cavity
Squamous cell carcinoma
Biopsy
Lesion
Osteosarcoma
Nasopharynx
Carcinoma
Parathyroid gland
Adenocarcinoma
Otitis media
Salivary gland
Cyst
Cholesteatoma
Dermatology
Non-Hodgkin lymphoma
Trachea
Hypothyroidism
Skin neoplasm
X-ray computed tomography
Philadelphia
Hearing impairment
Keratin
Infection
Thyroid
Sinusitis
Paranasal sinuses
Mechanics
Chemotherapy
Collagen
Colloid
Pathology
Neck
Clustering
Diffusion
Diane
Electronic
Larynx
Surface
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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
SaundersCopyright
SAUNDERS
ELSEVIER
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
DIAGNOSTIC SURGICAL PATHOLOGY OF THE HEAD AND NECK
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
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Notice
Knowledge and best practice in this Deld 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
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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 DataDiagnostic 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
617.5′10754—dc22
2008027012
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 2Dedication
To Diane, Ari, Stella, Ethan, and GracieContributors
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, TheWarren 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 DissectionPanna 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 Cavity
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, AssociateProfessor, 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 TractRoderick 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.
(

P r e f a c e
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 di erent 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 di erential diagnosis and more problematic areas. My hope is that
this text will help the surgical or oral pathologist when dealing with a di cult
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.
A c k n o w l e d g m e n t s
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 tumorBSC 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 plasmacytomaERMS 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 kilodaltonKFD 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 sarcomaMTB 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 rhabdomyosarcomaPsJOF 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
T3 triiodothyronine
T thyroxine4
TCO tracheopathia chondro-osteoplasticaTCVPTC 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 OrganizationTable of Contents
Copyright
Dedication
Contributors
Preface
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 SpecimensIndexChapter 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 o( er 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, de) nitions, and classi) cations 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.
Introduction
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
a( ecting the various locations of the anatomically complex UADT region. Similar to studies concerning
other organ systems, the spectrum of interest re+ ected in published investigations of UADT precursorsencompasses aspects of epidemiology and risk factors, clinical and pathologic classi) cation, molecular
1-3genetic characteristics, and natural history and evolution of such lesions.
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
4continue to be prevalent. 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
5document a synergistic e( ect when the two risk factors are combined. Increasing rates of smoking and
drinking among women appears to gradually decrease the predominant male-to-female ratio
6traditionally associated with the demographics of this disease. On the other hand, recent studies in
certain populations with follow-up data indicate that lower consumption of tobacco and alcohol
7translates to lower rates of both the incidence and the mortality related to head and neck cancer.
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
8disease and the development of preinvasive neoplastic changes to the same etiologic factors.
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
9-12with regional (and/or systemic) metastases at the time of diagnosis. Accordingly, there are limited
series of patients in which the histologic changes preceding squamous carcinoma have been sampled in
13-15a systematic approach and with documented follow-up. This bleak picture is changing slowly in
14,16selected regions where educational and outreach efforts are enhanced.
For decades, the main studies documenting the progression of squamous precursors to invasive cancer
17,18were observations established in the laryngeal glottis. Similar observations in the oral cavity were
19-21contributed primarily by the oral pathology literature. Of concern is the notion that these two
bodies of investigative literature have often used di( erent terminology and histologic de) nitions for
preinvasive/dysplastic lesions in these two anatomic locations of the UADT. In recent years, several
reports re+ ecting the attempts of task forces and working groups to standardize the terminology based
22-26on reproducible criteria have been published.
There are clinical, experimental, and morphologic lines of evidence supporting the concept that SCC
27-29of the UADT arises from noninvasive lesions of the squamous mucosa. 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
25,30,31intraepithelial neoplastic changes. 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 de) nitions based on the
32longer experience with intraepithelial neoplasia of the uterine cervix. 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 metaplasticsquamous 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 classi) cation systems have been proposed to characterize these early histologic changes in
33-36 37-43the UADT ; more than 20 classi) cations can be found for such lesions in the larynx. This
complicates both the comparison of the gross and microscopic de) nitions in published series and the
delineation of conclusions relating the morphologic terms to clinical behavior. The more recent
Ljubljana and World Health Organization (WHO) classi) cations have been gaining more recognition,
although the application of criteria by pathologists and the communication of the diagnostic terms to
22,25,30,44clinicians remain inconsistent.
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
45,46treatment of head and neck SCC (HNSCC). Furthermore, understanding and documenting the
morphologic and molecular abnormalities associated with this progression are likely to o( er insight into
the biology of HNSCC, while identifying markers of transformation that may help develop surrogate
47,48clinical endpoints in chemoprevention clinical trials.
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 (pseudostrati) ed, 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 pseudostrati) ed 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 TongueThe oral cavity is lined mostly by a nonkeratinized, strati) ed 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 super) cial 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
) laments, marking the increased di( erentiation 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
49ratio, resting on the basement membrane (Fig. 1-2A). Molecular data show that they are the only cell
type that expresses proliferation-associated antigens and the RNA component of telomerase within the
50normal mucosa (see Fig. 1-2B). By replacing the committed cells that undergo terminal
di( erentiation in the more super) cial layers of the epithelium, these basal cells ensure the epithelium’s
51turnover and thus have the role of stem cells. In keratinized epithelium, the super) cial layer is
entirely constituted by anucleated cells showing accumulation of intermediate ) laments, 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, re+ ect di( erences 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 + oor of the mouth, characterized by higher resiliency and subject to
lesser mechanical stress, are lined by nonkeratinized mucosa (Fig. 1-3A). 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 ) laments toward the super) cial 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 + oor 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 re+ ects 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 + oor of the mouth, possess thinner and shallower rete ridges and a less collagenized lamina
36propria.
The histologic variations within the mucosal lining of the tongue are re+ ective 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 a( ect the color of
the mucosa (see Fig. 1-3B). 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
52minor salivary glands in a fashion that can mimic invasive carcinoma.
Pharynx
Anatomically, the pharynx is divided into three compartments: oropharynx, nasopharynx, and
hypopharynx. Both the oropharynx and hypopharynx are lined by strati) ed, nonkeratinized squamous
epithelium with the submucosal compartments containing seromucinous glands and aggregates of
lymphoid tissue. The lining of the nasopharynx is approximately 60% strati) ed, nonkeratinized
squamous epithelium with the other 40% being pseudostrati) ed 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 mimic53intraepithelial neoplasia. The low magni) cation 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 magni) cation 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.
15). Similar features are observed at the transition between squamous and respiratory epithelia in the
53larynx in normal conditions and during the process of squamous metaplasia in the bronchial ciliated
54epithelium in response to irritants.
Figure 1-4 Morphologic variation within the squamous mucosa lining. The intermediate or transitional
areas of the mucosal lining between the pseudostrati) ed ciliated and the nonkeratinized squamous
epithelia in the pharynx may, on low magni) cation, 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.
Larynx
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 therepetitive 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 ) rst tracheal ring), and blends inferiorly into
the respiratory epithelium of the trachea.
The respiratory epithelium is a ciliated, pseudostrati) ed 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 di( erentiated 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
55belong to the di( use neuroendocrine system. Similar to the pharynx, areas between the squamous
and respiratory-type epithelia have a transitional appearance, characterized by progressive + attening 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
56the supraglottic larynx.
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 ) nally a section summarizing the correlation between
the histologic and clinical classi) cations (i.e., gross and microscopic features) and their risk of
progression.
Clinical and Gross Mucosal Changes of Injury
Leukoplakia
57The term leukoplakia, denoting white squamous mucosal patches, was coined by Schwimmer, a
Hungarian pathologist, in the second half of the 19th century. Currently, the WHO de) nition of
leukoplakia is “[a] predominantly white lesion of the oral mucosa that cannot be characterized as any
58other de) nable lesion.” This change represents a common type of the squamous mucosal response to
36some form of injury. Leukoplakia is not a histologic term, and its use as a speci) c 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
59-63with prominent surface keratinization. This appearance re+ ects 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 in+ ammatory and, less commonly,
63,64carcinogenic injuries. In the latter, the resulting epithelial hyperplasia and surface keratin
65formation can be associated with variable degrees of cytoarchitectural alteration of dysplasia/SIN.
Only the extent of these, as carefully de) ned microscopically, can help predict the risk of progression to
65invasive cancer. Several recent studies have emphasized that the preneoplastic nature of leukoplakia
is attributed to the histologic characterization of the clinically identi) ed white patch, namely, the
identi) cation 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
66microscopic changes associated with dysplasia/SIN.
Erythroplakia
Erythroplakia is also a lesion with a distinct gross appearance; it presents as a red, hyperemia-appearing
66,67mucosal surface with variably distant borders. The term erythroplasia was ) rst used by Qeyrat in
1911 to indicate a lesion of the glans penis with the appearance of an erythematous area and
67representing a premalignant process. 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 de) nes it as a “) ery
58red patch that cannot be characterized clinically or pathologically as another de) nable lesion.” This
alteration invariably represents the result of UADT carcinogens, usually the e( ect 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 in+ ammation. The thin mucosa is usually composed of atypical cells without signi) cant
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
66surface, erythroplakia is typically a depressed lesion below the level of the surrounding mucosa.
Erythroplakia is most commonly observed in thin squamous mucosa such as is found in the ventral
67,68tongue, + oor of the mouth, palatine arc, and retromolar trigone. 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
67,68surgical specimens from mucosa with the clinical appearance of erythroplakia.
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
67the two can coexist was made. Terms such as erythroleukoplakia, leukoerythroplakia, erosive
leukoplakia, speckled leukoplakia, and speckled erythroplakia have been used to describe the combined
69-72red and white areas of the oral mucosal changes.
Characterization of the signi) cance 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 classi) ed as leukoplakias may explain why some observers in the past foundsuch a high frequency of subsequent carcinoma in what was erroneously classi) ed as pure
73leukoplakia.
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 re+ ectance detection
systems (ViziLite Plus [Zila Pharmaceuticals Inc., Phoenix, AZ], MicroLux DL [AdDent Inc., Danbury,
CT]), toluidine blue mucosal staining, and narrow-emission tissue + uorescence (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 de) nitive evidence to suggest that they improve the
sensitivity or speci) city of oral cancer screening beyond conventional oral examination alone. The
74eN cacy of these various techniques was recently reviewed by Lingen and colleagues. Additional
studies to determine the clinical utility of these techniques are necessary before they become a
mainstream practice.
Oral Leukoplakia
Overview
The literature dealing with the spectrum of neoplastic changes in the mucosa of the oral cavity
69,75-77continues to expand. 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 diN culties in terms of reproducibility of diagnoses,
especially for hyperplastic keratinizing epithelium with minimal evidence of maturation abnormalities
30,78on histologic examination. 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
79confirmation. Only a fraction of the gross mucosal changes with a white leukoplakic mucosal
61,79appearance will contain histologic changes of dysplasia/SIN. These observations have been
con) rmed by several studies originating from di( erent geographic areas where tobacco use is
80prevalent.
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
80-82examination. The overlapping and variable terminology makes drawing conclusions from these
studies diN cult. Most studies were able to establish a higher prevalence of a variety of white oral lesions
81with the use of tobacco, smokeless tobacco, and alcohol. This discrepancy further stresses the
conceptual and biological di( erence existing between the term leukoplakia and the histologically
de) ned terms of dysplasia and/or intraepithelial neoplasia. There are ongoing attempts to address the
80issues of variable terminology and clinical and histologic definitions of leukoplakia.
65The peak age of incidence of oral leukoplakia is in the ) fth to seventh decade. 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
82 83cancer in the cervix uteri and the bronchus. The presence of this time interval indirectly supportsthe precursor role of dysplasia.
65Leukoplakia a( ects predominantly males. Percentages range from 54% (n = 3256) to 78% (n =
59710).
Etiology
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
61leukoplakia. 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 ) brosis, while qat chewing in
58,84-86Yemen appears to be the major risk factor for oral cancer and premalignant lesions. 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 brie+ y 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 immunode) ciency syndrome is
controversial. A speci) c type of dysplasia, termed hairy leukoplakia, can occur in patients with human
87immunode) ciency virus and those with clinically established acquired immunode) ciency syndrome.
This dysplasia is characterized by a ballooning, ground-glass appearance of the cells in the upper half
88of the epithelium and intranuclear inclusions. It typically affects the lateral edges of the tongue and is
89associated with a high incidence of human papillomavirus (HPV) and Epstein-Barr virus infection.
Most authors report that acquired immunode) ciency syndrome is associated with an increased
90,91incidence of malignancy, including cervical and anogenital squamous cell cancer, although some
92contest this ) nding. The increased incidence of HNSCCs in patients with acquired immunode) ciency
93,94syndrome is uncertain. 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% ) gure in all other reports), came from the same institution reporting increased occurrence of
87hairy leukoplakia in patients with acquired immunodeficiency syndrome (Table 1-3). 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
95of a particular type of preneoplastic lesion, namely, proliferative verrucous leukoplakia (PVL).
Table 1-3 Overall Progression Rate of Oral Leukoplakia to Invasive Cancer
Sideropenic dysphagia (Plummer-Vinson syndrome), a condition characterized by iron de) ciency
96anemia with frequent associated autoimmune diseases, a( ects the UADT with atrophy of the oral
mucosa and a predisposition to the development of multiple oral carcinomas, predominantly in the
96posterior oropharynx. Esophageal dysphagia also typically occurs.
97,98The premalignant potential of lichen planus is not accepted by all authors and not supported by
recent molecular data that indicate that the percentage of loss of heterozygosity at several chromosomal
99sites in lichen planus is lower in this lesion than in simple hyperplasia. In contrast, the occurrence of
a distinct type of dysplasia that shares some histologic features with lichen planus, that is,
hyperkeratosis, bandlike lymphocytic in) ltrate, hypergranulosis, called lichenoid dysplasia and distinct
88,99,100from true lichen planus, is generally accepted.
Syphilis, now rarely seen in the industrialized world, may be associated with the development of
58leukoplakia, which may undergo malignant transformation. Few cases of SCC of the lip arising in an
58atrophic epithelium in discoid lupus have been described. 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
58affecting the skin and the oral mucosa, has been described to be associated with SCC of the tongue.An increased incidence of SCC and associated premalignant lesions of the epidermis has been
101described in renal transplant recipients.
Sites of Occurrence
Thick white squamous mucosal patches are more common on the buccal gingival gutter (maxillary and
65,102mandibular sulci), followed by the palate and lips, alveolar ridge, and dorsal tongue. 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 a( ecting the thin mucosa of the ventral tongue, tonsil,
retromolar trigone, and hypopharynx is usually the result of carcinogenic exposure and should be
64,65,80,88,103viewed with heightened suspicion for harboring dysplasia/SIN. In men, 54% of
combined cases of dysplasia and invasive cancer are in the + oor of the mouth. Thus, leukoplakias at
59di( erent sites have di( erent risks of harboring signi) cant pathologic alterations. 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
80leukoplakia attributed to tobacco use only is estimated to be 4.3%.
Clinical Subtypes
Many descriptive, clinical variants of leukoplakia have been described. These can be reduced to two
58main types: those with a uniformly white appearance and those with a variegated appearance,
103designated, respectively, as homogeneous and speckled by some authors. Others have subdivided
104the ) rst type into leukoplakia simplex and verrucosa and designated the latter leukoplakia erosiva.
Several descriptive clinical variants are recognized within the homogeneous and nonhomogeneous
58groups.
Verrucous Hyperplasia
105Verrucous hyperplasia, originally termed oral + orid papillomatosis, 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
106papillomas, which show evidence of keratinization, and in the larynx. Verrucous hyperplasia was
105) rst described by Shear and Pindborg 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, + oor of the mouth, lip,
106and palate. 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
105,106epithelial dysplasia; and in 10% of patients, there was a typical SCC. The major di( erential
diagnosis is verrucous carcinoma as both lesions exhibit + orid papillary and verrucoid growth, and
some authors consider verrucous hyperplasia to represent a precursor of verrucous carcinoma. Suarez
106and colleagues emphasized the exophytic growth pattern of verrucous hyperplasia contrasted to that
of the downward, invasive growth exhibited by verrucous carcinoma. This di( erential 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
83,95,106-108to progress to SCC. 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
95use. This aggressive form often starts as a unifocal lesion, predominantly in mandibular or alveolarlocations and buccal mucosa, with gross appearance of a warty, somewhat papillary surface. The lesion
tends to rapidly become multifocal with a propensity to harbor signi) cant degrees of dysplastic
95epithelial alterations (Fig. 1-9). Silverman and Gorsky studied 54 patients with PVL, 17 of whom
107were included in the original report by Hansen and colleagues. Seventy percent of patients
developed carcinoma (mean, 7.7 years from initial diagnosis; range, 1–27 years); a second malignancy
107developed in another PVL site in 31.5% of the cases. In the ) nal report by Hansen and colleagues,
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
95 109radiation has o( ered no additional survival bene) t. Recently, Brennan and colleagues 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.
107Hansen and colleagues originally suggested 10 histologic stages in the continuum of PVL, which
106were reduced to four by Suarez and colleagues : clinical + at 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
108and colleagues 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, andfollow-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
Overview
Erythroplakia has often been mentioned in the context of discussing leukoplakia and/or premalignant
71lesions in general. The tendency of oral erythroplakia to harbor/progress to oral cancer was suggested
103by Pindborg and colleagues in a 1963 publication; this was followed by several reports by Mashberg
67,110,111and colleagues, who emphasized that “persistent asymptomatic erythroplakia rather than
110leukoplakia in high risk sites of the oral cavity is the earliest and primary sign of oral carcinoma.”
It is likely that the lower prevalence of oral erythroplakia compared to oral leukoplakia has resulted
in remarkably fewer publications de) ning the term and establishing its associated etiologic, clinical,
and pathologic features. While the clinical identi) cation 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
112infections, tuberculosis, and histoplasmosis.
Prevalence and Incidence
Most of the studies with epidemiologic data concerning oral erythroplakia were conducted in India and
66,113Southeast Asia, indicating prevalence rates of 0.02% to 0.83%, with the majority occurring in
68,114older individuals (sixth and seventh decades). In a study investigating the incidence of in situ
115carcinoma, which is the microscopic manifestation of most oral erythroplakia, Bouquot and Ephros
reported only six newly diagnosed cases per 1,000,000 persons each year, translating to 1500 cases
66diagnosed annually in the United States. Erythroplakia, however, is highly prevalent in patients with
110in situ and invasive oropharyngeal carcinoma (54% and 64%, respectively).
Etiology
Tobacco use and alcohol consumption represent the most signi) cant risk factors for the development of
114oral erythroplakia. 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 a( ects, most commonly, the mucosal surfaces of the soft palate, the + oor of the
114 68mouth, and the buccal mucosa. Shafer and Waldron reported gender-related di( erences in terms
of the mucosal sites a( ected; 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 a( ected. In men, this combined site
58was the least common site of occurrence. Erythroplakia does not usually a( ect the tongue. Bouquot
115and Ephros 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 lesionsperceived 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 di( erent 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
42,116,117combination of both. Some authors emphasize that while the term leukoplakia is a clinical
term, keratosis should be strictly a microscopic diagnosis based on total replacement of super) cial
118epithelial cells by keratin ) laments and dissolution of the nuclei. More recently, the term epithelial
119hyperplastic laryngeal lesion has been proposed. Although the term hyperplasia is the one used, the
120classi) cation is referred to as depicting dysplastic laryngeal lesions. 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
121keratosis) to atypical hyperplasia, dysplasia, CIS, and overt invasive cancer.
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 diN culties begin with the lack of uniformity and
119inconsistency of terminology.” A major concern with some of the potentially well-designed and
wellconducted 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
118,122definitions used by different groups conducting similar studies.
Laryngeal Leukoplakia
Overview
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
36covering, either thick, punctuate, thin, or even friable.”
Laryngologists use the term keratosis for thick white mucosal plaques and red for the thin
erythema123,124appearing epithelial changes. The term keratosis with and without atypia has historical support
123and has been used for a number of years. 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
125changes most likely to progress to invasive cancer. 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 ) rst described by Durant in 1880. This entity was further studied in the
126 1271920s by Pierce and Jackson. The latter eloquently de) ned 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 + at or raised, their surface rough or smooth, and they may
42be adjacent to normal or in+ amed mucosa. 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 de) nes its malignant potential. As for oral leukoplakia,
the clinical entity leukoplakia encompasses histologically heterogeneous lesions, ranging from simple
42,128hyperkeratosis to invasive carcinoma, as later discussed in detail. The presence and grade of
dysplasia dictate its biological potential, that is, its probability if developing into overt invasive cancer.
Etiology
The major carcinogens a( ecting the larynx and associated mucosal structures are cigarette smoke and
129alcohol. 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
130glottis. 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
131manner.
41Auerbach and colleagues, who had previously demonstrated a similar etiologic relationship with
bronchial dysplasia, also ) rmly 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
35These lesions have a striking predilection for males, with a male-to-female ratio ranging from 5:1 to
132 39 132 397:1 and 8:4. Most lesions occur in the ) fth to seventh decades, with a mean age of 52 to 59
years. A temporal gap exists between the occurrence of keratosis and CIS and invasive carcinoma, as for
133oral dysplasia. Miller and Fisher 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
82dysplasia, analogous to oral leukoplakia and to other anatomic examples of premalignancy. The
majority of leukoplakia occurs in the true vocal cord: 33% in both, 35% in either left or right, 11% in
132both vocal cords and interarytenoid areas.
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 signi) cance 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
58,134mucosal passages. 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 MetaplasiaMetaplasia 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.
Hyperplasia
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 super) cial 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 + at hyperplasia in which the basement membrane remains well
de) ned 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 de) ned 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 di( erential diagnostic diN culty with neoplastic changes. Both the + at, 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 + at 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-de) ned 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 de) ned and the proliferating epithelial “tongues” tend to anastomose, entrapping the stromal
compartment. This ) gure is somewhat tangentially oriented, accentuating the anastomotic tongues of
the epithelium.
Figure 1-12 A and B, Hyperplasia secondary to mucosal in+ ammation. The latter can obscure the
epithelium-stroma interface and cause reactive nuclear atypia or be largely con) ned 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 Increased nucleus-to-cytoplasm ratio, presence of nucleoli, hyperchromasia,
atypia pleomorphism
Mitotic Number and level of mitoses within the mucosa; presence of abnormalities in the mitotic
activity spindle, i.e., tripolar mitoses
Abnormal Reflected by the ratio between the differentiated component, composed of the prickly
maturation and squamous layers, and the undifferentiated component, composed of atypical cells.and Also reflected by the occurrence of premature keratinization within the epithelium
polarity 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 ) gures; 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 super) cial 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. Signi) cant 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
di( erentiation 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 ) gures, including atypical ones, are frequent and extend throughout the entire
mucosa, including its upper third. By de) nition, the changes are limited to the epithelium; stromal
invasion is absent. Typically, most CISs of the UADT are nonkeratinizing (Fig. 1-17A and B), although
keratinizing CIS can be encountered in the vocal cord or the oral cavity (see Fig. 1-17C).Figure 1-17 Carcinoma in situ (CIS). The ) ndings 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 ) gures,
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.
58,134The grading system, as described by the WHO, follows criteria similar to those accepted for
32other organs, particularly the cervix uteri. 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 di( erence 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/di( erentiation. Lesser-grade cytologic features and some maturation,
58,134however, characterize severe dysplasia. Several authors have stressed that the etiopathogenetic
factors associated with dysplasia and SCC of the UADT (i.e., alcohol and smoking) and cervix (HPV
120infection) are different. Furthermore, it has been pointed out that UADT dysplastic lesions may show
unique morphologic features not seen in cervical dysplasia; that is, super) cial 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
135,136an underassessment of their grade.Two main alternative classi) cation schemes to the WHO system have been proposed by Crissman and
124,125 35,119,120colleagues and Kambic and colleagues. They are both characterized by an emphasis
on cytologic features rather than the relative ratio of abnormal to di( erentiated cellular components
136,137within the epithelium. The system advocated by Crissman and colleagues recognizes a category
of keratinizing dysplasia to designate a lesion showing super) cial 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
119aneuploidy. Thus, they are included in a high-grade dysplasia group (SIN-laryngeal intraepithelial
124,125neoplasia III). These authors further stressed that abnormal di( erentiation was present in these
lesions in the form of aberrant keratinization (dyskeratosis), represented by single-cell keratinization
125and keratin pearls, occurring in the midst of the epithelium. Underreporting of keratinizing
dysplasia and its di( erence from classic CIS were con) rmed by others upon systematic review of
138 124,125laryngeal biopsy specimens. The system advocated by Crissman and colleagues proposed the
designation SIN (or laryngeal intraepithelial neoplasia) as an alternative to dysplasia. The proposed
advantages of the designation intraepithelial neoplasia are many. This de) nition 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
di( erent 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.
119,120,139Kambic and colleagues proposed for the larynx a distinction of dysplasia into simple,
abnormal, atypical hyperplasia and CIS. In this classi) cation, known as the Ljubljana classi) cation, 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 signi) cant cytologic atypia. The
occurrence of signi) cant 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 strati) cation and shows
119,120,139very frequent mitoses. The approximate correlation between the di( erent classi) cations
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 classi) cation of lesions
between the two groups. Thus, of 12 cases diagnosed as mild dysplasia by the WHO system, three were
reclassi) ed as simple, eight as abnormal, and one as atypical hyperplasia; of 19 cases of moderate
dysplasia, two were reclassi) ed as simple, 10 as abnormal, six as atypical hyperplasia, and one as CIS;
of 14 cases of severe dysplasia, one was reclassi) ed as simple, eight as atypical hyperplasia, and one as
140CIS. Nine lesions were placed in a group of large-cell hyperplasia, a category not described in the
140original Ljubljana classi) cation. Like other multitiered grading systems, the WHO system, which is
19the most commonly used in pathologic practice, has high inter- and intraobserver variability. Most
observers think the morphologic distinction between severe dysplasia and CIS is diN cult to establish
134and reproduce with consistency. Furthermore, if these two lesions may potentially have a di( erent
progression risk to overt cancer, advocating such a difference would be difficult to ascertain because the
134morphologic distinction between them cannot currently be reproduced.
Table 1-5 Classification Schemes That Histologically Characterize Precursor and Related Lesions
Squamous Intraepithelial2005 WHO Ljubljana Classification of SquamousClassification Neoplasia Intraepithelial Lesions
Squamous cell Squamous cell (simple) hyperplasia
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 (nuclearpleomorphism)
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 Increased nucleus size
(dyskeratosis)
Keratin pearls within rete pegs Atypical mitotic figures Increased number and size of
nucleoli Hyperchromasia
De) ning 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 di( erent 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
47features in gauging grades of SIN according to the WHO 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 de) ned by the relative relationship of
basal and parabasal (immature and normal proliferating cells) to maturing keratinocytes of the
intermediate zone and the super) cial protective keratotic layers. The determination of hyperplasia that
maintains normal maturation characteristics is often reversible when the o( ending 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 e( ect, genetic alterations produce an uncoupling of normal
maturation, and these maturation abnormalities are invariably associated with nucleus cytologic
131aberrations. Normal maturation results in an orderly mosaic-like pattern with similarly sized nuclei
maintaining an equidistant relationship. The distance is de) ned 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 ) nal 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. 1-18A 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. 1-18C 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 de) ne the degree of morphologic alterations with
speci) c 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 Atrophy
Rare mitosis confined to suprabasal layer Thin mucosa
Normal maturation Normal mucosal
maturation
Surface keratinization common
No nuclear
No nuclear pleomorphism
pleomorphism
SIN I (low grade)
Epithelial hyperplasia Some
proliferation of
Increased mitoses common (1–2 per high-power field)
basal-like cells
Three or more layers of basal-like cells
Increased
mitoses (1–2 perMinor nuclear pleomorphism
high-power field)
Minor nuclear
pleomorphism
Surface
maturation still
evident
SIN II (high grade)
Epithelial hyperplasia Proliferation of
basal-like cells
Mitoses in all layers common, including abnormal
involving the full
forms
thickness
Marked epithelial maturation abnormalities with
Prominent
immature basal-like cells constituting inner and middle
submucosal
one third or in combination with premature
changes
keratinization, including presence of pearls
Numerous
Prominent nuclear pleomorphism
mitoses at allIncreased chromatin staining 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 de) nition 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 + at 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 + at (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.
65In the largest series of leukoplakias studied to date, of 3256 oral cases, Waldron and Schaefer
found histologic evidence of neoplastic changes (dysplasia or overt cancer) in 20% of the cases: 12.2%
65mild to moderate dysplasia, 4.5% severe dysplasia, and 3.1% invasive carcinoma. The remaining
80% of the lesions had varying combinations of hyperorthokeratosis and acanthosis, without dysplasia.
64Similar percentages of dysplasia were found by Banoczy and Csiba 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.
64Thus, Banoczy and Csiba 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%,
64respectively. However, lesions with the appearance of erythroplakia harbor the highest percentage of
68high-grade dysplasia and overt cancer. Schaefer and Waldron, in a series of 65 oral cases, found that
689% of erythroplakias show low-grade dysplasia, 40% high-grade dysplasia, and 51% invasive SCC. In
111the series of Mashberg and colleagues (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 wasmore 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 re+ ects 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.
Larynx
In general, a review of the literature reveals numerous terms for what are interpreted as similar
123-125 141approaches for the grading of dysplasia/SIN. We believe, as do others, that the minor
variations between keratosis without atypia and keratosis with mild atypia are diN cult to separate with
reproducible certainty and are likely to represent neoplastic transformation and should be viewed as a
single entity. Although the subclassi) cation of the epithelial dysplasia/SIN of the UADT into histologic
grades analogous to other organ systems has not been well de) ned, there is a growing body of evidence
demonstrating that various grading systems have biological signi) cance in predicting the probability of
125 142progression. One of the ) rst classi) cation systems was reported by Kleinsasser, 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 de) ning SIN is, at best,
39,43,123,125,128,132,133,141-149arbitrary. Review of the literature supports this position. 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 de) nitions. 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
43,124,132epithelial alterations with little or no dysplasia/SIN.
The summary data reviewing the pertinent literature contain very few biopsy specimens graded as
moderate atypia, and those classi) ed as such have a frequency of progression to invasive carcinoma of
13.7%. This ) gure is not signi) cantly di( erent from the 15.3% reported for biopsies classi) ed 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
150keratinization and, as a result, were undergraded. 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
39,142,151,152dysplasia/SIN. 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
150observation is con) rmed in the excellent study of Hellquist and colleagues in which the dysplasia
they called well di( erentiated 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.
39The second important prognostic observation reported by Hellquist and colleagues 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 super) cial keratinization. This
morphologic pro) le is recognized by most experienced pathologists as a prominent feature of
highgrade SIN because of the evidence of maturation as re+ ected 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 ) vefold higher risk of neoplastic development has been calculated to be
conservative. Causative agents include carcinogens such as tobacco and alcohol, friction on the mucosal
73surface, and microscopic organisms such as C. albicans. It was recently proposed that the term
80leukoplakia be restricted in use to nonde) nable lesions. 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 de) nition 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
65in relation to the site. Thus, Waldron and Schafer, in a series of 3256 cases, found the incidence of
dysplasia and CIS to be disproportionately high in the + oor 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 di( erent 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
59mean observation time of 9.8 years (Table 1-9).
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
59overall incidence of malignant transformation in the series of Banoczy 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 di( erence 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
59among females. A similar bias in malignant transformation of females versus males (58% vs. 42%)
63was observed by Silverman and colleagues. The reasons for these gender-related di( erences 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
60,63,153excess risk of developing into SCC compared with leukoplakia arising in smokers. 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
) rmly 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
154severe epithelial dysplasia. 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 errorand/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
153it. Other authors had observed that the progression time from CIS into overt SCC is extremely
155variable. These ) ndings highlight that, although likely to include a preneoplastic phase, the natural
history of SCC may show significant patient-to-patient variations.
107,108A distinctive type of hyperplasia, PVL, has been described. This lesion was identi) ed
retrospectively and is characterized by a verrucous clinical appearance, an expanding and often
95multifocal growth pattern, and a high (up to 70%) rate of progression into invasive carcinoma. 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
exophytic107verrucous appearance, and thus the diagnosis can reliably be made only retrospectively. 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
95,107 95verrucous carcinoma. Notably 69% of the patients have no history of tobacco exposure. In
contrast, 78% show evidence of HPV 16 infection, highlighting the possible transforming role of this
156virus in this setting.
Larynx
The reported frequency of transformation of leukoplakia varies from 3.5% to 21%; the largest studies
157-160reported frequencies of 4.4% to 16% (Tables 1-10 to 1-12). As with oral dysplasia, the rate of
progression to overt cancer increases with the degree of dysplasia. Thus, in the series of Blackwell and
135colleagues, 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
135 35moderate dysplasia, and 33% for severe dysplasia/CIS (5/15). Kambic and colleagues 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
128the severity of dysplasia: 53% (9/17) for CIS and 18% (3/17) for moderate-severe dysplasia. The
progression rate of CIS to invasive carcinoma was found to be 63% in a group of 27 patients managed
161 162conservatively after a mean follow-up time of 9 months. In the series of Gillis and colleagues,
progression to CIS or invasive carcinoma was observed in three of seven patients with keratosis and ) ve
of 12 cases of atypia with or without keratosis; progression to invasive SCC was observed in three of
43eight cases of CIS. Norris and Peale 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: ) ve to SCC, four to CIS, and two to CIS with equivocal evidence of invasion. Hellquist
39and colleagues 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, ) ve 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
136than 2 years of follow-up and 57% more than 5 years. Crissman and colleagues 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 classi) ed
according to the Ljubljana classi) cation 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
351-10 to 1-12).
Table 1-10 Frequency of Progression of Laryngeal Leukoplakia and Dysplasia to Invasive SquamousCarcinoma
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 Olofsson158 (1987) 232 13
Plch et al.159 (1998) 227 4.4
McGavran et al.160 (1960) 84 3.5
Miller and Fisher133 (1971) 203 15.7
Blackwell et al.135 (1995) 62 21
Norris and Peale43 (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 LarynxOther investigators have stressed the importance of speci) c histologic parameters in predicting
136progression to invasive SCC. In particular, the occurrence of single-cell intraepithelial keratinization,
135pleomorphism, mitotic activity, and mucosa-associated in+ ammation has been found to confer an
136increased likelihood of progression to SCC. In the series of Crissman and colleagues, 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
162colleagues, 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
163field is prone to develop cancer, as first described by Slaughter and colleagues.
Sinonasal Region and Nasopharynx
Clinical and Epidemiologic Aspects
There continues to be a relative scarcity of literature dealing with both the histologic de) nitions 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
164-166carcinoma, few recent reports have concentrated on characterizing the pure intraepithelial
changes segregated from a large pool of invasive tumors. The diN culty in ) nding 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
167nasal cavity and paranasal sinuses. However, identi) cation of precursor mucosal changes is not
documented for woodworkers. The spectrum of hyperplastic, metaplastic, and neoplastic changes
168within the nasal epithelial lining has been well described in workers exposed to nickel fumes. In alongitudinal study designed to investigate the e( ects 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
169dysplasia/neoplasia. Barnes and Bedetti 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
170invasive SCC, reported to be discovered in 4% to 6% of cases of resected papillomas. 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
171paranasal sinuses, von Buchwald and Bradley 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 de) nitive need for
longterm 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
172invasive nasopharyngeal carcinoma. Pathmanathan and colleagues 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 identi) ed via a large screening program. The alterations were described as thickened
epithelium with loss of normal strati) cation 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.
173In a more recent report, Cheung and colleagues identi) ed 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 ofinvolvement 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 di( erentiation 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
174high-grade lesions. A similar report was also published by Pak and colleagues, who identi) ed 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
175Sheu and colleagues studied the immunohistochemical expression of p53 and bcl-2 in normal,
in+ amed, 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
172epithelium. Both this study and the previously mentioned report by Pathmanathan and colleagues
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 signi) cant dysplastic/intraepithelial neoplastic changes for
peripheral mucosal margins). The latter is an area that can be hampered by both technical and
interpretation diN culties. We believe that both diN culties 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
de) ne 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 strati) ed epithelia including the UADT mucosa. Comparing the frozen-section slides to their routinely
processed counterparts of the same tissue often con) rms an epithelial lining within the normal
histologic range (see Fig. 1-28B).Figure 1-27 Squamous mucosal frozen-section preparation. Orientation and technical quality.
Goodquality 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 signi) cant
in+ ammation is present should be allowed. The in+ ammation 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 in+ ammation, 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 diN cult 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 in+ ammation 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.
131).Figure 1-31 A–C, Stromal reaction and vascular proliferation. The ) broconnective tissue stroma in
these sections appears occupied by a darkly stained proliferative process that mimics on low
magni) cation and particularly in thick frozen-section preparations invasive carcinoma, considering that
the surface epithelium is also dysplastic. Closer inspection of this area, however, con) rms 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
176,177with a selective growth advantage. The ) rst 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 ) nally determines the phenotype of malignancy, although the order of events during
177this process may vary. A tumor progression model was additionally devised for SCC UADT in 1996
176by Califano and colleagues. 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
178within a single cell have been estimated to be necessary for SCC UADT development. Molecular
changes are believed to be morphologically expressed as di( erent grades of squamous intraepithelial
lesions, from squamous cell hyperplasia to invasive cancer. The latency period between carcinogen
179exposure and appearance of malignancy may last up to 25 years.
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 speci) c lifestyle, that is, chemical carcinogens, physical agents and micro-organisms,
180while some DNA damage may be also induced spontaneously. Initiation of precursor lesions in the
previously mentioned regions is mainly related to recognized carcinogens from alcohol and tobacco,
181,182such as polycyclic aromatic hydrocarbons, nitrosamines, aldehydes, and aromatic amines.
Interestingly, the di( erence in genetic and expression alterations in precursor lesions and SCC of the
oral cavity, oro- and hypopharynx, and larynx suggests that the genetic pro) le is predominantly related
183to histopathologic grade rather than site of origin of the lesions. It therefore seems reasonable to
group and evaluate precursor lesions and overt cancers of these regions (excluding tonsils) together. The
identi) cation 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
163The clinical concept of ) eld cancerization originally proposed by Slaughter and colleagues 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
188mutated cells, from which new (polyclonal) tumors independently arise. The histologically based
) eld cancerization concept has gradually been overtaken by the one established on molecular changes
185of the a( ected mucosa. The hypothesis, proposed by Bedi and colleagues and Califano and
185-187colleagues, advocates micrometastatic spreading or a monoclonal theory, which means that a
precancerous ) eld 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 ) eld and thus
188-190arise from a clonal origin.
Chromosomal Changes
The search for speci) c 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 ampli) cations. Classic cytogenetic studies of SCC UADT and of precursor
lesions have been limited by multiple impediments, including low frequency of mitotic ) gures from
direct preparations, suboptimal chromosome preparations, signi) cant complexity of cytogenetic
191-193changes, and obstacles in single-cell preparations. Nevertheless, karyotyping analyses,
additionally supplemented by new techniques such as multicolor + uorescence in situ hybridization and
spectral karyotyping have been adequately productive in the identi) cation of key genomic regions
involved in the development and progression of SCC UADT. Comparative genomic hybridization is aform of + uorescence 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
194-196paraN n-embedded specimens. Using comparative genomic hybridization, Brieger and
197colleagues 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
198arms, have been shown to be useful molecular indicators for detecting and establishing the behavior
of precursor lesions. DNA ploidy, detecting by + ow cytometry, image analysis, and molecular
cytogenetic analyses such as metaphase and interphase + uorescence 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
193,199-201their clinical behavior more objectively. Chromosomal aneuploidy was found to precede
malignant transformation and increased progressively with the severity of lesions in both the frequency
180,199of a( ected cells and in the number of a( ected chromosomes. 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,
201appears to be associated with progression to malignant growth.
Tumor Suppressor Gene Inactivation and Allelic Loss
Failure of growth inhibition is one of the most decisive changes in the process of carcinogenesis. Cell
202proliferation is controlled by the products of a TSG. Knudson 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 de) cit 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
179,203malignant alterations.
The correlation of speci) c patterns of genetic changes during the process of carcinogenesis in the
head and neck region is often limited by diN culties in obtaining tissue specimens from the same lesion
204over time. Despite these serious obstacles, numerous studies of LOH patterns provide promising data
176,186,201,204-208to supplement the genetic model of SCC development in the oral cavity and larynx.
The ) rst, and later re) ned, progression model in carcinogenesis of the head and neck region is entirely
176,186based on LOH analyses. 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 locus, and 17p13, where the p53 gene is located; 3p with at least three putative tumor1
suppressor loci, 13q21, 6p, and 8. Certain genetic events, such as 9p21 LOH, 3p LOH, and 17p13 have
184been found to be among the earliest events on the progression pathway. Sanz-Ortega and
206 209colleagues and Veltman and colleagues 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 identi) ed in precursor oral lesions, and the presence of one or both of these
205alterations has been associated with SCC development, probably even with its initiation.
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 is47,210-212impaired, ultimately leading to genomic instability. Approximately half of head and neck
cancers contain a mutation at 17p13, where the p53 gene resides, frequently in the codons 238-248 hot
213-215spot region. It has been suggested that the rate of mutations may be even higher when all 11
216exons of the p53 gene are sequenced. Loss of p53 function occurs in earlier phases of head and neck
176,186,217,218carcinogenesis, and consequent loss of p53 function results in progression from
210,212precursor lesions to overt SCC, which increases the likelihood of further genetic progression.
Overexpression of the p53 protein is frequently but not always associated with gene mutation. The
218predictive value of the p53 overexpression in SCC UADT and precursor lesions remains controversial.
217 INK4aGallo and colleagues reported that simultaneous p53 and p16 alterations in precursor
laryngeal lesions seem to have some malignant potential. On the contrary, the predictive value of p53
218,219overexpression appears to be less pronounced in oral lesions. However, Homann and
218colleagues 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
218second primary cancer.
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 identi) ed in mismatch repair
220genes HLH1 and HSH2. MSI is therefore considered an infrequent event in head and neck
carcinogenesis, but when it does occur, it shows some di( erent 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
45invasive SCC. However, the results of both studies are not completely comparable, as Ha and
45colleagues studied MSI only with microsatellite markers related to regions where LOH is a
predominant ) nding in SCC UADT and not with markers associated with regions characteristically
220changed in the hereditary nonpolyposis colon cancer (Bethesda markers). The results of Glavac and
220colleagues 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. Di( erent
categories of oncogenes signi) cantly contribute in the development of precursors and SCC UADT.
Important members of the cell cycle regulators are cyclin D1 and epidermal growth factor receptor
(EGFR). Cyclin D , located in the 11q13 chromosome region, has a central role in the cell cycle. It1
regulates the G1/S transition by phosphorylation and inactivation of the retinoblastoma gene, which is
considered a key event in cell cycle control. Gene ampli) cation and overexpression have been
221-223frequently described in SCC UADT and also in its precursor lesions. Cyclin D inhibitor, p161
gene, contributes to cell cycle control through decrease of Rb gene phosphorylation. Despite related but
opposite functions of genes, gain of cyclin D and loss of p16 are considered to be independent1
224,225mechanisms in G1/S phase dysregulation. It is believed that constitutive activation of the cyclin
D pathway can reduce or overcome certain mitogen requirements for cell proliferation and thus147contribute to oncogenic transformation.
Ampli) cation of the chromosome 11q13 is a frequently detected event in SCC UADT development,
226observed in 30% to 50% of cases. In addition to cyclin D , several genes that have potential1
functional importance for head and neck tumorigenesis are frequently coampli) ed in this region,
including the INT2 gene (a member of the ) broblast growth factor family), EMS1, FGF4, vascular
endothelial growth factor- β ε τ α, phosphatase-1a, and glutathione S-transferase p. INT2 gene
ampli) cation, 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 ampli) cation can also
227occur early in the UADT tumorigenesis process.
The EGFR a( ects cell division, migration, adhesion, di( erentiation, and apoptosis through a tyrosine
228kinase pathway. 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
229,230development.
Telomerase Reactivation
The telomerase enzyme is a multisubunit enzyme complex. A telomerase catalytic subunit functions as
231a reverse transcriptase that can synthesize the telomeric ends at each cell division. In normal tissue,
the telomerase remains undetectable, with the exception of germ cells and stem cells of renewable
232tissues. Several studies have con) rmed that reactivation of telomerase is one of the most frequent
events in human carcinogenesis, associated with cellular immortality, which contributes to the
231,233accumulation of genetic abnormalities and increase in genomic instability. 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
234-237with the degree of squamous intraepithelial lesions in laryngeal and oral epithelium.
Nevertheless, other genetic changes appear to be necessary for progression of these epithelial changes to
invasive SCC.
Genetic Progression Model
176,179,186Califano and colleagues 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 signi) cant growth advantage, may migrate to
186distances of several centimeters. 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.
Identi) cation of genetic alterations in precursor lesions also has prognostic signi) cance. Progressing
and nonprogressing cases of oral epithelial dysplasia show di( erent 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
204risk of progression to cancer compared with cases that retained both of these arms. A recentlypresented transcriptional progression model for head and neck cancer using array-based gene
expression pro) ling 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 signi) cantly up- or
downregulated when compared with the normal control tissue, whereas only 23 genes were altered in a
183comparison of the premalignant with the malignant group.
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
211these methods are still in various stages of testing and clinical trials. Regrettably, at present, no
single molecular biomarker can reliably predict the risk of cancer progression in di( erent 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
238characteristic of head and neck carcinogenesis possible. Although several markers, including loss of
chromosome regions 9p21-22 and 17p13, overexpression/ampli) cation of 11q13, EGFR overexpression,
telomerase reactivation, and aneuploid DNA content, generally signify an increased risk of malignant
176progression, various treatment modalities for di( erent grades of squamous intraepithelial lesions
and their prognostication still mostly rely on clinical data, adequate biopsy specimens, and
34,203histopathologic findings.
Molecular Markers of Dysplasia
Since the initial histologic characterization of premalignant conditions of the UADT, one of the major
advances in this ) eld has been the identi) cation of the molecular alterations with which they are
239associated (Table 1-13). While biologically justi) ed and crucial in reducing the variability intrinsic
139in a morphology-based system, the inclusion of molecular markers has yet to ) nd a role in the
classi) cation 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 ) rst
140been described to occur alongside the morphologic progression from normal to cancer. 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
EGFR170,246 + ++
Mib-1/PCNA49,51,245 + ++
p21248 + +
p53239,246,247 9–67% 33–85%
Aneuploidy136 33% 100%
+ ++Apoptosis249
bcl-2175 + ++
+, ++, focal and di( use 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,
re+ ecting abnormalities in either cellular di( erentiation or cell cycle control. Changes of the ) rst group
include those a( ecting the pro) le of keratin expression and were the ) rst 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
19,125CK19 has been proposed to constitute a marker of dysplasia, although this finding cannot reliably
49distinguish hyperplasia from true dysplasia.
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
51,240-243cells, has allowed an objective evaluation of the proliferative rate. 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
51,240,241progenitor cell. 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
49this antigen extends to suprabasal cells.
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
241,244,245grades. While negative in normal epithelium, p53 is found in 9.4% to 32% of low-grade
241,245and 33% to 50% of high-grade cases of dysplasia. Suprabasal expression of CK 19 and
proliferating cell nuclear antigen is associated with positivity for p53 in the majority of cases of
49dysplasia, highlighting the link existing between abnormal di( erentiation 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
246shows positivity.
Increasing percentages of EGFR positivity are also seen, seemingly associated with the dysplastic
244component. Increasing percentages of aneuploid populations are also observed in increasing grades,
119progressing from 33% of SIN I to 78% of SIN II and 100% of SIN III.
Apoptosis increases in parallel with the proliferative rate, as observed morphologically or by DNA in
241,247situ labeling techniques. 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
248nasopharynx.
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 canceras 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, a( ected in hereditary nonpolyposis colon cancer, the retinoic acid receptor β ε τ α, and the
249fragile histidine triad (FHIT) gene. While the identi) cation of the speci) c suppressor gene(s) located
at 3p14 and 3p21 whose loss is responsible for the development of cancer is still unresolved, the FHIT
171,250,251gene has recently been proposed to be a speci) c target of cigarette smoke carcinogens and
252shown to behave as a TSG in vitro. 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 suN cient for
malignant transformation. The occurrence of additional chromosomal losses was shown to confer a
253much higher risk of progression, comparable to losses at 3p and 9p alone. These included
253,254chromosomal sites 4q, 8p, 11q, and notably 17p. 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
253model envisioning loss of genetic material in chromosomes 3p and 9p loci as involved in initiation
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
204proliferations.
Dysplastic lesions of the nasopharynx have been shown to harbor clonal integration of the
EpsteinBarr virus, in concordance with the accepted role that this virus plays in the development of
176nasopharyngeal carcinoma. 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
255leukoplakia occurring in patients with human immunodeficiency virus.
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
256used to monitor epithelial maturation. One of the ) rst markers to be carefully investigated was the
expression of cytokeratins with the hope that expression of abnormal cytokeratins would signify
242abnormal epithelium. Unfortunately, cytokeratins vary greatly within dysplastic epithelium as does
242the phenotypic expression (morphology) re+ ecting genetic alterations. 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 identi) able surface cytoplasmic
257keratin, usually of high molecular weight. However, not all studies have been able to con) rm these
49,258observations. 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 con) rming abnormal DNA
151,152content have been performed by image analysis. Almost all high-grade dysplasia/SIN lesionshave 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 signi) es expression of neoplastic
change. Similar but more sophisticated observations documenting individual chromosomal polysomy in
259preinvasive epithelial changes have also been reported. Subsequent molecule-oriented studies have
identi) ed 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
260,261EGFR expression with high grades of SIN. Both increased p53 gene product and p53 mutations
have been identi) ed in noninvasive SIN and have been noted to increase in invasive
210,261carcinomas. 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
43recurrence when present in surgical margins.
Several recent studies provide strong evidence in support of augmenting traditional histopathologic
205examination with genetic testing. Mao and colleagues correlated LOH in a significant number of oral
leukoplakias at 9p21 and 3p14 with a greater probability of progression to HNSCC. This ) nding
262suggests the potential of microsatellite analysis in predicting cancer risk of oral leukoplakia. Rosin
204and colleagues 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.
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Res. 2000;6:321-322.Chapter 2
Squamous Cell Carcinoma of the Upper Aerodigestive System
Pieter J. Slootweg, Mary Richardson
Introduction
Squamous cell carcinoma (SCC) of the upper aerodigestive tract (UADT) is the most common malignant
1neoplasm of the mucosal lining of the upper food and air passages. In the Netherlands in 2000, 2400
new cases of head and neck cancer, mostly SCC, were registered as part of 69,000 new malignancies
2arising in a population of 15.9 million inhabitants. Worldwide statistics cited 616,000 new cases in
3 32000. It is evident that head and neck cancer, which carries an overall death risk of 54%, 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
4relative cancer burden and site-specific patterns for many areas of the world.
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
3,4cancer ranks third, and it is the fourth most common cancer in men worldwide. More than 90% of
all UADT cancers are SCCs occurring in the 6fth and sixth decades of life, with rates increasing with
5age. Furthermore, with a few exceptions, the incidence is higher in men than in women. Pertinent
epidemiologic data are briefly mentioned here for the various UADT sites.
Lip
The highest rates of lip cancer are in men from South Australia (13.5/100,000) and Canada
4,6(11/100,000 [Newfoundland 6shermen]). The lowest rates occur in Asia (0.9/100,000). The
4incidence in the black population of the United States is very low to nil. Lip cancer is uncommon in
4women. The risk of lip cancer seems to be decreasing.
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 6nds that the most common head and neck cancer,
7namely, oral cancer, ranks 11th worldwide and cancer of the pharynx ranks 20th. 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
3cancers of the nasopharynx. Within the European community, oral cancer constitutes approximately
84.2% of all cancers. The highest incidence among males (primary tumors of the pharynx) is reported
6,8from France (Bas-Rhin and Calvados), with annual rates of 40 per 100,000. The highest rates among6,9women occur in parts of India. In India, however, the sex distribution of oral cancer is more equal.
3In their overview of the worldwide incidence of cancers, Parkin and colleagues 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
6seventh among blacks and 12th among whites.
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 identi6ed
was the long-standing use of smokeless tobacco products (snuD). Recent updates (1970–1989) among
U.S. females reveal a decrease in the high-risk Southeast and several new high-risk areas along the
6Pacific and Florida coasts.
Tumors of the postcricoid region have historically been seen in Northern European women, especially
10,11those from rural Sweden, but also in those from the United Kingdom and Asia. In these regions,
11,12Plummer-Vinson syndrome (Paterson-Kelly syndrome, sideropenic dysphagia) was prevalent. The
syndrome is characterized by dysphagia, glossitis, iron-de6ciency 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
11approximately 15 years after the onset of Plummer-Vinson syndrome.
Larynx
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,
13,14and this ratio is reasonably consistent worldwide. The incidence is higher among black residents
15than white residents in the same geographic region. The highest incidence rates in men are reported
for Southern Europe (annual incidence, 14.7/100,000), with Western Europe having the second highest
4 16rates (annual incidence, 11.4/100,000). Coleman and colleagues observed a three- to fourfold
diDerential 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
17tobacco have a higher risk of laryngeal cancer than users of light (I ue-cured) tobacco. 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
18with a multiplicative model. 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
19of the herb Ilex paraguariensis (yerba mate). DeStefani and colleagues 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
20,21neck.
Sinonasal Cavities
Cancer of the nasal and paranasal sinuses is infrequent. In the United States, the incidence is 0.75 per100,000 persons. The most common site of occurrence is the maxillary sinus, which is aDected twice as
often as the nasal cavity. The least frequent areas involved are the ethmoid and sphenoid sinuses. The
22male-to-female ratio is 2:1. 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
231.4–1.2 for females) and certain African populations (2.5 in males and 1.8 in females).
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
24-28develop from exposure to hardwood, chrome pigment, and leather dust. Another agent frequently
22cited as being involved with cancer of the nasal cavity is thorotrast. Moreover, Epstein-Barr virus
(EBV), well-known in the context of nasopharyngeal carcinoma (NPC), and human papillomavirus
29-31(HPV) appear to play a role in the pathogenesis of a variety of sinonasal carcinomas.
Nasopharynx
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
32increases from north to south, two to three per 100,000 to 25 to 40 per 100,000, respectively. The
consumption of salt-cured 6sh (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
33 32,34incidence is low (0.7/100,000). EBV has been found in all forms of NPC.
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
32with low to moderate risk, an adolescent age peak has been noted.
Trachea
35SCC of the trachea has shown a strong male predominance of three times as many men as women.
36There is a strong association with cigarette smoking. Tracheal malignancy is most often seen (almost
3550%), with adenoid cystic carcinoma being the second most frequent type found (25%).
Analytic Epidemiology
The study of the epidemiology of head and neck cancer has identi6ed alcohol use and tobacco use as
1,8,17independent risk factors, and combined, they have a multiplicative risk. Tobacco products such
as cigarettes, cigars, snuD, and chews (e.g., betel quid, which consists of the leaf of the betel vine [Piper
9,21betel], areca nut, lime, and tobacco) are risk factors for head and neck cancer. Factors such as
dietary de6ciencies, after correcting for alcohol and tobacco use, particularly of vitamins A and C, iron,
9,21and certain trace elements, are thought to predispose to oral cancers. Other risks include previous
irradiation; work in furniture, asbestos-related, and nickel industries; poor oral hygiene; and infection
1,14with the EBV. The association between either lichen planus or marijuana smoking and risk of oral
37cancer is still controversial.
Exposure to alcohol and tobacco aDects various sites. With cigarette smoking, the gradient of the dose
response and the magnitude of the risk show diDerences by gender and by primary site. Some studies
8,17have found women to have a greater risk than men per pack-year stratum. The subsites within the
UADT that exhibit the greatest risk associated with alcohol exposure are the I oor of the mouth, the
38hypopharynx, and the supraglottis. Higher smoking-associated risk estimates have been reported forsubsites of the larynx (glottis) and hypopharynx. Smokeless tobacco has a high risk for the oral
17cavity. HPV has been associated with carcinomas arising in the palatine tonsils in a subset of young
39patients. Some studies have suggested this group of patients has better survival rates.
Case reports of head and neck cancer occurring within the 6rst two decades of life are rare. Other
patients with cancers in the 6rst two decades may be individuals with genetic disorders or children with
40laryngeal papillomatosis.
Syndromes
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
41syndrome.
Bloom syndrome is an autosomal recessive disorder characterized by a high incidence of cancer at a
young age. Twenty-eight of the initial 103 identi6ed as Bloom syndrome patients developed cancer,
and 6ve of these cancers were head and neck carcinomas (one each of the epiglottis, pyriform sinus,
42and larynx and two of the base of the tongue; age range, 26–34 years).
Fanconi anemia is a recessively inherited disorder associated with increased risk of malignancies,
43including head and neck tumors. 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
44the gingiva and buccal mucosa. Although the male-to-female ratio in Fanconi anemia is 2:1, the ratio
44is reversed among these patients with SCC. Patients with Fanconi anemia are known to be susceptible
to HPV-associated malignancies. HPV DNA has been demonstrated in specimens obtained from head
45and neck SCC in these patients.
Xeroderma pigmentosum is an autosomal recessive disease characterized by a DNA excision repair
de6cit. Damage to the chromosome is elicited by exposure to ultraviolet light. SCC on the anterior third
of the tongue is frequent within the 6rst two decades of life. These patients in the 6rst two decades have
an estimated 10,000 times greater frequency of tongue tumors than expected for that age group. SCC of
46the gingiva and palate also occurs with increased frequency in these patients.
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,
47which included malignancies of the oral cavity within its spectrum.
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
48patients also have a high incidence of second primary tumors.
In the immunologically compromised population, which would include organ transplant recipients as
well as patients with human immunode6ciency virus infection, there is known to be an increase in oral
tumors. A report of increased oral SCC in patients infected with human immunode6ciency virus has
49been noted. 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
50transplantation.
Etiology
1,8,51-54As outlined previously, the most important risk factors for SCC are alcohol and tobacco use,
1,8,55-57but there is also increasing evidence that viruses are implicated in at least some cases of SCC.
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 undiDerentiated and
58 59nonkeratinizing tumors but also in keratinizing SCCs. Proof that herpes simplex virus is implicated
in head and neck carcinogenesis is still lacking, although herpes simplex virus antigens have been
55observed in some oral cancers. The role of HPV as a risk factor for SCC has gotten considerable
60 61support during the past years, especially for nonkeratinizing SCC occurring in the tonsillar area as
31well as in the sinonasal tract. Meta-analyses of epidemiologic studies and multicenter case-control
studies have con6rmed 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-speci6c survival rate compared with the
HPVnegative group. Of the sinonasal carcinomas analyzed so far, 22% have been positive for any HPV
60type.
Recently, some evidence was presented that genetic predisposition also plays a role in the origin of
62,63SCC, although it has also been reported that environmental factors may contribute to familial
64,65aggregation of SCC. Possibly, it concerns the outcome of interplay between carcinogens and the
66ability to repair their damage.
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
67-69functions. 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
70not occur, causing apoptosis. In this way, cells with abnormal DNA cannot proliferate, and the
importance of a normally functioning p53 gene is exempli6ed by the observation that in many tumors,
71,72SCC included, p53 gene mutations are present.
The signi6cance 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
73gene mutations, and an association between p53 gene mutations and smoking has been
71,72observed. 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
74of p53 protein.
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
75-80varying from 10% to 35%, whereas the risk of developing a second malignancy from treatment to
80,81death has been reported as 4% to 6% per year. In a prospective study, the development of a
82second primary tumor was the main cause of death. Such tumors are considered synchronous if they
are diagnosed at the same time as or within a 6-month period of identi6cation of the primary lesion; if
second cancers are diagnosed 6 months or more after the diagnosis of the primary cancers, they are
76metachronous neoplasms.
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
80mucosa (if the intervening mucosa demonstrates dysplasia, it is considered a multicentric primary ),
76and the possibility that the second neoplasm represents metastasis should be excluded. Those secondprimary cancers are observed not only in the UADT but also in the lungs, the latter especially in cases of
77,78laryngeal SCC or in other body sites. Two independent variables in head and neck carcinomas
have been found to inI uence the occurrence of second metachronous cancer: anatomic site of the
80original primary tumor and age. Second primary tumors in the head and neck area are more often
77seen when the 6rst SCC is located in the oral cavity, oropharynx, or hypopharynx. Within the oral
cavity, patients with their primary tumor in the I oor 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
83sites. The oropharyngeal and hypopharyngeal sites associated with an increased frequency of second
83primary tumors are the base of the tongue (46%) and the pyriform sinus (34%), respectively.
Most second primary tumors are metachronous, although sometimes an unusually high proportion of
80synchronously occurring SCCs is found. 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
84,85patients. Second primary tumors adversely inI uence the prognosis of UADT SCC patients. Survival
at 5 years for patients with a second cancer in the 6rst 2 years was less than 50% and for those without
79a second primary, nearly 70%. Prevention and detection of these second primary tumors may play
78the most important role in improving overall survival rates in the future.
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
86these lesions, the designation second field tumors has been proposed.
Local and Distant Metastasis
SCC of the UADT predominantly metastasizes to the lymph nodes of the neck, the site of the involved
87nodes being dependent on the localization of the primary tumor (see Chapter 11). The adverse
inI uence of metastatic neck node deposits on patient survival is 6rmly established, the prognosis being
diminished approximately by half if lymph node metastases are present at presentation or during
88-92follow-up. Prognosis further worsens if the tumor spreads beyond the lymph node into the soft
88-90,93-97tissues of the neck; this growth pattern is known as extracapsular spread. Whether
microscopic extracapsular extension does have the same prognostic signi6cance as gross extracapsular
98spread has been a controversial issue. Recent studies, however, have indicated that the prognosis
99,100worsens in both situations. Extracapsular spread is only slightly correlated with nodal size; nodes
94less than 1 cm may already exhibit this feature. Soft-tissue deposits in the neck appear to have the
100,101same prognostic significance as nodal metastasis with extracapsular spread.
Not only extracapsular spread but also the presence of a desmoplastic stromal response in
tumor97positive lymph nodes has been shown to worsen prognosis. The prognostic signi6cance of neck node
disease justi6es a very meticulous examination of neck dissection specimens, as a high incidence of
micrometastases (<3 mm="" in="" _size29_="" has="" been="" found="" patients="" without=""
102clinically="" manifest="" neck="" node=""> However, one should realize that the prognostic
103,104significance of these tiny metastatic deposits has not yet been proven.
105-108Neck node disease also correlates with an increased risk of development of distant metastases.
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
106metastases compared with patients without this feature (19.1% vs. 6.7%). Originally, distant
109metastases de6ned as metastatic SCC at sites below the clavicle were considered rare. 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
110-1122-2). As the lungs are also the most common site of second primary tumors in patients withUADT SCC, it has not always been possible to answer the question of whether a lung lesion is a second
113,114primary tumor or a metastasis from UADT SCC. Currently, molecular analysis of the various
115-118lesions offers the solution for this diagnostic problem.
Figure 2-1 Autopsy specimen. A tumor originating in the I oor 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 PrognosisA UADT SCC is a malignant epithelial tumor with squamous diDerentiation characterized by the
119formation of keratin or the presence of intercellular bridges or both. This diagnosis is usually not
diQ cult to make, the most signi6cant diagnostic problem being very marked pseudoepitheliomatous
hyperplasia of the mucosa, often overlying a granular cell tumor or an infectious process that may be
120mistaken for SCC. However, when trying to infer data with prognostic signi6cance from the
histology, one enters an area replete with difficulties and uncertainties. In fact, tumor size and stage still
121represent the most signi6cant prognostic factors for a patient with a UADT SCC, 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 brieI y 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. DiDerent approaches have been followed to obtain prognostically
122relevant data from histologic examination. The 6rst attempts were made by Broders. His
classi6cation system was based on the proportion of the neoplasm resembling normal squamous
123epithelium. Although some authors report histologic grade to have prognostic signi6cance, UADT
SCC in most instances exhibits a heterogeneous cell population with diDerences in the degree of
diDerentiation, which may lead to a high degree of intraobserver and interobserver diDerences in the
histologic grading of a tumor. Furthermore, in practice, most UADT SCCs are graded as moderately
diDerentiated, which may explain the poor correlation between patient outcome and histologic grading
124,125based on degree of diDerentiation. 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 diDerences in survival rates
126between well and poorly differentiated tumors.
To obtain a more detailed morphologic evaluation of the growth potential of a UADT SCC, Jakobsson
127and colleagues 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
128colleagues. Some studies indicate that the value of this multifactorial grading system may improve
129-132when only the deeply invasive margins of the tumor are evaluated. Tumor features that are
assessed in this multifactorial grading system are degree of keratinization, nuclear pleomorphism, and
number of mitotic 6gures. Features related to the tumor-host relationship are pattern of invasion, stage
of invasion, and extent of peritumoral lymphoplasmacytic in6ltration. Each assessed feature is scored
from 1 to 4, and the scores for each morphologic feature are added together for a total malignancy
128score.
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
129-141tumors exhibiting diDuse spread with tiny strands or single cells (Fig. 2-3). Data on the speci6c
signi6cance 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-diDerentiated and poorly diDerentiated cases was shown to make an independent
133statistically significant contribution to the prediction of prognosis.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 in6ltrate, one study mentions an inverse correlation
138between extent of in6ltrate and incidence of neck node metastasis ; no prognostic signi6cance for
136,139this feature was found in other investigations. However, when analyzing the signi6cance of
142individual cellular components, the number of T lymphocytes appeared to have some relevance.
The host’s reaction to an SCC may be visible not only as a peritumoral lymphocytic in6ltrate but also as
143,144tumor-associated tissue eosinophilia, a feature of uncertain prognostic significance.
128Other histologic items that are not included in this multifactorial grading system but nevertheless
129,139,141,145-147are considered to be prognostically important are tumor thickness, perineural
129,146,148,149 137,140,150growth (Fig. 2-5), and vascular invasion (Fig. 2-6). The signi6cance of the
151density of tumor vessels in the stroma adjacent to the tumor is controversial. 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
152-154persisting epithelial embryologic structures. Those structures are found at the medial surface of
153,154the mandible and are known as Chievitz’ organ, or they may be present in association with
152,153intrabony nerves, probably representing odontogenic epithelial nests (Fig. 2-7), as well as in the
153anterior maxilla, probably representing a nasopalatine duct remnant. The intimate relationship
between these islands of epithelium and peripheral nerves could be erroneously interpreted to represent
153perineural and intraneural invasion.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
signi6cant, the pathologist contributes to an additional signi6cant prognostic parameter by evaluating
124the completeness of the primary excision. Almost all authors who have investigated the signi6cance
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
155-157margins ; others found the same negative inI uence in the event of tumor close to the margins
137,158,159(<5> or with patients having dysplasia or carcinoma in situ at the surgical
160-164margins. Probably the negative inI uence of positive surgical margins is due, at least partly, to
its close association with other tumor factors that have an adverse eDect on prognosis, especially T
165,166stage. Also, anatomic tumor location and site of the involved margin, mucosal versus deep soft
167tissue and/or bone, may play a signi6cant role and are worthy of inclusion in the surgical report. 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
168site. In this study, de6nition 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 suQ ciently radical, and hence the surgery was tabulated asincomplete. 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 6ve times higher than in the
cases with margins free of tumor or dysplasia, with recurrence at the primary site in cases of free
169margins being less than 5%.
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 diDerentiating inI ammatory 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 con6rmed on
permanent-section evaluation does not ensure local control of disease but has been shown to enhance
170local control. 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 6ndings such as pattern
of invasion, perineural invasion, and lack of lymphocytic response to more accurately guide and assess
171therapeutic intervention.
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 diDerentiation, 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
172stated because of prognostic signi6cance. A standard form as provided by the Royal College of
Pathologists may be helpful and will facilitate computer-based analysis when performing retrospective
173studies. Such guidelines and minimum data sets will produce reliable standardized data allowing
174prospective multicenter research projects.
In addition to studying conventional histopathologic aspects that could have prognostic signi6cance,
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 especiallyapplies to the rate of proliferation or prognostic signi6cance of p53 overexpression. Until now, these
175,176studies have provided no objective evidence of any association with patient outcome.
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 signi6cance for daily practice to
177-179date. 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
180epidermal growth factor receptor may allow new chemotherapy options.
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
181cells at sites judged to be tumor free by conventional histopathologic assessment, but whether this
169method will improve patient survival is debatable. Moreover, genetically altered cells found in
histologically normal mucosal margins are not necessarily tumor cells. They could signify expanding
86fields of genetically altered preneoplastic cells as well.
More promising is the report that gene expression pro6ling in oral and oropharyngeal SCCs predicts
182whether neck node metastasis is present.
Site-Specific Features
Nasopharynx
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 I oor 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 strati6ed squamous epithelium, intermediate
(transitional) epithelium, and ciliated epithelium within the nasopharynx have been mapped and
183outlined by Ali ; 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 de6ciency between the skull base and the most superior 6bers
of the superior constrictor muscle. The fossa overlies the foramen lacerum. Rosenmüller’s fossa is the
184-186most common site of origin for NPC.
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
187neck. 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
188retropharyngeal space.
Etiology
189The etiology of NPC is a multifactorial interaction of race, genetics, environment, and EBV. Reports189-191of familial clusters suggest a genetic component. Dietary factors have been proposed. Persons in
southeast China who eat nitrosamine-rich salted 6sh (Chinese style) have one of the highest incidences
of NPC, particularly the seafaring Tankas, for whom salted 6sh is a prominent dietary
192,193component. The dietary factors, however, have not explained the male-to-female ratio of 3:1
189,194(which is seen in both endemic and nonendemic areas) or the ubiquitous association with EBV.
The presence of EBV within the epithelial cells and not the lymphoid in6ltrate has been demonstrated
by various methodologies, including karyotyping, electron microscopy, in situ hybridization,
189,195-199polymerase chain reaction, and immunohistochemistry. High titers of immunoglobulin A
antibodies to EBV-speci6c antigens, viral capsid antigen, and early antigen have been reported to
189,194correlate with tumor burden, relapse, and clinical progression.
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
194of 9:1. In some intermediate- and low-risk areas, there is a bimodal age distribution, with peaks in
200,201the second and sixth decades. In the United States among blacks, the tumor has been reported
202to peak at 10 to 19 years of age. In areas of Africa, NPC accounts for approximately 10% to 20% of
196 203childhood malignancies, and in the Sudan, it is the most common pediatric cancer. In the high
196incidence region of Southern China, however, NPC is only rarely seen in children.
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).
194The majority of patients (60%–72%) will present with unilateral or bilateral cervical adenopathy.
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
204,205contains branches of the trigeminal nerve (Fig. 2-9). 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
206involvement. Other presentations or evidence of relapse of tumor may be paraneoplastic syndromes
such as hypertrophic osteoarthropathy syndrome (Pierre Marie syndrome), leukemoid reaction, and
207fever of unknown origin.
Figure 2-9 Schematic horizontal section through the nasopharynx (NP). a, adenoids; CA, carotidartery; 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
208presentation, 5% to 11% of patients have distant metastases. During the course of the disease, 50%
207to 60% of patients develop distant metastases. Autopsy series report the overall metastasis incidence
194,209,210to be 87%, with the common sites being bone, lung, and liver. The natural history of
disease progression is short, with 78% of metastases occurring within 18 months of the 6rst
194symptoms. After detection of systemic metastases, median survival is only approximately 6
211months. 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%
207vs. 84% UADT SCC). Approximately 25% of patients with evidence of metastatic disease will have
207involvement of the bone marrow.
A number of diDerent staging systems for NPC have been developed in diDerent parts of the
185,212-214 213world. The most recent TNM classi6cation by the American Joint Committee on Cancer
214and Union International Contre le Cancer (International Union Against Cancer) 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 modi6cation, which has reduced the number of
215stages without reducing the accuracy of predicting prognosis. Some advocate that the modi6ed
classi6cation of this system shows a more even distribution of patients among stages, with a greater
212power of predicting prognosis, than other classi6cation systems (Table 2-1). Unfortunately, there
has not been one single generally accepted classi6cation for comparison of treatments of NPC between
centers.
Table 2-1 Ho’s Classification and Modified Ho’s ClassificationPathologic Features
14NPC accounts for 3.7% of UADT tumors. All forms of NPC are derived from the surface epithelium of
216,217the nasopharynx, having ultrastructural features such as tono6laments and desmosomes of SCC.
Tumors with glandular differentiation do not form part of the histologic spectrum of NPCs.
The most recent World Health Organization (WHO) classi6cation has retained previous changes and
119added a new category of basaloid SCC (BSCC). When comparing the last two revisions of the WHO
218-220classi6cation with the 6rst one, there are signi6cant alterations, as shown in Table
2119,218-2202. The second edition of the WHO histologic typing of UADT tumors divides NPC into two
219broad histologic types: keratinizing SCCs and nonkeratinizing carcinomas. This dichotomy is based
on the observation that both nonkeratinizing types of NPC are associated with a positive EBV serology,
221marked propensity for cervical lymph node metastasis, and radiosensitivity. Irrespective of their
histologic subtypes, almost 100% of cases of NPC have demonstrable EBV-encoded small RNAs in the
195,208nuclei of their tumor cells, as demonstrated by in situ hybridization. The positive hybridization
signal in keratinizing NPC, however, is less in proportion to that of malignant cells, usually limited to
208basal cells, than in other histologic types of NPC.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
189keratinizing tumors (1) are infrequently seen in high-incidence areas ( (2) represent one fourth to
189one half of NPCs in low-incidence populations, (3) are less often associated with lymph node or
192 189distant metastases, (4) are usually not radiosensitive, (5) occur primarily in adults, and (6) have
189,222been associated with cigarette smoking.
The nonkeratinizing carcinoma group is subclassi6ed into diDerentiated and undiDerentiated
119subtypes. As mentioned earlier, these two subclassi6ed groups have overlapping histologic features
and similar epidemiologic and biological characteristics (frequent lymph node involvement and distant
metastases). NPC, nonkeratinizing, diDerentiated subtype, consists of cells in which squamous
diDerentiation 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
223well-de6ned borders reminiscent of urothelial transitional cell carcinoma, and thus this type of NPC
may mimic cylindrical cell carcinoma, an SCC type occurring in the sinonasal cavities and discussed
under that heading.
UndiDerentiated 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
119stroma. 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, diDerentiated
subtype and undiDerentiated subtype—is not always sharp. In one study, 26% of 363 NPCs examined
217had more than one histologic type. In biopsy specimens with more than one histologic type, the
217tumor is classi6ed by the predominant histologic type. Some have found the demarcation between
219,224the subtypes of nonkeratinizing carcinoma to be the most problematic. A practical approach is
to classify NPC as nonkeratinizing, diDerentiated subtype, if there is evidence of maturation (I attening
or spindling) within the tumor cords. The distinction between the nonkeratinizing carcinoma
diDerentiated subtype and the undiDerentiated 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 diDerential diagnostic problems other than for SCC at other
UADT sites. Nonkeratinizing NPC diDerentiated subtype may resemble, as already mentioned,
cylindrical cell carcinoma of the paranasal sinuses. Further details on the diDerential diagnosis of the
NPC undifferentiated type are mentioned when lymphoepithelioma is discussed.
Treatment and Prognosis
For treatment of NPC, irradiation is usually the 6rst choice. The survival of NPC patients is inI uenced
by age, sex, T and N stage, and histologic type; the nonkeratinizing, undiDerentiated subtype is far
223more radiosensitive than keratinizing SCC. For patients treated with radiotherapy, 5- and 10-year
225survival rates have been reported to be 58% and 47%, respectively. 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
189of locoregionally con6ned NPC. The keratinizing types of NPC have a poor response to irradiation
223and are, therefore, more amenable to surgical resection. Although improvements in radiation
technique have occurred, both local control and distant failure remain problems. Neoadjuvant
189chemotherapy studies have shown NPC to be sensitive to preirradiation chemotherapy.
Several features have prognostic signi6cance in NPC. Those features associated with a favorable
outcome are (1) female gender, (2) age younger than 40 years at onset, and (3) lymphoepithelioma
226histology. 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
226nerve involvement, and (5) distant metastases. Those features not appearing to have an impact on
prognosis are (1) unilateral or bilateral lymph nodes in the upper neck, (2) 6xed nodes, and (3)
226involvement of bone at the skull base. Tumor volume has also been shown to have prognostic
227significance.
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, I oor, 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 strati6ed 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 ori6ce, 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%
22of all those of the UADT. SCC represents approximately 65% of the malignancies in the sinonasal
14,228region. 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
14,229(1% each).
The majority of the tumors in this region present in a late stage (T3 and T4), as the initial presenting
signs are usually nonspeci6c. The nonspeci6c 6ndings were noted to delay diagnoses from 3 to 14
230months in one series. Extent of tumor at the time of diagnosis best correlates with prognosis rather
231than degree of differentiation, with the exception of anaplastic carcinoma.
22Regional metastases from sinonasal neoplasms are uncommon (9%–14% for SCC). Metastasis from
these tumors usually implies soft-tissue extension (antral tumors: cheek and soft palate; ethmoid tumors:
22medial canthal skin and nasopharyngeal extension). The maxillary sinus drains primarily to the
submandibular nodes. The lymphatic drainage of the ethmoid labyrinth is to the superior cervical
232nodes, and some drain directly posteriorly to the retropharyngeal nodes. With recent advances in
188imaging, assessment of retropharyngeal lymph nodes is possible.
233Although site-speci6c systems have been proposed, the only internationally recognized staging
234system is for maxillary and ethmoid tumors. In 1938, Ohngren 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
213 214Committee on Cancer and the Union International Contre le Cancer have adopted a T
classification for the maxillary sinus and ethmoid sinus, as noted in Appendix I.
Pathologic Features
In the histologic classi6cation 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
235was fully described by Ringertz 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.
236In the American literature more than a decade earlier, Quick and Cutler 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 eDects 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, justi6cation for the entity. Ewing’s histologic description was similar to
Ringertz’ description. Ewing, however, attributed the pattern of necrosis to the eDects of irradiation on
the tumor. Schneiderian carcinoma was also a term coined by James Ewing. This term referred to
poorly diDerentiated carcinomas originating from the schneiderian membrane and was never clearly
235,237defined as an entity. The term is infrequently used.
The term transitional carcinoma was used by later investigators to describe malignant transformationin 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
238,239tract. Also articles may be found that equate all three terms: transitional, schneiderian, and
240cylindrical cell carcinomas.
Clinical justi6cation for the separate classi6cation of cylindrical cell carcinoma and transitional cell
239carcinoma was proposed by Friedmann and Osborn in 1982. They observed cylindrical cell
carcinoma to have less tendency to spread via the lymphatics. Others, however, have reported
228,241,242cylindrical cell carcinoma to have a clinical course similar to that of conventional SCC. The
current WHO classi6cation recognizes cylindrical cell carcinoma as a synonym for nonkeratinizing
243carcinoma.
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
244nonkeratinizing SCC of the nasal cavity and paranasal sinuses or consider them to be just a subtype
245of SCC ; 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,
246making stromal invasion not immediately apparent. 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 in6ltration 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-de6ned interface with the adjacent stroma. B, At higher
magni6cation, 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 speci6c 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 con6rming the diagnosis of inverted papilloma, whereas their absence in
247conjunction with cellular atypia should cause concern that the diagnosis might be SCC.
Treatment and PrognosisFor patients with carcinoma of the sinonasal area, the probability of surviving for 5 years is
14approximately 50%. Within the nasal cavity, malignancy of the nasal vestibule and septum has a
228,248,249better prognosis, perhaps because of earlier diagnosis, than in the remainder of the nasal
cavity and paranasal sinuses. For patients with antral and ethmoidal disease, the probability of
229surviving 5 years is 48% and 68%, respectively. The 5-year survival rate for patients with T2, T3,
230and T4 cancers of the antrum is 73%, 41%, and 15%, respectively. There does not appear to be a
230signi6cant correlation of survival rates with the patient’s sex or age at time of presentation.
Although multimodality therapy does not seem to change the 5-year survival rate, it appears to have
230improved the local control of tumor. Factors limiting patient survival time are related to local
recurrence, nodal metastasis, soft-tissue extension to the palate or nasopharynx, proptosis, and orbital
22,250symptoms, as metastases account for approximately 10% of deaths.
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 identi6cation of a primary tumor site may be diQ cult; however, identi6cation of
the primary site has prognostic signi6cance. Malignancy of the hypopharynx/larynx in the United
States represents approximately 34% of all UADT cancers, the larynx being the most common at 28%
14and the hypopharynx representing 6.6% of UADT cancers. Globally, tumors of the larynx are the
15second most common tumor of the respiratory tract and the 11th most common cancer in men.
Hypopharynx
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 de6ned 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,
pearshaped, 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
251the larynx and outer aspect of the cricoid cartilage by a thin submucosal layer of muscle. 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.
Strati6ed 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%–
25215%). 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
252high rate of systemic metastases (20%–40%). There appears to be no relationship between the
degree of diDerentiation and the invasiveness of hypopharyngeal SCC, which means that its clinical
aggressiveness cannot be explained by a higher percentage of poorly diDerentiated cancers at this
253site. Some investigators have estimated the extent of submucosal spread to be anywhere from 1 to
2540.5 cm for the pyriform sinus and postcricoid area, respectively. This characteristic submucosal
spread may not be accurately assessed clinically or by radiographic modalities (computed tomography
255,256or magnetic resonance imaging).
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
255stage III or IV at presentation. Approximately one fourth of these patients will present with a mass in
255,257the neck and 70% will have lymph node disease at presentation. Upper and middle cervical
258nodes of levels II and III are most commonly involved.
Tumors of the pyriform sinus, particularly those involving the medial wall, frequently secondarily
255,259involve the larynx. The posterior hypopharyngeal wall tumors are usually exophytic and also
252frequently large at presentation (80% >5 cm). Tumors of the posterior hypopharyngeal wall
metastasize to upper and middle cervical nodes, and in more than 40% of patients, the retropharyngeal
252nodes are involved.
Carcinomas of the postcricoid area have shown a marked geographic variation in incidence. They are
associated with Plummer-Vinson syndrome and nutritional de6ciencies (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,
252and most local recurrences are due to unrecognized involvement of the paratracheal nodes.
The staging for the hypopharynx is primarily directed for tumors of the pyriform sinus. In the former
TNM classi6cation system, a 4- to 5-cm posterior pharyngeal wall tumor without laryngeal 6xation
260would remain a T1 lesion. The lesion, however, would have a prognosis similar to a T3 lesion. The
213,214most recent American Joint Committee on Cancer/Union International Contre le Cancer 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
255lesions (single-modality therapy). In one large study of tumors of the pyriform sinus, the overall
5255year disease-free survival rate for combined therapy was 65.2%. A decrease in survival rate after 2
10years is primarily due to distant metastasis and to second primary malignancies. The value of
10adjunctive chemotherapy in pyriform sinus malignancy is still unclear.
Larynx
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 6fth branchial arch
261(laryngotracheal anlage). These two regions fuse somewhere at the level of the ventricle.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
261histology. These anatomic barriers and the site of origin inI uence the growth and spread of
262laryngeal carcinoma.
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
252have a worse prognosis than infrahyoid tumors and behave similarly to hypopharyngeal tumors. 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 6brous tissue that contains certain lymphatics and blood vessels and
252attaches to the thyroid cartilage devoid of the tumor-resistant perichondrium. Tumors of the
anterior commissure may grow upward to the epiglottis or may penetrate the thyroid cartilage,
particularly if the thyroid cartilage has ossi6ed. 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 strati6ed squamous epithelium. The strati6ed 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 strati6ed squamous epithelium. The interface between the ciliated columnar epitheliumof 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
263have enlarged basaloid features; however, mitotic 6gures are con6ned to the basal cell layer. 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
264the limitations of the 6broelastic membranes and skeletal structures for an extended period of time.
This intralaryngeal compartmentalization has been the anatomic basis for various surgical
261procedures. The 6rst 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 6broelastic membranes that are subjacent to ventricular
265mucosa and in continuity with the elastic conus and quadrangular membrane, 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
preepiglottic 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 larynxand 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 (6bers 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
266approximately 30% to 35% of laryngeal tumors. 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
266laryngeal carcinomas. 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
267vocal cord) have been reported as high as 90%. The degree of anterior commissure involvement
appears to have prognostic signi6cance, with patients with a progressively heavier involvement of the
268anterior commissure subsite having a progressively worse outcome. The incidence of lymph node
252metastasis in T1 through T4 tumors is 1.9%, 16.7%, 25%, and 65%, respectively. 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.
269The concept of a transglottic lesion was 6rst presented in 1961 by McGavran and colleagues. 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
269aggressive clinical course with a high incidence of lymph node metastasis (52%). Transglottic
carcinomas are treated primarily by laryngectomy and lymph node dissections. They represent less than
2665% of all cases of laryngeal carcinoma. 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 de6ned anatomic subsites involved
and refrain from the term transglottic.
266The infraglottic or subglottic tumors are also rare, representing less than 5% of all the cases.
Tumors included in this category are tumors that involve the region between the lower edge of the true
270vocal cord (where the squamous epithelium ends) and the 6rst tracheal cartilage or extending 1 cm
266below the edge of the true cord. Other investigators have de6ned the subglottis as extending from
271the lower boundary of the glottis to the lower margin of the cricoid cartilage. 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 lymphnodes.
213The staging system for laryngeal carcinomas is mentioned in Appendix I. Several suggestions for
272,273alteration of the TNM classi6cation system have been proposed. 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
272separate group of subglottic tumors. 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
272millimeters of greatest surface extent only. 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
272fold mobility or 6xation should be classi6ed as T3 or T4. Finally, the N status should include
272number, size, site of metastasis, and presence of extracapsular spread. 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 inI ammation 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
273locus to the TNM classification had an impact on prognostic estimations.
Treatment and Prognosis
In addition to the inverse relationship of primary tumor size with prognosis, lymph node metastasis is
274another extremely important prognostic factor in laryngeal cancer. Both cervical metastasis and
disease-free survival rates have been shown to be related to depth of invasion; for tumors with a
275thickness of 3.25 mm or greater, an elective neck dissection is recommended.
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
276three or more positive lymph nodes (P 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
276patients with involvement of lower jugular and supraclavicular lymph nodes.
Extracapsular spread of carcinoma has signi6cant impact on survival, a factor that is still ignored in
213the TNM staging, which does not include this issue as a separate item worthy of being recorded. 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
274this phenomenon, it was only 17%. The presence of extracapsular spread, no matter the size of the
lymph node, should be included in the surgical pathology report. The prognostic signi6cance of
103micrometastases is still being assessed.
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 diQ culty 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 diQ cult
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 6gures. Grossly, the growths maybe I at 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
6nding in radiation-induced atypia. The tinctorial quality of the cytoplasm may be gray-blue on
hematoxylin-eosin–stained sections. Immunohistochemistry and I ow cytometry 6ndings are
nonspeci6c. When the examiner is trying to make the distinction between recurrent tumor and tissue
reaction, 6nding low-power granulation tissue architecture and similar degrees of cytologic atypia in
277both the endothelial cells and stroma aid in establishing the benign nature of the lesion.
Early cancer of the larynx is a term that has been used to describe malignant lesions limited to the
278mucosa similar to a variety of other sites, including the stomach, esophagus, cervix, and so on. The
early cancers of the larynx are usually located in the glottis. Unfortunately, the term has been used by
clinicians and pathologists to convey diDerent ideas. The clinical de6nition of early glottic cancer
implies a Tcis or T1 lesion, with full chordal motility and no risk of neck metastasis. The pathologic
de6nition describes a microscopically invasive carcinoma that transgresses the basement membrane but
279is con6ned to the lamina propria and has metastatic potential. 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 super6cial extending carcinoma (SEC;
280con6ned to the lamina propria) represent early glottic cancer. Biologically, invasion is present, as is
278the potential for metastasis.
Trachea
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 pseudostrati6ed 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
281all malignancies within the respiratory tract and 0.04% of all malignant neoplasms. Carcinoma is
the most common malignant tumor occurring in the trachea and accounts for approximately 80% to
282,28390% of all malignant tracheal neoplasms. 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
284most frequent site within 4 cm of the carina, while others have reported that 40% to 45% of tumors
285are seen in the upper third of the trachea and only 30% to 35% in the lower third. There are also
286reports of carcinoma developing in scars after tracheotomy. The tumor growth is often sessile and
obstructive in nature, producing asymmetric narrowing within the tracheal lumen. Approximately 10%
283of cases are shown to have a circumferential growth pattern.
Two histomorphologies, adenoid cystic carcinoma and SCC, constitute 75% to 85% of the
35,283,287carcinomas. In the North American surgical literature, adenoid cystic carcinoma
288predominates, whereas in radiotherapy series, SCC is more common.
Treatment and Prognosis
A review of the literature containing 321 cases found a 5-year survival rate of approximately 25% for
288SCC and 80% for adenoid cystic carcinomas. Approximately 17% to 40% of patients at the time of
283surgery for tracheal malignancies have tumor extension into the mediastinum. The status of positive
287surgical margins and positive lymph nodes has an adverse eDect on SCC. In the Grillo and287Mathiesen series, 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
287most eDective therapy. 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 inI uence, with the 5-year survival rate decreasing from 12% for
289patients receiving doses greater than 56 Gy to 5% for lower doses. Currently, no TNM classi6cation
exists for the trachea.
Lip
Clinical Features
290SCC of the lip represents 10% to 45% of UADT SCCs in various series. 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
291and the point of contact between the lips. Sun exposure appears to represent the most signi6cant
292,293etiologic factor. 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
214structures such as facial skin, mandibular bone, and tongue.
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
293lymph node involvement. The incidence of lymph node metastasis varied from 5% for T1 and T2
290tumors to 67% for T3 and T4 tumors; submental or submandibular nodes are the ones involved.
The incidence of metastasis has also been related to tumor thickness, invasion pattern, and perineural
294invasion. Perineural invasion may lead to tumor spread along the mental nerve into the mandible.
295This may become manifest by sensory disturbances and widening of the mandibular canal.
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 I oor of the mouth, the retromolar trigone, the tongue, the cheek, and
the hard palate. Because site-speci6c characteristics and clinicopathologic features for each site vary,
they are discussed separately for the various locations.
Tongue
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
214both parts. 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
290located at the mobile tongue. SCC is most often located at the lateral border, from which it may
extend into the adjacent I oor 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:
29220% to 40% for T1 tumors, 40% for T2 tumors, and 75% for T3 tumors. However, metastatic rates
292for the base of the tongue that belongs to the oropharynx are even higher: 70% for T1 cases. The
292lymph nodes mostly involved are those that lie in the jugulodigastric area.
Pathologic Features
When examining surgical specimens from the mobile tongue with SCC, one should realize that thetumor may penetrate deeply into the tongue muscle, often by skipping uninvolved areas. Moreover, the
possibility of perineural spread requires identi6cation 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
120myoblastoma with its pseudoepitheliomatous hyperplasia of the covering epithelium. 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
214muscles. The inI uence 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%
165 165for the latter group). Patients with T3N0 cancer have a 50% rate of death due to cancer. The
165T1N1 group have a 3-year survival rate of 80%, and the T2N1 group have a rate of 44%. The T3N1
rate for 3-year tumor-free survival is 13%. These findings indicate that increasing size of the tumor by T
165stage and the presence of nodal disease both signi6cantly decrease survival rates. In more general
terms, in other series, the 5-year survival rate ranges from 70% to 15% depending on the size of the
8,292tumor and the presence of nodal metastasis.
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
8,292chosen for treatment of the primary tumor. Tumor thickness in particular has a high predictive
296,297value for occult cervical metastasis and poor outcome, but its proper use in surgical pathology
has been hampered by the lack of uniform or comparable study groups, diversity in measurement
298techniques, and cutoff values that vary, to date, from 3 to 10 mm.
Floor of the Mouth
The I oor 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 I oor of the mouth represents 9% of all UADT
290SCCs and 15% to 20% of oral cavity cancers, surpassed only by cancers of the lip and tongue.
Anteriorly in the I oor of the mouth, ducts of the bilaterally located submandibular salivary glands
open into the oral cavity. SCC at this site may obstruct salivary I ow, 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
299assessing lymph nodes in patients with I oor-of-the-mouth cancer. Moreover, SCC may extend along
300these ducts.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 ori6ce. B, Tumor obstructing
the duct at a more proximal level.
SCC of the I oor 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 I oor 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,
290respectively. The submandibular lymph nodes represent the 6rst echelon involved. The 5-year
survival rate is also related to tumor size and drops from 90% to zero across the various tumor
8,290stages. One recent study mentions that in cancer of the I oor 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 signi6cant but the relationship between N
165status and survival not being significant.
Treatment of SCC of the I oor 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 6xed 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 I oor-of-the-mouth SCC without
290clinically manifested neck node disease is controversial.
At the I oor 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.
Cheek
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
292maxillary and mandibular alveolar mucosa. SCC at this site accounts for 8% of oral cavity cancers.
The tumor may spread diDusely 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 signi6cant 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
292upper cervical area. It should, however, be emphasized that patients with SCC of the cheek have a
301worse stage-for-stage survival rate than do patients with other oral cavity sites. Low stage and
301negative margins are not adequate predictors of local control. 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
292is required.
Alveolar Ridge
The mucosa covering the alveolar ridge of the upper and lower jaw is 6rmly 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 I oor 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
252lip. Tumors at this site may be ulcerating or exophytic. As they occur at sites naturally 6rmly
connected to bone, tumors at this location are always 6xed 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
302expansive and the latter as in6ltrative (Fig. 2-17). There are some indications that initially, whenY
only the alveolar ridge is involved, SCC exhibits an expansive growth pattern, whereas the in6ltrative
303pattern is associated with growth of the tumor into the basal bone, which is less easily resorbed. 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 6ndings 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 in6ltrative 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 diDuse 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
inI ammatory periodontal disease, SCC of the alveolar ridge may be confused with this a iction,
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 6rst 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.
221). 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
292upper jugular nodes. 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
304poorly diDerentiated, or display radiographic or histologic evidence of mandibular invasion. The
58year survival rate varies from 70% to 30% depending on the T stage. 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 super6cial erosion of thecortical 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
292with some type of neck-node dissection. 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
suQ cient mandibular bone is uninvolved to enable the surgeon to remain at a safe distance from the
305tumor. Evidence-based guidelines on what constitutes suQ cient mandibular bone, however, are not
available. In cases of atrophic edentulous jaws, this will almost always be impossible. If the tumor
292,305involves dentate jaw areas, a rim mandibulectomy may be performed. 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
302quite reliable in indicating the real extent of bone loss due to tumor. However, in cases of more
diDuse 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
306-308required. 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 diDuse tumor spread
within the mandible make any preoperative assessment of bone involvement by tumor unreliable; in
309these instances, bone-preserving surgery, therefore, is not possible.
Although the majority of SCCs have been reported to invade the jaw at the occlusal ridge, at least in
309the mandibles not previously irradiated, it has also been observed that the route of entry by whichthe 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
302plates may occur (see Fig. 2-24) ; this 6nding implies that not only horizontal rim mandibulectomies
but also sagittal or oblique osteotomy planes may be chosen to perform bone-preserving
305,310surgery. The ultimate decision on how to handle an SCC approaching or involving the mandible
311should be based on a combination of imaging techniques and good clinical judgment.
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
312surgical margins.
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 classi6ed 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 diDer 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
313in 64% of clinically N0 necks for SCC at this site.
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
292Treatment will usually be surgical, followed by irradiation for more extensive tumors. It should also
be noted that SCC at the retromolar trigone may mimic ameloblastoma by pronounced palisading of thecarcinoma 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
horseshoeshaped upper alveolar ridge mucosa, from which it cannot be demarcated because both consist of
mucosa 6rmly 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 6gure
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,
314Venezuela, Colombia, Panama, and some islands of the South Caribbean. In an area in India where
the habit of smoking cigars with the lighted end inside the mouth is prevalent, palatal cancer accounts
315for 45% of all oral cancers. Reverse smoking is done to keep the ashes from falling in food or on
314clothes and to extend the burning time of the cigar or cigarette. Incidence data include cases from
the soft and hard palates, one fourth of SCCs being located in the hard palate and the remaining ones
290occurring in the soft palate or uvula.
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
8required except in cases with more extensive tumors.
Oropharynx
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
292of occurrence.
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 classi6ed 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 ahigh frequency of neck node metastasis, for as many as 70% with T1 tumors, elective treatment of the
292neck is indicated. The metastases are mostly located in upper and middle cervical nodes.
252Contralateral or bilateral nodal metastases occur in 20% to 30% of cases. The prognosis for SCC
occurring at the base of the tongue varies from a 65% to 30% 5-year survival rate, depending on tumor
316stage.
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 diDerent 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 super6cially, 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
317histopathologically is necrotizing sialometaplasia. 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 diDerent 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
213,214space, a site also at risk of SCC of the retromolar area.
The diDerent behaviors of tumors of the tonsillar area proper and of the faucial pillars and soft palate
290are also demonstrated by a lower frequency of metastasis shown by tumors at the latter site. The
87lymph nodes most frequently involved are the cervical ones. Sometimes these metastases exhibit
cystic degeneration (Fig. 2-26), and, in cases of a yet undiscovered oropharyngeal primary SCC, these
318,319metastases may be mistaken for branchiogenic carcinoma. 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
320in faucial or lingual tonsillar crypt epithelium. None of these cases was a branchiogenic carcinoma.
Figure 2-26 A, Photomicrograph showing a cystic tumor in a neck node. B, Higher magni6cationshowing 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
321with surgical treatment of the neck is the preferred method for treating these patients. The prognosis
for SCC in the tonsillar area and the palate varies from an approximately 90% to a 20% 5-year survival
292rate, depending on tumor stage.
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
252at this site are T3 or T4. Tumors may extend cranially into the nasopharynx, posteriorly into the
prevertebral fascia, and caudally into the hypopharynx and pyriform sinuses. Neck node metastasis is
252present in 50% to 60% of cases, sometimes bilaterally in cases of tumor at or near the midline.
Treatment usually is by irradiation because surgery is technically diQ cult in this area and includes the
292neck nodes. Local control varies from 71% to 37%, depending on tumor stage.

Squamous Cell Carcinoma: Unusual Variants
Verrucous Carcinoma
Clinical Features
Verrucous carcinoma (VC) is de ned as a warty variant of SCC characterized by a
predominantly exophytic overgrowth of well-di erentiated keratinizing epithelium with
119 322locally aggressive pushing margins. Since its rst description by Ackerman in
1948, this tumor has been the subject of a continuous debate concerning diagnostic
323-327features and mode of treatment.
Its occurrence originally was related to the use of chewing tobacco or snu , although
this was never substantiated by controlled epidemiologic investigations. Moreover, HPV
328 329appears to be of etiologic significance, although not supported universally.
VC predominantly occurs in older people, the majority of cases being observed in
330individuals in their sixth decade or later, and has a higher incidence in males. The
sites in the head and neck area at which VC does occur are the oral cavity (56%) and the
326larynx (35%). Within the oral cavity, buccal mucosa and gingiva are the most
322frequently involved sites. VC is a rare oral carcinoma with an annual incidence rate of
331one to three cases for every million persons. When occurring in the larynx, the second
most frequently involved head and neck site, the vocal cords are the preferred
324location. 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
softtissue mass lacking induration and exhibiting a red, white, or red and white surface,
324depending on the amount of surface keratinization. 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
325malignancy. 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. 2-28A). The histology of this border zone has been described in
323detail by Jacobson and Shear, 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 in: ammatory epithelial hyperplasia (see Fig. 2-28B). The stroma adjacent to the
tumor almost always exhibits a chronic lymphoplasmacytic in ltrate. 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
323,325,327,332areas of ordinary SCC of varying grade. For these lesions, which
accounted for 20% in a series of 104 VC cases, the designation hybrid tumor has been
327,333used. 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
327versus 15 of 84 (17.9%) for VC in its strictest sense. The quantity of SCC within a VC
required for a lesion to qualify as a hybrid tumor has not been de ned. In line with the
axiom that the course of a tumor is determined by its less di erentiated component, a
wise approach is to diagnose all VCs with areas of SCC as a hybrid tumor and to treat
333them as SCC.
Figure 2-28 Photomicrograph showing the junction of verrucous carcinoma with normal
epithelium. The di erence 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 in: ammatory epithelial
119,325,330hyperplasia, squamous papilloma, conventional SCC, and PSCC. Lack of
cellular atypia serves to rule out conventional SCC and PSCC, the latter lesion to be
discussed more extensively under that speci c heading (see “Papillary Squamous Cell
334Carcinoma”). Distinguishing VC from squamous papilloma and reactive in: ammatory


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 nding
335may be helpful in di erentiating VC from benign lesions. Recording nuclear size with
image analysis has been suggested to be helpful in di erentiating VC from squamous
papilloma, as the cells in VC are, in general, larger (>300 μ υm) than those in papillomas
336(<250>
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 in: ammatory epithelial
hyperplasia and VC, as both are composed of thickened epithelium lacking cellular atypia
and a stromal component densely in ltrated by lymphocytes and plasma cells. It may be
helpful to realize that in reactive in: ammatory hyperplasia, the rete pegs in most
instances form an anastomosing network and exhibit slender extensions, whereas in VC,
330the rete pegs are broader and blunt. Moreover, suprabasal mitoses typically seen in
VC are absent in in: ammatory 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
332,337-339 339,340verrucous hyperplasia and proliferative verrucous leukoplakia.
337Verrucous hyperplasia was described rst by Shear and Pindborg in 1980 as a lesion
resembling VC both clinically and histologically, but di erent 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 diF cult 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
325,330,332,338,339hyperplasia and VC are in fact one and the same lesion. 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
332proliferations did so in a larger proportion of cases (53%). These site-related
di erences 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 di erent texture of the supporting connective tissue
and thus site dependent.
Alternatively, verrucous hyperplasia could be a precursor lesion that may progress to
341either VC or conventional SCC. Irrespective of whether one considers verrucous
hyperplasia to be an entity in its own right, a super cially 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 rst described by Hansen and
340colleagues. The lesion begins as a simple hyperkeratosis that in time becomes
exophytic and wartlike, and, nally, 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 : at thickened keratoses that have changed in
339-343clinical appearance by becoming more exophytic.
Treatment and Prognosis
Most authors mention surgery as the most e ective mode of treatment for
325,344,345VC. 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 nal 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
341 346of treatment. Ferlito and colleagues 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 e ective 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
347resected with preservation of laryngeal function. For oral cavity cases, surgery
326remains the preferred mode of treatment.
As the VC does not give origin to neck node metastasis, neck dissection does not form
119,325,327part of the treatment of VC. 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
327shown to have a higher tendency to recur locally.
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
348-350behaving SCC, the so-called anaplastic transformation. 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
325,327,330,351employed.
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
322-324,327,332,338either synchronously or metachronously. Because of the frequent
association of VC with metachronous and synchronous UADT SCC that may be as high as
327,33237%, 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
352pleomorphic spindle-shaped cells. Since its original description, several theories have
353,354been forwarded regarding the signi cance of the pleomorphic cells. 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 di erentiation toward cells with a mesenchymal
phenotype. Therefore, they have to be considered a variant of SCC in which the
pleomorphic component originates through dedi erentiation of the SCC
353-360component. Molecular pathology has recently provided convincing proof of an
360evolution of the sarcomatoid component from the conventional one. Metastasis is to
the cervical lymph nodes; the deposits may exhibit conventional SCC, SpCC, or both
355,357,361,362together.
Clinical Features
355,362An SpCC typically occurs in the oral cavity and the larynx ; less frequently, it may
arise in the sinonasal area and pharynx. Concerning age and sex, no di erences 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 di erent from conventional
359SCC (Fig. 2-29).

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
identi cation 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 di erentiation (both benign and
355,359,362,363malignant) sometimes are observed. There may be sharp borders
between SCC areas and the spindle cell component, but a gradual transition, with SCC
cells “dropping o ” from the epithelial nests or overlying squamous epithelium into the
352,359pleomorphic spindle cell areas, frequently may also be observed.
Ultrastructural examination may reveal epithelial features such as desmosomes or
356,359tono laments in the spindle cells. 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
359are keratin (AE1/AE3), K1, K18, and epithelial membrane antigen. Moreover,
double356labeling has indicated keratin and vimentin in individual spindle cells, thereby
illustrating the versatility of the intermediate lament phenotype. Recently, p63 has been
364reported as a useful marker for SpCC.
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 laments, especially myogenic markers, positivity for this
359marker does not rule out a diagnosis of SpCC. 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 xation 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 di erentiation morphologically as well
357as immunohistochemically shown by SCC cells.
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
365histomorphology. 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 identi es
them as part of a stromal reaction. Therefore, in these cases, a diagnosis of SpCC does not
apply. Moreover, the observation that stromal broblasts 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 broblastic and bizarre endothelial
stromal cells. The atypia in brous 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 diF cult 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
353spindle cell sarcomas and nodular fasciitis.
Nodular fasciitis may exhibit mitotic gures, 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 brosarcoma and leiomyosarcoma may be more diF cult. However, sarcomas in
the head and neck area located at mucosal surfaces are extremely rare, and, when they
do occur, an intervening brous 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 o ”or drop
o from the overlying squamous epithelium. This latter feature may be helpful in making
366the appropriate diagnosis. However, if SpCC occurs intraosseously, its distinction from
sarcomas with a spindle cell appearance may be extremely diF cult 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 di erential diagnosis of SpCC also includes the
recently recognized benign proliferative lesion that has been labeled in: ammatory
myo broblastic 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 gures lying in a myxoid or brous stroma; its
di erentiation from SpCC may prove to be extremely diF cult. Key features assisting in
di erentiating SpCC from the in: ammatory myo broblastic tumor are the absence of
dysplastic or carcinomatous epithelial components, lack of dropping o from the
367overlying squamous epithelium, and no atypical mitotic figures.
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 con rm 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, in: ammatory myo broblastic tumor of the
larynx, melanoma, and spindle cell sarcoma that may be helpful in the di erential
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
353mucosal surfaces at the UADT to be an SpCC.
This discussion on SpCC and its di erential diagnosis is nalized 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 gures may develop that should not be misinterpreted
277as tumor recurrences displaying the histomorphology of SpCC ; this was discussed
previously in the section on laryngeal SCC. Combined chemoradiation therapy frequently
shows similar ndings 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.
368,369An SpCC should not be confused with the so-called teratocarcinosarcoma. 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 di erentiated
epithelia, and rhabdomyosarcomatous, chondrosarcomatous, and neuroepithelial
di erentiation (Fig. 2-35). Although this tumor is considered by some authors to be part
353of the spectrum exhibited by SpCC, its far more complex histology and di erent
predilection site make its classi cation 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
370Treatment of SpCC is the same as for conventional SCC. Batsakis and colleagues
reviewed the lethality of SpCC in the head and neck and correlated their ndings 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.
370Batsakis and colleagues 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
371those of irradiated patients with disease of similar volume with the more typical SCC.
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 rst
372characterized in the UADT in 1986 by Wain and colleagues. Although identical
373,374basaloid tumors have been described in a variety of body sites, including the
375,376 377trachea, esophagus, lung, 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
372propensity for regional lymph nodal (80%) and systemic (60%) metastases.
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
372,376,378-394larynx. 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
391stage (stage III–IV).
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
follow391up). The justi cation 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 signi cantly contribute to this feature)
and (2) prevention of the diagnostic confusion of this variant with another entity having
a di erent prognosis (e.g., adenoid cystic carcinoma) or requiring a di erent 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
391consumed alcohol or both. There has also been one case of BSCC arising in a patient
387after radiotherapy for a previous neoplasm. Second primary tumors have also been
388,392,394reported in patients with BSCC.
The macroscopic descriptions of BSCC have been those of an exophytic
382,388,389 383,387mass as well as a : at lesion with central ulceration and marginal
389 391submucosal induration. The size of the lesions has ranged from 1 to 6 cm. A
tendency for prominent deep and lateral submucosal soft-tissue in ltration has been
388,395noted.
Pathologic Features
As the name implies, this tumor is biphasic with distinct histologic ndings. Perhaps the
most salient feature of this tumor is the intimate and often abrupt association of the
basaloid component with the squamous component (Fig. 2-36A and B). The basaloid
component of the tumor is de ned by four features: (1) solid growth of cells in a lobular
con guration, 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–Schi or Alcian blue
(see Fig. 2-36C and D). Ancillary features include small and large foci of necrosis within
central areas of tumor lobules (comedonecrosis; see Fig. 2-36E) and hyalinization of the
stroma, often in association with microcyst formation (Fig. 2-37; and see Fig. 2-36E).
372Wain and colleagues required the associated squamous component to be among the
following: invasive SCC that usually has a super cial location (usually well or moderately
di erentiated), overlying surface epithelium with dysplasia (usually severe dysplasia orcarcinoma in situ; Fig. 2-38), or focal squamous di erentiation 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













66,368,377of the basaloid cells ; individual cell necrosis; large vesicular nuclei; nucleoli;
378,396 376prominent mitotic activity, with some containing abnormal mitotic gures ;
383and a focal spindle cell component.
376,381,383,391Perineural invasion has not been a consistent nding. Moreover,
376lymphovascular in ltration has been observed in four of nine cases (44.4%). 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
383,391involvement.
Ultrastructurally, the basaloid cells were described as polygonal and the chromatin was
nely dispersed within pale nuclei. The cytoplasm was found to contain desmosomes,
rare tono laments, and free ribosomes. On electron microscopy of the cystlike spaces
identi ed on light microscopy, they were found to be lined with basement membrane
material and lled with loose stellate granules or replicated basal lamina arranged in
parallel stacks or globular masses. Squamous components contained well-formed
desmosomes and clumps of tono laments. None of the following were observed:
neurosecretory granules, myo laments with dense bodies, secretory granules, cytoplasmic
372organization, or cellular polarity.
Immunohistochemical staining features were investigated in 40 cases of BSCC reported
378by Banks and colleagues. Their ndings were as follows: 100% keratin staining with
34 β ε τ αE12 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 di usely but weakly with neuron-speci c
enolase. None of the tumors were positive for chromogranin, synaptophysin,
musclespecific 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 speci cally have shown weak to absent
376,378staining. The carcinoembryonic antigen has been found to be limited primarily to
the squamous component of the tumor, but rare ductal cell staining has been
376 376,378,385observed. Staining for actin has also had variable reports of positivity.
395Barnes and colleagues summarized their immunohistochemical ndings 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,
musclespecific 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
376BSCC. However, in another study, the better survival rate for aneuploid BSCC tumors
could not be con rmed: patients with aneuploid and diploid tumors both had
391unfavorable outcomes manifested by local recurrence or distant metastasis or both.


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 undi erentiated carcinoma,
396nonkeratinizing SCC, adenoid cystic carcinoma, or neuroendocrine carcinoma,
whereas the possibility of a basal cell adenocarcinoma also should be taken into
397account.
Di erentiating BSCC from sinonasal undi erentiated carcinoma may be a diagnostic
challenge. It is a very anaplastic neoplasm that rarely shows evidence of squamous
398differentiation. Sinonasal undi erentiated carcinoma is composed of cells with a high
nucleus-to-cytoplasm ratio that grows in con: uent 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
399many tumor cells (hyalinosis).
Nonkeratinizing SCC may enter into the di erential 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
di erential 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 di erentiation, prominent necrosis, and
400frequent mitotic gures, all features not typically seen in adenoid cystic carcinoma.
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 di erent 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-speci c actin has been found to be positive in approximately 60% of the cases of
376adenoid cystic carcinoma that have a cribriform pattern. In one series, no BSCC with
378a cribriform pattern reacted with muscle-speci c actin. Recent studies have found
p63 to be a useful marker for distinguishing adenoid cystic carcinoma from BSCC. p63
will di usely 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
401,402BSCC.
Another consideration in the di erential diagnosis is small cell (neuroendocrine)
carcinoma (SCEC), which is composed, on histologic examination, of sheets of small
403hyperchromatic cells showing nuclear molding and may occur in the same sites. This
tumor lacks stromal mucin or pseudoglandular cribriform patterns and rarely is
404connected to the surface mucosa. Immunohistochemistry may be useful in
di erentiating BSCC from SCEC. Neuron-speci c enolase may be positive in both tumors;
372however, unlike SCEC, BSCC lacks positivity for chromogranin and synaptophysin.
378,404Positivity for chromogranin or synaptophysin would exclude BSCC. The keratin
staining patterns are di erent in these two neoplasms as well; SCEC frequently shows a
404globular-appearing perinuclear staining pattern that is not observed in BSCC. It has
also been reported that BSCC reacts with the high-molecular-weight cytokeratin antibody
40534E12, which failed to show any reactivity with SCEC. Ultrastructurally, BSCC lacks
neuroendocrine di erentiation. SCEC, even poorly di erentiated, 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
397aggressiveness, which is exemplified by a blander histology.
Metastatic basal cell carcinoma of the skin, although uncommon, may enter the
406-408di erential diagnosis when the initial presentation is a lymph node metastasis.
The frequency of metastatic basal cell carcinoma in large series ranges from 0.0028% to
407,4080.55%. The size of the basal cell carcinoma has also been correlated with
408metastasis (3 cm in diameter had a 1.9% incidence of metastasis). In most cases of
metastatic basal cell carcinoma, the primary tumor is present when the metastasis is
406 406detected or the patient has a history of frequent recurrence. Clinical detection of a
skin lesion and biopsy con rmation 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
378the perceived advanced stage at presentation. Banks and colleagues, thought that,
stage for stage, the BSCC treatment and behavior were similar to those of conventional
387SCC. Luna and colleagues, 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 con rmation, they
found the biological behavior of BSCC similar to that of conventional SCC. Another report


383 381had come to a similar conclusion. In the series by Coppola and colleagues, 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 con: icts 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,
409systemic adjunctive chemotherapy should be investigated. Because of these clinical
and histologic features, BSCC should be recognized as a distinct variant of SCC.
Adenoid Squamous Cell Carcinoma
410In 1947, Lever rst 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
di erentiation. Several years later, Lever modi ed his concept, and others concurred that
411,412the gland-like spaces were the result of acantholysis of solid nests of SCC. Muller
412and colleagues suggested the name adenoid squamous cell carcinoma (ASCC) to avoid
confusion with adenoacanthoma of the endometrium. Other synonyms include
413-417pseudoglandular SCC, acantholytic SCC, and SCC with gland-like features.
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,
413predominantly in elderly men. 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
413with metastasis, both lymph node and visceral. 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
417would portend an unfavorable course.
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
418occurrence, accounting for 17 of 26 cases. The mean age at occurrence was 54.5
years (range, 41–75 years). Tumor size, when reported, was 2 cm or smaller. One patient
418 419with a lip lesion was immunocompromised. The largest single series of oral ASCC
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 rst reported

420intraoral case was in 1977 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
421colleagues 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 : oor of the
418 422mouth and the nasopharynx. Both patients were male and aged 42 and 58 years,
respectively, with no evidence of disease. Others have observed cases in the supraglottic
423 424larynx, the hypopharynx, and the sinonasal tract.
Pathologic Features
ASCC is included in the WHO classi cation of upper respiratory tract tumors under the
designation acantholytic SCC and de ned as an SCC in which pseudoglandular spaces or
119lumina result from acantholysis of tumor cells. On gross examination, the majority of
these lesions appear as ulcerations, hyperkeratotic surfaces, or exophytic, wart-like lesions
417and range in size from 0.4 to 12 cm.
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;
414Figs. 2-39 and 2-40). Prominent keratin pearl formation is usually present (Fig. 2-41).
In some instances, this acantholysis is suF cient to mimic a neoplastic angiomatous
425,426 365proliferation, similar to the one observed in SpCC. 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
412,417surface epithelium. 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.
427 413Speci c cytologic features, histochemical staining characteristics, and
422ultrastructure 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
417,425VIII–related antigen. The ultrastructural ndings have supported the squamous
origin with a few hemidesmosomes and attached tono laments and no glandular features
422(e.g., intracytoplasmic microvilli, secretory granules).
Differential Diagnosis




The di erential 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
424glandular component (adenocarcinoma) separates this lesion from ASC.
Treatment and Prognosis
The clinical behavior described in the WHO classi cation 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
422,424,428until now are too small to support this assumption. Treatment of these lesions
428is similar to treatment of conventional SCC.
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
429-431variety of body sites, including the uterine cervix, lung, and pancreas. ASC in the
432upper respiratory tract was de ned in 1968 by Gerughty and colleagues 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
432-442English-language literature. More than 50 unreported cases of oral ASC are
present in the les of the Armed Forces Institute of Pathology (Dr. Gary Ellis, personal
communication, 1996). Eighty- ve percent of Armed Forces Institute of Pathology cases
443arose from the tongue, the : oor of the mouth, and the tonsillar-palatine region. The
most common site of the cases in the literature is the larynx (in decreasing frequency:
433supraglottic, transglottic, glottic region) of which there are 20 reported cases. Other
432,434,435 432reported sites include the nose and paranasal sinuses, tongue, maxillary
436 432 437 437 437alveolus, : oor of the mouth, upper lip, nasopharynx, oropharynx, and
437-441hypopharynx.
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-tofemale ratio is 19:1, and the average patient age is 60.8 years; 25% had cervical lymph
433node metastasis, and the 5-year survival rate was 22% (two of nine patients).
The etiology has not been de ned. Unfortunately, in many reports, tumor staging was
not included and, therefore, direct comparisons by site, stage, and treatment are diF cult.
Evidence of the aggressive biological nature of ASC is best supported with the reported
432,433occurrence of lymph node metastasis (25%–80%), distant metastatic sites


433,440including the lung, liver, bone marrow, kidney, adrenal gland, and colon, and
432 433the 5-year survival rates of 25% and 22%. Owing to the lack of staging
information in the reported cases, however, no comparison with 5-year survival rates of
SCC can be made.
432In the series by Gerughty and colleagues (three tongue, two : oor 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
438carcinoma/ASC involving the larynx and hypopharynx were evaluated. 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 ndings described for ASC have been pulmonary lymphangitic
440 442carcinomatosis and possibly a radiation-induced lesion. ASC may be included in
443 430some classi cations of salivary gland neoplasms or as a variant of SCC and
444historically but inaccurately under mucoepidermoid carcinoma.
Pathologic Features
The gross description of these lesions has been of an erythroplakic, ulcerated area to a
432,441polypoid broad-based mass. Tumor size has ranged from 0.2 to 5 cm. The
432histologic criteria de ned by Gerughty and colleagues 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 di erentiation, (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–Schi stain retention after diastase digestion and Mayer’s mucicarmine. The tumor
cells were of three basic types: basaloid, squamous, and undi erentiated. 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.
432Since the description of Gerughty and colleagues, some modi cations have been
made. First, the strict requirement for intracytoplasmic mucin has not been a requisite for
443some examiners to make this diagnosis. This is re: ected in the WHO classi cation
119description of ASC. 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 super cial SCC. The deeply invasive submucosal aspect of the
445tumors frequently displays transformation from SCC to adenocarcinoma. Reports in
the literature have suggested this arrangement by reporting the initial biopsy containing
433,440SCC and subsequent resection showing ASC.
432The histogenesis of ASC is debatable. Gerughty and colleagues 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
444source. 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
432a glandular origin.
Immunocytochemistry studies have shown positive staining for the
high-molecularweight cytokeratins (LKL1) in both the squamous and glandular components. All
glandular components stained positive for carcinoembryonic antigen and
low-molecular437weight cytokeratins (19KD) while the squamous component was negative for both.
Differential Diagnosis
The di erential diagnosis of ASC includes ASCC, mucoepidermoid carcinoma,
nonkeratinizing SCC, and necrotizing sialometaplasia.
The rst entity in the di erential 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 diF cult. 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
437adenocarcinoma.
The third di erential diagnosis, nonkeratinizing SCC, may have rare mucin-containing
pseudoglandular structures; however, no areas of de nitive adenocarcinoma or
437keratinization typically are present. This lesion is more extensively discussed in the
section on sinonasal carcinoma.
The fourth di erential 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 con guration of the lesion is an
446important distinguishing characteristic. Necrotizing sialometaplasia is discussed in
more detail in Chapter 6 (“Salivary and Lacrimal Glands”). Coexistence of ASC with a
447salivary gland tumor has also been observed.
Treatment and Prognosis
ASC is considered to have an aggressive behavior in comparison to standard SCC and
432,447-450mucoepidermoid carcinoma. As mentioned earlier, owing to limited numbers
443for comparison, it is diF cult to determine whether the aggressiveness is site related or
432,448,449inherent to the tumor. The primary mode of recommended treatment is
441,449 433,450surgical. Radiation alone overall has had poor results, with a rare
439exception. Radiation combined with radical surgery, however, has been reported to
439improve local control.
Papillary Squamous Cell Carcinoma
In a 1988 article discussing squamous papillary neoplasms of the UADT, Crissman and
451colleagues proposed the term papillary carcinoma for a rare variant of SCC. This
lesion, named papillary squamous cell carcinoma (PSCC) in the current WHO
117 452classification, has also been described in other parts of the body such as the skin,
453 454 455uterine cervix, conjunctiva of the eye, and thymus. Within the UADT, PSCC
has been mentioned as making up part of the histologic spectrum shown by the clinical
334,339,340entity proliferative verrucous leukoplakia, a condition more extensively
discussed in the context of VC.











451In the study on papillary neoplasia in the adult UADT, Crissman and colleagues
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 con guration. The epithelium lining the brovascular 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 super cial 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
444 451,456sinus, and one in the oropharynx. Data on HPV involvement vary.
Clinical Features
In a series of 104 laryngeal cases identi ed in the les 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
457 456or fixation. Another preferred site of PSCC is the sinonasal tract.
Pathologic Features
The histologic features of PSCC are a papillary display of brovascular cores lined with
markedly dysplastic epithelium of normal or increased thickness. The
malignantappearing 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
451with varying degrees of surface keratinization. If no stromal invasion of the atypical
epithelium is observed, lesions should be called atypical papillary hyperplasia or PSCC in
458situ. Frequently, squamous neoplasms with papillary components contain
predominantly noninvasive areas, and it may require extensive histologic sampling to
341,451,456,457find areas of invasion.
Two histologic patterns have been identi ed in PSCC: papillary-frond or broad-based
exophytic growth (Figs. 2-46 and 2-47). The papillary pattern consisted of multiple, thin,
delicate liform, nger-like papillary projections. The papillae contained a delicate
brovascular core surrounded by the neoplastic epithelium. Tangential sectioning would
yield commonly one or occasionally a number of central brovascular 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 cauli: ower-like in growth pattern. Tangential sectioning
would yield a number of central brovascular cores, but the outer aspect was lobular, not
450papillary (see Figs. 2-46 and 2-47). Whether this subdivision is reproducible and of
459any value has been questioned.

Figure 2-46 Papillary squamous cell carcinoma. A and B, Papillary frond-like type.
Note delicate nger-like extensions of tumor extending up from and along the surface,
composed of dysplastic epithelium lining pencilate, brovascular 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 brovascular 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 di erential diagnosis
ranging from solitary papilloma to VC. Applying the criterion of invasion to diagnose
PSCC simpli es 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
341,451associated with recurrent papillomatosis or inverting papillomas. 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,
460-462however, is very rare. Moreover, PSCCs occur in older patients.
VC is another di erential diagnostic consideration. The fronded brovascular-based
epithelial growth pattern as well as the presence of signi cant cytologic atypia


distinguishes PSCC from the bland cytologic character of VC. VC has a more sessile base
with a con: uent downward “pushing border” rather than features of an in ltrative cell
341process 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
457exophytic type.
Lymphoepithelioma
Lymphoepithelioma, also called lymphoepithelial carcinoma, is a histologic variant of
463SCC that was rst reported by Regaud and Reverchon and independently by
464Schmincke. At present, it is de ned by the occurrence of a distinctive intermingling of
119undi erentiated carcinoma cells with a prominent lymphoid stroma.
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, : oor of the mouth, sinonasal
tract, larynx, trachea, hypopharynx, lung, thymus, stomach, skin, breast, uterine cervix,
vagina, and urinary bladder under a variety of terms: undi erentiated carcinoma of
nasopharyngeal type, undi erentiated 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
195,208,465-469association with EBV except in Chinese patients.
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,




470-472Southeast Asia, the Arctic regions, and Malaysia. 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
194cases in regions where nasopharyngeal cancer is endemic. In the United States, where
nasopharyngeal cancer represents only 0.2% of all cancers, 60% of these are
223lymphoepitheliomas. In contrast, in Chinese regions where nasopharyngeal cancer
represents 18% to 25% of all cancers, lymphoepithelioma accounts for more than 90% of
59,223these. Moreover, lymphoepithelioma is the most common type of nasopharyngeal
196cancer in young people (>90%). Other features speci c 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
183 194(1.3%), and a very high rate of systemic dissemination.
Similar to nasopharyngeal cancer in general, lymphoepithelioma usually arises on the
lateral or posterosuperior wall of the nasopharynx. The clinical appearance of the tumor
185may be exophytic, in ltrative, or ulcerative. Dickson found the gross appearance of
tumor in the nasopharynx to be exophytic in 74.2% of lesions, in ltrative 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
473eosinophilic nucleoli. The borders of the amphophilic cytoplasm are indistinct (Fig.
221748A). Frequently, spindle-shaped tumor cells with hyperchromatic nuclei are present.
The associated in ltrate is mixed and composed of T lymphocytes and may contain
226plasma cells, follicular dendritic cells, or abundant eosinophils. Individual tumor cells
474may be surrounded by the mixed in ltrate, resembling Hodgkin’s disease. The
presence of noncaseating granulomas negative for acid-fast bacilli, sarcoid-like
224granulomas, and localized amyloid has been reported in the adjacent stroma.


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 in ltrated by the mixed in: ammatory
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
194,475,476beneath an in: ammatory in ltrate; see Fig. 2-48B). These two types were
essentially descriptions of two growth patterns of an undi erentiated carcinoma.
Familiarity with these variations in the histomorphology of undi erentiated 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. 2-48C). Designation of lymphoepithelioma as a Regaud or a
Schmincke type does not have prognostic significance.
Various histologic ndings are reported to have an impact on the prognosis. The
477presence of a high density of follicular dendritic cells (S-100 positive) and
478eosinophils 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
224indicate a poor prognosis.



Con rming 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.
220848D). Others have used polymerase chain reaction for detecting EBV in paraF
nembedded tissue and tissue from ne-needle aspiration in patients with unknown primary
198,199 226tumors. The usefulness of tumor ploidy determination remains controversial.
Differential Diagnosis
Because of the frequently inconspicuous epithelial nature of undi erentiated carcinoma
including lymphoepithelioma and because its most common presentation is metastases to
cervical lymph nodes, the di erential diagnosis is diverse. Included in the di erential
diagnosis are Hodgkin’s disease, large cell lymphoma, lymphoid hyperplasia, melanoma,
and sinonasal undifferentiated carcinoma.
Hodgkin’s disease as a di erential diagnosis presents the most deceptive pitfall,
particularly if the initial histologic diagnosis is based on a cervical lymph node in a young
473,479patient with adenopathy. Lymph nodes containing undi erentiated carcinoma
exhibit varying degrees of nodal replacement by tumor. Capsular brosis and dense
bands of collagen entrapping discohesive tumor cells are histologic ndings that may be
473,474,479common to Hodgkin’s disease and lymphoepithelioma. The carcinoma cells
may have vesicular nuclei with prominent eosinophilic nucleoli suggestive of the
474mononuclear variants of Reed-Sternberg cells. Immunohistochemical stains are very
helpful in this dilemma. The undi erentiated carcinoma cells will be positive for
474cytokeratin and negative for leukocyte common antigen, LeuM1, L26, and UCHL1.
Undi erentiated carcinoma is morphologically easily mistaken for large cell lymphoma
(Fig. 2-49). Again, the immunohistochemical stains for cytokeratins (AE1/AE3) can be
480useful. The majority (97%) of nasopharyngeal cancers will be positive for
cytokeratins, with the caveat that cytokeratin positivity has been reported in rare
481lymphomas. Leukocyte common antigen positivity in undi erentiated carcinoma has
not yet been reported in the epithelial component.




Figure 2-49 Note the poorly di erentiated carcinoma cells of lymphoepithelioma
mimicking a lymphoma.
Lymphoid hyperplasia is a common nding in nasopharyngeal biopsy specimens and
should be included in the di erential diagnosis of the lymphoepithelioma type of
undi erentiated carcinoma when nasopharyngeal lymphoid hyperplasia accompanies
cervical adenopathy in a patient who tests positive for human immunode ciency virus
482type 1. Cytokeratin stains again should resolve this question. An increased incidence
of lymphoepithelioma in patients with acquired immunode ciency syndrome has not
483been observed.
Melanoma is rare in the nasopharynx. The nuclear features of undi erentiated
carcinoma and melanoma may be similar. The immunohistochemical staining patterns
for undi erentiated carcinoma are the reverse for melanoma. In undi erentiated
224carcinoma, HMB45 and S-100 are negative while cytokeratin is positive.
Sinonasal undi erentiated carcinoma is similar histomorphologically to
lymphoepithelioma. Cells of sinonasal undi erentiated carcinoma, however, are smaller,
are frequently associated with large areas of necrosis, do not usually contain
spindleshaped cells, are not associated with a positive serology for EBV, and are frequently
positive by immunohistochemical staining for neural markers (e.g., neuron-speci c
224enolase).
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 speci c subtypes of UADT SCC. There are, however, other
less frequently observed morphologic variants of SCC that have gained less attention. The





484rst to be discussed is the so-called desmoplastic SCC (DSCC). Clinically, this lesion
presents itself as a rm submucosal mass. Histologic examination demonstrates a brous
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 tono laments and desmosomes.
Because of the preponderance of brous tissue, the lesion may be mistaken for a benign
484spindle cell lesion, such as proliferative myositis or nodular fasciitis. 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 brous
stroma. B, Staining with antikeratin antibody serves to highlight the neoplastic
epithelium.



Figure 2-51 A, Photomicrograph showing bro-osseous tissue resembling brous
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
484tongue, it is not known whether this SCC subtype behaves di erently 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
280and hypopharynx. SEC is a poorly or moderately di erentiated in ltrating SCC
showing an entirely or predominantly super cial type of growth. Despite its intramucosal


280site, lymph node metastases may be present. 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 signi cance of distinguishing
280between conventional SCC and SEC is unclear.
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 di erentiated SCC may exhibit a nodular growth pattern with intervening
brous 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 con rm the diagnosis of poorly di erentiated 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
brous 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 di erentiated 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 di erentiation 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
365 425SpCC as well as in ASSC, 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 con rming
their epithelial nature (Fig. 2-55).




Figure 2-55 A, Low-power photomicrograph showing blood lakes surrounded by
pleomorphic cells. B, At higher magni cation, the nuclear pleomorphism of the cells that
cover brous 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 brous
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 identi cation of either macroscopic or
microscopic features having prognostic signi cance and necessitating additional
treatment. An adequate anatomic knowledge of the various head and neck sites from
485which tumor resection specimens are obtained is required in performing this task. 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.
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420 Goldman RL, Klein HZ, Sung M. Adenoid squamous cell carcinoma of the oral cavity.
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422 Zaatari GS, Santoianni RA. Adenoid squamous cell carcinoma of the nasopharynx andneck region. Arch Pathol Lab Med. 1986;110:542-546.
423 Hertenstein JC, Fechner RE. Acantholytic squamous cell carcinoma. Arch Otolaryngol
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424 Batsakis JG, Huser J. Squamous carcinomas with gland like (adenoid) features. Ann Otol
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425 Nappi O, Wick MR, Pettinato G, et al. Pseudovascular adenoid squamous cell carcinoma
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426 Zidar N, Gale N, Zupevc A, et al. Pseudovascular adenoid squamous-cell carcinoma of
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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
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1996;105:409-413.
Adenosquamous Carcinoma
429 Gluckmann A, Cherry CP. Incidence, histology, and response to radiation of mixed
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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
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432 Gerughty RM, Hennigar GR, Brown FM. Adenosquamous carcinoma of the nasal, oral
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433 Fujino K, Ito J, Kanaji M, et al. Adenosquamous carcinoma of the larynx. Am J
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435 Ogawa T. A clinicopathological study of adenocarcinomas of the nasal cavity and
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436 Napier SS, Gormley JS, Newlands C, et al. Adenosquamous carcinoma. A rare neoplasm
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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
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440 Zieske LA, Myers EN, Brown BM. Pulmonary lymphangitic carcinomatosis from
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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
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443 Ellis GL, Auclair PL, Gnepp DR, et al. Other malignant epithelial neoplasms. In: Ellis GL,
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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,
104107, 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
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448 Ferlito A. A pathologic and clinical study of adenosquamous carcinoma of the larynx:
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1976;30:379389.
449 El-Jabbour JN, Ferlito A, Friedmann I. Adenosquamous carcinoma. In: Ferlito A, editor.
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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;85:178184.
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 theupper 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.
Lymphoepithelioma
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
lymphoepitheliomalike 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;5:287309.
471 De-The G. Epidemiological evidence implicating the Epstein-Barr virus in Burkitt’s
lymphoma and nasopharyngeal carcinoma etiology, IARC Sci., 1978, IARC, Lyon,
285299, Publ. No. 20472 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
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1952. MS thesis
477 Nomori H, Watanabe S, Nakajima T, et al. Histiocytes in nasopharyngeal carcinoma in
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478 Looi LM. Tumour-associated tissue eosinophilia in nasopharyngeal carcinoma: A
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479 Carbone A, Micheau C. Pitfalls in microscopic diagnosis of undifferentiated carcinoma of
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480 Sugimoto T, Hashimoto H, Enjoli M. Nasopharyngeal carcinoma and malignant
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1990;100:742748.
481 Frierson HF, Bellafiore FJ, Gaffney MJ, et al. Cytokeratin in anaplastic cell large cell
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482 Shahab I, Osborne B, Butler J. Nasopharyngeal lymphoid tissue masses in patients with
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483 Melbye M, Cote TR, West D, et al. Nasopharyngeal carcinoma: An EBV-associated
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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."
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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 ( oor), 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 oor 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
1-3separates the nasal cavity from the orbit. 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 pseudostrati) ed (respiratory-type)
epithelium, which covers the entire nasal cavity with the exception of a small portion of the posterior
4roof. The latter is lined with the olfactory epithelium. 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
0040,1cells, round basal cells, and serous glands (Bowman’s glands) in the lamina propria.
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 oor, and posterior,
medial, and anterolateral walls. The roof forms the oor of the orbit, whereas the oor 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-) lled 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 pseudostrati) ed 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.
Nasopharynx
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
5,6called Rosenmüller’s fossa.
Approximately 60% of the nasopharyngeal mucosa is lined with strati) ed 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 pseudostrati) ed 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
7undergo oncocytic metaplasia, especially in older individuals. Bilateral oncocytic cysts and melanotic
8,9oncocytic metaplasia arising from these glands have been described. A prominent lymphoid
component with germinal centers is also present beneath the mucosa. These lymphoid elements can be
5,6present within the mucosal epithelium, forming the so-called lymphoepithelium.
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
10sinusitis in patients infected with human immunode) ciency virus (HIV). Developmental anomalies
that also may cause chronic sinusitis in children include hypoplasia of the maxillary sinuses, concha
11bullosa, a deviated uncinate process, and so-called Haller’s cells. Complications of rhinosinusitis
include secondary bacterial infection with extension into adjacent structures causing
pharyngotonsillitis. In addition, chronic allergic rhinitis plays a signi) cant role in the genesis of
in ammatory 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 bene) t from surgical intervention in the form of nasal lavage, the creation of
11a nasoantral window, or, more recently, functional endoscopic nasal surgery. Chronic sinusitis is also
a component of Kartagener’s syndrome. This syndrome also includes bronchiectasis and situs inversus
12-14and is due to a defective ciliary cytoskeleton lacking dynein arms. Occasionally, pathologists will
be asked to perform ultrastructural assessment of nasal biopsies in cases suspicious of Kartagener’s
syndrome."
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Mucous Impaction
Clinical Features
Mucous impaction is an uncommon in ammatory lesion that has also been called inspissated mucus or
15snotoma. 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 opaci) cation 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 diAerential diagnosis of mucous impaction includes myxoma, well-diAerentiated mucinous
adenocarcinoma, and embryonal rhabdomyosarcoma. The typical clinical history, the lack of
destruction or invasion of the maxillary bone, the presence of degenerating in ammatory 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 in ammatory process. Rarely, laryngeal stridor
16may occur due to impacted nasal/nasopharyngeal mucous secretions in the larynx.
Sinonasal Inflammatory Polyps
Clinical Features
Sinonasal in ammatory 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 in ammation, cytokine secretion, and collagen synthesis stimulated by eosinophils have all
17,18been implicated. They have been divided into inflammatory nasal and antrochoanal polyps.
In ammatory 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
airuid levels occupying the nasal cavity or paranasal sinuses. Large in ammatory polyps can destroy
19-21bone and extend into the nasopharynx, orbit, and cranial cavity. In ammatory nasal polyps
develop in approximately 20% of children with cystic ) brosis, and in some, they may be the initial
clinical manifestation of the disease. Children with in ammatory nasal polyps should be investigated
for cystic fibrosis.
Unlike in ammatory polyps, polyps of the antrochoanal type are more frequently seen in
22,23 24children, although this ) nding has not been reproduced in other studies. These lesions arise in
25the maxillary antrum and secondarily extend into the nasal cavity. Approximately 90% are solitary.
24,26They are the least common nasal polyps.
Pathologic Features
In ammatory 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
27epithelium with a variably thickened basement membrane. The epithelium often exhibits some
degree of squamous metaplasia. In some cases, this metaplastic epithelium shows a degree of atypia
28suggestive of dysplasia. The stroma is abundant and highly edematous or myxoid and contains a
mixed in ammatory in) ltrate composed of eosinophils, lymphocytes, and plasma cells (Fig. 3-1A).
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)
29genome has been demonstrated in mucosal lymphocytes of Chinese patients with nasal polyposis. The
stroma contains a variable number of ) broblasts and blood vessels. Typically, in ammatory polyps do
not contain seromucinous glands. Secondary changes include surface ulceration, ) brosis, infarction,
granulation tissue, deposition of a dense amyloid-like material, cartilaginous or osseous metaplasia,
glandular hyperplasia, and, sometimes, granuloma formation. Polyps associated with cystic ) brosis
contain fewer eosinophils and lack basement membrane thickening and submucosal hyalinization (see
30Fig. 3-1B). The mucin in cystic ) brosis is acidic and stains blue or purple with Alcian blue/periodic
acid–SchiA stain, in contrast to in ammatory polyps of the usual type, which contain neutral mucin
that stains pink/magenta.
Figure 3-1 A, In ammatory polyp showing thickened basement membrane, edematous stroma, and a
mixed in ammatory in) ltrate 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 ) brous stalk. Histologically, they lack the thick basement
0310,22membrane and the prominent in ammatory in) ltrate of in ammatory polyps. The stroma is
24variable but tends to be fibrotic and contains large vascular spaces with scant glandular elements.
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 ) broblasts (Fig. 3-2) are suI cient to
32,33raise the possibility of a malignant tumor. In most cases, the diAerential diagnosis elicited is an
embryonal rhabdomyosarcoma. The typical clinical history, the presence of a heavy in ammatory
in) ltrate, 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 myo) broblastic
derivation, and closely resemble radiation fibroblasts.
Figure 3-2 Atypical ) broblast in an in ammatory 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 angio) broma,
schneiderian papilloma, and squamous cell carcinoma. Nasopharyngeal angio) broma contains stromal
myo) broblasts with a spindle or stellate shape admixed with thick abnormal vessels not seen in polyps.
Nasal polyps also lack the thick ) brovascular 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. Identi) cation and treatment of etiologic factors
are necessary to prevent recurrences. Antrochoanal polyps may also recur if the stalk is not completely
resected.
Myospherulosis
Myospherulosis is a rare iatrogenic pseudomycotic lesion occurring in the nasal cavity, paranasal
34-36sinuses, middle ear, and soft tissues. Typically, patients with myospherulosis have a history of
surgery followed by packing of the nasal cavity with petrolatum-based ointment before the
34,36development of a nasal mass. Histologically, there is a prominent ) brous and chronic
in ammatory 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
34infections can be ruled out with a methenamine silver stain.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
37,38Tuberculosis in the upper respiratory mucosa is usually a manifestation of disseminated disease.
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 ) nd microorganisms in an
acid-fast stain. The diAerential 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
Sarcoidosis is a multisystemic disorder that most often aAects the lung and mediastinal lymph nodes.
Rarely, it also involves the upper respiratory tract, including the nasal cavity and paranasal
39-41sinuses. 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
40granulomas. Stains for acid-fast bacilli are negative, and there is no vasculitis or necrosis. The
diAerential diagnosis includes other granulomatous diseases, especially cholesterol granulomas,
tuberculosis, leprosy, and Wegener’s granulomatosis. Virtually all patients with sinonasal sarcoidosis
42have pulmonary and hilar nodal involvement. 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.
Leprosy
Clinical and Pathologic Features
Leprosy is a slowly progressive disease caused by Mycobacterium leprae. The infection aAects 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 aAects 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 ) lled with massive quantities of acid-fast
43,44bacilli. 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 ) broblasts, 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 diAerential diagnosis of tuberculoid leprosy includes sarcoidosis, tuberculosis, certain fungal
infections, and Wegener’s granulomatosis. All these latter entities have signi) cantly diAerent
epidemiologic ) ndings, 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 eAective drugs, adherence to treatment, and
supportive care measures.
Rhinoscleroma
Clinical Features
Rhinoscleroma is a chronic granulomatous disease that is endemic in parts of Central and South
45-48America, North and Central Africa, and certain areas of Eastern Europe. It is uncommon in North
49America. Rhinoscleroma is caused by the gram-negative rod Klebsiella rhinoscleromatis and aAects
50,51primarily the nasal cavity and nasopharynx. 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, orid, and ) brotic. 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
48of nodules causes a severe deformity referred to as Hebra’s nose. Recently, rhinoscleroma has been
52described as an opportunistic infection in HIV-affected individuals.
Pathologic Features
Pathologically, rhinoscleroma is also characterized by three phases: rhinitis or catarrhal, orid or
granulomatous, and ) brotic. In the catarrhal phase, the tissue changes are nonspeci) c 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 in ammatory in) ltrate 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 identi) ed in 1- to 2 mm–thick sections stained with toluidine blue. In the ) nal"
"
"
) brotic phase, there are variable degrees of ) brosis and the Mikulicz cells are absent or are diI cult to
identify.
Differential Diagnosis
The diAerential 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
S100 protein immunostaining, seen in SHML.
Treatment and Prognosis
The initial treatment of rhinoscleroma consists of prolonged antibiotic therapy using doxycycline,
cipro oxacin, ceforanide, rifampicin, or streptomycin. Antibiotic therapy is generally eAective. Surgery
and laser ablation of tissue deformities caused by ) brous masses in the late ) brous 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 classi) ed as acute fulminant/invasive sinusitis, chronic
53,54noninvasive/chronic indolent, “fungus ball” or mycetoma, and allergic. According to a recent
54review, the most common fungal sinusitis is allergic. Occasionally, the histologic distinction between
invasive fungal disease and a fungus ball or mycetoma is diI cult 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 nonspeci) c in ammatory reaction and often the use of Gomori methenamine silver and
periodic acid–SchiA stains is required to identify the hyphae. Chronic noninvasive infections have been
55 56 57 58associated with Aspergillus spp, Pseudallescheria boydii, Bipolaris spp, Sporothrix schenckii,
59 60Schizophylum commune, and, rarely, Mucor.
Acute fulminant or angioinvasive fungal infections are common in immunocompromised hosts,
0620,59particularly those with HIV infection and those with hematologic malignancies. Acute fungal
infections are characterized by acute in ammation, tissue necrosis, and numerous hyphae invading
blood vessels (Fig. 3-4). Mucormycosis (phycomycosis) is usually seen in association with poorly
63controlled diabetes mellitus, although it can also be seen in noncompromised hosts. It is an aggressive
infection that can quickly extend into soft tissues, orbit, and brain. Recognition is based on the
identi) cation of broad nonseptate hyphae. Other fungi capable of causing invasive fungal sinusitis
64-66 67 68 69 62include Aspergillus, Candida spp, cryptococcosis, Curvularia lunata, P. boydii, and
70Alternaria spp.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
71peripheral eosinophilia. Initially, this condition was attributed to infection with Aspergillus spp
because of the presence of dichotomous fungal hyphae and the histologic similarities to allergic
72bronchopulmonary aspergillosis. 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
0740,71genus being Bipolaris followed by Curvularia, Exerohilum, Alternaria, and Cladosporium.
Rhinosporidiosis is a chronic, super) cial, mucocutaneous infection primarily involving the nasal
75cavities, nasopharynx, and oral cavity. This infection, initially thought to be caused by
Rhinosporidium seeberi, now seems to be caused by the waterborne organism cyanobacterium
76Microcystis aeruginosa. It is endemic in India and Sri Lanka, where 90% of all infections occur.
77Rarely, cases are seen in the United States. 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
72,74identi) ed with Gomori methenamine silver or Fontana-Masson stain. 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 identi) cation of the organism responsible. Fungus balls
54are characterized by the presence of large numbers of noninvasive fungal colonies with pale centers.
Microscopically, rhinosporidiosis is characterized by hyperplastic respiratory or squamous epithelium
accompanied by a lymphoplasmacytic in) ltrate. 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 identi) cation of these structures in the surgical material or by smear
78preparations."
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).
79Recently, Tadros and colleagues 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 immunode) cient 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 diAerential diagnosis of fungal infections in the sinonasal tract includes a large number of
nonneoplastic 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 diI cult to exclude
based on morphologic grounds alone because vasculitis may be a focal ) nding 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 in) ltrate involving the
sinonasal tract. They also reveal the presence of an atypical lymphoid in) ltrate not seen in sinonasal
mycotic infections. Silver and periodic acid–SchiA 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,
80,81causative organisms, and underlying medical conditions. 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
aAected 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 ucytosine 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
81P. boydii. 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 de) nitive diagnosis and to drain
accumulations of pus.
80The treatment of allergic fungal sinusitis varies according to clinical features and extent of disease.
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%,
80whereas those with leukemia or renal disease had a survival rate of 20%. 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
82,83trauma in the sinonasal region. The metaplastic squamous cells may show focal nuclear atypia,
but there is overall maintenance of the lobular acinar architecture and the individual acini maintain
84smooth contours. The main signi) cance of necrotizing sialometaplasia is its recognition and
separation from squamous cell carcinoma and mucoepidermoid carcinoma. These tumors have a more
in) ltrative appearance, and, in the case of mucoepidermoid carcinoma, variable numbers of mucous
85and intermediate cells can also be identi) ed. Rare cases may recur or can obscure an underlying
86squamous cell carcinoma.
Amyloidosis
87Mufarrij and colleagues 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
88,89outlet. 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
in ammatory or allergic process, although cystic ) brosis, trauma, or neoplastic processes have also
90-92been implicated. 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,
93rhinorrhea, and nasal obstruction. Radiologically, there is opaci) cation of the aAected sinus; in
long91,94-96standing cases, erosion with destruction or sclerosis of the adjacent bone can also be present.
Pathologic Features
The gross appearance is characterized by a cyst ) lled with a mucoid or gelatinous secretion.
Microscopically, the cysts are lined with attened pseudostrati) ed ciliated columnar epithelium
accompanied by secondary changes such as ) brosis, 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 ) ndings. The characteristic clinical and radiologic ) ndings 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 ) fth or sixth decade of life. In the study by
97Wenig and HeAner, there were 27 males and four females with a median age of 58 years. The
symptoms at presentation are nonspeci) c and include rhinosinusitis, allergies, nasal obstruction,
stuI ness, 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
97surrounded by a thick, eosinophilic, hyalinized basement membrane (Fig. 3-6). 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 in ammatory in) ltrate resembling the stroma of in ammatory polyps.
Infrequently the larger glands may be intermixed with bland, smaller, uniform glands, which, on rare
occasions, may compose the entire lesion (see Fig. 3-6C 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 in) ltrating well-diAerentiated 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 diAerential diagnosis is a well-diAerentiated adenocarcinoma. Respiratory
epithelial adenomatoid hamartoma does not have the complex glandular growth with a back-to-back
cribriform pattern and lacks the in) ltrative growth and desmoplastic stroma of well-diAerentiated
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
98chondroid, stromal, and cystic areas. 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 aAected. The oldest patient
99reported in the literature was 69 years of age. The lesion has a predilection for male children. The
most common presentation is that of a nasal mass, often accompanied by respiratory diI culty. The
septum and middle turbinate are reported to be common sites of origin. The mean size in the series by
98 99McDermott and colleagues was 3.6 cm; however, Ozolek and colleagues 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 ) brocartilage 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 ) brocollagenous. The cystic areas may be
composed of blood-) lled 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
) ndings are hemorrhagic spaces suggestive of aneurysmal bone cyst, “chicken-wire” calci) cations,
) bro-osseous areas with immature woven bone suggestive of ) brous dysplasia, perivascular
hyalinization, and mitotic activity. Some of the cartilaginous nodules may be lined with respiratory
99epithelium. One of the cases reported by Ozolek and colleagues 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 in amed 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 diAerential 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 diI cult
and often necessitates a combined intranasal-neurosurgical approach. Erosion of the adjacent bone with
98intracranial extension was seen in one of the cases reported by McDermott and colleagues, 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
100,101encephalocele rather than a true neoplasm. Generally, it presents at birth or within the ) rst 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
1030,100communication with the cranial cavity.
Encephalocele is a developmental anomaly closely related to glial heterotopia. When located in the
100,102nasal cavity, encephalocele is virtually indistinguishable from glial heterotopia. By de) nition,
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 ) bers, and ) brovascular connective tissue. Neuronal elements are usually absent or
104scant, although on rare occasions they can be abundant. In long-standing lesions, the degree of
) brosis may obscure the true nature of the lesion. Immunohistochemical stains for glial ) brillary acidic
105protein and S-100 protein can be helpful in con) rming the diagnosis. Microscopically,
101-103,106encephaloceles consist of a mixture of neural and glial tissues.
Differential Diagnosis
The diAerential 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
107,108heterotopia have been described.
The diAerential diagnosis of encephalocele includes glial heterotopia, nasal teratoma, and also a true"
"
glioma. The characteristic clinical and radiologic ) ndings 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 suI cient. 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
103related to the midline closure of the face. 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 ) stula. 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 in ammatory 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
109discharging fistulous tract.
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
110infected and present as a mass or may be discovered incidentally upon radiologic imaging. With the
advent of head and neck magnetic resonance imaging, its existence appears to be more common than
111previously thought. 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 signi) cant lymphoid hyperplasia in the sinonasal region and nasopharynx is relatively
112 113uncommon. Rimarenko and Schwartz 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. 3-8A). 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 ) gures (see
Fig. 3-8B). The presence of a monomorphic cellular in) ltrate and cytologic atypia should be viewed
with suspicion. Care should be taken to exclude a neoplasm with a prominent lymphoid in) ltrate or a
lymphoepithelioma-type carcinoma, particularly in the nasopharynx. Rarely, Castleman disease or
114angiolymphoid hyperplasia can also present as a nasopharyngeal polypoid tumor. Rare cases of
plasma cell granuloma and in ammatory pseudotumors have also been reported in this
115-117location.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,
118,119hearing loss, and sore throat due to enlarged nasopharyngeal and palatine tonsils. 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 ) ndings were in) ltration 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
118,119 119in) ltration by sheets of plasma cells and immunoblasts. Wenig and colleagues 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
119findings was considered virtually diagnostic of HIV infection by these authors.
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
120,121cervical lymph nodes ; however, extranodal disease with involvement of the nasal cavity, orbit,
122-124and other head and neck sites is common. 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
123,124hypergammaglobulinemia."
Pathologic Features
Sinonasal SHML presents as nasal polyps or nodules with partial obstruction of the nasal cavity and is
histologically characterized by a diAuse polymorphic in) ltrate 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. 3-9A). 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 ) nding 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. 3-9B), CD68, and
1260,122Mac-387 antibodies are expressed by these cells.
Figure 3-9 A, Sinonasal Rosai-Dorfman disease. A mixed in ammatory cell in) ltrate 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 diAerential 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 pro) le of the histiocytes. The
S100 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
gramnegative 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
127There is no systematic treatment study of SHML. In general, SHML follows a benign clinical
123course ; in one study, ) ve of nine patients with sinonasal SHML experienced recurrences of their"
"
"
"
122lesion and four had persistent disease when last seen. Most patients undergo complete surgical
resection of their masses. However, patients with systemic manifestations or respiratory obstruction may
127need systemic therapy. In a literature review of all sites involved by SHML, Komp states that a
combination of vinca alkaloid, alkylating agents, and corticosteroids appears to be the most eAective.
Radiotherapy did not appear to be particularly eAective. 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
128,129the upper and lower respiratory tracts and kidneys. 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
130,131mastoiditis due to involvement of the eustachian tube. In most patients, there are also
130pulmonary or renal manifestations. 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
132,133altogether. 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
diI cult and inconclusive. The pathologic features to look for in these specimens are mucosal
ulceration, acute and chronic in ammation, vasculitis, necrosis, and granulomatosis. The in ammation
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 in ammatory 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 ) brinoid necrosis of the vessel wall accompanied by a prominent neutrophilic
in) ltrate. The in ammation and necrosis may involve part or the entire circumference of the aAected
vessel. Extravasated red blood cells, ) brin thrombi, and swollen endothelial cells are often seen.
Multinucleated giant cells and histiocytes are present in granulomatous vasculitis. Healed vasculitis is
characterized by concentric ) brosis surrounding an endothelium-lined vascular lumen. Frequently,
recognition of involved blood vessels is diI cult; 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 in ammatory in) ltrate
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 ) brinoid
131degeneration.
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
130depends on a constellation of clinical and histopathologic ) ndings. Devaney and colleagues
proposed the following criteria for the diagnosis of Wegener’s granulomatosis using head and neck
biopsy specimens: (1) The ) nding of necrosis, vasculitis, and granulomatous in ammation 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 aAected and suspicious if only one site is involved; (4) if none of the microscopic features are
present, the biopsy specimen is considered nonspeci) c 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 ) ndings needed to make
128a diagnosis.
Differential Diagnosis
The diAerential 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 identi) cation 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 in amed and ulcerated, it is rare to ) nd 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 diI cult 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 ) brosis (EAF) of the sinonasal tract is an exceedingly rare condition
134-138characterized by progressive submucosal perivascular ) brosis of unknown etiology. Occasional
135 139cases have been associated with granuloma faciale, and Loane and colleagues described it in a
patient with Wegener’s granulomatosis. EAF predominantly aAects 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 aAected, 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
in ammatory in) ltrate, non-necrotizing eosinophilic vasculitis, and ) brosis. The eosinophilic vasculitis
aAects submucosal capillaries and venules. The in ammatory in) ltrate is composed of numerous
eosinophils, with variable numbers of B and T lymphocytes, plasma cells, neutrophils, and
macrophages. The ) brosis consists of a distinctive perivascular concentric ) brosis with an “onion-skin”
appearance (Fig. 3-12). In later stages of the disease, whorls of collagen and reticulin ) bers are seen.
Typically, the in ammatory in) ltrate and the vasculitis become sparser as the ) brosis increases in
density."
Figure 3-12 Eosinophilic angiocentric ) brosis showing arterioles and small vessels nearly obliterated
by perivascular concentric (onion-skin) ) brosis. The in ammatory in) ltrate 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 ) brosis is not a typical ) nding in Wegener’s
granulomatosis; furthermore, giant cells, necrosis, and increased serum ANCAs are not seen in EAF.
Churg-Strauss syndrome has ) brinoid necrosis and granulomas that are absent in EAF. Granuloma
faciale is almost always seen in the face, more commonly aAects males, and exhibits prominent
vasculitis without concentric perivascular ) brosis. Mucosal ulceration, geographic or ) brinoid 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 eI cacy of
steroids and cytotoxic drugs in the management of EAF remains largely unknown.
Idiopathic Midline Destructive Disease
140Idiopathic midline destructive disease was the term proposed by Tsokos and colleagues 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
140patients described by Tsokos and colleagues 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
141,142abandoned, although as a clinical descriptive term, it may still be useful.
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
143recognized because of its better prognosis with more conservative treatment measures. Because the
histopathologic features of nasal destruction in cocaine abuse are not speci) c, the diagnosis rests"
heavily on a good clinical history and the identi) cation 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.
Neoplasms
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
144accounted for 25% of nasal tumors seen in the Institute of Laryngology and Otology in London, and
145 146Vrabec and Suh and colleagues 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,
re ecting dissimilar microscopic appearances; however, they are now classi) ed in three histologic
groups: fungiform (exophytic or everted) papillomas, inverted (squamous) papillomas, and cylindrical
147-149cell (oncocytic) papillomas. Schneiderian papillomas have been regarded as variants of a single
148 150entity; however, Michaels and Young and Michaels have recently contradicted this concept and
regarded these lesions as three separate entities. In a review of 191 cases, they did not ) nd 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
151-153hybridization and polymerase chain reaction. Human papillomavirus 6/11 has been the most
154common type detected. No association has been found between human papillomavirus and
154,155cylindrical cell papillomas.
Sinonasal papillomas occur in a wide age range, but most cases are seen in patients between 30 and
1570,14760 years of age. They are uncommon in children. Males are aAected at least twice as often as
1580,145females. Symptoms at presentation include unilateral nasal obstruction and stuI ness 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
159 1600,144been rarely described. In general, papillomas are unilateral ; 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
1610,156components. Exophytic papillomas constituted approximately 50% of the sinonasal tract
147 147,162papillomas reported by Hyams. They are almost exclusively found in the nasal septum.
Histologically, these lesions exhibit an exophytic pattern and are composed of papillary fronds with a
thin central core of ) brovascular tissue (Fig. 3-13). The surface of the papilloma is lined with a thick
160nonkeratinizing squamous epithelium also referred to as transitional epithelium. The lining may
contain intraepithelial mucous cysts and, less frequently, ciliated respiratory epithelium with small
147numbers of goblet cells. Unlike inverted papillomas, fungiform papillomas do not contain large
glycogenated squamous cells. Surface keratinization with formation of a granular cell layer, a chronic"
"
147inflammatory infiltrate, atypia, and mitotic activity are uncommon.
Figure 3-13 A, Exophytic or fungiform papilloma characterized by ) brovascular cores of variable size
lined with thick squamous epithelium. B, The squamous epithelium is well diAerentiated with no atypia,
keratinization, or mitotic activity.
In many authors’ experiences, inverted papilloma is the most common type of schneiderian
146,148,156,158,160-162papilloma. Most tumors are con) ned to the lateral nasal wall and
1610,146sinuses. The maxillary sinus is most commonly aAected, 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
146,157,160,162,163feature. The squamous component may contain areas with large clear cells with
147abundant cytoplasmic glycogen and rarely may demonstrate a moderate degree of atypia. Mitotic
) gures may be seen; however, they are usually few and are limited to the basal and parabasal
147,157,161,162layers. The stroma varies from ) brous to myxomatous. Chronic in ammation is more
frequently seen in inverted papillomas than in exophytic papillomas and occasionally may closely
resemble in ammatory polyps. Surface keratinization is uncommon; however, when present, the
146,147,156,162possibility of a squamous cell carcinoma should be excluded.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
147,148,164,165schneiderian papilloma. 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. 3-16A). Scattered mucous cells with intraepithelial mucous cysts are also commonly seen (see Fig.
3-16B). 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.